US 20090192325A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0192325 A1 Gallop et al. (43) Pub. Date: Jul. 30, 2009

(54) ENANTIOMERICALLY RESOLVING (21) Appl. No.: 12/358,532 ACYLOXYALKYL THOCARBONATES USED NSYNTHESIZING ACYLOXYALKYL (22) Filed: Jan. 23, 2009 CARBAMATE PRODRUGS Related U.S. Application Data (60) Provisional application No. 61/023.808, filed on Jan. (75) Inventors: Mark A. Gallop, Santa Clara, CA 25, 2008, provisional application No. 61/023,813, (US); Fenyei Yao, Mountain View, filed on Jan. 25, 2008, provisional application No. Cupertino,CA (US); Maria CA (US); J. Ludwikow, Ge Peng, 61/121,859, filed on Dec. 11, 2008. Mountain View, CA (US); Steven P. Publication Classification Raillard, Mountain View, CA (US) (51) Int. Cl. CI2P 7/62 (2006.01) Correspondence Address: CD7C 69/96 (2006.01) DORSEY & WHITNEY, LLP C07C38L/00 (2006.01) INTELLECTUAL PROPERTY DEPARTMENT (52) U.S. Cl...... 558/276; 435/135; 560/152 370 SEVENTEENTH STREET, SUITE 4700 DENVER, CO 80202-5647 (US) (57) ABSTRACT Methods of enzymatically resolving acyloxyalkyl thiocar (73) Assignee: XenoPort, Inc., Santa Clara, CA bonates useful in the synthesis of acyloxyalkyl carbamate (US) prodrugs are disclosed. Patent Application Publication Jul. 30, 2009 Sheet 1 of 5 US 2009/0192325 A1 SOO

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ENANTOMERICALLY RESOLVING a short half life in vivo, and when orally administered fre ACYLOXYALKYL THOCARBONATES USED quent dosing is required to maintain therapeutic levels in the INSYNTHESIZING ACYLOXYALKYL body. CARBAMATE PRODRUGS 0006. The (acyloxy)alkylcarbamate functionality has been widely used to prepare prodrugs for therapeutics con taining amine groups (Gogate et al., International Journal of 0001. This application claims the benefit under 35 U.S.C. Pharmaceutics 1987, 40, 235-248: Alexander et al., J. Med. S 119(e) of U.S. Provisional Application Ser. Nos. 61/023, Chem. 1988, 31,318-322; Sun et al., Bioorganic & Medicinal 808 filed Jan. 25, 2008: 61/023,813 filed Jan. 25, 2008; and Chemistry Letters 2001, 11, 1875-1879; Alexander et al., J. 61/121,859 filed Dec. 11, 2008, each of which is incorporated Med. Chem. 1991, 34, 78-81; and Gallop et al., U.S. Pat. No. by reference in its entirety. 6,972.341). Methods of synthesizing 1-(acyloxy)-alkyl car bamate prodrugs are disclosed in Gallop et al., U.S. Pat. No. FIELD 6,818,787, U.S. Pat. No. 6,927,036, U.S. Pat. No. 6,972,341, U.S. Pat. No. 7, 186,855, U.S. Pat. No. 7,026,351, U.S. Pat. 0002 Methods provided by the present disclosure relate to No. 7,109,239, and U.S. Pat. No. 7,227,028; Raillard et al., the enzymatic resolution of acyloxyalkylthiocarbonates use U.S. Pat. No. 7,232,924; Gallop and Bhat, WO 2005/010011; ful in the synthesis of acyloxyalkyl carbamate prodrugs. Raillard et al., U.S. Provisional Application No. 61/087,056 filed Aug. 7, 2008 and 61/087.038 filed Aug. 7, 2008, each of which is incorporated by reference in its entirety); and in BACKGROUND Alexander, U.S. Pat. No. 4,760,057, U.S. Pat. No. 4,916,230, 0003. The oral bioavailability of certain drugs can be and U.S. Pat. No. 5,684,018. One method, as outlined in FIG. improved by conversion to prodrugs. Certain prodrugs are 1, involves an acyloxyalkylthiocarbonate intermediate (Sun derivatives of the parent drug in which a functional group is et al., Bioorganic & Medicinal Chemistry Letters 2001, 11, “masked by a promoiety. Following administration to a 1875-1879; and Gallop et al., U.S. Pat. No. 7,026,351 and patient the prodrug is metabolized to release the parent drug. U.S. Pat. No. 7,227,028). The 1-(acyloxy)-alkyl group is an example of a promoiety 0007. A deficiency common to such methods for synthe that has been used to functionalize amine-containing drugs sizing acyloxyalkyl derivatives is that, except when the R such as pregabalin and baclofen. Substituent is hydrogen, the prodrugs are generated as race mates or diastereomeric mixtures. The presence of an addi 0004 Pregabalin ((3S)-(aminomethyl)-5-methyl-hex tional chiral center in the promoiety may lead to differences in anoic acid) is an FDA approved drug that is marketed for the the physical properties and in the pharmacokinetics of the treatment of for example, post herpetic neuralgia, peripheral prodrug. Complexities associated with the introduction of an diabetic neuropathy, fibromyalgia, and epilepsy. Pregabalinis uncontrolled Stereocenter in acyloxyalkyl promoieties have not absorbed from the lower gastrointestinal tract and exhibits led others to focus prodrug design efforts around the achiral a short half life in vivo, and therefore frequent dosing is acyloxymethyl moiety (R is hydrogen). Further, many (acy required to maintain therapeutic levels in the body when loxy)alkylcarbamate prodrugs generate formaldehyde as a orally administered. (3S)-1-Isobutanoyloxyethoxycarbo toxic metabolite during hydrolysis in vivo. In comparison nylaminomethyl-5-methyl-hexanoic acid, (3S)-1-isobu with acetaldehyde, formaldehyde shows greater acute mam tanoyloxyisobutoxycarbonylaminomethyl-5-methyl-hex malian toxicity and mutagenicity, and its oxidative metabolite anoic acid, and (3S)-1-benzoyloxyethoxy formate is associated with specific ocular toxicity in humans. carbonylaminomethyl-5-methyl-hexanoic acid a Furthermore, because the thiocarbonates do not have acidic examples of 1-(acyloxy)-alkyl carbamate prodrugs of pre or basic functional groups, they are not readily resolved by gabalin, which exhibit high bioavailability as pregabalin classical chemical methods. when dosed either orally or directly into the colon of a mam mal (Gallop et al., U.S. Pat. No. 6,972,341 and U.S. Pat. No. 0008 Thus, improved methods of synthesizing enantio 7,186,855; and Yao and Gallop, U.S. Provisional Application merically enriched acyloxyalkyl thiocarbonates are desir Nos. 61/023,808 filed Jan. 25, 2008 and 61/023,813 filed Jan. able. 25, 2008, each of which is incorporated by reference in its entirety). SUMMARY 0005. The 1-(acyloxy)-alkyl promoiety has also been used to provide prodrugs of baclofen, (t)-4-amino-3-(4-chlo 0009 Methods of enzymatically resolving racemic acy rophenyl)butanoic acid. Gallop et al., U.S. Pat. No. 7,109,239 loxyalkylthiocarbonate intermediates useful in the synthesis and U.S. Pat. No. 7,300,956 (each of which is incorporated by of enantiomerically and diastereomerically enriched acy reference in its entirety) disclose 1-(acyloxy)-alkyl carbam loxyalkyl carbamate prodrugs are disclosed. The methods are ate prodrugs of R-baclofen such as (3R)-4-(1S)-2-methyl applied to the synthesis of acyloxyalkyl carbamate prodrugs 1-(2-methylpropanoyloxy)propoxycarbonylamino-3-(4- of pregabalin and baclofen e.g., (3S)-(1R)-isobutanoyloxy chlorophenyl)butanoic acid. Baclofen is an analog of gamma ethoxycarbonylaminomethyl-5-methyl-hexanoic acid and aminobutyric acid (GABA) that selectively activates GABA (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro receptors, resulting in neuronal hyperpolarization. Baclofen poxycarbonylamino-3-(4-chlorophenyl)butanoic acid, is an FDA approved drug that is marketed for the treatment of respectively, with high chemical yield and diasteromeric spasticity and muscle relaxation. More recent studies have CXCSS. indicated that the R-isomer of baclofen is effective for treat 0010. In a first aspect, methods of enzymatically enriching ing gastroesophageal reflux disease (GERD). Baclofen and an enantiomeric mixture of a compound of Formula (I) are R-baclofen, like pregabalin, have poor colonic absorption and disclosed comprising: US 2009/0192325 A1 Jul. 30, 2009

I0023 R is chosen from C, alkyl, C. cycloalkyl, phenyl, Substituted phenyl, and C7- phenylalkyl, and O R2 O (I) 0024 reacting the enantiomerically enriched mixture hav ing at least 90% enantiomeric excess of one enantiomer of the compound of Formula (I) with N-hydroxysuccinimide to pro RI lsO usO ls s1 R3 vide the enantiomerically enriched mixture of the corre sponding compound of Formula (II). 0011 reacting the enantiomeric mixture with an enzyme 0025. In a fourth aspect, methods of synthesizing an acy to provide an enantiomerically enriched mixture having at loxyalkyl carbamate prodrug of Formula (III) are disclosed, least 90% enantiomeric excess of one enantiomer of the com comprising: pound of Formula (I), wherein: (0012) R' is chosen from C, alkyl, C. cycloalkyl, phenyl, Substituted phenyl, and C, phenylalkyl: (I) (0013 R’ is chosen from C, alkyl, C. cycloalkyl, O R2 O phenyl, Substituted phenyl, and Cze phenylalkyl; and (0014) R is chosen from C, alkyl, C. cycloalkyl, -s-s-s-s phenyl, Substituted phenyl, and C7- phenylalkyl. (II) 0015. In a second aspect, an enantiomerically enriched O R2 O O mixture of a compound of Formula (I) is disclosed, the mix ture having at least 90% enantiomeric excess of one enanti omer of the compound of Formula (I), - - - - (III) O R2 O O R2 O (I) R1 - O - O - N1- RI lsO usO ls s1 R3 wherein: 0026 reacting an enantiomeric mixture of a compound of 10016) R' is chosen from C, alkyl, C. cycloalkyl, Formula (I) with an enzyme to provide an enantiomerically phenyl, Substituted phenyl, and C7- phenylalkyl; enriched mixture having at least 90% enantiomeric excess of I0017 R is chosen from C alkyl, C. cycloalkyl, one isomer of the compound of Formula (I), wherein: phenyl, Substituted phenyl, and C7- phenylalkyl, and I0027) R' is chosen from C, alkyl, C. cycloalkyl, I0018 R is chosen from C alkyl, C. cycloalkyl, phenyl, Substituted phenyl, and C. phenylalkyl; phenyl, Substituted phenyl, and C. phenylalkyl is dis I0028 R is chosen from C, alkyl, C. cycloalkyl, closed. The enantiomerically enriched mixture is pre phenyl, Substituted phenyl, and C, phenylalkyl; and pared by steps comprising reacting an enantiomeric 0029 R is chosen from C alkyl, C. cycloalkyl, mixture of the compound of Formula (I) with an enzyme phenyl, Substituted phenyl, and C. phenylalkyl; to provide the enantiomerically enriched mixture. 0030 reacting the enantiomerically enriched mixture with 0019. In a third aspect, methods of synthesizing an enan N-hydroxysuccinimide to provide the enantiomerically tiomerically enriched mixture of an NHS-acyloxyalkylcar enriched mixture of the corresponding compound of Formula bonate compound of Formula (II) are disclosed comprising: (II); and 0031 reacting the enantiomerically enriched compound of Formula (II) with a drug, D-NHR, comprising at least one (I) primary or secondary amine group to provide the compound O R2 O of Formula (III), wherein -D is the drug without the at least one primary or secondary amine group and R is chosen from ------hydrogen and a group of a secondary amine. (II) O R2 O O BRIEF DESCRIPTION OF THE DRAWINGS 0032 FIG. 1 shows a reaction sequence for the synthesis - - - - of acyloxyalkyl carbamate prodrugs via racemic acyloxy O alkylthiocarbonate intermediates. 0033 FIG. 2 shows a reaction sequence using enzymatic 0020 reacting an enantiomeric mixture of a compound of resolution of acyloxyalkylthiocarbonate prodrug precursors Formula (I) with an enzyme to provide an enantiomerically to provide enantiomerically or diastereomerically enriched enriched mixture having at least 90% enantiomeric excess of acyloxyalkyl carbamate prodrugs. one isomer of the compound of Formula (I), wherein: 0034 FIG. 3 shows the structure of certain racemic acy (0021) R' is chosen from C, alkyl, C. cycloalkyl, loxyalkylthiocarbonates. phenyl, Substituted phenyl, and C7- phenylalkyl; 0035 FIG. 4 shows a summary of the enantiomeric selec I0022 R is chosen from C alkyl, C. cycloalkyl, tivity of certain enzymes towards acyloxyalkyl thiocarbon phenyl, Substituted phenyl, and C7- phenylalkyl, and ates. US 2009/0192325 A1 Jul. 30, 2009

