USOO8168828B2

(12) United States Patent (10) Patent No.: US 8,168,828 B2 Satyanarayana Reddy et al. (45) Date of Patent: May 1, 2012

(54) PROCESS FOR THE PREPARATION OF PCT Written Opinion of the International Searching Authority, PCT/ PREGABALN IN2008/000174, 3 pp., Date of Mailing: Oct. 11, 2010. Armstrong, A., et al., “Diastereoselective Conjugate Addition of Cyanide to C.B-Unsaturated Oxazolidinoncs: Enantioselective Syn (75) Inventors: Manne Satyanarayana Reddy, thesis of ent-Pregabalin and Baclofen.” SYNLETT, No. 10, pp. 1589 Hyderabad (IN); Srinivasan Thirumalai 1591 (Received Mar. 9, 2006). Rajan, Hyderabad (IN); Sajja “Pregabalin.” Drugs of the Future, 24(8): 8620870, (1999) (no Eswaraiah, Hyderabad (IN); Revu month). Satyanarayana, East Godavari (IN) Mita, T., et al., “Catalytic Enantioselective Conjugate Addition of Cyanide to C.B-Unsaturated N-Acylpyrroles,” J. A.M. Chem. Soc., 127, 514-515 (2005) (no month). (73) Assignee: MSN Laboratories, Limited, Andhra Concellón, J. M. and Concellón, C., “Aldol-type Reactions of Pradesh Hyderabad (IN) Unmasked Iodoacetic Acid with Carbonyl Compounds Promoted by Samarium Diiodidc: Efficient Synthesis of Carboxylic (*) Notice: Subject to any disclaimer, the term of this 3-Hydroxyacids and Their Derivatives.” J. Org. Chem., 71, No. 12, patent is extended or adjusted under 35 4428-4432 (2006) (no month). U.S.C. 154(b) by 0 days. Andruszkiewicz, R., and Silverman, R.B., “A Convenient Synthesis of 3-Alkyl-4-Aminobutanoic Acids.” Communications, pp. 953 (21) Appl. No.: 12/666,133 955(1989). Sammis, G.M. and Jacobsen, E.N., "Highly Enantioseleetive, Cata (22) PCT Filed: Mar. 24, 2008 lytic Conjugate Addition of Cyanide to O.f3-Unsaturated Imides. J. Am. Chem. Soc., 125:4442-4443 (2003). (86). PCT No.: PCT/N2008/000174 Yamamoto, K., et al., “Stereoselective Synthesis of (E)- Alkylideneseuccinates by Palladium-catalyzed Carbonylation.” The S371 (c)(1), Chemical Society of Japan, 58:3397-3398(1985). (2), (4) Date: Dec. 22, 2009 * cited by examiner (87) PCT Pub. No.: WO2009/001372 Primary Examiner — Joseph Kosack PCT Pub. Date: Dec. 31, 2008 Assistant Examiner — Matthew Coughlin (74) Attorney, Agent, or Firm — Hamilton, Brook, Smith & (65) Prior Publication Data Reynolds, P.C. US 2010/O179345 A1 Jul. 15, 2010 (57) ABSTRACT (30) Foreign Application Priority Data The present invention encompasses novel intermediates of pregabalin, namely 3-cyano-5-methylhexanamide (28) and Jun. 25, 2007 (IN) ...... 1344/CHFA2007 3-(amino methyl)-5 methylhexanamide (29), and processes Jan. 14, 2008 (IN) ...... 114f CHEA2008 for their preparation. The invention also encompasses a pro cess for converting the novel pregabalin intermediates into (51) Int. Cl. pregabalin, Formula (I): The present invention further pro C07C 237/06 (2006.01) vides a cost effective method for the synthesis of (S)-pregaba C07C 227/30 (2006.01) lin, which involves the recovery of mandelic acid and tartaric C07C 229/12 (2006.01) acid used in the resolution process and recycling them, (52) U.S. Cl...... 564/197; 562/553 increasing the yields of the final product formed, which sub (58) Field of Classification Search ...... 564/197 See application file for complete search history. stantially reduced the cost of the production.

(56) References Cited 28 U.S. PATENT DOCUMENTS 5,599,973 A 2f1997 Silverman et al. lulu NRR 5,637,767 A 6, 1997 Grote et al. 2003/0212290 A1 11, 2003 Burk et al. 29 2007/0197827 A1* 8, 2007 Kansal et al...... 564f1 NH2 O FOREIGN PATENT DOCUMENTS CZ. 297970 B6 5/2007 NRR EP O254685 A2 1, 1988 NH 1. 2 O OTHER PUBLICATIONS CAS Registry No. 766508-49-0, entered STN on Oct. 21, 2004.* Hong-Ju et al. Bioorg. Med. Chem. Lett. 2004, 14, 2537-2541.* lulu, OH English Translation of CZ 297970, translated Mar. 2011.* (S)-PREGABALIN International Search Report, PCT/IN2008/000174, 4 pp., Date of Mailing: Oct. 11, 2010. PCT International Preliminary Reporton Patentability, PCT/IN2008/ 000174, 1 pg., Date of Issuance of Report: Oct. 19, 2010. 19 Claims, 1 Drawing Sheet U.S. Patent May 1, 2012 US 8,168,828 B2

9.

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s 8 v: v3 vs& was8 3vs was vr8 & 3 & 3 : 3 & 8 s a (Sunoo) ul US 8,168,828 B2 1. 2 PROCESS FOR THE PREPARATION OF GAD (L-glutamic acid decarboxylase). (S)-pregabalin has a PREGABALN dose dependent protective effect on-seizure, and is a CNS active compound. (S)-pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the produc RELATED APPLICATIONS tion of GABA, one Of the brain's major inhibitory neu rotransmitters, which is released at 30 percent of the brains This application is the U.S. National Stage of International synapses. (S)-pregabalin has analgesic, anticonvulsant, and Application No. PCT/IN2008/000174, filed Mar. 24, 2008, anxiolytic activity. (S)-pregabalin is marketed under the trade which designates the U.S., published in English, and claims name LYRICAR). priority under 35 U.S.C. SS 119 or 365(c) to Indian provi 10 sional application no. 1344/CHF/2007, filed Jun. 25, 2007 and Indian patent application No.: 114/CHF/2008, filed on BACKGROUND OF THE INVENTION Jan. 14, 2008. The entire teachings of the above applications are incorporated herein by reference. Several processes were reported for the synthesis of (S)- 15 Pregabalin. One such process is illustrated in drugs of the future, 24 (8), 862-870 (1999), represented as scheme-1. In FIELD OF THE INVENTION which 3-isobutylglutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with The present invention encompasses novel intermediates of refluxing acetic anhydride. The reaction of the anhydride with pregabalin, namely 3-cyano-5-methylhexanamide of general NH-OH produces the glutaric acid mono-amide, compound formula-28 and 3-(aminomethyl)-5 methyl hexanamide of 4, which is resolved with (R)-1-phenylethylamine, yielding general formula-29, and processes for their synthesis. The the (R)-phenyl ethylamine salt of (R)-3-(carbamoylmethyl)- invention also encompasses a process for converting the novel 5-methylhexanoic acid, compound 5. Combining the salt pregabalin intermediates into pregabalin. 25 with an acid liberates the (R)-enantiomer, compound 6. It also encompasses a cost effective and economically use Finally, a Hoffmann's degradation with Br/NaOH provides ful method for the preparation of (S)-pregabalin. (S)-Pre (S)-Pregabalin. A disadvantage of this method is that, it gabalin is chemically known as (S)-(+)-3-(amino methyl)-5- requires separating the two enantiomer thereby resulting in methylhexanoic acid represented as a compound of formula the loss of half of the product, such that the process cost is 1. high.

