( 12 ) United States Patent

Home , Dextromethadone, Levomethadone

US010040752B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 040 ,752 B2 Mkrtchyan et al. (45 ) Date of Patent: Aug. 7 , 2018 (54 ) SYNTHESIS OF LEVOMETHADONE OTHER PUBLICATIONS HYDROCHLORIDE OR Mahmood , Synthesis ; 2011, No. 3, 490 - 496 . * DEXTROMETHADONE HYDROCHLORIDE Beckett et al. , “ Configurational studies in synthetic analgesics : the AND METHODS FOR USE THEREOF synthesis of (- ) -Methadone from D - ( - ) - Alanine ” , Journal of the Chemical Society , vol. 0 , No . 0 , Jan . 1 , 1957 , pp . 858 - 861 . @(71 ) Applicant: Cody Laboratories , Inc ., Cody, WY Portoghese et al ., " Synthesis , x - ray crystallographic determination , (US ) and opioid activity of erythro - 5 -methylmethadone enantiomers . Evidence which suggests that mu and delta opioid receptors possess (72 ) Inventors : Gnel Mkrtchyan , Cody, WY (US ); different stereochemical requirements ,” J . Med . Chem ., Jan . 1 , Qingwei Yao , Cody, WY (US ) 1982 , vol. 25 , No . 6 pp . 684 -688 . International Search Report and Written Opinion of the Interna ( 73 ) Assignee : Cody Laboratories , Inc ., Cody , WY tional Searching Authority for PCT /US2016 /048380 , dated Oct. 21, 2016 , 14 pages total . (US ) Moryl et al ., “ A phase I study of D -methadone in patients with chronic pain , " J. Opioid Management , 12 : 1 Jan ./ Feb . 2016 , pp . ( * ) Notice : Subject to any disclaimer , the term of this 47 - 55 . patent is extended or adjusted under 35 Attenburrow et al. , “ Analgesics. II . The synthesis of amidone and U .S .C . 154 (b ) by 0 days . some of its analogs, ” Journal of the Chemical Society ( 1949 ) pp . 510 -518 . (21 ) Appl. No . : 15 /245 , 935 Barnett et al ., “ Stereochemistry of Bockmuehl' s synthesis of metha done, ” Journal of Organic Chemistry ( 1976 ), 41 (4 ), pp . 710 - 711. Amani et al ., “ Crystal structure of 2 , 2 - diphenyl- 4 ( 22 ) Filed : Aug . 24 , 2016 dimethylaminopentanenitrile, C19H22N2” , Zeitschrift fuer Kristal lographie — New Crystal Structures (2005 ), 220 ( 4 ), pp . 549 -550 . (65 ) Prior Publication Data Ansermot et al. , " Substitution of (RS ) -Methadone by ( R ) -Metha US 2017 /0057909 A1 Mar. 2 , 2017 done ” , Arch Intern Med , Mar. 22 , 2010 , 170 (6 ), pp . 529 -536 . Schultz et al. , “ The Preparation and rearrangements of 1, 2 dimethylaminochloropropanes, ” Journal of the American Chemical Society ( 1948 ) , 70 , pp . 48 - 52 . Related U . S . Application Data Brode et al ., “ Rearrangement of the isomeric 1 , 2 - ( dimethylamino ) (60 ) Provisional application No . 62/ 209 , 168 , filed on Aug . chloropropanes. The synthesis of amidone ,” Journal of the Ameri can Chemical Society ( 1947 ) , 69 , p . 724 . 24 , 2015 . Bracher et al. “ A Novel Approach to Isomeric Pure ( + ) -Methadone , ” Sci. Phar. , ( 1996 ) , 64 , pp . 271 - 278 . (English language abstract (51 ) Int. Cl. provided ) C07C 221 / 00 ( 2006 .01 ) Poupaert , “ Dibenzo - 18 -crown - 6 as phase transfer catalyst in C07C 225 / 16 ( 2006 . 01 ) Bockmuehl' s synthesis of methadone ,” Journal of Chemical C07C 213 / 00 ( 2006 .01 ) Research , Synopses ( 1981 ) , ( 7 ) , 192 . C07C 227 / 18 ( 2006 . 01 ) Berge , et al. “ Pharmaceutical Salts ,” J . Pharma. Sci . 1977 ; 66 : 1 . European Pharmacopoeia 8 . 0 , Levomethadone hydrochloride C07C 253 /30 ( 2006 .01 ) Monograph of 01 /2008 : 1787 . (52 ) U .S . CI. Paterson et al ., “ Total synthesis of Aplyronine C ” , Org Lett 2013 , CPC ...... C07C 221 /00 ( 2013 . 01 ) ; C07C 213 / 00 15 , pp . 3118 -3121 . (2013 .01 ) ; C07C 225 / 16 ( 2013 .01 ) ; C07C Porter, “ Resolution of chiral drugs” , Pure & Appl Chem , 1991, vol. 63, No. 8 , pp . 1119 - 1122 . 227/ 18 (2013 . 01 ) ; C07C 253/ 30 ( 2013. 01 ) ; Bhattacharyya , “ Borohydride reductions in dichloromethane : a con C07B 2200/ 07 (2013 . 01 ) venient , environmentally compatable procedure for the methylation (58 ) Field of Classification Search of amines” , Synth . Commun . 1995 , 25 , pp . 2061 -2069 . USPCUDFL ...... 514 /663 , 646 , 649 See application file for complete search history . (Continued ) Primary Examiner — Pancham Bakshi ( 56 ) References Cited (74 ) Attorney, Agent, or Firm — Merchant & Gould , P. C . U .S . PATENT DOCUMENTS 2 ,497 ,739 A 2 / 1950 Pfister (57 ) ABSTRACT 2 , 540 ,636 A 2 / 1951 Stoughton 2 ,601 , 323 A 6 / 1952 Reid et al. Highly efficient methods for synthesis of levomethadone 4 ,048 ,211 A 9 / 1977 Barnett hydrochloride or dextromethadone hydrochloride are pro 4 , 242 , 274 A 12 / 1980 Taylor 6 ,143 ,933 A 11 /2000 Scheinmann et al. vided starting from D - alanine , or L - alanine, respectively , 2014 /0088155 A13 / 2014 Manfredi et al . with retention of configuration . Methods for treating a 2014 /0350302 Al 11 / 2014 Ismail et al subject are provided comprising administering a composi FOREIGN PATENT DOCUMENTS tion comprising an effective amount of levomethadone hydrochloride having not more than 10 ppm dextrometha GB 1124682 8 / 1968 WO 97 / 45551 12 / 1997 done . WO 2012 / 162635 11/ 2012 wo 2013 /077720 5 / 2013 22 Claims, 28 Drawing Sheets US 10 ,040 , 752 B2 Page 2

( 56 ) References Cited OTHER PUBLICATIONS Tajbakhsh et al. , “ Catalyst - free one - pot reductive alkylation of primary and secondary amines and N , N - dimethylation of amino acids using sodium borohydride in 2 , 2 , 2 - trifluoroethanol” , Synthe sis , 2011 , pp . 490 -496 . Weiberth et al ., “ Copper ( I ) -activated addition of Grignard reagents to nitriles . Synthesis of ketimines, ketones and amines ” , Journal of Organic Chemistry ( 1987 ) 52 , pp . 3901- 3904 . * cited by examiner U. S . Patentatent Aug. 7 , 2018 Sheet 1 of 28 US 10, 040 , 752 B2

HCI VYONMez" Phi?Me Levomethadonehydrochloride TEMVo?MePhºtoMe Dextromethadonehydrochloride

Step3 Step5 thenHCI Step3 Step5 EtMgBr thenHCI =EtMgBr

NMez NÇN NMez ÇN? (S)-2dimethylaminopropan1ol PhTVMePh Dextromethadonenitrile HOü (R)-2dimethylaminopropan101 PhMePh Levomethadonenitrile HOI

Step4 Step4 base; base; solvent Step2 Ph2CHCN solvent Step2 Ph2CHCN Step1 Step1 NMe2 mayangng D'(") NH2 forthecoast)*orMSO() orNSO NH2HO or(MSO HOY D-alanine HOI L-alanine NMez HCI NMez HCI FIG.1A FIG.1B cl U . S . Patent Aug . 7 , 2018 Sheet 2 of 28 US 10 ,040 ,752 B2

HCI NMezHCI S 23.PhinMe NMez Ph Levomethadonehydrochloride-40%overallyield PhimmePh Dextromethadonehydrochloride

3Step 90%- Step3 Step5 youshopa Step5 EtMgBrHCIthen 94% =EtMgBr thenHCI ,NMe NMez (R)-2dimethylaminopropan1ol (S)-2dimethylaminopropan101 Hovi HOL Me 70-80% CNCCN MePM Levomethadonenitrile CNN Ph Dextromethadonenitrile Step2A ?? Step2B soncanStep2A or Step2B Ph

Step4 base: Step4 NMez PhCHCN 60-70% NMez base: NH2 RI solvent NH2 Ph2CHCN solvent HO. N,-dimethylDalanine .HO N,-dimethylLalanine L-alaninol HO HO NMez1 NMez D'(") Step1A or Step1B Step1A ? Step1B >90% TSO TsoMSO( ) or(MSO) mise CiorMSOV. or NH2 NH2 D-alanine NMez HCI .HO L-alanine NMez HCI HO FIG,1C FIG.ID laCh U . S . Patent Aug. 7 , 2018 Sheet 3 of 28 US 10 ,040 , 752 B2

NMEZHCMe Ph hydrochloride PH Levomethadone - BFV NMezNMez Step5 propan-101dimethylamino)(R2 EtMgBr1) toluene HOHOHO 2)HCI 1507501 KOGU =removsoby Me hereMeKOGU LarecrystallizationMeinheptane Step2 NO NieHCI |LiAHA,THE THE Levomethadonenitrile N.-DieuDslarinet rre LAHA CNN eneth HOS Anar hydrochloride ve Isolevomethadone Levonxetadone Poraldehyuo. NMez CH, (formicacid) PM © HCOOH HC HO N,-dimethylDalanine g{fla??eristrile Me ÇANT ME NMez NH2 . Mere HCI D-Alamino *PlMe tal ???? 1Y CH { 1Step CHO /CPdH2, water NO KOBU * NaserteZncia * Injeks PP ,NH Steps3and4 3)EMB:2)OMHCI NaOH.Aqu)3 3)Ph?CHCN,KOBE NH2, alanineD- *2)KotBu,DMF HocMe HOVA 1)SOCl2 DMF FIG.2A D-Alanine TEOW losylateintermediate FIG.2B U . S . Patent Aug. 7 , 2018 Sheet 4 of 28 US 10 ,040 , 752 B2

NMez NMez ROman N.-dimethylDalanine HOW (R)-2dimethylaminopropan101 reduction Step1 Step2 NMe? reduction, X=CI,OR(Ralkylgroups) formaldehyde H2,Pd/C

)R( NMez O D-Alanine FIG.3 derivatization FIG.4 HO HO U . S . Patent Aug. 7 , 2018 Sheet 5 of 28 US 10 ,040 , 752 B2

E o?Me2HCI Me .Ph NÇN hydrochloride Ph Levomethadonenitrile PhMMe Levomethadone base; Ph base; CHCNPh-NMez| solvent PhuCHCN Solvent NMeal Step5 94%(isolatedyield) Steps3and4 HCI (MSO)D'" PhMeEtMgBr,)1 TSO 100°C 26MHCL

SOCI sulfonyl chloride orsulfonic anhydride base; solvent PhlyMe NMez Ph Levomethadonenitrile CNN PWDh HO. FIG.5 FIG.6 U . S . Patent Aug. 7 , 2018 Sheet 6 of 28 US 10 ,040 ,752 B2

Comodorodowadomoww undso

0800TL 00 . 3 5217 wooow mbinonimedicoontooshocobosco. 091$3,09%

7675 . 2

69796 oooooooooooooooo.velomodowodebr Sale0€$6y 0377 .13 6014 , 2 6952 . 3 tu

.conoscimedecided 0*$'S

FIG.7 U . S . Patent Aug. 7 , 2018 Sheet 7 of 28 US 10 ,040 , 752 B2

de . . . . . Oz WW

...... 04 ------

vVAm 0%

* 0%

* * www0%

* ws

. 08 *

* * 09 *

* 081

FIG.8 U . S . Patent Aug. 7 , 2018 SheetSheet 8 ofof 2828 US 10 ,040 ,752 B2

3.o do

4905ccocco 29

db.co O"15Op

7304 . 42**** < VONN *** XXXXXXXXXXXXXXXXXXX 7994UNXX NY . 2 8064 . 2 - .,kandandansonrabenimadetected 5243 . 2 9ZOE

V 69676NN 3286 . 3

4070 . 3 *

NNNNVV * 4238. 3 - tobe 1999 is 04 9420 , 3 .

598. . 2 .

asa05903949

onsiisimbismannamininauhassaatondé.www

.csmán,noskaadiansama

FIG.9 U . S . Patent Aug. 7 , 2018 Sheet 9 of 28 US 10 ,040 , 752 B2

.- wdo .

0634 . 0 . . ** . , , , ...... * - * - * - * - * - * - * - * - * ------weatheraroundthewomanwowwwwwwwwarm. 00856.woma 06

4.5 -bom.~dowowote

* oz * * * . * * .* . * ...... *. *. .* . . . *. * .*. . . . * *. *. *...... + . + . .+ . .+ ..+ .+ + . .+ . *. *. YUMLU » OCL?Z 2254 ZA 7994 , 2 W 09102 grzos 609780 i

'. 3206 . 3 4070 . w3 V >

4420 . 3 **** * 8993 wwwwwwwwww

M -.

.- . FIG.10 U . S . Patent Aug. 7 , 2018 Sheet 10 of 28 US 10 ,040 ,752 B2

- www Ludd$0

. ?? SI ?." 01$b0 00. 3

. $ 906 -

** 9680 . 2 - * * . IN - - - - . . . ww w . www. - - - - - + + + + + + + + + + + + +

OSELS .

COSUS . 60LL ' S 7933 , .IXA 7993 . 3 - $26 osa ' 5206207S*09SS 9472 . 3 .

140. 0 A

0622 . 40578

*...

IIOS U . S . Patent Aug. 7 , 2018 Sheet 11 of 28 US 10 ,040 ,752 B2

. woo

. ??,?????.???????

. ??? ...... , 1.5 .

. on

MYYsze 9033 . 2 .mo * * * * * * * * * * * * ** * * ** * ** * * ** ** * ** www

1200 inm .1x12 OSSUE -00 8091 67 6SSLA GILLO

TOOLS -nous 6646odobi 8153 . 3 0646 . 3 9045 . 3 retete - 9472.WA . 3 6910 0422ooooo . 24 FIG,12

•••••••••••••••••••••• U . S . Patent Aug. 7, 2018 Sheet 12 of 28 US 10 ,040 ,752 B2

: ? SeeWOOOOOOOM ?

?? * ? , ? | ????2. ????, 44 4 444" , e " , , " a , a" ," st " :" ", " a" a . . . ? “ ? , “? ? ? * * * * * *. * . * * ??* , ?

?? ”“ ? ? *

,”*-“

Very” …?!…wwwytowerent…“ ??????????????

: . . .

: C ? “ ? . . … … … 7? . 13FIG. U . S . Patent Aug . 7 , 2018 Sheet 13 of 28 US 10 ,040 , 752 B2

?? ….

" ??? … … 4 " + " ? " " + ' p ' ' ' ' ' ' alle= = ' ' ' ' ' , " ? ? … … www

.….

. . . … ? , ??????????aub h????? " " " " * * * * * " " " " " " " " " " " " " " " " " “ … … … … ??: ?? , .… : ??? ? :

… 25: 48 , ? ?* ? ? ? “ 3 * … ? ? “ ?? FIG.14 U . S . Patent Aug . 7 , 2018 Sheet 14 of 28 US 10 ,040 , 752 B2

.betaalbaresvarbiausiinsiemecinemacinerendeogdenandenbarnebaroccountsmed wddogOC060509 * * * ** * * 322 Hem

. . . .

une

w OL

i * * * * * * * * anka 08

ddeistinominacionin.commah 0600L

ibindl OLL

. 37 *

YYYY * :4 OCE09404

4*. . .. . ** ** 28 indricimivisionneminkinantikannanalo.co SI013 U . S . Patent Aug . 7 , 2018 Sheet 15 of 28 US 10 ,040 ,752 B2

425: -odo. . uddza!

. 33 . . . . .

-* $26924 -*,7 .

* 33 . 333 * 95 . ? 3 * * * * * * * * * * -' ' 22944444444444 * * * W21 8 . . 125 22 . 129 * kum. WA 82102

A V. . A ZOV

.V-

AY .VELSEX

. . 884

4,7m 3 ...... - 0f! .

WW"

* :94 . 91Old U . S . Patent Aug. 7, 2018 Sheet 16 of 28 US 10 ,040 ,752 B2

*450

*400

"7 .

wwwwwwwwwwwwwwwwwwww "

. 350 . .. . . m . . . . . SEST EELISONIEN...... ORDEN * 3067 .*4 * 2906

* 300 30.00 .wwwvminWVANYW *

Wideodomomoperemow.wwwwwwwwwwwwwwwwww* 097 WA . MAREK YaadSunsad 12905 23.30%1273915

. . welbojewowyopalcos-ojny o 003 nitor W

. uy wwwwwwwwwwwwwww12." doneONBranko

wwwwwwwwwwwwwwwwwwwww . 2WwiadceV

1 .004

wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww* . 60 .p

...... + ...... 2 .+ .- *. .+ .- .- + .+. .. .+ .- .+ + + S 00%. Quo 0,10 -900a 0.017 0.02 2930

FIG.17 U . S . Patent Aug. 7 , 2018 Sheet 17 of 28 US 10 ,040 ,752 B2

OS*

. .2

1 . 314 . 4

00'* VI.

3.50 69/9 6920 6789 .22 3 - 2 Enantiomer CN Methadone . 139 4.209 29 : L , Enaklom CN Methadone AreaLSPResolutionResud

49.45 49.43 7.12 . 097 SI w

. Area 27673 AutoScaled-Chromatogram 007 PeakResults 1220032 RT 4.314 02.09

1VathadoneCNratione/2.936 2MethadoreCNEnktima3.281125082

. Name

1.3 00% V444AL

-0.

RS wwwwwwwwwwwwwwwwwwwwwwwwwww 3. OSO LV- w . . . . . - - - 009 0.14 0.12 0.10 0.08 900 O.M 200 000

FIG.18 U . S . Patent Aug. 7, 2018 Sheet 18 of 28 US 10 ,040 ,752 B2

www www www www . www wwwwwwwwwwwww ?????? ??????????

1.Diphenylacetonitrile 2.Isolevomethadonenitrile ?.???ethad????tri 4.Levomethadone mente * * * * D ...... 5

-103 $8929wro 13

im * - * . - . - , - , - ULASAN * * * * * * * * ostes ...... nnnnnnnnnn ** ** * * * * * * * * * * * * *. wwwwwwwwwwww EVENEMENTEEEEE YANG * * * * * * * * * * * * * * * * * * * * * * * wwwwwwwwwwwwwww DX10MM1026 mentosemprendonounluonnonvakaum.n * * * * * * * * * * * * * * * * * * * * * * * * * * * * mmmm * * * wwwww wwwwwwwwwwww ** * * * * * * * * * * ** * ** * ** * ** * ** * ** * * W ELEK. wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww WWW. WYKK

i WWW l

ZWOWXXX A

woremeyecewa www wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww 31 FIG.19A U . S . Patent Aug. 7 , 2018 Sheet 19 of 28 US 10 , 040 , 752 B2

OAM

Prvey $ * ** ** * ** *

. . .. 355 , www ......

** ** 606. 99 375. 10

394 . 0 050 . 9 ??????

. .?' .

?.??

. Predeszs"quxNoMorcos091 . ??????????????? WOLX-1401039900An Owllvogugay * OJOBOY

** * FIG.19B U . S . Patent Aug. 7, 2018 Sheet 20 of 28 US 10 ,040 ,752 B2

. … . . …. . . . …...... …...... … . . . …. … . . …...... …. . . . … …. . …. . … .… . . . …. . . . . …. . ?

.you…

w ? 3

“? ? w

* .

rrr ???????????????????????.* r

-*.,

CLE_rrrrrrrrrrrrrrrrrrr

????? *- ”,“???????????????

,”

” ELEPPELL_

ELL *- .*” F

*. ??????? ????? ?????????tw. . . tw. vvvvvvvvvv.www . www . www … … . . … . . . … ??? FIG,190 atent Aug . 7 , 2018 Sheet 21 of 28 US 10 ,040 ,752 B2

???????????????????????? - - -. . * * * * ** * * * * - - - * * * * * * * * * * * * * * * * * * * * * * * wiwindowsanddownsio

*-+

-921 W A 6499 co .*- .

€

+- op whetherthe

reisthetherethat - RONOWwiewussimine Quapeciaki www 8 sibirisinden on28290CVCONV die sonu . :Sinsayyod instowwwww w216012wojupejeos-ojny W wogues ouobello

cinecomanacions 801620419XL6woneopen * * 1609910988zeuogueigoupedew2 YYY

- tirnar.inView

- - commandmanna

4 . 4 . 4 . 4 . 4 . 4 .

•

• 500 KOLOD 0300 0900 owo -0900 Cocco 0900 DAOZ U . S . Patent Aug. 7 , 2018 Sheet 22 of 28 US 10 ,040 , 752 B2

4 . - . - . - . - . , , , , .

. p

+,4-1.14

*.-4,

, Seconcionenfremmed. omocouden* .

*.111111111111111. .-> SUN *nsadyod WiscoCoos onypores-Lexojewoju Quote w auan eneenvocationscon

verter ced. . 190duroge . wwwwwwwwwwwww . olan

.sco uen.

so ...... 000 090 IZDIH U . S . Patent Aug. 7, 2018 Sheet 23 of 28 US 10 ,040 , 752 B2

wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww w . www

mmmmmmmmmmmmmmmmmmmmmm -

$ his

*. waterstatteteatatatatatatatatatakot

444.4

*vi

K11042-14OmmadAnDewiWOATHDLOS? 5. 2 ve

" 401*

Wh...... i n io presenzanom month agamanwwwwwwwwww

stos FIG.22 U . S . Patent Aug. 7 , 2018 Sheet 24 of 28 US 10 ,040 ,752 B2 10000398

$ 2990 ogey audio .09

. 1180 BIN BUODEYJÓLOAN WS Mirnica BESY BUUN KODBWYBlon04- 08

WeborewoX40polers-ojny .. 007 $ EVE MBIWDIODY BUCUKIO

280€ - EU usadozuosime in 3.091

. .001

, , , , , , , , , , , , , , , , ...... * * * * * * * * * * " " " ...... 7 Wwwwwwww

AL W -090 LOLO 050 0.40 0.30 .100 090 7777777777777777777777777777777777777777777777777777747 AO FIG.23 U . S . Patent Aug. 7, 2018 Sheet 25 of 28 US 10 ,040 , 752 B2

webojewoypabe-ony . inics

' ceronesia.comco

* ' ...... 000h. AU

FIG.24 U . S . Patent Aug. 7 , 2018 Sheet 26 of 28 US 10 ,040 , 752 B2

: 3???

* %

33 %333

: * * * * * * * * * * * * * * * *

* . . :38

* * * * * * * * * * * * * ??? . .

. "

-???: ???

?? ?? : ??? ???

«« *

? *

: * : 2 * ?

* ":* * « 3 ?? : : * * * * * * * * * * * * * * * * * * * * ???3 ?. 333 %

??? %

% . ?. 8:33 : % yy01 335 a&z'B{? 09DH U . S . Patent Aug. 7 , 2018 Sheet 27 of 28 US 10 ,040 ,752 B2

YYYY

** mindertrimmerierendemanieromdererformeer

*. 18.30WQXOason . Sondadoráci Water * * * * * * * * * xoxx wer

via * 04. 3 . 330 CXKESK89 . * ...... '

* 14

+ . us

*itinaniniriiiiiiiiiiiiiiiiii mondowwwmmmmmmmmmmmmmmmmmmmmm za OK*XXX

FIG.26A LLLLLLLLLL. - - * ...... 3 . 4 WO U . S . Patent Aug . 7 , 2018 Sheet 28 of 28 US 10 ,040 ,752 B2

- ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? - ? * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *

WON:00w8

** me

ww * * * ...... OLIWAS 2863* * * BOX * rrrr. . * * ** * * * ** + + + + ' 'Pr wwwm . in . ????????????????????????????????????????????d??????????????????????????????????????????????????????????? } 09860Room * 200%280 99999999999999999999999999 Beter

* 9999999999999999999999999999999999 3 wwwwwwwwwwwwwwwwwwwwwwwMo * FIG.26B 034 * 80% 2014- ????????????????????????????????????????????????d???????????????????????????? US 10 , 040 ,752 B2

