US 2016O137584A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0137584A1 Oniciu et al. (43) Pub. Date: May 19, 2016
(54) PROCESSES AND INTERMEDIATES FOR PREPARING AW-DICARBOXYLIC III ACID-TERMINATED DALKANEETHERS O O (71) Applicant: Gemphire Therapeutics Inc., O Northville, MI (US) RO pi iii. ORI R2 R3 R3 R2 (72) Inventors: Carmen Daniela Oniciu, Toulouse (FR); Otto Joseph Geoffroy, Gainsville, FL (US) compounds of formula (V), (73) Assignee: Gemphire Therapeutics Inc. V (21) Appl. No.: 14/942,765 O O (22) Filed: Nov. 16, 2015 O HO pi iii. OH Related U.S. Application Data R2 R3 R3 R2 (60) Provisional application No. 62/079,894, filed on Nov. 14, 2014. and corresponding salts of formula (IV). Publication Classification (51) Int. C. IV C07C 67/31 (2006.01) O O C07C5L/09 (2006.01) (52) U.S. C. O CPC ...... C07C 67/31 (2013.01); C07C51/09 --~-- n--> (M), (2013.01) (57) ABSTRACT The compounds made by the methods and processes of the The present disclosure provides a process for the preparation invention are particularly useful for administration in humans of compounds of formula (III), and animals. US 2016/O 137584 A1 May 19, 2016
PROCESSES AND INTERMEDIATES FOR PREPARING AW-DICARBOXYLIC ACID-TERMINATED DALKANEETHERS O O
O CROSS-REFERENCE TO RELATED RO pi iii. ORI APPLICATION R2 R3 R3 R2 0001. This application claims the benefit of U.S. Provi sional Application Ser. No. 62/079,894, filed Nov. 14, 2014, the disclosure of which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION 0002 C.Co-Dicarboxylic acid-terminated dialkane ethers have activity in lowering several plasma lipids, including Lp(a), triglycerides, VLDL-cholesterol, and LDL-choles terol, both in animals and in humans. See U.S. Pub. No. and corresponding salts of formula (IV): 2010/0256209. The compounds also are known to increase insulin sensitivity. See U.S. Pub. No. 2010/0256209. In par ticular, 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid) (also IV known as 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethyl hexanoic acid), whose USAN name is gemcabene, and its O O calcium salt (gemcabene calcium) have been intensively O studied in multiple clinical trials as a lipid lowering agent for --~- n--> (M), the treatment of patients with low high-density lipoprotein (HDL) and high low density lipoprotein (LDL). See Bays, H. E., et al., Amer. J. Cardiology, 2003, 92,538-543. Gemcabene wherein M' is an alkaline earth metal or alkali metal. has been clinically tested as an anti-hypertensive and anti 0007. The compounds made by the methods and processes of the invention are particularly useful for administration in diabetic agent in addition to the lipid lowering activity. humans and animals. 0003) A synthetic method for the preparation of 6,6'-oxy 0008. One aspect of the invention is a process for prepar bis(2,2-dimethyl-4-hexanoic acid) and other C.()-dicarboxy ing a compound of formula (III): lic acid-terminated dialkane ethers is described by Bisgaier, C. L. et al. in U.S. Pat. No. 5,648,387, which is incorporated herein by reference in its entirety. In addition, preparation and characterization of alcohol and water solvates of 6,6'-oxybis (2,2-dimethyl-4-hexanoic acid) calcium (gemcabene cal cium), for the treatment of dyslipidemia, Vascular disease, and diabetes are disclosed in U.S. Pat. No. 6,861,555, which is incorporated herein by reference in its entirety. Zhang. Yet al. also report a small scale synthesis of C-14- and tritiated wherein: gemcabene congeners in J Label Compa Radiopharm 2007. 0009 R is alkyl; 50, 602-604. 10010 R and Rare each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, 0004. The previously disclosed syntheses raise a number aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and of safety and environmental concerns when replicated on a 0011 in and mare each independently 0-4: scale larger than 1 kg. Thus, a need remains for safe and comprising: environmentally friendly processes for preparing C,c)-dicar 0012 (a) reacting a solution comprising a Substituted boxylic acid-terminated dialkane ethers on a large scale. acetic acid ester of formula (I): SUMMARY OF THE INVENTION 0005. These and other needs are met by the current disclo Sure, which provides general and industrially-scalable meth ods for the preparation of C.O)-dicarboxylic acid-terminated dialkane ethers and salts thereof. 0006. The present disclosure provides a process for the preparation of compounds of formula (III), US 2016/O 137584 A1 May 19, 2016
0013 with a deprotonating reagent to produce an inter mediate of formula (Ia): II 1\-h-N-6)-1N Ia M2 No 0024 wherein X is halo: R2 afor to produce a compound of formula (III). 0025. In other aspects, the compound of formula (III) is R3 hydrolyzed to produce a compound of formula (V). (0014 wherein M is Lior Zn; and 0015 (b) reacting the intermediate of formula (Ia) with a solution comprising a C.O)-halo-terminated dialkane ether of formula (II): O HO pi iii. OH II 1\-6)N-1'N-6-1N 0026. In some aspects, the compound of formula (V) is 0016 wherein X is a halogen; 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid). In other aspects, to produce a compound of formula (III). the salt of formula (IV) is the calcium salt of 6,6'-oxy-bis(2. 0017. A further aspect of the invention is the process for 2-dimethyl-4-hexanoic acid). preparing a compound of formula (III): 0027. In some aspects, the compound of formula (III) is a compound of formula (48).
48 O O R2No iii. O n----- R21 wherein: R22 R23 R22 R23 0018) R' is alkyl: 0019 RandR are eachindependently RandR are each 0028. In some aspects, the compound of formula (V) is a independently alkyl, cycloalkyl, cycloalkylalkyl, heterocy compound of formula (49). cloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and 49 0020 in and mare each independently 0-4: comprising: O O O 0021 (a) reacting a solution comprising an O-bromo HO iii. iii. OH acetic acid ester of formula (IX): R22 R23 R22 R23
IX O 0029. In some aspects, the salts of formula (IV) are salts of Br formula (50). ORI 50
O O 0022 with a metal, until the metal is essentially dis solved; - X^-n- On-n-rx's (M), 0023 (b) reacting the solution of step (a) with a solution R22 R23 R22 R23 comprising a C.O)-halo-terminated dialkane ether of for mula (II): US 2016/O 137584 A1 May 19, 2016
0030. A further aspect discloses a process for preparing a the compound of formula (50) is the calcium salt of 6,6'-oxy compound of formula (48): bis(2,2-dimethyl-4-hexanoic acid). 0042. In a further aspect, a compound of formula (48):
48 O O R N----- R21 R22 R23 R22 R23 R22 R23 wherein: 0031) R' is alkyl; 0043 wherein: 0032 R and R are each independently alkyl, 0044) R' is alkyl: cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy 0045 R’ and R are each independently alkyl, cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; cycloalkyl, cycloalkylalkyl, heterocycloalkyl, hetero and cycloalkylalkyl, arylalkyl, heteroaryl, or heteroaryla 0033 m is 0-4: lkyl; and comprising: 0046 m is 0-4: 0034 (a) reacting a first solution of a compound of 0047 comprising: formula (46): 0.048 (a) reacting a solution of a cyclic lactone of for mula (41):
46 O 41 HO R21 iii. O1 R22 R23
0035 with a halogen source to produce an intermediate of formula (47): 0049 with a deprotonating reagent to produce an inter mediate of formula (41a): 47 O X2 R21 41a. iii. O1 R22 R23 0036) wherein X* is F, Cl, or I and where R is alkyl: 0037 (b) reacting a second solution of the compound of formula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48). 0038. In some embodiments, step (a) is in the presence of 0050 wherein M is Lior Zn; triphenylphosphine. 0051 (b) reacting the intermediate of formula (41a) 0039. In one embodiment, the first compound of formula with a solution of an alkylhalide of formula (42): (46) and the second compound of formula (46) have identical R22X22 42 substituents R', R’ and R', and m is the same. In another embodiment, they are different. 0.052 wherein X* is halo: 0040. In other aspects, the compound of formula (48) is 0.053 to produce a compound of formula (43): hydrolyzed to produce a compound of formula (49). 43 O
R22 O
)m R22 R23 R22 R23 0.054 (c) reacting the solution of a compound of for 0041. In some aspects, the compound of formula (49) is mula (43) with a deprotonating reagent to produce an 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid). In other aspects, intermediate of formula (43a): US 2016/O 137584 A1 May 19, 2016
48 43a MNo O O R2 O R21 R22 O S. kn- N----- R22 R23 R22 R23 )m 0.063 (h) reacting the solution of a compound of for mula (48) with dilute acid to form (49). 0055 wherein M is Li or Zn; 0056 (d) reacting the intermediate of formula (43a) 49 with a solution of an alkylhalide of formula (44): O O R23X23 44 O HO iii. iii. OH 0057 wherein X* is halo: R22 R23 R22 R23 0.058 to produce a compound of formula (45): 0064. A further aspect is a process for preparing a com pound of formula (45):
45 O 45 O 23 O 23 O
)m )m
0059 (e) reacting the solution of a compound of for wherein: mula (45) with potassium tert-butoxide to produce an 0065 R’ and R are each independently alkyl, intermediate of formula (46): cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and 0066 m is 0-4: 46 comprising: 0067 (a) reacting a solution of a cyclic lactone of for HO R21 mula (41):
R22 R23 41 O
0060 (f) reacting the solution of a compound of for O mula (46) with a halogen source in the presence of triphenylphosphine to produce an intermediate of for mula (47): )m 0068 with a deprotonating reagent to produce an inter 47 mediate of formula (41a):
41a. Ms22 No R22 R23 2 O 0061 wherein X* is F, Cl, or I: 0062 (g) reacting the solution of a compound of for )m mula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48): 0069 wherein M is Lior Zn; US 2016/O 137584 A1 May 19, 2016
0070 (b) reacting the intermediate of formula (41a) For example, in the structure on the left-hand side of the with a solution of an alkylhalide of formula (42): schematic below there are nine hydrogens implied. The nine R22X22 42 hydrogens are depicted in the right-hand structure. Some times a particular atom in a structure is described in textual (0071 wherein X* is halo: formula as having a hydrogen or hydrogens as Substitution 0072 to produce a compound of formula (43): (expressly defined hydrogen), for example, —CHCH-. It is understood by one of ordinary skill in the art that the aforementioned descriptive techniques are common in the 43 chemical arts to provide brevity and simplicity to description O of otherwise complex structures. R23 O H H H )m H Br Br
H 0073 (c) reacting the solution of a compound of for H mula (43) with a deprotonating reagent to produce an H intermediate of formula (43a): H H
43a I0081 “Alkyl means a linear saturated monovalent hydro 23 carbon radical of one to six carbon atoms or a branched Ms No saturated monovalent hydrocarbon radical of three to 6 car bon atoms, e.g., methyl, ethyl, propyl. 2-propyl, butyl (in R22 O cluding all isomeric forms), or pentyl (including all isomeric forms), and the like. I0082 Alkylamino” means an —NHR group where R is alkyl, as defined herein. I0083) “Alkylsilyl” means an alkyl group substituted with 0074 wherein M is Li or Zn; at least one silyl group, as defined herein. 0075 (d) reacting the intermediate of formula (43a) I0084) “Amino” means - NH. with a solution of an alkylhalide of formula (44): I0085 “Aminoalkyl means an alkyl group substituted with at least one, specifically one, two or three, amino groups. R23X23 44 I0086) “Aryl means a monovalent six- to fourteen-mem (0076 wherein X* is halo: bered, mono- or bi-carbocyclic ring, wherein the monocyclic 0077 to produce a compound of formula (45). ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the Valency of the group DETAILED DESCRIPTION OF THE INVENTION may be located on any atom of any ring within the radical, Valency rules permitting. Representative examples include Abbreviations and Definitions phenyl, naphthyl, and indanyl, and the like. I0087 'Arylalkyl means an alkyl radical, as defined 0078. The following abbreviations and terms have the herein, Substituted with one or two aryl groups, as defined indicated meanings throughout: herein, e.g., benzyl and phenethyl, and the like. I0088 “Cycloalkyl means a monocyclic or fused bicyclic, saturated or partially unsaturated (but notaromatic), monova Abbreviation Meaning lent hydrocarbon radical of three to ten carbon ring atoms. o C. Degrees Celsius Fused bicyclic hydrocarbon radical includes bridged ring DMF Dimethylformamide systems. Unless stated otherwise, the Valency of the group DMSO Dimethyl Sulfoxide Et Ethyl may be located on any atom of any ring within the radical, Eq. Equivalent Valency rules permitting. One or two ring carbon atoms may HDL High-Density Lipoprotein be replaced by a C(O)— —C(S)—, or —C(=NH)— Hr Hour group. More specifically, the term cycloalkyl includes, but is LDA Lithium Diisopropylamide not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclo LDL Low-Densit Lipoprotein Lp(a) Lipoprotein (a) hexyl, cyclohexyl, or cyclohex-3-enyl, and the like. M Molar I0089. “Cycloalkylalkyl means an alkyl group substituted Min Minute with at least one, specifically one or two, cycloalkyl group(s) RT Room Temperature as defined herein. VLDL Very Low-Density Lipoprotein (0090 “Dialkylamino” means a NRR' radical where R and Rare alkyl as defined herein, oran N-oxide derivative, or 0079. The symbol “ ” means a single bond, and “—” a protected derivative thereof, e.g., dimethylamino, diethy means a double bond. lamino, N,N-methylpropylamino or N.N-methylethylamino, 0080 When chemical structures are depicted or described, and the like. unless explicitly stated otherwise, all carbons are assumed to (0091) “Halo' or “halogen” refers to fluorine, chlorine, have hydrogen Substitution to conform to a Valence of four. bromine, or iodine. US 2016/O 137584 A1 May 19, 2016
0092 “Haloalkyl mean an alkyl group substituted with dolyl, octahydroisoindolyl, decahydroisoquinolyl, tetrahy one or more halogens, specifically one to five halo atoms, e.g., drofuryl, and tetrahydropyranyl, and the derivatives thereof trifluoromethyl, 2-chloroethyl, and 2,2-difluoroethyl, and the and N-oxide or a protected derivative thereof. like. 0096 “Heterocycloalkylalkyl means an alkyl radical, as 0093. “Heteroaryl' means a monocyclic, fused bicyclic, defined herein, substituted with one or two heterocycloalkyl or fused tricyclic, monovalent radical of 5 to 14 ring atoms groups, as defined herein, e.g., morpholinylmethyl, N-pyrro containing one or more, specifically one, two, three, or four lidinylethyl, and 3-(N-azetidinyl)propyl, and the like. ring heteroatoms independently selected from —O—, (0097. As used herein, the term “silyl includes tri-lower —S(O) (n is 0, 1, or 2), —N— —N(R)—, and the remain alkylsilyl groups such as a trimethylsilyl group, a triethylsilyl ing ring atoms being carbon, wherein the ring comprising a group, an isopropyldimethylsilyl group, a t-butyldimethylsi monocyclic radical is aromatic and wherein at least one of the lyl group, a methyldiisopropylsilyl group, a methyl di-t-bu fused rings comprising a bicyclic or tricyclic radical is aro tylsilyl group and a triisopropylsilyl group; tri-lower alkylsi matic. One or two ring carbonatoms of any nonaromatic rings lyl groups substituted with one or two aryl groups such as a comprising a bicyclic or tricyclic radical may be replaced by diphenylmethylsilyl group, a butyldiphenylbutylsilyl group, a—C(O)— —C(S)—, or—C(=NH)—group. R is hydro a diphenylisopropylsilyl group and a phenyldiisopropylsilyl gen, alkyl, hydroxy, alkoxy, acyl, or alkylsulfonyl. Fused group. Preferably the silyl group is a trimethylsilyl group, a bicyclic radical includes bridged ring systems. Unless stated triethylsilyl group, a triisopropylsilyl group, a t-butyldimeth otherwise, the Valency may be located on any atom of any ring ylsilyl group or a t-butyldiphenylsilyl group, more preferably of the heteroaryl group, Valency rules permitting. When the a trimethylsilyl group. point of valency is located on the nitrogen, R is absent. More specifically, the term heteroaryl includes, but is not limited to, (0098 “Optional” or “optionally” means that the subse 1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyr quently described event or circumstance may or may not rolyl, imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H occur, and that the description includes instances where said indolyl (including, for example, 2,3-dihydro-1H-indol-2-yl event or circumstance occurs and instances in which it does or 2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, not. One of ordinary skill in the art would understand that with indolinyl, isolindolinyl, benzimidazolyl, benzodioxol-4-yl, respect to any molecule described as containing one or more benzofuranyl, cinnolinyl, indolizinyl, naphthyridiN-3-yl, optional Substituents, only sterically practical and/or syn phthalaziN-3-yl, phthalaziN-4-yl, pteridinyl, purinyl, thetically feasible compounds are meant to be included. quinazolinyl, quinoxalinyl, tetrazoyl pyrazolyl pyrazinyl, “Optionally substituted” refers to all subsequent modifiers in pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, a term. So, for example, in the term “optionally substituted benzoxazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquino arylCs alkyl optional Substitution may occur on both the linyl (including, for example, tetrahydroisoquinolin-4-yl or “Cs alkyl” portion and the “aryl” portion of the molecule tetrahydroisoquinolin-6-yl, and the like), pyrrolo3.2-cpy may or may not be substituted. A list of exemplary optional ridinyl (including, for example, pyrrolo3.2-cpyridin-2-ylor substitutions is presented below in the definition of “substi pyrrolo3.2-cpyridin-7-yl, and the like), benzopyranyl, thia tuted. Zolyl, isothiazolyl, thiadiazolyl, benzothiazolyl, benzothie 0099 “Optionally substituted alkyl means an alkyl radi nyl, and the derivatives thereof, or N-oxide or a protected cal, as defined herein, optionally substituted with one or more derivative thereof. group(s), specifically one, two, three, four, or five groups, 0094) “Heteroarylalkyl means an alkyl group, as defined independently selected from alkylcarbonyl, alkenylcarbonyl, herein, substituted with at least one, specifically one or two cycloalkylcarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, heteroaryl group(s), as defined herein. amino, alkylamino, dialkylamino, aminocarbonyl, alkylami 0095) “Heterocycloalkyl means a saturated or partially nocarbonyl, dialkylaminocarbonyl, cyano, cyanoalkylami unsaturated (but not aromatic) monovalent monocyclic group nocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy, of 3 to 8 ring atoms or a saturated or partially unsaturated (but halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl notaromatic) monovalent fused bicyclic group of 5 to 12 ring S(O) , alkenyl-S(O) , aminosulfonyl, alkylamino atoms in which one or more, specifically one, two, three, or sulfonyl, dialkylaminosulfonyl, alkylsulfonyl-NR (where four ring heteroatoms independently selected from O, S(O), R is hydrogen, alkyl, optionally substituted alkenyl, (n is 0, 1, or 2), N, N(R) (where R is hydrogen, alkyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl), alkylaminocar hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring bonyloxy, dialkylaminocarbonyloxy, alkylaminoalkyloxy, atoms being carbon. One or two ring carbon atoms may be dialkylaminoalkyloxy, alkoxycarbonyl, alkenyloxycarbonyl, replaced by a —C(O)— —C(S)—, or—C(=NH)—group. alkoxycarbonylamino, alkylaminocarbonylamino, dialky Fused bicyclic radical includes bridged ring systems. Unless laminocarbonylamino, alkoxyalkyloxy, and —C(O)NR'R'' otherwise stated, the Valency of the group may be located on (where RandR are independently hydrogen, alkyl, option any atom of any ring within the radical, Valency rules permit ally Substituted alkenyl, hydroxy, alkoxy, alkenyloxy, or ting. When the point of valency is located on a nitrogenatom, cyanoalkyl). R” is absent. More specifically the term heterocycloalkyl 0100 “Optionally substituted amino” refers to the group includes, but is not limited to, aZetidinyl, pyrrolidinyl, 2-ox —N(H)R or —N(R)R where each R is independently opyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-pip selected from the group: optionally substituted alkyl, option eridonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl, tet ally substituted alkoxy, optionally Substituted aryl, optionally rahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, substituted heterocycloalkyl, optionally substituted het thiamorpholinyl, perhydroazepinyl, pyrazolidinyl, imida eroaryl, acyl, carboxy, alkoxycarbonyl, - S(O)-(optionally Zolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridi substituted alkyl). —S(O)-optionally substituted aryl), nyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, —S(O)-(optionally substituted heterocycloalkyl). —S(O)- thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroin (optionally Substituted heteroaryl), and —S(O)-(optionally US 2016/O 137584 A1 May 19, 2016 substituted heteroaryl). For example, “optionally substituted 0108) "Optionally substituted heterocycloalkyl means a amino” includes diethylamino, methylsulfonylamino, and heterocycloalkyl group, as defined herein, optionally Substi furanyl-oxy-Sulfonamino. tuted with one, two, or three substituents independently 0101 “Optionally substituted aminoalkyl means an alkyl selected from acyl, acylamino, acyloxy, optionally substi group, as defined herein, Substituted with at least one, spe tuted alkyl, optionally Substituted alkenyl, alkoxy, alkeny cifically one or two, optionally Substituted amino group(s), as loxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, defined herein. amino, alkylamino, dialkylamino, nitro, aminocarbonyl, 0102) "Optionally substituted aryl' means an aryl group, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, as defined herein, optionally substituted with one, two, or alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alky three Substituents independently selected from acyl, acy laminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, lamino, acyloxy, optionally substituted alkyl, optionally Sub aminoalkoxy, or aryl is pentafluorophenyl. Within the stituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxy optional substituents on "heterocycloalkyl, the alkyl and carbonyl, alkenyloxycarbonyl, amino, alkylamino, alkenyl, either alone or as part of another group (including, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl, for example, the alkyl in alkoxycarbonyl), are independently dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfi optionally substituted with one, two, three, four, or five halo. nyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, 0109 “Optionally substituted heterocycloalkylalkyl dialkylaminosulfonyl, alkylsulfonylamino, aminoalkoxy, or means an alkyl group, as defined herein, Substituted with at aryl is pentafluorophenyl. Within the optional substituents on least one, specifically one or two, optionally Substituted het “aryl', the alkyland alkenyl, either alone or as part of another erocycloalkyl group(s) as defined herein. group (including, for example, the alkyl in alkoxycarbonyl), 0110. As used herein, “6,6'-oxybis(2,2-dimethyl-4-hex are independently optionally substituted with one, two, three, anoic acid) and “6-(5-carboxy-5-methyl-hexyloxy)-2.2- four, or five halo. dimethylhexanoic acid refer to the same chemical structure 0103 “Optionally substituted arylalkyl means an alkyl (3), as depicted below, and therefore they may be used inter group, as defined herein, Substituted with optionally Substi changeably. tuted aryl, as defined herein. 0104 “Optionally substituted cycloalkyl means a cycloalkyl group, as defined herein, Substituted with one, two, or three groups independently selected from acyl, acyloxy, acylamino, optionally substituted alkyl, optionally substi tuted alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, alkeny loxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, amino HO OH Sulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialky laminocarbonyl, nitro, alkoxyalkyloxy, aminoalkoxy, alky 0111. More specifically, it is to be understood that for the laminoalkoxy, dialkylaminoalkoxy, carboxy, and cyano. purposes of the present invention, the terms “6,6'-oxybis(2. Within the above optional substituents on “cycloalkyl, the 2-dimethyl-4-hexanoic acid) calcium.” “6-(5-carboxy-5-me alkylandalkenyl, either alone or as part of another Substituent thyl-hexyloxy)-2,2-dimethylhexanoic acid monocalcium on the cycloalkyl ring, are independently optionally Substi salt,” “CI-1027.” “gemcabene” (USAN nomenclature), and tuted with one, two, three, four, or five halo, e.g. haloalkyl, “compound 3’ name the same chemical structure. Therefore, haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl. it is to be understood that the names may also be used inter 0105 “Optionally substituted cycloalkylalkyl means an changeably. alkyl group Substituted with at least one, specifically one or two, optionally substituted cycloalkyl groups, as defined EMBODIMENTS herein. 0106 "Optionally substituted heteroaryl' means a het 0112. In one aspect, compounds of formula (III) and cor eroaryl group optionally Substituted with one, two, or three responding salts are prepared according to Scheme 1. Substituents independently selected from acyl, acylamino, acyloxy, optionally Substituted alkyl, optionally Substituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl, Scheme 1 alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro, O aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl, alkylsulfonyl, ami R2 nosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, ORI -- alkylsulfonylamino, aminoalkoxy, alkylaminoalkoxy, and R3 dialkylaminoalkoxy. Within the optional substituents on "het I eroaryl', the alkyl and alkenyl, either alone or as part of M2 another group (including, for example, the alkyl in alkoxy No X 1S-1N1'N-1N1pi X carbonyl), are independently optionally substituted with one, R2 II two, three, four, or five halo. 21 ORI e 0107 “Optionally substituted heteroarylalkyl means an alkyl group, as defined herein, Substituted with at least one, R3 specifically one or two, optionally substituted heteroaryl Ia group(s), as defined herein. US 2016/O 137584 A1 May 19, 2016