0036 FIG. 5 shows an example of the synthesis of the matic ring, cycloalkyl ring, or heterocycloalkyl ring. For pregabalin prodrug 3-((1R)-1-(2-methylpropanoyloxy) example, aryl includes a phenyl ring fused to a 5- to 7-mem ethoxycarbonylaminomethyl)(3S)-5-methylhexanoic acid. bered heterocycloalkyl ring containing one or more heteroa toms chosen from N, O, and S. For such fused, bicyclic ring DETAILED DESCRIPTION systems wherein only one of the rings is a carbocyclic aro matic ring, the radical carbon atom may be at the carbocyclic Definitions aromatic ring or at the heterocycloalkyl ring. Examples of 0037. A dash (“-”) that is not between two letters or sym aryl groups include, but are not limited to, groups derived bols is used to indicate a point of attachment for a moiety or from aceanthrylene, acenaphthylene, acephenanthrylene, substituent. For example, —CONH is bonded through the anthracene, aZulene, benzene, chrysene, coronene, fluoran carbon atom. thene, fluorene, hexacene, hexaphene, hexylene, as-indacene, 0038 A waved dash ("v"between two letters or symbols S-indacene, indane, indene, naphthalene, octacene, is used to indicate a point of attachment for a moiety or octaphene, octalene, ovalene, penta-2,4-diene, pentacene, Substituent and a chiral center at which two enantiomers can pentalene, pentaphene, perylene, phenalene, phenanthrene, be formed. The two enantiomers can be in equimolar quanti picene, pleiadene, pyrene, pyranthrene, rubicene, triph ties (forming a “racemate'), or a first enantiomer can be in enylene, trinaphthalene, and the like. In certain embodiments, excess of the second enantiomer (forming an “enantiomeric an aryl group can have from 6 to 20 carbon atoms (C-o), excess' or “enantiomeric mixture'). from 6 to 12 carbon atoms (C), and in certain embodi 0039) “Alkyl” by itself or as part of another substituent ments, from 6 to 10 carbonatoms (C-o). Aryl, however, does refers to a saturated or unsaturated, branched, or straight not encompass or overlap in any way with heteroaryl, sepa chain, monovalent hydrocarbon radical derived by the rately defined herein. removal of one hydrogen atom from a single carbon atom of 0043 Arylalkyl by itselfor as part of another substituent a parent alkane, alkene, or alkyne. Examples of alkyl groups refers to an acyclic alkyl radical in which one of the hydrogen include, but are not limited to, methyl; ethyls such as ethanyl. atoms bonded to a carbon atom, typically a terminal or sp ethenyl, and ethynyl; propyls such as propan-1-yl, propan-2- carbon atom, is replaced with an aryl group. Examples of yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), arylalkyl groups include, but are not limited to, benzyl, 2-phe prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1- nylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl 2-naph y1, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, thylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but 2-naphthophenylethan-1-yland the like. Where specific alkyl 2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien moieties are intended, the nomenclature arylalkanyl, arylalk 2-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the enyl, or arylalkynyl is used. In certain embodiments, an ary like. lalkyl group is C, so arylalkyl, e.g., the alkanyl, alkenyl or 0040. The term “alkyl is specifically intended to include alkynyl moiety of the arylalkyl group is Co and the aryl groups having any degree or level of Saturation, i.e., groups moiety is Co. in certain embodiments, an arylalkyl group is having exclusively single carbon-carbon bonds, groups hav Cesarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of ing one or more double carbon-carbon bonds, groups having the arylalkyl group is Cls and the aryl moiety is Co. one or more triple carbon-carbon bonds, and groups having 0044) “Compounds” of the present disclosure include any combinations of single, double, and triple carbon-carbon specific compounds within these formulae. Compounds may bonds. Where a specific level of saturation is intended, the be identified either by their chemical structure and/or chemi terms alkanyl, alkenyl, and alkynyl are used. In certain cal name. When the chemical structure and chemical name embodiments, an alkyl group can have from 1 to 20 carbon conflict, the chemical structure is determinative of the iden atoms (C-o) in certain embodiments, from 1 to 10 carbon tity of the compound. The compounds described herein may atoms (C-o), in certain embodiments from 1 to 8 carbon comprise one or more chiral centers and/or double bonds and atoms (Cs), in certain embodiments, from 1 to 6 carbon therefore may exist as Stereoisomers such as double-bond atoms (C), in certain embodiments from 1 to 4 carbon isomers (i.e., geometric isomers), enantiomers, or diastere atoms (C), and in certain embodiments, from 1 to 3 carbon omers. Accordingly, unless specifically indicated, any chemi atoms (CIs). cal structures within the scope of the specification depicted, in 0041 Alkoxycarbonyl by itself or as part of another whole or in part, with a relative configuration encompass all substituent refers to a radical –C(O)CR' where R' repre possible enantiomers and stereoisomers of the illustrated sents an alkyl or cycloalkyl group as defined herein. compounds including the Stereoisomerically pure form (e.g., Examples of alkoxycarbonyl groups include methoxycarbo geometrically pure, enantiomerically pure, or diastereomeri nyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, cally pure) and enantiomeric and stereoisomeric mixtures. cyclohexyloxycarbonyl, and the like. Enantiomeric and stereoisomeric mixtures may be resolved 0042 Aryl by itself or as part of another substituent into their component enantiomers or stereoisomers using refers to a monovalent aromatic hydrocarbon radical derived separation techniques or chiral synthesis techniques well by the removal of one hydrogen atom from a single carbon known to the skilled artisan. For example, resolution of the atom of a parent aromatic ring system. Aryl encompasses 5 enantiomers or diasteriomers may be accomplished, for and 6-membered carbocyclic aromatic rings, for example, example, by conventional methods such as crystallization in benzene: bicyclic ring systems wherein at least one ring is the presence of a resolving agent, or chromatography, using, carbocyclic and aromatic, for example, naphthalene, indane, for example a chiral high-pressure liquid chromatography and tetralin; and tricyclic ring systems wherein at least one (HPLC) column. ring is carbocyclic and aromatic, for example, fluorene. Aryl 0045 Compounds of the present disclosure may also exist encompasses multiple ring systems having at least one car in several tautomeric forms including the enol form, the keto bocyclic aromatic ring fused to at least one carbocyclic aro form, and mixtures thereof. Accordingly, the chemical struc US 2009/0192325 A1 Jul. 30, 2009

tures depicted herein encompass all possible tautomeric 0.052 “Enantiomer refers to one of a pair of molecular forms of the illustrated compounds. Compounds of the entities, which are mirror images of each other and non present disclosure also include isotopically labeled com Superposable. pounds where one or more atoms have an atomic mass dif 0053 “Enantiomeric excess” refers to the absolute value ferent from the atomic mass conventionally found in nature. of the difference between the mole or weight fractions of the Examples of isotopes that may be incorporated into the com (+) and the (-) enantiomers in a mixture of the two enanti pounds disclosed herein include, but are not limited to, H, omers. The percent enantiomeric excess is the enantiomeric *H, C, C, C, N, O, 7O, etc. Compounds may exist excess multiplied by 100. The enantiomeric excess is abbre in unsolvated forms as well as Solvated forms, including viated as e.e. 0054 “Enantiomeric mixture” refers to a mixture of a hydrated forms and as N-oxides. In general, compounds may compound having an enantiomeric ratio greater than 50:50 be hydrated, Solvated, or N-oxides. Certain compounds may but less than 100:0. exist in multiple crystalline, co-crystalline, or amorphous 0055 “Enantiomeric ratio” refers to the ratio of the per forms. Compounds of the present disclosure include pharma centage of one enantiomer in a mixture to that of the other ceutically acceptable salts thereof, or pharmaceutically enantiomer. acceptable solvates of the free acid form of any of the fore 0056 “Enantiomerically enriched” refers to a sample of a going, as well as crystalline forms of any of the foregoing. chiral Substance in which the enantiomeric ratio is greater 0046. Further, when partial structures of the compounds than 50:50 but less than 100:0. An enantiomerically enriched are illustrated, an asterisk (*) indicates the point of attach sample will have a non-Zero enantiomeric excess. ment of the partial structure to the rest of the molecule. 0057 “GABA analog refers to a compound having the 0047 “Cycloalkoxycarbonyl.” by itself or as part of Structure: another substituent, refers to the radical —C(O)CR' where R represents an cycloalkyl group as defined herein. Examples of cycloalkoxycarbonyl groups include, but are not R11 R12 Q limited to, cyclobutyloxycarbonyl, cyclohexyloxycarbonyl, HN and the like. OH 0048 “Cycloalkyl by itself or as part of another substitu R10 R13 ent refers to a saturated or partially unsaturated cyclic alkyl radical. Where a specific level of saturation is intended, the wherein: nomenclature cycloalkanyl or cycloalkenyl is used. 0058 R'' and R' are independently chosen from hydro Examples of cycloalkyl groups include, but are not limited to, gen, C alkyl, Substituted C. alkyl, Co aryl, Substituted groups derived from cyclopropane, cyclobutane, cyclopen Coo aryl, C7-6 arylalkyl, Substituted C7-6 arylalkyl, Cso tane, cyclohexane, and the like. In certain embodiments, a cycloalkyl, and Substituted Co cycloalkyl, cycloalkyl group is C-1s cycloalkyl, C-12 cycloalkyl, Cas 0059 R'' and R'' are independently chosen from hydro cycloalkyl, and in certain embodiments, C. cycloalkyl. gen, C alkyl, Substituted C. alkyl, Co aryl, Substituted 0049 “Diastereomer refers to a stereoisomer other than Coo aryl, C7-6 arylalkyl, Substituted C7-6 arylalkyl, Cso an enantiomer. Diasteroisomers (or diastereomers) are stere cycloalkyl, and substituted Co cycloalkyl: or R'' and R' oisomers not related as mirror images. Diasteroisomers are together with the carbonatom to which they are bonded form characterized by differences in physical properties, and by a Cso cycloalkyl, Substituted Cao cycloalkyl, Cohetero some differences in chemical behavior towards achiral as well cycloalkyl, or substituted Coheterocycloalkyl ring. as chiral agents. 0060. In certain embodiments of a GABA analog, each 0050 “Drug as defined under 21 U.S.C. S 321 (g)(1) Substituent group is independently chosen from halogen, means “(A) articles recognized in the official United States NH, OH, CN, COOH, C(O)NH, C(O)OR'', Pharmacopoeia, official Homeopathic Pharmacopoeia of the and—NR''," wherein each R'' is independently C, alkyl. United States, or official National Formulary, or any supple 0061. In certain embodiments of a GABA analog, each of ment to any of them; and (B) articles intended for use in the R" and R' is hydrogen. In certain embodiments of a GABA diagnosis, cure, mitigation, treatment, or prevention of dis analog, R'' is chosen from C, alkyl, Substituted C, alkyl, ease in man or other animals; and (C) articles (other than C. alkoxycarbonyl, Css cycloalkyl, C. cycloalkoxycar food) intended to affect the structure or any function of the bonyl, phenyl, Substituted phenyl, and C7- phenylalkyl, and body of man or other animals . . . 99. R' is hydrogen. In certain embodiments of a GABA analog, 0051 “Drug comprising at least one primary or secondary each of R'' and R' is hydrogen; R' is chosen from Ca amine group” means a drug having a primary amine group of alkyl, substituted C alkyl, C. alkoxycarbonyl, Cs the structure D-NH where —NH is a primary amine group cycloalkyl, C. cycloalkoxycarbonyl, phenyl, Substituted and D- is the remaining portion of the drug without the pri phenyl, and C, phenylalkyl; and R' is hydrogen. mary amine group; and/or a drug having a secondary amine 0062. In certain embodiments of a GABA analog, each of group of the structure D-NHR' wherein—NHR" is a second R", R', and R' is hydrogen; and R'' is chosen from isobu ary amine group Such that R is a group other than hydrogen tyl and 4-chlorophenyl. and D- is the remaining portion of the drug without the sec 0063. In certain embodiments, a GABA analog is chosen ondary amine group. Thus, a drug comprising at least one from pregabalin and baclofen. Furthermore, a number of primary or secondary amine group has the structure D-NHR'. GABA analogs with considerable pharmaceutical activity wherein -D is the drug without the at least one primary or have been synthesized and are included within the scope of secondary amine group and R is chosen from hydrogen and GABA analog (Satzinger et al., U.S. Pat. No. 4,024, 175; a group of a secondary amine. Silverman et al, U.S. Pat. No. 5,563,175: Horwell et al., U.S. US 2009/0192325 A1 Jul. 30, 2009

Pat. No. 6,020,370; Silverman et al., U.S. Pat. No. 6,028,214; acid, cinnamic acid, mandelic acid, methanesulfonic acid, Horwell et al., U.S. Pat. No. 6,103,932; Silverman et al., U.S. ethanesulfonic acid, 1.2-ethane-disulfonic acid, 2-hydroxy Pat. No. 6,117,906; Silverman, WO92/09560; Silverman et ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzene al., WO 93/23383; Horwell et al., WO 97/29101, Horwell et Sulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic al., US WO 97/33858; Horwell et al., WO 97/33859; Bryans acid, camphorsulfonic acid, 4-methylbicyclo2.2.2-oct-2- et al., WO 98/17627; Guglietta et al., WO 99/08671; Bryans ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropi et al., WO 99/21824; Bryans et al., 99/31057; Belliotti et al., onic acid, trimethylacetic acid, tertiary butylacetic acid, lau WO 99/31074; Bryans et al., WO 99/31075; Bryans et al., ryl Sulfuric acid, gluconic acid, glutamic acid, WO 99/61424; Bryans et al., 00/15611; Bryans, WO hydroxynaphthoic acid, Salicylic acid, Stearic acid, muconic 00/31020; Bryans et al., WO 00/50027: Bryans et al., WO acid, and the like; and salts formed when an acidic proton 02/00209: Bryans et al., J. Med. Chem. 1998, 41, 1838-1845: present in the parent compound is replaced by a metal ion, Bryans et al., Med. Res. Rev. 1999, 19, 149-177, Guglietta et e.g., an alkali metalion, an alkaline earthion, oran aluminum al., WO 99/08670; Bryans et al., WO 99/21824; Bryans et al., ion; or coordinates with an organic base such as ethanola GB 2374595, Barta et al., U.S. 2003/0195251; and Donevan mine, diethanolamine, triethanolamine, N-methylglucamine, et al., 2005/0070483). Pharmaceutically important GABA and the like. In certain embodiments, a pharmaceutically analogs include, for example, gabapentin, pregabalin, acceptable salt can be in the form of a hydrate or other solvate. vigabatrin, and baclofen. In certain embodiments, pharmaceutically acceptable addi 0064) “Heterocycloalkyl by itself or as part of another tion salts include metal salts such as Sodium, potassium, Substituent refers to a saturated or unsaturated cyclic alkyl aluminum, calcium, magnesium and Zinc salts, and ammo radical in which one or more carbon atoms (and certain asso nium salts such as isopropylamine, diethylamine, and dietha ciated hydrogen atoms) are independently replaced with the nolamine salts. In certain embodiments, a pharmaceutically same or different heteroatom; or to a parent aromatic ring acceptable salt is the hydrochloride salt. In certain embodi system in which one or more carbonatoms (and certain asso ments, a pharmaceutically acceptable salt is the Sodium salt. ciated hydrogen atoms) are independently replaced with the Pharmaceutically acceptable salts may be prepared by the same or different heteroatom Such that the ring system no skilled chemist, by treating a compound of Formula (III) with longer contains at least one aromatic ring. Examples of het an appropriate base in a Suitable solvent, followed by crys eroatoms to replace the carbon atom(s) include, but are not tallization and filtration. limited to, N. P. O, S, Si, etc. Examples of heterocycloalkyl 0068 “Pharmaceutically acceptable vehicle' refers to a groups include, but are not limited to, groups derived from pharmaceutically acceptable diluent, a pharmaceutically epoxides, azirines, thiranes, imidazolidine, morpholine, pip acceptable adjuvant, a pharmaceutically acceptable excipi erazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, ent, a pharmaceutically acceptable carrier, or a combination and the like. In certain embodiments, a heteroatom is chosen of any of the foregoing with which atherapeutic agent may be from O and N. administered to a patient and which does not destroy the 0065 “Parent aromatic ring system” refers to an unsatur pharmacological activity thereof and which is nontoxic when ated cyclic or polycyclic ring system having a conjugated at administered in doses Sufficient to provide a therapeutically (pi) electron system. Included within the definition of “parent effective amount of the compound. aromatic ring system” are fused ring systems in which one or 0069. “Phenylalkyl” refers to an acyclic alkyl radical in more of the rings are aromatic and one or more of the rings are which one of the hydrogen atoms bonded to a carbon atom, saturated or unsaturated. Such as, for example, fluorene, typically a terminal or sp carbon atom, is replaced with a indane, indene, phenalene, etc. Examples of parent aromatic phenyl group. In certain embodiments, a phenylalkyl group is ring systems include, but are not limited to, aceanthrylene, Cz phenylalkyl in which the alkyl group is C alkyl. acenaphthylene, acephenanthrylene, anthracene, azulene, 0070) “Prodrug” refers to a derivative of a pharmaceuti benzene, chrysene, coronene, fluoranthene, fluorene, cally active compound (drug) that undergoes a transformation hexacene, hexaphene, hexylene, as-indacene, S-indacene, under the conditions of use, such as within the body, to release indane, indene, naphthalene, octacene, octaphene, octalene, the active drug. Prodrugs are frequently, but not necessarily, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, pharmacologically inactive until converted into the active perylene, phenalene, phenanthrene, picene, pleiadene, drug. Prodrugs can be obtained by bonding a promoiety (de pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, fined herein), typically via a functional group, to a drug. For and the like. example, pregabalin prodrug (18) is metabolized within a 0066 “Pharmaceutically acceptable” refers to approved patient's body to form the parent drug pregabalin. or approvable by a regulatory agency of the Federal or a state 0071 "Promoiety” refers to a group bonded to a drug, government or listed in the U.S. Pharmacopoeia or other typically to a functional group of the drug, via bond(s) that are generally recognized pharmacopoeia for use in animals, and cleavable under specified conditions of use. The bond(s) more particularly in humans. between the drug and promoiety may be cleaved by enzy 0067 "Pharmaceutically acceptable salt” refers to a salt of matic or non-enzymatic means. Under the conditions of use, a compound, which possesses the desired pharmacological for example following administration to a patient, the bond(s) activity of the parent compound. Such salts include acid addi between the drug and promoiety may be cleaved to release the tion salts, formed with inorganic acids such as hydrochloric parent drug. The cleavage of the promoiety may proceed acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric spontaneously, Such as via a hydrolysis reaction, or may be acid, and the like; or formed with organic acids such as acetic catalyzed or induced by another agent, such as by an enzyme, acid, propionic acid, hexanoic acid, cyclopentanepropionic by light, by acid, or by a change of or exposure to a physical acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, or environmental parameter, such as a change oftemperature, Succinic acid, malic acid, maleic acid, fumaric acid, tartaric pH, etc. The agent may be endogenous to the conditions of acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic use. Such as an enzyme present in the systemic circulation to US 2009/0192325 A1 Jul. 30, 2009