SYNTHESIS OF LEVOMETHADONE In some embodiments , a highly efficient asymmetric HYDROCHLORIDE OR synthesis of levomethadone is provided using D -alanine as DEXTROMETHADONE HYDROCHLORIDE the starting material. The synthesis employs low cost, read ily available chemicals and produces levomethadone , or a AND METHODS FOR USE THEREOF 5 pharmaceutically acceptable salt thereof, in greater than BACKGROUND 40 % overall yield and greater than 99 % enantiomeric excess ( e . e . ) . In some embodiments , levomethadone hydrochloride Methadone hydrochloride is a long -acting opiate used for is provided in greater than 99 % enantiomeric excess with not more than 100 ppm , 50 ppm , or 10 ppm of an impurity treatmentof opiate dependence, opiate detoxification and for 10 selected from the group consisting of dextromethadone , treatment of chronic , severe pain . Methadone hydrochloride diphenylacetonitrile , levomethadone nitrile , isolevometha currently approved for use by the FDA is a racemic mixture done nitrile , and isolevomethadone . of levomethadone and dextromethadone , also known as In some embodiments , a process for preparing levometha DL -methadone , or ( R , S ) -methadone . done hydrochloride is provided comprising converting The active enantiomer of methadone for treatment of 15 D -alanine to N , N - dimethyl- D - alanine; reducing the N , N opiate dependence , opiate detoxification and for treatment of dimethyl- D - alanine to form N , N -dimethyl - D - alaninol; com chronic, severe pain is levomethadone , also known as bining the N .N - dimethyl- D - alaninol with an activating L -methadone , or R - ( - ) -methadone . Known methods for reagent to form an R - activated intermediate ; mixing the preparation of levomethadone may suffer from low overall R - activated intermediate and a base with diphenylacetoni yield and /or undesirable impurity profiles. 20 trile to provide levomethadone nitrile ; and exposing the Beckett et al. , J Chem Soc , 1957 , 858 - 861, provides a levomethadone nitrile to ethyl magnesium bromide , and chiral synthesis of levomethadone from D - Alanine in about hydrochloric acid , to provide levomethadone hydrochloride . 7 steps to produce levomethadone in about a 5 - 6 % overall In some embodiments , a process for preparing dex yield from D - alanine . tromethadone hydrochloride is provided comprising con U . S . Publication US2014 /0350302 provides a method for 25 verting L - alanine to N , N -dimethyl - L -alanine ; reducing the preparing levomethadone comprising racemic synthesis of N , N - dimethyl- L - alanine to form N , N - dimethyl- L - alaninol; methadone followed by resolution as a bromocamphor salt . combining the N , N - dimethyl - L - alaninol with an activating The resolution step introduces undesirable impurities and reagent to form an S - activated intermediate ; mixing the significantly reduces the overall yield of levomethadone . S -activated intermediate and a base with diphenylacetoni An efficient, low cost method for providing levometha - 30 trile to provide dextromethadone nitrile ; and exposing the done hydrochloride in good yield , high enantiomeric excess, dextromethadone nitrile to ethyl magnesium bromide , and and with a minimal impurity profile is desirable . hydrochloric acid , to provide dextromethadone hydrochlo On the other hand, dextromethadone , also known as ride . D -methadone , or ( S ) - ( + ) -methadone , is known to be prac - In some embodiments , a process for preparing levometha tically devoid of opioid activity, but maintains N -methyl - D - 35 done hydrochloride is provided comprising converting aspartate (NMDA ) receptor antagonism . Other NMDA D -alanine to D - alaninol; converting the D - alaninol to N , N receptor antagonists attenuate neuronal plasticity , reverse dimethyl- D - alaninol; combining the N , N - dimethyl- D -alani opioid analgesic tolerance , and alleviate chronic pain states . nol with an activating reagent to form an R - activated inter Moryl et al. , J Opioid Management , 12 : 1 January / Febru - mediate ; mixing the R - activated intermediate and a base ary 2016 , pp . 47 -55 , disclose a phase I study of D -metha - 40 with diphenylacetonitrile to provide levomethadone nitrile; done in patients with chronic pain . and exposing the levomethadone nitrile to ethyl magnesium U . S . Publication US 2014 /0088155 , Manfredi et al. , dis - bromide , and hydrochloric acid , to provide levomethadone closes use of D -methadone for the treatment of psychiatric hydrochloride . symptoms. In some embodiments , a process for preparing dex Therefore , efficient , low cost methods are desirable for 45 tromethadone hydrochloride is provided comprising con providing either dextromethadone hydrochloride or verting L - alanine to L - alaninol; converting the L - alaninol to levomethadone hydrochloride in good yield , high enantio N ,N -dimethyl - L -alaninol ; combining the N ,N -dimethyl - L meric excess , and with minimal impurity profiles . alaninol with an activating reagent to form an S - activated intermediate ; mixing the S - activated intermediate and a base SUMMARY 50 with diphenylacetonitrile to provide dextromethadone nitrile ; and exposing the dextromethadone nitrile to ethyl Highly efficient methods for synthesis of levomethadone magnesium bromide , and hydrochloric acid , to provide hydrochloride or dextromethadone hydrochloride are pro dextromethadone hydrochloride . vided starting from D - alanine, or L -alanine , respectively , In some embodiments , a process for preparing levometha with retention of configuration . Methods for treating a 55 done hydrochloride is provided comprising converting subject are provided comprising administering a composi - D - alanine to N ,N - dimethyl- D -alanine , wherein the convert tion comprising an effective amount of levomethadone ing comprises hydrogenating the D -alanine with formalde hydrochloride having not more than 10 ppm dextrometha - hyde and /or paraformaldehyde with a catalyst to form N , N done . dimethyl- D - alanine . In some embodiments , a method is provided to produce 60 In some embodiments , a process for preparing dex either levomethadone hydrochloride or dextromethadone tromethadone hydrochloride is provided comprising con hydrochloride in greater than 95 % , 98 % , 99 % , 99 . 5 % , or verting L -alanine to N , N -dimethyl - L -alanine , wherein the 99 . 9 % enantiomeric excess in greater than 40 % overall yield converting comprises hydrogenating the L -alanine with from D - alanine, or L - alanine , respectively . In one embodi - formaldehyde and / or paraformaldehyde with a catalyst to ment, a method is provided to produce enantiomerically 65 form N , N -dimethyl - L - alanine. pure levomethadone in greater than 40 % overall yield from In some embodiments , a process for preparing levometha D - alanine . done hydrochloride is provided comprising reducing the US 10 , 040 , 752 B2 N , N -dimethyl - D - alanine to form N , N - dimethyl- D -alaninol , ide, potassium t- butoxide , sodium t - butoxide , sodium wherein the reducing comprises exposing the N , N -dimethyl methoxide , potassium methoxide , sodium ethoxide , potas D - alanine to one or more reducing agents selected from sium ethoxide, sodium tert -pentoxide ( sodium tert -amox LiAlH4, BHZ/ THF , BHz/ Et O , BHZ/ BF3 Et20 , BHZ/ Me S , ide ), potassium tert- pentoxide (potassium tert- amoxide ) , NaBH _/ 12 , BH _/ cyanuric chloride, NaBH2CN /ZnCl2 , 5 sodium isopropoxide , and potassium isopropoxide. In a NaBH / ZnCl2, Zn (BH4 ) 2 , or NaBH _/ BFz . Et O . In a specific specific aspect , the base is potassium t -butoxide . In some aspect, the reducing agent is LiAlH , . embodiments , the solvent is selected from dimethylforma In some embodiments , a process for preparing dex - mide, dimethylacetamide, tetrahydrofuran , dimethyl sulfox tromethadone hydrochloride is provided comprising reduc - ide, N -methyl - 2 - pyrrolidone, dioxane , water, or a combina ing the N , N - dimethyl - L - alanine to form N , N -dimethyl - D - 10 tion thereof. In specific aspects , levomethadone nitrile is alaninol, wherein the reducing comprises exposing the N , N - formed in > 95 % , > 97 % , > 99 % , > 99 . 5 % , or > 99. 9 % enantio dimethyl- D -alanine to one or more reducing agents selected meric excess ( e . e . ) . In a specific aspect , levomethadone from LiAlH4, BHZ/ THF, BHZ/ Et20 , BHZ/ BF3 Et O , BHZ! nitrile is formed in > 99 % enantiomeric excess ( e .e .) . Me , S , NaBH / I , , BH /cyanuric chloride , NaBH CN / ZnC1, , In some embodiments , a process for preparing dex NaBH _ /ZnCl2 , Zn (BH _ ) 2 , or NaBH _ / BF2 .Et O . In a specific 15 tromethadone hydrochloride is provided comprising mixing aspect, the reducing agent is LiAlH4. an activated intermediate and a base with diphenylacetoni In some embodiments , a process for preparing levometha - trile to provide dextromethadone nitrile , wherein the mixing done hydrochloride is provided comprising reducing D - ala - comprises exposing the activated intermediate to a base and nine to form D - alaninol, wherein the reducing comprises diphenylacetonitrile in a solvent to form the dextrometha exposing the D - alanine to one or more reducing agents 20 done nitrile . In some embodiments , the base is selected from selected from LiAlH4, BHZ/ THF, BHZ/ Et O , BHZ/ BF2 Et, 0 , the group consisting of sodium hydroxide , potassium BHz/Me , S , NaBH _ / I2 , BHX/ cyanuric chloride , NaBHZCN / hydroxide, potassium t- butoxide , sodium t -butoxide , sodium ZnCl2 , NaBH _ ZnCl2 , Zn ( BH4) 2, or NaBH _ /BF3 . Et 0 . In a methoxide , potassium methoxide , sodium ethoxide, potas specific aspect , the reducing agent is Zn (BH4 ) 2 . sium ethoxide , sodium tert- pentoxide (sodium tert- amox In some embodiments , a process for preparing dex - 25 ide ) , potassium tert - pentoxide (potassium tert - amoxide ) , tromethadone hydrochloride is provided comprising reduc - sodium isopropoxide, and potassium isopropoxide . In a ing L - alanine to form L - alaninol, wherein the reducing specific aspect , the base is potassium t -butoxide . In some comprises exposing the L - alanine to one or more reducing embodiments , the solvent is selected from dimethylforma agents selected from LiAlH , BHZ/ THF, BH2/ Et , O , BH , mide , dimethylacetamide , tetrahydrofuran , dimethyl sulfox BFz Et O , BHZ/Me , S , NaBH _ / , BH cyanuric chloride , 30 ide, N -methyl - 2 - pyrrolidone , dioxane , water, or a combina NaBH CN / ZnCl2, NaBH _ ZnCl , , Zn (BH4 ) 2 , or NaBH _ tion thereof. In specific aspects , dextromethadone nitrile is BF3. Et20 . In a specific aspect , the reducing agent is formed in > 95 % , > 97 % , > 99 % , > 99. 5 % , or > 99 . 9 % enantio Zn (BH4 ) 2 meric excess ( e . e . ) . In a specific aspect, dextromethadone In some embodiments , a process for preparing levometha - nitrile is formed in > 99 % enantiomeric excess ( e . e . ) . done hydrochloride is provided comprising combining N , N - 35 In some embodiments , a process is provided for preparing dimethyl- D - alaninol with an activating reagent to form an levomethadone hydrochloride from D -alanine or dex activated intermediate , wherein the activating reagent is tromethadone hydrochloride from L - alanine, the process selected from thionyl chloride , methanesulfonyl chloride, comprising : converting D -alanine to N , N - dimethyl- D - alani p -toluenesulfonyl chloride, trifluoromethanesulfonyl chlo - nol or converting L - alanine to N , N -dimethyl - L - alaninol; ride , methanesulfonic anhydride, trifluoromethanesulfonic 40 combining the N , N - dimethyl- D - alaninol or the N , N - dim anhydride, or p - toluenesulfonic anhydride. ethyl- L - alaninol with an activating reagent to form a R - ac In some embodiments , a process for preparing dex - tivated intermediate or an S -activated intermediate, respec tromethadone hydrochloride is provided comprising com tively ; mixing the R - or S -activated intermediate and a base bining N , N - dimethyl- L -alaninol with an activating reagent with diphenylacetonitrile to provide levomethadone nitrile to form an activated intermediate , wherein the activating 45 or dextromethadone nitrile , respectively ; exposing the reagent is selected from thionyl chloride , methanesulfonyl levomethadone nitrile or dextromethadone nitrile to a Gri chloride, p - toluenesulfonyl chloride , trifluoromethanesulfo - gnard reagent of formula RMgX , where R is ethyl and nyl chloride, methanesulfonic anhydride , trifluoromethane X = C1, Br, or I, to form a reaction mixture ; and adding sulfonic anhydride , or p -toluenesulfonic anhydride . hydrochloric acid to the reaction mixture to provide In some embodiments , the activated intermediate is 50 levomethadone hydrochloride or dextromethadone hydro selected from ( R ) - 1 - chloro - N , N -dimethylpropan - 2 - amine chloride , respectively. HC1, ( R ) - 1 - chloro - N , N -dimethylpropan - 2 - amine , ( R ) - 2 - ( di In some embodiments , a process for preparing levometha methylamino )propyl 4 -methylbenzenesulfonate , or (R )- 2 - done hydrochloride is provided comprising : converting ( dimethylamino ) propyl methanesulfonate . In a specific D - alanine to N , N -dimethyl - D - alanine; reducing the N , N aspect , the activated intermediate is ( R ) - 1 - chloro - N , N - dim - 55 dimethyl- D - alanine to form N , N - dimethyl- D - alaninol; com ethylpropan - 2 - amine HCl. In another aspect, the activated bining the N , N - dimethyl- D -alaninol with an activating intermediate is isolated before being used in the reacting reagent to form an activated intermediate ; mixing the acti step , or is prepared and used in the next step without v ated intermediate and a base with diphenylacetonitrile to isolation . provide levomethadone nitrile ; and exposing the levometha In some embodiments , a process for preparing levometha - 60 done nitrile to ethyl magnesium bromide , and hydrochloric done hydrochloride is provided comprising mixing an acti - acid , to provide levomethadone hydrochloride , wherein the vated intermediate and a base with diphenylacetonitrile to exposing comprises adding ethyl magnesium bromide to a provide levomethadone nitrile , wherein the mixing com - stirred solution of levomethadone nitrile in an anhydrous prises exposing the activated intermediate to a base and solvent to form a reaction mixture ; heating the reaction diphenylacetonitrile in a solvent to form the levomethadone 65 mixture to 100° C . for 1 - 6 hrs ; cooling the reaction mixture nitrile . In some embodiments , the base is selected from the to ambient temperature ; adding hydrochloric acid to the group consisting of sodium hydroxide , potassium hydrox - reaction mixture with external cooling such that the reaction US 10 , 040 , 752 B2 temperature does not exceed 50° C .; and isolating the sition is provided comprising an effective amount of levomethadone hydrochloride . levomethadone hydrochloride having not more than 50 ppm In some embodiments , a process is provided for preparing of dextromethadone. In another aspect , a pharmaceutical levomethadone hydrochloride or dextromethadone hydro composition is provided comprising an effective amount of chloride , the process comprising obtaining N , N - dimethyl- 5 levomethadone hydrochloride having not more than 25 ppm D - alaninol or N , N -dimethyl - L - alaninol; combining the N , N - of dextromethadone . In another aspect , a pharmaceutical dimethyl- D -alaninol or the N , N -dimethyl - L -alaninol with composition is provided comprising an effective amount of an activating reagent to form a R -activated intermediate or levomethadone hydrochloride having not more than 10 ppm an S - activated intermediate , respectively ; mixing the R - or of dextromethadone . S - activated intermediate and a base with diphenylacetoni - 10 In some embodiments , a method for management of pain , trile to provide levomethadone nitrile or dextromethadone opioid detoxification , or maintenance of opioid addiction in nitrile , respectively ; and exposing the levomethadone nitrile a subject in need thereof is provided , comprising adminis or dextromethadone nitrile to a Grignard reagent of formula tering a pharmaceutical composition comprising an effective RMgX , where R is ethyl and X = C1, Br, or I, to form a amount of levomethadone hydrochloride having not more reaction mixture ; and adding hydrochloric acid to the reac - 15 than 100 ppm of an impurity selected from the group tion mixture to provide levomethadone hydrochloride or consisting of dextromethadone, diphenylacetonitrile , dextromethadone hydrochloride , respectively . levomethadone nitrile , isolevomethadone nitrile , and In some embodiments , a process is provided for preparing isolevomethadone ; and a pharmaceutically acceptable car levomethadone hydrochloride or dextromethadone hydro - rier . chloride , the process comprising obtaining N , N -dimethyl - 20 In some embodiments , a method for the management of D - alaninol or N , N -dimethyl - L - alaninol; converting the N , N - pain is provided selected from management of chronic dimethyl- D - alaninol or N , N - dimethyl- L - alaninol to malignant pain ;management of chronic non -malignant pain ; levomethadone nitrile or dextromethadone nitrile, respec - or management of pain severe enough to require daily , tively ; and converting the levomethadone nitrile or dex - around -the - clock , long- term opioid treatment comprising tromethadone nitrile to levomethadone hydrochloride or 25 administering a pharmaceutical composition comprising an dextromethadone hydrochloride , respectively . effective amount of levomethadone hydrochloride having In some embodiments , a process is provided for preparing not more than 100 ppm of an impurity selected from the levomethadone hydrochloride or dextromethadone hydro - group consisting of dextromethadone , diphenylacetonitrile , chloride , the process comprising obtaining N , N - dimethyl levomethadone nitrile , isolevomethadone nitrile , and D - alaninol or N , N - dimethyl- L - alaninol; and converting the 30 isolevomethadone; and a pharmaceutically acceptable car N , N - dimethyl- D - alaninol or N , N -dimethyl - L - alaninol to rier . levomethadone hydrochloride or dextromethadone hydro - In some embodiments , a method for opioid detoxification chloride , respectively. is provided selected from detoxification treatment of opioid In some embodiments , a process is provided for preparing addiction (heroin or other morphine - like drugs ) ; detoxifica levomethadone hydrochloride from D - alanine or dex - 35 tion treatment of opiate addiction , and facilitation of wean tromethadone hydrochloride from L - alanine , the process i ng from opiate medications after extended periods in the comprising: converting D - alanine or L - alanine to intensive care unit ( ICU ) , on the ward , or as an outpatient , levomethadone nitrile or dextromethadone nitrile , respec - comprising administering a pharmaceutical composition tively ; and converting the levomethadone nitrile or dex - comprising an effective amount of levomethadone hydro tromethadone nitrile to levomethadone hydrochloride or 40 chloride having not more than 100 ppm of an impurity dextromethadone hydrochloride, respectively . selected from the group consisting of dextromethadone , In some embodiments , a process for preparing levometha diphenylacetonitrile , levomethadone nitrile , isolevometha done hydrochloride is provided herein , wherein the done nitrile , and isolevomethadone ; and a pharmaceutically levomethadone hydrochloride comprises not more than acceptable carrier. 0 .05 % (500 ppm ) , 0 . 025 % (250 ppm ) , or 0 . 01 % ( 100 ppm ) of 45 In some aspects, a method for the maintenance of opioid an impurity selected from dextromethadone hydrochloride , addiction is provided that is maintenance treatment of opioid dextromethadone , isodextromethadone, isodextrometha addiction (heroin or other morphine- like drugs) , comprising done hydrochloride, isolevomethadone , isolevomethadone administering a pharmaceutical composition comprising an hydrochloride , levomethadone nitrile , dextromethadone effective amount of levomethadone hydrochloride having nitrile , isolevomethadone nitrile , isodextromethadone 50 not more than 100 ppm of an impurity selected from the nitrile , diphenylacetonitrile , 2S ) - 2 - [ [ ( 4 -methylphenyl )sul group consisting of dextromethadone , diphenylacetonitrile , phonyl] amino ]pentanedioic acid ( N -tosyl - L - glutamic acid ) ; levomethadone nitrile , isolevomethadone nitrile , and a tartaric acid , or a bromocamphor sulfonic acid , such as a isolevomethadone ; and a pharmaceutically acceptable car 3 - bromocamphor- 10 -sulfonic acid . rier. In some embodiments , a process for preparing levometha - 55 In some embodiments , a method for management of pain , done hydrochloride is provided herein , wherein the opioid detoxification , or maintenance of opioid addiction in levomethadone hydrochloride comprises not more than 100 a subject in need thereof is provided , comprising adminis ppm of an impurity selected from the group consisting of tering a pharmaceutical composition comprising an effective dextromethadone , diphenylacetonitrile , levomethadone amount of levomethadone hydrochloride having not more nitrile , isolevomethadone nitrile , and isolevomethadone . 60 than 100 ppm of an impurity selected from the group In some embodiments , a pharmaceutical composition is consisting of dextromethadone , diphenylacetonitrile , provided comprising an effective amount of levomethadone levomethadone nitrile , isolevomethadone nitrile , and hydrochloride having not more than 100 ppm of an impurity isolevomethadone ; and a pharmaceutically acceptable car selected from the group consisting of dextromethadone , rier, wherein the effective amount of levomethadone hydro diphenylacetonitrile , levomethadone nitrile, isolevometha - 65 chloride is an amount from 0 . 5 mg to 500 mg, 1 . 0 mg to 250 done nitrile , and isolevomethadone ; and a pharmaceutically - mg, or 2 mg to 50 mg levomethadone hydrochloride . In acceptable carrier. In one aspect, a pharmaceutical compo some aspects, the effective amount is selected from 2 . 5 mg, US 10 ,040 ,752 B2 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, X is (CH2 ) n , where n = 1 - 6 ; 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg. Y is CN or — C ( O )R14 ; 150 mg, 160 mg . 170 mg, 180 mg, 190 mg, 200 mg, 210 mg , R14 is alkyl, alkanyl, alkynyl, cycloalkyl, heterocyclyl, 220 mg, 230 mg, 240 mg, or 250 mg levomethadone hydrochloride . aryl, heteroaryl , alkoxy , aryloxy, aralkyl , or amino ; and In some embodiments , a method for management of pain , 5 * is a stereocenter selected from R or S configuration , opioid detoxification , ormaintenance of opioid addiction in wherein the stereocenter * is in an R configuration , and a subject in need thereof is provided , comprising adminis wherein the compound is present in greater than 90 % , 95 % , tering a pharmaceutical composition comprising an effective 97 % , 99 % , 99. 5 % , or 99 .9 % enantiomeric excess (e . e ) amount of levomethadone hydrochloride comprising not compared to the S isomer, or wherein the stereocenter * is in more than 50 ppm , 25 ppm , or 10 ppm of dextromethadone an S configuration , and wherein the compound is present in or a salt thereof. greater than 90 % , 95 % , 97 % , 99 % , 99 . 5 % , or 99 . 9 % In some embodiments , a method is provided for treating enantiomeric excess ( e . e ) compared to the R isomer. a subject in need thereof, comprising administering to the In some embodiments , a method for preparing an isolated subject a pharmaceutical composition comprising an effec compound according to Formula ( I ) , or pharmaceutically tive amount of dextromethadone hydrochloride having not acceptable salt thereof, is provided , wherein the method more than 100 ppm , notmore than 50 ppm , or not more than 10 ppm of an impurity selected from the group consisting of comprises converting a D -amino acid to an N , N -dialkyl levomethadone , diphenylacetonitrile , dextromethadone amino acid ; treating the N , N -dialkyl amino acid with a nitrile , isodextromethadone nitrile , and isodextrometha reducing agent to form an N ,N - dialkyl aminoalcohol; con done ; and a pharmaceutically acceptable carrier . In some| 20 verting the N , N - dialkyl aminoalcohol to an activated inter embodiments , the subject in need thereof is suffering from mediate comprising a halo group or a sulfonyl group ;mixing a disease or condition selected from the group consisting of the activated intermediate with a base and a diarylacetoni anxiety disorders, Alzheimer ' s disease , chronic pain , trile to provide a nitrile intermediate of formula (I ), wherein dementia , depression , neuropathic pain , anti -NMDA recep Y is CN ; and exposing the nitrile intermediate to a tor encephalitis , opioid analgesic tolerance , schizophrenia . 25 Grignard reagent and an acid to form the compound of stroke , and traumatic brain injury . In some embodiments , the formula ( I ), wherein Y is - C ( O ) R14 : pharmaceutical composition comprises an effective amount In some embodiments , a method for preparing an isolated of dextromethadone hydrochloride in an amount from 0. 5 compound according to Formula ( I) , or pharmaceutically mg to 500 mg, 1 . 0 mg to 250 mg, or 2 mg to 50 mg acceptable salt thereof, is provided , wherein Y = C ( O ) dextromethadone hydrochloride: or the effective amount is 30 R14 ; R1, R2, R3, R4 , R5, Ro , R7, R8, R9, Rio are indepen selected from 2 . 5 mg, 5 mg, 10 mg, 20 mg, 30 mg, or 40 mg dently H ; Rui is CH3, - CH (CH3 ) 2 , — CH2CH (CH3 ) 2 , dextromethadone hydrochloride . In some embodiments , a CH (CH3 )CH2CH3 , -or - CH _ Ph ; R12 and R13 are indepen dextromethadone hydrochloride composition is provided dently C1- 6 alkyl; R 14 is alkyl , alkenyl or aryl; n = 1 ; and * is comprising not more than 50 ppm , not more than 25 ppm , or in the R configuration in greater than 99 % e . e . not more than 10 ppm of levomethadone or a salt thereof. 35 In some embodiments , a method for preparing the isolated In some embodiments , an isolated compound according to compound of formula ( I) , or pharmaceutically acceptable Formula ( I) , or a pharmaceutically acceptable salt thereof, is salt thereof, is provided wherein R1, R2, R3, R4, R5, R . , R7, provided Rz, R9, R10 are independently H ; Rui is methyl; R12 and R 13 are independently methyl; R14 is ethyl; n = 1 ; and * is in the 40 R configuration in greater than 99 . 5 % e . e . BRIEF DESCRIPTION OF THE DRAWINGS FIG . 