-continued metal's valency value (1 for Li, 2 for Zn, etc.). M is selected O O from, for example, Zn, Na, Li, and Grignard reagents —Mg O Halo. More particularly, Halo is selected from the group ox^- N-so -as consisting of iodo, bromo, and chloro. I0122. In some embodiments, R is optionally substituted alkyl, optionally substituted cycloalkyl, optionally Substi III tuted cycloalkylalkyl, optionally substituted heterocy O O cloalkyl, optionally substituted heterocycloalkylalkyl, O O O (M), optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted het R2 R3 R3 R2 eroarylalkyl, optionally Substituted amino, optionally Substi I V tuted alkylamino, optionally Substituted aminoalkyl, option ally substituted dialkylamino, or optionally substituted 0113. In Scheme 1, an ester of formula (I) is reacted with alkylsilyl. a deprotonating reagent to produce an intermediate of for 0123. In one embodiment, the deprotonating agent is an mula (Ia). alkylmetal base. The alkylmetal base may be used a ratio from 0114. In other aspects, the compound of formula (III) is 0.5 eqto a slight equimolar excess relative to the bis-halide of hydrolyzed to produce a compound of formula (V). formula (2). 0.124 Organometallic reagents such as (R)-M a CO mercially available (Aldrich Chemical Co., Milwaukee, Wis., V FMC Lithium Lithco Product List, etc.). In some embodi O O ments, organometallic reagents can be prepared by well known methods (Kharasch et al., Grignard Reactions of Non O Metallic Substances; Prentice-Hall, Englewood Cliffs, N.J., HO pi iii. OH pp. 138-528 (1954) and Hartley; Patai, The Chemistry of the R2 R3 R3 R2 Metal-Carbon Bond, Vol. 4, Wiley: New York, pp. 159-306 and pp. 162-175 (1989)). 0115 Esters of formula (I) are commercially available 0.125. In some embodiments, the reaction of an (R)-M (Aldrich Chemical Co., Milwaukee, Wis.). In some embodi organometallic reagent with the ester of formula (I) to provide ments, an ester of formula (I) is prepared by well-known metal enolates, such as lithioenolates, can be performed using synthetic methods, for example, via esterification of isobu the general procedures described in March, J. Advanced tyric acid (commercially available, Aldrich Chemical Co., Organic Chemistry, Reactions Mechanisms, and Structure, Milwaukee, Wis.). 4th ed., 1992, pp. 920-929 and Eicher, Patai, The Chemistry of 0116. In some embodiments, R is alkyl. More particu the Carbonyl Group, pt. 1, pp. 621-693; Wiley: New York, larly, R is C-Cs alkyl. In otherembodiments, R' is methylor (1966). In other embodiments, the synthetic procedure ethyl. More particularly, R is ethyl. described in Comins, D. et al., Tetrahedron Lett. 1981, 22, I0117. In some embodiments, R and Rare each indepen 1085, can be used. dently selected from alkyl, cycloalkyl, cycloalkylalkyl, het I0126. In one embodiment, the reaction is performed by erocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, het adding an organic solution of (R)-M (approximately 0.5 to eroaryl, or heteroarylalkyl. In some embodiments, RandR approximately 1.5 eq) to a stirred, cooled (approximately 0° are selected from C-C alkyl, C-C cycloalkyl, heterocy C. to approximately -80°C.) Solution comprising an ester of cloalkyl, aryl, or heteroaryl. In one embodiment, RandR formula (I). In some embodiments, this step is performed are both C-C alkyl. More particularly, R and Rare both under an inert atmosphere. Such as nitrogen or argon gas. methyl. In other embodiments, RandR are both phenyl. In More particularly, (R)-M is added at such a rate that the other embodiments, R is methyl and R is o-tolyl. In one temperature of the reaction mixture remains within approxi embodiment, R and Rare the same. In other embodiments, mately one to five degrees of the initial temperature of the R° and Rare different. ester of formula (I). 0118. In some embodiments, M' is an alkaline earth metal I0127. Non-limiting examples of suitable organometallic or alkali metal. More particularly, M' is Ca or K. reagents include: 0119. In one embodiment, X is 1 or 2. 0.128 i. alkylmetal bases, such as methyllithium, n-bu 0120 In some embodiments, n and m are each indepen tyllithium, tert-butyllithium, sec-butyllithium, phenyl dently 0-4. In one embodiment, Rand Rare the same. In lithium, phenyl sodium, phenyl potassium, n-hexyl other embodiments, Rand Rare different. In one embodi lithium, n-heptyllithium, and n-octyllithium; ment, n and m are independently 1 or 2. In another embodi 0.129 ii. metal amide bases, such as lithium amide, ment, n is 0 and m is 1. In another embodiment, n is 1 and m Sodium amide, potassium amide, lithium tetramethylpi is 2. In another embodiment, n is 2 and m is 3. In another peridide, lithium diisopropylamide, lithium diethyla embodiment, n is 3 and m is 4. In another embodiment, both mide, lithium dicyclohexylamide, sodium hexamethyl in and mare 0. In another embodiment, both n and mare 1. In disilazide, and lithium hexamethyldisilazide: another embodiment, both n and mare 2. In another embodi 0.130 iii. hydride bases, such as sodium hydride and ment, both n and mare 3. In another embodiment, both n and potassium hydride; m are 4. 0.131I iv. metal amide bases, such as lithium diisopro 0121. In some embodiments, the deprotonating reagent is pylamide; and an organometallic reagent. More particularly, the organome 0.132 v. non-pyrophoric lithium derivatives, such as tallic reagent is (R)-M, wherein M is a metal, and p is the n-hexyllithium, n-heptyllithium, and n-octyllithium. US 2016/O 137584 A1 May 19, 2016
0.133 More particularly, the organometallic reagent is degrees of the initial temperature of the ester solution. An selected from n-butyllithium, n-hexyllithium, n-heptyl exemplary procedure, which describes large scale metalla lithium, and n-octyllithium in hexane Solutions of various tions using n-butyllithium at low temperatures is published in molar concentrations, but no less than 2M, commercially Ashwood, M. S. et al., Organic Process Research & Devel available in bulk quantities from commercial Suppliers, for opment 2004, 8, 192-200. example, Sigma-Aldrich FMC Lithium Lithco Product List. 0.139. In one embodiment, the organic solvent is tetrahy 0134. In some embodiments, the process is used for large drofuran, 2-methyltetrahydrofuran, or mixtures thereof. scale production of compounds of formula (III) or formula 0140. In another embodiment, the metallation reagent is (V) and corresponding salts of formula (IV). In one embodi selected from LDA, n-hexyllithium and n-heptyllithium. ment, the organometallic reagent in the large scale process is 01.41 Exemplary procedures in which the metallation selected from n-hexyllithium, n-heptyllithium, and n-octyl agent is n-hexyllithium are described in Baenziger, M. et al. lithium. Org. Proc. Res. Dev. 1997, 1,395, Bishop, B. et al., US Pub 0135 Suitable organic solvents for the reaction of the ester no. 2006/0149069 A1 (WO2004078109), and Li, G. et al., US of formula (I) with the deprotonating agent include, but are Pub. No. 2007/0105857 (WO2007044490). Exemplary pro not limited to, dichloromethane, diethyl ether, tetrahydrofu cedures in which metallation reagents used are selected from ran, 2-methyltetrahydrofuran, dimethylformamide, dimethyl n-hexyllithium and n-heptyllithium are found in Harmata, M. Sulfoxide, benzene, toluene, Xylene, hydrocarbon solvents et al., Chem. Commun. 2003, 2492-2493. See also Lochmann, (such as pentane, hexane, and heptane), and mixtures thereof. L. et al., U.S. Pat. No. 3,971,816: Lipton, M. F. et al., Organic 0136. More particularly, in some embodiments, the Process Research & Development 2003, 7,385-392, which organic solvent or mixture of solvents is chosen in order to describes preparations of lithioesters. influence favorably to optimize conversion to the lithioeno 0142. In all examples, the progress of the reaction can be late by modulating the concentration of the lithium aggregate followed using an appropriate analytical method, such as (RLi)x(-LiX)y formation, as described in Gossage, R. A. et thin-layer chromatography or high-performance-liquid chro al., Angew. Chem. Int. Ed. 2005, 44, 1448-1454. More par matography. ticularly, the solvent is selected from tetrahydrofuran, 2-me 0143. In some embodiments, after the deprotonation step, thyltetrahydrofuran, and mixtures thereof. In one embodi the C,c)-halo-terminated dialkane ether of formula (II) in an ment, the lithium reagent/solvent system in the large scale appropriate solvent is added to the intermediate of formula process is n-hexyllithium and hexane (See Stoufferet al., U.S. (Ia) to provide a compound of formula (III). In some embodi Pat. No. 6,239,300). ments, the dialkane ether of formula (II) is added with cooling 0137 In some embodiments, the reaction of the ester of and stirring. More particularly, the addition is performed at a formula (I) with the deprotonating agent is performed in the rate such as the temperature variations are no more than five presence of additives. Additives may be added, for example, degrees of the initial temperature of the ester. to improve the selectivity of lithiation by breaking up the 0144. In some embodiments, the reaction mixture can be lithium oligomers and stabilize the lithiated intermediate. quenched with an aqueous solution (such as sodium chloride, Particularly, solvents such as DMSO or chelating additives ammonium chloride, etc.), and the product can be isolated by Such as diamines, tetraalkylureas, and cyclic alkylureas, are typical workup methods. Suitable solvents for solubilizing a used. Non-limiting examples of Such chelating additives compound of formula (III) include, but are not limited to, include, but are not limited to, 1,3-dimethyl-3,4,5,6-tetrahy dichloromethane, diethyl ether, tetrahydrofuran, 2-methyltet dro-2(1H)-pyrimidinone (DMPU), hexamethylphosphora rahydrofuran, benzene, toluene, Xylene, hydrocarbon Sol mide (HMPA), N.N.N',N'-tetramethylethylenediamine vents (such as pentane, hexane, and heptane), and mixtures (TMEDA), and bis(N,N'-dimethylaminoethyl)ether. Exem thereof. plary procedures are described in Wu, J.-P. et al., Tetrahedron (0145. In one embodiment, after the reaction is deemed Letters 2009, 50,5667-5669 (large scale lithiation using LDA Substantially complete by using an appropriate analytical and bis(N,N'-dimethylaminoethyl)ether)), Van der Veen, R. method, the reaction mixture containing the compound of H. et al., J. Org. Chem. 1985, 50, 342-346 (for the LDA formula (III) is hydrolyzed in the presence of an alkaline earth HMPT reaction tandem), Dehmlow, E. V. et al., Synthetic metal salt or base, or oxide, or alkali metal salt or base. The Communications 1998, 18, 487-494 ("Phase Transfer Cata salt formation is accomplished by treating the compound of lytic Preparation of the Dipolar Aprotic Solvents DMI and formula (III) with an oxide, base, or salt in refluxing alcohols DMPU”), Beck, A. K. et al., “N,N-Dimethylpropyleneurea”, for 2 to 96 hours. Typical examples include, but are not in Encyclopedia of Reagents for Organic Synthesis. New limited to, hydrolysis with KCO in a refluxing mixture of York: John Wiley & Sons, 2001, Mukhopadhyay, T. et al., DMSO and water. Further suitable procedures are referenced Helvetica Chimica Acta 1982, 65,385-391 (“Substitution of in Houben-Weyl, Methoden der Organische Chemie, Georg HMPT by the Cyclic Urea DMPU as a Cosolvent for highly Thieme Verlag Stuttgart 1964, vol. XII/2, pp. 143-210 and Reactive Nucleophiles and Bases'). 872-879, or Anderson, N. G., Practical Process Research & 0138. In some embodiments, the reaction of the ester of Development, Academic Press, London, 2000, pp. 93-94 and formula (I) with the deprotonating agent can be performed by 181-182. adding a solution comprising an ester of formula (I) to a 0146 In yet another embodiment, the process comprises stirred, cooled organic solution (approximately 20° C. to treating a solution of a compound of formula (III) in a water approximately -80° C.) of (R)-M (approximately 0.5 to miscible solvent with an aqueous solution of a base. More approximately 1.5 eq). In some embodiments, the reaction is particularly, the water-miscible solvent is selected from performed under an inert atmosphere, such as nitrogen or DMF, DMSO, acetone, methanol, isopropyl alcohol, and argon gas. Preferably, the Solution comprising an ester of ethanol. formula (I) is added at such a rate that the temperature of the 0.147. In yet another embodiment, the process comprises reaction mixture remains within approximately one to five treating a solution of the compound of formula (III) in a US 2016/O 137584 A1 May 19, 2016
water-immiscible solvent with an aqueous solution of a base. 0162 (g) humidifying the precipitate resultant from More particularly, the water-immiscible solvent is selected step (f) to obtain a crystalline salt of C.O)-dicarboxylic from toluene, xylene, methyl ethyl ketone, and methyl isobu acid-terminated dialkane ether of formula (IV). tyl ketone. 0148. In yet another embodiment, the process comprises (0163. In some embodiments, the metal salt of an O.co treating a solution of the compound of formula (III) in a dicarboxylic acid-terminated dialkane ether of formula (IV) water-miscible solvent with an aqueous solution of calcium is isolated in a specific and consistently reproducible poly hydroxide or calcium oxide. More particularly, the water morph. miscible solvent is selected from DMF, DMSO, acetone, 0164. In a further embodiment, the process further com methanol, isopropyl alcohol, and ethanol. prises the preparation of a C.O)-dicarboxylic acid-terminated 0149. In another embodiment, the process further com dialkane ether, wherein the process comprises the steps of: prises performing an aqueous work-up of the Solution of step (b) in order to isolate an organic fraction of the compound of 0.165 (a) reacting a solution comprising a Substituted formula (III). acetic acid ester of formula (I) with a deprotonating 0150. In another embodiment, the process further com reagent to produce an intermediate of formula (Ia); prises the step of treating the crude compound of formula (III) 0166 (b) reacting the intermediate of formula (Ia) with with a hydroxide or oxide of an alkali or earth alkaline metal a solution comprising a C.O)-halo-terminated dialkane in a suitable solvent. ether of formula (II): 0151. In another embodiment, the process further com prises the step of precipitating the salt of the O.co-dicarboxylic 0.167 (c) performing an aqueous work-up of the solu acid-terminated dialkane ether of formula (IV) in the pres tion of step (b) in order to isolate an organic Solution of ence of an organic solvent. the compound of formula (III); and 0152. In another embodiment, the process further com 0168 (d) treating the crude compound of formula (III) prises the step of removing the organic layer by evaporation to of step (c) with a hydroxide or oxide of an alkali or earth afford crude crystalline C,c)-dicarboxylic acid-terminated alkaline metal in a Suitable solvent. dialkane ether salt of formula (IV) as an alcohol solvate or hydrate. 0169. In a further embodiment, the process further com 0153. In another embodiment, the process further com prises the preparation of a crystalline Salt of a C.O)-dicarboxy prises the step of adding one or more anti-solvents to the Solid lic acid-terminated dialkane ether of formula (IV), wherein so that the salt of the C,c)-dicarboxylic acid-terminated dial the process comprises the steps of kane ether of formula (IV) is insoluble. 0170 (e) precipitating the salt of the C,c)-dicarboxylic 0154) In another embodiment, the process further com acid-terminated dialkane ether of formula (IV) in the prises the step of humidifying the precipitate to obtain a presence of an organic solvent; or, alternatively, remov crystalline Salt of C. ()-dicarboxylic acid-terminated dialkane ing the organic layer by evaporation to afford crude ether of formula (IV). crystalline C,c)-dicarboxylic acid-terminated dialkane 0155. In a further embodiment, the process further com ether salt of formula (IV) in the form of an alcohol prises the preparation of a crystalline salt of a C.O)-dicarboxy solvate or hydrate; lic acid-terminated dialkane ether of formula (IV) at multi 0171 (f) adding one or more anti-solvents to the solid of kilogram Scale, wherein the process comprises the steps of step (e) in which the salt of the C,c)-dicarboxylic acid 0156 (a) reacting a solution comprising a Substituted terminated dialkane ether of formula (IV) is insoluble; acetic acid ester of formula (I) with a deprotonating and reagent to produce an intermediate of formula (Ia); 0157 (b) reacting the intermediate of formula (Ia) with 0172 (g) humidifying the precipitate resultant from a solution comprising a C.O)-halo-terminated dialkane step (f) to obtain a crystalline salt of C.O)-dicarboxylic ether of formula (II): acid-terminated dialkane ether of formula (IV). 0158 (c) performing an aqueous work-up of the solu 0173. In a particular embodiment, the invention provides a tion of step (b) in order to isolate an organic Solution of method for the preparation of crystalline 6,6'-oxybis(2.2- the compound of formula (III); dimethyl-4-hexanoic acid) calcium of formula (VIII), 0159 (d) treating the crude compound of formula (III) wherein the process comprises the steps of: of step (c) with a hydroxide or oxide of an alkali or earth 0.174 (a) reacting a solution of ethyl isobutyrate of for alkaline metal in a Suitable solvent; mula (IXa) 0160 (e) precipitating the salt of the C,c)-dicarboxylic acid-terminated dialkane ether of formula (IV) in the presence of an organic solvent; or, alternatively, remov IXa ing the organic layer by evaporation to afford crude crystalline C,c)-dicarboxylic acid-terminated dialkane ether salt of formula (IV) in the form of an alcohol OEt solvate or hydrate; 0.161 (f) adding one or more anti-solvents to the solid of step (e) in which the salt of the O.co-dicarboxylic acid terminated dialkane ether of formula (IV) is insoluble; 0.175 with a deprotonatingp 9. reagent9. to pproduce a com and pound of formula (X): US 2016/O 137584 A1 May 19, 2016
X Scheme 2 M2 No O
a1 Yor OEt --
IX M2 0176 (b) reacting the ethyl lithiobutyrate of step (a) with a solution of bis(4-chlorobutylether) of formula No Hal 1-1N1'N-1N1a Hal 21 XI (XI): OEt
XI X O O Hal 1-1N1'N-1-1a Hal O EtO OEt 0177 (c) performing an aqueous work-up of the solu tion of step (b) in order to isolate an organic Solution of 3 crude diethyl 6,6'-oxybis(2,2-dimethyl-4-hexanoate) of formula (3):
O O 3 O O O Ca2+ O O
O 4 EtO OEt 0185. In a particular embodiment, the invention provides a method for the preparation of a C.O)-dicarboxylic acid-termi 0.178 (d) treating the crude diethyl 6,6'-oxybis(2.2- nated dialkane ether, wherein the process comprises the steps dimethyl-4-hexanoate) of formula (3) of step (c) with a of: calcium hydroxide or calcium oxide of an alkali or earth 0186 (a) reacting a solution of ethyl isobutyrate of for alkaline metal in a Suitable solvent; mula (IX) with a deprotonating reagent; 0179 (e) precipitating the 6,6'-oxybis(2,2-dimethyl-4- 0187 (b) reacting the ethyl lithiobutyrate of step (a) hexanoic acid) calcium of formula (4): with a solution of bis(4-chlorobutylether) of formula (XI): 0188 (c) performing an aqueous work-up of the solu 4 tion of step (b) in order to isolate an organic Solution of crude diethyl 6,6'-oxybis(2,2-dimethyl-4-hexanoate) of O O formula (3): O C a2+ 0189 (d) treating the crude diethyl 6,6'-oxybis(2.2- O O dimethyl-4-hexanoate) of formula (3) of step (c) with a calcium hydroxide or calcium oxide of an alkali or earth alkaline metal in a Suitable solvent. 0190. In a further embodiment, the process further com 0180 in the presence of an organic solvent, or, alter prises the preparation of 6,6'-oxybis(2,2-dimethyl-4-hex natively, removing the organic layer by evaporation to anoic acid) calcium of formula (4), wherein the process com afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4- prises the steps of hexanoic acid) salt of formula (4) as an alcohol Solvate 0191 (e) precipitating the 6,6'-oxybis(2,2-dimethyl-4- or hydrate; hexanoic acid) calcium of formula (4) in the presence of 0181 (f) adding one or more anti-solvents to the solid of an organic solvent; or, alternatively, removing the step (e) in which 6,6'-oxybis(2,2-dimethyl-4-hexanoic organic layer by evaporation to afford crude crystalline acid) calcium of formula (4) is insoluble; and 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid) salt of for 0182 (g) humidifying the precipitate resultant from mula (4) as an alcohol Solvate or hydrate; step (f) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- 0.192 (f) adding one or more anti-solvents to the solid of hexanoic acid) calcium of formula (4). step (e) in which 6,6'-oxybis(2,2-dimethyl-4-hexanoic 0183 In some embodiments, the 6,6'-oxybis(2,2-dim acid) calcium of formula (4) is insoluble; and ethyl-4-hexanoic acid) calcium of formula (4) is isolated in a 0193 (g) humidifying the precipitate resultant from specific and consistently reproducible polymorph. step (f) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- 0184. In a further embodiment, compounds of formula (3) hexanoic acid) calcium of formula (4). and corresponding salts (4) are prepared according to Scheme 0194 In another aspect, compounds of formula (III) and 2. corresponding salts may be prepared under certain conditions US 2016/O 137584 A1 May 19, 2016