which the prodrug is administered or the acidic conditions of (0077. “Therapeutically effective amount” refers to the the stomach or the agent may be Supplied exogenously. amount of a compound that, when administered to a subject 0072 “Racemate” refers to an equimolar mixture of a pair for treating a disease or disorder, or at least one of the clinical of enantiomers. symptoms of a disease or disorder, is sufficient to affect Such treatment of the disease, disorder, or symptom. A “therapeu 0073 “Solvate” refers to a molecular complex of a com tically effective amount can vary depending, for example, on pound with one or more solvent molecules in a stoichiometric the compound, the disease, disorder, and/or symptoms of the or non-stoichiometric amount. Such solvent molecules are disease or disorder, severity of the disease, disorder, and/or those commonly used in the pharmaceutical art, which are symptoms of the disease or disorder, the age, weight, and/or known to be innocuous to a patient, e.g., water, ethanol, and health of the patient to be treated, and the judgment of the the like. A molecular complex of a compound or moiety of a prescribing physician. An appropriate amount in any given compound and a solvent can be stabilized by non-covalent instance can be readily ascertained by those skilled in the art intra-molecular forces Such as, for example, electrostatic or capable of determination by routine experimentation. forces, van der Waals forces, or hydrogen bonds. The term 0078 Reference is now made in detail to certain embodi “hydrate' refers to a solvate in which the one or more solvent ments of compounds, compositions, and methods. The dis molecules are water. In certain embodiments, compounds of closed embodiments are not intended to be limiting of the the present disclosure and salts thereof may form Solvates. claims. To the contrary, the claims are intended to cover all 0074 “Substituted” refers to a group in which one or more alternatives, modifications, and equivalents. hydrogenatoms are independently replaced with the same or different Substituent group(s). In certain embodiments, each Methods of Enantiomeric Enrichment Substituent is independently chosen from halogen, —OH, —CN, —CF =O. —NO, C- alkoxy, C. alkyl, 0079 Methods provided by the present disclosure include —COOR' wherein R' is chosen from hydrogen and C methods of enzymatically enriching an enantiomeric mixture alkyl, and N(R') wherein each R" is independently cho of an acyloxyalkyl thiocarbonate of compound of Formula Sen from hydrogen and C alkyl. In certain embodiments, (I): each Substituent is independently chosen from halogen, —OH, -CN. —CF —OCF =O. —NO, C- alkoxy, C. alkyl, -COOR, N(R'), and – CONCR'); O R2 O (I) wherein each R" is independently chosen from hydrogen and Calkyl. In certain embodiments, each Substituent is chosen ls lis ls R3 from C alkyl, -OH, and —NH2. R1 O O s1 0075 “Sustained release” refers to release ofatherapeutic or preventive amount of a drug oran active metabolite thereof comprising the step of reacting the enantiomeric mixture with over a period of time that is longer than that of a conventional an enzyme to provide an enantiomerically resolved mixture formulation of the drug. For oral formulations, the term “sus having at least 90% enantiomeric excess of one enantiomer of tained release' typically means release of the drug within the the compound of Formula (I), wherein: gastrointestinal tract lumen over a time period ranging, for 0080) R' is chosen from C, alkyl, C. cycloalkyl, example, from about 2 to about 30 hours, and in certain phenyl, Substituted phenyl, and C7- phenylalkyl: embodiments, over a time period ranging from about 4 to I0081) R' is chosen from C, alkyl, C. cycloalkyl, about 24 hours. Sustained release formulations achieve thera phenyl, Substituted phenyl, and C, phenylalkyl; and peutically effective concentrations of the drug in the systemic I0082 R is chosen from C alkyl, C. cycloalkyl, circulation over a prolonged period of time relative to that phenyl, Substituted phenyl, and C. phenylalkyl. achieved by oral administration of a conventional formulation I0083. In certain embodiments of a compound of Formula of the drug. (I), R is chosen from methyl, ethyl, n-propyl, isopropyl. 0076 “Treating or “treatment of any disease or disorder n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, refers to arresting or ameliorating a disease, disorder, or at sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, and cyclo least one of the clinical symptoms of a disease or disorder, hexyl. In certain embodiments of a compound of Formula (I), reducing the risk of acquiring a disease, disorder, or at least R" is chosen from methyl, ethyl, n-propyl, isopropyl. n-butyl, one of the clinical symptoms of a disease or disorder, reduc isobutyl, phenyl, and cyclohexyl. In certain embodiments of a ing the development of a disease, disorder or at least one of the compound of Formula (I), R is chosen from methyl, n-pro clinical symptoms of the disease or disorder, or reducing the pyl, isopropyl, and phenyl. risk of developing a disease or disorder or at least one of the I0084. In certain embodiments of a compound of Formula clinical symptoms of a disease or disorder. "Treating or (I), R is chosen from methyl, ethyl, n-propyl, isopropyl, “treatment also refers to inhibiting the disease or disorder, n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl. In cer either physically, (e.g., stabilization of a discernible symp tain embodiments of a compound of Formula (I), R is chosen tom), physiologically, (e.g., stabilization of a physical param from methyl, ethyl, n-propyl, and isopropyl. In certain eter), or both, and to inhibiting at least one physical parameter embodiments of a compound of Formula (I), R is chosen which may or may not be discernible to the patient. In certain from methyl, n-propyl, and isopropyl. embodiments, “treating or “treatment” refers to delaying the I0085. In certain embodiments of a compound of Formula onset of the disease or disorder or at least one or more symp (I), R is chosen from methyl, ethyl, n-propyl, isopropyl, toms thereof in a patient which may be exposed to or predis n-butyl, isobutyl, sec-butyl, phenyl, and cyclohexyl. In cer posed to a disease or disorder even though that patient does tain embodiments of a compound of Formula (I), R is chosen not yet experience or display symptoms of the disease or from methyl, ethyl, n-propyl, and isopropyl. In certain disorder. embodiments of a compound of Formula (I), R is methyl. US 2009/0192325 A1 Jul. 30, 2009

I0086. In certain embodiments of a compound of Formula (I), R' is chosen from methyl, isopropyl. n-propyl, and phe nyl; R is chosen from methyl, isopropyl, and n-propyl; and (I) R is methyl. O R2 O 0087. In certain embodiments of a compound of Formula (I), each Substituent is independently chosen from halogen, -s-s-s-s —OH, -CN. —CF =O. —NO, C- alkoxy, C alkyl, (II) —COOR' wherein R' is chosen from hydrogen and C O R2 O O alkyl, and N(R'), wherein each R" is independently cho Sen from hydrogen and C alkyl. 0088. In certain embodiments, the enantiomerically - - - - resolved mixture has an enantiomeric excess of the Renan tiomer and the enzyme is a lipase chosen from Candida rugosa, Candida cylindracea, and Candida antarcticalipase reacting an enantiomeric mixture of a compound of Formula B (I) with an enzyme to provide an enantiomerically enriched 0089. In certain embodiments, the enantiomerically mixture having at least 90% enantiomeric excess of one iso resolved mixture has an enantiomeric excess of the Senanti mer of the compound of Formula (I), wherein R' is chosen omer and the enzyme is a lipase chosen from porcine liver from C alkyl, C. cycloalkyl, phenyl, Substituted phenyl, esterase, Candida antarctica lipase A, and Candida antarc and C79 phenylalkyl; R is chosen from C. alkyl, Cs. ticalipase B. cycloalkyl, phenyl, Substituted phenyl, and Cze phenylalkyl; 0090. In certain embodiments, the enzyme is Candida ant and R is chosen from C, alkyl, C. cycloalkyl, phenyl, arcticalipase A, R' is isopropyl, R is isopropyl, R is methyl, Substituted phenyl, and C7- phenylalkyl; and reacting the and the enantiomerically resolved mixture has an enantio enantiomerically enriched mixture having at least 90% enan meric excess of the Senantiomer of the compound of Formula tiomeric excess of one isomer of the compound of Formula (I) (I). with N-hydroxysuccinimide to provide the enantiomerically 0091. In certain embodiments, the enzyme is Candida ant enriched mixture of the compound of Formula (II). arcticalipase B, R' is isopropyl, R is methyl, R is methyl, 0096 Coupling of an enantiomerically enriched acyloxy and the enantiomerically resolved mixture has an enantio alkylthiocarbonate of Formula (I) with N-hydroxysuccinim meric excess of the Renantiomer of the compound of For ide may be accomplished following the protocols described in mula (I). Gallop et al., U.S. Pat. No. 7,227,028. For example, a com 0092. In certain embodiments, the enantiomerically pound of Formula (II) may be obtained by contacting a thio resolved mixture has an enantiomeric excess of either the carbonate compound of Formula (I) with an oxidant in the R-enantiomer of a compound of Formula (I) or the S-enanti presence of N-hydroxysuccinimide. omer of the compound of Formula (I), which exhibits an at least about 90% e.e., at least about 92% e.e., at least about 0097. In certain embodiments, the oxidant is a peroxy 94% e.e., at least about 96% e.e., at least about 98% e.e., and acid, a peroxide, oZone or oxygen. In certain embodiments, in certain embodiments at least about 99% e.e. the oxidant is a stoichiometric or catalytic amount of a tran sition metal compound. In certain embodiments, the oxidant 0093. Enantiomeric resolution of racemic compounds of is a peroxy acid, a peroxide, ozone or oxygen with a catalytic Formula (I) can be accomplished using an enzyme such as an amount of a transition metal compound. Examples of peroxy esterase, a protease, or a lipase. An example of a useful acids useful in the synthesis of NHS-acyloxyalkylcarbonates esterase is porcine liver esterase. Examples of useful lipases of Formula (II) include peroxyacetic acid, m-chloroperoxy include Candida rugosa, Candida cylindracea, Candida ant benzoic acid, peroxytrifluoroacetic acid, peroxydifluoroace arctica lipase A, and Candida antarctica lipase B. Other tic acid, peroxyfluoroacetic acid, peroxytrichloroacetic acid, potentially useful enzymes are known in the art and can be peroxydichloroacetic acid, peroxychloroacetic acid, peroX identified using routine screening methods. The enzymatic ytribromoacetic acid, peroxydibromoacetic acid, peroxybro resolution can be carried out in an appropriate solvent or moacetic acid, peroxychlorodifluoroacetic acid, peroxypen cosolventatan appropriate temperature Such as from about 5° tafluoropropionic acid, peroxybenzoic acid, C. to about 60° C., and in certain embodiments, from about p-fluoroperoxybenzoic acid, pentafluoroperoxybenzoic acid, 20° C. to about 27°C. The enzyme may be suspended in the p-trifluoroperoxybenzoic acid, o-nitroperoxybenzoic acid, solvent or immobilized on a support. Examples of useful m-nitroperoxybenzoic acid, p-nitroperoxybenzoic acid, 3.5- solvents include isopropyl ether and methyl-tert-butyl ether dinitroperoxybenzoic acid, monoperoxySuccinic acid, (MTBE), and about 1% water may be useful as a cosolvent. monoperoxymaleic acid, monoperoxy-o-phthalic acid, per The reaction can be continued for from about a few hours to oxytrifluoromethanesulfonic acid, peroxymethanesulfonic about several days until a desired enantiomeric enrichment acid, p-tolueneperoxysulfonic acid, peroxybenzene Sulfonic and/or yield is obtained. The reaction conditions may be acid and salts thereof. In certain embodiments, the peroxy selected and optimized using known methods. acid is chosen from peroxyacetic acid, m-chloroperoxyben 0094 Chemical structures of certain racemic acyloxy Zoic acid, monoperoxy-o-phthalic acid, monoperoxymaleic alkylthiocarbonates and the ability of certain enzymes to acid, peroxytrifluoroacetic acid or salts thereof. In other enantiomerically resolve the acyloxyalkylthiocarbonates are embodiments, the peroxy acid is peroxyacetic acid, m-chlo shown in FIG.3 and FIG. 4, respectively. roperoxybenzoic acid, magnesium monoperoxy-o-phthalate, 0095 Methods provided by the present disclosure include and salts thereof. In certain embodiments, the peroxy acid methods of synthesizing an enantiomerically enriched NHS may be synthesized by contacting a urea-hydrogen peroxide acyloxyalkylcarbonate of Formula (II), comprising: complex with an acid anhydride. In certain embodiments, the US 2009/0192325 A1 Jul. 30, 2009 peroxy acid may be synthesized by contacting a urea-hydro gen peroxide complex with maleic anhydride. -continued (III) 0098. In certain embodiments, the molar ratio of oxidant O R2 O to an acyloxyalkylthiocarbonate of Formula (I) is from about 10:1 to about 1:1. In certain embodiments, the molar ratio of R1 O O oxidant to a thiocarbonate of Formula (I) is from about 3:1 to about 1:1. R4 0099. In certain embodiments, a solvent is used in the synthesis of NHS-acyloxyalkylcarbonates of Formula (II). reacting an enantiomeric mixture of a compound of Formula Useful solvents for the reaction include acetic acid, dichlo (I) with an enzyme to provide an enantiomerically enriched romethane, dichloroethane, chloroform, ethyl acetate, tolu mixture having at least 90% enantiomeric excess of one iso ene, chlorobenzene, xylene, acetonitrile, methyl tert-butyl mer of the compound of Formula (I), wherein R' is chosen ether, cyclohexane, and a mixture of any of the foregoing. In from C alkyl, C. cycloalkyl, phenyl, Substituted phenyl, certain embodiments, the solvent is chosen from acetic acid, and C79 phenylalkyl; R is chosen from C. alkyl, Cs. dichloromethane, dichloroethane, and a mixture of any of the cycloalkyl, phenyl, Substituted phenyl, and Cze phenylalkyl; foregoing. R is chosen from C. alkyl, C. cycloalkyl, phenyl, Substi tuted phenyl, and C7- phenylalkyl, and reacting the enantio 0100. In certain embodiments, the synthesis of NHS-acy merically enriched mixture having at least 90% enantiomeric loxyalkylcarbonates of Formula (II) may be carried out a excess of one isomer of the compound of Formula (I) with temperature from about -20°C. to about 80°C., from about N-hydroxysuccinimide to provide the enantiomerically -20° C. to about 25°C., and in certain embodiments, from enriched mixture of the corresponding compound of Formula about 25° C. to about 60° C. (II); and reacting the enantiomerically enriched mixture of 0101. In certain embodiments, synthesis of NHS-acyloxy the compound of Formula (II) with a drug, D-NHR, com alkylcarbonates of Formula (II) may be performed in the prising at least one primary or secondary amine group to presence of an inorganic base such as an alkali metal bicar provide the compound of Formula (III), wherein -D is the bonate or alkali metal carbonate salt, and in certain embodi drug without the at least one primary or secondary amine ments, sodium bicarbonate. In certain embodiments, the Syn group and R is chosen from hydrogen or a group of the thesis of NHS-acyloxyalkylcarbonates of Formula (II) may secondary amine. be performed in the presence of an organic base Such as 0104. In certain embodiments, the enantiomerically triethylamine, tributylamine, diisopropylethylamine, dimeth resolved mixture has an enantiomeric excess of either the ylisopropylamine, N-methylmorpholine, N-methylpyrroli R-enantiomer of a compound of Formula (III) or the S-enan dine, N-methylpiperidine, pyridine, 2-methylpyridine, 2.6- tiomer of the compound of Formula (III), which exhibits an at dimethylpyridine, 4-dimethylaminopyridine, 1,4- least about 90% e.e., at least about 92% e.e., at least about diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7- 94% e.e., at least about 96% e.e., at least about 98% e.e., and ene, or 1,5-diazabicyclo4.3.0 undec-7-ene. In other in certain embodiments at least about 99% e.e. embodiments, the organic base is chosen from triethylamine, 0105. In certain embodiments of methods of synthesizing diisopropylethylamine, N-methylmorpholine, and pyridine. compounds of Formula (III), the drug is chosen from R-ba In certain embodiments, synthesis of NHS-acyloxyalkylcar clofen and pregabalin. In certain embodiments, methods pro vided by the present disclosure may be used for the prepara bonates of Formula (II) may be performed in the absence of a tion of (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy) base. propoxycarbonylamino-3-(4-chlorophenyl)butanoic acid; 0102. In certain embodiments, the enantiomerically 1-(R)-3-(1-(2-methylpropanoyloxy)ethoxy resolved mixture has an enantiomeric excess of either the carbonylaminomethyl) (3S)-5-methylhexanoic acid; or a R-enantiomer of a compound of Formula (II) or the S-enan pharmaceutically acceptable salt of any of the foregoing. tiomer of the compound of Formula (II), which exhibits an at 0106. In certain embodiments, methods provided by the least about 90% e.e., at least about 92% e.e., at least about present disclosure may be used for the preparation of a 94% e.e., at least about 96% e.e., at least about 98% e.e., and 1-(acyloxy)-alkyl carbamate prodrug of R-baclofen of For in certain embodiments at least about 99% e.e. mula (a): 0103 Methods provided by the present disclosure include synthesizing a compound of Formula (III), comprising: (a) O R2 O (I) O R2 O -s-s-s-s -s-s-s-s-sCOOH (II) O R2 O O