1A shows a general synthetic route provided for 45 preparation of levomethadone hydrochloride . ( R ) - 2 - N , N R dimethyl alaninol ( C ) is prepared from D - alanine . An acti Ril vated intermediate ( D , D ' or D " ) of the N , N - dimethyl - alaninol is prepared and treated with diphenylacetonitrile to R12NN *XY form levomethadone nitrile ( E ) which is treated with a 50 Grignard reagent, then HCl to form levomethadone hydro R13 R10 chloride. FIG . 1B shows a general synthetic route provided for preparation of dextromethadone hydrochloride . ( S ) - 2 -N , N RO dimethyl alaninol ( C ) is prepared from L - alanine . An acti Rs 55 vated intermediate of the N , N -dimethyl alaninol is prepared and treated with diphenylacetonitrile to form dextrometha wherein R1, R2, R3, R4, Rs, R ., R7, Rs, Ry, Rio are done nitrile which is treated with a Grignard reagent, then independently H , amino , C1- 6 alkyl, alkenyl, alkynyl , halo , HC1 to form dextromethadone hydrochloride . hydroxyl , carbocyclic , heterocyclic , or aryl; FIG . 1C shows two alternative routes for preparation of Rji is H , acyl, amino , amido , azido , carboxyl , alkyl, aryl, 60 levomethadone hydrochloride from D - alanine with retention aralkyl, halo , guanidinyl, oxo , sulfanyl , sulfenyl, sulfonyl, of configuration . heterocyclyl, heteroaryl, or hydroxyl; FIG . 1D shows two alternative routes for preparation of R12 , R13 are independently H , acyl, alkyl, alkyenyl, alky - dextromethadone hydrochloride from L - alanine with reten nyl, aralkyl, aryl, carboxyl, cycloalkyl, heterocyclic , or other tion of configuration . amino ( in the case of hydrazide ) or R12 and R13 together with 65 FIG . 2A shows one specific embodiment of the method the nitrogen atom to which they are attached , form a ring for preparation of levomethadone hydrochloride in about 5 having 4 - 8 atoms. steps from D -alanine . Conversion of D - alanine to N , N US 10 ,040 , 752 B2 10 dimethyl alanine is followed by reduction with LiAlH4 and FIG . 19C shows C18 reverse phase HPLC analysis of subsequent conversion of the resulting amino alcohol to levomethadone nitrile after second recrystallization with levomethadone HCl. heptane exhibiting 100 % purity at 210 nm . FIG . 2B shows another specific embodimentwith sequen - FIG . 20 shows chiral HPLC chromatogram for compara tial Zn ( BHX) reduction -CH , O /HCO , H dimethylation of 5 tive racemic methadone . Two enantiomers are seen in about D - alanine and subsequent conversion of the resulting amino a 1 : 1 ratio . alcohol to levomethadone HC1. FIG . 21 shows chiral HPLC chromatogram for FIG . 3 shows one embodiment for formation of N , N - levomethadone prepared according to the disclosure . A dimethyl D - alanine ( B ) by treating D - alanine starting mate - single enantiomer with e . e . > 99 % is shown . rial ( A ) with formaldehyde , hydrogen and palladium on 10 FIG . 22 shows a representative C18 reverse phase HPLC carbon (Pd / C ) . chromatogram of levomethadone hydrochloride . Less than FIG . 4 shows one embodiment for formation of ( R ) - 2 - 100 ppm of diphenylacetonitrile , isolevomethadone nitrile , ( dimethylamino ) propan - 1 - ol ( C ) by direct reduction of N , N and levomethadone nitrile impurities are detected at 210 nm . dimethyl D -alanine ( B ) or via derivatization of B followed FIG . 23 shows a representative C18 reverse phase UPLC by reduction . 15 chromatogram with baseline resolution of a mixture of ( 1 ) FIG . 5 shows three embodiments for activation of ( R ) - 2 - benzophenone , ( 2 ) starting material reagent diphenylac ( dimethylamino )propan - 1 - ol (C ) by thionyl chloride to form etonitrile , (3 ) impurity isolevomethadone nitrile , ( 4 ) inter intermediate ( D ), ( R ) - 1 - chloro - N , N - dimethylpropan - 2 - mediate levomethadone nitrile, and (5 ) product Levometha amine HCl; or conversion of ( C ) to a sulfonate ester such as done , run according to method of Example 4C . D ' and D " , where D ' is (R )- 2 - ( dimethylamino )propyl 20 FIG . 24 shows a representative C18 reverse phase UPLC 4 -methylbenzenesulfonate ; and D " is ( R ) - 2 -( dimethyl - chromatogram of levomethadone hydrochloride prepared amino )propyl methanesulfonate . The activated intermediate according to the disclosure . Less than 100 ppm of dipheny D , D ' or D " is treated with a base and diphenylacetonitrile to lacetonitrile , isolevomethadone nitrile , and levomethadone form levomethadone nitrile ( E ) . nitrile impurities are detected at 210 nm . FIG . 6 shows one embodiment for the synthesis of 25 FIG . 25A shows one route for the synthesis of N , N levomethadone hydrochloride from levomethadone nitrile dimethyl - L - alaninol from L -alanine . ( E ) . FIG . 25B shows one route for the synthesis of dex FIG . 7 shows a 1H -NMR spectrum of N , N -dimethyl tromethadone nitrile from N , N - dimethyl- L - alaninol. D - alanine , intermediate B , in MeOH - d4 at 300 MHz. FIG . 25C shows one route for the synthesis of dex FIG . 8 shows 13C -NMR spectrum of N , N - dimethyl D - ala - 30 tromethadone hydrochloride from dextromethadone nitrile . nine, intermediate B , in MeOH - d4 at 75 MHz . FIG . 26A shows a reference chiral chromatogram of a FIG . 9 shows ' H -NMR spectrum of crude ( R ) - 2 - ( N , N - mixture of levomethadone hydrochloride and dextrometha dimethylamino ) propan - 1 - ol ( N , N -dimethyl D -alaninol ) in done hydrochloride . CDC12 at 300 MHz. FIG . 26B shows a chiral chromatogram of dextrometha FIG . 10 shows a magnified portion of FIG . 9 , ' H -NMR 35 done hydrochloride prepared according to the disclosure . spectrum of crude N , N -dimethyl D - alaninol, intermediate C , in CDC1 , at 300 MHz from about d 0 . 1 - 4 . 0 ppm . DETAILED DESCRIPTION FIG . 11 shows a ' H -NMR spectrum of crude intermediate D , ( R ) - 1 - chloro - N , N - dimethylpropan - 2 -amine HCl, in Definitions MeOH -d4 at 300 MHz . 40 FIG . 12 shows a magnified portion of FIG . 11, ' H -NMR As used herein , the terms “ administration ” and “ admin spectrum of crude intermediate D , ( R ) - 1 - chloro - N , N - dim - istering ” refer to the act of giving a drug , prodrug, or other ethylpropan - 2 - amine HCl, in MeOH - d4 at 300 MHz from agent , or therapeutic treatment ( e . g ., compositions of the about d 1 -5 ppm . present application ) to a subject (e .g . , a subject or in vivo , in FIG . 13 shows ' H -NMR spectrum of levomethadone 45 vitro , or ex vivo cells , tissues, and organs ) . Exemplary routes nitrile , intermediate E . of administration to the human body can be through the eyes FIG . 14 shows a magnified portion of FIG . 13 , ' H -NMR ( ophthalmic ) , mouth (oral , e . g ., immediate release , con spectrum of levomethadone nitrile , intermediate E , from trolled release , fast melt , etc . ) , skin ( topical or transdermal about 0 . 6 to 3 ppm . or sublingual) , nose (nasal ) , lungs ( inhalant) , oral mucosa FIG . 15 shows a 13C -NMR spectrum of levomethadone 50 (buccal ) , ear, rectal, vaginal, by injection ( e . g . , intrave nitrile , intermediate E , showing the presence of 14 magneti - nously , subcutaneously , intratumorally , intraperitoneally , cally different C atoms. intramuscularly , etc . ) and the like . FIG . 16 shows a magnified portion of FIG . 15 13C -NMR The term “ comprising ” refers to a composition , com spectrum of levomethadone nitrile , intermediate E , from pound , formulation or method that is inclusive and does not about 120 - 145 ppm . 55 exclude additional elements or method steps. FIG . 17 shows chiral HPLC chromatogram for The term “ consisting of” refers to a compound, compo levomethadone nitrile , intermediate E , of example 3 . A sition , formulation , or method that excludes the presence of single enantiomer with e . e . > 99 % is shown . any additional component or method steps . FIG . 18 shows chiral HPLC chromatogram for compara The term " consisting essentially of” refers to a composi tive racemic methadone nitrile . Two enantiomers are seen in 60 tion , compound, formulation or method that is inclusive of about a 1: 1 ratio . additional elements or method steps that do not materially FIG . 19A shows C18 reverse phase HPLC separation of affect the characteristic (s ) of the composition , compound , a mixture of ( 1) diphenylacetonitrile , ( 2 ) isolevomethadone formulation or method . nitrile , ( 3 ) levomethadone nitrile , and ( 4 ) levomethadone . The term “ compound ( s ) ” refers to any one or more FIG . 19B shows C18 reverse phase HPLC analysis of 65 chemical entity , pharmaceutical, drug , and the like that can levomethadone nitrile after first recrystallization with hep - be used to treat or prevent a disease , addiction , illness , tane exhibiting 99 . 6 % purity at 210 nm . sickness , or disorder of bodily function . Compounds com US 10 , 040 , 752 B2 prise both known and potential therapeutic compounds. A The phrase " pharmaceutically acceptable ” refers to those compound can be determined to be therapeutic by screening compounds , materials , compositions , and /or dosage forms using the screening methods of the present application . A which are , within the scope of sound medical judgment, “ known therapeutic compound ” refers to a therapeutic com suitable for use in contact with the tissues of human beings pound that has been shown ( e . g . , through animal trials or 5 and animals without excessive toxicity , irritation , allergic prior experience with administration to humans) to be effec response, or other problem or complication , commensurate with a reasonable benefit / risk ration . tive in such treatment. In other words , a known therapeutic The phrase "pharmaceutically - acceptable carrier ” refers compound is not limited to a compound efficacious in the to a pharmaceutically - acceptable material, composition or treatment of disease or condition (e . g. , chronic pain ). 1 10 vehicle , such as a liquid or solid filler, diluent, excipient, The terms “ analog " and " derivative ” are interchangeable solvent or encapsulating material, involved in carrying or and refer to a natural or non - natural modification of at least transporting the subject selenium containing compound or one position of a given molecule . For example , a derivative analogue or derivative from one organ , or portion of the of a given compound or molecule is modified either by body, to another organ , or portion of the body . Each carrier addition of a functional group or atom , removal 01of aa funcTunc - 15 must be acceptable ” in the sense of being compatible with tional group or atom or change of a functional group or atom the other ingredients of the formulation and not injurious to to a different functional group or atom ( including, but not the patient. Some examples of materials which may serve as limited to , isotopes ) . pharmaceutically -acceptable carriers include : ( 1 ) sugars , The term “ composition ( s )” refers to the combination of such as lactose , glucose and sucrose ; ( 2 ) starches , such as one ormore compounds with or without another agent, such 20 corn starch and potato starch ; (3 ) cellulose , and its deriva as but not limited to a carrier agent. ( e . g . , one or more tives , such as sodium carboxymethyl cellulose , ethyl cellu levomethadone compounds with a carrier , inert or active ), lose , microcrystalline ecellulose , and cellulose acetate ; ( 4 ) making the composition especially suitable for diagnostic or powdered tragacanth ; (5 ) malt ; (6 ) gelatin ; ( 7) talc ; ( 8 ) therapeutic use in vitro , in vivo or ex vivo . excipients , such as cocoa butter and suppository waxes ; ( 9 ) The term " component” refers to a constituent part of a 25 oils , such as peanut oil, cottonseed oil , safflower oil, sesame compound , or a composition . For example , components of a oil , olive oil , corn oil and soybean oil ; ( 10 ) glycols , such as composition can include a compound , a carrier , and any propylene glycol; ( 11 ) polyols , such as glycerin (glycerol ) , other agent present in the composition . sorbitol, mannitol and polyethylene glycol; ( 12 ) esters, such The term " effective amount” refers to the amount of a as ethyl oleate and ethyl laurate ; ( 13 ) agar ; ( 14 ) buffering composition or compound sufficient to effect beneficial or 30 agents , such as magnesium hydroxide and aluminum desired results . An effective amount can be administered in hydroxide ; (15 ) lubricants , such as magnesium stearate , one or more applications or dosages and is not intended to calcium stearate , zinc stearate , sorbitan monostearate , be limited to a particular formulation or administration sucrose monopalmitate , glycerol dibehenate , and stearic route . acid ; ( 16 ) alginic acid ; ( 17 ) pyrogen - free sterile water ; ( 18 ) Opioid receptor agonists ( sometimes abbreviated as opi- 35 isotonic saline ; ( 19 ) Ringer ' s solution ; ( 20 ) ethyl alcohol; oid agonists, or “ opioids ” ) can also be called opiates. (21 ) phosphate buffer solutions ; (22 ) polymers and time The term “ hydrate ” refers to a compound disclosed herein release agents ; ( 23 ) bioavailability enhancers and bioavail which is associated with water in the molecular form , i . e . , in ability controllers/ inhibitors ; and (23 ) other non - toxic com which the H - OH bond is not split , and may be represented , patible substances employed in pharmaceutical formula for example , by the formula RxH20 , where R is a compound 40 tions . disclosed herein . A given compound may form more than The term " ppm ” refers to parts per million . For example , one hydrate including, for example , monohydrates as used to refer to an impurity such as dextromethadone , (RxH2O ), dihydrates (R2X2 H2O ), trihydrates (Rzx3 H2O ), " ppm ” means parts per million of dextromethadone in a and the like . The term “ inhibitory ” or “ antagonistic ” refers particular sample . to the property of a compound that decreases, limits , or 45 The term “ salts ” can include acid addition salts or addi blocks the action or function of another compound tion salts of free bases. Preferably , the salts are pharmaceu The term “modulates ” refers to a change in the state ( e . g . tically acceptable . Examples of acids which may be activity or amount of a compound from a known or deter employed to form pharmaceutically acceptable acid addition mined state . salts include , but are not limited to , salts derived from " Optional” or " optionally ” refers to a circumstance in 50 nontoxic inorganic acids such as nitric , phosphoric , sulfuric , which the subsequently described event or circumstance or hydroiodic , hydrobromic , hydrochloric , hydrofluoric , may or may not occur, and that the description includes phosphorous, as well as salts derived from nontoxic organic instances where said event or circumstance occurs and acids such as aliphatic mono - and dicarboxylic acids , phe instances in which it does not. “ Optionally ” is inclusive of nyl -substituted alkanoic acids , hydroxyl alkanoic acids , embodiments in which the described conditions is present 55 alkanedioic acids, aromatic acids , aliphatic and aromatic and embodiments in which the described condition is not sulfonic acids , and acetic , trifluoroacetic , maleic , succinic , present. For example, " optionally substituted phenyl” means or citric acids. Non - limiting examples of such salts include that the phenyl may or may not be substituted , and that the napadisylate , besylate , sulfate , pyrosulfate , bisulfate , sulfite , description includes both unsubstituted phenyl and phenyl bisulfite , nitrate , phosphate , monohydrogenphosphate , dihy wherein there is substitution . " Optionally ” is inclusive of 60 drogenphosphate , metaphosphate , pyrophosphate , chloride , embodiments in which the described conditions is present bromide , iodide , acetate , trifluoroacetate , propionate , capry and embodiments in which the described condition is not late , isobutyrate , oxalate , malonate , succinate , suberate , present. sebacate , fumarate , maleate , mandelate , benzoate , chlo The terms" patient” or “ subject ” are used interchangeably robenzoate , methylbenzoate , dinitrobenzoate , phthalate , and refer to any member of Kingdom Animalia . Preferably 65 benzenesulfonate , toluenesulfonate , phenylacetate , citrate , a subject is a mammal, such as a human , domesticated lactate , maleate , tartrate , methanesulfonate , and the like . mammal or a livestock mammal. Also contemplated are salts of amino acids such as arginate US 10 ,040 , 752 B2 13 14 and the like and gluconate , galacturonate (see , for example , clinical symptoms, or enhancement or improvement of the Berge, et al. “ Pharmaceutical Salts ," J . Pharma. Sci. 1977 ; condition , disorder or disease . 66 : 1 ) . The term “ toxic ” refers to any detrimental or harmful The term “ pharmaceutically acceptable salts ” includes , effects on a subject, a cell , or a tissue as compared to the but is not limited to , salts well known to those skilled in the 5 same cell or tissue prior to the administration of the toxicant. art, for example , mono - salts ( e . g . alkali metal and ammo - The term “ prodrug ” refers to a pharmacologically active nium salts ) and poly salts ( e . g . di - or tri - salts , ) of the or more typically an inactive compound that is converted compounds of the invention . Pharmaceutically acceptable into a pharmacologically active agent by a metabolic trans salts of compounds of the disclosure are where , for example , formation . Prodrugs of a compound of any of the formulae an exchangeable group , such as hydrogen in OH , 10 above are prepared by modifying functional groups present - NH - , or — P ( = O ) (OH ) - , is replaced with a pharma - in the compound of any of the formulae above in such a way ceutically acceptable cation ( e .g . a sodium , potassium , or that the modifications may be cleaved in vivo to release the ammonium ion ) and can be conveniently be prepared from parent compound . In vivo , a prodrug readily undergoes a corresponding compound disclosed herein by , for example , chemical changes under physiological conditions ( e . g ., are reaction with a suitable base . In cases where compounds are 15 hydrolyzed or acted on by naturally occurring enzyme( s ) ) sufficiently basic or acidic to form stable nontoxic acid or resulting in liberation of the pharmacologically active agent. base salts, administration of the compounds as salts may be Prodrugs include compounds of any of the formulae above appropriate . Examples of pharmaceutically acceptable salts wherein a hydroxy , amino, or carboxy group is bonded to are organic acid addition salts formed with acids that form any group that may be cleaved in vivo to regenerate the free a physiological acceptable anion , for example , tosylate , 20 hydroxyl, amino or carboxy group , respectively . Examples methanesulfonate , acetate , citrate , malonate , tartarate , suc - of prodrugs include , but are not limited to esters ( e . g ., cinate , benzoate , ascorbate , alpha - ketoglutarate , and alpha - acetate , formate , and benzoate derivatives of compounds of glycerophosphate . Suitable inorganic salts may also be any of the formulae above or any other derivative which formed , including hydrochloride, hydrobromide, sulfate , upon being brought to the physiological pH or through nitrate , bicarbonate , and carbonate salts . Pharmaceutically 25 enzyme action is converted to the active parent drug . Con acceptable salts may be obtained using standard procedures ventional procedures for the selection and preparation of well known in the art , for example , by reacting a sufficiently suitable prodrug derivatives are described in the art (see , for basic compound such as an amine with a suitable acid example , Bundgaard . Design of Prodrugs. Elsevier, 1985 ) . affording a physiologically acceptable anion . Alkali metal The term " purified ” or “ to purify ” or “ substantially puri ( for example , sodium , potassium or lithium ) or alkaline 30 fied ” refers to the removal of inactive or inhibitory compo earth metal ( for example , calcium ) salts of carboxylic acids nents or impurities (e . g ., contaminants ) from a composition can also be made . to the extent that 10 % or less , e . g . , 10 % , 9 % , 8 % , 7 % , 6 % , The term “ substituted ” in connection with a moiety refers 5 % , 4 % , 3 % , 2 % , 1 % , 0 .5 % , 0 . 1 % , 0 .05 % ( 500 ppm ), to a further substituent which is attached to themoiety at any 0 .025 % ( 250 ppm ) , 0 .01 % ( 100 ppm ) , 0 .005 % ( 50 ppm ) , acceptable location on the moiety . Unless otherwise indi- 35 0 .0025 % (25 ppm ) , 0 .001 % ( 10 ppm ), 0 .0005 % ( 5 ppm ) , cated , moieties can bond through a carbon , nitrogen , oxy - 0 .0001 % ( 1 ppm ) or less , of the composition is not active gen , sulfur, or any other acceptable atom . Examples of compounds or pharmaceutically acceptable carrier. substituents include, but are not limited to amines, alcohols , The term “ isolated ” refers to the separation of a material thiols , ethers , alkenes, alkynes , epoxides, aziridines , oxi- or compound from at least one other material or compound ranes , azetidines, dihydrofurans , pyrrolidines , pyrans , pip - 40 in a mixture or from materials or compounds that are eridines, aldehydes , ketones, esters , carboxylic acids, car - naturally associated with the material or compound . For boxylates, imines, imides , azides , azo groups , eneamines , example , a compound synthesized synthetically is separated alkyl halides , alkenyl halides, alkynyl halides , aryl halides , from a starting material or an intermediate . phosphines, phosphine oxides , phophinites, phosphonites , The term “ alkyl ” refers to a branched or unbranched phosphites , phohsphonates , phosphates , sulfates , sulfoxides , 45 saturated hydrocarbon group of 1 to 24 carbon atoms. sulfonyl groups , sulfoxyl groups, sulfonates , nitrates , Preferred " alkyl” groups herein contain 1 to 16 carbon nitrites, nitriles , nitro groups, nitroso groups, cyanates , thio - atoms; i. e . C . 16 alkyl. Examples of an alkyl group include, cyanates , isothiocyanates , carbonates , acyl halides , perox - but are not limited to , methyl, ethyl, propyl, iso - propyl, ides, hydroperoxides , hemiacetals , hemiketals , acetals , ket- butyl, iso - butyl, secondary -butyl , tertiary - butyl, pentyl, iso als , orthoesters , orthocarbonate esters , sulfides, disulfides, 50 pentyl, neo -pentyl , hexyl, iso - hexyl, 3 -methylpentyl , 2 , 3 sulfonic acids , sulfonic acids, thiones , thials , phosphodies - dimethylbutyl, neo - hexyl, heptyl, octyl, nonyl, decyl, unde ters , boronic acids , and boronic esters . cyl , dodecyl, tridecyl, tetradecyl, pentadecyl, and hexadecyl. The terms" treating ” , “ treat ” or “ treatment” refer to thera Most preferred are “ lower alkyl” which refer to an alkyl peutic treatment where the object is to slow down ( e . g . , group of one to six , more preferably one to four, carbon lessen or postpone the onset of) an undesired physiological 55 atoms. The alkyl group may be optionally substituted with condition , disorder or disease , or to obtain beneficial or an acyl, amino , amido , azido, carboxyl , alkyl, aryl, halo , desired results such as partial or total restoration or inhibi- guanidinyl, oxo , sulfanyl, sulfenyl, sulfonyl, heterocyclyl, tion in decline of a parameter , value , function or result that heteroaryl, or hydroxyl group . had or would become abnormal. Beneficial or desired results The term “ alkali metal” refers to metallic salts include , include , but are not limited to , alleviation of symptoms; 60 but are not limited to , appropriate alkali metal ( group la ) diminishment of the extent or vigor or rate of development salts , alkaline earth metal ( group Ila ) salts , and other physi of the condition , disorder or disease ; stabilization ( i . e . , not ological acceptable metals . Such salts can be made from worsening ) of the state of the condition , disorder or disease ; aluminum , calcium , lithium , magnesium , potassium , sodium delay in onset or slowing of the progression of the condition , and zinc . disorder or disease ; amelioration of the condition , disorder 65 The term “ alkenyl” refers to a straight or branched carbon or disease state ; and remission (whether partial or total) , chain containing at least one carbon - carbon double bond . In whether or not it translates to immediate lessening of actual exemplary embodiments , “ alkenyl” refers to a hydrocarbon US 10 , 040 , 752 B2 15 16 containing 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 or 10 carbon atoms, i. e . C1- 10 3 - cyclopropylphenoxy, 3 - ethylphenoxy , 4 - tert- butylphe alkenyl. Examples of an alkenyl group include, but are not noxy, 3 -pentafluoroethylphenoxy , and 3 -( 1 ,1 , 2, 2 - tetrafluo limited to , ethene , propene , butene , pentene , hexene , hep - roethoxy ) phenoxy . tene, octene , nonene and decene. In some embodiments , the The term “ alkoxy ” refers to oxy -containing groups sub alkenyl group is a vinyl or allyl group . The alkenyl group 5 stituted with an alkyl, or cycloalkyl group . Examples may be optionally substituted with an amino , alkyl, halo , or include , without limitation , methoxy , ethoxy , tert -butoxy , hydroxyl group . and cyclohexyloxy . Most preferred are “ lower alkoxy " groups having one to six carbon atoms. Examples of such The term “ amido ” refers to either a C - amido group such groups include methoxy, ethoxy , propoxy, butoxy, iso as — CONR 'R " or an N amido group such as NR 'COR en " 10 propoxy , and tert -butoxy groups. wherein R ' and R " as used in this definition are indepen The term “ aralkoxy” refers to oxy - containing aralkyl dently hydrogen , alkyl, alkenyl, alkynyl, alkoxy, carbocy groups attached through an oxygen atom to other groups . clic , heterocylic , aryl, or aralkyl. A " sulfoamido ” group “ Lower aralkoxy ” groups are those phenyl groups attached includes the NR S02 R " . Most preferably , R ' and R " to lower alkoxy group as described above . Examples of such are hydrogen , alkyl, aryl, or aralkyl. 