according to Scheme 3, which utilizes a Reformatsky reac another embodiment, both n and mare 2. In another embodi tion. In Scheme 2, an O-bromoacetic acid ester of formula ment, both n and mare 3. In another embodiment, both n and (XV) is reacted with a bis(haloalkyl)ether of formula (II) and m are 4. a metal to provide a compound of formula (III). Examples of (0200. In some embodiments, M' is an alkaline earth metal Reformatsky reactions are described in Jun, I. Molecules or alkali metal. More particularly, M' is Ca or K. 2012, 17, 14249-14259. Exemplary procedures of Refor 0201 In one embodiment, the reaction is performed in the matsky reactions are collected on-line, on the Organic Chem presence of a metal selected from Zinc, magnesium, manga istry Portal at www.organic-chemistry.org/namedreactions/ nese, and indium. More particularly, the reaction is performed reformatsky-reaction.shtm (last visited Nov. 12, 2014). in the presence of zinc. 0202 In one embodiment, the reaction is performed using a solvent selected from toluene, xylene, ethers, tetrahydrofu Scheme 3 ran, diethyl ether, methyl t-butyl ether, and 2-methyltetrahy drofuran. In other embodiments, aqueous solutions of cal pi iii. Br O X 1n 1N1 'Nu-1N1\ X cium or ammonium chloride can be optionally used, as ORI II described in Bieber, L. W., J. Org. Chem. 1997, 62, 9061 9064. R2 R3 XV 0203. In some embodiments, initiators and/or catalysts are O O employed. Examples of initiators and catalysts include, but are not limited to, iodine (see Zitsman, J. et al. Tetrahedron ox^- O n-n-so -e- Letters 1971, 44, 4201-4204, and Johnson, P.Y. et al., J. Org. R2 R3 R3 R2 Chem. 1973, 38, 2346-2350). For MCPBA and MMPP see Bieber, L. W. J. Org. Chem. 1997, 62,9061-9064. III 0204. In one embodiment, the C-bromoester of formula O O (XV) is cooled to -20°C. to 0°C. In some embodiments, the O reaction is performed in an inert atmosphere. Such as nitrogen --~n- N-n-so (M), or argon gas. R2 R3 R3 R2 0205. In some embodiments, the C-bromoester of formula IV (XV) is further treated with approximately 1 to 2.5 eq of a metal, more particularly 1 eq, in a solvent. More particularly, 0.195. In other aspects, the compound of formula (III) is the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or hydrolyzed to produce a compound of formula (V). toluene. 0206. In one example, the suspension is stirred until the metal is essentially dissolved. V 0207. In one embodiment, if necessary, a catalyst is added O O as a reaction initiator. The bis(halo)ether of formula (II) is then added at a flow rate that maintains the temperature O between 0 and 10° C. during addition. Alternatively, the solu HO pi iii. OH tion of the metallated C-bromoester of formula (XV) is added R2 R3 R3 R2 dropwise into the bis(halo)ether of formula (II) solution in an appropriate solvent. (0196) In some embodiments of formula (V), R is alkyl. 0208. The reaction mixture is then warmed to RT. If the More particularly, R' is C1-C8 alkyl. In other embodiments, reaction is not complete as determined by an appropriate R" is methyl or ethyl. More particularly, R is ethyl. analytical method the mixture is then heated at 40 to 60° C. for (0197) In some embodiments, R and Rare each indepen several hours, particularly 50° C. for 4 hours. dently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, 0209. In some embodiments, the reaction mixture is kept heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or het under vigorous stirring for several hours or up to 2 days until eroarylalkyl. In some embodiments, R and Rare selected the conversion to the desired product has ceased. from C-Cs alkyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In one embodiment, R and R are both C-Cs 0210. After the reaction is deemed substantially complete alkyl. More particularly, R and Rare both methyl. In other using an appropriate analytical method, the reaction mixture embodiments, RandR are both phenyl. In other embodi containing the compound of formula (III) may be subjected to ments, R is methyl and R is o-tolyl. In one embodiment, R workup and extraction in an organic solvent. and Rare the same. In other embodiments, R and Rare 0211. The crude product may be hydrolyzed in the pres different. ence of an alkaline earth metal salt or base, oxide, or alkali 0198 In some embodiments, X is 1 or 2. metal salt or base to yield the diacid of formula (IV), as 0199. In some embodiments, n and m are each indepen described for the examples in Scheme 2. dently 0-4. In one embodiment, R and R are the same. In 0212. In some embodiments, the process further com other embodiments, R and Rare different. In one embodi prises performing an aqueous work-up of the solution to ment, n and m are independently 1 or 2. In another embodi isolate an organic fraction of the compound of formula (III). ment, n is 0 and m is 1. In another embodiment, n is 1 and m 0213. In one embodiment, the process further comprises is 2. In another embodiment, n is 2 and m is 3. In another the step of treating the crude compound of formula (III) with embodiment, n is 3 and m is 4. In another embodiment, both a hydroxide or oxide of an alkali or earth alkaline metal in a in and mare 0. In another embodiment, both n and mare 1. In suitable solvent. US 2016/O 137584 A1 May 19, 2016
0214. In one embodiment, the process further comprises the step of precipitating the salt of the O.co-dicarboxylic acid II terminated dialkane ether of formula (IV) in the presence of an organic solvent. 1n-h-N-N-1S 0215. In another embodiment, the process further com prises the step of removing the organic layer by evaporation to wherein X is halo: afford crude crystalline C,c)-dicarboxylic acid-terminated 0226 (c) performing an aqueous work-up of the solu dialkane ether salt of formula (IV) as an alcohol solvate or tion of step (b) in order to isolate an organic fraction of hydrate. the compound of formula (III); 0227 (d) treating the crude compound of formula (III) 0216. In one embodiment, the process further comprises of step (c) with a hydroxide or oxide of an alkali or earth the step of adding one or more anti-solvents to the Solid so that alkaline metal in a Suitable solvent; the salt of the O.co-dicarboxylic acid-terminated dialkane 0228 (e) precipitating the salt of the C,c)-dicarboxylic ether of formula (IV) is insoluble. acid-terminated dialkane ether of formula (IV) in the 0217. In one embodiment, the process further comprises presence of an organic solvent; or, alternatively, remov the step of humidifying the precipitate to obtain a crystalline ing the organic layer by evaporation to afford crude salt of a C.O)-dicarboxylic acid-terminated dialkane ether of crystalline C,c)-dicarboxylic acid-terminated dialkane formula (IV). ether salt of formula (IV) as an alcohol solvate or 0218. In some embodiments, the process is used for large hydrate; scale production of compounds of formula (III) or formula 0229 (f) adding one or more anti-solvents to the solid of (V) and corresponding salts of formula (IV). step (e) in which the salt of the C,c)-dicarboxylic acid 0219. In yet another embodiment, the process comprises terminated dialkane ether of formula (IV) is insoluble; treating a solution of a compound of formula (III) in a water and miscible solvent with an aqueous solution of a base. More 0230 (g) humidifying the precipitate resultant from particularly, the water-miscible solvent is selected from step (f) to obtain a crystalline salt of a C.O)-dicarboxylic DMF, DMSO, acetone, methanol, isopropyl alcohol, and acid-terminated dialkane ether of formula (IV). ethanol. 0231. In some embodiments, the C,c)-dicarboxylic acid terminated dialkane ether of formula (IV) is isolated in a 0220. In yet another embodiment, the process comprises specific and consistently reproducible polymorph. treating a solution of the compound of formula (III) in a 0232. In a particular embodiment, the invention provides a water-immiscible solvent with an aqueous solution of a base. method for the preparation of a C.O)-dicarboxylic acid-termi More particularly, the water-immiscible solvent is selected nated dialkane ether, wherein the process comprises the steps from toluene, xylene, methyl ethyl ketone, and methyl isobu of: tyl ketone. 0233 (a) reacting a solution comprising an O-bromo 0221. In yet another embodiment, the process comprises acetic acid ester of formula (XV): treating a solution of the compound of formula (III) in a water-miscible solvent with an aqueous solution of calcium hydroxide or calcium oxide. More particularly, the water XV miscible solvent is selected from DMF, DMSO, acetone, O methanol, isopropyl alcohol, and ethanol. Br 0222. In yet another embodiment, the process comprises ORI treating a solution of a compound of formula (III) in a water R2 R3 immiscible solvent with an aqueous solution of calcium hydroxide or calcium oxide. More particularly, the water immiscible solvent is selected from toluene, xylene, methyl with a metal, until the metal is essentially dissolved; ethyl ketone, and methyl isobutyl ketone. 0234 (b) reacting the solution of step (a) with a solution 0223) In a particular embodiment, the process for prepar comprising a C,c)-halo-terminated dialkane ether of for ing the salt of a compound of formula (III) comprises: mula (II) 0224 (a) reacting a solution comprising an O-bromo acetic acid ester of formula (XV): II 1n-h-'N-6)-1a XV O wherein X is halo: Br 0235 (c) performing an aqueous work-up of the solu ORI tion of step (b) in order to isolate an organic fraction of R2 R3 the compound of formula (III); and 0236 (d) treating the crude compound of formula (III) of step (c) with a hydroxide or oxide of an alkali or earth with a metal, until the metal is essentially dissolved; alkaline metal in a Suitable solvent. 0225 (b) reacting the solution of step (a) with a solution 0237. In one embodiment, the process for preparing a comprising a C.O)-halo-terminated dialkane ether of for crystalline salt of a C,c)-dicarboxylic acid-terminated dial mula (II) kane ether of formula (IV) comprises: US 2016/O 137584 A1 May 19, 2016
0238 (e) precipitating the salt of the C,c)-dicarboxylic 0247 (e) precipitating the 6,6'-oxybis(2,2-dimethyl-4- acid-terminated dialkane ether of formula (IV) in the hexanoic acid) calcium of formula (4) presence of an organic solvent; or, alternatively, remov ing the organic layer by evaporation to afford crude crystalline C,c)-dicarboxylic acid-terminated dialkane 4 ether salt of formula (IV) as an alcohol solvate or hydrate; O O O C a?" 0239 (f) adding one or more anti-solvents to the solid of O O step (e) in which the salt of the O.co-dicarboxylic acid terminated dialkane ether of formula (IV) is insoluble; and in the presence of an organic solvent; or, alternatively, 0240 (g) humidifying the precipitate resultant from removing the organic layer by evaporation to afford step (f) to obtain a crystalline salt of a C.O)-dicarboxylic crude crystalline 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid-terminated dialkane ether of formula (IV). acid) salt of formula (4) as an alcohol Solvate or hydrate; 0241. In one embodiment, the process for the preparation 0248 (f) adding one or more anti-solvents to the solid of of a crystalline form of 6,6'-oxybis(2,2-dimethyl-4-hexanoic step (e) in which 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of formula (4), wherein the process comprises the steps of: acid) calcium of formula (4) is insoluble; and 0249 (g) humidifying the precipitate resultant from 0242 (a) reacting a solution of an O-bromo-isobutyric step (f) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- acid ester of formula (XX): hexanoic acid) calcium of formula (4). 0250 In a particular embodiment, the invention provides a method for the preparation of a C.O)-dicarboxylic acid-termi nated dialkane ether, wherein the process comprises the steps Br of: OEt 0251 (a) reacting a solution of an O-bromo-isobutyric acid ester of formula (XX) in a suitable solvent or mix ture of solvents, under inert atmosphere, with a metal, until the metal is essentially dissolved; 0243 in a suitable solvent or mixture of solvents, under inert atmosphere, with a metal, until the metal is 0252 (b) reacting the solution of step (a) with a solution essentially dissolved; of bis(4-chlorobutylether) of formula (XXI) in a suitable solvent or mixture of solvents; 0244 (b) reacting the solution of step (a) with a solution of bis(4-chlorobutylether) of formula (XXI): 0253 (c) performing an aqueous work-up of the solu tion of step (b) in order to isolate an organic Solution of crude diethyl 6,6'-oxybis(2,2-dimethyl-4-hexanoate) of XXI formula (4): Hal 1N1a-'N-1N-1- Hal 0254 (d) treating the crude diethyl 6,6'-oxybis(2.2- dimethyl-4-hexanoate) of formula (4) of step (c) with a calcium hydroxide or calcium oxide of an alkali or earth in a suitable solvent or mixture of solvents; alkaline metal in a Suitable solvent. 0245 (c) performing an aqueous work-up of the solu 0255. In a further embodiment, the process further com tion of step (b) in order to isolate an organic Solution of prises the preparation of 6,6'-oxybis(2,2-dimethyl-4-hex crude diethyl 6,6'-oxybis(2,2-dimethyl-4-hexanoate) of anoic acid) calcium of formula (4), wherein the process com formula (4): prises the steps of 0256 (e) precipitating the 6,6'-oxybis(2,2-dimethyl-4- 3 hexanoic acid) calcium of formula (4) in the presence of an organic solvent; or, alternatively, removing the O O organic layer by evaporation to afford crude crystalline O 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid) salt of for EtO OEt mula (4) as an alcohol Solvate or hydrate; 0257 (f) adding one or more anti-solvents to the solid of step (e) in which 6,6'-oxybis(2,2-dimethyl-4-hexanoic 0246 (d) treating the crude diethyl 6,6'-oxybis(2.2- acid) calcium of formula (4) is insoluble; and dimethyl-4-hexanoate) of formula (4) of step (c) with a 0258 (g) humidifying the precipitate resultant from calcium hydroxide or calcium oxide of an alkali or earth step (f) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- alkaline metal in a Suitable solvent; hexanoic acid) calcium of formula (4). US 2016/O 137584 A1 May 19, 2016
0259 A further aspect is a process for preparing a com comprising: pound of formula (48) using a Williamson ether synthesis: 0272 (a) reacting a solution of a compound of formula (46a): 48 O O
46a O R R22 R23 N-----R22 R23 HO R21 iii. o1 wherein: 0260 R is alkyl; R22 R23 0261) R' and R are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; 0273 with a halogen source to produce a compound of and formula (47): 0262 m is 0-4: comprising: 0263 (a) reacting a first solution of a compound of formula (46): 47 O X23 R21 46 iii. o1 O R22 R23 HO R21 iii. O1 R22 R23 0274 wherein X* is F, Cl, or I: 0275 (b) reacting a solution of a compound of formula 0264 with a halogen source to produce a compound of (46b): formula (47):
47 O 46b O X2 R21 HO R21 iii. o1 pi O1 R22 R23 R22 R23 0265 wherein X* is F, Cl, or I: 0266 (b) reacting a second solution of a compound of 0276 with the intermediate of formula (47) in the pres formula (46) with the intermediate of formula (37) in the ence of base to form a compound of formula (48a). presence of base to form a compound of formula (48). 0267 In some embodiments, step (a) is in the presence of 0277. In some embodiments, the compound of formula triphenylphosphine. (46a) is different than the compound of formula (46b). In 0268 A further aspect is a process for preparing a com Some embodiments, the compound of formula (46a) is the pound of formula (48a) using a Williamson ether synthesis: same as compound (46b). 0278. Some embodiments further comprise the step of reacting the Solution of a compound of formula (45):
45 wherein: 0269) R' is alkyl; (0270. R’ and R are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and with potassium tert-butoxide to produce an intermediate of 0271 m and n are each in is 0-4: formula (46). US 2016/O 137584 A1 May 19, 2016
0279. Some embodiments further comprise the step of with a deprotonating reagent to produce an intermediate of reacting an intermediate of formula (43a): formula (41a). 0283 Some embodiments further comprise the step of 43a hydrolyzing the compound of formula (48) to produce a com MNo pound of formula (49). R22 O 49 O O )m O HO iii. iii. OH wherein M is Lior Zn; with a solution of an alkylhalide of formula (44): R22 R23 R22 R23 R23X23 44 0284. In some embodiments, the compound of formula wherein X* is halo: (48) is the di-tert-butyl ester of 6,6'-oxy-bis(2,2-dimethyl-4- to produce a compound of formula (45). 0280 Some embodiments further comprise the step of hexanoic acid) (14). reacting the solution of a compound of formula (43):
43
0285 Another aspect is a process for preparing a com pound of formula (49): with a deprotonating reagent to produce an intermediate of formula (43a). 0281. Some embodiments further comprise the step of 49 reacting the intermediate of formula (41a): O O
O 41a. HO iii. iii. OH MSo R22 R23 R22 R23 2 O wherein: )m 0286 R’ and R are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; wherein M is Lior Zn; and with a solution of an alkylhalide of formula (42): R22X22 42 0287 m is 0-4: comprising: wherein X is halo: to produce a compound of formula (43). 0288 (a) reacting a solution of a cyclic lactone of for 0282. Some embodiments further comprise the step of mula (41): reacting a solution of a cyclic lactone of formula (41):
41 41 O US 2016/O 137584 A1 May 19, 2016
0289 with a deprotonating reagent to produce an inter mediate of formula (41a): 46
41a. HO R21
R22 R23
0300 wherein R’ is tert-butyl: 0301 (f) reacting the solution of a compound of for mula (46) with a halogen source to produce an interme 0290 wherein M is Li or Zn; diate of formula (47): 0291 (b) reacting the intermediate of formula (41a) with a solution of an alkylhalide of formula (42): 47 R22X22 42 O 0292 wherein X* is halo: X23 R21 0293 to produce a compound of formula (43): iii. O1 R22 R23
43 O 0302 wherein X* is F, Cl, or I: R22 O 0303 (g) reacting the solution of a compound of for mula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48): )m
0294 (c) reacting the solution of a compound of for mula (43) with a deprotonating reagent to produce an intermediate of formula (43a): R2 O R21
43a S.------N---- R22 R23 R22 R23
0304 (h) reacting the solution of a compound of for mula (48) with dilute acid to form 6,6'-oxy-bis(2,2-dim ethyl-4-hexanoic acid) (49).
0295 wherein M is Li or Zn; 0296 (d) reacting the intermediate of formula (43a) with a solution of an alkylhalide of formula (44): R23X23 44 0297 wherein X* is halo: 0298 to produce a compound of formula (45): R22 R23 R22 R23
45 0305. In some embodiments, step (f) is performed in the O presence of triphenylphosphine, SOCl or SOBr. in pyridine or trialkylamine, or phosphorus (III) bromide or iodide. 23 O 0306 More particularly, in one embodiment, step (f) is carried out in the presence of triphenylphosphine. )m 0307 Some embodiments further comprise the step of 0308 (i) treating the crude diethyl 6,6'-oxybis(2,2-dim 0299 (e) reacting the solution of a compound of for ethyl-4-hexanoate) of formula (49) of step (h) with a mula (45) with potassium tert-butoxide to produce an calcium hydroxide or calcium oxide of an alkali or earth intermediate of formula (46): alkaline metal in a Suitable solvent. US 2016/O 137584 A1 May 19, 2016 18
0309 Some embodiments further comprise the step of 0321 with a deprotonating reagent to produce an inter 0310 () precipitating the 6,6'-oxybis(2,2-dimethyl-4- mediate of formula (41a): hexanoic acid) calcium of formula (50): 41a. 22 50 Ms No
O O 2 O O 1 R22<-n- R23 n-->R22 R23 (M), 0322 wherein M is Lior Zn; 0311 in the presence of an organic solvent; or, alterna 0323 (b) reacting the intermediate of formula (41a) tively, removing the organic layer by evaporation to with a solution of an alkylhalide of formula (42): afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4- R22X22 42 hexanoic acid) salt of formula (50) as an alcohol solvate or hydrate. 0324 wherein X* is halo: 0325 to produce a compound of formula (43): 0312 Some embodiments further comprise the step of 0313 (k) adding one or more anti-solvents to the solid 43 of step () in which 6,6'-oxybis(2,2-dimethyl-4-hex O anoic acid) calcium of formula (50) is insoluble. 0314) Some embodiments further comprise the step of R22 O 0315 (1) humidifying the precipitate resultant from step (k) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- )m hexanoic acid) calcium of formula (50). 0316. Another aspect is a process for preparing a com 0326 (c) reacting the solution of a compound of for pound of formula (48): mula (43) with a deprotonating reagent to produce an intermediate of formula (43a): 48 O O 43a R2 O R21 MNo No iii. N----- R22 O R22 R23 R22 R23 wherein: )m 0317 R’ is alkyl; 0318 R’ and R are each independently alkyl, 0327 wherein M is Lior Zn; cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy 0328 (d) reacting the intermediate of formula (43a) cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl: with a solution of an alkylhalide of formula (44): R23X23 44 0319 m and n are each independently 0-4: 0329 wherein X* is halo: comprising: 0330 to produce a compound of formula (45): 0320 (a) reacting a solution of a cyclic lactone of for mula (41): 45 O R23 41 O O R22
O )m
0331 (e) reacting the solution of a compound of for mula (45) with potassium tert-butoxide to produce an intermediate of formula (46): US 2016/O 137584 A1 May 19, 2016
0345 Another embodiment further comprises the step of 46 performing an aqueous work-up of the Solution of step (g) to O isolate an organic solution of the compound of formula (48). (0346) In some embodiments, X’ and X’ are each inde HO iii. -R" pendently F, Cl, or I. R22 R23 (0347. In some embodiments, R is tert-butyl. (0348. In some embodiments, R’ is methyl, ethyl, or meth 0332 where R is alkyl: ylphenyl. 0333 (f) reacting the solution of a compound of for (0349. In some embodiments, R’ is methyl. mula (46) with a halogen source to produce an interme 0350. In some embodiments, R is methyl, ethyl, or meth diate of formula (47): ylphenyl. 0351. In some embodiments, R is methyl. 47 0352. In another embodiment, the compound of formula (48) is the di-tert-butyl ester of 6,6'-oxy-bis(2,2-dimethyl-4- hexanoic acid). R22 R23 0334 wherein X* is F, Cl, or I and where R is alkyl: 0335 (g) reacting a solution of the compound of for mula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48). > --~x-k 0336. In some embodiments, step (f) is in the presence of triphenylphosphine. 0337 Another embodiment further comprises the step of 0353 Another aspect is a process for preparing 6,6'-oxy performing an aqueous work-up of the solution of step (b) to bis(2,2-dimethyl-4-hexanoic acid): isolate an organic solution of the compound of formula (43). 0338 Another embodiment further comprises the step of performing an aqueous work-up of the solution of step (d) to 3 isolate an organic solution of the compound of formula (45). O O 0339. Another embodiment further comprises the step of performing an aqueous work-up of the solution of step (e) to O isolate an organic solution of the compound of formula (46). HO OH 0340 Another embodiment further comprises the step of performing an aqueous work-up of the Solution of step (f) to isolate an organic solution of the compound of formula (47). comprising: 0341 Another embodiment further comprises the step of hydrolyzing the compound of formula (48) to produce a com 0354 (a) reacting a solution of a cyclic lactone: pound of formula (49). 51 O
O
R22 R23 R22 R23 0355 with a deprotonating reagent to produce an inter 0342 Another embodiment further comprises treating a mediate: solution of a compound of formula (48) with dilute acid. 0343 Some embodiments further comprise treating a solution of a compound of formula (48) in a water-immiscible 51a. solvent with dilute acid, wherein the water-immiscible sol M322 O vent is selected from dichloromethane, diethyl ether, tetrahy drofuran, 2-methyltetrahydrofuran, benzene, toluene, Xylene, hydrocarbon Solvents such as pentane, hexane, and heptane, 2. O and mixtures thereof. 0344 Another embodiment further comprises treating a solution of a compound of formula (48) with a dilute acid selected from the group consisting of trifluoroacetic acid, formic acid, hydrochloric acid, and Sulfuric acid. 0356) wherein M is Lior Zn; US 2016/O 137584 A1 May 19, 2016 20
0357 (b) reacting the intermediate of step (a) with a 0366 (f) reacting a first solution of a compound of step solution of an alkylhalide (e) with a halogen source to produce an intermediate: HC X22 52
13a 0358 wherein X* is halo: O 0359 to produce a compound: O
53 s----k O
HC O 0367 wherein X* is F, Cl, or I: 0368 (g) reacting a second solution of a compound of step (e) with the intermediate of step (f)) in the presence of base to form a compound:
0360 (c) reacting the solution of the compound of step (b) with a deprotonating reagent to produce an interme diate:
5.3a MNo 0369 (h) reacting the solution of a compound of step (g) H3C O with dilute acid to form 6,6'-oxy-bis(2,2-dimethyl-4- hexanoic acid).