- - - - C US 2009/0192325 A1 Jul. 30, 2009

wherein: 0117. In certain embodiments of compounds of Formula 0107) R' is chosen from methyl, ethyl, n-propyl, isopro (b), R is isopropyl, and R is methyl. pyl. n-butyl, isobutyl, Sec-butyl, tert-butyl, n-pentyl, isopen 0118. In certain embodiments of compounds of Formula tyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, and (b), the carbon to which R is bonded is of the S-configura cyclohexyl; and tion. I0108 RandR are independently chosen from hydrogen, 0119. In certain embodiments of compounds of Formula methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu (b), the carbon to which R is bonded is of the R-configura tyl, phenyl, and cyclohexyl. tion. 0109. In certain embodiments of compounds of Formula I0120 In certain embodiments of compounds of Formula (a), R is isopropyl, and R is isopropyl. (b), the compound is 1-(R)-3-(1-(2-methylpropanoyloxy) ethoxycarbonylaminomethyl) (3S)-5-methylhexanoic acid 0110. In certain embodiments of compounds of Formula or a pharmaceutically acceptable salt thereof, or a pharma (a), the carbon to which Risbonded is of the S-configuration. ceutically acceptable Solvate of any of the foregoing. 0111. In certain embodiments of compounds of Formula I0121. In certain embodiments of methods of synthesizing (a), the carbon to which R is bonded is of the R-configura a compound of compounds of Formula (III), the drug is pre tion. gabalin, R' is isopropyl, R is methyl, the enzyme is Candida 0112. In certain embodiments of compounds of Formula antarctica lipase B, and the compound of Formula (III) is (a), the compound is (3R)-4-(1S)-2-methyl-1-(2-methyl 3-({(1R)-1-(2-methylpropanoyloxy)ethoxy propanoyloxy)propoxycarbonylamino-3-(4-chlorophenyl) carbonylaminomethyl)(3S)-5-methylhexanoic acid: butanoic acidora pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any of the foregoing. 0113. In certain embodiments of methods of synthesizing O O compounds of compounds of Formula (III), the drug is R-ba clofen, R' is isopropyl, R is isopropyl, the enzyme is Can R1 O1 (R) O N COOH. dida antarcticalipase A, and the compound of Formula (III) H is (3R)-4-(1S)-2-methyl-1-(2-methylpropanoyloxy)pro poxycarbonylamino-3-(4-chlorophenyl)butanoic acid: S. O 0.122 Conversion of a compound of Formula (I) to the Y1 corresponding NHS-acyloxyalkylcarbonate of Formula (II) us (R) O and coupling with a drug can be accomplished, for example, o1SNo r following the protocols described in Gallop et al., U.S. Pat. OH No. 7,227,028, which provide the free acid form of the cor responding prodrug of Formula (III). For example, a NHS acyloxyalkyl carbonate of Formula (II) or a salt thereof may be reacted with a primary or secondary amine-containing drug of formula D-NHR' or a salt thereof to provide a com C pound of Formula (III) as shown in Scheme 1. 0114. In certain embodiments, methods provided by the present disclosure may be used for the preparation of a Scheme 1 1-(acyloxy)-alkyl carbamate prodrug of pregabalin of For O R2 O O mula (b): -s-s-s-s + D-NHR He (b) O R2 O O (II) ------. O R2 O ls us ul D s RI O O N1 wherein: (III) I0115I R' is chosen from methyl, ethyl, n-propyl, isopro pyl. n-butyl, isobutyl, Sec-butyl, tert-butyl, n-pentyl, isopen wherein R' and R are as defined herein, and R is chosen tyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, and from hydrogen and a moiety of a secondary amine-containing cyclohexyl; and drug D-NHR'. Methods of synthesizing 1-(acyloxy)-alkyl I0116 R is chosen from hydrogen, methyl, ethyl, n-pro carbamate prodrugs from 1-(acyloxy)alkyl N-hydroxysuc pyl, isopropyl. n-butyl, isobutyl, sec-butyl, phenyl. and cyclo cinimidyl carbonate intermediates are disclosed in Gallop et hexyl. al., U.S. Pat. No. 6,818,787, U.S. Pat. No. 6,927,036, U.S. US 2009/0192325 A1 Jul. 30, 2009

Pat. No. 6,972,341, U.S. Pat. No. 7, 186,855, and U.S. Pat. No. comprising reacting an enantiomeric mixture of the com 7,227,028; Raillardet al., U.S. Pat. No. 7,232,924; and Gallop pound of Formula (I) with an enzyme to provide an enantio and Bhat, WO 2005/010011, each of which is incorporated by merically enriched mixture of a compound of Formula (I) reference in its entirety. having at least 90% enantiomeric excess of one enantiomer of 0123. In certain embodiments, the reaction depicted in the compound of Formula (I), wherein R' is chosen from C. Scheme 1 may be carried out in an appropriate solvent Such alkyl, C. cycloalkyl, phenyl, Substituted phenyl, and C7. as, for example, acetone, acetonitrile, dichloromethane, phenylalkyl; R is chosen from C, alkyl C. cycloalkyl, dichloroethane, chloroform, toluene, tetrahydrofuran, diox ane, dimethylformamide, dimethylacetamide, N-methylpyr phenyl, substituted phenyl, and C7.9 phenylalkyl; and R is rolidinone, dimethyl sulfoxide, pyridine, ethyl acetate, chosen from C alkyl, C. cycloalkyl, phenyl, Substituted methyl tert-butyl ether, methanol, ethanol, isopropanol, tert phenyl, and C7 phenylalkyl. butanol, water, or combinations of any of the foregoing. In certain embodiments, the solvent is chosen from acetone, 1-(Acyloxy)-Alkyl Carbamate Prodrugs acetonitrile, dichloromethane, toluene, tetrahydrofuran, pyri I0128 Compounds provided by the present disclosure dine, methyl tert-butyl ether, methanol, ethanol, isopropanol, include compounds of Formula (III) or a pharmaceutically water, and combinations of any of the foregoing. In certain acceptable salt thereof, or a pharmaceutically acceptable sol embodiments, the solvent is a mixture of acetonitrile and vate of any of the foregoing, prepared by the methods dis water. In certain embodiments, the solvent is a mixture of closed herein. Compounds of Formula (III) prepared accord acetonitrile and water, with a volume ratio of acetonitrile to water from about 1:5 to about 5:1. In certain embodiments, ing to the disclosed methods may be included in the solvent is a mixture of methyl tert-butyl ether and water. In pharmaceutical compositions, which further comprise at least certain embodiments, the solvent is a mixture of methyl tert one pharmaceutically acceptable vehicle. butyl ether and water, with a volume ratio of methyl tert-butyl I0129. Compounds of Formula (III) or a pharmaceutically ether to water from about 20:1 to about 2:1. In certain embodi acceptable salt thereof or a pharmaceutically acceptable sol ments, the solvent is a mixture of methyl tert-butyl ether and vate of any of the foregoing obtained by the methods dis water, wherein the methyl tert-butyl ether contains from closed herein or a pharmaceutical composition thereof may about 10% to about 50% acetone by volume. In certain be used in therapeutic application for treatment of an appro embodiments, the Solvent is chosen from dichloromethane, priate disease. water, and a combination thereof. In certain embodiments, the I0130 Compounds of Formula (III) in which D-NHR" is solvent is a biphasic mixture of dichloromethane and water. pregabalin and pharmaceutical compositions thereof may be In certain embodiments, the solvent is a biphasic mixture of used in the treatment of movement disorders, gastrointestinal dichloromethane and water containing from about 0.001 disorders, psychotic disorders, mood disorders, anxiety dis equivalents to about 0.1 equivalents of a phase transfer cata orders, sleep disorders, pulmonary disorders, neurodegenera lyst. In certain embodiments, the phase transfer catalyst is a tive disorders, inflammatory disease, neuropathic pain, mus tetraalkylammonium salt. In certain embodiments, the phase culoskeletal pain, migraine, hot flashes, faintness attacks, transfer catalyst is a tetrabutylammonium salt. urinary incontinence, ethanol withdrawal syndrome, and pre 0.124. In certain embodiments, the reaction depicted in mature ejaculation. Pregabalin has also shown efficacy in Scheme 1 may be carried out at a temperature from about controlled studies for treating neuropathic pain of varying -20°C. to about 40°C., from about -20°C. to about 25°C., etiologies, as well as depression, anxiety, psychosis, faintness from about 0°C. to about 25°C., and in certain embodiments, attacks, hypokinesia, cranial disorders, neurodegenerative from about 25° C. to about 40° C. disorders, panic disorders, inflammatory disease, insomnia, 0.125. In certain embodiments, the reaction depicted in gastrointestinal disorders, urinary incontinence and ethanol Scheme 1 may be performed in the absence of a base. In withdrawal syndrome (Magnus, Epilepsia 1999, 40, S66-72). certain embodiments, the reaction depicted in Scheme 1 may The pharmacological activity of (3S)-aminomethyl-5-hex be performed in the presence of an inorganic base such as an anoic acid is believed to be effected through binding to the alkali metal bicarbonate oran alkali metal carbonate salt, and C28 Subunit of Voltage-gated calcium channels and the con in certain embodiments, the inorganic base is sodium bicar comitant reduction in the synaptic release of neurotransmit bonate. In certain embodiments, the reaction depicted in ters such as noradrenaline, glutamate, and Substance P (Tay Scheme 1 may performed in the presence of an organic base lor et al., Epilepsy Res 2007, 73, 137-50). Accordingly, Such as triethylamine, tributylamine, diisopropylethylamine, administering 1-(acyloxy)-alkyl carbamate prodrugs of pre dimethylisopropylamine, N-methylmorpholine, N-meth gabalin can be expected to be useful in treating diseases and ylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyri disorders associated with C.26 subunit of Voltage-gated cal dine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4- cium channels. In clinical trials, (3S)-aminomethyl-5-hex diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7- anoic acid has been shown to be effective in treating diseases ene or 1,5-diazabicyclo4.3.0 undec-7-ene, and in certain and disorders including, for example, perioperative and post embodiments, the organic base is chosen from triethylamine, operative pain (Dahl et al., Acta Anaesthesiol Scand 2004, 48, diisopropylethylamine, N-methylmorpholine, and pyridine. 1130-1136); musculoskeletal and neuropathic pain (Gallop et 0126 The general synthetic methods provided by the al., WO 02/100347; Zareba, Drugs Today 2005, 41(8), 509 present disclosure are shown in FIG. 2. A general synthetic 16; and Blommel and Blommel, Am J Health Syst Pharm scheme for 3-((1R)-1-(2-methylpropanoyloxy)ethoxy 2007, 64(14), 1475-82); chemotherapy-induced pain (Rao et carbonylaminomethyl)(3S)-5-methylhexanoic acid is al., Cancer 2007, 110(9), 2110-8; and Saif and Hashmi, Can shown in FIG. 5. cer Chemother Pharmacol 2008, 61,349-354); general anxi ety disorder (Rickels et al., Arch Gen Psychiatry 2005, 62. Intermediates 1022-1030); anxiety (Pohl et al., J. Clin Psychopharmacol 0127 Compounds of the present disclosure include acy 2005, 25, 151-8); post-herpetic neuralgia and painful diabetic loxyalkylthiocarbonates of Formula (I) prepared by steps peripheral neuropathy (Freynhagen et al., Pain 2005, 115, US 2009/0192325 A1 Jul. 30, 2009