Scheme-1: O OH O O O O O Ac2O 1)NH3(aq). MTBE HO Her -- O reflux 2) HCI

O CH3 CH3 NH2 CH3

CH3 CH3 CH3 2 3 4 (R)-(+)- phenylethylamine O GE O OH O O H3N

1) NaOH, Br. O O HN a i 2) HCI St. NH2 CH CH CH Pregabalin (R)-6 5

A few stereo selective processes for the synthesis of (S)- Formula-1 Pregabalin have been disclosed. For example, U.S. Pat. No. 1. NH, 5.599.973 discloses the preparation of (S)-Pregabalin using s Stoichiometric (+)-4-methyl-5-phenyl-2-oxazolidinone as a r chiral auxiliary that may be recycled. In general, however, OH that route is of limited use for scale-up, principally due to the 65 low temperature required for the reactions, the use of pyro Pregabalin is also known as Y-aminobutyric acid or (S)-3- phoric reagent such as butyl lithium, and due to side reactions, isobutyl GABA. (S)-pregabalin has been found to activate which resulted in a low overall yield. US 8,168,828 B2 3 4 Another process is disclosed in U.S. Patent Application In 1989, Silverman reported a convenient synthesis of Publication No. 2003/0212290, which discloses asymmetric 3-alkyl-4-amino acids compounds in Synthesis, Vol. 12, hydrogenation of a cyano-Substituted olefin, compound 7, to 953-954 (1989). Using 2-alkenoic esters as a substrate, a produce a cyano precursor of (S)-3-(amino methyl)-5-methyl series of GABA analogs were produced by Michael addition hexanoic acid, compound 8, as seen in Scheme 2. of nitro methane to C.B-unsaturated compounds, followed by hydrogenation at atmospheric pressure of the nitro compound to amine moiety as depicted in Scheme 4. Scheme-2: CN RR)- N (R,R) 10 Scheme-4: MeDuPHOSRh(COD)" BF4 COR N-" -- O 15 12 OEt He

YcoR O ON 13 Subsequent reduction of the nitrile with compound 8 by OR catalytic hydrogenation produces (S)-Pregabalin. The cyano hexenoate starting material, compound 7, is prepared from O HN 2-methyl propanal and acrylonitrile (Yamamoto et al. Bull. 25 Chem. Soc. Jap., 58,3397 (1985)). However, the disclosed 14 method requires carbon monoxide under high pressure, rais ing serious problems in adapting this scheme for production scale processes. Further resolution of compound 14 may be employed to A process published by G. M. Sammis, et al., J. Am. Chem. 30 resolve Pregabalin. This, of course, results in the loss of 50 Soc., 125(15), 4442-43 (2003), takes advantage of the asym percent of the product, a serious disadvantage. However, the metric catalysis of cyanide conjugate addition reactions. The disclosed methodology reveals that the nitro compound can method discloses the application of aluminium salencatalysts serve as an intermediate for the synthesis of 3-alkyl-4-amino to the conjugate addition of hydrogen cyanide to C.B-unsat acids. urated imides as shown in scheme-3. Reportedly, TMSCN is 35 Due to the activity of GABA as an inhibitory neurotrans a useful source of cyanide that can be used in the place of mitter, and its effect on convulsive states and other motor HCN. Although the reaction is highly selective, this process is dysfunction, development of a drug which can stimulate the not practicable for large scale production due to the use of release of GABA has become important. Pregabalin a GAD highly poisonous reagents. Moreover, the last reductive step activator has the ability to stimulate the release of GABA and requires high pressure hydrogen, which only adds to the 40 to Suppress seizures while avoiding the undesirable side difficulties required for adapting this scheme for a production effect of ataxia. It has been discovered that anticonvulsant scale process. effect of isobutyl-GABA is stereoselective. That is, S-isomer of Pregabalin shows better anticonvulsant activity than the R-stereoisomer. Thus, it would be beneficial to have an effi Scheme-3: 45 cient process for the synthesis of the (S)-isomer of pregabalin. O O The consumption of pregabalin has increased in high Vol us --- --TMSCN, iPrCH, Cat umes and all the reported processes provide very poor yields Ph N H of (S)-pregabalin. Hence there is a need to develop a method 50 of preparation of pregabalin, which provides high yields, is 9 cost effective and commercially viable, and which can be O O CN adapted to an industrial scale. --- Ph N H BRIEF DESCRIPTION OF THE INVENTION 55 10 O CN 5% mol PtO, The present invention relates to a process for the prepara 500 psi H2 He tion of novel intermediate compounds namely 3-cyano-5- HO methyl hexanamide, hereafter designated as compound of 10 60 general formula-28 and 3-(amino methyl)-5 methylhexana HN mide, hereafter designated as compound of general formula O 29, which are the key intermediates in the novel route for the synthesis of pregabalin. HO The first aspect of the present invention deals with a pro Pregabalin 65 cess for the preparation of novel intermediate of general for mula-28, which is useful for the synthesis of pregabalin. The process comprises of US 8,168,828 B2 5 6 a) condensation of aldehyde compound of formula-15. a) Hydrolyzing the diester compound of formula-21,

Formula-15 Formula-21 ---, N COOEt COOEt

with an O-halo ester compound of formula-16, 10 in presence of a suitable alkali metal or alkaline earth metal base in a suitable solvent gives the carboxylic acid Formula-16 compound of formula-22,

15 susOR 3 Formula-22

in the presence of Zinc metal and a suitable catalyst, in a --- or suitable polar solvent provides B-hydroxy ester com pound of formula-17, b) reacting the carboxylic acid compound of formula-22 with a suitable amine (NHRR), in presence of a suit able organic solvent gives an amino amide compound of Formula-17 general formula-23, 25 lulu OR3

Formula-23 b) hydrolysis of the B-hydroxy ester compound of formula O 17, with an alkali or alkaline metal base, in a protic 30 solvent provides a f-hydroxy acid compound of for mula-18, > -s.

35 c) reacting the amide compound of general formula-23 Formula-18 with a suitable cyanide source in presence of a phase transfer catalyst in a Suitable solvent gives cyanide com pound of general formula-28, lulu OH 40 c) reacting the 3-hydroxy acid compound of formula-18, with an halogenating agent in an aprotic solvent, fol lowed by Subsequent reaction with a secondary amine Formula-28 NHRR of formula-19, provides a B-halo amide com pound of formula-20, 45 lulu NRR

Formula-20

50 --- NRR The second aspect of the present invention relates to the preparation of novel intermediate of general formula-29, use ful in the synthesis of pregabalin. The process for the synthe d) treating the B-halo amide compound of formula-20, with sis of the novel intermediate comprises of: an cyanide source in an polar aprotic solvent, provides 55 a) Reaction of 3-isobutylglutaric acid anhydride com the novel intermediate the 3-cyano amide, compound of pound of formula-3, formula-28,