15 groups include benzyloxy , l - phenylethoxy , 3 -trifluo The term “ alkynyl” refers to a straight or branched carbon romethoxybenzyloxy , 3 - trifluoromethylbenzyloxy, 3 , 5 -dif chain containing at least one carbon -carbon triple bond . In luorobenyloxy , 3 -bromobenzyloxy , 4 - propylbenzyloxy , exemplary embodiments , “ alkynyl” refers to a hydrocarbon 2 - fluoro - 3 -trifluoromethylbenzyloxy , and 2 - phenylethoxy. containing 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 or 10 carbon atoms, i. e ., C2- 10 The term “ acyl” refers to C ( OR wherein R used in alkynyl. Examples of an alkynyl group include , but are not 20 this definition is hydrogen , alkyl, alkenyl, alkynyl, carbo limited to , ethyne , propyne, butyne, pentyne , hexyne , hep - cyclic , heterocylic , aryl, or aralkyl. Most preferably , R is tyne , octyne, nonyne and decyne. The alkynyl group may be hydrogen , alkyl, aryl, or aralkyl. optionally substituted with an amino , alkyl, halo , or The term “ carboxyl” refers to — R ' C ( O ) OR " , wherein hydroxyl group . R ' and R " as used in this definition are independently The term “ aryl” refers to a carbocyclic aromatic system 25 hydrogen , alkyl, alkenyl, alkynyl, carbocyclic , heterocylic , containing one , two or three rings wherein such rings may heterocyloalkyl, aryl, ether, or aralkyl, or R ' can additionally be attached together in a pendant manner or may be fused . be a covalent bond . “ Carboxyl ” includes both carboxylic acids, and carboxylic acid esters . The term " carboxylic acid ” The term “ fused ” means that a second ring is present (i . e. , refers to a carboxyl group in which R " is hydrogen , or a salt . attached or formed ) by having two adjacent atoms in comJos is 30 Such acids include formic , acetic , propionic , butryic , valeric mon ( i. e ., shared ) with the first ring . The term “ fused ” is 30 acid , 2 -methyl propionic acid , oxirane -carboxylic acid , and equivalent to the term " condensed .” The term “ aryl” cyclopropane carboxylic acid . The term " carboxylic acid embraces aromatic groups such as phenyl , naphthyl, tetra ester ” or “ ester” refers to a carboxyl group in which R " is hydronaphthyl, tetralin , indane , indene , and biphenyl. The alkyl, alkenyl, alkynyl, carbocyclic , heterocylic , aryl, or aryl group may optionally be substituted with an aminoO ,, os35 aralkyl. Examples of carboxylic acids include , but are not alkyl, halo , hydroxyl, carbocyclic , heterocyclic , or another limited to formic acid , acetic acid , propionic acid , butanoic aryl group . acid , pentanoic acid , hexanoic acid , heptanoic acid , octanoic The term “ cycloalkyl” refers to a monocyclic saturated or acid , nonanoic acid , decanoic acid , cyclopropanecarboxylic partially saturated carbon ring , wherein the number of ring acid , cyclobutanecarboxylic acid , cyclopentanecarboxylic atoms is indicated by a range of numbers. In exemplary 40 acid , cyclohexanecarboxylic acid , cycloheptanecarboxylic embodiments , “ cycloalkyl” refers to a carbon ring as defined acid , cyclooctanecarboxylic acid , or cyclononanecarboxylic above containing 3 - 12 ring atoms ( i. e . C2. 12 cycloalkyl) . As acid . used herein , cycloalkyl encompasses monocyclo , bridged , The term " carbonyl” refers to refers to a C = 0 moiety , spiro , fused , bicyclo and tricyclo ring structures. Examples also known as an “ oxo ” group . of a cycloalkyl group include , but are not limited to , cyclo - 45 The term " heterocycle ” or “ heterocyclyl” or " heterocyclic propyl, cyclobutyl , cyclopentyl, cyclopentenyl, cyclohexyl, ring ” or “ het” refers to an optionally substituted , saturated or cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, deca unsaturated , aromatic or non - aromatic cyclic hydrocarbon lin , adamantyl, and cyclooctyl. The cycloalkyl group may be with 3 to 12 , or 5 to 6 , carbon atoms, wherein at least one optionally substituted with an amino , alkyl , halo , or of the ring atoms is an O , N , S , Por Se . For example , in some hydroxyl group . 50 embodiments , a ring N atom from the heterocyclyl is the The term “ aralkyl” refers to aryl- substituted alkyl moi - bonding atom to - C ( O ) to form an amide , carbamate , or eties. Preferable aralkyl groups are “ lower aralkyl” groups urea . In exemplary embodiments , " heterocyclyl” refers to a having aryl groups attached to alkyl groups having one to six cyclic hydrocarbon as described above containing 4 , 5 , or 6 carbon atoms. Examples of such groups include benzyl, ring atoms ( i. e ., C4- 6 heterocyclyl) . Examples of a hetero diphenylmethyl, triphenylmethyl, phenylethyl , and dipheny - 55 cyclic group include , but are not limited to , aziridine , lethyl. The terms benzyl and phenylmethyl are interchange - oxirane , thiirane , azetidine , oxetane, thietane, pyrrolidine , able . imidazole , tetrahydrofuran , pyran , thiopyran , thiomorpho The term “ aryloxy ” refers to aryl groups, as defined line, thiomorpholine S -oxide , oxazoline , tetrahydrothio above, attached to an oxygen atom . The aryloxy groupsmay phene, piperidine , tetrahydropyran , thiane, imidazolidine , optionally be substituted with a halo , hydroxyl, or alkyl 60 oxodioxolenyl , oxazolidine, thiazolidine , dioxolane , dithi group . Examples of such groups include phenoxy , 4 - chloro - olane , piperazine , Oxazine , dithiane , dioxane , pyridinyl, 3 - ethylphenoxy , 4 -chloro - 3 -methylphenoxy , 3 - chloro - 4 - eth - furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, thienyl, ylphenoxy , 3 , 4 -dichlorophenoxy , 4 -methylphenoxy , 3 - trif 1, 2 ,3 - triazolyl, 1, 2 ,4 - triazolyl, indolyl, imidazolyl, thiazolyl, luoromethoxyphenoxy , 3 - trifluoromethylphenoxy, thiadiazolyl , pyrimidinyl, oxazolyl , triazinyl, and tetrazolyl . 4 - fluorophenoxy , 3 ,4 - dimethylphenoxy, 5 - bromo - 2 - fluoro - 65 Exemplary heterocycles include benzimidazole , dihydroth phenoxy , 4 -bromo - 3 - fluorophenoxy , 4 - fluoro - 3 -methylphe - iophene, dioxin , dioxane , dioxolane, dithiane , dithiazine, noxy , 5 ,6 ,7 ,8 - tetrahydronaphthyloxy, 3 - isopropylphenoxy, dithiazole , dithiolane , furan , indole , 3 -H indazole , 3- H US 10 , 040 , 752 B2 18 indole , indolizine, isoindole , isothiazole, isoxazole ,morpho - hydrazide ) or R ' and R " together with the nitrogen atom to line, oxazole, oxadiazole , oxathiazole, oxathiazolidine , which they are attached , form a ring having 4 -8 atoms. Thus, oxazine, oxadiazine , piperazine , piperidine, purine , pyran , the term “ amino ” , includes unsubstituted , monosubstituted pyrazine , pyrazole , pyridine, pyrimidine, pyrimidine , ( e . g ., monoalkylamino or monoarylamino ) , and disubsti pyridazine , pyrrole , pyrrolidine , tetrahydrofuran , tetrazine , 5 tuted ( e . g . , dialkylamino or aralkylamino ) amino groups . thiadiazine , thiadiazole , thiatriazole , thiazine , thiazole , thio Amino groups include NH2, methylamino , ethylamino , phene, triazine , and triazole . The heterocycle may be option dimethylamino , diethylamino , methyl- ethylamino , pyrroli ally substituted with an amino , alkyl , alkenyl, alkynyl, halo , din - 1 -yl or piperidino , morpholino , etc . Other exemplary hydroxyl, carbocyclic , thio , other heterocyclic , or aryl " amino " groups forming a ring include pyrrolyl, imidazolyl, group . In some embodiments , the heterocyclyl is unsubsti - 10 pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl , tuted . pyrimidinyl, pyridazinyl, indolizinyl, imidazolyl , isoindolya, The term "heteroaryl ” refers to a cyclic hydrocarbon , indolyl, indazolyl, purinyl, quinolizinyl. The ring containing where at least one of the ring atoms is an O , N , S , P or Se , the amino group may be optionally substituted with another the ring is characterized by delocalized [ pi ] electrons (aro - amino , alkyl , alkenyl, alkynyl, halo , or hydroxyl group . maticity shared among the ring members , and wherein the 15 The term " amine ” refers to a primary , secondary or number of ring atoms is indicated by a range of numbers. tertiary amino group of the formula — NR ' R " wherein R ' and Heteroaryl moieties as defined herein have C , N , S , Por Se R " as used in this definition are independently hydrogen , bonding hands. For example , in some embodiments , a ring acyl, alkyl, alkyenyl, alkynyl, aralkyl, aryl, carboxyl, N atom from the heteroaryl is the bonding atom to - C ( O ) cycloalkyl, heterocyclic , or other amino ( in the case of to form an amide , carbamate , or urea . In exemplary embodi - 20 hydrazide ) or R ' and R " together with the nitrogen atom to ments , " heteroaryl” refers to a cyclic hydrocarbon as which they are attached , form a ring having 4 - 8 atoms. Thus , described above containing 5 or 6 ring atoms (i . e . C5- 6 the term “ amino " , as used herein , includes unsubstituted , heteroaryl) . Examples of a heteroaryl group include, but are monosubstituted ( e . g ., monoalkylamino or monoarylamino ) , not limited to , pyrrole , furan , thiene , oxazole, thiazole , and disubstituted ( e . g . , dialkylamino or aralkylamino ) amino isoxazole , isothiazole , imidazole , pyrazole , oxadiazole , thia - 25 groups . Amino groups include — NH2, methylamino , ethyl diazole, triazole , tetrazole , pyridine , pyrimidine , pyrazine , amino , dimethylamino , diethylamino , methyl- ethylamino , pyridazine , and triazine . The heteroaryl may be optionally pyrrolidin - 1 -yl or piperidino , morpholino , etc . Other exem substituted with an amino , alkyl, alkenyl, alkynyl, halo , plary “ amino " groups forming a ring include pyrrolyl, hydroxyl, carbocyclic , thio , other heterocyclic , or aryl imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, group . In some embodiments , the heteroaryl is substituted or 30 pyrazinyl, pyrimidinyl , pyridazinyl, indolizinyl, imidazolyl, unsubstituted heteroaryl . In some embodiments , the het isoindolyl, indolyl , indazolyl, purinyl, quinolizinyl. The ring eroaryl comprises an optionally substituted C5- 6 heteroaryl containing the amino group may be optionally substituted comprising one or more N , S , or O ring atoms. with another amino , alkyl, alkenyl, alkynyl, halo , or The term “ hydroxy ” or “ hydroxyl” refers to the substitu hydroxyl group . ent OH . 35 The term " alcohol ” refers to “ hydroxy ” or “ hydroxyl” The term “ oxo ” refers to the substituent = 0 . refers to the substituent — OH . The term “ nitro ” refers to NO2. The term “ amino alcohol” refers to a functional group The term “ azido ” refers to Nz. containing both an alcohol and an amine group . As used The term " sulfur analog ( s )” refers to an analogue of a herein , " amino alcohols " also refers to amino acids as compound of interest in which one or more selenium atoms 40 defined above having a carbon bound to an alcohol in place have been replaced by one or more sulfur atoms, respec - of the carboxylic acid group . In exemplary embodiments , tively . the term " amino alcohol” refers to an amino alcohol as The term “ sulfanyl” refers to — SR ' where R ' as used in defined above wherein the amine is bound to the carbon this definition is hydrogen , alkyl , alkenyl, alkynyl , carbo adjacent to the alcohol- bearing carbon . In exemplary cyclic , heterocylic , aryl, or aralkyl . 45 embodiments , “ amino alcohol” refers to an amine and The term " sulfenyl” refers to — SOR ' where R ' as used is alcohol- containing moiety as described above containing 1 , this definition is hydrogen , alkyl, alkenyl, alkynyl, carbo 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 or 12 carbon atoms ( i . e . , C1- 12 cyclic , heterocylic , aryl, or aralkyl1 . amino alcohol) . Examples of amino alcohols include, but are The term " sulfonyl” refers to — SO , R ' where R ' refers to not limited to , ethanolamine , heptaminol, isoetarine , norepi hydrogen , alkyl, alkenyl, alkynyl, carbocyclic , heterocylic , 50 nephrine , propanolamine , sphingosine , methanolamine , aryl, or aralkyl. In particular embodiments , R ' is methyl, 2 -amino - 4 -mercaptobutan - 1 -ol , 2 - amino - 4 - (methylthio )bu trifluoromethyl, benzyl, or 4 -methylbenzyl . tan - 1 -ol , cysteinol , phenylglycinol, prolinol , 2 -amino - 3 The term “ ketone ” refers to a moiety containing at least phenyl -1 -propanol , 2 -amino - 1 -propanol , cyclohexylglyci one carbonyl group where the carbonyl carbon is bound to nol, 4 -hydroxy -prolinol , leucinol, tert -leucinol , two other carbon atoms. In exemplary embodiments , 55 phenylalaninol, a - phenylglycinol, 2 -pyrrolidinemethanol , “ ketone ” refers to a carbonyl- containing moiety as described tyrosinol , valinol, serinol, 2 -dimethylaminoethanol , histidi above containing 3 , 4 , 5 , 6 , 7 , 8 , 9 or 10 carbon atoms ( i. e . nol, isoleucinol, leucinol , methioninol, 1- methyl - 2 -pyrroli C3- 10 ketone ). Examples of a ketone group include , but are dinemethanol , threoninol, tryptophanol, alaninol, argininol, not limited to , acetone , butanone , pentanone, hexanone , glycinol, glutaminol, 4 -amino -5 -hydroxypentanamide , heptanone , octanone , nonanone , decanone , cyclobutanone , 60 4 -amino - 5 -hydroxypentanoic acid , 3 - amino - 4 - hydroxybu cyclopentanone , cyclohexanone , cycloheptanone, cyclooc- tanoic acid , lysinol, 3 -amino - 4 -hydroxybutanamide , and tanone , cyclononanone and cyclodecanone. 4 -hydroxy -prolinol . The term “ amino ” refers to a primary, secondary or The term “ amino acid ” refers to a group containing a tertiary amino group of the formula — NR ' R " wherein R ' and carboxylic acid and an amine bound to the carbon atom R " as used in this definition are independently hydrogen , 65 immediately adjacent to the carboxylate group , and includes acyl, alkyl, alkyenyl, alkynyl, aralkyl, aryl, carboxyl, both natural and synthetic amino acids. Examples of amino cycloalkyl, heterocyclic , or other amino ( in the case of acids include, but are not limited to , arginine , histidine, US 10 , 040 , 752 B2 19 20 lysine , aspartic acid , glutamic acid , serine , threonine , The term " dextromethadone hydrochloride” refers to asparagine , glutamine, cysteine, selenocysteine, glycine , (6S ) -6 - (dimethylamino ) -4 ,4 -diphenylheptan - 3 -one hydro proline, alanine , valine, isoleucine , leucine, methionine , chloride ; also known as ( + ) - ( S ) -6 - (dimethylamino )- 4 ,4 - di phenylalanine , tyrosine, and tryptophan . The carboxyl is phenyl - 3 -heptanone . substituted with H , a salt , ester, alkyl, or aralkyl. The amino 5 The term “ levomethadone nitrile ” refers to ( 4R ) - 4 - ( dim group is substituted with H , acyl, alkyl, alkenyl, alkynyl, ethylamino ) - 2 , 2 - diphenylpentanenitrile . carboxyl, cycloalkyl, aralkyl, or heterocyclyl. The term “ dextromethadone nitrile ” refers to (4S ) - 4 The term “ ether ” refers to the group _ R _ 0 _ R " ( dimethylamino ) 2 , 2 - diphenylpentanenitrile . The term “ N , N -dimethyl D - alaninol” refers to ( R ) - 2 wherein R ' and R " as used in this definition are indepen 10 ( dimethylamino ) propan - 1 - ol. dently hydrogen , alkyl, alkenyl, alkynyl, carbocyclic , het The term “ N , N - dimethyl L - alaninol” refers to ( S ) - 2 erocylic , aryl, or aralkyl, and R ' can additionally be a ( dimethylamino )propan - 1 - ol. covalent bond attached to a carbon . The term “ isolevomethadone nitrile ” refers ( 3R ) The term “ halogen ” refers to a fluorine, chlorine, bromine isomisomethadone nitrile , to (3R ) - 4 - ( dimethylamino ) - 3 -methyl or iodine atom . 15 2 , 2 -diphenylbutanenitrile . The term “ halide” or “ halo ” refers to a functional group The term “ isodextromethadone nitrile ” refers to ( 3S ) containing an atom bond to a fluorine , chlorine , bromine or isomethadone nitrile , or ( 3S ) - 4 - ( dimethylamino ) - 3 -methyl iodine atom . Exemplary embodiments disclosed herein may 2 , 2 - diphenylbutanenitrile . include “ alkyl halide ,” “ alkenyl halide, ” “ alkynyl halide, ” The term “ isolevomethadone ” refers to (5R )- isometha “ cycloalkyl halide, " " heterocyclyl halide, ” or “ heteroaryl 20 done , (5R ) - 6 - (dimethylamino ) - 5 -methyl - 4 , 4 - diphenyl halide” groups. In exemplary embodiments , “ alkyl halide ” hexan - 3 -one . refers to a moiety containing a carbon -halogen bond con - The term “ isodextromethadone ” refers to (5S )- 6 -( dimeth taining 1 , 2 , 3, 4 , 5 , 6 , 7, 8 , 9 or 10 carbon atoms ( i. e ., C1- 10 ylamino ) -4 , 4 -diphenylheptan - 3 -one . alkyl halide ). Examples of an alkyl halide group include , but The term “ diphenylacetonitrile refers to 2 , 2 - diphenylac are not limited to , fluoromethyl, fluoroethyl , chloromethyl, 25 etonitrile . chloroethyl , bromomethyl, bromoethyl, iodomethyl and The term " catalyst” or " cat .” refers to a substance that iodoethyl groups . Unless otherwise indicated , any carbon speeds up a chemical reaction , but is not consumed by the containing group referred to herein can contain one or more reaction . As used herein , unless otherwise specified , carbon -halogen bonds. By way of non - limiting example , a examples of a catalyst include palladium on active carbon C , alkyl group can be , but is not limited to , methyl, fluo - 30 (Pd / C ) , Pd/ C /FeCl3 , Pd / C /Fe ( III ) hydroxide or oxide , romethyl, difluoromethyl, trifluoromethyl, chloromethyl, Pd/ Al2O3, Pt/ C , Pt/ Al2O3 , Pd/ BaSO4 , Raney Ni- catalyst, dichloromethyl, trichloromethyl, bromomethyl, dibromom Urushibara Ni- catalyst , rhodium on active carbon , Raney ethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodom - nickel, ruthenium black , PtO2, Pt/ C and platinum black , ethyl, chlorofluoromethyl, dichlorofluoromethyl, and difluo ZnCl2 , and Zn . In specific embodiments , the catalyst is a rochloromethyl. 35 palladium on carbon Pd / C catalyst selected from 2 % Pd / C , In the compounds described herein , heteroatoms are 2 . 5 % Pd / C , 3 % Pd/ C , 5 % Pd / C , 10 % Pd / C , or 5 % capable of bearing multiple different valencies . By way of Pd/ BaSO4. In a specific embodiment , the catalyst is palla non - limiting example , S , Se and N can be neutral or hold a dium on charcoal (Pd / C ) wet catalyst ( for example , 10 % positive charge, and O can be neutral or hold a positive or catalyst, LOD 50 % ) . negative charge . 40 The term “ reducing agent” refers to a reducing agent Regioisomers or regio - isomers are structural isomers that selected from the group consisting of lithium aluminum are positional isomers consisting of different compounds hydride ( LiAlH _ ) , borane tetrahydrofuran complex solution with the same molecular formula comprising one or more (BHZ / THF ), borane diethyl ether complex solution (BHZ ! functional group ( s ) or other substituent( s ) that change ( s ) Et , 0 ) , borane /boron trifluoride diethyl etherate (BHZ / BF , position on a parent structure . 45 Et , O ) , borane dimethyl sulfide complex (BH /Me , S ) , Enantiomers are defined as one of a pair of molecular sodium borohydride and iodine (NaBH _/ 12 ) , sodium boro entities which are mirror images of each other and non - hydride and sulfuric acid (NaBHXH , SO4) , NaBH / cyanuric superimposable . chloride, sodium cyanoborohydride and zinc chloride Diastereomers or diastereoisomers are defined as stereoi- (NaBH CN /ZnCl , ) , sodium borohydride and zinc chloride somers other than enantiomers. Diastereomers or diastereoi- 50 (NaBH _ / ZnCl , ) , zinc borohydride ( Zn (BH _ ) , ), and sodium somers are stereoisomers not related as mirror images. borohydride boron trifluoride etherate (NaBH _ /BF . Eto ) . Diastereoisomers are characterized by differences in physi - The term “ alcoholic solvent” refers to a solvent compris cal properties . ing a hydroxyl group attached to a carbon atom . In some Unless otherwise specified , when a compound having embodiments , the alcoholic solvent is selected from metha " not more than x % " or " not more than y ppm ” of an 55 nol, ethanol, isopropyl alcohol, tert- amyl alcohol, benzyl impurity is disclosed , the x % or y ppm refers to the area of alcohol, isobutanol, 2 - butanol, n -butanol , and tert -butanol . the principle peak in a chromatogram obtained with the The term “ polar aprotic solvent" is used to refer to any reference compound . Unless otherwise specified , the chro known polar aprotic solvent. In some embodiments , the matogram is an HPLC chromatogram . polar aprotic solvent is selected from 1 , 4 - dioxane , tetrahy The term " levomethadone” refers to (OR ) - 6 -( dimethyl - 60 drofuran , ethyl acetate , acetone, N , N - dimethylformamide , amino ) - 4 , 4 - diphenylheptan - 3 -one . N -methylformamide , dimethylacetamide, N -methylpyrroli The term “ dextromethadone ” refers to (6S ) -6 - ( dimethyl- done , acetonitrile , and dimethylsulfoxide. amino )- 4 , 4 -diphenylheptan -3 -one . The term “ hydrocarbon solvent” refers to any known The term “ levomethadone hydrochloride ” refers to (6R ) - hydrocarbon solvent. In some embodiments , the hydrocar 6 - ( dimethylamino ) - 4 , 4 - diphenylheptan - 3 - one hydrochlo - 65 bon solvent is selected from benzene , cyclohexane, hexane, ride; also known as ( - ) - ( R ) -6 - ( dimethylamino ) - 4 , 4 - diphe ligroin , pentane , heptane , petroleum ether, toluene , or nyl- 3 - heptanone . xylene . US 10 ,040 , 752 B2 21 22 The term " halogenated solvent ” refers to any known mide , and allylmagnesium bromide . In a preferred embodi halogenated solvent. In some embodiments , the halogenated ment, the Grignard reagent is ethyl magnesium bromide solvent is selected from dichloromethane, chloroform , 121 , 2 . (EtMgBr ) . dichloroethane and benzotrifluoride ( a , a , a - trifluorotolu As used herein , and unless otherwise specified , “ Ac ” ene ) . 5 means acetyl, " aq ” means aqueous , " Ar ” means argon , The term “ ether solvent ” refers to a solvent comprising an " cat. " means catalytic , “ DCE ” means 1 , 2 - dichloroethane , ether moiety ( C — 0 C bonds ). In some embodiments , the “ DCM ” means dichloromethane , “ DIEA ” means diisopro ether solvent is selected from diethyl ether , diisopropyl p ylethylamine, “DME ” means 1 , 2 -dimethoxyethane , ether, THF, DME , dioxane , and MTBE . “ DMF” means dimethylformamide , “ DMF- DMA ” means The term “ acid ” refers to a Bronsted - Lowry acid that is 10 N , N -dimethylformamide dimethylacetal, “ e . e . ” means capable of releasing a proton , H + ion . In some embodiments, enantiomeric excess , " equiv ” means equivalent( s ) , “ Et" the acid is an organic acid that is an organic compound with means ethyl, “ EtOAc” means ethyl acetate , “ EtOH ” means acidic properties comprising one or more carbon atoms, for ethanol, “ h ” or “ hr” means hour( s ), “ KOtBu ” or “ t - BuOK ” example , formic acid , acetic acid , trifluoroacetic acid , pro means potassium tert -butoxide , “ KOH ” means potassium pionic acid , butyric acid , valeric acid , caproic acid , oxalic 15 hydroxide, “MTBE ” means methyl tert -butyl ether , “ Me” acid , lactic acid , malic acid , citric acid , benzoic acid , car- meansmethyl , “ MeCN ” means acetonitrile , “MeOH ” means bonic acid , phenol, uric acid , taurine , trifluoromethanesul- methanol, “ min ” means minute ( s ) , “ Ms” means mesyl fonic acid , and aminomethylphosphonic acid . In some (CH2S02 ), “ NaOH ” means sodium hydroxide, “ PE ” embodiments , the acid is an organic carboxylic acid . In some means petroleum ether, “ PPA ” means polyphosphoric acid , embodiments , the organic carboxylic acid is selected from 20 “ RT” or “ rt ” means room temperature, " t - BuOH ” means formic acid , acetic acid , trifluoroacetic acid , propionic acid , tert - butanol, “ t - Bu?Na” or “ NaOtBu ” means sodium tert butyric acid , valeric acid , caproic acid , oxalic acid , lactic butoxide, “ TEA ” means triethylamine , " TFA ” means trif acid , malic acid , citric acid , and benzoic acid . In some luoroacetic acid , “ THF ” means tetrahydrofuran , " o - Tol” embodiments , the acid is an inorganic acid or mineral acid , means o - tolyl ( 2 -CH2CH ) , “ p - Tol” means p - tolyl for example , sulfuric acid , hydrochloric acid , nitric acid , 25 ( 4 - CH3CH2 ), and " Ts” means tosyl (p -CH2C6H _ S02— ) . phosphoric acid , boric acid , hydrofluoric acid , hydrobromic The term “ NMDA ” or “ NMDAR ” refers to N -methyl - D acid , and perchloric acid . aspartate receptor, which is a glutamate receptor subtype . An The term “ base ” refers to a Bronsted - Lowry base that is NMDA receptor antagonist , or NMDA antagonist , is a capable of accepting H + ions . In some embodiments , a base compound that inhibits the action of the NMDA receptor. is selected from sodium hydroxide (NaOH ) , potassium 30 NMDA antagonists have been investigated for treatment of hydroxide (KOH ) , calcium hydroxide (Ca ( OH )2 ) , sodium anxiety disorders , Alzheimer ' s disease , chronic pain , carbonate (Na2CO3 ) , potassium carbonate (K2CO3 ), sodium dementia , depression , neuropathic pain , anti -NMDA recep bicarbonate (NaHCO3 ), potassium bicarbonate (KHCO3 ), tor encephalitis , opioid analgesic tolerance , schizophrenia , trisodium phosphate (NazPO4 ) , tripotassium phosphate stroke , and traumatic brain injury . (K2PO4 ) , disodium phosphate (Na2HPO4 ) , dipotassium 35 A chemical term that is not otherwise defined herein is phosphate (K2HPO4 ) , sodium acetate (NaOAc ) , potassium understood as being defined in Hawley ' s Condensed Chemi acetate (KOAc ) , potassium tert -butoxide (KOtBu ) , sodium cal Dictionary , 15th Ed . Wiley - Interscience , 2007 . tert- butoxide (NaOtBu ), other potassium and sodium alkox Methods ides such as sodium methoxide , potassium methoxide, Highly efficient methods for synthesis of levomethadone sodium ethoxide, potassium ethoxide , sodium isopropoxide, 40 hydrochloride or dextromethadone hydrochloride are pro sodium tert -pentoxide (sodium tert -amoxide ), potassium vided starting from D -alanine , or L -alanine , respectively , tert -pentoxide (potassium tert- amoxide ) , and potassium iso - with retention of configuration . Methods for treating a propoxide ; or lithium alkoxides such as lithium methoxide , subject are provided comprising administering a composi or lithium tert -butoxide ; or organolithium compounds such tion comprising an effective amount of levomethadone as methyllithium , n -butyllithium , sec -butyllithium , isopro - 45 hydrochloride having not more than 10 ppm dextrometha pyllithium , tert- butyllithium , or phenyllithium ; or a lithium done . amide . In some embodiments , a weak base is selected from Production of Levomethadone Hydrochloride from TEA and DIEA . D - Alanine The term “Grignard reagent” as used herein refers to a In one embodiment, a method for preparing levometha reagent which may be generated by any known method , 50 done hydrochloride , or an analog or prodrug thereof, is generated in situ , or a commercial reagent of formula RM9X provided with retention of configuration . FIG . 