3 0361 wherein M is Li or Zn; O O
0362 (d) reacting the intermediate of step (c) with a O solution of an alkylhalide: HO OH HC X2: S4 0363 wherein X* is halo: 0370. A further aspect is a process for preparing crystal 0364 to produce a compound: line 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid) calcium:
26 O 4 HC O O O O C a?" O O
0365 (e) reacting the solution of a compound of step (d) wherein the process comprises: with potassium tert-butoxide to produce an intermedi 0371 (a) reacting a solution of a cyclic lactone: ate:
51 12 O
HO O -k US 2016/O 137584 A1 May 19, 2016 21
0372 with a deprotonating reagent to produce an inter mediate: 12 O
51a. HO O -k M322 O
2. O 0383 (f) reacting a first solution of a compound of step (e) with a halogen source to produce an intermediate:
13a 0373 wherein M is Li or Zn; O 0374 (b) reacting the intermediate of step (a) with a solution of an alkylhalide X23 O -k HC X22 52 0375 wherein X’ is halo: 0376 to produce a compound: 0384 wherein X* is F, Cl, or I: 0385 (g) reacting a second solution of a compound of step (e) with the intermediate of step (f)) in the presence 53 of base to form a compound:
0377 (c) reacting the solution of the compound of step (b) with a deprotonating reagent to produce an interme diate: 0386 (h) reacting the solution of a compound of step (g) with dilute acid to form 6,6'-oxy-bis(2,2-dimethyl-4- hexanoic acid): 5.3a MSNo23 3 HC O O O
O HO OH
0378 wherein M is Li or Zn; 0387 (i) treating the crude diethyl 6,6'-oxybis(2,2-dim 0379 (d) reacting the intermediate of step (c) with a ethyl-4-hexanoate) of step (h) with a calcium hydroxide solution of an alkylhalide: or calcium oxide of an alkali or earth alkaline metal in a HC X2: S4 suitable solvent; 0380 wherein X* is halo: 0388 () precipitating the 6,6'-oxybis(2,2-dimethyl-4- 0381 to produce a compound: hexanoic acid) calcium of step (i)
4 26 O O O C a?" O O
0389 in the presence of an organic solvent; or, alterna 0382 (e) reacting the solution of a compound of step (d) tively, removing the organic layer by evaporation to with potassium tert-butoxide to produce an intermedi afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4- ate: hexanoic acid) salt as an alcohol Solvate or hydrate; US 2016/O 137584 A1 May 19, 2016 22
0390 (k) adding one or more anti-solvents to the solid 0402 to produce a compound of formula (43): of step () in which 6,6'-oxybis(2,2-dimethyl-4-hex anoic acid) calcium is insoluble; and 0391 (1) humidifying the precipitate resultant from step 43 (k) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- O hexanoic acid) calcium. R22 O 0392. In some embodiments, step (f) is in the presence of triphenylphosphine. 0393. In some embodiments, the alcohol solvate or )m hydrate obtained in step () is stirred with tetrahydrofuran with Subsequent addition of one or more anti-solvents to obtain the crystalline form of 6,6'-oxybis(2,2-dimethyl-4- 0403 (c) reacting the solution of a compound of for hexanoic acid) calcium described in step (k). mula (43) with a deprotonating reagent to produce an 0394. A further aspect is a process for preparing a com intermediate of formula (43a): pound of formula (45):
43a 45 O MNo
23 R22 O O
)m )m wherein: 04.04 wherein M is Li or Zn; 0395 R’ and R are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy 0405 (d) reacting the intermediate of formula (43a) cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; with a solution of an alkylhalide of formula (44): and R23X23 44 0396 m is 0-4: comprising: 0406 wherein X* is halo: 0397 (a) reacting a solution of a cyclic lactone of for 0407 to produce a compound of formula (45). mula (41): 04.08 In some embodiments, m is 1. 04.09. In some embodiments, Rand Rare the same. In 41 other embodiments, Rand Rare different. O
O ADDITIONAL EMBODIMENTS
Embodiment 1 m 0410 A process for preparing a compound of formula 0398 with a deprotonating reagent to produce an inter (III): mediate of formula (41a): III
41a. O O M2 O RO pi iii. ORI R2 R3 R3 R2
wherein: 0411) R' is alkyl: 0399 wherein M is Li or Zn; 0412 R and R are each independently alkyl, 04.00 (b) reacting the intermediate of formula (41a) cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy with a solution of an alkylhalide of formula (42): cloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroaryla R22X22 42 lkyl; and 0401 wherein X* is halo: 0413 n and mare each independently 0-4: US 2016/O 137584 A1 May 19, 2016 comprising: crystalline form the C,c)-dicarboxylic acid-terminated dial 0414 (a) reacting a solution comprising a Substituted kane ether salt of formula (IV). acetic acid ester of formula (I): Embodiment 7 0425 The process of any of embodiments 1-6, further comprising the step of adding one or more anti-solvents so that the salt of the C,c)-dicarboxylic acid-terminated dialkane ORI ether of formula (IV) is insoluble. R3 Embodiment 8 0426. The process of any of embodiments 1-7, further 0415 with a deprotonating reagent to produce an inter comprising the step of humidifying the precipitate to obtain a mediate of formula (Ia): crystalline salt of a C,c)-dicarboxylic acid-terminated dial kane ether of formula (IV). Ia Embodiment 9 0427. The process of any of embodiments 1-8, further comprising the step of hydrolyzing the compound of formula (III) to produce a compound of formula (V).
0416) wherein M is Lior Zn; and V 0417 (b) reacting the intermediate of formula (Ia) with O O a solution comprising a C.O)-halo-terminated dialkane O ether of formula (II) HO pi iii. OH R2 R3 R3 R2 II
Embodiment 10 0418 wherein X is halo: 0428 The process of any of embodiments 1-9, comprising 0419 to produce a compound of formula (III). treating a solution of a compound of formula (III) in a water Embodiment 2 miscible solvent with an aqueous solution of a base, wherein 0420. The process of embodiment 1, further comprising the water-miscible solvent is selected from DMSO, DMF, the step of performing an aqueous work-up of the Solution of methanol, isopropyl alcohol, and ethanol. step (b) to isolate an organic solution of the compound of formula (III). Embodiment 11 Embodiment 3 0429. The process of any of embodiments 1-10, compris 0421. The process of any of embodiments 1-2, further ing treating a solution of a compound of formula (III) in a comprising the step of treating the crude compound of for water-immiscible solvent with an aqueous solution of a base, mula (III) with an aqueous solution of a hydroxide or oxide of wherein the water-immiscible solvent is selected from tolu an alkali or earth alkaline metal. ene, Xylene, methyl ethyl ketone, and methyl isobutyl ketone. Embodiment 4 Embodiment 12 0422 The process of any of embodiments 1-3, further comprising the step of precipitating the salt of the C,c)-dicar 0430. The process of any of embodiments 1-11, compris boxylic acid-terminated dialkane ether of formula (IV) in the ing treating a solution of a compound of formula (III) in a presence of an organic solvent. water-miscible solvent with an aqueous solution of calcium hydroxide or calcium oxide, wherein the water-miscible sol Embodiment 5 vent is selected from DMSO, DMF, acetone, methanol, iso 0423. The process of any of embodiments 1-4, further propyl alcohol, and ethanol. comprising the step of removing the organic layer by evapo ration to afford crude crystalline C,c)-dicarboxylic acid-ter Embodiment 13 minated dialkane ether salt of formula (IV) in the form of an alcohol solvate or hydrate. 0431. The process of any of embodiments 1-12, compris ing treating a solution of a compound of formula (III) in a Embodiment 6 water-immiscible solvent with an aqueous solution of cal 0424 The process of any of embodiments 1-5, wherein the cium hydroxide or calcium oxide, wherein the water-immis alcohol solvate or hydrate is stirred with tetrahydrofuran with cible solvent is selected from toluene, xylene, methyl ethyl Subsequent addition of one or more anti-solvents to obtain the ketone, and methyl isobutyl ketone. US 2016/O 137584 A1 May 19, 2016 24
Embodiment 14 Embodiment 27 0432. The process of any of embodiments 1-13, wherein 0445. The process of any of embodiments 1-26, whereinn step (a) is performed under inert atmosphere. and m are different. Embodiment 15 Embodiment 28 0433. The process of any of embodiments 1-14, wherein 0446. The process of any of embodiments 1-27, whereinn the deprotonating reagent is selected from hexyllithium and and m are each 1. heptyllithium. Embodiment 29 Embodiment 16 0447 The process of any of embodiments 1-28, wherein 0434. The process of any of embodiments 1-15, wherein the compound of formula (III) is 6,6'-oxy-bis(2,2-dimethyl the solvent in step (a) is selected from dichloromethane, 4-hexanoic acid) (Compound 3). diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dim ethylformamide, dimethyl sulfoxide, benzene, toluene, Xylene, hydrocarbon solvents such as pentane, hexane, and 3 heptane, and mixtures thereof. O O
Embodiment 17 O 0435 The process of any of embodiments 1-16, wherein EtO OEt the solvent in step (b) is dichloromethane, diethyl ether, tet rahydrofuran, 2-methyltetrahydrofuran, benzene, toluene, Xylene, hydrocarbon solvents such as pentane, hexane, and heptane, and mixtures thereof. Embodiment 30 Embodiment 18 0448. A process for preparing 6,6'-oxy-bis(2,2-dimethyl 4-hexanoic acid): 0436 The process of any of embodiments 1-17, wherein X is F, Cl, or I. 3 Embodiment 19 O O 0437. The process of any of embodiments 1-18, wherein X is C1. O HO OH Embodiment 20 0438. The process of any of embodiments 1-19, wherein R" is methyl or ethyl. comprising: 0449 (a) reacting a solution comprising a Substituted Embodiment 21 acetic acid ester of formula (IXa): 0439. The process of any of embodiments 1-20, wherein R" is ethyl. IXa Embodiment 22 0440 The process of any of embodiments 1-21, wherein OEt R’ is methyl, ethyl, or phenyl. Embodiment 23 0441 The process of any of embodiments 1-22, wherein 0450 with a deprotonating reagent to produce an inter R’ is methyl. mediate of formula (X): Embodiment 24 X 0442. The process of any of embodiments 1-23, wherein M2 R is methyl, ethyl, or phenyl. No Embodiment 25 ano, 0443) The process of any of embodiments 1-24, wherein R is methyl. Embodiment 26 0451 wherein M is Li or Zn; 0452 (b) reacting the intermediate of formula (X) with 0444 The process of any of embodiments 1-25, wherein n a solution comprising a C.O)-halo-terminated dialkane and m are the same. ether of formula (XI) US 2016/O 137584 A1 May 19, 2016
XI O O O EtO OEt 0453 wherein X is halo; and 0454 (c) hydrolyzing the crude diethyl 6,6'-oxybis(2. 2-dimethyl-4-hexanoate); 0462 (d) treating the crude diethyl 6,6'-oxybis(2.2- 0455 to produce 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic dimethyl-4-hexanoate) of formula (3) of step (c) with a acid). calcium hydroxide or calcium oxide of an alkali or earth alkaline metal in a Suitable solvent; Embodiment 31 0463 (e) precipitating the 6,6'-oxybis(2,2-dimethyl-4- hexanoic acid) calcium of formula (4): 0456. A process for preparing crystalline 6,6'-oxybis(2.2- dimethyl-4-hexanoic acid) calcium of formula (4): 4
O O 4 O Ca2+ O O O O O Ca2+ O O 0464 in the presence of an organic solvent; or, alterna tively, removing the organic layer by evaporation to afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4- 0457 wherein the process comprises: hexanoic acid) salt of formula (4) as an alcohol Solvate 0458 (a) reacting a solution of ethyl isobutyrate of for or hydrate; mula (IX) 0465 (f) adding one or more anti-solvents to the solid of step (e) in which 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of formula (4) is insoluble; and IX 0466 (g) humidifying the precipitate resultant from O step (f) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- hexanoic acid) calcium of formula (4). ORI Embodiment 32 0467. The process of embodiment 31, wherein the alcohol solvate or hydrate obtained in step (f) is stirred with tetrahy 0459 with a deprotonating reagent to produce a com drofuran with Subsequent addition of one or more anti-sol pound of formula (X): vents to obtain the crystalline form of 6,6'-oxybis(2,2-dim ethyl-4-hexanoic acid) calcium described in step (g). 2 X Embodiment 33 M No 0468. The process of any of embodiments 31-32, wherein the solid obtained according to step (d) is stirred with tetrahy afor drofurane with Subsequent addition of one or more anti-sol vents to obtain the crystalline form of 6,6'-oxybis(2,2-dim ethyl-4-hexanoic acid) calcium described in step (g). 0460 (b) reacting the ethyl lithiobutyrate of step (a) Embodiment 34 with a solution of bis(4-chlorobutylether) of formula 0469. The process of any of embodiments 31-32, compris (XI): ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- hexanoate) of formula (3) in a water-immiscible solvent with XI an aqueous solution of a base, wherein the water-miscible solvent is selected from DMSO, DMF, acetone, methanol, Ha 1N1\-1 'N-1-1N Ha isopropyl alcohol, and ethanol. Embodiment 35 0461 (c) performing an aqueous work-up of the solu tion of step (b) in order to isolate an organic Solution of 0470 The process of any of embodiments 31-32, compris crude diethyl 6,6'-oxybis(2,2-dimethyl-4-hexanoate) of ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- formula (3): hexanoate) of formula (3) in a water-immiscible solvent with US 2016/O 137584 A1 May 19, 2016 26 an aqueous solution of a base, wherein the water-immiscible Embodiment 39 solvent is selected from toluene, xylene, methyl ethyl ketone, and methyl isobutyl ketone. 0482. The process of embodiment 38, further comprising the step of performing an aqueous work-up of the solution of Embodiment 36 step (b) to isolate an organic Solution of the compound of 0471. The process of any of embodiments 31-32, compris formula (III). ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- hexanoate) of formula (3) in a water-miscible solvent with an Embodiment 40 aqueous Solution of calcium hydroxide or calcium oxide, 0483 The process of any of embodiments 38-39, further wherein the water-miscible solvent is selected from DMSO, comprising the step of treating the crude compound of for DMF, acetone, methanol, isopropyl alcohol, and ethanol. mula (III) with a hydroxide or oxide of an alkali or earth Embodiment 37 alkaline metal. 0472. The process of any of embodiments 31-32, compris ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- Embodiment 41 hexanoate) of formula (3) in a water-immiscible solvent with 0484 The process of any of embodiments 38-40, further an aqueous solution of a calcium hydroxide or calcium oxide, comprising the step of precipitating the Salt of the C,c)-dicar wherein the water-immiscible solvent is selected from tolu boxylic acid-terminated dialkane ether of formula (IV) in the ene, Xylene, methyl ethyl ketone, and methyl isobutyl ketone. presence of an organic solvent. Embodiment 38 0473 A process for preparing a compound of formula Embodiment 42 (III): 0485 The process of any of embodiments 38-41, further comprising the step of removing the organic layer by evapo ration to afford crude crystalline C,c)-dicarboxylic acid-ter minated dialkane ether salt of formula (IV) in the form of an alcohol solvate or hydrate. Embodiment 43 0486 The process of any of embodiments 38-42, wherein the alcohol solvate or hydrate is stirred with tetrahydrofuran with Subsequent addition of one or more anti-solvents to wherein: 0474) R' is alkyl: obtain the crystalline form the C,c)-dicarboxylic acid-termi 0475 R and R are each independently alkyl, nated dialkane ether salt of formula (IV). cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy cloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroaryla Embodiment 44 lkyl; and 0487. The process of any of embodiments 38-43, further 0476 n and m are each independently 0-4: comprising the step of adding one or more anti-solvents so comprising: that the salt of the C,c)-dicarboxylic acid-terminated dialkane 0477 (a) reacting a solution comprising an O-bromo ether of formula (IV) is insoluble. acetic acid ester of formula (XV): Embodiment 45 XV 0488. The process of any of embodiments 38-44, further O comprising the step of humidifying the precipitate to obtain a Br crystalline salt of a C,c)-dicarboxylic acid-terminated dial ORI kane ether of formula (IV). Embodiment 46 0478 with a metal, until the metal is essentially dis 0489. The process of embodiment 38-45, further compris solved; ing the step of hydrolyzing the compound of formula (III) to 0479 (b) reacting the solution of step (a) with a solution produce a compound of formula (V). comprising a C.O)-halo-terminated dialkane ether of for mula (II): V
II O O O x1a-ha-'N-(N-n HO pi iii. OH R2 R3 R3 R2 0480 wherein X is halo: 0481 to produce a compound of formula (III). US 2016/O 137584 A1 May 19, 2016 27
Embodiment 47 Embodiment 58 0490 The process of any of embodiments 38-46, compris 0501. The process of any of embodiments 38-57, wherein ing treating a solution of a compound of formula (III) in a R’ is methyl, ethyl, or phenyl. water-miscible solvent with an aqueous solution of a base, wherein the water-miscible solvent is selected from DMSO, Embodiment 59 DMF, methanol, isopropyl alcohol, and ethanol. 0502. The process of any of embodiments 38-58, wherein Embodiment 48 R’ is methyl. 0491. The process of any of embodiments 38-47, compris ing treating a solution of a compound of formula (III) in a Embodiment 60 water-immiscible solvent with an aqueous solution of a base, (0503. The process of any of embodiments 38-59, wherein wherein the water-immiscible solvent is selected from tolu R is methyl, ethyl, or phenyl. ene, Xylene, methyl ethyl ketone, and methyl isobutyl ketone. Embodiment 61 Embodiment 49 0492. The process of any of embodiments 38-48, compris 0504 The process of any of embodiments 38-60, wherein ing treating a solution of a compound of formula (III) in a R is methyl. water-miscible solvent with an aqueous solution of calcium hydroxide or calcium oxide, wherein the water-miscible sol Embodiment 62 vent is selected from DMSO, DMF, acetone, methanol, iso 0505. The process of any of embodiments 38-61, wherein propyl alcohol, and ethanol. in and m are the same.
Embodiment 50 Embodiment 63 0493. The process of any of embodiments 38-49, compris 0506. The process of any of embodiments 38-62, wherein ing treating a solution of a compound of formula (III) in a in and mare different. water-immiscible solvent with an aqueous Solution of cal cium hydroxide or calcium oxide, wherein the water-immis cible solvent is selected from toluene, xylene, methyl ethyl Embodiment 64 ketone and methyl isobutyl ketone. (0507. The process of any of embodiments 38-63, wherein in and m are each 1. Embodiment 51 0494 The process of any of embodiments 38-50, wherein Embodiment 65 step (a) is performed under inert atmosphere. 0508. The process of any of embodiments 38-64, wherein Embodiment 52 the metal is selected from the group consisting of zinc, mag nesium and indium. 0495. The process of any of embodiments 38-51, wherein the deprotonating reagent is selected from alkyl-lithium, aryl Embodiment 66 lithium, dialkyl-zinc, or alkali metal salts of hexamethyldisi lilaZanes. (0509. The process of any of embodiments 38-65, wherein catalysts or initiators are optionally used in step (a). Embodiment 53 0496 The process of any of embodiments 38-52, wherein Embodiment 67 the solvent in step (a) is selected from tetrahydrofuran, 2-me 0510. The process of any of embodiments 38-66, wherein thyltetrahydrofuran, or toluene. catalysts or initiators are selected from the group consisting of benzoyl peroxide, 3-chloroperbenzoic acid or magnesium Embodiment 54 monoperoxyphthalate. 0497. The process of any of embodiments 38-53, wherein X is F, Cl, or I. Embodiment 68 Embodiment 55 0511. The process of any of embodiments 38-67, wherein the compound of formula (III) is 6,6'-oxy-bis(2,2-dimethyl 0498. The process of any of embodiments 38-54, wherein X is C1. 4-hexanoic acid) (Compound 3). Embodiment 56 0499. The process of any of embodiments 38-55, wherein R" is methyl or ethyl. Embodiment 57 EtO OEt 0500. The process of any of embodiments 38-56, wherein R" is ethyl. US 2016/O 137584 A1 May 19, 2016 28
Embodiment 69 0520 wherein the process comprises: 0521 (a) reacting a solution of an O-bromo-isobutyric 0512 A process for preparing 6,6'-oxy-bis(2,2-dimethyl acid ester of formula (XX): 4-hexanoic acid):
XX
3 Br OEt O O
O EtO OEt 0522 in a suitable solvent or mixture of solvents, under inert atmosphere, with a metal, until the metal is essen tially dissolved; comprising: 0523 (b) reacting the solution of step (a) with a solution of bis(4-chlorobutylether) of formula (XXI): 0513 (a) reacting a solution comprising an O-bromo acetic acid ester of formula (XX): XXI Hal 1N1 N1 Nu-1N1\ Hal
XX O 0524 in a suitable solvent or mixture of solvents: 0525 (c) performing an aqueous work-up of the solu Br tion of step (b) in order to isolate an organic Solution of OEt crude diethyl 6,6'-oxybis(2,2-dimethyl-4-hexanoate) of formula 4;
0514 with a metal, until the metal is essentially dis solved; 4 O O 0515 (b) reacting the solution of step (a) with a solution comprising a C.O)-halo-terminated dialkane ether of for O mula (XXI): EtO OEt
XXI 0526 (d) treating the crude diethyl 6,6'-oxybis(2.2- 1-1-1'N-1N1S dimethyl-4-hexanoate) of formula (4) of step (c) with a X X calcium hydroxide or calcium oxide of an alkali or earth alkaline metal in a Suitable solvent; 0516 wherein X is halo; and 0527 (e) precipitating the 6,6'-oxybis(2,2-dimethyl-4- hexanoic acid) calcium of formula (4): 0517 (c) hydrolyzing the crude diethyl 6,6'-oxybis(2. 2-dimethyl-4-hexanoate); 0518 to produce 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic 4 acid). O O O Ca2+ Embodiment 70 O O 0519. A process for preparing crystalline 6,6'-oxybis(2.2- dimethyl-4-hexanoic acid) calcium of formula (4): 0528 in the presence of an organic solvent; or, alterna tively, removing the organic layer by evaporation to afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4- 4 hexanoic acid) salt of formula (4) as an alcohol Solvate or hydrate; O O 0529 (f) adding one or more anti-solvents to the solid of O Ca2+ step (e) in which 6,6'-oxybis(2,2-dimethyl-4-hexanoic O O acid) calcium of formula (4) is insoluble; and 0530 (g) humidifying the precipitate resultant from step (f) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- hexanoic acid) calcium of formula (4). US 2016/O 137584 A1 May 19, 2016 29
Embodiment 71 wherein: 0538) R' is alkyl; 0531. The process of embodiment 70, wherein the alcohol 0539 R’ and R are each independently alkyl, solvate or hydrate obtained in step (f) is stirred with tetrahy cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy drofuran with Subsequent addition of one or more anti-sol cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; vents to obtain the crystalline form of 6,6'-oxybis(2,2-dim and ethyl-4-hexanoic acid) calcium described in step (g). 0540 m is 0-4: comprising: Embodiment 72 0541 (a) reacting a solution of a cyclic lactone of for mula (41): 0532. The process of any of embodiments 70-71, wherein the solid obtained according to step (d) is stirred with tetrahy drofurane with Subsequent addition of one or more anti-sol 41 vents to obtain the crystalline form of 6,6'-oxybis(2,2-dim O ethyl-4-hexanoic acid) calcium described in step (g). O Embodiment 73 0533. The process of any of embodiments 70-72, compris )m ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- hexanoate) of formula (4) in a in a water-miscible solvent 0542 with a deprotonating reagent to produce an inter with an aqueous Solution of a base, wherein the water-mis mediate of formula (41a): cible solvent is selected from DMSO, DMF, acetone, metha nol, isopropyl alcohol, and ethanol. 41a. Embodiment 74 0534. The process of any of embodiments 70-72, compris ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- hexanoate) of formula (4) in a water-immiscible solvent with an aqueous solution of a base, wherein the water-immiscible solvent is selected from toluene, xylene, methyl ethyl ketone, and methyl isobutyl ketone. (0543 wherein M is Li or Zn; Embodiment 75 0544 (b) reacting the intermediate of formula (41a) 0535 The process of any of embodiments 70-72, compris with a solution of an alkylhalide of formula (42): ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- R22X22 42 hexanoate) of formula (4) in a water-miscible solvent with an (0545 wherein X* is halo: aqueous Solution of calcium hydroxide or calcium oxide, 0546 to produce a compound of formula (43): wherein the water-miscible solvent is selected from DMSO, DMF, acetone, methanol, isopropyl alcohol, and ethanol. 43 Embodiment 76 O 0536 The process of any of embodiments 70-72, compris ing treating a solution of ethyl 6,6'-oxybis(2,2-dimethyl-4- hexanoate) of formula (4) in a water-immiscible solvent with an aqueous solution of calcium hydroxide or calcium oxide, )m wherein the water-immiscible solvent is selected from tolu ene, Xylene, methyl ethyl ketone, and methyl isobutyl ketone. 0547 (c) reacting the solution of a compound of for mula (43) with a deprotonating reagent to produce an Embodiment 77 intermediate of formula (43a): 0537. A process for preparing a compound of formula (48): 43a M23 48 Yo O O R2No iii. O n-k-k- R21 r)m 0548 wherein M is Lior Zn; US 2016/O 137584 A1 May 19, 2016 30
0549 (d) reacting the intermediate of formula (43a) Embodiment 81 with a solution of an alkylhalide of formula (44): 0560. The process of any of embodiments 77-80, further R23X23 44 comprising the step of performing an aqueous work-up of the 0550 wherein X* is halo: Solution of step (0 to isolate an organic Solution of the com 0551 to produce a compound of formula (45): pound of formula (47). Embodiment 82 45 O 0561. The process of any of embodiments 77-81, further R23 comprising the step of hydrolyzing the compound of formula O R22 (48) to produce a compound of formula (49).