254–63); sleep disorders (Sabatowski et al., Pain 2004, 109, liability of narcotic agents (Robson et al., U.S. Pat. No. 4,126, 26-35; and Hindmarch et al., Sleep 2005, 28(2), 187-93); 684); in the treatment of emesis (Bountra et al., U.S. Pat. No. ethanol withdrawal syndrome (Becker et al., Alcohol & Alco 5,719.185); as an anti-tussive for the treatment of cough holism 2006, 41(4), 399-406); fibromyalgia (Crofford et al., (Kreutner et al., U.S. Pat. No. 5,006,560); in treating neuro Arthritis and Rheumatism 2005, 52, 1264-73); restless legs pathic pain such as trigeminal neuralgia (Bowsher, Br: Med. syndrome (Sommer et al., Acta Neruol Scand 2007, 115(5), Bull. 1991,47(3), 655-66; Fromm et al., Neurology 1981, 31, 347–50); pain associated with spinal cord injury (Siddall et 683-7; and Ringel and Roy, Ann Neurol 1987, 21(5), 514-5): al., Neurology 2006, 67(10), 1792-800): social phobia (Pande and in treating musculoskeletal pain Such as painful lower et al., J. Clin Psychopharmacol 2004, 24(2), 141-149); uri back spasm (Dapas et al., Spine 1985, 10(4), 345-9; and nary incontinence (Barrett US 2005/0090550; and Segal et Raphael et al., BMC Musculoskeletal Disorders 2002, 3(17), al., WO 00/61135); hot flashes (Guttuso, Neurology 2000, 54, Epub 2002 Jun. 20); tension-type headaches (Freitag, CNS 2161-2163; Loprinzi et al., Mayo Clin. Proc. 2002, 77, 1159 Drugs 2003, 17(6), 373-81); and radiculopathy (Zuniga et al., 1163; Jeffery et al., Ann. Pharmacother. 2002, 36,433-435: Anesthesiology 2000, 92(3), 876-880). Cundy, U.S. patent and Guttuso et al., Obstet. Gynecol. 2003, 101, 337-345): application Ser. No. 12/139,057 filed Jun. 13, 2008 (incorpo rapid ejaculation (Taylor et al., US 2004/0176456), vulvo rated by referenced herein in its entirety) disclose the use of dynia (Ben-David et al., Anesth, Analg. 1999, 89, 1459–60); 1-(acyloxy)-alkyl carbamate prodrugs of R-baclofen in com and others. bination with GABA analog prodrugs for treating spasticity, 0131 Cundy, U.S. patent application Ser. No. 12/139,057 and Benson et al., U.S. application Ser. No. 10/266,169 filed filed Jun. 13, 2008 (which is incorporated by referenced in its Nov. 6, 2008 (which is incorporated by referenced in its entirety) discloses the use of 1-(acyloxy)-alkyl carbamate entirety) disclose the use of 1-(acyloxy)-alkyl carbamate pro prodrugs of GABA analogs such as pregabalin for treating drugs of R-baclofen for treating neuropathic and musculosk spasticity; Tran, WO 2007/027477 and WO 2007/027476 eletal pain, including muscle spasms due to musculoskeletal (each of which is incorporated by reference in its entirety) conditions such as back spasm in the lumbar, thoracic and/or discloses the use of 1-(acyloxy)-alkyl carbamate prodrugs of cervical regions. GABA analogs for treating Vulvodynia and premature ejacu I0134. In certain embodiments of compounds of Formula lation, respectively; Barrett and Cundy, US 2008/0161393 (III), a primary or secondary amine-containing drug, (which is incorporated by reference in its entirety) disclose D-NHR, is chosen from acebutolol, adaprolol, adrenalone, the use of 1-(acyloxy)-alkyl carbamate prodrugs of GABA adrogolide, aladapcin, alatrofloxacin, albendazole, albuterol, analogs for treating migraine, fibromyalgia, amyotrophic lat albutoin, alendronate, alestramustine, aletamine, alinidine, eral sclerosis, irritable bowel syndrome, social phobia, Par aliskiren, alizapride, alniditan, alprafenone, alprenolol. kinson's disease, asthma, cough, or chronic obstructive pull alprenoXime, altromycin A, altromycin C, amantadine, monary disease; and the use of 1-(acyloxy)-alkyl carbamate amidephrine, amifostine, amikacin, amiloride, aminole prodrugs of GABA analogs for treating restless legs Syn Vulinic acid, a minorex, amlodipine, amoSulalol, amoxapine, drome, hot flashes, and urinary incontinence is disclosed in amphetamine, amphotericin B, amrubicin, amselamine, Barrett and Canafax, US 2005/0192353, Barrett and Gallop, amthamine, anabasine, angiopeptin, anisperimus, aprinocid, US 2004/0254246, and Barrett, US 2005/0090550 (each of arbekacin, arbutamine, argiopine, arotinolol, aspartame, which is incorporated by reference in its entirety), respec aspoxicillin, atenolol, avizafone, azoxybacilin, baclofen, tively. bactobolin, balanol, balofloxacin, bambuterol, bamethan, (0132) Compounds of Formula (III) in which D-NHR" is baogongteng A, barusiban, batoprazine, becampanel, R-baclofen and pharmaceutical compositions thereof may be befunolol, belactosin A, belactosin C, benanomicin B, used in the treatment of spasticity, gastro-esophageal reflux benazepril, berlafenone, betahistine, betaxolol, bevantolol, disease, emesis, cough, narcotic addiction or abuse, alcohol biemnidin, binospirone, bisoprolol, boholmycin, bopindolol. addiction or abuse, nicotine addiction orabuse, urinary incon brasilicardin A, brinzolamide, bunolol, bupropion, butabin tinence, neuropathic pain, and musculoskeletal pain such as dide, buteranol, butofilolol, butopamine, butoxamine, cald painful lower back spasm. aret, cambendazole, cambrescidins, capraZamycin, capromo 0133) A principal pharmacological effect of baclofen in relin, capsavanil, carbidopa, carbuterol, carteolol, carvedilol. mammals is reduction of muscle tone and the drug is fre cefaclor, cefcanel, cefcanel daloxate, cefiminox, cefprozil, quently used in the treatment of spasticity (Price et al., Nature ceftizoxime, celiprolol, ceranapril, cetefloxacin, chlo 1984, 307, 71-4). Spasticity is associated with damage to the rotetain, chlortermine, cilaZapril, cimaterol, cimetidine, cina corticospinal tract and is a common complication of neuro calcet, ciprofloxacin, circinamide, cisapride, cispentacin, logical disease. Diseases and conditions in which spasticity clonidine, cloranolol, clorprenaline, colterol, cyclobenda may be a prominent symptom include cerebral palsy, multiple Zole, cyclothialidine, cystamine, cystocin, cytaramycin, Sclerosis, stroke, head and spinal cord injuries, traumatic dabelotine, dactimicin, dalargin, dalbavancin, daunorubicin, brain injury, anoxia, and neurodegenerative diseases. Patients D-cycloserine, decaplanin, deferoxamine, delapril, delavird with spasticity complain of stiffness, involuntary spasm, and ine, delfaprazine, delucemine, demexiptiline, denopamine, pain. These painful spasms may be spontaneous or triggered deoxymethylspergualin, deoxynegamycin, deoxynojirimy by a minor sensory stimulus, Such as touching the patient. cin, deoxyspergualin, desipramine, desloratadine, deterenol, Baclofen is also useful in controlling gastro-esophageal dexpropranolol, diacetolol, dihydrexidine, dilevalol, reflux disease (van Herwaarden et al., Aliment. Pharmacol. dimethoxyphenethylamine, dinapsoline, dirithromycin, dob Ther: 2002, 16, 1655-62: Ciccaglione et al., Gut 2003, 52, utamine, donitriptan, dopamine, dopexamine, doripenem, 464-70; Andrews et al., U.S. Pat. No. 6,117,908; and Fara et dorzolamide, doxorubicin, droxidopa, droximavir, dulloxet al., WO 02/096404); in promoting alcohol abstinence in alco ine, duramycin, ecenofloxacin, ecteinascidins, efegatran, holics (Gessa et al., WO 01/26638); in promoting smoking eflomithine, eglumegad, elarofiban, enalapril, enalkiren, cessation (Gessa et al., WO 01/08675); in reducing addiction enkastins, enoxacin, enviroXime, ephrinephrine, epibatidine, US 2009/0192325 A1 Jul. 30, 2009 12 epirubicin, epithalon, eremomycin, ersentilide, ertapenem, tabilautide, tabimorelin, tafenoquine, tageflar, tolamolol, tali esafloxacin, esmolol, esperamicin A1, etintidine, begron, tamsulosin, targinine, tazolol, tecalcet, telavancin, etryptamine, examorelin, exaprolol, exatecan, eZlopitant, temocapril, terbutaline, tertatolol, tetrafibricin, tetrahydrazo fasudil, fenbendazole, fenfluramine, fenmetazole, line, tetrindol, theprubicin, thiabendazole, thiofedrine, thraz fenoldopam, fenoterol, fenyripol, fepradinol, ferulinolol, fle arine, tiamdipine, tiamenidine, tianeptine, tienoxolol, tigecy camide, flubendazole, fludorex, fluoxetine, fluparoxan, flu cline, tilisolol, timolol, tinazoline, tiotidine, tipifamib, Virucin B2, fluvoxamine, formoterol, fortimicin A, fosopam tiprenolol, tipropidil, tirofiban, tocamide, tolaZoline, tomox ine, froVatriptan, fudosteine, gaboXadol, galarubicin, gatnon, etine, topixantrone, toSufloxacin, tramazoline, trandolapril, garenoxacin, garomefrine, gatifloxacin, gemifloxacin, tranexamic acid, tranylcypromine, triamterene, trovafloxa cin, troxipide, tuftsin, tulathromycin B, tulobuterol, ubistatin, gilatide, giracodazole, gludopa, halofuginone, helvecardin A, ulifloxacin, utibapril, Vestipitant, Vicenistatin, vigabatrin, helvecardin B, hispidospermidin, histaprodifen, hydrostatin Vildagliptin, Viloxazine, Vofopiitant, Voglibose, Xamoterol, A, ibopamine, ibutamoren, icadronate, icatibant, icofun Ximelagatran, Xylometazoline, Zabiciprilat, Zelandopam, gipen, idarubicin, imidapril, immepip, immepyr, immucillin Ziconotide, Zilpaterol, Zorubicin, C.-methyltryptophan, C.-me H. impentamine, indeloxazine, inogatran, isodoxorubicin, thylepinephrine, (-)-cicloprolol, (-)-nebivolol, (+)- isofagomine, janthinomycins, kahalalide F. kaitocephalin, isamoltan, (+)-Sotalol, (R)-(+)-amlodipine, (S)-noremo kanamycin, ketamine, L-4-oxalysine, labetalol, ladostigil, pamil, 1-ethyl-6-fluoro-1,21-aminoepothilone B, 4-dihydro lagatide, landiolol, lanicemine, lanomycin, lapatinib, lazabe 4-oxo-7-(1-piperazinyl)-1,4-dihydro-4-oxo-7-(piperazinyl)- mide, L-dopa, lenapenem, lerisetron, leurubicin, leustroduc 3-quinolinecarboxylic acid, 7-OXostaurosporine, sin A. leuStroducsin B. leustroducsin C, leustroducsin H, 8-napthyridine-3-carboxylic acid, and 1-cyclopropyl-6- levobunolol, L-histidinol, L-homothiocitrulline, lisinopril, fluoro-1. Other secondary or primary amine-containing drugs litoxetine, lobendazole, lobophorin A, loracarbef, lotrafiban, D-NHR' are described in various compendia available to a L-thiocitrulline, lubazodone, lysobactin, mabuterol, man skilled chemist, such as, for example, the Merck Index, 14" Zamines, maprotiline, maropitant, mebendazole, mecamy Edition, 2006 or the Physicians Desk Reference, 62" Edi lamine, mefloquine, melagatran, meluadrine, memantine, tion, 2007. Accordingly, secondary or primary amine-con mepindolol, meropenem, mersacidin, metaproterenol, met taining drugs D-NHR' described in such references are araminol, metazoline, methoctramine, methyldopa, meth encompassed by the present disclosure. The corresponding ylphenidate, metoclopramide, metolol, metoprolol, mety 1-(acyloxy)-alkyl carbamate prodrug synthesized according rosine, mexiletine, michellamine B, micronomicin, to the methods provided by the present disclosure and phar midafotel, midaxifylline, mideplanin, milacamide, milnacip maceutical compositions thereof may be used to treat a dis ran, mitoxantrone, moexipril, mofegiline, moxifloxacin, ease for which the parent secondary or primary amine-con mureidomycins, mycestericin E, n-3(R)-2-piperidin-4-yl) taining drug is therapeutically effective. ethyl-2-piperidone-1-yl)acetyl-3(R)-methyl-3-alanine, nad 0135) In certain embodiments, D-NHR" is chosen from olol, napsamycins, nardeterol, N-desmethylmilameline, alendronate, amifostine, rac-baclofen, R-baclofen, carbi nebivolol, neboglamine, nebracetam, nepicastat, neramex dopa, clonidine, ciprofloxacin, cisapride, daunorubicin, ane, neridronate, nemifidide, nifedipine, nimodipine, doxorubicin, fenoldopam, fenoterol, gabapentin, gentamy nipradillol, noberastine, noberastine, nocodazole, nolomirole, cin, kanamycin, levodopa, meropenem, metazoline, neomy norepinephrine, norfloxacin, nomicotine, nortopixantrone, cin, pamidronate, pregabalin, tobramycin, tranexamic acid, nortriptyline. nuvanil, oberadillol, octreotide, olamufloxacin, olcegepant, olradipine, orbifloxacin, orienticins, oritavancin, trovafloxacin, and vigabatrin. In certain embodiments, oseltamivir, osutidine, ovothiol A, ovothiol B, oxfendazole, D-NHR' is chosen from R-baclofen and pregabalin. In certain oxibendazole, oxmetidine, OXolide, oXprenolol, pafenolol. embodiments, D-NHR" is a GABA analog as defined herein. palau'amine, palindore, pamatolol, pamidronate, papuamide A, papuamide B, parbendazole, parodilol, paromomycin, EXAMPLES paroxetine, paroxetine, pasireotide, paZufloxacin, pelagiomi 0.136 The following examples describe in detail enzy cin C, penbutolol, perindopril, phendioxan, phospholine, matic resolution of acyloxyalkyl thiocarbonates, enantio picumeterol, pindolol, p-iodorubidaZone, pipedimic acid, pir merically or diasteromerically enriched compounds synthe buterol, pixantrone, pluraflavin A, pluraflavin B, poststatin, sized using the disclosed methods, and use of enzymatically practolol, pradimicin, pradimicin B, pradimicin D. pradimi resolved acyloxyalkylthiocarbonates in the synthesis of acy cin E. pradimicin FA-2, pradofloxacing pramipexole, pranid loxyalkyl carbamate prodrugs. It will be apparent to those ipine, praZosin, pregabalin, premafloxacin, prenalterol, skilled in the art that many modifications, both to materials primidolol, prisotinol, prizidilol, procainamide, procaterol, and methods, may be practiced without departing from the propafenone, propanolol, protriptyline, proxodolol, pseu Scope of the disclosure. doephedrine, pyloricidin B. pyridazomycin, quinapril, quin terenol, R-(+)-aminoindan, ralfinamide, ramipril, Description 1 ramoplanins, ranitidine, rasagiline, ravidomycin, reboxetine, remacemide, repinotan, reproterol, restricticin, rhodopeptins, General Experimental Protocols rilmazafone, rimiterol, risotilide, ritodrine, ruboxyl, sabaru 0.137 All reagents and solvents were purchased from bicin, Safinamide, Safingol, salbostatin, salbutamol, Salme commercial Suppliers and used without further purification or terol, Sampatrilat, Sarizotan, Seglitide, seproxetine, manipulation. Seraspenide, Sertraline, SetaZindol, Sezolamide, Sibanomicin, I0138 Proton NMR spectra (400 MHz) were recorded on a sibenadet, silodosin, Sitafloxacin, Sacoromycin, Solabegron, Varian AS 400 NMR spectrometer equipped with an Solpecainol, Soterenol, sparfloxacin, sperabillins, spinorphin, autosampler and data processing computation. CDC1 (99. spisulosine, squalamine, styloguanidine, Sulfinalol, Sul 8% D), DMSO-d (99.9% D), or MeOH-d (99.8+% D)were fonterol, Suloctidil, Sulphazocine, Sulphostin, Sumanirole, used as solvents unless otherwise noted. The CHCl, DMSO US 2009/0192325 A1 Jul. 30, 2009 d, or MeOH-d solvent signals were used for calibration of the individual spectra. Determination of enantiomeric excess -continued (e.e.) of intermediates was accomplished by H NMR spec troscopy in the presence of the diamagnetic enantiomerically pure chiral co-solvent (R)-(-)-2.2.2-trifluoro-1-(9-anthryl) O H ethanol (Pirkle-alcohol) and in comparison with H NMR O O N spectra of the corresponding racemic samples under similar conditions. r OH O O 0139 All thiocarbonates were synthesized by following a two-step reaction sequence. The enzymatic reactions were d carried out using from about 5 wt-% to about 10 wt-% enzyme in water at room temperature with stirring or shaking. The I0142 For example, 1-(S)-3-(1-(2-methylpropanoyloxy) progress of the reactions and enzyme selectivity was moni ethoxycarbonylaminomethyl)(3S)-5-methylhexanoic acid tored using 'H-NMR with (R)-(-)-2.2.2-trifluoro-1-(9-an (d) was prepared by reacting (2S)-2-hydroxy-4-methylpen thryl)ethanol as the chiral Solvating agent (e.g., Pirkle or tan-3-one (a) and 4-nitrophenyl chloroformate in the pres Hoover reagents). ence of triethylamine (TEA) in dichloromethane (DCM) to provide (1S)-1,3-dimethyl-2-oxobutyl (4-nitrophenoxy) for 0140) Enantiomeric excess was determined using chiral mate (b). (1S)-1,3-Dimethyl-2-oxobutyl (4-nitrophenoxy) HPLC with a reverse phase column. For example, to deter formate was then reacted with pregabalin in a mixture of mine enantiomeric excess, a Waters 2795 HPLC with a chiral tetrahydrofuran (THF) and water to provide (3S)-3-((S)-1, Technologies ChiralCel OJ-RH 4.6x150 mm column was 3-dimethyl-2-oxobutoxy)carbonylaminomethyl-5-methyl used. The column temperature was 35° C. and the mobile hexanoic acid (c). Intermediate (c) was then reacted overnight phases were (A) 20 mM potassium phosphate monobasic with meta-chloroperoxybenzoic acid (mCPBA) (2.5 eq.) and buffer (pH 2.5) and (B) 2% buffer/8% water/90% acetonitrile sodium bicarbonate (NaHCO) (1 eq.) in dichloromethane (ACN). Ten (10) uL of sample (1.0 mg/mL) was injected into (DCM) at room temperature to provide 1-(S)-3-(1-(2-me the column and detected using a Waters 996 PDA at 210 nm. thylpropanoyloxy)ethoxycarbonylaminomethyl)(3S)-5- 0141. The absolute configuration of the enzymatically methylhexanoic acid (d). resolved thiocarbonates was confirmed by derivatizing the 0143. Other enantiomerically or diastereomerically pure thiocarbonates to compounds of known stereochemistry and compounds were prepared using similar methods and replac comparing the retention times on a chiral HPLC column. For ing (2S)-2-hydroxy-4-methylpentan-3-one with an appropri example, compounds having known Stereochemistry were ate compound having known and specific Stereochemistry, prepared using Baeyer-Villiger oxidation, according to the and replacing pregabalin with an appropriate drug, such as following scheme. gabapentin, baclofen, or others. Example 1 Chloroalkylmethanethiocarbonates (1a-1c) 0144. To a stirred solution of chloroalkyl-chloroformate in O s"O dichloromethane (DCM) was added a solution of sodium OH ON methanethiolate (CH SNa) (1.0 eq.) in water at 0°C. and TEADCM 0.02 eq. of tetrabutylammonium bromide. The reactants were stirred at 0° C. for 30 min and then diluted with dichlo romethane (DCM). The dichloromethane layer was allowed 8. to separate, then washed with water and brine, and dried with anhydrous Sodium sulfate (Na2SO4). After rotary evaporation to remove the solvent, the corresponding chloroalkyl methanethiocarbonate (1) was obtained. O 0145 1-Chloro-2-methylpropyl methylthioformate (1a): O O H-NMR (CDC1): 8 1.05 (d. J=5.6 Hz, 3H), 1.07 (d. J=5.6 pregabalin --- Hz, 3H), 2.18 (m. 1H), 2.38 (s, 3H), 6.34 (d. J–5.6 Hz, 1H) THF, water ppm. O 0146) Chlorobutyl methylthioformate (1b): 'H-NMR (CDC1): 80.97 (t, J=7.6 Hz,3H), 1.51 (sextet, J=7.6 Hz, 2H), b 2.02 (m, 2H), 2.40 (s, 3H), 6.48 (t, J=6.0 Hz, 1H) ppm. 0147 Chloroethyl methylthioformate (1 c): 'H-NMR (CDC1): 8 1.80 (d. J=5.6 Hz, 3H), 2.37 (s.3H), 6.57 (q, J=5.6 HZ, 1H) ppm.