Formula-3 Formula-28 60

lulu NRR

65 An alternate process for the preparation of novel interme diate of general formula-28, comprises of the following steps, US 8,168,828 B2 7 8 b) with a secondary amine NHRR of general formula-19, straight chain or branched hydrocarbon groups, generally in a Suitable solvent, provides a compound of general having specified number of carbon atoms. A “C. alkyl formula-26, refers to alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl. n-butyl, sec-butyl, iso-butyl, t-butyl, Formula-26 pent-1-yl, pent-2-yl, pent-3-yl 3-methylbut-1-yl, 3-methyl but-2-yl, 2-methylbut-2-yl, 2.2.2-trimethyleth-1-yl, n-hexyl and the like. HO O As used herein, the term “cycloalkyl refers to saturated 10 monocyclic and bicyclic hydrocarbon rings, generally having NRR a specified number of carbonatoms that comprise the ring i.e. C-7 cycloalkyl refers to a cycloalkyl group having 3,4,5,6 and 7 carbon atoms as ring members. Examples of monocy 15 clic groups include, without limitation, cyclopropyl, cyclobu c) reaction of compound of general formula-26, with thio tyl, cyclopentyl, cyclohexyl, and the like. Examples of bicy clic cycloalkyl groups include without limitation, bicyclo nyl chloride followed by ammonia provides the diamide 1.1.0 butyl, bicyclo 1.1.1 pentyl, bicyclo[2.1.0 pentyl, compound of general formula-27. bicyclo[2.1.1 hexyl, bicyclo[2.2.0 hexyl, bicyclo3.1.0 hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.0]heptyl and the Formula-27 like. As used herein, the term “aryl-C alkyl refers to an aryl group attached to the Substrate through an alkyl group con HN O taining one to six carbon atoms. The term “aryl refers to 25 monovalent or divalent aromatic groups respectively includ ing 5 and 6 membered monocyclic aromatic groups that con NRR tain zero to four heteroatom independently selected from nitrogen, oxygen and Sulfur. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl pyranyl. 30 furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triaz d) subjecting the compound of formula-27 to Hoffman's olyl, tetrazolyl pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, degradation provides the compound of general formula pyrazinyl, pyradazinyl, pyrimidinyl, and the like. The aryl 29, groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above. 35 Examples of multicyclic aryl groups include, without limita Formula-29 tion, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, NH2 benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimi dazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, indolizinyl and the like. The aryl --- NRR 40 groups may be attached to the Substrate at any ring atom, unless such attachment would violate Valence requirements. The third aspect of the present invention encompasses the Aryl groups may include one or more nonhydrogen Substitu novel process for the preparation of (S)-pregabalin involving ents unless such substitution would violate Valence require the novel intermediates, 3-cyano-5-methylhexanamide com ments. Useful substituents include, without limitation alkyl, pounds of general formula-28 and 3-(amino methyl)-5-me 45 alkenyl, alkynyl, haloalkyl, alkoxy, halo, hydroxy, mercapto, thylhexanamide, compounds of general formula-29. nitro, amino, alkyl amino and the like. The fourth aspect of the present invention relates to an The first aspect of the present invention deals with a pro improved cost effective and economically useful method for cess for the preparation of novel intermediate of general for the preparation of (S)-pregabalin. mula-28, which is useful for the synthesis of pregabalin. The Advantages of the Present Invention: 50 process comprises of Provides a novel process for the preparation of (S)-pre a) condensation of aldehyde compound of formula-15. gabalin with high yields and high purity. Provides novel intermediate compounds of formulae 23, 28, 29, 30 and 31. Formula-15 Provides a novel process for the preparation of intermedi 55 ate compound of formula-29. Eco-friendly and cost effective process. ---, BRIEF DESCRIPTION OF THE DRAWINGS with an O-halo ester compound of formula-16, 60 FIG. 1: Illustrates the powder X-ray diffraction pattern of crystalline Pregabalin. Formula-16 DETAILED DESCRIPTION OF THE INVENTION 65 susOR Unless otherwise indicated, this disclosure uses definitions provided below. As used herein, the term “alkyl refers to US 8,168,828 B2 9 10 wherein R is a C- alkyl, C-7 cycloalkyl, or aryl-C hydroxide, potassium hydroxide and the like; carbonates of alkyl, alkali metals such as sodium carbonate, potassium carbonate and X is a halogen, and the like and bicarbonates of alkali metals such as sodium in the presence of Zinc metal and a suitable catalyst, in a bicarbonate, potassium bicarbonate and the like, preferably suitable polar solvent provides (3-hydroxy ester com potassium hydroxide. Suitable solvents that can be used in the pound of formula-17, hydrolysis include but are not limited to alcoholic solvents Such as methanol, , isopropanol preferably methanol and the like; water and their mixtures. Formula-17 Step (c) involves the reaction of B-hydroxy acid compound 10 with a halogenating agent to provide a B-halo acid chloride derivative which on Subsequent reaction with a secondary lulu OR3 amine (NHRR) provides a B-halo amide derivative. The halogen in B-position may be a chlorine or . The Suitable halogenating agent that can be used in the reaction wherein R is as defined above, 15 but not limited to, are thionyl chloride (SOCl), b) hydrolysis of the (3-hydroxy ester compound of for trichloride (PCl), (PCls), phos mula-17, with an alkali or alkaline metal base, in a protic phorus oxychloride (POCl), (PBr), Solvent provides a 3-hydroxy acid compound of for phosphorus pentabromide (PBrs) and the like, preferably mula-18, thionyl chloride in an aprotic solvent. Solvents that can be used in the reaction include, without limitation, aromatic hydrocarbon solvents like toluene, Xylene, or halogenated Formula-18 Solvents such as dichloromethane, chloroform, ethylene dichloride and the like, preferably toluene. In the Subsequent step (d) the chloro group is Substituted by lulu OH 25 cyano group by reacting it with a cyanide source Such as but not limited to; hydrogen cyanide, acetone cyanohydrin, an c) reacting the 3-hydroxy acid compound of formula-18, alkali metal cyanide like Sodium cyanide, potassium cyanide with an halogenating agent in an aprotic solvent, fol or an alkaline earth metal cyanide like magnesium cyanide lowed by Subsequent reaction with an secondary amine and the like, preferably sodium cyanide, in a polar aprotic NHRR of formula-19, provides a B-halo amide com 30 solvent dimethylsulfoxide, dimethyl foramide, ethyl acetate, pound of formula-20, tetrahydrofuran, etc and their mixtures thereof preferably a mixture of dimethyl sulfoxide and ethyl acetate. An alternate process for the preparation of novel interme Formula-20 diate of general formula-28, comprises of the following steps, 35 a) Hydrolyzing the diester compound of formula-21, lulu. NRR Formula-21 wherein R and R are same or different and are each independently selected from either hydrogen, C. 40 N COOEt alkyl, C-7 cycloalkyl, aryl-C alkyl, aryl or chiral aux iliaries (S/R) like 4-phenyl-2-oxazolidone, N-octyl glu COOEt camine, 1-phenyl ethylamine and the like. d) treating the B-halo amide compound of formula-20, with 45 in presence of a suitable alkali metal or alkaline earth an cyanide source in an polar aprotic solvent, provides metal base in a suitable solvent gives the carboxylic acid the novel intermediate the 3-cyano amide, compound of compound of formula-22, formula-28,

Formula-22 50 Formula-28 --- or lulu NRR 55 b) reacting the carboxylic acid compound of formula-22 wherein R and R are as defined above. with a suitable amine (NHRR), in presence of a suit Step (a) involves the condensation of aldehyde compound able organic solvent gives an amide compound of gen with the C-halo ester in presence of Zinc metal, using a eral formula-23, catalyst preferably methane Sulfonic acid in a polar solvent like tetrahydrofuran, dimethyl acetamide, dimethylsulfoxide 60 Formula-23 and the like preferably tetrahydrofuran. The halogen of the O C.-halo ester may be chlorine or bromine, preferably bromine. Step (b) involves the hydrolysis of the (B-hydroxy ester derivative to the corresponding acid with a suitable base in a > -ss. suitable solvent. Suitable inorganic bases that can be used in 65 the reaction include but are not limited to hydroxides of alkali wherein R and R2 are same or different and are each and alkaline earth metals such as lithium hydroxide, sodium independently selected from either hydrogen, C. US 8,168,828 B2 11 12 alkyl, C-7 cycloalkyl, aryl-C alkyl, aryl or chiral aux presence of thionyl chloride in a suitable aprotic solvent like iliaries (S/R) like 4-phenyl-2-oxazolidone, N-octyl glu cyclohexane, dichloromethane, trichloromethane, 1,2-di camine, 1-phenyl ethylamine and the like, choloroethane, toluene, Xylene, tetrahydrofuran, 2-meth c) reacting the amide compound of general formula-23 yltetrahydrofuran, and the like; preferably toluene. with a suitable cyanide source in presence of a phase The cyanide Source which is used in step c) is selected from transfer catalyst in a Suitable solvent gives cyanide com the group consisting of but not limited to hydrogen cyanide, pound of general formula-28, acetone cyanohydrin, an alkali metal cyanide like sodium cyanide, potassium cyanide oran alkaline earth metal cyanide like magnesium cyanide; trimethylsilyl cyanide and the like; Formula-28 10 preferably potassium cyanide. The reaction is carried out in the presencefor absence of a phase transfer catalyst which is selected from the group con lulu NRR sisting of but not limited to tetra butyl ammonium , 15 tetra propyl ammonium bromide, tributylbenzyl ammonium wherein R and R are as defined above. bromide, tetra octyl ammonium bromide, tetrabutyl ammo In step a) the suitable alkali metal or alkaline earth metal nium iodide, tetrabutyl ammonium hydrogen Sulfate, benzyl base used for hydrolysis is selected from hydroxides like trimethyl ammonium chloride, benzyl triethyl ammonium Sodium hydroxide, potassium hydroxide, lithium hydroxide, chloride, tetra butyl ammonium acetate, tetra butyl ammo cesium hydroxide, magnesium hydroxide, calcium hydrox nium iodide, ethyl triphenyl phosphonium bromide, more ide and the like; carbonates of alkali and/or alkaline earth preferably tetra butyl ammonium bromide or alkali iodides metals such as Sodium carbonate, potassium carbonate and like sodium iodide, potassium iodide and lithium iodide. The the like and bicarbonates of alkali and/or alkaline earth metals polar protic solvent used is selected from methanol, ethanol, Such as sodium bicarbonate, potassium bicarbonate and the n-propanol, isopropanol, n-butanol, and isobutanol; or water, like, preferably potassium hydroxide in a suitable alcoholic 25 or a mixture of water and alcohols; or it can be performed in Solvent like methanol, ethanol, isopropanol, n-propanol, presence of a polar aprotic solvent like dimethylsulfoxide or n-butanol, isobutanol, preferably methanol. a mixture of dimethylsulfoxide and water or acetate. In the step b) the condensation of the amine with the car The present aspect of the invention is represented in Scheme boxylic acid compound of formula-22 is carried out in the 5.