m 49 O O 0552) (e) reacting the solution of a compound of for O mula (45) with potassium tert-butoxide to produce an HO iii. iii. OH intermediate of formula (46): R22 R23 R22 R23
46 O Embodiment 83 HO R21 0562. The process of any of embodiments 77-82, compris iii. O1 ing treating a solution of a compound of formula (48) with R22 R23 dilute acid. 0553 where R is alkyl: Embodiment 84 0554 (f) reacting the solution of a compound of for 0563 The process of any of embodiments 77-83, compris mula (46) with a halogen source to produce an interme ing treating a solution of a compound of formula (48) in a diate of formula (47): water-immiscible solvent with dilute acid, wherein the water immiscible solvent is selected from dichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, 47 O toluene, Xylene, hydrocarbon solvents such as pentane, hex ane, and heptane, and mixtures thereof. X2 R21 iii. O1 Embodiment 85 R22 R23 0564. The process of any of embodiments 77-84, compris ing treating a solution of a compound of formula (48) with a 0555 wherein X* is F, Cl, or I and where R is alkyl: dilute acid selected from the group consisting of trifluoroace 0556 (g) reacting a solution of the compound of for tic acid, formic acid, hydrochloric acid, and Sulfuric acid. mula (46) with the intermediate of formula (47) in the presence of base to form a compound of formula (48). Embodiment 86 Embodiment 78 0565. The process of any of embodiments 77-85, further 0557. The process of embodiment 77, further comprising comprising the step of performing an aqueous work-up of the the step of performing an aqueous work-up of the Solution of Solution of step (g) to isolate an organic solution of the com step (b) to isolate an organic solution of the compound of pound of formula (48). formula (43). Embodiment 87 Embodiment 79 0566. The process of any of embodiments 77-86, wherein 0558. The process of any of embodiments 77-78, further X’ and X’ are each independently F, Cl, or I. comprising the step of performing an aqueous work-up of the Solution of step (d) to isolate an organic solution of the com Embodiment 88 pound of formula (45). 0567. The process of any of embodiments 77-87, wherein Embodiment 80 R’ is tert-butyl. 0559 The process of any of embodiments 77-79, further Embodiment 89 comprising the step of performing an aqueous work-up of the Solution of step (e) to isolate an organic Solution of the com 0568. The process of any of embodiments 77-88, wherein pound of formula (46). R’ is methyl, ethyl, or methylphenyl. US 2016/O 137584 A1 May 19, 2016 31
Embodiment 90 0577 (b) reacting the intermediate of step (a) with a 0569. The process of any of embodiments 77-89, wherein solution of an alkylhalide R’ is methyl. HC X22 52 Embodiment 91 0578 wherein X’ is halo: 0570. The process of any of embodiments 77-90, wherein 0579 to produce a compound: R’ is methyl, ethyl, or methylphenyl. Embodiment 92 53 0571. The process of any of embodiments 77-91, wherein O R’ is methyl. H3C O Embodiment 93 0572. The process of any of embodiments 77-92, wherein the compound of formula (38) is the di-tert-butyl ester of 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid). 0580 (c) reacting the solution of the compound of step (b) with a deprotonating reagent to produce an interme diate:
> ------k 5.3a
Embodiment 94 HC O 0573 A process for preparing 6,6'-oxy-bis(2,2-dimethyl 4-hexanoic acid):
0581 wherein M is Lior Zn; O O 0582 (d) reacting the intermediate of step (c) with a O solution of an alkylhalide: HO OH HC X2: S4 comprising: 0583 wherein X* is halo: 0574 (a) reacting a solution of a cyclic lactone: 0584 to produce a compound:
51 26 O H3C O HC
0575 with a deprotonating reagent to produce an inter mediate: 0585 (e) reacting the solution of a compound of step (d) with potassium tert-butoxide to produce an intermedi ate: 51a.
12 O
HO Ouk
0576 wherein M is Li or Zn; US 2016/O 137584 A1 May 19, 2016 32
0586 (f) reacting a first solution of a compound of step 0592 with a deprotonating reagent to produce an inter (e) with a halogen source to produce an intermediate: mediate:
13a 51a. O MNo X2 -k O a O
0587 wherein X* is F, C1, or I; 0588 (g) reacting a second solution of a compound of 0593 wherein M is Lior Zn; step (e) with the intermediate of step (f)) in the presence 0594 (b) reacting the intermediate of step (a) with a of base to form a compound: solution of an alkylhalide HC X22 52 0595 wherein X’ is halo: 0596 to produce a compound:
> --~x-k 53 O
0589 (h) reacting the solution of a compound of step (g) H3C O with dilute acid to form 6,6'-oxy-bis(2,2-dimethyl-4- hexanoic acid):
3 0597 (c) reacting the solution of the compound of step O O (b) with a deprotonating reagent to produce an interme O diate: HO OH
5.3a Ms23 No
Embodiment 95 HC O 0590 A process for preparing crystalline 6,6'-oxybis(2.2- dimethyl-4-hexanoic acid) calcium (4):
4 0598 wherein M is Lior Zn; O O 0599 (d) reacting the intermediate of step (c) with a solution of an alkylhalide: O O O Ca2+ HC X2: S4 0600 wherein X* is halo: 0601 to produce a compound: wherein the process comprises: 0591 (a) reacting a solution of a cyclic lactone: 26 O HC 51 O HC
0602 (e) reacting the solution of a compound of step (d) with potassium tert-butoxide to produce an intermedi ate: US 2016/O 137584 A1 May 19, 2016
0610 (k) adding one or more anti-solvents to the solid 12 of step () in which 6,6'-oxybis(2,2-dimethyl-4-hex O anoic acid) calcium is insoluble; and 0611 (1) humidifying the precipitate resultant from step HO O -k (k) to obtain crystalline 6,6'-oxybis(2,2-dimethyl-4- hexanoic acid) calcium (4).
0603 (f) reacting a first solution of a compound of step Embodiment 96 (e) with a halogen source to produce an intermediate: 0612. The process of embodiment 95, wherein the alcohol solvate or hydrate obtained in step () is stirred with tetrahy 13a drofuran with Subsequent addition of one or more anti-sol O vents to obtain the crystalline form of 6,6'-oxybis(2,2-dim ethyl-4-hexanoic acid) calcium described in step (k). X2 O -k Embodiment 97 0613 A process for preparing a compound of formula 0604 wherein X* is F, Cl, or I: (48): 0605 (g) reacting a second solution of a compound of step (e) with the intermediate of step (f)) in the presence of base to form a compound: R2 O R21 S.----~ iii. O1 R22 R23
wherein: 0614) R' is alkyl: 0615 R’ and R are each independently alkyl, 0606 (h) reacting the solution of a compound of step (g) cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy with dilute acid to form 6,6'-oxy-bis(2,2-dimethyl-4- cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; hexanoic acid): and 0616 m is 0-4: 3 comprising: O O 0.617 (a) reacting a first solution of a compound of formula (46): O HO OH 46 O 0607 (i) treating the crude diethyl 6,6'-oxybis(2,2-dim HO R21 ethyl-4-hexanoate) of step (h) with a calcium hydroxide iii. O1 or calcium oxide of an alkali or earth alkaline metal in a R22 R23 suitable solvent; 0608 () precipitating the 6,6'-oxybis(2,2-dimethyl-4- 0618 with a halogen source to produce a compound of hexanoic acid) calcium of step (i) formula (47):
4 47 O O O X2 R21 O 2 -X- ~x. Ca R22 R23
0609 in the presence of an organic solvent; or, alterna 0619 wherein X* is F, Cl, or I: tively, removing the organic layer by evaporation to 0620 (b) reacting a second solution of a compound of afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4- formula (46) with the intermediate of formula (47) in the hexanoic acid) salt as an alcohol Solvate or hydrate; presence of base to form a compound of formula (48). US 2016/O 137584 A1 May 19, 2016 34
Embodiment 98 Embodiment 101 0624 The process of embodiments 97-100, further com 0621. The process of embodiment 97, further comprising prising the step of reacting the intermediate of formula (41a): the step of reacting the Solution of a compound of formula (45): 41a. MNo 45 a O
)m
wherein M’ is Li or Zn; with a solution of an alkylhalide of formula (42): with potassium tert-butoxide to produce an intermediate of R22X22 42 formula (46). wherein X is halo: Embodiment 99 to produce a compound of formula (43). Embodiment 102 0622. The process of embodiments 97-98, further com 0625. The process of embodiments 97-101, further com prising the step of reacting an intermediate of formula (43a): prising the step of reacting a solution of a cyclic lactone of formula (41):
43a MNo 41 R23 O
)m wherein M is Lior Zn; with a deprotonating reagent to produce an intermediate of with a solution of an alkylhalide of formula (44): formula (41a). Embodiment 103 0626. The process of any of embodiments 97-102, further 44 comprising the step of hydrolyzing the compound of formula (48) to produce a compound of formula (49). wherein X* is halo: 49 to produce a compound of formula (45). O O O Embodiment 100 HO iii. iii. OH R22 R23 R22 R23 0623 The process of embodiments 97-99, further com prising the step of reacting the solution of a compound of formula (43): Embodiment 104 0627. The process of any of embodiments 97-103, wherein the compound of formula (38) is the di-tert-butyl 43 ester of 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid).
with a deprotonating reagent to produce an intermediate of formula (43a). US 2016/O 137584 A1 May 19, 2016 35
Embodiment 105 0628. A process for preparing a compound of formula 43a (45): MNo R22 O
45 O R23 )m O R22 0636 wherein M is Lior Zn; )m 0637 (d) reacting the intermediate of formula (43a) with a solution of an alkylhalide of formula (44): comprising: R23X23 44 0629 (a) reacting a solution of a cyclic lactone of for mula (41): 0638 wherein X* is halo: 0639 to produce a compound of formula (45).
41 O 45 O O R23 O R22 )m )m 0630 with a deprotonating reagent to produce an inter mediate of formula (41a): Embodiment 106
41a. 0640 The process of any of embodiments 97-103, further Ms.22 No comprising the steps of 0641 (e) treating the crude diethyl 6,6'-oxybis(2.2- 2. O dimethyl-4-hexanoate) of formula (49) of step (h) with a calcium hydroxide or calcium oxide of an alkali or earth alkaline metal in a Suitable solvent; 0642 (f) precipitating the 6,6'-oxybis(2,2-dimethyl-4- hexanoic acid) calcium of formula (50): 0631 wherein M is Li or Zn;
0632 (b) reacting the intermediate of formula (41a) 50 with a solution of an alkylhalide of formula (42): R22X22 42 O O O 0633 wherein X* is halo: -X- ~x. (M), 0634 to produce a compound of formula (43): 0643 in the presence of an organic solvent; or, alterna 43 O tively, removing the organic layer by evaporation to afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4- R23 O hexanoic acid) salt of formula (50) as an alcohol solvate or hydrate; 0644 (g) adding one or more anti-solvents to the Solid )m of step () in which 6,6'-oxybis(2,2-dimethyl-4-hex anoic acid) calcium of formula (50) is insoluble; and 0635 (c) reacting the solution of a compound of for 0.645 (h) humidifying the precipitate resultant from mula (43) with a deprotonating reagent to produce an step (k) to obtain crystalline 6,6'-oxybis(2,2-dimethyl intermediate of formula (43a): 4-hexanoic acid) calcium of formula (50). US 2016/O 137584 A1 May 19, 2016 36
Embodiment 107 43a 0646 A process for preparing a compound of formula Ms23 No (48):
r))m 0654 wherein M is Li or Zn; R22 R23 0655 (d) reacting the intermediate of formula (43a) with a solution of an alkylhalide of formula (44): 0656 wherein X* is halo: comprising: 0657 to produce a compound of formula (45): 0647 (a) reacting a solution of a cyclic lactone of for mula (41): 45 O R23 41 R22 O
)m
0658 (e) reacting the solution of a compound of for mula (45) with potassium tert-butoxide to produce an intermediate of formula (46): 0648 with a deprotonating reagent to produce an inter mediate of formula (41a): 46 O
41a. HO R21; Ms.22 No ~~~~ R22 R23 2. O 0659 (f) reacting the solution of a compound of for mula (46) with a halogen source to produce an interme diate of formula (47):
47 (0649 wherein M is Li or Zn; O 0650 (b) reacting the intermediate of formula (41a) with a solution of an alkylhalide of formula (42): X23 R21 R22X22 42 S----- R22 R23 0651 wherein X* is halo: 0660 wherein X* is F, Cl, or I: 0652 to produce a compound of formula (43): 0661 (g) reacting the solution of a compound of for mula (46) with the intermediate of formula (47) in the 43 presence of base to form a compound of formula (48): O
R23 O 48 O O )n: R2 O R21 No1 R22<-n- R23 N--R22 R23 Y 0653 (c) reacting the solution of a compound of for mula (43) with a deprotonating reagent to produce an 0662 (h) reacting the solution of a compound of for intermediate of formula (43a): mula (48) with dilute acid to form (49). US 2016/O 137584 A1 May 19, 2016 37
wherein: 49 0671) R' and R are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocy O O cloalkylalkyl, arylalkyl, heteroaryl, or heteroarylalkyl; O and HO iii. iii. OH 0672 m is 0-4: R22 R23 R22 R23 comprising: 0673 (a) reacting a solution of a cyclic lactone of for mula (41): Embodiment 108 0663 The process of embodiment 107, wherein the com 41 pound of formula (48) is: O O 3 O O )m O HO OH 0674) with a deprotonating reagent to produce an inter mediate of formula (41a):
Embodiment 109 41a. 0664. The process of embodiments 107-108, further com prising any of the following steps: 0665 (i) treating the compound of formula (49) of step (h) with a calcium hydroxide or calcium oxide of an alkali or earth alkaline metal in a suitable solvent; 0.666 () precipitating the compound of formula (50): 0675 wherein M is Lior Zn; 50 0676 (b) reacting the intermediate of formula (41a) with a solution of an alkylhalide of formula (42): O O R22X22 42 O - X^-n- ~~~x. (M), 0677 wherein X’ is halo: R22 R23 R22 R23 0678 to produce a compound of formula (43):
0667 wherein M' is Ca or K and X is 1 or 2: 43 0668 in the presence of an organic solvent; or, alterna O tively, removing the organic layer by evaporation to afford a crude crystalline salt of formula (50) as an R22 O alcohol solvate or hydrate; 0669 (k) adding one or more anti-solvents to the solid of step () in which the compound of formula (50) is )n: insoluble; and humidifying the precipitate resultant from Step (k) to obtain 0679 (c) reacting the solution of a compound of for crystalline compound of formula (50). mula (43) with a deprotonating reagent to produce an 0670 A further aspect is a process for preparing a com intermediate of formula (43a): pound of formula (45):
43a 23 45 M NO
R22 O
0680 wherein M is Lior Zn; US 2016/O 137584 A1 May 19, 2016 38
0681 (d) reacting the intermediate of formula (43a) with a solution of an alkylhalide of formula (44): Scheme 5 44 R R2 0682 wherein X* is halo: RO 0683 to produce a compound of formula (45). (cf. Nx Etherification 0684 In some embodiments, m is 1. O 0685. In some embodiments, Rand Rare the same. In other embodiments, Rand Rare different. 51 General Synthesis of C.Co-Dicarboxylic Acid-Terminated Dialkane Ethers R R2 0686 Four different methodologies are presented for pre 2 RO paring C,c)-dicarboxylic acid-terminated dialkane ethers: (1) (CfSNOH -DCC, (RO)BF4 e etc. - the Reformatsky reaction; (2) acid catalyzed ether synthesis; O (3) alkylation; and (4) Williamson ether synthesis. 52 0687 (1) The Reformatsky Reaction: 0688 Compounds of formula (III) and corresponding R R2 R2 RI salts may be prepared under certain conditions using a Refor RO OR matsky reaction according to Scheme 4. Ethyl 2-bromoisobu tyrate XV and halo-butyl ethers II under various conditions O ^ S^X. O including solvents such as THF, methyl t-butyl ether or and ethyl ether, and Zinc Such as Zinc powder with catalytic 53 amount of iodine or chlorotrimethylsilane, or highly active Rieke R. Zinc, and at temperatures between 0°C. to 70° C. or in refluxing solvent. Such procedures are described in Cui, (0691 (3) Alkylation Method: H.; et al.; Org. & Biomed. Chem. 2013, 10(14), 2862-2869 (0692 Compounds of formula (III) and corresponding and Gaudemar-Bardone. F.; et al.; Synthesis, 1987, 12, 1130 salts may be prepared using an alkylation method according 1133. to Scheme 6. The results of the alkylation studies are pre sented in Table 1, using the general synthesis described in Scheme 6. Scheme 4
Br O X 1N1,N1pi N-1N1aiii. X ORI II e R2 R3 XV ORI O O O ox^- n-n-so -- I R2 R3 R3 R2 O O III O O O --~~ ~x. O R2 R3 R3 R2 III --~~R2 R3 n-n-soR3 R2 (M), IV TABLE 1 0689 (2) Acid-Catalyzed Ether Synthesis Alkylation results for gemcabene diethyl ester and analogs. 0690 Compounds of formula (III) and corresponding acids and salts may be prepared using an acid-catalyzed ether R2 R3 X base l l Yield (%) synthesis reaction according to Scheme 5. For instance, esters of type 53 can be synthesized by dimerization of alcohols of Me Me C LDA 1 1 O Me Me Br LHMDS 1 1 O type 52, using the by the reaction pathway described in Me Me Br LDA 1 1 24: Scheme 7, where alcohols 52 are prepared by methods known Me Me I LDA 1 1 98 in the art (e.g., for n=3 in two steps by alkylation of benzyl (n-BuLi) protected 4-bromobutanol (commercially available from Me Me Br LDA O 1 85 Sigma-Aldrich) with an alkyl isobutyrate (commercially Me Me I LDA 1 1 91 available from various Suppliers, such as Sigma-Aldrich), and (n-HexylLi) Subsequent hydrogenation. US 2016/O 137584 A1 May 19, 2016 39
TABLE 1-continued -continued Alkylation results for gencabene diethyl ester and analogs. O O R2 R3 X base l l Yield (%) R O R21 Me p-Tolyl I LDA 1 1 89 O ;: iii. O1 Me Me Bir LDA 2 1 79 Me Me Bir LDA 2 2 89 R22 R23 R23 R23 48 *The bromide contained some chloride that lowered the yield 0693. Using n-hexyllithium or n-butyllithium to generate the LDA produced comparable results. The use of n-hexyl lithium is known to be safe and environmentally friendly, TABLE 2 therefore Such a methodology is largely scalable at multiki logram batches. LiHMDS failed to generate any product. Finally, using larger groups (p-tolyl) on the ester did not Williamson Ether Synthesis Results hinder the alkylation reaction. (0694 (4) Williamson Ether Synthesis: 2. 22 23 24 0695 Compounds of formula (III) and corresponding R R R l l X Yieldield (%)(% salts may be prepared using a Williamson ether synthesis according to Scheme 7. The results for various compounds Et Methyl Methyl 1 1 Br O using the Williamson Ether Synthesis method are listed in Et Methyl Methyl 1 1 I trace Table 2, using the general synthesis described in Scheme 7. t-butyl Methyl Methyl 1 1 Br 34% t-butyl Methyl Methyl 1 1 I 40%
Scheme 7
O O
N-s-sO R2 + to-s-s O R’ 0696. During the Williamson ether synthesis, the ethyl R22 R23 R22 R23 esters produced primarily trans-esterification products. 47 46 Replacing the ethyl ester with t-butyl ester prevented the NaH, DMF trans-esterification from occurring. A representative method s starting from inexpensive and safe starting materials is out lined in Scheme 7a.