O O Example 2 O mCPBA Racemic Acyloxyalkylmethanethiocarbonates (2a OH NaHCO, DCM 2h) 0.148. A chloroalkylmethanethiocarbonate prepared according to Example 1 was added to a mixture of a carboxy

US 2009/0192325 A1 Jul. 30, 2009

Candida rugosa (Sigma-Aldrich) (12.5 g) in pH 7.2 phos 0.025 g of lipase from Candida rugosa was added, followed phate buffered saline (1 L) was stirred at room temperature. by 10 mL of phosphate buffer. The mixture was stirred at The reaction was monitored by 'H-NMR using the chiral room temperature for ca. 24 hrs. The reaction mixture was Solvating agent (R)-(-)-2.2.2-trifluoro-1-(9-anthryl)ethanol. diluted with ether and the organic solution filtered through a The reaction was stirred overnight. The reaction mixture was pad of Celite R545. The ether solution was washed with water then diluted with ether, and the ether layer separated and (2 times) and brine, and dried over anhydrous Sodium Sulfate filtered through a pad of Celite(R) 545 to remove the enzyme. (NaSO). The solvent was evaporated under reduced pres The ether layer was washed with aqueous sodium bicarbonate sure to provide 0.16 g (64% yield) of the title compound (7). (NaHCO) (5 times) and brine, and dried over anhydrous 'H-NMR using a chiral Solvating agent showed a single iso sodium sulfate (NaSO). After rotary evaporation to remove merand the absolute configuration was confirmed by deriva the solvent, 30.4 g of the title compound (4) was obtained. tization to a compound having a known Stereochemistry. 'H-NMR using a chiral solvating agent confirmed the pres ence of a single isomer. The absolute configuration was deter Example 8 mined by derivatization to a compound having known Stere ochemistry. 'H-NMR (CDC1): 80.96 (d. J=6.8 Hz, 6H), 1.16 (1R)-1-Methylthiocarbonyloxybutyl 2-methylpro (d. J=6.8 Hz, 3H), 1.17 (d. J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), panoate (8) 2.32 (s.3H), 2.56 (septet, J=7.2 Hz, 1H), 6.67 (d. J=5.6 Hz, 1H) ppm. 0163 A mixture of methylthiocarbonyloxybutyl 2-meth ylpropanoate (2c) (0.5 g) and Candida cylindracea (Sigma Example 5 Aldrich) (0.025g) in 2 mL of diisopropylether and 10 mL of (1R)-1-Methylthiocarbonyloxyethyl Benzoate (5) pH 7.2 phosphate buffer was shaken for ca. 24 hrs at room 0160 A mixture of 1-methylthiocarbonyloxyethyl ben temperature. The reaction mixture was diluted with diisopro Zoate (2g) (50 g) and lipase from Candida rugosa (2.50 g) in pylether and filtered through a Celite R 545 pad. The organic pH 7.2 phosphate buffered saline (500 mL) was stirred at solution washed with water (2 times) and brine, and dried room temperature. The reaction was monitored by H-NMR over anhydrous sodium sulfate (NaSO). Following removal using the chiral Solvating agent (R)-(-)-2.2.2-trifluoro-1-(9- of the solvent by rotary evaporation, 0.147 g of the title anthryl)ethanol. The reaction was complete after ca. 12 hours. compound (8) was obtained. 'H-NMR using a chiral solvat The reaction mixture was diluted with ether and the ether ing agent showed a single isomer and the absolute configu layer separated and filtered through a pad of Celite R 545 to ration was confirmed by derivatization to a compound having remove the enzyme. The ether layer was washed with aque a known stereochemistry. ous sodium bicarbonate (NaHCO) (5 times) and brine, and dried over anhydrous sodium sulfate (Na2SO). After the Example 9 solvent was removed by rotary evaporation, 22 g of the title compound (5) was obtained. 'H-NMR using a chiral solvat (1R)-Methylthiocarbonyloxybutyl Butanoate (9) ing agent showed a single isomer and the absolute configu 0164. A mixture of 1-methylthiocarbonyloxybutyl ration was confirmed by derivatization to a compound having butanoate (2e) (0.5 g) and Candida antarcticalipase B (No a known stereochemistry. 'H-NMR (CDC1): & 1.65 (d. J=5.6 vozyme 435) (75 mg) in 2 mL of isopropyl ether and 20 mL Hz, 3H), 2.35 (s, 3H), 7.20 (q, J=5.6 Hz, 1H), 7.45 (m, 2H), of pH 7.2 phosphate buffer was shaken on an orbital shaker at 7.58 (m. 1H), 8.06 (m, 2H) ppm. room temperature. The reaction was monitored by 'H-NMR Example 6 using the chiral Solvating agent ((R)-(-)-2.2.2-trifluoro-1-(9- (1S)-Methylthiocarbonyloxyethyl Benzoate (6) anthryl)ethanol. After 24 hours, the reaction was diluted with diisopropylether and filtered through a pad of Celite(R) 545. 0161. A mixture of 1-methylthiocarbonyloxyethyl ben The ether layer was washed with water and brine, and dried Zoate (2g) (38 g) and lipase acrylic resin containing Candida with anhydrous sodium sulfate (NaSO). Following rotary antarcticalipase B (Novozyme 435, Sigma-Aldrich) (3.8 g) evaporation to remove the solvent, 0.21 g of the title com in pH 7.2 phosphate buffered saline (1.6 L) was stirred at pound (9) was obtained. Chiral HPLC indicated an enantio room temperature. The reaction was monitored by 'H-NMR meric excess of 99% e.e. The absolute configuration was using the chiral Solvating agent (R)-(-)-2.2.2-trifluoro-1-(9- confirmed by derivatization to a compound having a known anthryl)ethanol. The reaction was complete in ca. 10 days. Stereochemistry. The reaction mixture was then diluted with ether, and the ether layer separated and filtered through a pad of Celite(R) Example 10 545 to remove the enzyme. The ether supernatant was washed with water (5 times) and brine, and dried over anhydrous (1R or 1S)-2-Methyl-1-methylthiocarbonyloxypro sodium sulfate (NaSO). After the solvent was removed by pyl Benzoate (10) rotary evaporation, 15.1 g of the title compound (6) was obtained. 'H-NMR using a chiral solvating agent showed a 0.165. A mixture of 2-methyl-1-methylthiocarbonylox single isomer and the absolute configuration was confirmed ypropylbenzoate (2h) (7 g) and Candida rugosa (0.7g) in a by derivatization to a compound having a known stereochem solvent (10 mL of isopropyl ether and 80 mL of pH 7.2 istry. phosphate buffer saline) was shaken on an orbital shaker at room temperature. The reaction was monitored by H-NMR Example 7 with chiral solvating agent. After ca. 7 days, 'H-NMR showed (1R)-2-Methyl-1-methylthiocarbonyloxypropyl that only one isomer remained. The reaction mixture was Butanoate (7) diluted with ether and ether layer was separated. The ether 0162 To a solution of 2-methyl-1-methylthiocarbonylox layer was filtered through a pad of Celite(R) 545, washed with ypropylbutanoate (2d) (0.5 g) in 2 mL of diisopropyl ether, water and brine, and dried with anhydrous sodium sulfate US 2009/0192325 A1 Jul. 30, 2009

