(12) Patent Application Publication (10) Pub. No.: US 2003/0225149 A1 Blazecka Et Al

US 2003O2251.49A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0225149 A1 Blazecka et al. (43) Pub. Date: Dec. 4, 2003

(54) PROCESS FOR PREPARING HIGHLY (52) U.S. Cl...... 514,400; 514/419; 514/561; FUNCTIONALIZED 514/567; 548/339.1; 548/495; GAMMA-BUTYROLACTAMS AND 562/443; 562/553 GAMMA-AMINO ACDS (57) ABSTRACT (76) Inventors: Peter G. Blazecka, Windsor (CA); The invention relates to a process for preparing highly James Guy Davidson III, Howell, MI functionalized Y-butyrolactams and Y-amino acids by reduc (US); Ji Zhang, Ann Arbor, MI (US) tive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA ana Correspondence Address: log with desirable medicinal activity. Heidi M. Berwen Warner-Lambert Company 2800 Plymouth Road Ann Arbor, MI 48105 (US) X O

(21) Appl. No.: 10/365,430 O ------(22) Filed: Feb. 13, 2003 X Related U.S. Application Data Michi.d (60) Provisional application No. 60/376.991, filed on Apr. X = Br, Cl O 30, 2002. Publication Classification Me OH (51) Int. Cl.' ...... A61K 31/4172; A61K 31/405; Me NH2 A61K 31/198; CO7C 229/06; Pregabalin CO7C 229/38; CO7D 233/66; CO7D 209/18 US 2003/0225149 A1 Dec. 4, 2003

PROCESS FOR PREPARING HIGHLY SUMMARY OF THE INVENTION FUNCTIONALIZED GAMMA-BUTYROLACTAMS AND GAMMA-AMINO ACIDS 0006 These and other needs are met by the present invention which provides a process for preparing a com CROSS REFERENCE TO RELATED pound of formula I APPLICATIONS 0001. This application claims benefit of priority from U.S. Provisional Application No. 60/376,991, filed on Jun. 14, 2002. OH FIELD OF THE INVENTION R2 NHR 0002 The invention relates to a process for preparing highly functionalized Y-butyrolactams and Y-amino acids by reductive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA ana 0007 wherein: log with desirable medicinal activity. 0008 R is H., (C-C)alkyl, (C-C)cycloalkyl, BACKGROUND OF THE INVENTION aryl, (CH2)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH)-heteroaryl, wherein n is 0, 1, 2, 0003 Pregabalin (3-Aminomethyl-5-methyl-hexanoic or 3; and acid) is a 3-substituted Y-aminobutyric acid (GABA) analog that exhibits an array of useful medicinal properties, as 0009 R and R are each independently H, straight disclosed in WO93/23383 and U.S. Pat. No. 6,306,910, both or branched (C-C)alkyl, a straight or branched of which are assigned to the same assignee as the instant (C-C)alkenyl, (C-C)cycloalkyl, alkylcycloalkyl, application. alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or Substituted phenyl, 0010 comprising: 0011 (a) treating mucochloric or mucobromic acid 1 wherein X is C1 or Br with ROH, wherein R" is (C-C)alkyl, -CH2-phenyl, or -CH-Sub Stituted phenyl, in the presence of acid to provide Pregabalin

0004 Synthetic approaches to pregabalin generally com O O X X mence from a linear precursor. For instance, WO 93/23383 ROH O -- O; discloses a route commencing from 5-methyl-hexanoic acid H that requires 8 transformations. A recently disclosed alter X X native Strategy commences with the enantioSelective conju OH OR gate addition of S-C methylbenzyl amine to 2-Methylene 1. 2A succinic acid dimethyl ester (Michael J. Mayer, Trip Report, Synthetic Pathways 9" Symposium on the Latest Trends in Organic Synthesis, Albany Molecular Sciences Technical 0012 (b) conjugate addition of RRCMo. Report Vol. 5, No. 19 (2001), p. 9; also available at http:// wherein R and R2 are as defined above and albmolecular.logical.net/features/tekrepS/vol05/no19/last wherein Mo is MgBr, CuBr, or B(OH), to 2A, to visited Feb. 6, 2003). The reaction provides a mixture of provide 3A diastereomers, which can be separated, and the requSite diastereomer is then converted to pregabalin via 6 additional O O StepS. X X R2RCMo 0005. A shortcoming of either of these approaches, par O --> O; ticularly in Scale-up and production contexts, is that they R2 require a multitude of Steps and purification operations. AS X a result, there is a need for a process for Synthesizing OR i R ORi pregabalin and other 3-Substituted Y amino acids that mini 2A 3A mizes the total number of Synthetic transformations and Simplifies purification StepS. US 2003/0225149 A1 Dec. 4, 2003

0013 (c) hydrogenation of 3A to provide 4A 0018 (b) conjugate addition of

O -e- O; and

OR OR

0014) (d) reductive amination of 4A under hydro genation conditions using ammonium formate or RNH, wherein R is H., (C-C)alkyl, (C- C.)cycloalkyl, aryl, (CH-)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH2)-het eroaryl, wherein n is 0, 1, 2, or 3, followed by 0020 wherein M is B(OH), to 2 to provide 3B, wherein hydrolyisis 66 is absent or is a bond;