Scheme-5 O O OH O

t -- Her N COOE lul H X susOR catalystZn, lulu, OR

COOEt 21 15 16 17 |tion poli X OH O

HXu-Y --- on lulu, OH N COOH 24 Amidation 18 Amidation O 22 1. halogenation, N NRR aprotic solvent HX 2. NHRR, Cyanation 23 base N 19 onto CN X O

--- COOH Amidation CN O --CN ---- NRR 22 S. NRR aproticpolar 2O solvent 28 28a) R1 = ethyl, R2 = ethyl 28b) R = H, R2 = 1-phenyl ethyl Wherein in RandR2 are same or different and are each independently selected from either hydrogen, C1-12 alkyl, C3-7 cycloalkyl, aryl-C1-6 alkyl, aryl or chiral auxillaries (SR) like 4-phenyl-2-oxazolidone, N-octylglucamine, 1-phenyl ethylamine and the like; R3 is a C-12 alkyl, C-7 cycloalkyl, or aryl-C1-6 alkyl, and X is a halogen, US 8,168,828 B2 13 14 The second aspect of the present invention relates to the b) reaction of compound of general formula-26, with thio preparation of novel intermediate of general formula-29, use nyl chloride followed by ammonia provides the diamide ful in the synthesis of pregabalin. The process for the synthe compound of general formula-27. sis of the novel intermediate comprises of a) Reaction of 3-isobutylglutaric acid anhydride com Formula-27 pound of formula-3,

HN Formula-3 10 NRR

15 c) subjecting the compound of formula-27 to Hoffman's degradation provides the compound of general formula with a secondary amine NHRR of general formula-19, 29, in a Suitable solvent, provides a compound of general formula-26,

Formula-29 NH2 25

Formula-26 NRR

HO 30 In the step a) of the above process the suitable solvent that NRR can be used include, without limitation, aromatic hydrocar bon Solvents like toluene, Xylene, or halogenated solvents such as dichloromethane, chloroform, ethylene dichloride 35 and the like, preferably dichloromethane. In the step b) of the above process the suitable solvent that can be used include, without limitation, aromatic hydrocar bon Solvents like toluene, Xylene, or halogenated solvents such as dichloromethane, chloroform, ethylene dichloride 40 and the like, preferably dichloromethane. wherein R and R are same or different and are each In the step c) of the above process the amide in subjected to independently selected from C-2 alkyl, C-7 Hoffmann's degradation using conventional methods known cycloalkyl, aryl-C alkyl, aryl or chiral auxiliaries in prior art. (S/R) like 4-phenyl-2-oxazolidone, N-octyl glucamine, The second aspect of the present invention is represented in 1-phenyl ethylamine and the like. scheme-6.

Scheme-6 O O NHRR HO O HN O 19 SOCl O He Her DCM, HCI NRR, DCM. NRR NH3 sol.

26 27 1. aq. NH3 bromine aq. NaOH N HCI DCM US 8,168,828 B2 15 16 -continued

NHRIR NH2 19 O DCM, DCC DMAP, cyclohexane NRR HN O 29

OH

4 Wherein in RandR2 are same or different and are each independently selected from C1-12 alkyl, C3-7 cycloalkyl, aryl-C-6 alkyl, aryl or chiral auxillaries (SR) like 4-phenyl-2-oxazolidone, N-octylglucamine, 1-phenyl ethylamine and the like.

The third aspect of the present invention relates to the c) treating the diastereomeric salt of formula-30, with a process for the preparation of (S)-pregabalin involving the base provides the compound of formula-31, novel intermediates compounds namely 3-cyano-5-methyl hexanamide compounds of general formula-28 and 3-(ami nomethyl)-5-methylhexanamide compounds of general for Formula-31 mula-29. The process comprises of 25 a) Reducing cyano group of the B-cyano amide, compound 1. R of formula-28, N

Formula-28 30 CN O wherein R and R are as defined above, NRR d) hydrolysis of the compound of formula-31, with a base in a Suitable solvent provides (S)-pregabalin compound 35 of formula-1, with a suitable reducing agent provides the amino amide derivative, compound of formula-29, NH2 40 Formula-29 NH2 lulu, OH (S)-pregabalin

NRR 45 e) purification of the (S)-pregabalin formed in the previous step, provides highly pure (S) pregabalin Substantially free of impurities. In Step a) the cyano moiety of the compound of formula-28 wherein in R and R2 are same or different and are each 50 is reduced to give the amine compound of formula-29. The independently selected from either hydrogen, C. reduction can be performed using a number of catalysts in alkyl, C., cycloalkyl, aryl-C alkyl, aryl or chiral aux presence of hydrogen. These include, without limitation het iliaries (S/R) like 4-phenyl-2-oxazolidone, N-octyl glu erogeneous catalysts containing from about 0.1% to about camine, 1-phenyl ethylamine and the like. 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, b) reacting the amino derivative, compound of formula-29, 55 Ru and Ir, including oxides and combination thereof, which with optically active organic acid provides a diastereo are typically supported on various materials including Al-O. meric salt of formula-30, C. CaCO, SrCO, BaSO, MgO, SiO, TiO, ZrO and the like. Many of these metals including Pd may be doped with an amine, Sulfide or a second metal Such as Pb, Cu and Zn. Formula-30 60 NH2 Useful catalysts include raney nickel, palladium catalyst Such as Pd/C, Pd/SrCO, Pd/Al-O, Pd/MgO, Pd/CaCO, Pd/BaSO, PdO, Pd Black, PdCl and the like. Other useful lulu, NRRoOAA catalysts Rh/C, Ru?C, Re/C, PtC), Rh/C, RuO. The reaction 65 is typically carried out in the presence of one or more polar Solvents including without limitation water, alcohols, ethers, wherein R and Rare as defined above, ester and acids such as, methanol, ethanol, isopropyl alcohol, US 8,168,828 B2 17 18 tetrahydrofuran, ethyl acetate, acetic acid and the like. The bicarbonate and the like, most preferably potassium hydrox preferred reducing agent in the present embodiment is Raney ide. Suitable solvents that can be used in the hydrolysis nickel in presence of hydrogen. include but are not limited to; alcoholic solvents such as Step b) involves the separation of the recemic mixtures of methanol, ethanol, isopropanol and the like: water: and their compound of formula-29 by treating it with optically active mixtures.