(NaSO). Rotary evaporation afforded 1.48 g of the title 735, 6 units/mg) were added to 500 uL phosphate buffer compound as colorless oil. The Stereochemistry was not con (0.4–0.8M, pH 7.5) and shaken on an Eppendorf thermomixer firmed for this compound. at 1,000 rpm at a temperature of 29° C. After ca. 43 hours, chiral HPLC analysis indicated an enantiomeric excess of Example 11 99% e.e. for the title compound (13). (1R)-2-Methyl-1-methylthiocarbonyloxypropyl Example 14 Acetate (11) 0166 Following the procedure of Example 9, and substi (1S)-2-Methyl-1-methylthiocarbonyloxypropyl tuting 2-methyl-1-methylthiocarbonyloxypropyl acetate (2f) Butanoate (14) for 1-methylthiocarbonyloxybutylbutanoate (2e), the title 0170 2-Methyl-1-methylthiocarbonyloxypropyl compound (11) was obtained (54% yield) with an enantio butanoate (2d) (1 g) was dissolved in 20 mL of MTBE, meric excess of 94% e.e. saturated with 1% of water, 1.3 g of PLE/MPEG (7.5%, 60 mg/1 g) was added, and the mixture shaken at room tempera Description 3 ture for 24 hrs. Hexane was added to the reaction mixture and Preparation of PLE/MPEG after filtration through a Celite R545 pad, the organic solution was washed with water, aqueous sodium bicarbonate 0167 To a solution of porcine liver esterase (PLE) (NaHCO) and brine, and dried over anhydrous sodium sul (Sigma-Aldrich, 7.5 g) in 2,000 mL of water was added fate (Na2SO). After evaporating the solvent under reduced poly(ethylene glycol)monomethyl ether (MPEG) (Scientific pressure the title compound (14) was obtained (0.29 g, 58% Polymer Products, Inc., 5000 Mw). The resulting mixture was yield). The absolute configuration was determined by deriva stirred until a clear solution was obtained. One-hundred (100) tization to a compound having known Stereochemistry. mL of acetonitrile was added to the solution to prevent glass ware breakage during lyophilization. The mixture was stirred Example 15 for another 30 minto form a clear solution. The solution was then lyophilized to afford PLE/MPEG (50 mg/1 g) as a fluffy, (1S)-1-Methylthiocarbonyloxybutyl 2-methylpro white powder. panoate (15) 0171 A mixture of 22 mL methyl-tert-butyl ether Example 12 (MTBE) and 0.22 mL water was stirred until a clear solution (1S)-2-Methyl-1-methylthiocarbonyloxypropyl was obtained (ca. 5 hrs). To this solution was added methylth 2-methylpropanoate (12) iocarbonyloxybutyl 2-methylpropanoate (2c) (1.11 g) and PLE/MPEG (50 mg/1 g, 1.5 g). The resulting suspension was (0168 A mixture of 990 mL methyl-tert-butylether stirred at room temperature. The reaction was monitored by (MTBE) and 10 mL water was stirred until a clear solution H-NMR using a chiral solvating agent. After ca. 5 days, the was obtained (ca. 5 hrs). To this solution was added 2-methyl reaction was quenched by filtration through a pad of Celite(R) 1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) 545. The Supernatant was washed with water, aqueous (50 g) and PLE/MPEG (50 mg/1 g, 7.5 g). The resulting sodium bicarbonate (NaHCO) and brine, and dried over Suspension was stirred at room temperature. The reaction was anhydrous sodium sulfate (NaSO). Rotary evaporation of monitored by 'H-NMR using a chiral solvating agent. After the solvent afforded 0.22 g the title compound (15) (40% 'H-NMR showed only one enantiomer remained in the reac yield). The enantiomeric excess was 88% e.e. as determined tion mixture (ca. 48 hrs), the reaction was quenched by filtra by chiral HPLC. tion through a pad of Celite(R) 545. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO) Example 16 and brine, and dried over anhydrous Sodium Sulfate (NaSO). After rotary evaporation, the title compound (12) (1S)-1-Methylthiocarbonyloxybutyl Butanoate (16) was obtained with 70% yield. The enantiomeric excess of the (0172. A mixture of 33 mL methyl-tert-butyl ether S-enantiomer was 100% e.e. as determined by chiral HPLC. (MTBE) and 0.33 mL water was stirred until a clear solution H-NMR (CDC1): 8 0.96 (d. J=6.8 Hz, 6H), 1.16 (d. J=6.8 was obtained (ca. 5 hrs). To this solution was added methylth Hz, 3H), 1.17 (d. J=6.8 Hz, 3H), 1.98-2.07 (m. 1H), 2.32 (s, iocarbonyloxybutylbutanoate (2e) (2.0 g) and PLE/MPEG 3H), 2.56 (septet, J–7.2 Hz, 1H), 6.67 (d. J–5.6 Hz, 1H) ppm. (60 mg/1 g; 12.65 g). The resulting Suspension was stirred at 'H-NMR with chiral solvating agent (R)-(–)-2.2.2-trifluoro room temperature. The reaction was monitored by H-NMR 1-(9-anthryl)ethanol: 80.98 (d. J=6.8 Hz, 3H), 0.99 (d. J=6.8 using a chiral Solvating agent. After ca. 5 days, the reaction Hz, 3H), 1.19 (d. J=7.2 Hz, 1.5H), 1.19 (d. J=6.8 Hz, 1.5H), was quenched by filtration through a pad of Celite R545. The 1.20 (d. J=6.8 Hz, 1.5H), 1.20 (d. J–7.2 Hz, 1.5H), 2.01-2.09 Supernatant was washed with water, aqueous sodium bicar (m. 1H), 2.341 (s, 1.5H), 2.44 (s, 1.5H), 2.59 (septet, J–7.2 bonate (NaHCO) and brine, and dried over anhydrous HZ, 0.5H), 2.59 (septet, J=6.8 Hz, 0.5H), 6.70 (d. J=5.6 Hz, sodium sulfate (NaSO). Evaporation of the solvent afforded 0.5H), 6.70 (d. J=5.2 Hz, 0.5H) ppm. 0.20 g (20% yield) of the title compound (16). The enantio meric excess as determined by chiral HPLC was 90% e.e. Example 13 Alternate Synthesis of (1S)-2-Methyl-1-methylthio Example 17 carbonyloxypropyl-2-methylpropanoate (13) (1S)-2-Methyl-1-methylthiocarbonyloxypropyl 0169 2-Methyl-1-methylthiocarbonyloxypropyl 2-meth Acetate (17) ylpropanoate (2b) (119 mg) in 100 u, 0.4 Mphosphate buffer (0173 Twenty (20) mL of methyl-tert-butyl ether (MTBE) (pH 7.5) and Candida antarcticalipase A (4-6 LL, Novozyme and 0.2 mL of water were shaken for 4 hrs until the solution US 2009/0192325 A1 Jul. 30, 2009 was clear at which time 1 g of 2-methyl-1-methylthiocarbo 0177. For comparison, racemic 1-methylthiocarbony nyloxypropyl acetate (2f) was added, followed by 1.32 g of loxyethyl-2-methylpropanoate: 'H-NMR in presence of (R)- PLE/MPEG (60 mg/1 g). The mixture was shaken on an (-)-2.2.2-trifluoro-1-(9-anthryl)ethanol as chiral solvating orbital shaker for 7 hrs. Hexane was added and the mixture agent (CDC1): 81.18 (m, 6H), 1.49 (d. J=5.2 Hz, 1.5H), 1.50 was filtered through Celite(R) 545 pad. The organic solution (d. J=5.6 Hz, 1.5H), 2.33 (s, 1.5H), 2.34 (s, 1.5H), 2.55 was washed with water, aqueous sodium bicarbonate (septet, J–7.2 Hz, 0.5H), 2.56 (septet, J–7.2 Hz, 0.5H), 6.92 (NaHCO) solution and brine, and dried over anhydrous (q, J=5.6 Hz, 0.5H), 6.92 (q, J=5.6 Hz, 0.5H) ppm. sodium sulfate (NaSO). After evaporation of solvent, 0.32g Step B: (1R)-Isobutanoyloxyethoxycarbonyloxy} (64% yield) of the title compound (17) was obtained having Succinimide (18b) an enantiomeric excess of 64% e.e. The absolute configura tion was determined by independent stereospecific synthesis 0178 and by derivatization to a compound having known stere ochemistry. O l lsO CHCOOOH/CHCOOH Example 18 O O s1 NHS, DCM (3S)-(1R)-Isobutanoyloxyethoxycarbonylami nomethyl-5-methyl-hexanoic Acid (18) (3) Step A: (1R)-1-Methylthiocarbonyloxyethyl-2-meth O ylpropanoate (3) 0174

O O Candida antarctica

l us Phosphatelipase buffB s O S 1. Ospinale buTTer 0179. In a 20-L jacketed reaction vessel equipped with a mechanical stirrer, an internal thermometer and a nitrogen inlet was added (1R)-1-methylthiocarbonyloxyethyl-2-meth (2a) ylpropanoate (3) (1.44 kg, 7 mol), and N-hydroxysuccinim ide (1.61 kg, 14 mol) in dichloromethane (DCM) (8 L). The O l O resulting Suspension was cooled to 9°C. A solution of per acetic acid in acetic acid (32%, 4.98 kg, 4.4 L; 21 mol) was s --- slowly added while maintaining the reaction temperature between 9° C. and 15° C. The reaction mixture was then (3) stirred at 9°C. for ca. 23 hours. 0180. The reaction mixture was then diluted with water (3 L) and the organic phase was separated. The organic phase 0175 A 20-L, multi-necked, cylindrical reactor, fitted was washed with water (2x2 L), Saturated potassium bicar with a mechanical stirrer, a nitrogen inlet and an outlet con bonate solution (4 L) and a solution of sodium thiosulfate nected to an oxidation bath and a bleach bath (14% NaOCl) to (350g in water 4 L). The organic phase was dried over sodium oxidize liberated methanethiol and acetaldehyde was charged sulfate (NaSO) and volatiles were removed under vacuum, with racemic 1-methylthiocarbonyloxyethyl-2-methylpro resulting in the crude product as a white-solid. To this solid panoate (2a) (5.32 kg, 25.8 mol) and 0.8 M phosphate buffer was added 2-propanol (3 L) and hexane (3 L). The resulting (10 L, pH 7.0). Solid supported Candida antarcticalipase B slurry was warmed to 30° C. for 30 minutes. The resulting (125 g, Novozyme 435) was slowly added while the solution slurry was cooled for two hours using an ice-bath. The prod was stirred. The reaction mixture was stirred at room tem uct was collected by filtration. The filter cake was washed perature (22-24°C.) for ca. 18 hours. with hexane (4 L) and dried under vacuum to provide the title 0176 The reaction mixture was then diluted with methyl compound (18b) as a white solid (1 kg, 50% yield). "H-NMR tert-butyl ether (MTBE) (8 L) and the organic phase sepa (CDC1): 1.17 (d. J=6.8 Hz, 3H), 1.18 (d. J=6.8 Hz,3H), 1.60 rated. The organic phase was washed with phosphate buffer (d. J=5.6 Hz, 3H), 2.58 (m. 1H), 2.83 (s, 4H), 6.80 (q, J=5.2 (0.57 M, 2x5 L), water (10 L) and brine (7 L). The solid HZ, 1H) ppm. Supported enzyme was removed by filtration and the organic Step C; (3S)-(1R)-Isobutanoyloxyethoxycarbony phase was dried over sodium sulfate (NaSO), filtered and laminomethyl-5-methyl-hexanoic Acid (18) concentrated by rotary evaporation to afford the title com 0181 pound (3) as a light yellow oil. The product was further concentrated at 65°C. under reduced pressure to provide 2.45 kg of the title compound (3) (92% yield). 'H-NMR (CDC1): & 1.17 (d.J=70 Hz,3H), 1.18 (d.J=7.6 Hz,3H), 1.59 (d. J=5.6 Hz, 3H), 2.34 (s, 3H), 2.55 (septet, J–7.2 Hz, 1H), 6.92 (q, J–5.6 Hz, 1H) ppm. "H-NMR in presence of (R)-(-)-2.2.2- trifluoro-1-(9-anthryl)ethanol as chiral Solvating agent (CDC1): 81.17 (d. J=7.2 Hz, 3H), 1.18 (d. J–7.2 Hz, 3H), 1.48 (d. J=5.6 Hz, 3H), 2.33 (s, 3H), 2.56 (septet, J–7.2 Hz, 1H), 6.92 (q, J–5.6 Hz, 1H) ppm. US 2009/0192325 A1 Jul. 30, 2009 18

presence of chiral Solvating agent, (R)-(-)-2.2.2-trifluoro-1- -continued (9-anthryl)ethanol: & 1.18 (m, 6H), 1.50 (d. J=5.2 Hz, 1.5H), MtBEWater 1.50 (d. J=5.6 Hz, 1.5H), 2.33 (s, 1.5H), 2.34 (s, 1.5H), 2.55 HN1N1 Ncoon -- (septet, J–7.2 Hz, 0.5H), 2.56 (septet, J–7.2 Hz, 0.5H), 6.92 (q, J=5.6 Hz, 0.5H), 6.92 (q, J=5.6 Hz, 0.5H) ppm. Step B: (1R)-Isobutanoyloxyethoxycarbonyloxy} Succinimide (18b) 0185. The title compound (18b) was prepared from com pound (1R)-methylthiocarbonyloxyethyl 2-methylpro --~~. panoate (3) by following the method disclosed in Example 10 of Gallop et al., U.S. Pat. No. 7,227,028. 'H NMR (CDC1, 400 MHz): & 1.17 (d. J=6.8 Hz, 6H), 1.56 (d. J=5.6 Hz, 3H), N 2.55 (m. 1H), 2.82 (s, 4H), 6.80 (q, J=5.2 Hz, 1H) ppm. (18) Step C; (3S)-(1R)-Isobutanoyloxyethoxycarbony 0182. A 20-L pilot plant equipped with a mechanical stir laminomethyl-5-methyl-hexanoic Acid (18) rer and a nitrogen inlet was charged with NHS-carbonate, 0186 Compound (18b) (52.8g, 0.193 mol) and pregabalin (1R)-1-(5-methylene-2-oxazolidinyloxycarbonyloxy)ethyl (31.7g, 0.199 mol) were stirred in a mixture of acetonitrile 2-methylpropanoate (18b), 1.31 kg, 4.7 mol) and (S)-pre and water (200 mL, 4:1) at room temperature for 16 h, and the gabalin (431 g; overall 1.2 eq. of pregabalin) in a mixture of acetonitrile removed in vacuo. The residue was partitioned methyl tert-butyl ether (MTBE) and water (3:1; 10 L). The between MTBE and water, the MTBE layer was then washed resulting Suspension was stirred for 24 hours at room tem with water then brine, and dried over anhydrous sodium sul perature. fate (NaSO). Removing the solvent in vacuo afforded the 0183 The reaction mixture was then diluted with water (3 title compound (18) (61.3g, 100% yield) as a colorless oil. "H L). The organic phase was separated and washed with water NMR (CDC1,400 MHz): 8 0.90 (d. J=6.4 Hz, 3H), 0.92 (d. (3x3 L), aqueous sulfuric acid (5%, 4 L), and water (4 L). The J=6.4 Hz,3H), 1.17 (m,8H), 1.47 (d.J=5.6 Hz, 2.7H), 1.50 (d. organic phase was dried over Sodium sulfate (Na2SO4) and J=5.6 Hz, 0.3H), 1.66 (hept, J=6.8 Hz, 1H), 2.19 (m. 1H), 2.27 volatiles were removed under vacuum to provide the title (dd, J=15.2, 7.6 Hz, 1H), 2.37 (dd, J=15.2, 5.2 Hz, 1H), 2.54 compound (18) as a clear, viscous-oil (1.33 kg, 89% yield). (hept, J=6.8 Hz, 1H), 3.08 (m. 1H), 3.32 (m. 1H), 5.00 (br, t, J=6.2 Hz, 0.9H), 5.91 (br, t, J=6.2 Hz, 0.1H), 6.76 (q, J=5.6 Example 19 HZ, 1H) ppm. Alternate Synthesis of (3S)-(1R)-Isobutanoyloxy ethoxycarbonylaminomethyl-5-methyl-hexanoic Example 20 Acid (18) (3S)-(1S)-Isobutanoyloxyisobutoxycarbonylami Step A: (1R)-Methylthiocarbonyloxyethyl 2-methyl nomethyl-5-methyl-hexanoic Acid (20) propanoate (3) Step A: (1S)-2-Methyl-1-methylthiocarbonyloxypro 0184 Methylthiocarbonyloxyethyl-2-methylpropanoate pyl 2-methylpropanoate (12) (180g), prepared as described in Gallop et al., U.S. Pat. No. 0187. A mixture of MTBE (990 mL) and water (10 mL) 7,227,028, and lipase from Candida antarcticalipase B (No was stirred for 5 huntil a clear solution was obtained. To this vozyme 435), immobilized on acrylic resin, (8.0 g) was solution was added 2-methyl-1-methylthiocarbonyloxypro stirred in phosphate buffered saline, pH 7.2, (1.6 L) at room pyl 2-methylpropanoate (2b) (50g), prepared as described in temperature. The progress of the reaction was monitored by Gallop et al., U.S. Pat. No. 7,227,028, and a non-covalent H-NMR using the chiral solvating agent (R)-(+)-2.2.2-trif complex of porcine liver esterase (PLE), with methoxypoly luoro-1-(9-anthryl)ethanol and was complete within ca. 16 h. ethylene glycol (MPEG) (5 wt %, 75 g) prepared according to The reaction mixture was diluted with ether and the ether the method described by Heiss and Gais, Tetrahedron Lett., layer separated and filtered through a pad of Celite R to 1995,36,3833-3836; and Heiss and Gais, Tetrahedron Asym remove the enzyme. The ether phase was washed repeatedly metry, 1997, 8, 3657-3664. The resulting suspension was with water then brine, and dried over anhydrous sodium sul stirred at room temperature and the reaction periodically fate (Na2SO). Removal of the solvent in vacuo afforded a monitored by 'H-NMR using the chiral solvating agent (R)- quantitative yield (90 g) of the title compound (3) as a single (+)-2.2.2-trifluoro-1-(9-anthryl)ethanol. After ca. 48 h, enantiomer. The absolute configuration was established by: 'H-NMR indicated that only one enantiomer remained in the (i) conversion to compound (18b) (see Step B); (ii) reaction of reaction mixture at which time the reaction was quenched by (18b) with gabapentin to afford 1-(C-(R)-isobutanoyloxy filtration through a pad of CeliteR). The supernatant was ethoxy)carbonyl)aminomethyl-1-cyclohexane acetic acid; washed with water, aqueous sodium bicarbonate (NaHCO) and (iii) correlation with the product formed by stereoselec then brine, and dried over anhydrous sodium sulfate tive Baeyer-Villiger oxidation of 1-(C-(R)-isobu (NaSO). After removing the solvent in vacuo, the title com tanoylethoxy)carbonyl)aminomethyl-1-cyclohexane acetic pound (12) was isolated as a single S-enantiomer (as deter acid as described in Gallop et al., U.S. Pat. No. 6,927,036. H mined by HPLC using a chiral column) in 70% yield. The NMR (CDC1,400 MHz): & 1.16 (d. J=7.6 Hz, 3H), 1.18 (d. absolute configuration was established by: (i) conversion to J=7.0 Hz, 3H), 1.50 (d. J=5.6 Hz, 3H), 2.34 (s, 3H), 2.55 compound (20b) (see Step B); (ii) reaction of (20b) with (hept, J–7.2 Hz, 1H), 6.92 (q, J=5.6 Hz, 1H) ppm. "H NMR in R-baclofen to afford 4-(1S)-isobutanoyloxyisobutoxycar US 2009/0192325 A1 Jul. 30, 2009