1A depicts a where R is an alkyl, alkenyl, or aryl group , and X is 1 , Br, general synthetic scheme provided for preparation of or Cl. In some embodiments , the Grignard reagent is made levomethadone hydrochloride . In the first steps D - alanine in situ , for example , with magnesium shavings and an alkyl ( A ) is converted to N , N - dimethyl D - alaninol ( C ) . Step 3 halide, or the Grignard reagent may be purchased as a 55 comprises activation of N ,N -dimethyl D - alaninol (C ) , by reagent. In some embodiments , the Grignard reagent is used chlorination or formation of a sulfonate ester , and exposing in a Grignard reaction under anhydrous conditions, for the resultant active intermediate (D or D ') to a base and example in an ether solvent, with a nitrile intermediate diphenylacetonitrile to form levomethadone nitrile ( E ) . The according to the disclosure , followed by treatment with an levomethadone nitrile ( E ) is treated with a Grignard reagent, acid to form a compound according to the disclosure. In 60 then HCl to form levomethadone hydrochloride. some embodiments , the Grignard reaction is performed with In one embodiment , a highly efficient asymmetric syn a copper activating compound such as CuBr/ H2O + , by the thesis of levomethadone hydrochloride is provided starting method of Weiberth et al ., J Org Chem 52 , 3901 ( 1987) , from D - alanine, and resulting in levomethadone hydrochlo which is incorporated herein by reference . In some embodi- ride in greater than 20 % , greater than 30 % , or preferably ments, the Grignard reagent is selected from methylmagne - 65 greater than 40 % overall yield using readily available sium bromide , methylmagnesium chloride , ethylmagnesium chemicals . In some embodiments , a process is provided for bromide, ethylmagnesium chloride, phenylmagnesium bro the production of levomethadone hydrochloride in 25 -60 % , US 10 ,040 , 752 B2 23 24 30 - 50 % or 35 -45 % overall yield from D - alanine , wherein Paterson et al. , Org Lett 2013 , 15 , 3118 -3121 ; each of which the levomethadone hydrochloride is provided in greater than is incorporated by reference . In one specific embodiment, 95 % , 97 % , 99 % 99 .5 % , or 99. 9 % e .e . D -alanine A is converted to N ,N - dimethyl D - alanine B via In some embodiments, a process is provided for the hydrogenation in the presence of formaldehyde and Pd / C , as production of levomethadone hydrochloride in greater than 5 shown in FIG . 3 and Example 1 . In another embodiment, 20 % , greater than 30 % , or preferably greater than 40 % from D -alanine A is converted to N , N - dimethyl D -alanine B with D - alanine , wherein the levomethadone hydrochloride com - formaldehyde /Zn by a modification of a literature method prises not more than 0 . 5 % , 0 . 25 % , 0 . 1 % , 0 .05 % , 0 .025 % , ( Tetrahedron Lett. 2007, 48 , 7680 - 7682 ) . In a further 0 .01 % . 0 .005 % , 0 . 001 % , 0 .0005 % , or 0 .0001 % of an impu - embodiment, D - alanine A is converted to N , N -dimethyl rity selected from dextromethadone, isodextromethadone , 10 D -alanine B with formaldehyde , NaBH _ / ZnCl, by a modi isolevomethadone, levomethadone nitrile , dextromethadone fication of a literature method (Synth . Commun . 1995 , 25 , nitrile , isolevomethadone nitrile , isodextromethadone 2061 - 2069 ) . In another embodiment, D - alanine A is con nitrile , diphenylacetonitrile , 2 (S )- 2 - [[ (4 -methylphenyl ) sul- verted to N ,N -dimethyl D -alanine B with paraformaldehyde, phonyl] amino ]pentanedioic acid (N - tosyl- L - glutamic acid ); NaBH4 in 2 ,2 ,2 - trifluoroethanol by a modification of a a tartaric acid , or a bromocamphor sulfonic acid , such as a 15 literature method (Synthesis , 2011, 490 -496 ) . In some 3 -bromocamphor - 10 - sulfonic acid . embodiments , D - alanine ( A ) is dimethylated to form N , N In some embodiments , a process is provided for the dimethyl ( D ) -alanine ( B ) in water in the presence of form production of levomethadone hydrochloride in greater than aldehyde and H2, Pd /C at a temperature of 30 - 90° C ., 40 -80° 20 % , greater than 30 % , or preferably greater than 40 % from C ., or 45 - 60° C ., for example , as shown in Example 1 . D - alanine , wherein the levomethadone hydrochloride com - 20 In some embodiments , intermediate compound N , N - di prises not more than 0 . 5 % , 0 .25 % , 0 . 1 % , 0 .05 % , 0 . 025 % , methyl D - alanine ( B ) , is isolated and purified by any known 0 .01 % . 0 . 005 % , 0 . 001 % , 0 . 0005 % , or 0 . 0001 % of dex - means , including recrystallization and / or chromatography, tromethadone or dextromethadone hydrochloride. before employing in the next step . In other embodiments , In some embodiments , a process is provided for the intermediate compound N , N - dimethyl ( D ) - alanine ( B ) , is production of levomethadone hydrochloride in greater than 25 employed in the next step without further purification . In 95 % , 97 . 5 % , or 99 % e . e ., wherein the levomethadone some embodiments , intermediate compound N , N -dimethyl hydrochloride comprises not more than 10 ppm , 5 ppm , 1 D -alanine ( B ) , is isolated and recrystallized from an alco ppm , 0 . 5 ppm , or no detectable impurity selected from holic solvent, a polar aprotic solvent, hydrocarbon solvent, ( 2S ) - 2 - [ [ ( 4 -methylphenyl ) sulphonyl ] amino ]pentanedioic or a mixture of two or more thereof. In some embodiments , acid ( N - tosyl- L - glutamic acid ) ; a tartaric acid , or a bromo - 30 compound N , N - dimethyl D -alanine ( B ) is recrystallized camphor sulfonic acid , such as a 3 - bromocamphor- 10 - sul- from a mixture of an alcoholic solvent and a polar aprotic fonic acid . solvent. In some embodiments , intermediate compound In one embodiment, a preferred chiral route of synthesis N , N - dimethyl D - alanine ( B ) is recrystallized from a mixture to levomethadone hydrochloride from D - alanine is pro - of an alcoholic solvent and a polar aprotic solvent in a ratio vided , as shown in FIG . 2A , resulting in better than 40 % 35 selected from 1 : 10 to 10 : 1 , 1 : 10 to 1 : 1 , 1 : 2 to 1 : 8 , or 1 : 5 v / v . overall yield in > 99 % e . e. In some embodiments , intermediate B is recrystallized from Synthesis of N , N - Dimethyl- D - Alaninol from D - Alanine a mixture of an alcoholic solvent and a polar aprotic solvent In some embodiments, D -alanine is converted to N , N - wherein the alcoholic solvent is selected from methanol , dimethyl- D - alaninol in two steps, as shown in FIG . 2B . In ethanol, isopropyl alcohol , and a mixture thereof; and one embodiment, D -alanine is treated with zinc borohydride, 40 wherein the polar aprotic solvent is selected from acetone , which is generated in situ by the reaction of sodium boro ethyl acetate , and a mixture thereof. In some embodiments , hydride and zinc chloride in THF , to give D - alaninol inter - the crude intermediate B is recrystallized by warming to mediate which is converted to N , N - dimethyl D - alaninol 30 -70° C ., 40 - 60° C ., or 50 -60° C . in a solvent or solvent with formaldehyde and formic acid . In another embodiment, mixture and allowed to cool, followed by isolation of as shown in FIG . 2A , conversion of D - alanine ( A ) to 45 crystalline intermediate B . N , N - dimethyl D - alanine ( B ) is performed via hydrogenation In some embodiments , N , N - dimethyl D -alanine B , or its in the presence of formaldehyde and Pd / C , then reduced to acid chloride or alkyl ester derivatives B ', is treated with a form N , N -dimethyl - D - alaninol. In some embodiments, N , N - reducing agent in an ether solvent and or hydrocarbon dimethyl- D -alaninol is provided in > 90 % yield , for solvent to form ( R ) - 2 - ( dimethylamino )propan - 1 - ol, C , as example , as shown in Example 1 . 50 outlined in FIG . 4 . In a specific embodiment, N , N - dimethyl In some embodiments, as shown in FIG . 1C , D -alanine D -alanine B is treated with lithium aluminum hydride , ( A ) is converted to dimethyl- D -alanine ( B ) in step 1A , then LiAlH4, in a solvent selected from diethyl ether , THF, DME , reduced to ( R ) - 2 - ( dimethylamino ) propan - 1 -ol ( C ) in step dioxane, MTBE , or toluene to form (R )- 2 - (dimethylamino ) 2A . Alternatively , D - alanine ( A ) is reduced to form D - al- propan - 1 -o1 , C , for example , as described in Example 2 . In aninol in step 1B , then dimethylated to form (R )- 2 -( dimeth - 55 some embodiments , (R )- 2 -( dimethylamino ) propan - 1 -ol , C , ylamino ) propan - 1 - ol ( C ) in step 2B . The (R ) - alcohol ( C ) is is provided by treating N , N - dimethyl D - alanine B with a activated by chlorination to form intermediate ( D ), or ( C ) is reducing agent selected from BHZ/ THF, BH2/ Et , O , BH / converted to a sulfonate ester ( e . g . , D ' or D " ) . The activated BF3 Et20 , or BHz/ Me , S in an ether or hydrocarbon solvent. intermediate D , D ' or D " is treated with a base and diphe - In some embodiments , ( R ) - 2 - ( dimethylamino )propan - 1 -ol , nylacetonitrile to form levomethadone nitrile ( E ; ( R ) - 4 - 60 C , is provided by treating N , N - dimethyl D -alanine B with (dimethylamino ) - 2 , 2 -diphenylpentanenitrile ) . The nitrile NaBH4/ cyanuric chloride in an ether solvent. In some ( E ) is converted to levomethadone by a Grignard reaction embodiments , ( R ) - 2 - ( dimethylamino )propan - 1 -ol , C , is pro with ethylmagnesium bromide . Levomethadone hydrochlo - vided by treating N , N -dimethyl D -alanine B with ride is produced following exposure to HC1. NaBH3CN / ZnCl2 in an ether solvent and / or an alcoholic In one embodiment, D - alanine ( A ) is dimethylated to 65 solvent. In some embodiments , ( R ) - 2 - ( dimethylamino ) pro form N , N -dimethyl D - alanine ( B ) by a modification of any pan - 1 - ol, C , is provided by treating N , N - dimethyl D -alanine known method , for example , see, WO 2012 /162635 ; and B with NaBH _/ BF3 . Et20 in an ether solvent, for example by US 10 ,040 , 752 B2 25 26 a modification of Organic Chemistry : An Indian Journal, with NaOH , and extracted with MTBE , then dried to form 2012 , 8 , 1 -4 . In a specific embodiment, N , N - dimethyl D - ala - N , N - dimethyl- D - alaninol as an oil . nine B is treated with lithium aluminum hydride, LiAlH , in Preparation of Levomethadone Nitrile from N , N -Dim THF at 0° C ., then heated to reflux for 16 h to form ethyl - D - Alaninol Via Activated Intermediate . ( R ) -2 - (dimethylamino )propan - 1- ol, C , as described in 5 In some embodiments , (R )- 2 -( dimethylamino ) propan - 1 Example 2 . In some embodiments , intermediate (R ) -2 -( di ol, C , is converted to levomethadone nitrile E via an acti methylamino )propan - 1 -ol , C , is isolated as an oil and used vated intermediate , D , or D '( D " ) , as shown in FIG . 5 . In directly in the next step . some embodiments, ( R ) - 2 - (dimethylamino ) propan - 1 - ol, C , is treated with thionyl chloride, SOC12, to form the chloro In another embodiment, as shown in FIGS. 1C and 2B , 10 intermediate D , or treated with a sulfonyl chloride to form D -alanine is reduced to D -alaninol with Zn (BH4 ) 2 , which sulfonyl intermediate D '. The activated intermediate, can be conveniently prepared from NaBH4 and ZnCl2 . The selected from D or D ' ( D " ) , is treated with diphenylacetoni crude D -alaninol obtained in an aqueous media from this trile and a base to form levomethadone nitrile E . reduction process is subjected to an Eschweiler - Clarke In some embodiments , the chiral amino alcohol C is Reaction with formaldehyde and formic acid to produce the 15 converted to chloride D by dissolving in a halogenated desired N , N - dimethyl D -alaninol . This synthetic sequence solvent, cooling to below room temperature, e . g . from 0 -5° was found to be simple and readily scalable . C ., then adding SOC1 , and heating to 30 - 70° C . , 35 -60° C . , In some embodiments , the reduction is run under anhy - or to reflux temperature to form chloro intermediate D . In drous conditions . In other embodimentsments , the reduction is some embodiments , the halogenated solvent is DCM , or performed under an inert atmosphere. In a particular aspect, 20 CHC1z , or alternatives to chlorinated solvents , for example the reaction is run in anhydrous THF. In some aspects , after PhCFz . In some embodiments , the reaction mixture is completion of the reaction , excess borohydride is quenched evaporated and intermediate D is isolated , but not purified with methanol and the product, D -alaninol , is liberated as a prior to performing the next step . In some embodiments , the salt in aqueous medium by treatment with phosphoric acid . chiral amino alcohol C is converted to chloride D by treating In another aspect, the phosphoric acid aids the precipitation 25 with SOC1, at - 10 - 5° C ., then heating to 30 - 70° C ., 35 -60° of zinc salts such as zinc phosphate . In further aspects , the C . , or to reflux temperature . In some embodiments , chloro D - alaninol in aqueous medium is used in the next step intermediate D is treated with diphenyl acetonitrile to give without isolation . In another aspect , the method comprises optically pure levomethadone nitrile E in the presence of a filtration of inorganic salts, and / or precipitation of inorganic suitable base and appropriate solvent( s ) . In some embodi salts . 30 ments , the base is selected from one or more of KOtBu , In the second step , D - alaninol is converted to N , N - NaOtBu , other K or Na alkoxides such as methoxide , dimethyl D - alaninol. In some aspects , the conversion com - ethoxide, isopropoxide , tert -pentoxide , KOH , and NaOH . In prises reductive alkylation with formaldehyde and formic some embodiments , the solvent is selected from a polar acid in water as solvent by heating at 110° C . In some aprotic solvent, an ether solvent, water, or any combination aspects, in order to isolate the product, water , formaldehyde 35 thereof . In some embodiments , the polar aprotic solvent is and formic acid were removed by evaporation in vacuo , with DMF, DMA , or DMSO . In some embodiments , the ether the product, N , N - dimethyl D -alaninol , maintained in salt solvent is THF or dioxane . In a specific embodiment, form . Residual formaldehyde was optionally further intermediate D is dissolved in DMF, and treated with KOtBu removed by treatment with sodium bisulfite to form a water under Ar to prepare a first reaction mixture, and a separate soluble bisulfite adduct. The product was then extracted with 40 second reaction mixture of diphenylacetonitrile is prepared MTBE by evaporating the reaction mixture to a minimal in DMF with KOtBu . In some embodiments , the reaction is volume of water and basifying to generate the free amino performed in the presence of a dibenzo 18 - crown - 6 phase alcohol with a 50 % aqueous sodium hydroxide solution . transfer reagent in DMSO / aq NaOH . The second reaction In a specific embodiment, N , N -dimethyl D - alaninol is mixture is transferred to the first reaction mixture and prepared from D - alanine in a two - step process . A first step 45 allowed to stir at ambient r. t ., then heated for 2 - 24 , 4 - 20 , or comprises reduction of D - alanine to D - alaninol with 5 - 15 h at a temp of from 30 - 120° C . , 35 - 75° C . , or 40 -50° Zn ( BH4 ) 2 generated in - situ from the reaction of NaBH , with C . to form levomethadone nitrile , E . In some embodiments , ZnCly. In some aspects , the generation of Zn ( BH ) , is run in the levomethadone nitrile is purified prior to carrying to the a solvent selected from diethyl ether, THF, DME , dioxane , next reaction step . In some embodiments , the levometha MTBE , or toluene for 0 . 5 - 24 h , 1 - 12 , 3 - 6 h at a temperature 50 done nitrile is purified by chromatography or recrystalliza from 20 - 50 , or 30 - 45° C . In some aspects , following gen - tion . In some embodiments , the levomethadone nitrile is eration of the Zn (BH4 ) 2 , the D - alanine is added to the purified by recrystallization from a hydrocarbon solvent. In Zn (BH ) , at a temperature of not more than about 25° C ., some embodiments , the levomethadone nitrile is recrystal then temperature is gradually increased to reflux with evo - lized from heptane . lution of Hy. The reaction is allowed to reflux from about 55 In some embodiments , the levomethadone nitrile , inter 2 - 16 , 3 - 8 or 4 - 6 hr, then cooled to 0 -25 , 4 - 15 or 5 - 10° C . mediate E , is characterized by one or more of RP - HPLC , prior to quench with methanol. In some aspects , after stirring chiral HPLC , elemental analysis , specific optical rotation , and dilution with water, phosphoric acid is added to a pH of ' H -NMR , and 13 C -NMR . In some embodiments , the 3 . 5 - 4 . 0 . This aids in precipitating zinc phosphate and keep levomethadone nitrile prepared by the methods provided ing D - alaninol in solution as a salt . Following filtration to 60 herein comprises a single enantiomer ( E ) in > 99 % e . e . by remove zinc phosphate , the filtrate is neutralized by addition chiral HPLC . See intermediate E in FIG . 17 , compared to of NaOH to pH 8 . 5 - 9 . 5 to form free amine . The crude methadone nitrile , shown in FIG . 18 . ' H -NMR for interme D - alaninol is treated with formaldehyde and formic acid and diate E is shown in FIGS . 13 and 14 . 13C -NMR of inter heated to reflux for 6 - 16 h to form N , N - dimethyl- D - alaninol mediate E is shown in FIGS. 15 - 16 . as a formate salt. Sodium bisulfite is added and reaction 65 In some embodiments , the chiral alcohol C is treated with stirred for 1 - 16 h , 2 - 10 , or 3 - 6 h to ensure removal of a sulfonyl chloride, for example para - toluene sulfonyl chlo formaldehyde . The reaction mixture is concentrated , basified ride ( TsCl) or methanesulfonyl chloride (MsCl ) , para -tolu US 10 , 040 , 752 B2 27 28 ene sulfonyl anhydride ( Ts anhydride ) or methanesulfonyl DMF, is added prior to the diphenylacetonitrile to enhance anhydride (Ms anhydride ), to form the activated sulfonyl solubility . The mixture is stirred and cooled to 0 - 15° C ., or intermediate D ' or D " , for example , ( R ) - 2 - ( dimethylamino ) not more than 10° C . Potassium t -butoxide is added , and the propyl 4 -methylbenzenesulfonate , D ' or ( R ) - 2 - ( dimethyl reaction mixture is gradually heated to an elevated tempera amino )propyl methanesulfonate , D " . Intermediate D ' or D " 5 ture of from 35 - 70 , 40 -60 , or about 50° C . for from 2 - 16 , or is treated with diphenyl acetonitrile in the presence of a 2 - 4 hrs at the elevated temperature . The reaction mixture is suitable base in ( an ) appropriate solvent( s ) to give optically cooled to from 0 - 15 , or notmore than 10° C ., then quenched pure levomethadone nitrile E . In some embodiments , the with dilute HC1, and extracted with an organic solvent, e . g . , solvent is selected from THF, DMF or a mixture thereof. In toluene . The aqueous phase is treated with aq . NaOH at some embodiments, the ratio of THF :DMF is varied from 10 pH = 10 to form the free base and extracted with MTBE , and 1 : 10 to 10 : 1 v / v . In specific embodiments , the ratio of dried over sodium sulfate , then concentrated . The crude THF :DMF is selected from 4 : 1 , 3 : 1 , 2 : 1 , 1: 1 , 1 :2 , 1 : 3 or 1 : 4 . solid product is suspended and or dissolved in one or more In some embodiments , the base is selected from one ormore solvents , heated , and cooled to provide a needle - like crys of KOtBu , NaOtBu, other K or Na alkoxides such as 16 talline product levomethadone nitrile . methoxide, ethoxide , isopropoxide , t -pentoxide , KOH , and Preparation of Levomethadone Hydrochloride from NaOH . In some embodiments , the solvent is selected from Levomethadone Nitrile a polar aprotic solvent, an ether solvent, water, or any In some embodiments , levomethadone nitrile is converted combination thereof. In some embodiments , the polar apro to levomethadone hydrochloride by use of a Grignard addi tic solvent is DMF, DMA , or DMSO . In some embodiments , 20 tion with ethyl magnesium bromide . In the final step , the ether solvent is THF or dioxane . levomethadone nitrile reacts with Grignard reagent ethyl In some embodiments , intermediate C , ( R ) -2 -( dimethyl magnesium bromide to give an imine intermediate which amino )propan - 1 - ol, is activated by treating with a sulfonyl upon acid hydrolysis yields levomethadone hydrochloride. chloride , or sulfonyl anhydride , and a base to form inter - Levomethadone free base is obtained after basification of the mediate D ', ( R )- 2 - ( dimethylamino ) propyl 4 -methylbenzene - 25 reaction mixture with NaOH and extraction with an organic sulfonate , or intermediate D " , ( R ) -2 - (dimethylamino )propyl solvent such as MTBE . Treatment of the crude levometha methanesulfonate , by as shown in FIG . 5 , by methods done base with aqueous HCl produces the levomethadone known in the art . In some embodiments , the sulfonyl chlo - hydrochloride final product. ride is selected from methanesulfonyl chloride or p - tolu - 20 In some embodiments , levomethadone nitrile is converted eneulfonyl chloride. to levomethadone hydrochloride by treating with ethylmag In some embodiments , N ,N -dimethyl D - alaninol is nesium bromide , as shown in FIG . 6 . In some embodiments , treated with p - toluenesulfonyl chloride ( tosyl chloride or the ethyl magnesium bromide is made in situ , for example TsCl) in the presence of potassium tert - butoxide and the with magnesium shavings and ethyl bromide, or the ethyl resulting tosylate intermediate is subjected to alkylation with 35 magnesium bromide may be purchased as a reagent. In some diphenylacetonitrile using potassium tert -butoxide as the embodiments , the ethyl magnesium bromide is performed base to give levomethadone nitrile along with isolevometha - with CuBr/HO + , by the method of Weiberth et al. , J Org done nitrile . The undesired isomer , isolevomethadone Chem 52 , 3901 ( 1987) , which is incorporated herein by nitrile , can be removed by recrystallization with an organic reference. In one embodiment, the levomethadone nitrile is solvent such as heptane to give the desired pure levometha - dissolved in an anhydrous hydrocarbon solvent to form a done nitrile . reaction mixture . In some embodiments , the hydrocarbon In another aspect, a “ one -pot " procedure for the alcohol solvent is selected from xylene or toluene . Ethylmagnesium activation / alkylation process is performed by pre -mixing of bromide in an ether solvent is added slowly under Ar to the N , N - dimethyl D - alaninol with tosyl chloride in anhydrous 45 reaction mixture and the reaction mixture is warmed to THF and subsequent treatment with potassium tert- butoxide remove the ether solvent and heated for between 0 . 5 - 18 h at to produce a tosylated activated intermediate . The in situ an elevated temperature between 30 - 125° C ., 50 - 110° , or generated tosylate of the amino alcohol is subjected to 80 - 100° C . After cooling to ambient temperature and aque alkylation with diphenylacetonitrile using potassium tert ous HCl is added with optional external cooling . After HCl butoxide as the base in dimethylformamide (DMF ) to give is added , the reaction mixture is heated to facilitate the a mixture of levomethadone nitrile and isolevomethadone hydrolysis of the imine intermediate to form levomethadone nitrile in a ratio of approximately 75: 25 . Pure levometha - hydrochloride . After basification with NaOH , levometha done nitrile is obtained by recrystallization from heptane. done free base is extracted , dried and treated with an HC1 In specific embodiments , the N , N - dimethyl- D - alaninol is 55 solution to form the levomethadone hydrochloride final converted to levomethadone nitrile by first preparing an product . After removal of water , the crude product is recrys activated intermediate , then alkylating with diphenylac - tallized from an alcohol solvent, hydrocarbon solvent, and / etonitrile. In some aspects , the N , N - dimethyl- D - alaninol is or a polar aprotic solvent to form crystalline levomethadone dissolved in a polar aprotic solvent. In some embodiments , hydrochloride . In some embodiments , the product is recrys the polar aprotic solvent is selected from THF or DMF. After 60 tallized from methanol, ethanol, and/ or acetone , or a mixture stirring and cooling to a temperature of from 0 - 15° C ., or not thereof to produce the product levomethadone hydrochlo more than 10° C ., tosyl chloride is added , then a base is ride . added, for example , potassium t - butoxide. The solution is The process according to FIG . 1C , via steps 1B and 2B , allowed to come to ambient temperature and stirred for 65 was performed three times to provide three lots of 30 - 90 minutes . Then diphenylacetonitrile is added . In some levomethadone hydrochloride from D -alanine . Test results embodiments a second polar aprotic solvent, for example are shown in Table 1 . US 10 , 040 ,752 B2 29 30 TABLE 1 Test results from three Levomethadone HCI lots Characteristic * Specification Lot # 1 Lot # 2 Lot # 3 Appearance White or almost White , crystalline White , crystalline White , crystalline crystalline powder powder powder powder Assay 99 . 0 % to 101. 0 % 99 . 4 % 99 . 5 % 99 . 4 % (Potentiometric (dried basis ) Titration ) Identification A - 125° to - 135° - 130° - 130° - 130° ( Specific Optical (dried substance ) Rotation ) Identification B 239° C . -242° C . Not tested Not tested Not tested (Melting Point) Identification C Matches EP Meets Meets Meets ( IR ) reference requirements requirements requirements spectrum reference of methadone hydrochloride Identification D Meets EP Not tested Not tested Not tested ( Chlorides ) Requirement Loss on Drying NMT 0 . 5 % 0 . 20 % 0 . 20 % 0 . 10 % Sulfated Ash NMT 0 . 1 % 0 . 10 % 0 . 0 % 0 . 0 % Appearance of Clear ( EP 2. 2 . 1) Clear and Clear and Clear and Solution and Colorless ( EP Colorless Colorless Colorless 2 . 2 . 2 , Method II ) Acidity and See the TEST Meets Meets Meets Alkalinity section requirements requirements requirements Related NMT 0 . 5 % Not Detected Not Detected Not Detected substances by HPLC : Dextromethadone Related NMT 0 . 1 % Not Detected Not Detected Not Detected substances by HPLC : Any impurities Related NMT 0 . 5 % Not Detected Not Detected Not Detected substances by HPLC : Total Impurities Residual Solvents Conforms to USP Conforms Conforms Conforms < 467 > MTBE : 4 ppm MTBE : 5 ppm MTBE : 2 ppm Acetone : 107 ppm Acetone : 175 ppm Acetone : 70 ppm Methanol : 42 ppm Methanol: 26 ppm Methanol : 36 ppm Toluene : 39 ppm Toluene : 24 ppm Toluene: 24 ppm Heavy Metals Conforms to USP Conforms Conforms Conforms < 232 > Heavy Metals : Report results 3 ppm 5 ppm 14 ppm Zinc * per European Pharmacopoeia 8 . 0 , Levomethadone hydrochlorideMonograph of 01/ 2008 : 1787 corrected 6 . 5 . pp . 2614 - 2615 .