Scheme-7 NH2 O Reduction He !--- NRR NRR 29 29 28a) R1 = ethyl, R = ethyl 29a) R1 = ethyl, R = ethyl 28b). R1 = H, R2 = 1-phenyl ethyl 29b) R1 = H, R2 = 1-phenyl ethyl OAA (optically active orgnic acid)

aqueous base a NRR --- NRR-OAA 31 30 31a). R1 = ethyl, R = ethyl 30a) R1 = ethyl, R = ethyl, OAA = D(-)tartaric acid 31b) R = H, R2 = 1-phenyl ethyl 30b) R = H, R2 = 1-phenyl ethyl, OAA = D(-)tartaric acid

ston

Wherein in R1 and R2 are same or different and are each independently selected from either hydrogen, C1-12 alkyl, C-7 cycloalkyl, aryl-C6 alkyl or chiral auxillaries (S,R) like 4-phenyl-2-oxazolidone, N-octylglucamine, 1-phenyl ethylamine and the like, wherein OAA is an optically active organic acid is selected from mandelic acid, camphor sulfonic acid and tartatic acid, organic acid to provide the diasteriomeric salt of formula-30. The fourth aspect of the present invention relates to a cost The chiral resolving agent is selected from optically active effective and economically useful method for the preparation acid (OAA) like mandelic acid, camphor Sulfonic acid and of (S)-pregabalin. Though a number of methods are known in tartaric acid, most preferably tartaric acid. The reaction is 45 prior art for the synthesis of (S)-pregabalin they are burdened performed in a suitable alcoholic solvent like methanol, etha withdrawbacks such as use of toxic chemicals or high costs of nol, isopropanol, n-propanol, n-butanol, isobutanol; and production etc. water or their mixtures thereof. The present invention has developed a cost effective pro Step c) involves the treatment of the diastereomeric salt of cess for the synthesis of (S)-pregabalin, by increasing the formula-30 with base which may include but not limited to 50 yields of the final product formed, and the recovery of the alkali and alkali metal hydroxides, carbonates, hydrogen car costly reagents used in the process and recycling them, which bonates such as Sodium hydroxide, potassium hydroxide, has reduced the cost of the production substantially. Sodium carbonate, potassium carbonate, Sodium hydrogen carbonate or potassium hydrogen carbonate and the like, pref A process for the production of (S)-pregabalin disclosed in erably sodium hydroxide, in a suitable solvent like chloro 55 U.S. Pat. No. 5,637,767 utilizes S-(+) mandelic acid for the hydrocarbon like dichloromethane, trichloromethane, 1,2- resolution of the racemic mixture of pregabalin. The yield of dichloroethane, preferably dichloromethane, to provide a free pregabalin was found to be very low and the amount of S-(+) base of formula-31, which on subsequent (in-situ/or after mandelic acid consumed was very high. The consumption of isolation as a free base) hydrolysis provides (S)-Pregabalin. S-(+) mandelic acid is very high i.e. nearly at the ratio of 2 The hydrolysis in step d) can be carried out with a suitable 60 moles per one mole of (S)-pregabalin resolved. It is observed base in a suitable solvent. Suitable inorganic bases which can that only a partial amount of (S)-pregabalin is involved in the be used in the reaction include but are not limited to hydrox formation of the diastereomeric salt per mole of S-(+) man ides of alkali and alkaline metals such as lithium hydroxide, delic acid added. To enrich the chiral purity, the diastereo Sodium hydroxide, potassium hydroxide and the like; carbon meric salt it is treated with additional mandelic acid in the ates of alkali and alkaline metals such as sodium carbonate, 65 Subsequent step. This leads to the addition of lager amounts of potassium carbonate and the like and bicarbonates of alkali S-(+) mandelic acid, most of which remains unreacted in the and alkaline metals such as Sodium bicarbonate, potassium reaction mixture, which is lost during workup. US 8,168,828 B2 19 20 To overcome the above drawbacks the present invention The process for the recovery of S (+) mandelic acid com has devised a method to recover the S-(+) mandelic acid from prises of the mother liquors (filtrate) and recycle it, so that it can again a) Separation of diastereomeric mandelate salt of (S)-pre be used in the reaction. This resulted in the decrease in the gabalin, from a solution obtained by the treatment of (R 5 & S) mixture of pregabalin with S (+) mandelic acid in overall amount of S-(+) mandelic acid consumed. The inven isopropanol and water mixture, tion further involves the recovery of (S)-pregabalin from the b) collecting the mother liquor from step a) and distilling mother liquors (filtrate) which led to the substantial increase off the solvent to obtain a residue, in the final product. These two aspects have assisted in c) dissolving the residue in water, and on Subsequent acidi decreasing the cost of production to a large extent. The enan- 10 fication with concentrated hydrochloric acid to adjust tiomeric mixture of pregabalin (34) used for resolution in the the pH to 2 to 3, present embodiment can be prepared by any of the methods d) cooling the reaction mixture, depicted in scheme-8. e) separating the solid S (+) mandelic acid by filtration.

Scheme-8 ---.CN O O NH2 ) / S.COOEt HOOC 28 32 21 NaCN, reduction NaOB:s ethanol, HO gl.acetic acid

NH2 1. KOH, CN O

lu- NR2R3 s . Raneyt Ni, EtOC2 COEt2 29 NH2 H2 ethanol 33

COOH recycle OH 34

HOOC

S-(+)-mandelic acid

OH GE) 9 mother liquors S-(+)-mandelic acid NH3 OOC (filtrate) -- containing recovery S. (S)-mandelic acid & COOH (R) & (S)-pregabalin (R) & (S)-pregabalin 35 aC. bu