Scheme 7 a. O O R22 O O 1) LDA, R22I He R23 2) LDA, R2I )m )m 41 45 Rio O Br or I, Ph3P 24 2 -- R21 N---- THF HO R22 R23 46 NaH, DM/ O US 2016/O 137584 A1 May 19, 2016 40
0697 The preparation of alcohol 46 begins with, for or the bromide of formula (47) may be directly prepared from example, the alkylation of 6-caprolactone using LDA and the alcohol and coupled by the Williamson ether synthesis iodomethane, followed by ring opening with potassium t-bu methodology. toxide. Other alkylation methodologies for 6-caprolactone 0698 Exemplary compounds and intermediates that may may be used, such as ring opening with t-butoxide. The iodide be prepared by these methods are included in Table 3. TABLE 3 List of Compounds
i Structure Name
1 N-1N1a O 1N1,N1 I 4-Iodobutyl ether 2 O O 6-(5-Ethoxycarbonyl-5- methyl-hexyloxy)-2,2- O dimethylhexanoic 1No 1N acid ethyl ester
3 O O 6-(5-Carboxyl-5-methyl hexyloxy)-2,2- O dimethylhexanoic acid HO OH
4 O O Gemcabene
O Ca2+ O O
5 N-1-N-1- O 1N1N1 Br 4-Bromobutyl ether 6 6-Benzyloxy-2,2- O dimethylhexanoic acid ethyl ester 1n O O
7 O 6-Hydroxy-2,2- dimethylhexanoic acid ethyl 1n OH ester O
8 O 6-Bromo-2,2- dimethylhexanoic 1n Br acid ethyl O ester
9 6-Benzyloxy-2,2- O dimethylhexanoic acid O HO
11 6-Benzyloxy-2,2- O dimethylhexanoic acid tert butyl ester O O
12 O 6-Hydroxy-2,2- dimethylhexanoic acid t-butyl > --~" ester
US 2016/O 137584 A1 May 19, 2016 42
TABLE 3-continued
List of Compounds
Structure Name
22 3-(Tetrahydro-pyran-2- yloxy)-propan-1-ol
23 2-3-(4-Bromobutoxy)- propoxy-tetrahydropyran
3-(4-Bromobutoxy)-propan 24 N-1-N-1- O 1N1N OH 1-ol
1-Bromo-4-(3- 25 N-1N1- O 1N1a Br bromopropoxy)-butane
26 3,3-Dimethyl-oxepan-2-one
27 5-(Tetrahydro-pyran-2- yloxy)-pentan-1-ol
O 2-5-(5-Bromopentyloxy)- 28 "Nu-1S-1a-'N-1N1-1' pentyloxy-tetrahydropyran
5-(5-Bromopentyloxy)- 29 HO 1N1N1\1\1\1\O Br pentan-1-ol
1-Bromo-5-(5- 30 Br 1N1\1\1\1\1\O Br bromopentyloxy)-pentane
O 2-5-(4-Bromobutoxy)- 31 Br 1N-1-N-N-1-N-1Nu-' pentyloxy-tetrahydropyran
5-(4-Bromobutoxy)-pentan-1- 32 Br 1N1,N19N-1N1-N-19 ol
1-Bromo-5-(4-bromobutoxy)- 33 Br 1N1 S-1 'N-1S-1a- Br pentane
General Synthesis of Gemcabene isobutyrate in the presence of LDA, which is freshly prepared from diisopropylamine/n-hexyl lithium or n-butyl lithium, to (0699 Alkylation Approach: provide the diester 2 in a high yield. Alternate examples in 0700 A representative synthesis of gemcabene is shown which the LDA was prepared using either butyllithium or in Scheme 8. In this representative example, 4-Chlorobutyl hexyllithium produced comparable yields. The diester 2 was ether was converted into 4-iodobutyl ether 1 with NaI in saponified to provide the diacid 3, followed by transformation acetone in 95% yield. The alkyl iodide was treated with ethyl into gemcabene calcium 4. US 2016/O 137584 A1 May 19, 2016
Scheme 8 O
3.1 eq. NaI, O C 1Su-1a-'Nu-1N1a C -e-acetOne I 1-1a-'N-1-1a I ---- reflux, 1 HNPr, THF, 3 eq. 48 h, 95%0 nHexLi -78° C. to r.t., 24 h, 91% O O 1No O 1N He10 eq 2.2 M, KOH, EtOHVH2O 55° C. 20 h, 84%
2 O O
O CaO, EtOH HO OH, -e- reflux, 2d, 82%
3 O O
O -O O- Cat
Gemcabene 4
0701 Unexpectedly, experiments using 4-chloro- and 4-bromobutyl ethers did not undergo O-alkylation of ethyl Scheme 10 isobutyrate to produce diester 2. No evidence of a coupling product was found using 4-chlorobutyl ether as a starting 1n-1\-'N-1S-1a -e-LiBr, Bu4NBr material (Scheme 9). C C cat. H2O, 95° C. 48 H, 45% yield O Scheme 9 1No
X 1N1\u-N-1N1- Br ->5 X = BriC at 2:1 n-BuLi, HNPr2, 5 (X = Br) -78°C. to r.t., 3 days O O
O O ~...~xo~. 2 ~ x^-n- N-X-ra 24% yield -- 2 O Try 1 LiHMDS, -78°C. to 60°C, 24h no coupling Try 2 n-BuLi, HNPr2, -78°C. to r,t, 24 h no coupling ~...~. 0702. The use of 4-bromobutyl ether as a starting material 2b resulted in the formation of diester 2, but with different reac tion kinetics (Scheme 10). US 2016/O 137584 A1 May 19, 2016 44
(0703 Reformatsky Approach: 0704. Gemcabene may be prepared using a Reformatsky coupling reaction between ethyl 2-bromoisobutyrate and Scheme 13 4-chalobutyl ethers (Scheme 11) under various conditions. O These conditions include various solvents (such as THF, methyl-t-butyl ether, and ethyl ether), various types of zinc 1N O OH (Zinc powder with catalytic amounts of iodine or chlorotrim ethylsilane or highly active Rieke(R) zinc), and various reac acid tion temperatures between 0° C. to 70° C. ether
O Scheme 11 O ~k. -- c1a1a-'N1-1Ne.
Zn, THFor ether 0708 Williamson Ether Synthesis: y r.t. 24 h., then reflux 24h 0709 Another representative example of a process for O O preparing gemcabene is shown in the Willaimson ether syn thesis in Scheme 14. Alcohol 7 was treated with sodium hydride in the presence of corresponding bromide 8. Bromide ~ x~~ N-X- 8 was prepared by alkylating 1,4-dibromobutane with ethyl 2 isobutyrate.
(0705 Acid-Catalyzed Ether Synthesis: Scheme 14 0706 Gemcabene may be synthesized by dimerization of alcohols, such as alcohol 7 below, using the by the reaction O pathway described in Scheme 12. Alcohol 7 was prepared in two steps by alkylation of benzyl protected 4-bromobutanol with an alkyl isobutyrate, followed by hydrogenation. - + 1)n-1\-" LDA, THF -78° C. tort Scheme 12 O O Y-->O LDA B1a1) 1' uC ~~~ OH ~ x~ Br 7 8 This C. to r.t. NaH, DMF 5° C. tort
O O
--O ~~~~ O X- Br 14T H2, 10% Pol/C O 0710. If trans-esterification occurs instead of the expected 1n OH displacement reaction, the bromide 8 may be converted to the O iodide before proceeding with the reaction. 0711. To reduce the trans-esterification products and pro 7 duce higher yield of the desired products, the ethyl esters may be replaced with sterically-hindered esters, such as, but not 0707 Dimerization of alcohol 7 in the presence of various limited to, t-butyl esters. A representative example of this acid catalysts, such as sulfuric acid or nalfion NR50 (acidic process is shown in Scheme 15. In this example, hydrolysis of resin), in organic solvents, such as ethers or hydrocarbons, intermediate 6 to form acid 9, followed by t-butylation in the may produce gemcabene. This process may result in a com presence of for example, isourea 10, produces the t-butyl plex mixture of products formed due to trans-esterification ester. The protected t-butyl ester 11 can be hydrogenated to (Scheme 13). afford alcohol 12 (Scheme 15) in quantitative yield. US 2016/O 137584 A1 May 19, 2016 45
-continued O Scheme 15
O O -k + LDA + Br 1N1-N-
~~~~ O THF-78°C. tort. 6 O
oil. EtOH,55° C. > O Br
13
0713 Alcohol 12 was reacted in with bromide 13 in the --O presence of hydrating agents, such as, but not limited to Sodium hydride, in aprotic dipolar solvents, such as, but not limited to, DMF. In this representative example, gemcabene di-t-butyl ester was obtained by reacting bromide 13 with alcohol 12 in the presence of sodium hydride and DMF at 5° C., followed by warming to room temperature and stirring for 20 hours (Scheme 17).
Scheme 17 O O
> O B. c. O OH
13 12 NaH, DMF 5° C. tort. 11 Boris Pd(C > x~x-k O
> O OH 0714 Unexpectedly, there was no indication of the trans 12 esterification products. Some unreacted alcohol 12 and bro mide 13 were present in the crude NMR, along with some elimination product from the bromide. However, yields and 0712. The corresponding bromide 13 may be prepared by conversions improved with longer reaction times and when alkylation of 1,4-dibromobutane with t-butyl isobutyrate. The using more than 1 equivalent of sodium hydride and bromide. t-butyl isobutyrate may be prepared by trans-esterification of methyl isobutyrate using sodium tert-butoxide in 51% yield 0715 Bromide 13 was converted to the iodide by refluxing with sodium iodide inacetone. Further, iodide 15 was reacted according to the literature procedure (Scheme 16). with alcohol 12, as described in Scheme 18.
Scheme 18 Scheme 16 O O I + > OH o1 ~...~ ox 15 12 NaH, DMF Nob. Et2O 5° C. tort US 2016/O 137584 A1 May 19, 2016 46 > <------k-continued is -continued 3'- 0716. The experiment produced slightly higher yield than the bromide. Once again, no trans-esterification side products were present in the crude material. The elimination byproduct was present in higher amounts. The remainder was unreacted alcohol 12 and a trace of the iodide 15. The gemcabenet-butyl Synthesis of the 5-5, 5-4, 4-3 Analogs of Gemcabene diester was converted to gemcabene diacid 3 with 10%TFA in Diethyl Ester dichloromethane. 0718 Three analogs of gemcabene diethyl ester (com pounds 19, 20, 21 in Scheme 20) were prepared by the alky Alkylation Method: Other C. Co-Dicarboxylic lation method using the appropriate dibromide compounds. Acid-Terminated Dialkane Ethers
Synthesis of Scheme 20 6,6'-oxybis(2-methyl-2-(p-tolyl)hexanoic acid) 19 O O 0717. As shown in Scheme 19, the alkylation process of Scheme 8 in alkylation method may be used to produce other ~ x~~x's- C.()-dicarboxylic acid-terminated dialkane ethers, such as 6,6'-oxybis(2-methyl-2-(p-tolyl)hexanoic acid) 18. Ethyl 2O p-tolylacetate was C.-methylated with iodomethane in the O tionpresence with of4-iodobutyl LDA to give ether the with ester LDA 16, followedto give the by diester O-alkyla- 17. 1no 1x--> O~-X- n1 The dicarboxylic acid 18 was obtained by saponification of 7 O with aqueous KOH in ethanol. 21 O Scheme 19 ~~~~X. On 1 + CHI --> JuC -78°LDA, C. THF tort O 1no 0719 Each analog was prepared in the same fashion, alter ing only the dibromide compounds. A representative proce O dure for preparing compound 21 is shown in Scheme 17. 1No Scheme 21
16 p-TsOH
16 1-1a-'N-1--1a O LDA, THF -78° C. tort O O 1N1 No O 1no O o1n 22
17 HO 1n 1aO O -- HO 1N1--" 22 KOH, EtOH 55° C. NaH, THF reflux, 20 hours US 2016/O 137584 A1 May 19, 2016 47
-continued -continued O O
N-1-1- O 1n 1\ O ~ x~~xsors 23 19 p-TsOH MeOH, rt. 18 hours 0721. A comparable but slightly lower yield was seen in the alkylation with ethyl isobutyrate to prepare analog 20. For "Nu-1N1\ O 1n 1\ OH each analog, the alkylation produced the desired analogs in 24 favorable yields. CBr, Ph3P SYNTHETIC EXAMPLES THF, 3 hours Example 1 N-1-1a 1N-1- Br 0722 Gemcabene calcium prepared from ethyl isobu 25 tyrate according to Scheme 23.
LDA, THF -78° C. tort Scheme 23 85% yield
O (R)-M, ORI He solvent, T1 M = Li; R = nHex, nHep, noct, NSiMe3) --~~-X-O solvent = THF, THF/hexanes, THF/heptane 21 T1 = -78°C. to RT T2 = -78°C. to 50° C. Hal = Cl, Br, I 0720. In the representative example for producing analog M2 1N1,N19N-1-1a No Hal Hal 21, propane diol was protected with a THP group to prepare 2 protected alcohol 22. The protected alcohol was reacted with 21 1,4-dibromobutane in the presence of sodium hydride to pre OEt solvent, T2 pare bromide 23 after reflux for 20 hours in THF. A significant amount of unreacted alcohol 22 was recovered. Running the la reaction in DMF may result in an increased yield. The THP O O group present in bromide 23 was removed by stirring in O methanol with p-toluenesulfonic acid to prepare alcohol 24. EtO OEt The alcohol was converted to the bromide by treatment with carbon tetrabromide and triphenylphosphine to generate the 3 dibromide 25 in 91% yield. Once the dibromide was pre pared, the alkylation with ethyl isobutyrate was conducted in H2O?solvent mixtures the same fashion as with gemcabene in Scheme 4. Ethyl Base: Ca(OH)2 or CaO isobutyrate was deprotonated with LDA at -78°C. followed O O by the addition of dibromide 26, and the reaction was subse quently warmed to room temperature to provide diester 21. O 2 The procedures were repeated for compounds 19 and 20. In x^- ~x. Ca the case of compound 19, the alkylation with dibromide 26 (Scheme 22) provided diester 19. 4 0723. In the first step of the reaction, ethyl isobutyrate is Scheme 22 deprotonated in the presence of a suitable non-pyrophoric lithium derivative, such as n-hexyllithium, n-heptyllithium, 1n-1-1N1-1N1 a Br and n-octyllithium. The reaction is performed by either the 26 addition of the halo-ester of formula (6) to the lithiation agent O in a suitable solvent, or, conversely, by addition of the lithia LDA, THF tion agent to the halo-ester Solution in a suitable solvent. To an -78° C. tort ethyl isobutyrate solution in a Suitable organic solvent is 1N 89% yield added under stirring approximately 1 to approximately 2.2 eq of the lithium derivative at approximately 2.5 M concentra tion under an inert atmosphere such as nitrogen or argo gas at US 2016/O 137584 A1 May 19, 2016 48 a rate of approximately 1.5 moles per hour. The solution is -continued maintained at a constant temperature within the range of approximately -78°C. to approximately -10°C. Optionally, O O the base is diluted in a suitable organic solvent before addi O 2 tion. Suitable organic solvents include, but are not limited to, dichloromethane, diethyl ether, tetrahydrofuran, 2-methytet O1x- ~x. Ca rahydrofuran, dimethylformamide, dimethyl sulfoxide, ben 8 Zene, toluene, Xylene, hydrocarbon Solvents (such as pentane, hexane, and heptane), and mixtures thereof. After addition of the base, the reaction mixture is allowed to stir for approxi 0725. In a typical procedure, ethyl C.-bromoisobutyrate of mately 1 hr to approximately 12 hr. Then bis(halobutyl)ether, formula (10) is treated at 0°C. with 1 eq of powdered zinc dissolved in a suitable solvent, is added, preferably at a rate under an inert atmosphere, such as nitrogen or argon gas. The Such that the reaction-mixture temperature remains within mixture is stirred at approximately 0°C. to approximately 10° approximately one to five degrees of the initial reaction C. until nearly all the zinc has reacted (approximately 3 hr). mixture temperature. A suitable bis(halobutyl)ether is a bis Alternatively, iodine is added to initiate the reaction. Bis (chloro), bis(bromo), or a bis(iodo)ether. These compounds (halobutyl)ether of formula (6) (0.5 eq), is added dropwise to are commercially available, for example, from FCH Group the flask over 1 hr., and the mixture is allowed to warm to 25° Reagents for Synthesis, or can be prepared as described, for C. over several hours, after which time the mixture is heated instance, in Mueller R. et al., J. Med. Chem. 2004, 47,5183 5197. After completion of the addition, the reaction-mixture at 50° C. for 1 hr and cooled. Aqueous ammonium chloride is temperature can be adjusted to within a temperature range of added to the mixture, and the aqueous layer is extracted with approximately -20° C. to approximately RT, preferably to an organic solvent, dried over a drying agent, and evaporated approximately RT. The reaction mixture is allowed to stir to give the crude product. until the reaction is Substantially complete, as determined using an appropriated analytical method, such as thin-layer Example 3 chromatography or high-performance liquid chromatogra phy. Then, the reaction mixture is quenched, and the diester compound of formula (7) is isolated by workup. Gemcabene Diethyl 7.7"-oxybis(2,2-dimethylheptanoate) is then synthesized by reacting the diester of formula (7) with a metal salt, base, or oxide according to the protocol described 0726 above for the formation of the C,c)-dicarboxylic acid-termi nated dialkane ether salt of formula (IV). Example 2 to X-----~-X- O O 0724 Gemcabene prepared from ethyl O-bromoisobu tyrate of formula (10) according to Scheme 24. 0727 Diethyl 7.7"-oxybis(2,2-dimethylheptanoate) may be prepared according to the processes of Examples 1 or 2 above, wherein the C,c)-halo-terminated dialkane ether of Scheme 24 formula (2) is bis(halopentyl)ether. O M Solvent, T Br e Example 4 OEt Hal 1\-1N1'Nu-1N1a Hal 6 Ethyl 7-((6-ethoxy-5,5-dimethyl-6-oxohexyl)oxy)-2, 10 solvent, T2 2-dimethylheptanoate M = Zn solvent = THF, THF/hexanes, THF/heptane 0728 T1 = -78°C. to RT T2 = -78°C. to 50° C. Hal = Cl, Br, I O O O O OEt EtO O EtO OEt O
7 0729. Ethyl 7-((6-ethoxy-5,5-dimethyl-6-oxohexyl)oxy)- H2O?solvent mixtures 2,2-dimethylheptanoate may be prepared according to the Base: Ca(OH)2 or CaO processes of Examples 1 or 2 above, wherein the O.co-halo terminated dialkane ether of formula (2) is 1-chloro-5-(4- chlorobutoxy)pentane. US 2016/O 137584 A1 May 19, 2016 49
Example 5 tography eluted with heptane/ethyl acetate (40: 1) to give the desired product (18.3g, 95% yield) as a yellow oil: "H NMR Ethyl 6-((5-ethoxy-4,4-dimethyl-5-oxopentyl)oxy)- (300 MHz, CDC1) 3.43 (t, 4H, J=6.3 Hz), 3.22 (t, 4H, J=6.9 2,2-dimethylhexanoate Hz), 1.91 (m, 4H), 1.67 (m, 4H). 0730 Example 8 6-(5-Ethoxycarbonyl-5-methyl-hexyloxy)-2,2-dim O ethyl-hexanoic acid ethyl ester (2) O OEt EtO 0736
O O O 0731 Ethyl 6-(5-ethoxy-4,4-dimethyl-5-oxopentyl)oxy)- O 2,2-dimethylhexanoate may be prepared according to the pro cesses of Examples 1 or 2 above, wherein the O.co-halo ~~~~ ~x's- terminated dialkane ether of formula (2) is 1-halo-4-(3- chloropropoxy)butane. 0737 To a stirred solution of diisopropylamine (1.19 g, 11.8 mmol) in anhydrous THF (20 mL) cooled in a dry ice Example 6 bath was added hexyllithium (2.3M, 5.1 mL, 11.8 mmol), and the mixture was stirred for 40 minutes. Ethyl isobutyrate Diethyl 6,6'-oxybis(2-methyl-2-(p-tolyl)hexanoate) (1.37 g, 11.8 mmol) was added drop-wise, and 30 minutes later 4-iodobutyl ether (1.63 g, 4.27 mmol) was added. After 0732 addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was O O poured into cold 1 NHCl solution (50 mL) and then extracted with MTBE (3x30 mL). The combined extracts were washed O with 2% sodium thiosulfate (50 mL) and brine (30 mL), dried EtO OEt over sodium sulfate, and concentrated under reduced pres Sure. The residue was purified through a silica-gel flash chro matography eluted with a gradient of heptane/ethyl acetate (40:1 to 10:1) to give the desired diester (1.40 g, 91% yield) as a colorless oil: "H NMR (300 MHz, CDC1) & 4.11 (q, 4H, J–7.2 Hz), 3.37 (t, 4H, J=6.6 Hz), 1.52 (m, 8H), 1.29 (m, 4H), 0733 Diethyl 6,6'-oxybis(2-methyl-2-(p-tolyl)hex 1.24 (t, 6H, J=7.2 Hz), 1.16 (s, 12H); 'C NMR (75 MHz, anoate) may be prepared according to the process of Example CDC1,) & 17798, 70.68, 60.13, 42.11, 40.48, 30.17, 25.05, 1, above, wherein the compound of formula (I) is ethyl 2-o- 21.59, 14.21. tolyl-propionate. Diethyl 6,6'-oxybis(2-methyl 2-o-tolyl hexanoate) may also be prepared according to the process of Example 9 Example 2, above, wherein the compound of formula (9) is 6-(5-Carboxyl-5-methyl-hexyloxy)-2,2-dimethyl ethyl 2-bromo-2-o-tolyl-propionate. hexanoic acid (3) Example 7 0738 4-Iodobutyl ether (1) O O 0734 O HO OH
N-1a-1\ O 1N1\1 I 0739. To a stirred solution of 6-(5-ethoxycarbonyl-5-me (0735. Acetone (previously dried over 4. A molecular sieve, thyl-hexyloxy)-2,2-dimethyl-hexanoic acid ethyl ester (2.68 200 mL) was added to a stirred mixture of 4-chlorobutyl ether g, 7.48 mmol) in absolute ethanol (50 mL) was added aqueous (10.0g, 50.2 mmol) and sodium iodide (24.9 g, 166 mmol. 3.3 KOH (2.2 M, 34 mL, 74.8 mmol), and the mixture was stirred eq.), and the mixture was heated at reflux for 48 h. The at 55° C. for 24 h. The reaction mixture was cooled to room reaction mixture was cooled to room temperature and then temperature and then concentrated under reduced pressure to filtered. The inorganic solid was rinsed with acetone (100 remove ethanol. The remaining mixture was extracted with mL), and the filtrate was concentrated under reduced pres MTBE (50 mL), and the extract was discarded. The aqueous sure. The residue was taken up in MTBE (200 mL). The layer was acidified with 3 NHCl (30 mL) slowly. The result resulting mixture was washed with water (200 mL), 2% ing mixture was extracted with MTBE (3x30 mL). The com sodium thiosulfate (200 mL), and brine (200 mL) sequen bined extracts were dried over sodium sulfate and concen tially and then concentrated under reduced pressure. The trated under reduced pressure. The residue was purified crude product was purified through a silica-gel flash chroma through a silica-gel flash chromatography eluted with hep US 2016/O 137584 A1 May 19, 2016 50 tane/ethyl acetate (from 4:1 to 2:1) to give the desired diacid to give 4-bromobutyl ether (1.29 g, 45% yield, containing (1.53 g, 84% yield) as a white solid: 'H NMR (300 MHz, ~30% 4-bromobutyl 4-chlorobutyl ether) as a colorless oil: CDC1) & 3.37 (t, 4H, J=5.1 Hz), 1.49 (m, 8H), 1.35 (m, 4H), "H NMR (300 MHz, CDC1) & 3.44 (t, 8H, J=6.0 Hz), 1.97 1.19 (s, 12H). (m, 4H), 1.71 (m, 4H). 0740 Alternate synthesis from the di-tert-butyl ester: 0741. The di-tert-butyl ester of gemcabene (0.25 g, 0.36 Example 12 mmol) was dissolved in dichloromethane (5 mL) and trifluo roacetic acid (0.5 mL). The mixture was stirred at room temperature for 20 hours. After 20 hours, the solution was 6-Benzyloxy-2,2-dimethylhexanoic acid ethyl ester concentrated and dried to a constant weight under high (6) vacuum. The experiment produced the desired diacid (105 mg, 97% yield) as a colorless solid: "H NMR (300 MHz, 0746 CDC1) & 11.23 (s. 2H), 3.37 (t, 4H, J=5.1 Hz), 1.49 (m, 8H), 1.35 (m, 4H), 1.19 (s, 12H). Example 10 O Gemcabene Calcium (4) 1Yo O 0742 0747 Ethyl isobutyrate (4.0 g, 34.4 mmol) was dissolved O O in dry THF (50 mL) under argon. The flask was cooled in a dry O Ca2+ ice/acetone bath, and 2M LDA (21 ml, 42 mmol) was added O O drop-wise over 5-10 minutes. The solution stirred for 30 minutes, and benzyl 4-bromobutyl ether (8.0 g, 32.9 mmol) was added. The solution slowly warmed to room temperature 0743 To a stirred solution of 6-(5-carboxyl-5-methyl and stirred overnight. After 18 hours at room temperature, hexyloxy)-2,2-dimethyl-hexanoic acid (1.34g, 4.43 mmol) water (50 ml) was added along with ethyl acetate (50 mL). in absolute ethanol (30 mL) was added CaO (0.25 g, 4.43 The layers were separated, and the ethyl acetate layer was mmol), and the mixture was stirred at reflux for two days. The extracted with 5% hydrochloric acid solution (50 ml), fol reaction mixture was cooled to room temperature, diluted lowed by brine (50 mL). The ethyl acetate extract was dried with MTBE (30 mL), and then stirred for two hours. The over Sodium Sulfate, filtered, and concentrated. The remain mixture was settled for 30 minutes and then filtered. The crop ing oil was purified on silica gel (200 g), eluting with 1:20 (4.32 g) was dried at 80°C. for 24 hunder high vacuum to give ethyl acetate?heptanes. The experiment generated 8.6 g (95% a white solid (1.29 g). To the solid was added DIUF water (0.26g, 14.4 mmol), and the mixture was stirred at 100°C. for yield) of 6-benzyloxy-2,2-dimethylhexanoic acid ethyl ester five hours and then dried under high vacuum at 95°C. for 1 h as a clear oil. "H NMR (300 MHz, CDC1) & 7.40-7.25 (m, and then at room temperature overnight to give the desired 5H), 4.51 (s. 2H), 4.12 (q, 2H, J=7.2 Hz), 3.48 (t, 2H, J=6.6 product (1.24g, 82% yield, 99.9% HPLC purity) as a white Hz), 1.64-1.53 (m, 4H), 1.39-1.32 (m, 5H), 1.17 (s, 6H). solid: "H NMR (300 MHz, DO-TSP) & 3.51 (t, 4H, J=6.9 Hz), 1.55 (m, 4H), 1.46 (m, 4H), 1.26 (m, 4H), 1.07 (s, 12H): Example 13 'C NMR (75 MHz, DO-1,4-dioxane) & 188.05, 70.51, 43.36, 40.71, 29.25, 25.43, 21.27. 6-Hydroxy-2,2-dimethylhexanoic acid ethyl ester (7) Example 11 0748 4-Bromobutyl ether (5) 0744) O