In some embodiments , the levomethadone hydrochloride (CH3 )2 , - CH (CH3 ) CH2CH3 , - or- CH Ph ; R12 and R13 are is characterized by one or more of chiral HPLC , RP - HPLC , independently C1- 6 alkyl; R 14 is alkyl, alkenyl or aryl; n = 1 ; IR , 13 C -NMR , and ' H -NMR . In some embodiments , and * is in the R configuration in greater than 99 % e . e . levomethadone hydrochloride is provided comprising not 30 Preparation of Dextromethadone Hydrochloride from more than 100 ppm , 50 ppm , or 10 ppm of dextromethadone , L -Alanine as detected by the chiral HPLC ; and not more than 100 ppm , A process for preparation of dextromethadone hydrochlo 50 ppm , or 10 ppm of an impurity selected from dipheny - ride from L - alanine is shown in FIG . 1B . In some embodi lacetonitrile , levomethadone nitrile , isolevomethadone sements , as shown in FIG . 1D , a process for preparing nitrile, and isolevomethadone as detected by reverse phase dextromethadone hydrochloride is provided comprising HPLC . converting L - alanine to N , N -dimethyl - L - alanine ; reducing In some embodiments , a compound according to Formula the N , N - dimethyl- L -alanine to form N , N - dimethyl- L -alani ( I ) or pharmaceutically acceptable salt thereof, is provided , nol ; combining the N , N - dimethyl- L - alaninol with an acti wherein the substituents are as provided herein . In some 60 vating reagent to form an activated intermediate ; mixing the embodiments , an isolated and/ or purified compound accord - activated intermediate and a base with diphenylacetonitrile ing to Formula ( I ) or pharmaceutically acceptable salt to provide dextromethadone nitrile ; and exposing the dex thereof, is provided , wherein the substituents are as provided tromethadone nitrile to ethyl magnesium bromide , and herein . In some embodiments , an isolated and / or purified hydrochloric acid , to provide dextromethadone hydrochlo compound according to formula (I ) is provided , wherein 65 ride . Y = C ( O ) R , 4 ; R1 , R2 , Rz, R4, Rz, R . , R7, Re , Ro , Rio are In other embodiments , as shown in FIG . 1D , a process for independently H ; Ru is CH3, - CH (CH3 ) 2 , CH2CH preparing dextromethadone hydrochloride is provided com US 10 ,040 ,752 B2 31 32 prising converting L - alanine to L - alaninol; converting the chloride , p - toluenesulfonyl chloride, trifluoromethanesulfo L - alaninol to N , N - dimethyl- L - alaninol; combining the N , N nyl chloride , methanesulfonic anhydride, trifluoromethane dimethyl -L -alaninol with an activating reagent to form an sulfonic anhydride, or p - toluenesulfonic anhydride . activated intermediate ; mixing the activated intermediate In some embodiments, the activated intermediate is and a base with diphenylacetonitrile to provide dextrometha - 5 selected from ( S ) - 1 - chloro - N , N - dimethylpropan - 2 - amine done nitrile; and exposing the dextromethadone nitrile to HC1, ( S ) - 1 - chloro - N , N - dimethylpropan - 2 - amine, ( S ) - 2 - (di ethylmagnesium bromide , and hydrochloric acid , to provide methylamino ) propyl 4 -methylbenzenesulfonate , or ( S ) - 2 dextromethadone hydrochloride. A specific embodiment is (dimethylamino )propyl methanesulfonate . In a specific shown in FIGS . 25A - 25C . aspect, the activated intermediate is ( S ) - 1 - tosyl - N , N - dim In another embodiment, a highly efficient asymmetric 10 ethylpropan -2 - amine HCl. In another aspect, the activated synthesis of dextromethadone hydrochloride is provided intermediate is isolated before being used in the next step , or starting from L -alanine , and resulting in dextromethadone is prepared and used in the next step without isolation . hydrochloride in greater than 95 % , 97 % , 99 % 99. 5 % , or In some embodiments, a process for preparing dex 99 . 9 % e . e . tromethadone hydrochloride is provided comprising mixing In some embodiments , a process is provided for the 15 an activated intermediate and a base with diphenylacetoni production of dextromethadone hydrochloride comprising trile to provide dextromethadone nitrile , wherein the mixing not more than 0 . 5 % , 0 .25 % , 0 . 1 % , 0 .05 % , 0 . 025 % , 0 .01 % . comprises exposing the activated intermediate to a base and 0 .005 % , 0 . 001 % , 0 .0005 % , or 0 . 0001 % of an impurity diphenylacetonitrile in a solvent to form the dextrometha selected from levomethadone , isolevomethadone , isodex done nitrile. One specific embodiment, where the activated tromethadone , dextromethadone nitrile , levomethadone 20 intermediate is ( S ) - 1 - tosyl- N , N - dimethylpropan - 2 - amine , is nitrile , isodextromethadone nitrile , isolevomethadone shown in FIG . 25B . In some embodiments , the activated nitrile , diphenylacetonitrile , 2 ( R ) - 2 - [ [ ( 4 -methylphenyl ) sul- intermediate is mixed with diphenylacetonitrile, then a base phonyl] amino ]pentanedioic acid (N - tosyl- L - glutamic acid ); is added , selected from the group consisting of sodium a tartaric acid , or a bromocamphor sulfonic acid , such as a hydroxide , potassium hydroxide, potassium t -butoxide , 3 - bromocamphor - 10 - sulfonic acid . 25 sodium t -butoxide , sodium methoxide , potassium methox In some embodiments , a process is provided for the ide , sodium ethoxide, potassium ethoxide, sodium iso production of dextromethadone hydrochloride comprising propoxide , and potassium isopropoxide . In a specific aspect, not more than 0 . 5 % , 0 .25 % , 0 . 1 % , 0 .05 % , 0 . 025 % , 0 .01 % . the base is potassium t - butoxide. In some embodiments , the 0 .005 % , 0 . 001 % , 0 .0005 % , or 0 . 0001 % of levomethadone solvent is selected from dimethylformamide , dimethylacet or levomethadone hydrochloride . 30 amide, tetrahydrofuran , dimethyl sulfoxide, N - methyl- 2 Synthesis of N , N - Dimethyl- L - Alaninol pyrrolidone , dioxane , water , or a combination thereof. In In some embodiments , a process for preparing dex - specific aspects , dextromethadone nitrile is formed in > 95 % , tromethadone hydrochloride is provided comprising con - > 97 % , > 99 % , > 99 . 5 % , or > 99 . 9 % enantiomeric excess verting L - alanine to N , N -dimethyl - L - alanine , wherein the ( e . e . ) . In a specific aspect, dextromethadone nitrile is formed converting comprises hydrogenating the L -alanine with 35 in > 99 % enantiomeric excess ( e. e .) . formaldehyde and / or paraformaldehyde with a catalyst to Preparation of Dextromethadone Hydrochloride from form N , N - dimethyl- L - alanine . Dextromethadone Nitrile In some embodiments , a process for preparing dex - In some embodiments , dextromethadone nitrile is treated tromethadone hydrochloride is provided comprising reduc with a Grignard reagent such as ethyl magnesium bromide , ing the N , N -dimethyl - L - alanine to form N , N -dimethyl - D - 40 and hydrochloric acid , to provide dextromethadone hydro alaninol, wherein the reducing comprises exposing the N , N - chloride , wherein the exposing comprises adding ethylmag dimethyl- D -alanine to one or more reducing agents selected nesium bromide to a stirred solution of dextromethadone from LiAlH4, BHZ/ THF , BHZ/ Et20 , BHZ/ BF3 Et20 , BHZ! nitrile in an anhydrous solvent to form a reaction mixture ; Me S , NaBH4/ 12 , BH _ /cyanuric chloride , NaBH2CN /ZnCl2 , heating the reaction mixture ; cooling the reaction mixture to NaBH _ / ZnC12 , Zn (BH _ ) , or NaBH _ /BF2 . Et O . In a specific 45 ambient temperature ; adding hydrochloric acid to the reac aspect, the reducing agent is LiAlH4. tion mixture with external cooling such that the reaction In some embodiments , a process for preparing dex - temperature does not exceed 50° C . ; and isolating the tromethadone hydrochloride is provided comprising reduc - levomethadone hydrochloride. In some embodiments, the ing L - alanine to form L - alaninol, wherein the reducing reaction mixture of dextromethadone nitrile and about 2 comprises exposing the L - alanine to one or more reducing 50 equivalents of ethylmagnesium bromide is heated to 100° C . agents selected from LiAlH4, BHZ/ THF , BHz/ Et20 , BHZ/ for 1 - 6 hrs , then cooled prior to treating with HCl. One BF , Et O , BHZ/ Me , S , NaBH _ /12 , BH / cyanuric chloride , specific embodiment is shown in FIG . 25C . NaBH2CN /ZnCl2 , NaBH _/ ZnCl2, Zn (BH4 ) 2 , or NaBH _ In some embodiments , dextromethadone hydrochloride is BF3. Et 0 . In a specific aspect, the reducing agent is provided comprising not more than 0 .05 % (500 ppm ), Zn (BH4 ) 2 . 55 0 .025 % ( 250 ppm ), or 0 .01 % ( 100 ppm ) of an impurity In some embodiments , the L - alaninol is dimethylated by selected from levomethadone hydrochloride , levometha any known means to form N , N - dimethyl- D -alaninol . In one done , isolevomethadone , isolevomethadone hydrochloride , embodiment, L - alaninol is treated with formaldehyde and isosextromethadone , isodextromethadone hydrochloride , formic acid and heated to provide N , N -dimethyl - L -alaninol . dextromethadone nitrile , levomethadone nitrile , isodex A specific embodiment is shown in FIG . 25A . 60 tromethadone nitrile , isolevomethadone nitrile , diphenylac Preparation of Dextromethadone Nitrile from N ,N -Dim - etonitrile , 2R ) -2 -[ [( 4 -methylphenyl ) sulphonyl ] amino ]pen ethyl- L - Alaninol Via Activated Intermediate tanedioic acid ( N - tosyl- L - glutamic acid ) ; a tartaric acid , or In some embodiments , a process for preparing dex - a bromocamphor sulfonic acid , such as a 3 - bromocamphor tromethadone hydrochloride is provided comprising com - 10 -sulfonic acid . bining N , N - dimethyl- L - alaninol with an activating reagent 65 In some embodiments , a process for preparing dex to form an activated intermediate , wherein the activating tromethadone hydrochloride is provided herein , wherein the reagent is selected from thionyl chloride, methanesulfonyl dextromethadone hydrochloride comprises not more than US 10 , 040 , 752 B2 33 34 100 ppm of an impurity selected from the group consisting ing the nitrile intermediate to a Grignard reagent and an acid of levomethadone , diphenylacetonitrile , dextromethadone to form the compound of formula ( I ) wherein Y is C ( O ) nitrile , isodextromethadone nitrile , and isodextromethadone . R14 In some embodiments , a pharmaceutical composition is In some embodiments , the alkyl groups of the dialkyl provided comprising an effective amount of dextrometha - 5 amino acid are selected from C1- 6 alkyl groups. In some done hydrochloride having not more than 100 ppm of an embodiments , the Grignard reagent is selected from RMgX impurity selected from the group consisting of levometha where R is C1- 6 alkyl and X is I , Br, or Cl. In some done , diphenylacetonitrile , dextromethadone nitrile , isodex embodiments , the Grignard reagent is ethyl magnesium tromethadone nitrile , and isodextromethadone ; and a phar- bromide . In some embodiments , the chiral amino acid is a maceutically -acceptable carrier. In one aspect, a 0 D - amino acid . In some embodiments , the reducing agent is pharmaceutical composition is provided comprising an selected from one or more of LiAlH4, BHZ/ THF, BHZ/ Et, 0 , effective amount of dextromethadone hydrochloride having BHz/ BF3 Et20 , BHZ/ Me , S , NaBH _ / 12 , BH4/ cyanuric chlo not more than 50 ppm of levomethadone . In another aspect, ride , NaBH CN /ZnCl2 , or NaBH _ /BFz . Et O . In some a pharmaceutical composition is provided comprising an is embodiments , the activated intermediate is formed by effective amount of dextromethadone hydrochloride having exposing the dialkylamino alcohol to thionyl chloride and not more than 25 ppm of levomethadone . In another aspect, the halo group is a chloro group . In some embodiments , the a pharmaceutical composition is provided comprising an sulfonyl group is selected from a mesyl group or a tosyl effective amount of dextromethadone hydrochloride having group . not more than 10 ppm of levomethadone . 20 In some embodiments , an isolated compound is provided In some embodiments , a method for preparing a com according to Formula ( 1 ) , or pharmaceutically acceptable pound according to Formula (I ) or pharmaceutically accept salt thereof, wherein the stereocenter * is an R configuration , able salt thereof, is provided , in greater than 90 % , 95 % , 97 % , 99 % , 99 . 5 % , or 99 . 9 % e . e compared to the S isomer. 25 In some embodiments , a compound is provided according to Formula ( I) , or pharmaceutically acceptable salt thereof, wherein the stereocenter * is an S configuration in greater than 90 % , 95 % , 97 % , 99 % , 99 .5 % , or 99. 9 % e. e compared to the * R isomer . RI 30 In some embodiments , a method for preparing a com Ru pound according to Formula ( I ) , or pharmaceutically accept _ able salt thereof, is provided comprising isolating or puri -12 N * Xv fying the compound according to Formula ( 1 ) , or pharmaceutically acceptable salt thereof. In some embodi R13 R10 ments , the isolating and or purifying comprises recrystalli zation , or chromatographic purification of the compound R7 according to Formula ( 1 ) , or pharmaceutically acceptable salts thereof. In some embodiments , the compound or salt is recrystallized from an alcohol solvent, hydrocarbon solvent, 40 and /or a polar aprotic solvent to form crystalline compound wherein R1, R2, R3, R4, R5, Ro, R7, R8, R9, Rio are of Formula ( I) , or pharmaceutically acceptable salt thereof . independently H , amino , C1- 6 alkyl, alkenyl, alkynyl, halo , In some embodiments , R1, R2, R3, R4, R5, R . , R7, R3, R2, hydroxyl, carbocyclic , heterocyclic , or aryl; Rio are independently H , C1- 6 alkyl, or halo . In some Rui is H , acyl, amino , amido , azido, carboxyl, alkyl, aryl , embodiments , R1, R2, R3, R4, Rs, R . , R7, R8, R9, Rio are aralkyl, halo , guanidinyl , oxo , sulfanyl, sulfenyl, sulfonyl, 45 independently H and Y is - C (O )R14 . heterocyclyl, heteroaryl, or hydroxyl; In some embodiments , Rui is selected from H , CH3 , R12, R13 are independently H , acyl, alkyl, alkyenyl, alkynyl, CH ( CH3) 2 , CH - CH( CH3 ) 2 , CH( CH?) CH2CH , aralkyl , aryl, carboxyl, cycloalkyl , heterocyclic , or other - CH2- pyrrolidinyl , CH CH SCHz, 4CH Ph , - CH2 amino (in the case of hydrazide ) or R12 and R13 together with indol- 3 -yl , CH ,OH , CH (OH )CH3 , — CH SH , CH , Ph the nitrogen atom to which they are attached , form a ring 50 OH , CH2C (= O )NH2 CH2CH2C (= O )NH2 , having 4 - 8 atoms. CH, COH, CH?CH , CO, H , ( CH? ) NHA, X is (CH ) , where n = 1 - 6 ; (CH2 ) 2NHC ( = NH2) NH2, or — CH2- imidazol- 4 - yl. Y is CN or C ( O )R14 ; In some embodiments , n = 1, 2 , 3, 4 , 5 or 6 . In specific R14 is alkyl, alkanyl, alkynyl, cycloalkyl, heterocyclyl, aryl, embodiments , n = 1. heteroaryl, alkoxy , aryloxy , aralkyl, or amino ; and 55 In some embodiments , R12 and R13 are independently * is a stereocenter selected from R or S configuration . C1- 6 alkyl. In specific embodiments , R12 and R13 are inde In some embodiments , a method for preparing a com pendently methyl, ethyl, n - propyl, i -propyl , n - butyl, i- butyl , pound according to formula ( I ) is provided , comprising sec -butyl , or t -butyl . In some embodiments , R . and R , zare converting a chiral amino acid selected from a D - amino acid independently methyl or ethyl. In some embodiments , R12 or an L - amino acid , to a dialkyl amino acid ; treating the 60 and R13 are independently methyl. dialkyl amino acid with a reducing agent to convert the I n some embodiments , R1 , R12 , R13 are each indepen carboxyl group to a hydroxyl group and form a dialkyl dently methyl . aminoalcohol ; converting the dialkyl aminoalcohol In some embodiments , Y is - C ( O )R14 where R14 is C1- 6 hydroxyl group to a halo group or a sulfonyl group to form alkyl. In some embodiments , R14 is CH3, - CH2CH3, an activated intermediate ; mixing the activated intermediate 65 CH (CH3 )2 , CH2CH ( CH3) 2, CH (CH3 ) CH2CH3 , with a base and a diarylacetonitrile to provide a nitrile C ( CH3) 3 , or (CH2 ) mCH2 where m = 1 , 2 , 3 , 4 , 5 or 6 . In intermediate of formula ( I) wherein Y is CN ; and expos - a specific embodiment, R14 is CH2CH3, US 10 ,040 , 752 B2 35 36 In some embodiments , a compound according to formula according to Formula ( I ) , or pharmaceutically acceptable (I ) or pharmaceutically acceptable salt thereof, is provided salt thereof, wherein the substituents are as defined herein , wherein R1, R2, Rz, R4, Rs, R ., Rz, Rg, R9, Rio are wherein the stereocenter * is in the R or S configuration ; and independently H , Ru is Me, R 12 and R13 are independently wherein the compound according to Formula ( I ) or pharma Me, R 4 is Et, and n = 11 , and * is in the R configuration in 5 ceutically acceptable salt thereof, is an isolated compound in greater than 97 % , 99 % , 99 . 5 % or 99 . 9 % e . e. greater than 90 % , 97 % , 95 % , 99 % , 99 . 5 % , or 99 . 9 % In other embodiments , a compound according to formula enantiomeric excess , as determined by chiral HPLC ; and ( b ) ( I) or pharmaceutically acceptable salt thereof, is provided a pharmaceutically acceptable carrier . wherein R?, Rz, Rz, R4, R5, R . , R7, Rg, Ry, Rio are Compositions independently H , R11 is Me, R12 and R13 are independently 10 In some embodiments the disclosure provides a pharma Me, Ria is Et, and n = 1, and * is in the S configuration in ceutical composition comprising a pharmaceutically effec greater than 97 % , 99 % , 99 . 5 % or 99 . 9 % e . e . tive amount of levomethadone hydrochloride having not In some embodiments , a compound is provided according more than 0 .05 % (500 ppm ), 0 .025 % ( 250 ppm ), 0 .01 % ( 100 to Formula (I ) or pharmaceutically acceptable salt thereof, ppm ), 0 .005 % ( 50 ppm ), 0 .0025 % (25 ppm ) , or 0 .001 % ( 10 that is not methadone. In some embodiments, a compound is 15 ppm ), of an impurity selected from the group consisting of provided according to Formula ( I ) that is not p - hydroxy d extromethadone , diphenylacetonitrile, levomethadone methadone . In some embodiments , a compound is provided nitrile , isolevomethadone nitrile , and isolevomethadone . according to Formula ( I ) that is not levomethadone . In some embodiments the disclosure provides a pharma In some embodiments , a compound is provided according ceutical composition comprising a pharmaceutically effec to formula (I ) that is an isolated compound . 20 tive amount of dextromethadone hydrochloride having not In some embodiments , a compound is provided according more than 0 .05 % ( 500 ppm ) , 0 .025 % (250 ppm ), 0 .01 % ( 100 to formula (I ) that is a purified compound . ppm ), 0 .005 % ( 50 ppm ) , 0 . 0025 % ( 25 ppm ), or 0 .001 % ( 10 In some embodiments , an intermediate or final compound ppm ), of an impurity selected from the group consisting of is provided comprising one or more " protecting groups ” levomethadone , diphenylacetonitrile , dextromethadone ( - PG ) , as described in Greene and Wuts , “ Protective Groups 25 nitrile , isodextromethadone nitrile , and isodextromethadone . in Organic Synthesis ” , 2nd Ed ., John Wiley & Sons, Inc ., According to another aspect, the present invention pro New York , 1991 , which is incorporated herein by reference . vides a pharmaceutical composition , which comprises a As used herein , the term " chiral chromatography ” or therapeutically - effective amount of one or more compounds “ chiral HPLC ” refers to a chromatographic technique of the present invention or a pharmaceutically -acceptable employing a chiral stationary phase (CSP ) . For example , the 30 salt , ester or prodrug thereof, together with a pharmaceuti chiral stationary phase may be selected from Pirkle - type cally -acceptable diluent or carrier. CSP , a cyclodextrin -type CSP , a protein -bound CSP , or a Pharmaceutically acceptable carriers include: ( 1 ) sugars, cellulose - derived CSP. See Porter , Pure & Appl Chem such as lactose , glucose and sucrose ; ( 2 ) starches , such as 63 (8 ): 1119 - 1122 , 1991 , which is incorporated herein by corn starch and potato starch ; (3 ) cellulose, and its deriva reference . In some embodiments , the chiral HPLC is per - 35 tives , such as sodium carboxymethyl cellulose , ethyl cellu formed with a cellulose - derived CSP . In some embodiments, lose, microcrystalline ecellulose , and cellulose acetate ; ( 4 ) the cellulose derived CSP is a cellulose -based HPLC col- powdered tragacanth ; ( 5 ) malt ; ( 6 ) gelatin ; ( 7 ) talc ; ( 8 ) umn . excipients , such as cocoa butter and suppository waxes ; ( 9 ) In some embodiments , an isolated compound according to oils , such as peanut oil , cottonseed oil , safflower oil , sesame Formula (I ) is provided by variations of the methods pro - 40 oil, olive oil, corn oil and soybean oil ; ( 10 ) glycols , such as vided herein , wherein the substituents are as defined herein , propylene glycol; ( 11) polyols , such as glycerin , sorbitol, wherein the stereocenter* is in the Ror S configuration , and mannitol and polyethylene glycol; ( 12 ) esters , such as ethyl wherein the compound according to Formula ( I) is an oleate and ethyl laurate ; ( 13 ) agar ; ( 14 ) buffering agents , isolated compound in greater than 90 % , 97 % , 95 % , 99 % , such as magnesium hydroxide and aluminum hydroxide ; 99 .5 % , or 99 . 9 % enantiomeric excess, as determined by 45 ( 15 ) lubricants , such as magnesium stearate , calcium stear chiral HPLC . ate , zinc stearate , sorbitan monostearate , sucrose mono In some embodiments , methods are provided for prepa - palmitate, glycerol dibehenate , and stearic acid ; ( 16 ) alginic ration of a compound according to Formula (I ) , or pharma acid ; ( 17 ) pyrogen - free sterile water ; ( 18 ) isotonic saline ; ceutically acceptable salt thereof , wherein the substituents ( 19 ) Ringer ' s solution ; ( 20 ) ethyl alcohol; (21 ) phosphate are as defined herein , wherein the stereocenter * is in the R 50 buffer solutions; (22 ) polymers and time release agents ; ( 23 ) or S configuration , and wherein the compound according to bioavailability enhancers and bioavailability controllers / in Formula ( I ) is an isolated compound in greater than 90 % , hibitors ; and (23 ) other non - toxic compatible substances 97 % , 95 % , 99 % , 99 . 5 % , or 99 . 9 % enantiomeric excess, as employed in pharmaceutical formulations . determined by chiral HPLC . Other non - toxic compatible substances include optional In some embodiments , pharmaceutical compositions are 55 flavorings and / or sweeteners . provided comprising a compound according to Formula (I ) , In another embodiment, compositions of the disclosure or pharmaceutically acceptable salt thereof, wherein the can optionally further comprise one or more flavoring substituents are as defined herein , wherein the stereocenter * agents . The optional flavoring agent is added to increase is in the R or S configuration ; and wherein the compound patient acceptability and compliance with the recommended according to Formula ( 1 ) is an isolated compound in greater 60 dosing schedule . The flavoring agents that may be used than 90 % , 97 % , 95 % , 99 % , 99 . 5 % , or 99 . 9 % enantiomeric include those flavors known to the skilled artisan , such as excess, as determined by chiral HPLC , and a pharmaceuti - natural and artificial flavors . These flavorings may be chosen cally acceptable carrier. from synthetic flavor oils and flavoring aromatics and /or In some embodiments , a method of treating chronic pain , oils , oleoresins and extracts derived from plants , leaves , or of opioid detoxification , is provided , comprising admin - 65 flowers, fruits , and so forth , and combinations thereof. istering a pharmaceutical composition to a subject in need Non - limiting representative flavor oils include spearmint oil , thereof, wherein the composition comprises ( a ) a compound cinnamon oil, oil of wintergreen (methyl salicylate ), pep US 10 , 040 , 752 B2 37 38 permint oil , clove oil, bay oil, anise oil , eucalyptus oil , intramuscular , subcutaneous, intramedullary , intrathecal , thyme oil, cedar leaf oil , oil of nutmeg , allspice, oil of sage , intraventricular , intravenous , intraperitoneal, or intranasal mace , oil of bitter almonds, and cassia oil . Also useful administration . In some embodiments , dosage forms for flavorings are artificial, natural and synthetic fruit flavors transmucosal administration include , but are not limited to such as vanilla , and citrus oils including , without limitation , 5 fast melt, buccal or sublingual dosage forms. lemon , orange , lime, grapefruit, and fruit essences including Pharmaceutical compositions suitable for use in the pres apple , pear, peach , grape , strawberry , raspberry , cherry , ent application include compositions wherein the active plum , pineapple , apricot and so forth . These flavoring agents ingredients ( e . g . , levomethadone , levomethadone hydro may be used in liquid or solid form and may be used chloride , levomethadone hydrobromide , a compound of individually or in admixture . Commonly used flavors 10 formula I, and combinations thereof) , comprising not more include mints such as peppermint, menthol, artificial vanilla , than 500 ppm , 100 ppm , 50 ppm , 10 ppm , or 1 ppm of an cinnamon derivatives, and various fruit flavors, whether impurity selected from the group consisting ofdextrometha employed individually or in admixture. Other useful flavor done , diphenylacetonitrile , levomethadone nitrile , ings include aldehydes and esters such as cinnamyl acetate , isolevomethadone nitrile , and isolevomethadone , is con cinnamaldehyde , citral diethylacetal, dihydrocarvyl acetate , 15 tained in an effective amount to achieve the intended pur eugenyl formate , p -methylamisol , and so forth may be used . pose . For example , in a preferred embodiment , an effective In a specific aspect , the flavoring is selected from a cherry amount of a pharmaceutical composition comprises an or orange flavoring. amount of levomethadone hydrochloride comprising not Various sweeteners can be optionally used in the tablet, more than 500 ppm , 100 ppm , 50 ppm , 10 ppm , or 1 ppm of liquid , capsule , lozenge or troche formulations of the dis - 20 an impurity selected from the group consisting of dex closure. Examples of carbohydrates and sweeteners include tromethadone , diphenylacetonitrile , levomethadone nitrile , monosaccharides such as glucose and fructose , disaccha - isolevomethadone nitrile , and isolevomethadone. Determi rides such as maltose , sucrose , other ordinary sugars , sugar nation of effective amounts is well within the capability of alcohols such as xylitol, sorbitol, glycerin and erythritol, those skilled in the art, especially in light of the disclosure polysaccharides such as dextrin and cyclodextrin , and oli - 25 provided herein . gosaccharides such as fructo - oligosaccharide , galacto -oli - Pharmaceutical compositions suitable for use in the pres gosaccharide and lacto -sucrose . Other sweeteners include ent application include compositions wherein the active natural sweeteners such as thaumatin , stevia extract, Luo ingredients ( e . g . , dextromethadone , dextromethadone Han Guo (Lo Han fruit ) , rebaudioside A , glycyrrhizinic acid , hydrochloride , dextromethadone hydrobromide, a com etc . and synthetic sweeteners such as saccharin , aspartame, 30 pound of formula I , and combinations thereof) , comprising azesulfame potassium , etc . not more than 500 ppm , 100 ppm , 50 ppm , 10 ppm , or 1 ppm Optionally various FD & C dyes or opacifiers can be of an impurity selected from the group consisting of employed in the compositions . In various aspects , the FD & C levomethadone , diphenylacetonitrile , dextromethadone dye is selected from one or more of FD & C Red No. 3 , Red nitrile , isodextromethadone nitrile , and isodextromethadone , No. 40 , Red No . 33 , Yellow No. 6 , Yellow No . 6 lake, Yellow 35 is contained in an effective amount to achieve the intended No . 5 lake , Yellow No . 5 , Green No. 3 , Blue No . 1 and Blue purpose . For example , in a preferred embodiment, an effec No . 2 . In one aspect , the opacifier is titanium dioxide . In one tive amount of a pharmaceutical composition comprises an specific aspect, a composition is provided comprising amount of dextromethadone hydrochloride comprising not FD & C Red No. 40 and FD & C Red No . 33 . In another more than 500 ppm , 100 ppm , 50 ppm , 10 ppm , or 1 ppm of specific aspect, a composition according to the disclosure is 40 an impurity selected from the group consisting of provided comprising FD & C Yellow No. 6 , Yellow No . 6 levomethadone, diphenylacetonitrile , dextromethadone lake , and Yellow No . 