mother liquors S-(+)-mandelic acid - recovery -- containing Sr. (S)-mandelic(filtrate) acid & YcoOH (S)-pregabalin (S)-pregabalin 1 (S)-pregabalin US 8,168,828 B2 21 22 The process for the recovery of pregabalin comprises of dichloromethane. Distilled off the solvent under reduced a) Separation of diastereomeric mandelate salt of (S)-pre pressure, at a temperature below 40° C. to yield the title gabalin, from a solution obtained by the treatment of (R compound as a residue. & S) mixture of pregabalin with S (+) mandelic acid in Yield: 19 grams. isopropanol and water mixture, 5 Step c): Preparation of 3-chloro-N,N-diethyl-5-methylhex b) collecting the mother liquor from step a) and distilling anamide off the solvent to obtain a residue, To a solution of 3-hydroxy-5-methylhexanoic acid (3.5 c) dissolving the residue in water, and on Subsequent acidi grams) intoluene (18 ml), thionyl chloride (5.2 ml) was added fication with concentrated hydrochloric acid to adjust and heated to 75° C. The reaction mixture was stirred at the pH to 2 to 3, cooling the reaction mixture and sepa 10 75-80° C. for 2 hrs, and the solvent was distilled off under rating the solid S (+) mandelic acid by filtration, reduced pressure and temperature below 60°C. The reaction d) collecting the mother liquors from step c) and treating it mixture was cooled to 0-5°C., diethylamine was added and with a base to adjust the pH to 6-7, stirred at 0-5°C. for 30 min. Quenched the reaction mixture e) cooling the reaction mixture to precipitate the pregaba 15 with water. The reaction mass was extracted with toluene. The lin, solvent was distilled offunder reduced pressure and tempera f) Separating the Solid pregabalin by filtration. ture below 75° C. to obtain the title compound as a residue. Analysis of Particle Size Distribution of Pregabalin: Yield: 3.6 grams. A Malvern laser diffraction instrument was used to charac Step d): Preparation of 3-cyano-N,N-diethyl-S-methylhex terize the particle size distribution of pregabalin. anamide Instrument model: Malvern Mastersizer 2000 A suspension of 3-chloro-N,N-diethyl-5-methyl-hexana Technique used: Dry method mide (1 gram), Sodium cyanide (0.5 gram) in dimethylsulfox Instrument Parameters: ide (10 ml) was heated to 75°C. and stirred at this temperature i) Material RI: 1.500 for 25 hrs. The reaction mixture was then cooled to 25-30°C. ii) Dispersant RI: 1,000 25 and quenched with water. The reaction mixture was extracted iii) Analysis model: general purpose with ethyl acetate. The ethyl acetate layer was washed with iv) Sensitivity: Normal water and distilled off under reduced pressure at a tempera The process described in the present invention was dem ture below 60° C. to obtain the title compound as a residue. onstrated in examples illustrated below. These examples are Yield: 0.7 gram. provided as illustration only and therefore should not be 30 construed as limitation of the scope of the invention. Example-2 EXAMPLES Preparation of 3-cyano-N,N-diethyl-5-methylhexanamide Example 1 35 (Alternate Method) Preparation of 3-cyano-N,N-diethyl-5-methylhexanamide Step a): Preparation of 5-methylhex-2-enoic Acid To a solution of diethyl-2-(3-methylbutylidine) malonate Step a): Preparation of tertiary butyl-3-hydroxy-5-methyl 40 (10 grams) in methanol (4 ml) cooled to 5°C., a solution of hexanoate potassium hydroxide (6.75 grams in 11 ml of methanol) was A solution of tetrahydrofuran (250 ml), Zinc dust (57 added and stirred for 30 min at 7-9°C. The reaction mixture grams) and methane Sulfonic acid (5 ml) was heated to reflux was heated to reflux temperature for 4.5 hours. The solvent and stirred for 1 hour. Added isovalaraldehyde (50 grams) was distilled off and quenched with water. The reaction mass followed by tert-butyl bromoacetate (17 grams) to the reac 45 was extracted with methylene chloride 20 ml. The pH of the tion mixture. Stirred for twenty minutes. Added tert-butyl reaction mixture was adjusted to 2 with hydrochloric acid. bromoacetate (157 grams) and stirred for 1 hour at reflux The resulting reaction mixture was extracted with dichlo temperature. The reaction mixture was cooled to 25-35°C. romethane. The solvent was distilled off completely under and poured into Solution of precooled concentrated hydro reduced pressure at 40°C. to obtain the title compound as a chloric acid. The reaction mixture was extracted with ethyl 50 solid. acetate. The organic layer washed with sodium bicarbonate Yield: 4.2 grams. solution, followed by water and dried over sodium sulfate. Step b): Preparation of N,N-diethyl-5-methylhex-2-enamide The solvent was distilled off under reduced pressure at a To a solution of 5-methylhex-2-enoic acid (formula-3) (20 temperature below 50° C. to get the title compound as a grams) in dichloromethane (250 ml), 2 ml of dimethyl for residue. 55 Yield: 92 grams. mamide was added. To this mixture thionyl chloride (24.1 Step b): Preparation of 3-hydroxy-5-methylhexanoic acid grams) was added. The reaction mixture was stirred for 2.5 To a solution of potassium hydroxide (11 grams) in metha hours at 28-29°C. The reaction mixture was cooled to 0-5°C. nol (50 ml), tertiary butyl-3-hydroxy-5-methylhexanoate (40 and diethylamine was added to the reaction mixture at 5-8°C. grams dissolved in 40 ml methanol) was added very slowly 60 until the pH reached to 8.5. The reaction mixture was stirred with constant stirring at 20-30° C. The reaction mixture for 1.5 hours at 0-5°C. The reaction mixture was quenched Stirred for 4 hour at 20-30°C. Distilled off the Solvent under with water. Separated the aqueous and organic layers. The reduced pressure at temperature below 45° C. Added water organic layer was washed with 5% sodium bicarbonate solu (90 ml) to the reaction mixture and washed the aqueous layer tion and was dried over anhydrous sodium Sulphate. The with dichloromethane. Discarded the organic layer and 65 solvent was distilled off completely under vacuum to provide adjusted the pH aqueous layer to 2.0 using concentrated the title compound as Solid. hydrochloric acid. Extracted the reaction mixture with Yield: 17 grams US 8,168,828 B2 23 24 Step c): Preparation of 3-cyano-N,N-diethyl-5-methylhex (9.5 grams) was added followed by ammonia solution (38 ml) anamide and Raney nickel (19 grams). Hydrogen pressure of 4.0 Added 3.46 grams of compound N,N-diethyl-5-methyl kg/cm was applied and the reaction mixture was stirred at hex-2-enamide (formula-4-a) to a mixture of 0.863 gram of 30°C. for 22 hours. The reaction mixture was filtered through potassium cyanide and 3.5 grams of ethanol. Stirred the reac 5 tion mixture for 18 hours at 25-40° C. Added 4.45 ml of a hyflow bed. The solvent was distilled off under reduced hexane to the reaction mixture. Added 0.875 gram of glacial pressure at a temperature below 60° C. Water (200 ml) was acetic acid to the reaction mixture at 35° C. Quenched the added to the reaction mixture and pH adjusted to 2 with reaction mixture with water. Separated the organic and aque concentrated hydrochloric acid. The aqueous layer was ous phases. Extracted the aqueous phase with hexane. extracted with dichloromethane. The pH of aqueous layer Washed the organic layer with water. Distilled the organic 10 was adjusted to 8.0, with 50% sodium hydroxide. The aque phase under reduced pressure to get the title compound as a ous layer was extracted with dichloromethane. The solvent residue was distilled off completely under atmospheric pressure to Yield: 2.38 grams obtain the title compound as a residue. Yield: 7.5 grams Example 3 15 Example 5 Preparation of 3-aminomethyl-N,N-diethyl-5-methylhexanamide Preparation of 3-(aminomethyl)N,N-diethyl-5-methylhexanamide Stepa): Preparation of 3-(2-(diethylamino)-2-oxoethyl)-me thylhexanoic acid D(-) tartarate salt To a solution of 3-isobutyl glutaric anhydride (5 grams) in 3-methyl amino N,N-diethyl-5-methyl hexanamide (10 dichloromethane (10 ml), added diethyl amine (4.3 grams) and stirred the reaction mixture for 12 hrs at 25° C. The grams) was Suspended in water and added D (-) tartaric acid reaction mixture was quenched with water (10 ml) and the pH (7 grams). The reaction mixture was slowly heated to 40-45° of the reaction mixture adjusted to 1.0 using hydrochloric 25 C. and stirred for 30 min and filtered to remove the un acid. The organic layer was separated and the aqueous layer dissolved material. The filtrate was cooled to 20° C. and was extracted with dichloromethane. The organic layers were stirred at 15-20° C. for 1 hour. Filtered the solid obtained, combined and the solvent distilled off to provide the title washed with water and dried the material at 40-45° C. to compound as a residue. obtain the title compound. Yield: 6.5 grams 30 Yield: 6.1 grams. Step b): Preparation of N',N'-diethyl-3-isobutylpentane dia Specific optical Rotation: C =-9.2° (c=1, water) mide To a solution of 3-(2-(diethylamino)-2-oxoethyl)-methyl Example 6 hexanoic acid (1 gram obtained in step-a) in dichloromethane (10 ml) and dimethylformamide (0.2 ml), thionyl chloride 35 Preparation of 3-(amino methyl) (0.5 gram) was added at a temperature below 5°C. Stirred the N,N-diethyl-5-methylhexanamide L(+) tartarate salt reaction mixture for 2 hrs. Ammonia Solution (4 ml) was added to the reaction mixture at a temperature below 5°C. and 3-methyl amino N,N-diethyl-5-methyl hexanamide (10 stirred for 30 min. The reaction was quenched with water and gm) was Suspended in water and added L(+) tartaric acid (7.0 the two layers were separated. The organic layer was washed 40 gm). The reaction mixture was slowly heated to 40-45° C. and with 2% hydrochloric acid followed by water. The solvent stirred for 30 min and filtered to remove the un-dissolved was distilled off to dryness to provide a title compound as a material. The filtrate was cooled to 20° C. and stirred at solid. 