bonylamino-(3R)-(4-chlorophenyl)-butanoic acid; and (iii) (CDC1, 400 MHz): & 1.65 (d. J=5.6 Hz, 3H), 2.35 (s, 3H), correlation with the product formed in Example 18 of Gallop 7.20 (q, J=5.6 Hz, 1H), 7.45 (m, 2H), 7.58 (m, 1H), 8.06 (m, et al., U.S. Pat. No. 7,227,028. 'H NMR (CDC1,400 MHz): 2H) ppm. 80.96 (d. J=6.8 Hz, 6H), 1.16 (d.J=6.8 Hz,3H), 1.17 (d. J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), 2.32 (s, 3H), 2.56 (hept, J–7.2 Step B: (1R)-Benzoyloxyethoxycarbonyloxy} HZ, 1H), 6.67 (d. J=5.6 Hz, 1H). "H NMR with chiral solvat Succinimide (21b) ing agent, (R)-(-)-2.2.2-trifluoro-1-(9-anthryl)ethanol: Ö 0191 The title compound (21b) was prepared from com 0.98 (d. J=6.8 Hz, 3H), 0.99 (d. J=6.8 Hz, 3H), 1.19 (d. J=7.2 pound (5) by following the method disclosed in Example 10 HZ, 1.5H), 1.19 (d. J=6.8 Hz, 1.5H), 1.20 (d. J=6.8 Hz, 1.5H), of Gallop et al., U.S. Pat. No. 7,227,028. 'H NMR (CDC1, 1.20 (d. J=7.2 Hz, 1.5H), 2.01-2.09 (m, 1H), 2.34 (s, 1.5H), 400 MHz): & 1.75 (d. J=5.6 Hz, 3H), 2.82 (s, 4H), 7.07 (q, 2.444 (s, 1.5H), 2.591 (hept, J=7.2 Hz, 0.5H), 2.59 (hept, J=5.4 Hz, 1H), 7.45 (m,2H), 7.59 (m, 1H),8.05 (m, 2H) ppm. J=6.8 Hz, 0.5H), 6.70 (d. J=5.6 Hz, 0.5H), 6.70 (d. J=5.2 Hz, Step C; (3S)-(1R)-Benzoyloxyethoxycarbony 0.5H). laminomethyl-5-methyl-hexanoic Acid (21) Step B: {(1S)-Isobutanoyloxyisobutoxycarbony 0.192 Compound (21b) (25.5g, 83.1 mmol) and pregaba loxy} Succinimide (20b) lin (13.6 g. 85.4 mmol) were stirred in a mixture of acetoni trile and water (100 mL, 4:1) for 16 hat room temperature, 0188 The title compound (20b) was prepared from com and then the acetonitrile was removed in vacuo. The residue pound (12) by following the method disclosed in Example 10 was partitioned between MTBE and water, the MTBE layer washed repeatedly with water then brine, and then dried over of Gallop et al., U.S. Pat. No. 7,227,028. anhydrous sodium sulfate (NaSO). Removing the solvent in vacuo afforded the title compound (21) as a colorless oil Step C; (3S)-(1S)-Isobutanoyloxyisobutoxycarbo (29.09 g, 100% yield). "H NMR (CDC1,400MHz): 80.88 (t, nylaminomethyl-5-methyl-hexanoic Acid (20) J=6.8 Hz, 6H), 1.17 (m, 2H), 1.60 (d. J=5.2 Hz, 3H), 1.64 (m, 1H), 2.17 (m. 1H), 2.27 (dd, J=7.6, 15.2 Hz, 1H), 2.35 (dd. 0189 Compound (20b)(10.21 g, 33.9 mmol) and pregaba J=15.2, 5.6 Hz, 1H), 3.11 (m. 1H), 3.28 (m, 1H), 5.06 (br, t, lin (5.5g, 34.6 mmol) were stirred in a mixture of acetonitrile J=6.4 Hz, 0.83H), 5.97 (br, t, J=6.4 Hz, 0.13H), 7.03 (m. 1H), and water (60 mL, 4:1) for 6 hat room temperature, and then 7.41 (m, 2H), 7.54 (m, 1H), 8.03 (m, 2H) ppm. the acetonitrile was removed in vacuo. The residue was par titioned between MTBE and water, the MTBE layer washed Example 22 repeatedly with water then brine, and dried over anhydrous (3R)-4-(1S)-2-Methyl-1-(2-methylpropanoyloxy) Sodium Sulfate (Na2SO4). Removing the solvent in vacuo propoxycarbonylamino-3-(4-chlorophenyl)bu afforded the title compound (20) as a colorless oil (11.65 g, tanoic Acid (22) 100% yield). H NMR (CDC1, 400 MHz): 8 0.90 (t, J=6.8 0193 The title compound (22) may be synthesized by Hz, 6H), 0.97 (J=6.8 Hz, 6H), 1.18 (d. J=6.8 Hz,3H), 1.18 (d. adapting the procedures described in Example 17. J–7.2 Hz, 3H), 1.19 (m, 2H), 1.67 (hept, J=6.8 Hz, 1H), 2.03 (m. 1H), 2.12 (m, 1H), 2.07 (m, 2H), 2.56 (hept, J–7.2 Hz, Step A: (1S)-1-Methylthiocarbonyloxyethyl-2-meth 1H), 3.17 (m. 1H), 3.29 (m, 1H), 4.95 (brit, J=6.0 Hz, 0.83H), ylpropanoate (12) 5.74 (br. t, J=6.0 Hz, 0.17H), 6.55 (d. J=5.2 Hz, 0.83H), 6.61 (brid, J=4.4 Hz, 0.17H). 0.194 Example 21 Candida antarctica lipase A (3S)-(1R)-Benzoyloxyethoxycarbonylaminom Her ethyl-5-methyl-hexanoic Acid (21) Phosphate buffer Step A: (1R)-1-Methylthiocarbonyloxyethyl Ben CC Zoate (5) (2b) O (0190. 1-Methylthiocarbonyloxyethyl benzoate (2g) (50 Y1 g), prepared as described in Gallop et al., U.S. Pat. No. 7,227, O - O - S - 028, and lipase from Candida rugosa (2.5 g) were stirred in phosphate buffered saline, pH 7.2, (0.5 L) at room tempera ture. The progress of the reaction was monitored by H-NMR (12) using the chiral Solvating agent (R)-(+)-2.2.2-trifluoro-1-(9- anthryl)ethanol and was complete within 16 h. The reaction 0.195 A 20-L, multi-necked, cylindrical reactor, fitted mixture was diluted with ether and the ether layer separated with a mechanical stirrer, a nitrogen inlet and an outlet con and filtered through a pad of Celite(R) to remove the enzyme. nected to an oxidation bath, and a bleach bath (14% NaOCl) The ether phase was washed repeatedly with aqueous sodium to oxidize liberated methanethiol and acetaldehyde is charged bicarbonate then brine, and dried over anhydrous sodium with racemic 2-methyl-1-methylthiocarbonyloxypropyl sulfate (NaSO). Removing the solvent in vacuo afforded 22 2-methylpropanoate (2b) (5.32 kg, 25.8 mol) and 0.8 Mphos g of the title compound (5) as a single enantiomer. "H NMR phate buffer (10 L, pH 7.0). Solid supported Candida antarc US 2009/0192325 A1 Jul. 30, 2009 20 ticalipase A (125 g, Novozyme 735, Novozyme: Chirazyme Step C; (3R)-4-(1S)-2-Methyl-1-(2-methylpro L-5, Roche Diagnostics; or other suppliers) is slowly added panoyloxy)propoxycarbonylamino-3-(4-chlo while stirred. The reaction mixture is stirred at room tempera rophenyl)butanoic Acid (22) ture (22-24°C.) for ca. 18 hours. (0200 0196. The reaction mixture is diluted with methyl tert butyl ether (MTBE) or alternatively dichloromethane (DCM) (8 L) and the organic phase separated. The organic phase is washed with phosphate buffer (0.57 M, 2x5 L), water (10 L) and brine (7 L). The solid supported enzyme is removed by filtration and the organic phase is dried over Sodium Sulfate (NaSO), filtered, and concentrated by rotary evaporation to afford the title compound (12). (20b) Step B: {(1S)-Isobutanoyloxyisobutoxycarbony HN COOH MBE/Water loxy} Succinimide (20b) He 0197)

C o Y1 o O s ls CH3COOOH/CH3COOH 1No s1 NHS, DCM --~~. DC H

(12)

C N-1 O O E O (22) us N 1No o1 0201 A 20-L pilot plant equipped with a mechanical stir O rer and a nitrogen inlet was charged with NHS-carbonate, (20b) 1-S-III (isobutyryloxy)isobutyroxycarbonyloxy-2,5-pyr rolidinedione (20b), 1.31 kg, 4.7 mol) and (R)-baclofen (431 g; overall 1.2 eq. of R-baclofen) in a mixture of methyl tert-butyl ether (MTBE) and water (3:1; 10 L). The resulting Suspension is stirred for 24 hours at room temperature. 0198 In a 20-L jacketed reaction vessel equipped with a 0202 The reaction mixture is then diluted with water (3 mechanical stirrer, an internal thermometer and a nitrogen L). The organic phase is separated and washed with water inlet is added (1S)-1-methylthiocarbonyloxyethyl-2-methyl (3x3 L), aqueous sulfuric acid (5%, 4 L), and water (4 L). The propanoate (12) (1.442 kg, 7 mol), and N-hydroxysuccinim organic phase is dried over Sodium Sulfate (Na2SO4) and ide (1.610 kg, 14 mol) in dichloromethane (DCM) (8 L). The volatiles are removed under vacuum to provide the title com resulting Suspension is cooled to 9°C. A Solution of peracetic pound (22). acid in acetic acid (32%, 4.98 kg, 4.4 L 21 mol) is slowly 0203 Finally, it should be noted that there are alternative added while maintaining the reaction temperature between 9 ways of implementing the embodiments disclosed herein. C. and 15°C. The reaction mixture is then stirred at 9°C. for Accordingly, the present embodiments are to be considered as 23 hours. illustrative and not restrictive. Furthermore, the claims are not (0199 The reaction mixture is then diluted with water (3 L) to be limited to the details given herein, and are entitled their and the organic phase is separated. The organic phase is full scope and equivalents thereof. washed with water (2x2 L), Saturated potassium bicarbonate What is claimed is: solution (4 L) and a solution of sodium thiosulfate (350 g in 1. A methodofenantiomerically enriching an enantiomeric water 4 L). The organic phase is dried over Sodium Sulfate mixture of a compound of Formula (I), comprising: (NaSO4) and Volatiles are removed under vacuum, resulting in the crude product as a white-solid. To this solid is added 2-propanol (3 L) and hexane (3 L). The resulting slurry is (I) warmed to 30° C. for 30 minutes. The resulting slurry is O R2 O cooled for two hours using an ice-bath. The product is col lected by filtration. The filter cake is washed with hexane (4 R1 - O - O - s1- L) and dried under vacuum to provide the title compound (20b). US 2009/0192325 A1 Jul. 30, 2009 21

reacting the enantiomeric mixture with an enzyme to pro vide an enantiomerically enriched mixture having at least 90% enantiomeric excess of one enantiomer of the O (II) compound of Formula (I), wherein: O R2 O R" is chosen from C, alkyl, C. cycloalkyl, phenyl, Substituted phenyl, and C. phenylalkyl; R1 ul-iO O ulo1 R is chosen from C, alkyl, C. cycloalkyl, phenyl, O. Substituted phenyl, and C. phenylalkyl; and R is chosen from C, alkyl, C. cycloalkyl, phenyl, 13. The method of claim 12, comprising reacting the enan Substituted phenyl, and C7 phenylalkyl. tiomerically enriched mixture of a compound of Formula (II) 2. The method of claim 1, wherein the enantiomerically with a drug comprising a primary or secondary amine group enriched mixture has an enantiomeric excess of the Risomer to provide a compound of Formula (III): and the enzyme is a lipase chosen from Candida rugosa, Candida cylindracea, and Candida antarcticalipase B. (III) 3. The method of claim 1, wherein the enantiomerically O R2 O enriched mixture has an enantiomeric excess of the S isomer and the enzyme is a lipase chosen from porcine liver esterase, RI - O - O - N1-D Candida antarcticalipase A, and Candida antarcticalipase B. 4. The method of claim 1, wherein the enzyme is Candida 14. The method of claim 13, wherein the drug is chosen antarctica lipase B, R' is isopropyl, R is methyl, R is from R-baclofen and pregabalin. methyl, and the enantiomerically enriched mixture has an 15. The method of claim 13, wherein the drug is R-ba enantiomeric excess of the Renantiomer of the compound of clofen, R is isopropyl, R is isopropyl, R is methyl, the Formula (I). enzyme is Candida antarcticalipase A, and the compound of 5. The method of claim 1, wherein the enzyme is Candida Formula (III) is (3R)-4-(1S)-2-methyl-1-(2-methylpro antarctica lipase A, R' is isopropyl, R is isopropyl, R is panoyloxy)propoxycarbonylamino-3-(4-chlorophenyl)bu methyl, and the enantiomerically enriched mixture has an tanoic acid: enantiomeric excess of the Senantiomer of the compound of Formula (I). 6. The method of claim 1, wherein R' is chosen from methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu tyl, tert-butyl, n-pentyl, isopentyl, Sec-pentyl, neopentyl, 1.1- O. diethoxyethyl, phenyl, and cyclohexyl. N r(R) 7. The method of claim 1, wherein R is chosen from OH methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, Sec-bu tyl, phenyl, and cyclohexyl. 8. The method of claim 1, wherein R is methyl. 9. The method of claim 1, wherein: C R" is chosen from methyl, isopropyl. n-propyl, and phenyl: R is chosen from methyl, isopropyl, and n-propyl; and 16. The method of claim 13, wherein the drug is S-pregaba R is methyl. lin, R is isopropyl, R is methyl, R is methyl, the enzyme is Candida antarcticalipase B, and the compound of Formula 10. The method of claim 1, wherein each substituent is (III) is 3-({(1R)-1-(2-methylpropanoyloxy)ethoxy independently chosen from halogen, —OH, -CN. —CF, carbonylaminomethyl)(3S)-5-methylhexanoic acid: =O, NO, Calkoxy, C-alkyl, -COOR' wherein R' is chosen from hydrogen and Cls alkyl, and —N(R'). wherein each R" is independently chosen from hydrogen and O O Calkyl. 11. An enantiomerically enriched mixture of a compound ls (S) O. of Formula (I), prepared by the method of claim 1. O1 (R) O H r 12. The method of claim 1, comprising reacting the enan OH tiomerically enriched mixture having at least 90% enantio meric excess of one enantiomer of the compound of Formula s (I) with N-hydroxysuccinimide to provide the corresponding enantiomerically enriched mixture of an NHS-acyloxyalkyl carbonate compound of Formula (II):