5 lake. nitrile , isodextromethadone nitrile , and isodextromethadone . The compositions may be formulated for any route of In one embodiment, a levomethadone hydrochloride com administration , in particular for oral , rectal, transdermal, position is provided that is an oral concentrate comprising an subcutaneous , intravenous , intramuscular or intranasal 45 effective amount of levomethadone hydrochloride , and citric administration . acid ,methylparaben , poloxamer 407 , propylene glycol, pro The compositions may be formulated in any conventional pylparaben , purified water , sodium citrate dihydrate , and form , for example , as oral tablets , dispersible tablets, tablets sucrose . In some aspects , the composition further comprises for oral suspension , disket dispersible tablets , capsules , cherry flavor and one or more red dyes. In a specific caplets , solution , oral solution , oral concentrate , suspen - 50 embodiment , a composition is provided that is an oral sions, dispersions, troche , syrups, sprays, gels , supposito - concentrate comprising 10 mg /mL levomethadone hydro ries, patches and emulsions . In specific embodiments, the chloride , and citric acid , methylparaben , poloxamer 407 , composition is in the form of oral tablet, oral solution , oral propylene glycol, propylparaben , purified water , sodium concentrate , or tablet for oral suspension . citrate dihydrate, and sucrose. In some aspects , the compo As is well known in the medical arts , dosages for any one 55 sition further comprises cherry flavor and one or more red subject may depend upon many factors , including the dyes . patient' s size , body surface area , age , the particular com - In one embodiment, a levomethadone hydrochloride com pound to be administered , sex , time and route of adminis - position is provided that is an oral concentrate comprising an tration , general health , and interaction with other drugs effective amount of levomethadone hydrochloride , citric being concurrently administered . Depending on the target 60 acid , purified water , and sodium benzoate . In a specific sought to be altered by treatment, pharmaceutical composi - embodiment , a composition is provided that is an oral tions may be formulated and administered systemically or concentrate comprising 10 mg/ mL levomethadone hydro locally . Techniques for formulation and administration may chloride , citric acid , purified water , and sodium benzoate . be found in the latest edition of “ Remington ' s Pharmaceu In one embodiment, a levomethadone hydrochloride com tical Sciences” (Mack Publishing Co , Easton Pa .) . Suitable 65 position is provided that is an oral tablet comprising an routes may , for example , include oral or transmucosal effective amount of methadone hydrochloride , and magne administration , as well as parenteral delivery , including sium stearate , microcrystalline cellulose , and starch . In US 10 , 040 , 752 B2 39 40 specific embodiments , compositions are provided compris - aspect, a dextromethadone hydrochloride composition is ing 5 mg or 10 mg levomethadone hydrochloride, and provided that is a dispersible tablet comprising 40 mg of magnesium stearate , microcrystalline cellulose , and starch . dextromethadone hydrochloride and dibasic calcium phos In one embodiment, a levomethadone hydrochloride com - phate , microcrystalline cellulose , magnesium stearate , col position is provided that is a dispersible tablet for oral 5 loidal silicon dioxide , pregelatinized starch , and stearic acid . suspension comprising an effective amount of levometha - In one embodiment, a dextromethadone hydrochloride done hydrochloride and dibasic calcium phosphate , micro - composition is provided that is a dispersible tablet for oral crystalline cellulose , magnesium stearate , colloidal silicon suspension comprising an effective amount of dextrometha dioxide, pregelatinized starch , and stearic acid . In a specific done hydrochloride and colloidal silicon dioxide , monobasic aspect, a levomethadone hydrochloride composition is pro - 10 potassium phosphate , magnesium stearate , microcrystalline vided that is a dispersible tablet comprising 40 mg of cellulose , pregelatinized starch , and stearic acid . In some levomethadone hydrochloride and dibasic calcium phos - aspects , the composition further comprises orange flavor and phate , microcrystalline cellulose , magnesium stearate , col- yellow dye . In a specific aspect, a dispersible tablet com loidal silicon dioxide , pregelatinized starch , and stearic acid . position is provided comprising 40 mg dextromethadone In one embodiment, a levomethadone hydrochloride com - 15 hydrochloride, colloidal silicon dioxide , monobasic potas position is provided that is a dispersible tablet for oral s ium phosphate , magnesium stearate , microcrystalline cel suspension comprising an effective amount of levometha - lulose, pregelatinized starch , stearic acid , FD & C Yellow No . done hydrochloride and colloidal silicon dioxide, monobasic 6 , Yellow No . 6 lake, and Yellow No . 5 lake, and orange potassium phosphate , magnesium stearate , microcrystalline flavor. cellulose , pregelatinized starch , and stearic acid . In some 20 In one embodiment, composition is provided that is a aspects, the composition further comprises orange flavor and dextromethadone oral solution comprising an effective yellow dye . In a specific aspect , a dispersible tablet com amount of dextromethadone hydrochloride , alcohol, benzoic position is provided comprising 40 mg levomethadone acid , citric acid , flavoring , glycerin , sorbitol, and water . In hydrochloride , colloidal silicon dioxide , monobasic potas - some embodiments , the composition further comprises fla sium phosphate , magnesium stearate , microcrystalline cel - 25 voring (lemon ) and coloring FD & C Red No . 40 and FD & C lulose, pregelatinized starch , stearic acid , FD & C Yellow No. Yellow No . 6 , and either 1 mg/ mL , or 2 mg/ mL dex 6 , Yellow No . 6 lake , and Yellow No . 5 lake , and orange tromethadone hydrochloride . flavor. In one embodiment, a levomethadone hydrochloride com In one embodiment, composition is provided that is a position is provided that is an intravenous composition levomethadone oral solution comprising an effective amount 30 comprising an effective amount of dextromethadone hydro of levomethadone hydrochloride , alcohol, benzoic acid , chloride and chlorobutanol, and sodium chloride in sterile citric acid , flavoring, glycerin , sorbitol, and water . In some water . In specific embodiments a composition is provided embodiments , the composition further comprises flavoring comprising dextromethadone hydrochloride at a concentra (lemon ) and coloring FD & C Red No . 40 and FD & C Yellow tion of 10 mg/ mL with chlorobutanol preservative 0 . 5 % , in No. 6 , and either 1 mg/ mL , or 2 mg/ mL levomethadone 35 sterile saline. hydrochloride . In some specific embodiments , an effective amount of In one embodiment, a levomethadone hydrochloride com - dextromethadone hydrochloride is selected from 2 . 5 mg, 5 position is provided that is an intravenous composition mg, 10 mg, 20 mg , 30 mg, or 40 mg. comprising an effective amount of levomethadone hydro - Administration chloride and chlorobutanol, and sodium chloride in sterile 40 In some embodiments the disclosure provides a method of water . In specific embodiments a composition is provided treating a subject in need thereof, comprising administering comprising levomethadone hydrochloride at a concentration a composition comprising an effective amount of levometha of 10 mg/ mL with chlorobutanol preservative 0 . 5 % , in done hydrochloride having not more than 500 ppm , 100 sterile saline . ppm , 50 ppm , or 10 ppm of an impurity selected from the In some specific embodiments, an effective amount of 45 group consisting of dextromethadone , diphenylacetonitrile , levomethadone hydrochloride is selected from 2 . 5 mg, 5 mg, levomethadone nitrile , isolevomethadone nitrile , and 10 mg, 20 mg, 30 mg, or 40 mg. isolevomethadone . In one embodiment, a dextromethadone hydrochloride Indications for levomethadone hydrochloride composi composition is provided that is an oral concentrate compris tions provided herein may be selected from management of ing an effective amount of dextromethadone hydrochloride , 50 chronic malignant and non -malignant pain , management of citric acid , purified water, and sodium benzoate . In a specific pain severe enough to require daily , around - the -clock , long embodiment, a composition is provided that is an oral term opioid treatment; detoxification treatment of opiate concentrate comprising 10 mg/ mL dextromethadone hydro - addiction (heroin or other morphine - like drugs ); mainte chloride , citric acid , purified water , and sodium benzoate . nance therapy for opiate addiction , and to facilitate weaning In one embodiment, a dextromethadone hydrochloride 55 from opiate medications after extended periods in the ICU , composition is provided that is an oral tablet comprising an on the ward , or as an outpatient. In some embodiments , effective amount of dextromethadone hydrochloride , and compositions are provided for short term or long term magnesium stearate , microcrystalline cellulose , and starch . administration to a subject in need thereof for treatment of In specific embodiments , compositions are provided com - pain and / or addiction . prising 5 mg or 10 mg dextromethadone hydrochloride , and 60 In some embodiments , an effective amount of levometha magnesium stearate , microcrystalline cellulose , and starch . done hydrochloride is selected from 0 .01 - 500 mg, 0 .05 -300 In one embodiment, a dextromethadone hydrochloride mg, 0 . 1 - 250 mg, 1 - 100 mg, or 2 -80 mg per dose . In some composition is provided that is a dispersible tablet for oral specific embodiments , the effective amount is selected from suspension comprising an effective amount of dextrometha - 1 mg, 1 .5 mg, 2 . 5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, done hydrochloride and dibasic calcium phosphate , micro - 65 50 mg , 60 mg, 70 mg, 80 mg, 90 mg , 100 mg, 125 mg, 150 crystalline cellulose , magnesium stearate , colloidal silicon mg, 175 mg, 200 mg, 225 mg or 250 mg per dose . In some dioxide, pregelatinized starch , and stearic acid . In a specific embodiments , the levomethadone hydrochloride is present US 10 ,040 , 752 B2 41 42 in 0 . 1, 0. 25 , 0 .5 , 1, 1. 5 , 2 , 2 .5 , 3 , 4 , 5 , 10 , 15 , 20 , 30, 40 , or follows: CDC13 = 7. 25 ppm ; DMSO -06 = 2. 49 ppm ; 50 mg /mL in the composition . In some specific embodi CD , OD = 3 . 30 ppm . Peak multiplicities are designated as ments , the effective amount of the levomethadone hydro follows: s , singlet ; d , doublet; dd , doublet of doublets ; t , chloride is present at a concentration selected from 5 triplet ; dt, doublet of triplets ; q , quartet; br, broadened ; and mg/mL , 5 mg/ 5 mL , or 2 .5 mg/ 5 mL , in the composition . 5 m , multiplet. Coupling constants are given in Hertz (Hz ) . In some embodiments , the levomethadone hydrochloride Mass spectra (MS ) data are obtained using a mass spec composition is administered one per day ( 9 . d . ) , twice per trometer with MALDI- TOF , APCI or ESI ionization . day ( b . i. d . ) , three times per day ( t . i. d . ) , four times per day ( q . i .d .) , or more . In some embodiments , the composition is Example 1. A . N ,N -dimethyl D - alanine ( B ) not for administration in an as needed basis . 10 In some embodiments , methods for treating a subject in Step 1 : Dimethylation of D - alanine ( A ) by hydrogenation need thereof are provided comprising administering a com - with formaldehyde in the presence of Pd/ C to form N ,N position comprising an effective amount of dextrometha dimethyl D -alanine ( B ) . done hydrochloride, wherein the subject is suffering from a This step was carried out by following literature proce disease or disorder affecting an NMDA receptor. In some 15 dures with modifications. See WO 2012 / 162635 ; and Pat embodiments , methods are provided for treating anxiety e rson et al. , Org Lett 2013 , 15 , 3118 - 3121 ; each of which is disorders, Alzheimer ' s disease, chronic pain , dementia , incorporated by reference . depression , neuropathic pain , anti- NMDA receptor encepha To a solution of D -alanine ( A ) (50 . 0 g , 561 mmol) in litis, opioid analgesic tolerance , schizophrenia , stroke , and water (800 mL ) was added formaldehyde ( 37 % , 125 mL , traumatic brain injury , comprising administering a compo - 20 1 ,680 mmol) and Pd /C ( 10 % Pd, 20 g ) . After the flask was sition comprising an effective amount of a dextromethadone purged with Ar for 10 min and with H , three times , the hydrochloride having not more than 100 ppm , not more than reaction mixture was stirred at 50° C . under H2 ( 35 psi) for 50 ppm or not more than 10 ppm levomethadone hydro 20 hrs . The reaction mixture was then heated to reflux for 1 chloride . In some embodiments, the effective amount is h and filtered while hot through a short pad of celite . The selected from an amount of from 0 . 5 mg to 500 mg, 1 . 0 mg 25 filtrate was concentrated under reduced pressure . More to 250 mg, or 2 mg to 50 mg dextromethadone hydrochlo - water ( 200 mL each time, 3 times ) was added and the ride having not more than 100 ppm , not more than 50 ppm reaction concentrated in order to remove the unreacted or not more than 10 ppm levomethadone hydrochloride . formaldehyde . Residual water was removed azeotropically In some specific embodiments , the effective amount of with toluene (3x100 mL ) . ' H -NMR analysis revealed com dextromethadone hydrochloride is selected from 1 mg, 1 . 5 30 plete consumption of the starting material and clean and mg, 2 .5 mg, 5 mg, 10 mg , 20 mg, 30 mg, 40 mg, 50 mg, 60 essentially quantitative production of the N , N -dimethylated mg, 70 mg, 80 mg, 90 mg , 100 mg, 125 mg, 150 mg, 175 product . The crude product was recrystallized with hot mg , 200 mg, 225 mg or 250 mg per dose . In some embodi- EtOH / acetone (50 ml/ 250 mL ) at 55 -60° C . to give 41 . 36 g ments, the dextromethadone hydrochloride is present in 0 . 1 , (63 . 0 % ) product as a white solid ; another crop ( 11 . 38 g , 0 .25 , 0 .5 , 1 , 1. 5 , 2 , 2 .5 , 3, 4 , 5 , 10 , 15 , 20 , 30 , 40 , or 50 35 17 . 3 % ) was obtained after the mother liquor was concen mg/mL in the composition . In some specific embodiments, trated and the residual recrystallized from the same solvent the effective amount of the dextromethadone hydrochloride system ; further purification of the remaining product in the is present at a concentration selected from 5 mg/ mL , 5 mg / 5 mother liquor was not pursued and the material was saved mL , or 2 . 5 mg/ 5 mL , in the composition . for future use . ' H NMR (300 MHz, MeOH - d . ) 8 3 .65 ( q , In some embodiments , the dextromethadone hydrochlo - 40 J = 7. 1 Hz, 1H ), 2 . 86 (s , 6H ), 1. 51 ( d , J= 7 . 1 Hz , 3H ) ppm , as ride composition is administered one per day (q .d . ) , twice shown in FIG . 7 . 13C NMR (75 MHz, MeOH -d .) 8 172 . 1 , per day ( b . i . d . ), three times per day ( t. i. d . ) , four times per 6 6 . 0 , 40 . 1 , 11. 6 ppm as shown in FIG . 8 . day ( q . i . d . ), or more . In someembodiments , the composition is not for administration in an as needed basis . Example 1 . B . N , N - dimethyl D - alanine ( B ) 45 EXAMPLES A larger scale dimethylation was carried out with 100 g D - Ala in 500 mL water with 250 mL formaldehyde , 30 g In the examples below , temperatures are provided in Pd / C , and 40 psi H , pressure , and worked up in accordance degrees Celsius and all parts and percentages are by weight, with Example 1A . Product was recrystallized from 100 unless otherwise specified . Reagents may be purchased from 50 mL /500 mL (EtOH :Acetone ) to yield 110 . 5 g N , N -dimethyl commercial suppliers , such as Sigma - Aldrich Chemical D -alanine ( B ) ( 85 % yield ) . Product was characterized by Company, and may be used without further purification H -NMR as in example 1A . unless otherwise indicated . Reagents may also be prepared following standard literature procedures known to those Example 2 . ( R ) - 2 - (dimethylamino )propan - 1 -ol ( C ) skilled in the art . Solvents may be purchased from commer - 55 cial suppliers , or may be purified using standard methods Step 2 : Reduction of N , N - dimethyl D -alanine ( B ) with known to those skilled in the art , unless otherwise indicated . lithium aluminum hydride to form ( R ) - 2 - (dimethylamino ) The compound structures in the examples below were propan - 1 -ol ( C ) . confirmed by one or more of the following methods: proton To a stirred solution of N , N -dimethyl D -alanine ( B ) ( 2 . 34 magnetic resonance spectroscopy, mass spectroscopy, and 60 g , 20 mmol) prepared in Step 1 in THF ( 30 mL ) was added melting point. Proton magnetic resonance (' H NMR ) spectra LiAlH4 ( 1 . 14 g , 30 mmol) in portions at 0° C . and the were determined using an NMR spectrometer operating at resulting reaction mixture heated to reflux for 16 h . After 300 MHz field strength . Chemical shifts are reported in the cooling to rt, the reaction was carefully quenched with 10 form of delta ( 8 ) values given in parts per million (ppm ) mL sat . NaHCO3 and stirred for 10 min to generate a thick relative to an internal standard , such as tetramethylsilane 65 suspension . DCM (50 mL ) was then added and the organic ( TMS) . Alternatively , ' H NMR spectra were referenced to layer separated by decantation . To the remaining pasty signals from residual protons in deuterated solvents as residual were added DCM (50 mL ) and anhydrous Na2SO4 US 10 , 040 , 752 B2 43 44 (about 10 g ) and mixture vigorously stirred . The DCM layer - 50 .3° ( c 0 . 70 , EtOH ) ( literature value - 49- 50 . 2°) . Litera was then separated . The residual was stirred with another ture Data : - 50 .2° ( c 0 .71 , EtOH ) (U . S . Pat. No. 6 , 143, two portions of DCM (50 mL each ). The combined DCM 933A ); - 49° (C . J. Barnett and J. C . Smirz , J Org Chem layer was dried over Na2SO4 and concentrated at 35° C . 1976 , 41, 710 ) ; and [ a ] ' ) - 49°, c 1 . 3 , EtOH (Beckett et al. , under reduced pressure to give 1 . 40 g of crude ( R ) - 2 - 5 J Chem Soc , 1957 , 858 -61 ) . ( dimethylamino ) propan - 1 - ol ( C ) as a volatile oil (yield : 68 % ) which was used directly in the next step . ' H NMR Example 4 . A . Chiral HPLC Method for ( 300 MHz, CDC12 ) 8 3 . 43 (dd , J = 5 . 0 and 10 . 5 Hz, 1H ) , 3 . 30 Levomethadone Nitrile (t , q J = 10 . 2 Hz, 1H ), 2 .79 ( m , 1H ) , 2 . 25 ( s , 6H ) , 0 .87 ( d , J = 6 . 6 Hz, 3H ) ppm , shown in FIGS . 9 and 10 . 10 Analytical Chiral High Pressure Liquid Chromatography ( chiral HPLC ) of the levomethadone nitrile ( E ) was per Example 3 . ( R ) - 4 - (dimethylamino ) - 2 , 2 -diphenyl formed under the following conditions. For example , chiral pentanenitrile . Step 3 : Synthesis of levomethadone HPLC Conditions for comparative rac -Methadone Nitrile nitrile ( E ) from ( R ) - 2 - (dimethylamino )propan - 1 - ol and Levomethadone Nitrile (E ) of Example 3 were as ( C ) and diphenylacetonitrile 15 follows. Chiral HPLC was performed using a chiral station To a solution of the crude amino alcohol C (550 mg, 5 . 33 ary phase Column: Phenomenex Lux 3 mm , Cellulose - 3 , mmol ) prepared in Step 2 in chloroform (5 mL ) was care 150x4 .6 mm , Part No . 00 % -4492 - E0 , with Mobile Phase fully added a solution of 1 . 0 mL SOC1, in CHC1z ( 5 mL ) at 90 : 10 : 0 . 1 n -Hexane : Isopropanol : Diethylamine at Column 0° C . The reaction mixture was stirred at rt for 10 min and 20 Temperature of 300° C . with a Flow Rate of 1 . 0 mL /min , and then heated to reflux for 1 h . After cooling to rt , the solvent UV monitoring at Wavelength 254 nm , with Injection Vol and volatiles were removed under vacuum to give 781 mg of ume of 5 uL , following dissolving the Sample in 200 proof crude product D , ( R ) - 1 - chloro - N , N -dimethylpropan - 2 ethanol. amine HC1, as a solid product ( yield : 93 % ) which was used Chiral HPLC chromatogram by this method of directly in the following step . 25 levomethadone nitrile intermediate ( E ) from Example 3 To a stirred solution of the above ( R ) - 1 - chloro - N , N - revealed the presence of a single enantiomer ( e . e . > 99 % ) , as dimethylpropan - 2 - amine HCl, intermediate D , in DMF ( 5 .0 shown in FIG . 17 . In comparison , a chiral HPLC chromato mL ) was added KOtBu (617 mg, 5 . 5 mmol ) under Ar. The gram of racemic Methadone Nitrile performed under the resulting mixture was stirred at rt for 10 min . In a separate same conditions is shown in FIG . 18 , showing presence of flask containing diphenylacetonitrile , Ph , CHCN , (773 mg, 30 two enantiomers in about a 1: 1 ratio . The limit of detection 4 . 0 mmol) in DMF ( 5 mL ) was added KOtBu (494 mg, 4 . 4 (LOD / limit of quantitation ( LOQ ) for levomethadone mmol) and the reaction mixture was stirred under Ar at rt for nitrile / dextromethadone nitrile by this chiral HPLC method , 30 min to generate a reddish yellow solution , which was based on initial evaluation 10 / 100 ppm (LOD /LOQ ). No transferred via cannula to the first flask . The resulting dextromethadone nitrile was detected by chiral HPLC . reaction mixture was stirred at rt for 150 min and at 45° C . 35 for 15 h . After cooling to rt , the reaction mixture was poured Example 4 . B . Reverse- Phase HPLC Method into water (40 mL ) and extracted with EtoAc ( 25 mLx2 ). The combined organic extracts were washed with water and Analytical Reverse- Phase (RP ) -High Pressure Liquid brine , and dried over Na SO4. Removal of solvent gave 1 . 11 Chromatography ( RP -HPLC ) of the final product and inter g crude product. ' H NMR analysis revealed that the crude 40 mediates disclosed herein was performed under the follow product mixture consists of diphenylacetonitrile, levometha - ing conditions. RP -HPLC was performed using a C18 sta done nitrile ( E ) , its regio - isomer i . e ., 2 , 2 -diphenyl - 3 -methyl - tionary phase with a Gemini® 5 um C18 110 Å , LC Column 4 - dimethylaminobutyronitrile ( stereochemistry un - as - 150x4 . 6 mm , Part : 00F -4435 - E0 . The method was run under signed ) in a ratio of 9 % :67 % : 24 % , corresponding to a ratio HPLC Conditions: Mobile phase : 100 mL : 900 mL (mobile of 74 % : 26 % between levomethadone nitrile ( E ) and its 45 phase B ( pH 9 .25 ) : ACN / H , O ( 5 : 4 mixture ) ) ; at a Flow rate regio - isomer . of 1 mL /min , at 35° C . , and with monitoring at 210 nm . Recrystallization from heptane ( 10 mL ) gave 824 mg of Preparation of RP HPLC buffer was as follows. levomethadone nitrile (( R ) -4 -( dimethylamino )- 2 ,2 -diphe - A : Dissolve 6 .9 g of NaH2PO4 + H2O in 2000 mL of water. nylpentanenitrile ) ( E ) which was 89 % pure , with impurities Add 10 . 8 g of Dodecyl Sulfate , Sodium Salt and mix until being small amounts of diphenylacetonitrile and the regio - 50 well dissolved . Filter . Adjust the pH to 7 . 9 with triethylam isomer of E as revealed by ' H NMR . Pure samples of ine . levomethadone nitrile ( E ) were obtained by further recrys B : Combine 1460 mL of buffer with 300 mL acetonitrile tallization from the same solvent. and 240 mL of methanol and mix well . Adjust the apparent For levomethadone nitrile, intermediate E : ' H NMR ( 300 pH of mobile phase to a target range of 9 . 3 with 50 % MHz , CDC13 ) 8 7 . 28 - 7 .41 (m , 10H ), 2 .69 ( dd , J = 6 . 5 and 55 aqueous sodium hydroxide or 85 % aqueous phosphoric acid 13 .6 Hz, 1H ), 2 .54 (m . 1H ) , 2 . 24 (dd , J = 5 . 9 and 13 . 7 Hz , solution . 1H ) . 2 . 14 ( s , 6H ) , 0 . 92 ( d , J = 6 . 5 Hz, 3H ) ppm , shown in An RP -HPLC chromatogram of a mixture of relevant FIGS. 13 and 14 . 13C NMR (75 Hz , MeOH - d .) 8 141. 4 , intermediates and product is shown at FIG . 19A . As shown 140 . 7 , 128 . 72 , 128 .65 , 127 . 8 , 127 .6 , 127 . 4 , 127 . 2 , 122 . 8 , in FIG . 19A , this HPLC method results in baseline resolu 55 . 4 , 49 .6 , 43 .31 , 39 . 9 ppm , shown in FIGS. 15 and 16 . 60 tion of a mixture of ( 1 ) starting material reagent dipheny Specific optical rotation : [ a ]25 ) - 50. 3° ( c 0 .70 , EtOH ). lacetonitrile , ( 2 ) impurity isolevomethadone nitrile , ( 3 ) Elemental analysis : Calc ' d for C , H , N , : C , 81. 97 % ; H , intermediate levomethadone nitrile , and (4 ) product 7 . 97 % ; N , 10 . 06 % . Found : C , 81. 46 % ; H , 8 .01 % ; N , levomethadone . A representative RP -HPLC chromatogram 10 . 00 % . Chiral HPLC revealed the presence of a single of levomethadone hydrochloride is shown in FIG . 22 ; less enantiomer of intermediate ( E ) ( e . e . > 99 % ) under conditions 65 than 100 ppm of diphenylacetonitrile , isolevomethadone shown in Example 4 . A . The optical purity of levomethadone nitrile , and levomethadone nitrile impurities are detected at nitrile was further confirmed by its optical rotation , [ c ] ºSD 210 nm . The RP - HPLC method of example 4B was able to US 10 ,040 ,752 B2 45 46 quantify the regioisomer impurities and starting materials NH _ C1, which was filtered off . The filtrate was concentrated with at least 10 ppm accuracy . and co - evaporated with toluene ( 2x2 mL ) to azeotropically remove the water. The solid crude was dissolved in a Example 4 .C . Reverse -Phase UPLC Method minimum amount of methanol and triturated with acetone . 5 The solid was filtered and dried to give 386 mg of crystalline product levomethadonelevon hydrochloride . An additional 82 mg Analytical Reverse -Phase (RP ) -Ultra High Pressure Liq - was obtained from the acetone filtrate after concentration uid Chromatography (RP - UPLC ) of the final product and and recrystallization . Yield of levomethadone hydrochloride intermediates disclosed herein was performed under the from intermediate E : 94 % . following conditions . RP -HPLC was performed using a For levomethadone hydrochloride: Chiral HPLC : one Waters Acquity BEH Shield RP 18 , 1 . 7 um , 2 . 1x100 . The 10 single enantiomer ( e . e . > 99 % ) , as shown in Example 6 and method was run under UPLC Conditions: 85 % Mobile phase FIG . 21 . Specific optical rotation : [ a ] 25 , - 135 . 4° ( c = 1 . 96 , A ( buffer :organic mixture ) and 15 % Mobile Phase B (50 :50 EtOH ) : m . . ( H . O ) . 240 . 6 - 241. 3° C . IH NMR (300 MHz. Acetonitrile to water mixture ) and at a flow rate of 0 .48 MeOH - d . ) 87. 38 - 7 .54 ( m , 8H ) , 7 .22 - 7 . 45 ( d , J = 7 . 5 Hz , 2H ) , mL /min , at 40° C . , and with monitoring at 220 nm . Prepa 3 . 10 - 3 . 17 ( m , 2H ) , 2 . 87 (s , 3H ) , 2 .84 ( s , 3H ) , 2 . 53 - 2 . 66 ( m , ration of RP UPLC mobile phase A was as follows. 15 1H ) , 2 . 07 - 2 . 20 ( m , 2H ) , 0 .89 ( t. J = 7 .2 Hz, 3H ), 0 .61 ( d . A : Dissolve 6 . 9 g of NaH PO XH2O in 2000 mL ofwater . J = 6 . 9 Hz ) ppm . 13C NMR (75 Hz, MeOH -da ) 8 213 .4 , Add 10 .8 g of Dodecyl Sulfate , Sodium Salt and mix until 140 . 7 , 139 . 9 , 129 .2 , 128 . 91, 128 .90 , 128 . 6 , 127 .84 , 127 .80 , well dissolved . Filter . Adjust the pH to 7 .9 with triethylam - 65 .7 , 60 .6 , 41. 0 , 40 .1 , 37 .4 , 33. 3 , 13 .5 , 8 . 12 ppm . Elemental ine. analysis : Calc ’ d for C21H , CINO : C , 72 .92 % ; H , 8 . 16 % ; N , B : Combine 1460 mL of buffer with 300 mL acetonitrile 20 4 .05 % . Found : C , 72 .95 % ; H , 8 . 06 % ; N , 4 . 13 % . and 240 mL of methanol and mix well. Adjust the apparent pH of mobile phase to a target range of 8 . 8 with 50 % Example 6 . Chiral HPLC Method for levometha aqueous sodium hydroxide or 85 % aqueous phosphoric acid done hydrochloride; ( - )- (R )- 6 -( dimethylamino )- 4 ,4 solution . diphenyl- 3 -heptanone hydrochloride An RP -UPLC chromatogram of a mixture of relevant 25 intermediates and product is shown at FIG . 23 . As shown in Analytical Chiral High Pressure Liquid Chromatography FIG . 23 , this UPLC method results in baseline resolution of (chiral HPLC ) of the levomethadone hydrochloride from a mixture of ( 1 ) benzophenone, ( 2 ) starting material reagent Example 5 was performed under the following conditions . diphenylacetonitrile , ( 3 ) impurity isolevomethadone nitrile , Column : Phenomenex 5 um Cellulose - 4 , 150x4 . 6 mm , ( 4 ) intermediate levomethadone nitrile , and ( 5 ) product 30 part no . 00F -4491 - E0 or a Phenomenex 5 um Cellulose - 4 , levomethadone . A representative RP -UPLC chromatogram 250x4 . 6 mm , part no . 00G - 4491- EO ; Mobile Phase A : of levomethadone hydrochloride is shown in FIG . 24 ; less n - Hexane + 0 . 1 % Diethylamine ; Mobile Phase B : Isopropa than 100 ppm of diphenylacetonitrile , isolevomethadone nol + 0 . 1 % Diethylamine run at a Gradient of 98 : 2 mobileA : nitrile , and levomethadone nitrile impurities are detected at mobile B at Flow : 1 . 5 mL /minute , with a Column Tempera 210 nm . The RP -UPLC method of example 4C was able to 35 ture of 25° C .; and Run Time: > 4 minutes ; with Sample quantify the regioisomer impurities and starting materials Preparation : 20 mg/mL Levomethadone in Ethanol and with at least 100 ppm accuracy . monitored at Wavelength :254 nm or 292 nm . ( - ) - ( R ) - 6 ( Dimethylamino ) - 4 , 4 -diphenyl - 3 -heptanone hydrochloride Example 5 . ( - ) - ( R ) - 6 - ( Dimethylamino ) - 4 , 4 -diphe ( levomethadone hydrochloride ) product of Example 5 was nyl- 3 -heptanone hydrochloride. Synthesis of 40 characterized by chiral HPLC and RP -HPLC , by the meth Levomethadone Hydrochloride from Levometha ods of Examples 6 and 4B , respectively. done Nitrile ( E ) Chiral HPLC of levomethadone HCl product is shown in FIG . 21 , compared to FIG . 20 , showing chiral HPLC of To a stirred solution of levomethadone nitrile ( 400 mg, comparative racemic methadone HC1. Based on initial 1 . 44 mmol) in anhydrous toluene ( 2 mL ) in a 10 mL flask 45 screening , the limit of detection (LOD ) / limit of quantitation equipped with a condenser, ethylmagnesium bromide ( 3 .0M (LOQ ) for dextromethadone impurity by this chiral HPLC in ether , 1 . 0 mL ) was added dropwise under Argon . The method is 10 / 100 ppm (LOD /LOQ ) . The levomethadone reaction mixture was heated to remove the ether solvent hydrochloride produced by the route shown in Examples 1 - 3 through the condenser ( a slow flow of Ar was applied from and 5 comprises not more than 100 ppm , 50 ppm , or 10 ppm top of the condenser to assist the removal of ether ) . After 50 of dextromethadone , as detected by the chiralHPLC method ether was removed , the reaction was heated to 100° C . for 3 .5 hours . The reaction mixture was cooled to ambient The LOD /LOQ for these impurities by the method of temperature and 6M HCl (3 mL ) was carefully added Example 4B was in the 10 ppm range . See FIG . 19A for ( exthothermic , external cooling was necessary when adding RP -HPLC of a mixture of diphenylacetonitrile , levometha HCl). The reaction was then stirred at 50° C . for 20 min 55 done nitrile , isolevomethadone nitrile , and isolevometha before cooling to ambient temperature . The reaction mixture done . The levomethadone hydrochloride produced by the was neutralized with 20 mL 10 % Na , CO , ( rapidly evolves route shown in Examples 1 - 3 and 5 comprises notmore than gas ) and extracted with EtoAc ( 2x15 mL ) . The combined 100 ppm , 50 ppm , or 10 ppm of an impurity selected from organic extracts were washed with brine and dried over diphenylacetonitrile , levomethadone nitrile , isolevometha Na S04. After removal of the solvents , a thick oil ( 470 mg) 60 done nitrile , and isolevomethadone as detected by reverse was obtained phase HPLC method of Example 4B . H NMR analysis indicated total consumption of the nitrile starting material and the crude contains a mixture of Example 7 . Synthesis of N ,N -Dimethyl D - Alaninol levomethadone and the imine intermediate . This crude was ( C ) from D - Alanine ( A ) stirred with 6M HCl solution ( 3 mL ) at 65° C . and concen - 65 trated to about one third of the total volume under reduced In this example , N -dimethyl D - alaninol (C ) is obtained pressure. Acetone ( 3 mL ) was then added to precipitate the from D -alanine ( A ) in a single pot representative of Opera US 10 ,040 , 752 B2 47 48 tional Step 1. 5 - L RBF was charged with 1 . 2 L THF and water ( Karl Fisher ) , 5 mol % MTBE ( 1H -NMR ) ( 4 . 3 wt % ) cooled to 0° C . ZnCl, (166 . 0 g , 1 . 2 mol, 1 . 2 eq ) was added so the dry material was determined to be 95 . 7 % pure ( 100 in portions under stirring . After stirring for 10 min , ZnCl2 g crude corresponds to 95 . 4 g or 0 . 