15-20°C. for 1 hour. Filtered the Solid obtained washed with Yield: 0.6 gram water and dried the material at 40-45° C. to obtain the title Step-c): Preparation of 3-aminomethyl-N,N-diethyl-5-meth 45 compound ylhexanamide Yield: 5.9 grams. To an aqueous Solution of sodium hydroxide (2.8 grams in Specific optical Rotation: C =+9.2° (c=1, water) 3 ml of water), bromine (0.5 ml) was added and cooled to 5° C. N',N'-diethyl-3-isobutylpentane diamide (0.6 gram, from Example 7 the step-b) was added to the reaction mixture. Heated the 50 reaction mixture to 80° C. and stirred for two hours. The Preparation of (S)-Pregabalin reaction mixture was cooled to 30°C., quenched with water and the pH was adjusted to 2.0 using hydrochloric acid. Ethyl The tartarate salt of 3-aminomethyl N,N-diethyl-5-methyl acetate was added to the reaction mixture, stirred and the two hexanamide (10 grams) was dissolved in water (15 ml) and layers were separated. The pH of the aqueous layer was 55 dichloromethane (25 ml) was added to it. The pH of reaction adjusted to 9 using Sodium hydroxide and extracted with mixture was adjusted to 9-10 by addition of sodium hydrox dichloromethane. Distilling off the solvent below 40°C. pro ide solution (3.0gm NaOH in 3.0 ml of water) and stirred for vided the title compound as a residue. 10-15 min at 20-25°C. The aqueous and organic layers were Yield: 0.5 gram separated. The aqueous layer was extracted with dichlo 60 romethane. The aqueous layer was taken up for recovery of Example 4 tartaric acid. The solvent was distilled off from combined organic layer to obtain a residue. Potassium hydroxide (5.0 Preparation of grams) and water (5.0 ml) was added to the residue and heated 3-aminomethyl-N,N-diethyl-5-methylhexanamide to 115°C., the reaction was stirred at this temperature for 20 65 hours. The reaction mixture was cooled to 30° C. and the pH To a solution of potassium hydroxide (19 grams) in metha adjusted to 4.0 using concentrated hydrochloric acid. The nol (114 ml), 3-cyano-N,N-diethyl-5-methyl hexanamide reaction mixture was heated to 80° C. and stirred for 45 min US 8,168,828 B2 25 26 and filtered. The filtrate was cooled to 5° C. and stirred for Example 11 ninety minutes. The precipitated solid was filtered and washed with cool water. The solid was dried at 50–55°C. to Recovery of Pregabalin from Filtered Mother yield (S)-Pregabalin. Liquors Yield: 3.0 grams. 5 The solvent from the filtrate completely distilled off under Example 8 reduced pressure. Isopropyl alcohol (10 ml) and water (5 ml) was added to the obtained mass. The contents were heated to Preparation of (S)-Pregabalin reflux temperature and stirred for 30 minutes. The contents 10 were cooled to 0-5°C. and stirred for 2 hrs. The obtained solid The tartarate salt of 3-aminomethyl N,N-diethyl-5-methyl was filtered off and washed with a mixture of isopropyl alco hexanamide (10 grams) was dissolved in water (15 ml) and hol and water. The solid was dried at 50–55°C. to obtain pure dichloromethane (25 ml) was added to it. The pH of reaction (S) Pregabalin. mixture was adjusted to 9-10 by addition of sodium hydrox Yield: 0.6 grams; Specific Optical Rotation: C-+ ide solution (3.0 grams in 3.0 ml of water) and stirred for 15 11.0° (c=1, water) 10-15 min at 20-25°C. The aqueous and organic layer was separated. The aqueous layer was extracted with dichlo Reference Example-A romethane. The solvent was distilled off from combined organic layer to obtain a residue. Potassium hydroxide (5.0 Formation of Diastereomeric Salt of (S)-Pregabalin gram), water (10 ml) and methanol (10 ml) was added to the To a solution of racemic pregabalin (1.2 kg) in isopropanol obtained residue and heated it to 70-75° C., the reaction was (24.0 lit) and water (0.72 lit), added S-(+) mandelic acid (1.6 stirred at this temperature for 18 hours. The reaction mixture kg) and the reaction mixture was heated to 50–55°C. with was cooled to 30° C. and the pH adjusted to 4.0 using con constant stirring. The reaction mixture was first cooled to centrated hydrochloric acid. The reaction mixture was heated 25 25-35° C. and then very slowly it was cooled to 0-5° C. to 80° C. and stirred for 45 min and filtered. The filtrate was Filtered the solid to get the diastereomeric salt. cooled to 5°C. The solid formed was filtered and washed with Yield: 0.9 kg. cool water. The solid was dried at 50-55° C. to yield (S)- Pregabalin. Reference Example-B Yield: 3.6 grams. 30 Preparation of (S)-Pregabalin Example 9 The mandalate salt of (S)-pregabalin (1.0 kg) was dis Purification of (S)-Pregabalin 35 solved in tetrahydrofuran (20 lit) and water (0.6 lit). The mixture was heated to 60-65° C. and slowly cooled to 0-5°C. A mixture of pregabalin (5 grams), isopropyl alcohol (100 and stirred for one hour. Filtered the solid and washed with ml) and water (25 ml) was heated to reflux temperature. The chilled tetrahydrofuran (0.1 lit). Spin dried the material to reaction mixture was stirred for 30 min at reflux temperature. obtain the title compound. The reaction mixture was filtered and the filtrate was cooled 40 Yield: 0.45 kg to 0-5°C. The reaction mixture was stirred for 2 hours at 0.5° Example 12 C. The solid obtained was filtered, washed with mixture of isopropyl alcohol and water, and dried to get the pure pre gabalin. Recovery of Mandelic Acid Yield: 3.8 grams. 45 Distilled off the solvent from mother liquors of reference Particle size distribution: D(0.1): 6.007 um; D(0.5): 43.844 example-(A) and (B) separately under reduced pressure to um; D(0.9): 203.873 um; D(1.00):508.24 um. obtain residue. The residues were combined and suspended in water (2.0 lit) and acidified the reaction mixture with hydro Example 10 chloric acid to adjust the pH to 2. The mixture was heated to 50 reflux and stirred for 4 hours. Slowly cooled the reaction Recovery of R-isomer of 3-(aminomethyl) mixture to 0-5° C. and stirred for one hour. Filtered the N,N-diethyl-5-methylhexanamide and D(-) tartaric precipitated Solid and spin dried it to obtain mandelic acid, acid which was dried at 45°-50° C. Yield: 1.1 kg. The mother liquors of example-5 and the aqueous layer of 55 Specific Optical Rotation: C-+152 (c-2.8, water) the example-7 and/or example-8, were combined and basified the reaction mixture with sodium hydroxide to adjust the pH Example 13 to 8.5. The reaction mixture extracted with methylene chlo ride. Distilled off the solvent to get the R-isomer of 3-(methyl Recovery of Pregabalin amino) N.N-diethyl-5-methyl hexanamide. The aqueous 60 layer was treated with hydrochloric acid to adjust the pH to 2. The mother liquors from the example-12 was taken and Slowly cooled the reaction mixture to 0-5°C. and stirred for neutralized with sodium hydroxide (20%) to adjust the pH to one hour. Filtered the precipitated solid and spin dried it to 6.7. The reaction mixture cooled to 0-5° C. The reaction obtain D(-) tartaric acid, which was dried at 45°-50° C. mixture was stirred for 30 minutes at 0-5°C. The precipitated Yield: 3.0 grams (R-isomer). 65 solid was filtered off and washed with chilled isopropyl alco Yield: 5.0 grams (D(-) tartaric acid) hol to get pregabalin. Specific Optical Rotation: C.I'-12° (c-20, water) Yield: 0.65 kg. US 8,168,828 B2 27 28 Example-14 Formula-26 Resolution of Pregabalin using Recovered S (+)-Mandelic Acid HO O