1n O OH *N-1-1-1-1- 0745) A sealed tube was charged with a magnetic stirring 0749 6-Benzyloxy-2,2-dimethylhexanoic acid ethyl ester bar, lithium bromide (2.21 g, 25.5 mmol), tetrabutylammo (9.6 g., 34.7 mmol) was dissolved in ethyl acetate (100 mL) nium bromide (0.82 g, 2.55 mmol, 0.1 eq.), water (0.022 g, and added to 20% palladium on carbon (0.8 g). The mixture 1.22 mmol) and 4-chlorobutyl ether (1.99 g, 10.0 mmol). The was hydrogenated at 40 psi hydrogen in a Parr apparatus for mixture was stirred at 95°C. for 48 h. The mixture was diluted 24 h. The mixture was then purged with nitrogen and filtered with heptane (30 ml) and water (20 mL), and the layers were through a pad of celite and concentrated. The experiment separated. The organic layer was washed with brine (20 mL), produced 6-hydroxy-2,2-dimethyl-hexanoic acid ethyl ester dried over anhydrous Sodium sulfate, and concentrated under (5.8 g. 88% yield) as a clear oil. "H NMR (300 MHz, CDC1) reduced pressure. The residue was purified through a silica 84.10 (q,2H, J–7.2 Hz), 3.57 (t, 2H, J=5.4 Hz), 1.51-1.45 (m, gel chromatography eluted with heptane/ethyl acetate (40:1) 4H), 1.33-1.23 (m, 5H), 1.13 (s, 6H). US 2016/O 137584 A1 May 19, 2016 51
Example 14 Example 16 6-Benzyloxy-2,2-dimethylhexanoic acid tert-butyl 6-bromo-2,2-dimethylhexanoic acid ethyl ester (8) ester (11) 0750 0754)
O
1N Br O > --O (0751 Ethyl isobutyrate (10.0g, 86.0 mmol) was dissolved 0755 6-benzyloxy-2,2-dimethylhexanoic acid (2.50 g, 9.98 mmol) was dissolved in dichloromethane (50 mL) with in dry THF (100 mL) under argon. The flask was cooled in a t-butyl-dicyclohexyl isourea (4.50 g. 16.05 mmol). The mix dry ice/acetone bath, and 2MLDA (51.8 ml, 103.6 mmol) was ture stirred for 72 hat room temperature under argon. After 72 added drop-wise over 5-10 minutes. The solution stirred for h, the mixture was filtered to remove DCU. The filtrate was 30 minutes, and 1,4-dibromobutane (22.3 g, 103 mmol) was washed with saturated sodium bicarbonate solution (50 mL). added. The solution slowly warmed to room temperature and The dichloromethane was dried over sodium sulfate, filtered, stirred overnight. After 18 hat room temperature, water (100 and concentrated. The remaining oil was filtered through ml) was added along with ethyl acetate (100 mL). The layers silica gel (30 g) with 10% ethyl acetate/heptanes. The experi were separated, and the ethyl acetate layer was extracted with ment generated 2.20 g (72% yield of 6-Benzyloxy-2,2-dim 5% hydrochloric acid solution (100 ml) followed by brine ethylhexanoic acid tert-butyl ester as a clear oil. "H NMR (100 mL). The ethyl acetate extract was dried over sodium (300 MHz, CDC1) & 7.35-7.25 (m, 5H), 4.50 (s. 2H), 3.48 (t, Sulfate, filtered, and concentrated. The remaining oil was 2H, J=6.3 Hz), 1.62-1.49 (m, 4H), 1.42 (s.9H), 1.40-1.37 (m, purified twice on silica gel (200 g), eluting with 1:10 ethyl 2H), 1.11 (s, 6H). acetate?heptane. The experiment generated 12.2 g (56% yield) of 6-bromo-2,2-dimethylhexanoic acid ethyl ester as a Example 17 clear oil. "H NMR (300 MHz, CDC1) & 4.14 (q, 2H, J=7.2 6-Hydroxy-2,2-dimethylhexanoic acid t-butyl ester HZ), 3.52 (t, 2H, J=56.9Hz), 1.88-1.82 (m, 2H), 1.58-1.36 (m, (12) 2H), 1.36 (t, 3H, J–7.2 Hz), 1.18 (s, 6H). 0756) Example 15 6-Benzyloxy-2,2-dimethylhexanoic acid (9) 0752 > -- 0757 6-Benzyloxy-2,2-dimethylhexanoic acid tert-butyl O ester (2.20 g, 7.18 mmol) was dissolved in ethyl acetate (40 mL) and added to 10% palladium on carbon (1.35 g). The O mixture was hydrogenated at 40 psi hydrogen in a Parr appa HO ratus for 48 h. The mixture was then purged with nitrogen and filtered through a pad of celite and concentrated. The experi ment produced 6-hydroxy-2,2-dimethyl-hexanoic acid t-bu 0753. 6-Benzyloxy-2,2-dimethylhexanoic acid ethyl ester tyl ester (1.60 g, 100% yield) as a clear oil. "H NMR (300 (7.40g, 26.6 mmol) was dissolved in ethanol (120 mL) with MHz, CDC1) & 3.65 (t, 2H, J=6.6 Hz), 1.58-1.50 (m, 4H), potassium hydroxide (7.40 g, 132 mmol) and water (40 mL). 1.43 (s, 9H), 1.39-1.30 (m, 2H), 1.12 (s, 6H). The solution was heated to 50-60° C. overnight. After 18 h, Example 18 the Solution was cooled to room temperature and concen 6-Bromo-2,2-dimethylhexanoic acid tert-butyl ester trated to remove ethanol. Water (150 mL) was added, and the solution was extracted with heptanes (100 mL). The layers (13) were separated and the aqueous layer was acidified to pH-2 0758 with concentrated hydrochloric acid. The product was extracted twice with ethyl acetate (50 mL). The combined ethyl acetate extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The experi Br ment produced 4.72 g (72% yield) of 6-benzyloxy-2,2-dim ethylhexanoic acid as a white solid. "H NMR (300 MHz, CDC1) & 7.35-7.25 (m, 5H), 4.50 (s. 2H), 3.48 (t, 2H, J=6.6 Hz), 1.64-1.53 (m, 4H), 1.40-1.37 (m, 2H), 1.19 (s, 6H). US 2016/O 137584 A1 May 19, 2016 52
(0759 t-Butyl isobutyrate (1.90 g, 13.1 mmol) was dis 3.38 (t, 4H, J=6.9 Hz), 1.55-1.45 (m, 8H), 1.43 (s, 18H), solved in dry THF (40 mL) under argon. The flask was cooled 1.35-1.25 (m, 4H), 1.11 (s, 12H). HRMS (ESI): M+NH in a dry ice/acetone bath, and 2MLDA (7.2 mL, 14.4 mmol) =432.3684. found 432.3696. was added drop-wise over 5-10 minutes. The solution stirred for 30 minutes, and 1,4-dibromobutane (8.0 g, 37 mmol) was added. The solution slowly warmed to room temperature and Example 20 stirred overnight. After 18 hat room temperature, water (50 ml) was added along with ethyl acetate (50 mL). The layers 6-Iodo-2,2-dimethylhexanoic acid t-butyl ester (15) were separated, and the ethyl acetate layer was extracted with 5% hydrochloric acid solution (50 ml) followed by brine (50 0764 mL). The ethyl acetate extract was dried over sodium sulfate, filtered, and concentrated. The remaining oil was purified twice on silica gel (30 g), eluting with 1:20 ethyl acetate/ O heptane. The experiment generated 1.0 g (28% yield) of 6-bromo-2,2-dimethylhexanoic acid t-butyl ester as a clear > I oil. "H NMR (300 MHz, CDC1) & 3.42 (t, 2H, J=6.9 Hz), O 1.88-1.83 (m, 2H), 1.58-1.36 (m, 2H), 1.47 (s, 9H), 1.14 (s, 6H). Example 19 0765 6-Bromo-2,2-dimethylhexanoic acid tert-butyl ester (0.66 g. 2.36 mmol) was dissolved in acetone (30 mL) 6-(5-tert-Butoxycarbonyl-5-methylhexyloxy)-2.2- with sodium iodide (0.90 g. 6.0 mmol). The mixture was dimethyl-hexanoic acid tert-butyl ester (14) heated to reflux for 2 hunder argon. The mixture was cooled to room temperature, filtered, and concentrated. Heptane (30 0760 mL) was added along with water (30 mL). The layers were separated, and the heptanes was dried over sodium sulfate, filtered, and concentrated. The experiment produced 6-iodo O O 2,2-dimethylhexanoic acidt-butyl ester (0.71 g, 92% yield) as > O -k a colorless oil. "H NMR (300 MHz, CDC1) & 3.19 (t, 2H, J=6.6Hz), 1.86-1.76(m,2H), 1.51-1.34 (m,2H), 1.45 (s.9H), x^- ~x. 1.13 (s, 6H). 0761 Sodium hydride (60%, 50 mg, 1.25 mmol) was mixed with DMF (5 mL) under argon. The flask was cooled in Example 21 a waterfice batch, and 6-hydroxy-2,2-dimethylhexanoic acid t-butyl ester (0.26g, 1.20 mmol) was added. The mixture was Ethyl 2-p-tolylpropionate (16) stirred for 10-20 minutes at 5°C. when 6-bromo-2,2-dimeth ylhexanoic acidt-butyl ester (0.35 g, 1.25 mmol) in DMF (1.0 0766 mL) was added. The mixture was slowly warmed to room temperature and stirred overnight under argon. After 20 hat room temperature, water (20 mL) was added, and the product was extracted with diethyl ether (2x20 mL). The combined O ether extracts were washed with water (20 mL), dried over Sodium sulfate, filtered, and concentrated. The remaining oil 1No was purified on silica gel eluting with 10% ethyl acetate/ heptanes. The experiment produced the d-t-butyl ester of gemcabene (0.17 g., 34% yield) as a clear oil. "H NMR (300 MHz, CDC1) & 3.38 (t, 4H, J=6.9 Hz), 1.55-145 (m, 8H), 0767 To a stirred solution of ethyl p-tolylacetate (1.78 g. 1.43 (s, 18H), 1.35-1.25 (m, 4H), 1.11 (s, 12H). 10.0 mmol) in anhydrous THF (15 mL) cooled in a dry ice 0762. Alternate Procedure: bath was added lithium diisopropylamide (2 M., 5.0 mL, 10 0763 Sodium hydride (60%, 50 mg, 1.25 mmol) was mmol) drop-wise. After the mixture was stirred for 30 min mixed with DMF (5 mL) under argon. The flask was cooled in utes, iodomethane (1.42g, 10.0 mmol) was added drop-wise. a waterfice batch, and 6-hydroxy-2,2-dimethylhexanoic acid After addition, the reaction mixture continued to be stirred at t-butyl ester (0.26g, 1.20 mmol) was added. The mixture was -78°C. for 30 minutes and then at room temperature over stirred for 30-40 minutes at 5°C. when 6-iodo-2,2-dimethyl night. The reaction was quenched with cold 1 NHCl solution hexanoic acid t-butyl ester (0.50 g, 1.53 mmol) was added. (20 mL), and the resulting mixture was extracted with MTBE The mixture was slowly warmed to room temperature and (2x30 mL). The combined extracts were washed with 2% stirred overnight under argon. After 20hat room temperature, sodium thiosulfate (50 mL), brine (30 mL), dried over anhy water (20 mL) was added, and the product was extracted with drous sodium sulfate, and concentrated under reduced pres diethyl ether (2x20 mL). The combined ether extracts were Sure. The crude product was purified through a silica-gel flash washed with water (20 mL), dried over sodium sulfate, fil chromatography eluted with heptane/ethyl acetate (60:1) to tered, and concentrated. The remaining oil was purified on give the desired product (1.37 g. 71% yield) as a light yellow silica gel eluting with 10% ethyl acetate/heptanes. The oil: "H NMR (300 MHz, CDC1) & 7.19 (d. 2H, J–7.8 Hz), experiment produced the d-t-butyl ester of gemcabene (0.20 7.13 (d. 2H, J=7.8 Hz), 4.11 (m, 2H), 3.67 (q, 1H, J=7.2 Hz), g, 40% yield) as a clear oil. H NMR (300 MHz, CDC1) & 2.33 (s.3H), 1.47 (d. 3H, J–7.2 Hz), 1.20 (t, 3H, J=7.2 Hz). US 2016/O 137584 A1 May 19, 2016 53
Example 22 extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified through a Diethyl 6,6'-oxybis(2-methyl-2-(p-tolyl)hexanoate) silica-gel flash chromatography eluted with heptane/ethyl (17) acetate (from 6:1 to 2:1), followed by lyophilization to give the desired dicarboxylic acid (0.56 g. 64% yield, 98.7% 0768 HPLC purity) as a colorless oil: "H NMR (300 MHz, CDC1) 87.24 (m, 4H), 7.13 (m, 4H), 3.50 (m, 1H), 3.40 (m, 2H), 3.32 (m. 1H), 2.33 (s.3H), 2.31 (s.3H), 2.16 (m, 2H), 1.83 (m,2H), 1.58 (m, 4H), 1.50 (s, 3H), 1.46 (s, 3H), 1.40 (m, 4H); 'C 1No NMR (75 MHz, CDC1) & 182.60, 182.39, 141.25, 141.04, 136.43, 129.10, 125.92, 125.81, 69.99, 69.96, 50.38, 50.31, 38.95, 38.39, 30.25, 30.23, 24.09, 23.71, 22.06, 20.90. Example 24 3-(Tetrahydropyran-2-yloxy)-propan-1-ol (22) 0769 To a stirred solution of diisopropylamine (0.68 g. 0772 6.8 mmol) in anhydrous THF (15 mL) cooled in a dry ice bath was added hexyllithium (2.3 M, 2.9 mL, 6.8 mmol), and the mixture was stirred for 40 minutes. Ethyl 2-p-tolylpropionate (1.30 g. 6.76 mmol) was added drop-wise; 30 minutes later, followed by addition of 4-iodobutyl ether (0.93 g, 2.5 mmol). After addition, the reaction mixture was slowly warmed to - OO room temperature and stirred for three days. The reaction mixture was poured into cold 1 NHCl solution (30 mL) and 0773) 1..3-Propanediol (34.2 g, 0.45 mol) and p-toluene then extracted with MTBE (3x30 mL). The combined sulfonic acid monohydrate (0.66 g, 3.47 mmol) were dis extracts were washed with 2% sodium thiosulfate (50 mL) solved in a mixture of THF (100 mL) and dichloromethane and brine (50 mL), dried over sodium sulfate, and concen (30 mL). The flask was cooled in an ice bath, and 3,4-dihy trated under reduced pressure. The residue was purified dropyran (12.0 g, 0.14 mol) was added drop-wise over 20-30 through a silica-gel flash chromatography eluted with a gra minutes. After 2 hours of stirring, the ice bath was removed, dient of heptane/ethyl acetate (40:1 to 10:1) to give the and the reaction was stirred at room temperature for 2 hours. desired diester (1.10 g, 89% yield) as a light yellow oil: "H After 2 hours, the reaction was slowly poured into water (500 NMR (300 MHz, CDC1) & 7.19 (d, 4H, J=8.4 Hz), 7.11 (d. mL) that contained potassium carbonate (12 g). The product 4H, J=8.4 Hz), 4.11 (q, 4H, J–7.2 Hz), 3.34 (t, 4H, J=6.6 Hz), was extracted with ethyl acetate (2x250 mL). The combined 2.32 (s, 6H), 2.03 (m, 2H), 1.87 (im, 2H), 1.54 (m, 4H), 1.51 ethyl acetate extracts were washed with water (2x250 mL) (s, 6H), 1.22 (m, 4H), 1.18 (t, 6H, J=7.2 Hz); 'C NMR (75 and brine (100 mL), dried over sodium sulfate, filtered, and MHz, CDC1) & 176.32, 141.10, 136.06, 128.98, 125.82, concentrated. The crude oil was purified by column chroma 70.62, 60.62, 49.80, 39.08, 30.21, 22.70, 21.44, 20.90, 14.08. tography on silica gel (250 g), eluting with 3:1 heptane/ethyl acetate. The procedure generated 7.24 g (32% yield) of 3-(tet Example 23 rahydropyran-2-yloxy)-propan-1-ol, as a colorless oil. "H 6,6'-Oxybis(2-methyl-2-(p-tolyl)hexanoic acid) (18) NMR (300 MHz, CDC1) & 4.59 (t, 1H, J=2.4 Hz), 3.98-3.78 (m, 4H), 3.77-3.50 (m, 2H), 2.37 (t, 1H, J=5.7 Hz), 1.90-1.70 (0770 (m, 4H), 1.60-1.53 (m, 4H). Example 25 2-3-(4-Bromobutoxy)-propoxy-tetrahydropyran HO OH (23) 0774 - O 0771) To a stirred solution of diester diethyl 6,6'-oxybis(2- methyl-2-(p-tolyl)hexanoate) (1.07 g. 2.11 mmol) in absolute ethanol (20 mL) was added aqueous KOH (2.2 M., 9.6 mL. 21 0775 3-(Tetrahydropyran-2-yloxy)-propan-1-ol (7.24 g, mmol), and the mixture was stirred at 55° C. for 48 h. The 45.2 mmol) was dissolved in dry THF (120 mL) under argon reaction mixture was cooled to room temperature and then with 60% sodium hydride (3.6 g. 54.2 mmol). The mixture concentrated under reduced pressure to remove ethanol. The was stirred for 30 minutes at room temperature. 1,4-dibro remaining mixture was diluted with water (10 mL) and then mobutane (12.0g, 55.5 mmol) was added and the mixture was acidified with 3 NHCl (10 mL) slowly. The resulting cloudy heated to reflux for 22 h. After 22 h, the solution was cooled mixture was extracted with MTBE (3x30 mL). The combined to room temperature and poured into water (150 mL) and US 2016/O 137584 A1 May 19, 2016 54 extracted with ethyl acetate (100 mL). The ethyl acetate was Example 28 dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude oil was purified by column chro 6-(4-Ethoxycarbonyl-4-methylpentyloxy)-2,2-dim matography on silica gel (200 g), eluting with 5% to 50% ethylhexanoic acid ethyl ester (21) ethyl acetate/heptane. The procedure generated 2.71 g (20% yield) of 2-3-(4-bromobutoxy)-propoxy-tetrahydropyran 0780 as a colorless oil. "H NMR (300 MHz, CDC1) & 4.59 (t, 1H, J=2.4 Hz), 3.88-3.78 (m, 2H), 3.53-3.42 (m, 8H), 2.00- 1.52 O (m. 12H).
Example 26 --~~-X-O
3-(4-Bromobutoxy)-propan-1-ol (24) 0781 Ethyl isobutyrate (1.60 g, 13.8 mmol) was dissolved in dry THF (15.0 mL) under argon. The flask was cooled in a 0776 dry ice/acetone bath, and 2MLDA (6.5 mL) was added drop wise over 5-10 minutes. The solution was stirred for 30 min utes at -78° C. 1-Bromo-4-(3-bromopropoxy)butane (693 "N-1-1N1-1N mg, 2.53 mmol) was added, and the Solution slowly warmed to room temperature and stirred overnight. After 18 h, water (25 mL) was added with ethyl acetate (25 mL). The layers 0777 2-3-(4-Bromobutoxy)-propoxy-tetrahydropyran were separated, and the ethyl acetate extract was washed with (2.70 g.9.14 mmol) was dissolved in methanol (60 mL) under 10% hydrochloric acid solution (25 mL), dried over sodium argon at room temperature. p-Toluenesulfonic acid monohy Sulfate, filtered, and concentrated. The remaining oil was purified by column chromatography on silica gel (20 g). drate (5.21 g, 27.4 mmol) was added and the solution stirred eluting with 5% to 10% ethyl acetate/heptanes. The experi overnight at room temperature. After 18 h, the solution was ment generated 0.74 g (85% yield) of 6-(4-ethoxycarbonyl concentrated under reduced pressure. To the remaining oil 4-methylpentyloxy)-2,2-dimethyl-hexanoic acid ethyl ester was added ethyl acetate (80 mL) and saturated sodium bicar as a colorless oil. "H NMR (300 MHz, CDC1) & 4.10 (q, 4H, bonate solution (80 mL) in portions. After mixing for 20 J–7.2 Hz), 3.39-3.35 (m, 4H), 1.58-1.48 (m, 8H), 1.3-1.2 (m, minutes, the layers were separated, and the ethyl acetate 8H), 1.16 (m, 12H). HRMS (ESI): M+H"=373.2948. found extract was dried over Sodium sulfate, filtered, and concen 373.2948. trated. The remaining oil was purified by flash column chro matography on silica gel (30 g), eluting with 20% to 50% Example 29 ethyl acetate?heptanes. The procedure generated 1.59 g (82% yield) of 3-(4-bromobutoxy)-propan-1-ol as a colorless oil. 5-(Tetrahydropyran-2-yloxy)-pentan-1-ol (27) H NMR (300 MHz, CDC1) & 3.77 (t, 2H, J=5.7 Hz), 3.59 (t, 2H, J=6.0 Hz), 3.50-3.42 (m, 4H), 2.00-1.68 (m, 6H). 0782 Example 27 1-Bromo-4-(3-bromopropoxy)butane (25) - O 0778 0783 1.5-Pentanediol (40.9 g, 0.45 mol) and p-toluene sulfonic acid monohydrate (0.66 g, 3.47 mmol) were dis solved in a mixture of THF (100 mL) and dichloromethane "N-1-1N1-1N (30 mL). The flask was cooled in an ice bath, and 3,4-dihy dropyran (12.0 g, 0.14 mol) was added drop-wise over 20-30 minutes. After 2 hours of stirring, the ice bath was removed, (0779) 3-(4-Bromobutoxy)-propan-1-ol (1.59 g, 7.53 and the reaction stirred at room temperature for 2 hours. After mmol) was dissolved in THF (25 mL) under argon at room 2 hours, the reaction was slowly poured into water (500 mL) temperature. The flask was placed in a water bath to maintain that contained potassium carbonate (12 g). The product was room temperature. Carbon tetrabromide (3.75g, 11.3 mmol) extracted with ethyl acetate (2x250 mL). The combined ethyl and triphenylphosphine (2.94g, 11.3 mmol) were added, and acetate extracts were washed with water (2x250 mL) and the reaction stirred for 3 hat room temperature. Heptane (30 brine (100 mL), dried over sodium sulfate, filtered, and con mL) was added, and the mixture was filtered and concen centrated. The crude oil was purified by column chromatog trated. The remaining oil was purified by column chromatog raphy on silica gel (250 g), eluting with 3:1 heptane/ethyl raphy on silica gel (25 g), eluting with 4% ethyl acetate/ acetate. The procedure generated 20.4 g (72% yield) of 5-(tet heptanes. The experiment generated 1.82 g (91% yield) rahydropyran-2-yloxy)-pentan-1-ol, as a colorless oil. "H 1-bromo-4-(3-bromopropoxy)butane as a clear oil. "H NMR NMR (300 MHz, CDC1) & 4.58 (t, 1H, J=2.7 Hz), 3.90-3.75 (300 MHz, CDC1) & 3.55-3.42 (m, 8H), 2.13-2.05 (m, 2H), (m. 2H), 3.67 (t, 2H, J=0.6 Hz), 3.54-3.36 (m, 2H), 2.37 (m, 1.99-1.90 (m, 2H), 1.76-1.67 (m, 2H). 2H), 1.85-1.42 (m, 4H), 1.60- 1.53 (m, 12H). US 2016/O 137584 A1 May 19, 2016 55
Example 30 Example 32 2-5-(5-Bromopentyloxy)-pentyloxy-tetrahydropyran 1-Bromo-5-(5-bromopentyloxy)-pentane (30) (28) 0788 0784)
1)N-1\-1N1 S-1)n-1\ Br
0789 5-(5-Bromopentyloxy)-pentan-1-ol (2.74 g, 10.82 ------mmol) was dissolved in THF (50 mL) under argon at room temperature. The flask was placed in a water bath to maintain 0785 5-(Tetrahydropyran-2-yloxy)-pentan-1-ol (3.76 g. room temperature. Carbon tetrabromide (5.38 g. 16.2 mmol) 19.9 mmol) was dissolved in dry THF (30 mL) under argon and triphenylphosphine (4.26 g. 16.2 mmol) were added and with 60% sodium hydride (0.88 g. 22 mmol). The mixture the reaction stirred for 3 hat room temperature. Heptane (50 was stirred for 30 minutes at room temperature. 1,5-dibro mL) was added, and the mixture was filtered and concen mopentane (4.6 g. 20 mmol) was added, and the mixture was trated. The remaining oil was purified by column chromatog heated to reflux for 22 h. After 22 h, the solution was cooled raphy on silica gel (80 g), eluting with 4% ethyl acetate/ to room temperature and poured into water (150 mL) and heptanes. The experiment generated 1.82 g (91% yield) extracted with ethyl acetate (100 mL). The ethyl acetate was 1-bromo-5-(5-bromopentyloxy)-pentane as a clear oil. "H dried over sodium sulfate, filtered, and concentrated under NMR (300 MHz, CDC1) & 3.45-3.39 (m, 8H), 1.94-1.85 (m, reduced pressure. The crude oil was purified by column chro 4H), 1.65-1.48 (m, 8H). matography on silica gel (200 g), eluting with 5% to 50% ethyl acetate?heptane. The procedure generated 1.49 g (21% Example 33 yield) of 2-5-(5-bromopentyloxy)-pentyloxy-tetrahydropy ran as a colorless oil. "H NMR (300 MHz, CDC1) & 4.59 (t, 7-(6-Ethoxycarbonyl-6-methylheptyloxy)-2,2-dim 1H, J=2.7 Hz), 3.89-3.70 (m, 2H), 3.53-3.35 (m, 8H), 1.91 ethylheptanoic acid ethyl ester (19) 1.39 (m, 18H). 0790 Example 31
5-(5-Bromopentyloxy)-pentan-1-ol (29) O O 0786) ~...~~xo~.