926 mol N , N - dimethyl dissolved to give a slightly cloudy solution . NaBH . (90 .8 g , 2 . 4 mol, 2 . 4 eq ) was added in portions while maintaining the 5 To a solution of the crude alcohol ( 108 . 0 g crude , 1 . 0 mol ) reaction temperature at 0° C . The resulting mixture was in 2 . 0 L anhydrous THF in a 20 L reactor was added heated to 40° C . for 4 h to give a white suspension . The reaction mixture was then cooled to 0° C . and D -alanine para -toluene sulfonyl chloride ( TsC1) (203 . 4 g , 1 .07 mol) ( 89 . 1 g , 1 mol, 1 eq ) was added in one portion . The ice bath portion wise at 0° C . under agitation and the reaction was removed and the reaction mixture warmed to rt and mixture was agitated for 5 min till fully dissolved . Potassium heated to 40° C . , at which temperature rapid hydrogen gas 10 t- butoxide (KOtBu ) ( 125 . 4 g , 1 . 12 mol) was added slowly as evolution started . The reaction mixture was maintained at fine powders at 0° C . A white precipitate started to form 40° C . for 1 h until rapid hydrogen gas evolution ceased . The immediately after KOtBu was introduced . The reaction was reaction mixture was then heated to gentle reflux ( bath slowly warmed to 25° C . and agitated for 1 . 0 h . DMF ( 6 . 0 T = 70° C .) for 5 h . The reaction mixture was cooled to 0° C . L ) was added followed by diphenyacetonitrile ( 155 . 0 g , and carefully quenched by dropwise addition of 0 .5 L MeOH 15 0 . 800 mol) . After the resulting mixture was agitated for 10 at 0° C . The mixture was left to warm to rt and stirred min and cooled to 0° C . , KOtBu ( 108 . 0 g 0 .96 mol) was overnight to give a viscous grey suspension . The reaction added in small portions at 0° C . The reaction mixture was mixture was diluted with water ( 1 L ) . H2PO2 ( 75 mL ) was slowly warmed to rt ( 30 min ), sampled and analyzed by then slowly added and the mixture (pH ~ 4 ) was thoroughly HPLC (49 . 4 % conversion to product ) and then warmed to stirred until a fine white / grey suspension resulted (about 6 20 50° C . and left to run overnight. Samples were taken and h ). The resulting mixture was filtered through a short pad of analyzed by HPLC at 40 min (64 . 7 % conversion to product) Celite covered with a filter paper and the filter cake was and 16 h ( 84 . 2 % conversion to product; levomethadone washed with water ( 200 mLx4 ) . The combined filtrate was nitrile / isolevomethadone nitrile in 76 : 24 ratio ) . concentrated down to about 300 mL in volume on a rotavap . The reaction mixture was cooled to 0° C . and quenched The white solid that precipitated out was again filtered off 25 with 4 . 0 L of 0 . 5 M HCl to attain a pH ~ 2 and then washed and washed with 75 mLx2 water to give about 500 mL final with PhMe ( 1. 5 Lx2 ). The aqueous phase was basified with solution containing the crude D - alaninol. a solution of 48 g NaOH in 0 .6 L water to attain a pH of - 10 The aqueous solution was neutralized with NaOH (40 g ) and extracted with MTBE (2 . 0 LX2 ) . The MTBE extracts at 0° C . Formaldehyde (37 % , 186 mL , 2 .5 eq ) was added at were washed with H2O ( 2 .0 L ) and 30 % brine (0 .6 L ) , dried 0° C . followed by formic acid ( 189 mL, 5 eq ) . The resulting 30 over Na SO . ( 100 g ) , filtered and concentrated to give reaction mixture was stirred at 110° C . for 12 h . The reaction 177 .52 g of the crude product as a white solid . The crude mixture was evaporated to dryness at 55° C . and co - product was triturated overnight with petroleum ether ( 180 evaporated with water (200 mLx2 ) . The residue was sus - mL ) , and the product was obtained as a white solid ( 105 . 05 pended in 125 mL water and treated with NaHSO3 (60 g ). g ) after filtration and drying and analyzed by HPLC ( 97 .4 % After stirring overnight, a sample of the mixture was ana - 35 purity by HPLC ) . HPLC analysis of the crude product after lyzed by ' H NMR . trituration with pet ether showed the ratio of levomethadone The reaction mixture was concentrated down to a volume nitrile / isolevomethadone nitrile to be 97 . 4 : 2 . 6 ) . of about 200 - 300 mL and cooled to 0° C . Cold 50 % NaOH The product ( E ) was further purified by a first recrystal ( 100 mL ) was added at 0° C . to the reaction mixture while lization : 105 . 5 g of product were dissolved in 320 mL of stirring , leading to oiling out of the product . The product was 40 heptane at 80° C . and left to stand at rt overnight. The extracted by thoroughly mixing with MTBE ( 300 mL ) and product was obtained as white solid ( 90 .66 g ) and analyzed decanting into an Erlenmyer flask . The product was further by HPLC (99 .6 % purity ) . HPLC analysis of levomethadone extracted by mixing thoroughly with MTBE ( 200 mLx4 ) nitrile after first recrystallization with heptane showed and decanting into the Erlenmyer flask . The combined levomethadone nitrile purity by HPLC of 99. 6 % , monitored MTBE extracts were dried over Na SO , ( 120 g ) overnight 45 at 210 nm , as shown in FIG . 19B . under stirring . Na , SO , was filtered off , the residue washed The product was further purified by a second recrystalli with MTBE (50 mLx2 ) . The combined filtrates were evapo zation : 90 .66 g of product were dissolved in 270 mL of rated in vacuo to give 101. 0 g of crude product. ' H NMR heptane at 80° C . and left to stand at rt overnight. The revealed the presence of 5 mol % MTBE corresponding to product was obtained as white solid ( 85 .88 g , 38 % yield ) and 96 wt % or 96 . 7 g ( 94 % ) of the crude product . 50 analyzed by HPLC . HPLC analysis of levomethadone nitrile The N , N - dimethyl D - alaninol was analyzed by HPLC , after first recrystallization with heptane showed levometha 1H -NMR and Karl Fisher analysis . ' H -NMR ( 300 MHz, done nitrile purity by HPLC of 100 % ,monitored at 210 nm , MeOH - d ) 8 3 . 62 ( dd , J = 6 . 0 and 11 . 0 Hz , 1H ) , 3 .44 (dd , as shown in FIG . 19C . The product levomethadone nitrile J = 6 . 2 and 11 . 0 Hz, 1H ), 2 .63 ( sext, J = 6 . 4 Hz, 1H ) , 2 .29 ( s , ( E ) was analyzed by proton NMR . ? H -NMR ( 300 MHz , 6H ) , 1 . 04 ( d , J = 6 . 7 Hz, 3H ) ppm . Water content was 55 MeOH - d . ) 8 7 . 27 - 7 .42 ( m , 10H ) , 2 .70 ( dd , J = 6 . 5 and 13 . 7 determined by Karl Fisher method to be 1 . 4 % by mass. Hz, 1H ) , 2 .55 ( sext , J = 6 . 4 Hz , 1H ) , 2 .25 (dd , J = 5 . 8 and 13 . 7 The reaction was repeated three other times providing a Hz , 1H ) , 2 . 15 ( s , 6H ) , 0 .93 ( s , J = 6 . 5 Hz) ppm . total of 400 g of crude product as yellow oil . Combined products were dried under molecular sieves before being Example 9 . Synthesis of Levomethadone used in Unit Operation 2 for the synthesis of levomethadone 60 Hydrochloride from Levomethadone Nitrile ( E ) nitrile . A 2 - L three neck flask equipped with a condenser and an Example 8 . Synthesis of Levomethadone Nitrile ( E ) Ar inlet / outlet was charged with levomethadone nitrile from N ,N -Dimethyl D - Alaninol ( C ) ( 125. 3 g, 0 .450 mol ) and anhydrous toluene (450 mL ) under 65 Ar. The reaction mixture was cooled to 0° C . with an Starting crude alcohol N , N -dimethyl D - alaninol prepared ice -water bath and ethyl magnesium bromide ( 3 .0M in ether, by the method of Example 7 was characterized with 0 . 28 % 300 mL ) was added dropwise through an addition funnel US 10 , 040 , 752 B2 49 50 over 20 min . After the Grignard reagent was added , the was slowly warmed to rt and stirred for 30 min till gas condenser was arranged for distillation . The reaction mix evolution ceased before heated to reflux for 16 h . The ture was slowly heated to 40° C . and then to 60° C . till ether reaction mixture was then cooled to rt and diluted with 200 was all distilled off . The reaction was then heated to reflux mL of water . H2PO2 ( ~ 21 mL ) was added dropwise and the ( bath : 110° C . ) for 3 hours . After being cooled to 0° C . 5 resulting white suspension was stirred at rt for 2 h to cause (ice -water bath ) , the Ar lines were removed and the reaction precipitation of inorganic salts . The resulting mixture (pH system was opened to the air . The reaction was carefully ~ 3 . 4 ) was filtered through a short pad of Celite . The filter quenched by dropwise addition of 15 ml of water followed cake was washed sequentially with water ( 50 mLx2 ) and by 6M HC1 ( 750 mL ) under cooling ( ice -water bath ) . The MeOH (25 mLx2 ) . The combined filtrate (pH 3 . 4 ) was reaction mixture was gradually heated to 70° C . and stirred 10 concentrated to about 150 - 200 mL of total volume. The for 3 h at this temperature to ensure the complete hydrolysis precipitated inorganic salt in the concentrated filtrate was of the imine intermediate as revealed by HPLC . The reaction filtered and washed with a small amount of water. The mixture was cooled to ambient temperature and neutralized combined filtrate ( pH - 2 . 6 ) was saved for use in the next by dropwise addition of a solution of 215 g NaOH in 540 mL step for the synthesis of N , N - dimethyl- L - alaninol. The crude water under cooling ( ice -water bath ) . After warming to 15 L - alaninol was characterized in aqueous solution by ambient temperature , the resulting mixture (pH ~ 10 ) was ' H -NMR at pH 2 .6 . 'H - NMR ( 300 MHz, D20 ) 83. 68 (dd , extracted with MTBE ( 1 . 0 Lx4 ) . The combined organic J = 3 . 7 and 12 . 1 Hz , 1H ) , 3 . 47 ( dd , J = 7 . 1 and 12 . 1 Hz, 1H ) , extracts were washed with water ( 1 L ) and brine ( 1 L ) and 3. 31 - 3. 41 (m , 1H ), 1. 17 (d , J = 6 . 7 Hz , 3H ). dried over Na ,SO . ( 200 g ) . After concentrating under The acidic aqueous solution (pH 2 .6 ) containing the crude reduced pressure to about 250 - 300 mL of total volume ( total 20 L -alaninol was neutralized with NaOH ( 8 . 1 g ) at 0° C . to pH mass ~ 260 g ) , the crude levomethadone free base was 8 .0 . Formaldehyde ( 37 mL , 2 . 5 eq ) was added at 0° C . treated with 6M HCl ( 100 mL ) under cooling ice -water followed by formic acid (38 mL , 5 eq ) . The resulting bath ) . After stirring at rt for 15 min , solvents and volatiles reaction mixture (PH 2 . 5 ) was heated to reflux ( bath T 110° were removed under reduced pressure at 50° C . and then 60° C . ) and the progress of the reaction was monitored by C . Residual water was removed by co - evaporation with 25 H -NMR in D , O . After the dimethylation reaction went to toluene (150 mLx2 ). The resulting reaction crude was completion as judged by H -NMR , the reaction mixture was further co -evaporated with acetone ( 150 mLx2 ) to give the COOcooled to rt and evaporated at 55° C . till about 100 mL of crude product as a free flow solid . total volume and co - evaporated co - evaporated with water Purification : the solid crude was taken up with hot metha - (200 mLx2 ) to - 100 ml in volume. Sat. NaHSO , ( 20 mL ) nol ( 80 mL ) and triturated with acetone ( 240 mL ) at gentle 30 was added to the concentrated reaction mixture and the reflux for 15 min . The resulting mixture was gradually resulting mixture stirred at rt for 3 . 5 h . The solid precipitate cooled to ambient temperature . After stirring overnight, the was filtered and washed with water ( 10 mLx3 ) . The com solid precipitate was filtered , washed with cooled acetone bined clear filtrate (pH ~ 3 . 0 ) was treated with solid NaOH (50 mLx2 ) and dried in a vacuum oven at 65° C . for 8 h to (15 g ) at 0° C . to give a free flow pasty liquid (pH ~ 10 ) give 114 . 8 g of levomethadone hydrochloride as white 35 which was extracted with MTBE (200 mLx4 ) . The aqueous crystalline powders . The mother liquor was concentrated to layer was analyzed by H -NMR which revealed that signifi dryness and triturated with 100 mL acetone under gentle cant amount of the product was still in the aqueous phase . reflux . After cooling to rt and stirring overnight, a second Four more extractions with MTBE ( 200 mL each ) were crop of the product (28 .3 g ) was obtained after filtration and performed . The combined MTBE extracts were dried over washing with cooled acetone ( 20 mlx2 ). Total yield : 143. 1 40 MgSO4 ( 30 g ) and concentrated at 20 - 25° C . under reduced g (92 % ) . The final mother liquor was concentrated and the pressure to give 9 .49 g of crude product as an oil. H NMR residue saved for further purification . Characterization of showed a 1 : 6 . 4 molar ratio between residual MTBE and the levomethadone hydrochloride prepared in Example 9 . Chiral product, corresponding to a 88 % content or 8 . 35 g of HPLC : one single enantiomer ( e . e . > 99 % ) . Specific optical N , N - dimethyl D - alaninol ( 40 . 5 % yield ) . The product N , N rotation : [ a ] 25 - 130° ( c = 5 . 0 % , water ) . 1H -NMR (300 45 dimethyl D - alaninol was characterized by 1H -NMR and MHz, MeOH - d .) 8 7 .38 -7 .49 (m , 8H ) , 7 .23 (d , J = 7 .5 Hz , 13 C -NMR . ' H -NMR (300 MHz, MeOH -da ) 8 3 .62 (dd , 2H ), 3 . 07 - 3 . 16 ( m , 2H ) , 2 . 85 ( s , 6H ) , 2 .53 - 2 .66 ( m , 1H ) , J = 6 . 0 and 11. 0 Hz, 1H ) , 3 .44 (dd , J = 6 . 2 and 11. 0 Hz, 1H ) , 2 .07 - 2 .20 ( m , 2H ) , 0 . 89 ( t , J = 7 . 2 Hz, 3H ) , 0 .60 ( d , J = 6 . 7 Hz , 2 .63 (sext , J = 6 . 4 Hz, 1H ) , 2 . 29 ( s , 6H ) , 1 . 04 ( d , J = 6 . 6 Hz, 3H ) ppm . 13 C - NMR ( 75 MHz , D20 ) 8 216 . 75 , 140 . 20 , 3H ) ppm . 13 C -NMR ( 75 MHz, MeOD ) & 63. 15, 60 .63 , 139. 50 , 129. 23 , 129. 10 , 129. 80 , 129. 11 , 65. 68 , 60 .35 , 40 . 75 , 50 39. 96 , 10 . 18 ppm . 40 .57 , 33. 65 , 13. 63 , 8 .53 ppm . Example 11. Synthesis of Dextromethadone Nitrile Example 10 . Synthesis of N , N - Dimethyl from N , N -Dimethyl L - Alaninol L - Alaninol from L - Alanine 55 Synthesis of dextromethadone nitrile from N , N - Dimethyl A synthetic route for preparation of N , N - Dimethyl L - Al- L - Alaninol was performed by the route shown in FIG . 25B . aninol from L - alanine is shown in FIG . 25A . A 1 L -RBF was To a stirred solution of N , N - dimethyl L - alaninol ( 9 .49 g charged with ZnCl2 (33 g , 240 mmol) and THF ( 240 mL ) crude containing 12 % MTBE , - 80 mmol ) in 100 mL anhy under Ar. After stirring for 10 min , NaBH4 ( 18 . 2 g , 480 drous THF was added para - toluene sulfonyl chloride ( TsC1 ) mmol) was added in portions and the resulting mixture 60 ( 17 . 2 g , 90 mmol) portion wise at 0° C . Potassium t -butoxide stirred at rt for 16 h . After cooling to 0° C . , L - alanine ( 17 . 8 (KOtBu ) ( 10 . 1 g , 90 mmol) was added in portions as fine g , 200 mmol) was added portionwise at 0° C . The reaction powders at 0° C . White precipitate started to form immedi mixture was warmed to rt over 30 min and heated to reflux ately after KOtBu was added . The reaction mixture was (bath T = 70° C .) for 5 h . Formation of grey particles, slowly warmed to rt and stirred for 45 min to give the presumably metallic Zn , was noticed . After cooling to rt , the 65 tosylate crude. DMF (300 mL ) was then added followed by reaction was carefully quenched by dropwise addition of diphenyacetonitrile ( 12 . 6 g , 65 mmol ) . After the resulting 150 mL MeOH at 0° C . over 30 min . The reaction mixture mixture was degassed for 10 min and cooled with ice water US 10 , 040 , 752 B2 51 bath , KOtBu ( 8 . 4 g , 75 mmol) was added in small portions dextomethadone hydrochloride. The solid crude was tritu at 0° C . The reaction mixture was slowly warmed to rt and rated with acetone ( 10 mL ) under gentle reflux for 15 min . then to 50° C . and the reaction mixture was stirred at this The resulting mixture was slowly cooled to rt and the solid temperature for 15 h . After cooled to rt , the reaction mixture precipitate was filtered , washed with acetone (5 mLx2 ) and was poured into 400 mL 0 . 3M HC1 at 0° C . and the resulting 5 dried in a vacuum oven at 65° C . for 4 h to give 3 .83 g of mixture (pH ~ 2 . 2 ) was washed with PhMe ( 200 mLx2 ). The dextomethadone hydrochloride as white crystalline pow aqueous phase was basified with a solution of 5 g NaOH in ders . The mother liquor was concentrated to dryness and 15 ml water and the resulting mixture (pH ~ 10 ) and triturated with 5 mL acetone under gentle reflux . After extracted with MTBE ( 150 mL , then 100 mLx2 ) . The cooling to rt , a second crop of the product ( 0 . 75 g ) was MTBE extracts were washed with water ( 100 mL ) and brine 10 ( 100 mL ) and dried over Na2SO4 (20 g ) . After concentration obtained after filtration and washing with cooled acetone (2 at 55 - 60° C . on under reduced pressure , the semisolid crude mlx2 ) . Total yield : 4 . 58 g ( 88 % ). Enantiomeric purity , e . e ( 12 . 7 g ) was triturated with 30 mL pet ether at reflux . After > 99 % ( Chiral HPLC , one single enantiomer ) . Chiral chro standing overnight at rt , the solid precipitate was filtered and matogram of dextromethadone hydrochloride is shown at washed with pet ether ( 3 mLx2 ) to give 5 . 70 g of crude 155 FIG . 26B . Specific optical rotation : [ a ] d : + 127 .4° ( c = 5 . 0 % , dextromethadone nitrile as an off white solid . The solid H20 , 25° C . ) . The product dextromethadone hydrochloride crude was dissolved in 20 mL heptane at 80 -85° C . After was further characterized by ' H - and 13 C -NMR . H - NMR cooling to rt and stirring overnight, the solid was filtered and (300 MHz, MeOH - d . ) 8 7 . 36 - 7 .49 ( m , 8H ) , 7 .23 ( d , J = 7 . 7 washed with heptane ( 3 mLx2 ) . After drying under vacuum Hz, 2H ) , 3 . 07 - 3 . 16 ( m , 2H ) , 2 . 85 ( s , 6H ) , 2 . 53 - 2 .66 ( m , 1H ) , at 50° C . for 2 h , pure dextromethadone nitrile ( 3 . 5 g , 29 . 6 % 202.07 - 2 . 20 ( m , 2H ) , 0 . 88 (t , J = 7 . 2 Hz, 3H ), 0 .59 ( d , J = 6 . 7 Hz, based on diphenylacetonitrile ) was obtained as white pow 3H ) ppm . "°C - NMR (75 MHz, MeOH -d . ) 8 213 .68 , 140 .67 , ders . HPLC revealed a purity of 99 . 8 % of the final dex - 139 . 82 , 129 . 20 , 128 . 88 , 128 .84 , 128 .56 , 127 . 84 , 127 .80 , tromethadone nitrile product . The dextromethadone nitrile 65 .69 , 60. 60 , 41. 19 , 40 . 22 , 37. 14 , 33 .29 , 13. 29 , 8 .04 . was characterized by ' H -NMR and 13C -NMR . ' H - NMR ( 300 MHz, MeOH - d . ) 8 7 . 31 - 7 . 45 ( m , 10H ) , 2 .70 ( dd , J = 4 .4 25 REFERENCES CITED and 13 .6 Hz, 1H ) , 2 .58 (sext , J = 6 . 2 Hz , 1H ), 2 .41 (dd , J = 7 . 1 and 13 . 8 Hz , 1H ) , 2 .15 ( s , 6H ) , 0 .91 ( s , J = 6 . 5 Hz ) ppm . Amani et al .; Zeitschrift fuer Kristallographie New Crystal 13 C -NMR ( 75 MHz, MeOD ) 8 141. 03 , 140 .56 , 128 .51 , Structures ( 2005 ), 220 ( 4 ) , 549 - 550 ; Crystal structure of 128 .47 , 127 .63 , 127 . 56 , 126 . 90 , 126 .81 , 122 .44 , 55 .77 , 2 , 2 - diphenyl- 4 -dimethylaminopentanenitrile , 49 .62 , 41 .55 , 38 .78 , 13. 11 ppm . 30 C19H22N2 . Ansermot et al. , Arch Intern Med 170 ( 6 ), 529 - 536 , Mar. 22 , Example 12 . Synthesis of Dextromethadone 2010 ; Substitution of ( R , S ) -Methadone by ( R ) -Metha Hydrochloride from Dextromethadone Nitrile done Synthesis of dextromethadone hydrochloride was per - 35 Attenburrow et al ., Journal of the Chemical Society (1949 ) formed by the route illustrated in FIG . 25C . A 100 -mL three 510 - 18 ; Analgesics. II . The synthesis of amidone and neck flask equipped with a condenser , an Ar inlet and an some of its analogs outlet was charged with dextromethadone nitrile ( 4 . 18 g , 15 Barnett et al ., Journal of Organic Chemistry (1976 ), 41( 4 ) , mmol) and anhydrous toluene ( 20 mL ). The reaction mixture 710 - 11 ; Stereochemistry of Bockmuehl' s synthesis of was cooled to 0° C . with an ice water bath and ethyl 40 methadone magnesium bromide (3 . 0 M in ether. 10 mL ) was added Beckett et al. , J Chem Soc , 1957 , 858 - 861; Configurational dropwise via syringe to an addition funnel over 2 min under studies in synthetic analgesics . Synthesis of ( - ) -metha Argon . After the Grignard reagent was added , the condenser done from D ( - ) -alanine . was arranged for distillation . The reaction mixture was Berge , et al. “ Pharmaceutical Salts ,” J . Pharma. Sci. 1977 ; slowly heated to 40° C . and then to 60° C . till ether was all 45 66 : 1 distilled off. The reaction was then heated to reflux (bath : Bhattacharyya , Synth . Commun . 1995 , 25 , 2061- 2069 ; 110° C . ) for 3 h . After being cooled to 0° C . ( ice water bath ), Borohydride reductions in dichloromethane : a conve the Ar lines were removed and the reaction system was nient, environmentally compatable procedure for the opened to the air. The reaction was carefully quenched by methylation of amines . dropwise addition of 1 mL water followed by 6M HC1 ( 25 50 Bracher et al. , Scientia Pharmaceutica (Sci . Pharrn . ) 64 , mL ) under cooling (ice water bath ) . The reaction mixture 271 - 278 ( 1996 ) ; Ein neuer Zugang zu isomerenreinem was then stirred at 75° C . for 3 h to ensure complete ( + ) -Methadon ( A Novel Approach to Isomeric Pure ( + ) hydrolysis of the imine intermediate as revealed by HPLC Methadone ) analysis . The reaction mixture was cooled to ambient tem - Brode and Hill , Journal of the American Chemical Society perature and neutralized by dropwise addition of a solution 55 ( 1947 ) , 69 , 724 ; Rearrangement of the isomeric 1 , 2 of 7 . 4 g NaOH in 20 mL water under cooling . The resulting (dimethylamino ) -chloropropanes . The synthesis of ami mixture ( pH ~ 10 ) was then extracted with MTBE (50 done . mLx3 ) . The combined organic extracts were washed with European Pharmacopoeia 8 . 0 , Levomethadone hydrochlo water ( 100 mL ) and brine ( 100 mL ) and dried over Na , so ride Monograph of 01/ 2008 : 1787 corrected 6 . 5 . pp . 2614 ( 10 g ) . After concentrated under reduced pressure to about 60 2615 . 10 mL of total volume (mass ~ 13 g ) , the crude product was Moryl et al. , Journal of Opioid Management 12 :1 , January / treated with 6 M HCl ( 3 mL ) at under cooling ( ice water February 2016 , 47 -55 ; A phase I study of D -methadone in bath ) and stirred at rt for 15 min . Solvents and volatiles were patients with chronic pain removed under reduced pressure at 50 -60° C . Residual water Paterson et al. , Org Lett 2013 , 15 , 3118 -3121 ; Total synthe was removed by co - evaporation with toluene ( 10 mLx2 ) . 65 sis of Aplyronine C The resulting reaction crude was further co -evaporated with Porter, Pure & Appl Chem 63 ( 8 ): 1119 - 1122 , 1991 , Resolu methanol ( 10 mL ) and acetone ( 10 mL ) to give the crude tion of chiral drugs US 10 , 040 , 752 B2 53 54 Poupaert, Journal of Chemical Research , Synopses ( 1981 ), 6 . The process of claim 5 , wherein the R - activated inter ( 7 ) , 192 , Dibenzo - 18 -crown - 6 as phase transfer catalyst in mediate is selected from the group consisting of (R )- 1 Bockmuehl' s synthesis of methadone chloro -N ,N - dimethylpropan - 2 -amine HCI, (R )- 1 - chloro - N , Schultz et al ., Journal of the American Chemical Society N -dimethylpropan - 2 -amine , ( R ) - 2 - (dimethylamino ) propyl (1948 ), 70 , 48 -52 ; Preparation and rearrangements of 1 ( or 5 4 -methylbenzenesulfonate , and ( R ) - 2 -( dimethylamino ) pro 2 ) - dimethylamino 2 ( or 1 ) - chloropropanes pyl methanesulfonate . Tajbakhsh et al . , Synthesis , 2011 , 490 -496 ; Catalyst- free 7 . The process of claim 5 . wherein the S - activated inter one- pot reductive alkylation of primary and secondary mediate is selected from the group consisting of (S ) - 1 amines and N , N - dimethylation of amino acids using chloro - N , N -dimethylpropan -2 -amine HCI, ( S ) - 1 -chloro - N , sodium borohydride in 2 , 2 , 2 - trifluoroethanol 10 N dimothyluronan 2 amine Weiberth et al ., Journal of Organic Chemistry ( 1987 ) 52 , N - dimethylpropan - 2 - amine , (S ) - 2 - (dimethylamino ) propyl 3901- 3904 , Copper( I) -activated addition of Grignard 4 -methylbenzenesulfonate , and (S ) -2 - ( dimethylamino) pro reagents to nitriles . Synthesis of ketimines , ketones and pyl methanesulfonate . amines . 8 . The process of claim 6 or claim 7 , wherein the U . S . Pat . No. 2 ,497 ,739 15 R -activated intermediate or the S -activated intermediate is U . S . Pat . No . 2 , 540 ,636 isolated and used in the reacting step ; or the R -activated U . S . Pat . No . 2 , 601, 323 intermediate or the S - activated intermediate is used directly U . S . Pat . No . 4 , 048 ,211 in the next reacting step without isolation after the activated U . S . Pat. No . 4 , 242, 274 intermediate is formed . U . S . Pat. No . 6 , 143 , 933 20 9 . The process of claim 6 or claim 7 , wherein the mixing U .S . Publication US2014 /0088155 comprises exposing the R - or S - activated intermediate to a U . S . Publication US2014 /0350302 base and diphenylacetonitrile in a solvent to form the WO 2012 /162635 levomethadone nitrile or dextromethadone nitrile, respec SK 287446 B6 tively . We claim : 25 10 . The process of claim 9 , wherein the levomethadone 1 . A process for preparing levomethadone hydrochloride nitrile or dextromethadone nitrile is formed in > 99 % from D - alanine or dextromethadone hydrochloride from enantiomeric excess ( e . e . ) . L - alanine , the process comprising : 11. The process of claim 9 , wherein the base is selected reducing the D -alanine to form D -alaninol or reducing the from the group consisting of sodium hydroxide , potassium L - alanine to form L - alaninol; and 30 hydroxide , potassium t - butoxide , sodium t - butoxide , sodium converting the D - alaninol to form the N , N -dimethyl - D - methoxide , potassium methoxide , sodium ethoxide , potas alaninol or converting the L - alaninol to N , N - dimethyl sium ethoxide , sodium tert -pentoxide , potassium tert -pen L -alaninol ; toxide sodium isopropoxide , and potassium isopropoxide . combining the N , N -dimethyl - D -alaninol or the N , N -dim - 12 . The process according to claim 11, wherein the base ethyl - L - alaninol with an activating reagent to form a 35 is potassium t - butoxide . R -activated intermediate or an S - activated intermedi- 13 . The process of claim 9 , wherein the solvent is selected ate , respectively ; from the group consisting of dimethylformamide, dimethy mixing the R - or S -activated intermediate and a base with lacetamide, tetrahydrofuran , dimethyl sulfoxide, N -methyl diphenylacetonitrile to provide levomethadone nitrile 2 -pyrrolidone , dioxane , and water, or a combination thereof. or dextromethadone nitrile , respectively ; and 40 14 . The process of claim 1 , wherein the exposing com exposing the levomethadone nitrile or dextromethadone prises nitrile to a Grignard reagent of formula RMgX , where adding the Grignard reagent having formula RMgX , Ris ethyl and X = C1, Br, or I , to form a reaction where R is ethyl and X = Br, to a stirred solution of mixture; and levomethadone nitrile or dextromethadone nitrile in an adding hydrochloric acid to the reaction mixture to pro - 45 anhydrous solvent to form the reaction mixture ; vide levomethadone hydrochloride or dextrometha heating the reaction mixture to a temperature above done hydrochloride, respectively . ambient temperature ; 2 . The process for preparing levomethadone hydrochlo cooling the reaction mixture ; ride according to claim 1 , wherein the converting step adding hydrochloric acid to the reaction mixture ; and comprises: 50 isolating the levomethadone hydrochloride or the dex reducing the D - alanine to form D - alaninol; and tromethadone hydrochloride from the reaction mixture, converting the D -alaninol to form the N , N -dimethyl - D respectively . alaninol. 15 . The process of claim 1 , wherein the levomethadone 3 . The process of claim 1 or claim 2 , wherein the reducing hydrochloride or the dextromethadone hydrochloride is pro comprises exposing the D - alanine or L -alanine to one or 55 duced in > 99 % enantiomeric excess ( e . e . ) . more reducing agents selected from the group consisting of 16 . The process of claim 1 , wherein the levomethadone LiAlH4, BHZ/ THF , BHz/ Et O , BHZ/ BF3 Et20 , BHZ/ Me S , hydrochloride comprises not more than 0 .05 % (500 ppm ), NaBH _/ 12 , BH4/ cyanuric chloride, NaBH2CN /ZnCl2 , 0 .025 % (250 ppm ), or 0 .01 % (100 ppm ) of an impurity NaBH _ / ZnCl2 , Zn ( BH4) 2 , and NaBH _ /BF3 .Et20 . selected from the group consisting of dextromethadone 4 . The process of claim 3 , wherein the reducing agent is 60 hydrochloride , dextromethadone , isodextromethadone , iso LiAlH4 or Zn (BH4 ) 2 dextromethadone hydrochloride , isolevomethadone , 5 . The process of claim 1 , wherein the activating reagent isolevomethadone hydrochloride , levomethadone nitrile , is selected from the group consisting of thionyl chloride , dextromethadone nitrile , isolevomethadone nitrile , isodex methanesulfonyl chloride , p - toluenesulfonyl chloride, trif tromethadone nitrile , diphenylacetonitrile , 2 ( S ) - 2 - [ [ ( 4 luoromethanesulfonyl chloride, methanesulfonic anhydride, 65 methylphenyl) sulphonyl ] amino ] pentanedioic acid ( N - tosyl trifluoromethanesulfonic anhydride , and p - toluenesulfonic L - glutamic acid ), a tartaric acid , and a bromocamphor anhydride . sulfonic acid . US 10 ,040 ,752 B2 55 56 17 . The process of claim 1, wherein the dextromethadone 19 . The process of claim 1, wherein the dextromethadone hydrochloride comprises not more than 0 .05 % ( 500 ppm ), hydrochloride comprises not more than 100 ppm of an 0 .025 % (250 ppm ), or 0 .01 % ( 100 ppm ) of an impurity impurity selected from the group consisting of levometha selected from the group consisting of levomethadone hydro done , diphenylacetonitrile , dextromethadone nitrile , isodex metha . 5 tromethadone nitrile , and isodextromethadone . chloride, levomethadone, isolevomethadone, isolevometha - 5 1 20 . The process of claim 14 , wherein the heating to above done hydrochloride, isodextromethadone, isodextrometha ambient temperature is heating the reaction mixture at a done hydrochloride, dextromethadone nitrile , temperature up to the reflux temperature of the anhydrous levomethadone nitrile , isodextromethadone nitrile , solvent. isolevomethadone nitrile , diphenylacetonitrile , 2 ( R ) - 2 - [ [ ( 4 - 21. The process of claim 14 , wherein the cooling com methylphenyl) sulphonyl ] amino ]pentanedioic acid ( N - tosyl- prises cooling to a temperature at or below ambient tem L - glutamic acid ), a tartaric acid , and a bromocamphor perature . sulfonic acid . 22 . The process of claim 14 , further comprising adding 18 . The process of claim 1, wherein the levomethadone water or aqueous hydrochloric acid to quench the reaction hydrochloride comprises not more than 100 ppm of an 15 after. cooling the reaction mixture , wherein impurity selected from the group consisting of dextrometha the adding water or hydrochloric acid is performed at a done, diphenylacetonitrile , levomethadone nitrile , temperature not to exceed 50° C . isolevomethadone nitrile , and isolevomethadone. * * * *