To a solution of racemic pregabalin (1.2 kg) in isopropanol NRR (24 lit) and water (0.7 lit), added recovered S-(+) mandelic acid (1.2 kg) and the reaction mixture was heated to 50–55°C. with constant stirring. The reaction mixture was first cooled 10 to 25-35° C. and then very slowly it was cooled to 0-5°C. The wherein R and Rare as defined above; reaction mixture was filtered to isolate the diastereomeric salt b) reacting the compound of Formula-26 with thionyl chlo formed. ride followed by ammonia to produce the diamide com Yield: 0.79 kg. 15 pound of Formula-27.

We claim: 1. A compound represented by the following structural Formula-27 formula: HN O NH2 NRR lu NRNRoOAA, 25 wherein R and R are as defined above: or an enantiomer thereof, wherein: c) subjecting the compound of Formula-27 to Hoffman's R and R are each ethyl, and 30 degradation to produce a compound of Formula-29, OAA is D-(-)-tartaric acid or L-(+)-tartaric acid. 2. A process for the preparation of a compound of Formula Formula-29 30, NH2 35 Formula-30 lu NRR NH2 wherein R and Rare as defined above; and lulu, NRNRoOAA 40 d) reacting the compound of Formula-29 with D-(-)-tar taric acid in a solvent to produce the compound of For mula-30. wherein R and R2 are each independently hydrogen, 3. A process for the preparation of a compound of Formula unsubstituted C- alkyl, C-7 cycloalkyl, aryl C. 1, comprising: alkyl, or aryl, or 45 a) reducing cyano group of a B-cyano amide compound of R and R, taken together with the nitrogen to which they Formula-28, are bound, form a chiral auxiliary (S/R) selected from 4-phenyl-2-oxazolidinone, N-octylglucamine and 1-phenylethylamine; and Formula-28 50 CN O OAA is D-(-)-tartaric acid, the process comprising: NRR a) reacting a compound of Formula-3, with a reducing agent in a solvent to produce the amino 55 amide compound of Formula-29, Formula-3

Formula-29 NH2 60

--- NRR

with a secondary amine NHRR, wherein R, and Rare 65 wherein R and R2 are each independently hydrogen, as defined above, in a solvent to produce a compound of unsubstituted C- alkyl, C-7 cycloalkyl, aryl-C Formula-26, alkyl, or aryl, or US 8,168,828 B2 29 30 RandR, taken together with the nitrogen to which they hexanamide with a solvent, thereby recovering the are bound, form a chiral auxiliary (S/R) selected from R-isomer of 3-methylamino-N,N-diethyl-5-methylhex 4-phenyl-2-oxazolidinone, N-octylglucamine and anamide. 1-phenylethylamine 9. A process for the preparation of a diastereomeric tartrate b) reacting the compound of Formula-29 with D-(-)-tar 5 salt of 3-methylamino-N,N-diethyl-5-methylhexanamide taric acid in a solvent to produce diastereomeric salt of and for recovery of D (-) tartaric acid, comprising: Formula-30, a) treating an (R and S) mixture of 3-methylamino-N,N- diethyl-5-methylhexanamide with D (-) tartaric acid in Formula-30 10 water, thereby forming the diastereomeric tartrate salt of NH2 the S-isomer of 3-methylamino-N,N-diethyl-5-methyl hexanamide and a mother liquor, and separating the diastereomeric tartrate salt from the mother liquor; lulu, b) basifying the mother liquor from step a) and extracting 15 the R-isomer of 3-methylamino-N,N-diethyl-5-methyl wherein Rand R are as defined above and OAA is hexanamide with a solvent; D-(-)-tartaric acid; c) acidifying the mother liquor from step b) with concen c) treating the diastereomeric salt of Formula-30 with a trated hydrochloric acid to adjust the pH to 2 to 3: base to produce the compound of Formula-31, d) cooling the mother liquor from step c), thereby forming Solid D (-) tartaric acid; and Formula-31 e) separating the Solid D (-) tartaric acid by filtration, NH2 thereby recovering D (-)tartaric acid. 25 10. The process of claim 3, wherein the substantially pure compound of Formula-1 produced in step e) has a mean --N- NRR particle size in the range of 50-90 Lum and D (v. 0.9) in the range of 170-230 um. wherein RandR are as defined above; 11. The process of claim 4, wherein the transition metal is d) hydrolyzing the compound of Formula-31 with a base in 30 Ni, Pd, Pt, Rh, Re, Ru, Ir, or a combination thereof. a solvent to produce a compound of Formula-1, 12. The compound of claim 1, or an enantiomer thereof, wherein OAA is L-(+)-tartaric acid. 13. A compound represented by the following structural Formula-1 formula: NH2 35

--- OH 40 and; e) removing impurities from the compound of Formula-1 lulu, NRROAA, formed in step d) to produce the compound of Formula-1 substantially free of impurities. wherein R and R are each independently hydrogen, 4. The process of claim 3, wherein the reduction of the 45 unsubstituted C- alkyl, C., cycloalkyl, aryl C. cyano group in step a) is performed using hydrogen and the alkyl, or aryl, or reducing agent is Raney nickel, a transition metal, an oxide R and R, taken together with the nitrogen to which they thereof or a combination thereof. are bound, form a chiral auxiliary (S/R) selected from 5. The process of claim 4, wherein the reducing agent is 4-phenyl-2-oxazolidinone, N-octylglucamine and Raney nickel. 50 1-phenylethylamine; and OAA is D-(-)-tartaric acid or 6. The process of claim3, wherein the solvent used in step a) is an alcohol, ether, ester, acid or water. L-(+)-tartaric acid. 7. The process of claim3, wherein the solvent used in step 14. The compound of claim 13, represented by the follow b) is methanol, ethanol, isopropanol, n-propanol, n-butanol, ing structural formula: isobutanol, water or a mixture of water and alcohol. 55 8. A process for the preparation of a diastereomeric tartrate NH salt of the S-isomer of 3-methylamino-N,N-diethyl-5-meth 1. o OH O ylhexanamide and for the recovery of the R-isomer of 3-me thylamino-N,N-diethyl-5-methylhexanamide, comprising: ---- 0 HO OH. a) treating an (R and S) mixture of 3-methylamino-N,N- 60 NRR diethyl-5-methylhexanamide with D (-) tartaric acid in water, thereby forming the diastereomeric tartrate salt of the S-isomer of 3-methylamino-N,N-diethyl-5-methyl hexanamide and a mother liquor, and separating the 15. The process of claim 2, wherein R and R are each diastereomeric tartrate Salt from the mother liquor, and 65 ethyl. b) basifying the mother liquor from step a) and extracting 16. The process of claim 3, wherein R and R are each the R-isomer of 3-methylamino-N,N-diethyl-5-methyl ethyl. US 8,168,828 B2 31 32 17. A process for the preparation of a compound of For b) treating the diastereomeric salt of Formula-30 with a mula-1, comprising: base to produce the compound of Formula-31, a) reacting a compound of Formula-29,

Formula-31 NH2 Formula-29 NH2 --- NRR, NRR 10 wherein RandR are as defined above: c) hydrolyzing the compound of Formula-31 with a base in with D-(-)-tartaric acid in a solvent to produce a diaste a solvent to produce a compound of Formula-1, reomeric salt of Formula-30, 15 Formula-1 Formula-30 NH2 NH2

2O lulu, OH, --N- NRRoOAA and; wherein R and R2 are each independently hydrogen, d) removing impurities from the compound of Formula-1 unsubstituted C- alkyl, C-7 cycloalkyl, aryl-C to produce the compound of Formula-1 substantially alkyl, or aryl, or 25 free of impurities. RandR, taken together with the nitrogen to which they 18. The compound of claim 17, wherein RandR are each are bound, form a chiral auxiliary (S/R) selected from ethyl. 4-phenyl-2-oxazolidinone, N-octylglucamine and 19. The compound of claim 14, wherein RandR are each 1-phenylethylamine; and ethyl. OAA is D-(-)-tartaric acid UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,168,828 B2 Page 1 of 1 APPLICATIONNO. : 12/666133 DATED : May 1, 2012 INVENTOR(S) : Manne Satyanarayana Reddy et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Claim 3, column 29, line 25, delete the and insert:

Formula-31

Claim 17, column 31, line 20, delete the chemical compound and insert:

NRROAA Formula-30

Signed and Sealed this Twenty-sixth Day of June, 2012

David J. Kappos Director of the United States Patent and Trademark Office