0791) Ethylisobutyrate (1.60 g, 13.8 mmol) was dissolved 1n-1\-1N1)n-1\-1N Br in dry THF (15.0 mL) under argon. The flask was cooled in a dry ice/acetone bath and 2MLDA (6.2 mL) was added drop wise over 5-10 minutes. The solution was stirred for 30 min 0787 2-5-(5-Bromopentyloxy)-pentyloxy-tetrahydro utes at -78° C. 1-Bromo-5-(5-bromopentyloxy)-pentane pyran (1.40g, 4.15 mmol) was dissolved in methanol (30 mL) under argon at room temperature. p-Toluenesulfonic acid (800 mg, 2.53 mmol) was added and the solution slowly monohydrate (2.38g, 12.5 mmol) was added, and the solution warmed to room temperature and stirred overnight. After 18 stirred overnight at room temperature. After 18 h, the solution h, water (25 mL) was added with ethyl acetate (25 mL). The was concentrated under reduced pressure. To the remaining layers were separated and the ethyl acetate extract was oil was added ethyl acetate (100 mL) and saturated sodium washed with 10% hydrochloric acid solution (25 mL), dried bicarbonate solution (80 mL) in portions. After mixing for 20 over Sodium Sulfate, filtered, and concentrated. The remain minutes, the layers were separated, and the ethyl acetate ing oil was purified by column chromatography on silica gel extract was dried over Sodium sulfate, filtered, and concen (20g), eluting with 5% to 10% ethyl acetate/heptanes. The trated. The remaining oil was purified by flash column chro experiment generated 0.87 g (89% yield) of 7-(6-ethoxycar matography on silica gel (30 g), eluting with 20% to 50% bonyl-6-methylheptyloxy)-2,2-dimethylheptanoic acid ethyl ethyl acetate/heptanes. The procedure generated 1.0 g (95% ester as a colorless oil. "H NMR (300 MHz, CDC1) & 4.12 (q, yield) of 5-(5-bromopentyloxy)-pentan-1-ol as a colorless 4H, J=7.2 Hz), 3.38 (t, 4H, J=6.6 Hz), 1.58-1.49 (m, 8H), oil. "H NMR (300 MHz, CDC1) 83.65 (t, 2H, J=6.6 Hz), 3.42 1.38-1.2 (m, 14H), 1.16 (s, 12H). HRMS (ESI): M+H" (t, 6H, J=6.6 Hz), 1.93-1.84 (m, 2H), 1.62-1.40 (m. 10H). =387.3105 found 387.3.108. US 2016/O 137584 A1 May 19, 2016 56
Example 34 Example 36 2-5-(4-Bromobutoxy)-pentyloxy-tetrahydropyran 1-Bromo-5-(4-bromobutoxy)-pentane (32) (31) 0796 0792
1N1 S-1 N-1)-N-1- 1S-1N1'N-1N1\-'N-' Br O 0797 5-(4-Bromobutoxy)-pentan-1-ol (1.62 g. 6.77 mmol) was dissolved in THF (30 mL) under argon at room temperature. The flask was placed in a water bath to maintain 0793 5-(Tetrahydropyran-2-yloxy)-pentan-1-ol (6.0 g, room temperature. Carbon tetrabromide (3.36 g. 10.2 mmol) 31.8 mmol) was dissolved in dry THF (100 mL) under argon and triphenylphosphine (2.66 g., 10.2 mmol) were added, and with 60% sodium hydride (2.60 g, 39.0 mmol). The mixture the reaction stirred for 3 hat room temperature. Heptane (50 was stirred for 30 minutes at room temperature. 1,4-dibro mL) was added and the mixture was filtered and concentrated. mobutane (9.0g, 41.7 mmol) was added, and the mixture was The remaining oil was purified by column chromatography heated to reflux for 22 h. After 22 h, the solution was cooled on silica gel (40 g), eluting with 4% ethyl acetate?heptanes. to room temperature and poured into water (150 mL) and The experiment generated 1.40 g (70% yield) 1-bromo-5-(4- extracted with ethyl acetate (100 mL). The ethyl acetate was bromobutoxy)-pentane as a clear oil. "H NMR (300 MHz, dried over sodium sulfate, filtered, and concentrated under CDC1) & 3.47-3.39 (m, 8H), 2.0-1.84 (m, 4H), 1.76-1.47 (m, reduced pressure. The crude oil was purified by column chro 6H). matography on silica gel (200 g), eluting with 5% to 50% ethyl acetate?heptane. The procedure generated 2.41 g (24% Example 37 yield) of 2-5-(4-bromobutoxy)-pentyloxy-tetrahydropyran as a colorless oil. "H NMR (300 MHz, CDC1) & 4.57 (t, 1H, 7-(5-Ethoxycarbonyl-5-methylhexyloxy)-2,2-dim J=2.7 Hz), 3.89-3.70 (m, 2H), 3.51-3.47 (m, 8H), 1.99-1.38 ethylheptanoic acid ethyl ester (33) (m. 16H). 0798 Example 35
5-(4-Bromobutoxy)-pentan-1-ol (35) O 0794 ~...~~-X-O
0799. Ethylisobutyrate (1.60 g, 13.8 mmol) was dissolved 1-1-N-N-1-1-N-' in dry THF (15.0 mL) under argon. The flask was cooled in a dry ice/acetone bath and 2MLDA (6.5 mL) was added drop 0795 2-5-(4-Bromobutoxy)-pentyloxy-tetrahydropy wise over 5-10 minutes. The solution was stirred for 30 min ran (2.41 g, 7.45 mmol) was dissolved in methanol (60 mL) utes at -78° C. 1-Bromo-5-(4-bromobutoxy)-pentane (765 under argon at room temperature. p-Toluenesulfonic acid mg, 2.53 mmol) was added, and the Solution slowly warmed monohydrate (4.25g, 22.6 mmol) was added, and the Solution to room temperature and stirred overnight. After 18 h, water stirred overnight at room temperature. After 18 h, the solution (25 mL) was added with ethyl acetate (25 mL). The layers was concentrated under reduced pressure. To the remaining were separated, and the ethyl acetate extract was washed with oil was added ethyl acetate (80 mL) and saturated sodium 10% hydrochloric acid solution (25 mL), dried over sodium bicarbonate solution (80 mL) in portions. After mixing for 20 Sulfate, filtered, and concentrated. The remaining oil was minutes, the layers were separated, and the ethyl acetate purified by column chromatography on silica gel (20 g). extract was dried over Sodium sulfate, filtered, and concen trated. The remaining oil was purified by flash column chro eluting with 5% to 10% ethyl acetate/heptanes. The experi matography on silica gel (25 g), eluting with 20% to 50% ment generated 0.74 g (79% yield) of 7-(5-Ethoxycarbonyl ethyl acetate?heptanes. The procedure generated 1.62 g (91% 5-methylhexyloxy)-2,2-dimethylheptanoic acid ethyl ester as yield) of 5-(4-bromobutoxy)-pentan-1-ol as a colorless oil. a colorless oil. "H NMR (300 MHz, CDC1) & 4.14 (q, 4H, "H NMR (300 MHz, CDC1,) & 3.65 (m. 2H), 3.42 (t, 6H, J–7.2 Hz),343-3.38 (m, 4H), 1.59-1.55 (m,8H), 1.40-1.2 (m, J=6.6 Hz), 3.47-3.39 (m, 6H), 1.99-190 (m, 2H), 1.76-1.32 12H), 1.19 (m, 12H). HRMS (ESI): M+H"=373.2948. (m, 6H). found 373.2948. US 2016/O 137584 A1 May 19, 2016 57
Example 38 wherein: R" is alkyl; 3.3-Dimethyl-oxepan-2-one (25) R° and R are each independently alkyl, cycloalkyl, 0800 cycloalkylalkyl, heterocycloalkyl, heterocycloalkyla lkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and in and mare each independently 0-4: comprising: (a) reacting a solution comprising a Substituted acetic acid ester of formula (I):
0801 Caprolactone (2.0 g, 17.5 mmol) was dissolved in dry THF (40 mL) under argon. The flask was cooled in a dry ice/acetone bath, and 2MLDA (10 mL. 20 mmol) was added ORI drop-wise over 5-10 minutes. The solution was stirred for 50 minutes at -78°C. Iodomethane (2.9 g, 20.5 mmol) was R3 added, and the Solution slowly warmed by removing the acetone bath and replacing it with an ice/water bath. After 1 with a deprotonating reagent to produce an intermediate of hour, the ice/water bath was replaced with a dry ice/acetone formula (Ia): bath, and 2M LDA (10 mL. 20 mmol) was added drop-wise over 5-10 minutes. The solution was stirred for 50 minutes at -78°C. Iodomethane (5.8 g., 41 mmol) was added, and the Ia solution slowly warmed to 0°C. over 2 h. Water (50 mL) was added with diethyl ether (25 mL). The layers were separated, and the ether extract was washed with 10% hydrochloric acid solution (25 mL), dried over sodium sulfate, filtered, and concentrated. The remaining oil was purified by column chro matography on silica gel (50 g), eluting with 40% ethyl acetate?heptanes. The experiment generated 0.40 g (16% yield) of 3.3-dimethyl-oxepan-2-one as a colorless oil. "H wherein M is Lior Zn; and NMR (300 MHz, CDC1) & 4.04 (t, 2H, J=6.0 Hz), 1.65-1.50 (b) reacting the intermediate of formula (Ia) with a solution (m, 4H), 1.30-1.20 (m, 2H), 1.16 (s, 6H). comprising a C,c)-halo-terminated dialkane ether of for OTHER EMBODIMENTS mula (II): 0802. The foregoing disclosure has been described in Some detail by way of illustration and example, for purposes II of clarity and understanding. The invention has been described with reference to various specific and preferred 1N-N-1'Nu-hs-1N embodiments and techniques. However, it should be under stood that many variations and modifications can be made wherein X is halo: while remaining within the spirit and scope of the invention. to produce a compound of formula (III). It will be obvious to one of skill in the art that changes and 2. The process of claim 1, further comprising the step of modifications can be practiced within the scope of the performing an aqueous work-up of the Solution of step (b) to appended claims. Therefore, it is to be understood that the isolate an organic solution of the compound of formula (III). above description is intended to be illustrative and not restric 3. The process of claim 1, further comprising the step of tive. treating the crude compound of formula (III) with an aqueous 0803. The scope of the invention should, therefore, be solution of a hydroxide or oxide of an alkali or earth alkaline determined not with reference to the above description, but metal. should instead be determined with reference to the following appended claims, along with the full scope of equivalents to 4. The process of claim 1, further comprising the step of which such claims are entitled. precipitating the Salt of the C.O)-dicarboxylic acid-terminated What is claimed is: dialkane ether of formula (IV): 1. A process for preparing a compound of formula (III): IV
O O O O --~4-N---> (M), O R2 R3 R3 R2 RO pi iii. ORI R2 R3 R3 R2 in the presence of an organic solvent, wherein M' is Ca or K and X is 1 or 2. US 2016/O 137584 A1 May 19, 2016
5. The process of claim 1, further comprising the step of comprising: removing the organic layer by evaporation to afford crude (a) reacting a solution comprising a Substituted acetic acid crystalline C.O)-dicarboxylic acid-terminated dialkane ether ester: salt of formula (IV) in the form of an alcohol solvate or hydrate, wherein the alcohol solvate or hydrate is stirred with tetrahydrofuran with subsequent addition of one or more anti-solvents to obtain the crystalline form of the C,c)-dicar boxylic acid-terminated dialkane ether salt of formula (IV). OEt 6. The process of claim 1, further comprising the step of adding one or more anti-solvents so that the Salt of the O.co dicarboxylic acid-terminated dialkane ether of formula (IV) with a deprotonating reagent to produce an intermediate: is insoluble. 7. The process of claim 1, further comprising the step of humidifying the precipitate to obtain a crystalline salt of a M2No C.co-dicarboxylic acid-terminated dialkane ether of formula (IV). 2 OEt 8. The process of claim 1, further comprising the step of hydrolyzing the compound of formula (III) to produce a com pound of formula (V). wherein M is Li or Zn; (b) reacting the intermediate of step (a) with a solution V comprising a C.(I)-halo-terminated dialkane ether: O O HO ------pi iii. OH R2 R3 R3 R2 wherein X is halo; and (c) hydrolyzing the crude diethyl 6,6'-oxybis(2,2-dim 9. The process of claim 1, comprising treating a solution of ethyl-4-hexanoate) to produce 6,6'-oxy-bis(2,2-dim a compound of formula (III) in a water-miscible solvent with ethyl-4-hexanoic acid). an aqueous solution of a base, wherein the water-miscible 12. A process for preparing crystalline 6,6'-oxybis(2.2- solvent is selected from DMSO, DMF, methanol, isopropyl dimethyl-4-hexanoic acid) calcium: alcohol, and ethanol; or treating a solution of a compound of formula (III) in a water-immiscible solvent with an aqueous solution of a base, wherein the water-immiscible solvent is O O selected from toluene, Xylene, methyl ethyl ketone, and O Ca2+ methyl isobutyl ketone. O O 10. The process of claim 1, wherein the compound of formula (III) is 6,6'-oxy-bis(2,2-dimethyl-4-hexanoic acid). wherein the process comprises: (a) reacting a solution of ethyl isobutyrate: O O
O EtO OEt
ORI 11. A process for preparing 6,6'-oxy-bis(2,2-dimethyl-4- hexanoic acid): with a deprotonating reagent to produce a compound:
O O M2 O No HO OH 2 OEt US 2016/O 137584 A1 May 19, 2016 59
wherein M is Li or Zn; comprising: (b) reacting the ethyl lithiobutyrate of step (a) with a solu (a) reacting a first solution of a compound of formula (46): tion of bis(4-chlorobutylether):
46
Hal 1N1N1 N-1-1a Hal HO R21
(c) performing an aqueous work-up of the solution of step R22 R23 (b) in order to isolate an organic Solution of crude diethyl 6,6'-oxybis(2,2-dimethyl-4-hexanoate): with a halogen source to produce a compound of formula (47): O O
O EtO OEt 47
X23 R21
(d) treating the crude diethyl 6,6'-oxybis(2,2-dimethyl-4- R22 R23 hexanoate) of step (c) with a calcium hydroxide or cal cium oxide of an alkali or earth alkaline metal in a suitable solvent to produce 6,6'-oxybis(2,2-dimethyl-4- wherein X* is F, Cl, or I; and hexanoic acid) calcium; (b) reacting a second solution of a compound of formula (e) precipitating the 6,6'-oxybis(2,2-dimethyl-4-hexanoic (46) with the intermediate of formula (47) in the pres acid) calcium of step (d): ence of base to form a compound of formula (48). 14. The process of claim 13, further comprising the step of O O reacting the Solution of a compound of formula (45): O - x^- ~x. Ca2+ 45
in the presence of an organic solvent; or, alternatively, removing the organic layer by evaporation to afford crude crystalline 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid) salt as an alcohol Solvate or hydrate; (f) adding one or more anti-solvents to the Solid of step (e) in which 6,6'-oxybis(2,2-dimethyl-4-hexanoic acid) cal with potassium tert-butoxide to produce an intermediate of cium is insoluble; and formula (46). (g) humidifying the precipitate resultant from step (f) to 15. The process of claim 13, further comprising the step of obtain crystalline 6,6'-oxybis(2,2-dimethyl-4-hexanoic reacting an intermediate of formula (43a): acid) calcium. 13. A process for preparing a compound of formula (48): 43a M23 48 Yo O O R22 O R2S.------ON-->s- R21 R22 R23 R22 R23 ), wherein: wherein M' is Li or Zn; R’ is alkyl: with a solution of an alkylhalide of formula (44): R’ and R are each independently alkyl, cycloalkyl, R23X23 44 cycloalkylalkyl, heterocycloalkyl, heterocycloalkyla lkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and wherein X* is halo m is 0-4: to produce a compound of formula (45). US 2016/O 137584 A1 May 19, 2016 60
16. The process of claim 13, further comprising the step of 20. The process of claim 13, wherein the compound of reacting the solution of a compound of formula (43): formula (48) is the di-tert-butyl ester of 6,6'-oxy-bis(2.2- dimethyl-4-hexanoic acid).
43 O O
O HO OH
21. A process for preparing a compound of formula (48): with a deprotonating reagent to produce an intermediate of formula (43a). 48 17. The process of claim 13, further comprising the step of reacting the intermediate of formula (41a): O O R2No1 <-n- O n-is-- R21 41a. R22 R23 R22 R23 MSo a O wherein: R’ is alkyl: ), R’ and R are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkyla lkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and wherein M’ is Lior Zn; m is 0-4: with a solution of an alkylhalide of formula (42): comprising: R22X22 42 (a) reacting a solution of a cyclic lactone of formula (41): wherein X is halo to produce a compound of formula (43). 41 18. The process of claim 13, further comprising the step of reacting a solution of a cyclic lactone of formula (41):
41 ),
with a deprotonating reagent to produce an intermediate of formula (41a):
41a. with a deprotonating reagent to produce an intermediate of formula (41a). 19. The process of claim 13, further comprising the step of hydrolyzing the compound of formula (48) to produce a com pound of formula (49). m
O O wherein M is Lior Zn; O (b) reacting the intermediate of formula (41a) with a solu HO iii. iii. OH tion of an alkylhalide of formula (42): R22 R23 R22 R23 R22X22 42 wherein X* is halo: US 2016/O 137584 A1 May 19, 2016
to produce a compound of formula (43): (g) reacting the Solution of a compound of formula (46) with the intermediate of formula (47) in the presence of 43 O base to form a compound of formula (48):
R22 O 48 O O R2 O R21 (c) reacting the Solution of a compound of formula (43) S.----- n-is-as with a deprotonating reagent to produce an intermediate R22 R23 R22 R23 of formula (43a): (h) reacting the Solution of a compound of formula (48) 43a with dilute acid to form a compound of formula (49).
49 O O
O HO iii. iii. OH wherein M is Lior Zn; R22 R23 R22 R23 (d) reacting the intermediate of formula (43a) with a solu tion of an alkylhalide of formula (44): 22. The process of claim 21, wherein the compound of R23X23 44 formula (48) is: wherein X* is halo: to produce a compound of formula (45): O O
45 O HO OH
23. The process of claim 21, further comprising any of the following steps: (i) treating the compound of formula (49) of step (h) with a (e) reacting the Solution of a compound of formula (45) calcium hydroxide or calcium oxide of an alkali or earth with potassium tert-butoxide to produce an intermediate alkaline metal in a Suitable solvent; of formula (46): () precipitating the compound of formula (50):
46 50
HO R21 O O O R22 R23 --~R22 R23 n-n-soR22 R23 (M), (f) reacting the Solution of a compound of formula (46) with a halogen Source to produce an intermediate of formula (47): wherein M' is Ca or K and x is 1 or 2: in the presence of an organic solvent; or, alternatively, 47 removing the organic layer by evaporation to afford a crude crystalline salt of formula (50) as an alcohol sol vate or hydrate; (k) adding one or more anti-solvents to the Solid of step () R22 R23 in which the compound of formula (50) is insoluble; and (1) humidifying the precipitate resultant from step (k) to wherein X* is F, Cl, or I: obtain crystalline compound of formula (50). US 2016/O 137584 A1 May 19, 2016 62
24. A process for preparing a compound of formula (45): (b) reacting the intermediate of formula (41a) with a solu tion of an alkylhalide of formula (42): R22X22 42 45 O R23 wherein X* is halo: R22 O to produce a compound of formula (43):
)m 43 wherein: R’ and R are each independently alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkyla lkyl, arylalkyl, heteroaryl, or heteroarylalkyl; and m is 0-4: comprising: (a) reacting a solution of a cyclic lactone of formula (41): (c) reacting the solution of a compound of formula (43) with a deprotonating reagent to produce an intermediate 41 of formula (43a):
43a
with a deprotonating reagent to produce an intermediate of formula (41a):
41a. wherein M is Lior Zn; (d) reacting the intermediate of formula (43a) with a solu tion of an alkylhalide of formula (44): R23X23 44 wherein X* is halo: to produce a compound of formula (45). wherein M is Lior Zn; k k k k k