O H), RNH2 O HCONH4, Ho R2 Hydrolysis

R2 OR OR Me OR 4A 2 O 3B

0.015 What is also provided is a process for preparing pregabalin

NH2 Pregabalin He- O; and

OR OR 0016 comprising: 3B 4B 0017 (a) treating mucochloric or mucobromic acid 1 wherein X is C1 or Br with ROH, wherein R" is (C-C)alkyl or -CH2-aryl, in the presence of acid, to provide 2 0022 (d) reductive amination of 4B using ammo nium formate, followed by hydrolyisis

O O O X X ROH X O --> O; H Me H), HCO2NH4, O Hydroloysis - Pregabalin. X X Me OH OR 4B US 2003/0225149 A1 Dec. 4, 2003

0023. What is also provided is a process for preparing a 0030) (c) hydrogenation of 3C to provide 4C compound of formula I

NR --> NR1; and OH R2 NHR

0031) (d) hydrolysis of 4C 0024 wherein: 0025 R is H., (C-C)alkyl, (C-C)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH2)-heteroaryl, wherein n is 0, 1, 2, Hydrolysis or 3; and NR --> I. 0026 R and R are each independently H, straight or branched (C-C)alkyl, a straight or branched (C-C)alkenyl, (C-C)cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or Substituted phenyl, 0032) What is also provided is a process for preparing 0027 comprising: pregabalin 0028 (a) reductive amination of mucochloric or mucobromic acid 1 wherein X is Cl or Br, using a reducing agent in the presence of ammonium formate or RNH, wherein R is (C-C)alkyl, (C-C7)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH)-heterocyclo, heteroaryl, or (CH)-het NH2 eroaryl, wherein n is 0, 1, 2, or 3, and an acid Me catralyst, to provide 2C Pregabalin

O O 0033 comprising: X X o - I - NR: 0034 (a) reductive amination of mucochloric or RNH2 1s mucobromic acid 1 wherein X is C1 or Br using a reducing agent in the presence of benzylamine or X X 1-phenyl-ethylamine to provide 2D OH 1. 2C

O O X X H or Me: 0029 (b) conjugate addition of RRCM, H wherein Mo is MgBr, CuBr, or B(OH), to 2C to o - Benzylonline amine or - || N provide 3C X 1-Phenyl-ethylamine X Ph OH 1. 2D

0035 (b) conjugate addition of NR -> NR1; Me r Me US 2003/0225149 A1 Dec. 4, 2003

0036) wherein M is MgBr, CuBr, or 0039) ; and 0040 (d) hydrolysis of 4D

Hydrolysis Me Yr. --> Pregabalin. Me

0037 wherein M is B(OH), to 2 to provide 3B, wherein 0041 What is also provided is a process for reductively ss is absent or is a bond; aminating mucohalic acid, comprising: 0042 (a) contacting mucochloric or mucobromic acid 1 wherein X is Cl or Br with a reducing agent, an acid catalyst, and RNH2, wherein R is H, (C-C)alkyl, (C-C)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH-)-heteroaryl, wherein n is 0, 1, 2, or 3; to provide 2E

O O X X

R3NH2. 3. X X OH 1. 2E

DETAILED DESCRIPTION OF THE INVENTION 0043. The invention processes for preparing 3-substituted Yaminobutyric acids disclosed herein possess a number of advantages. Firstly, they give rise to 3-Substituted Y-amino butyric acids in a minimum number of Steps and under mild 3D conditions. Secondly, they make use of generally inexpen Sive and readily available reagents. Thirdly, they exploit the Synthetic potential of mucohalic acid. 0044) Mucochloric acid 1 (2,3-dichloro-4-oxo-2- butenoic acid) and mucobromic acid (2,3-dibromo-4-oxo-2- butenoic acid) are commercially available and inexpensive 0038 (c) hydrogenation of 3D to provide 4D Starting materials. Both molecules are characterized by the presence of a carbon-carbon double bond with Z configu ration, two halogen atoms, and two carbonyl groups. This high degree of functionality makes both mucochloric and mucobromic acid particularly useful building blocks for the Synthesis of a variety of biologically active heterocycles, Such as Substituted 1,5-dihydropyrrol-2-ones, pyrrolidines, and Y-lactams, and Y-amino acids Such as pregabalin.

O O Cl Br

O O

Cl Br OH OH Mucochloric Acid Mucobromic Acid US 2003/0225149 A1 Dec. 4, 2003

0.045. Mucobromic and mucochloric acid surprisingly have not been commonly employed in organic Synthesis as -continued C-4 building blocks. Presumably, this is because of the many O O reactive sites in the molecules, their poor Stability under basic conditions, and the perception among those of ordi Step E OH nary skill in the art of the difficulties associated with the NR --- Selective manipulation of the halogen atoms in the presence R2 R NHR of the other functional groups. R2' R2 0046. In spite of these perceived difficulties, mucohalic acid is the keystone of the invention processes disclosed 5A I herein. AS Summarized in Scheme 1, the processes differ in the relative Sequence of the reaction Steps, but both rely on the use of mucohalic acid as a Synthetic platform for the elaboration of the 3-substituted Yaminobutyric acid frame 0047 Pregabalin is readily prepared by either of these work. Thus, in Route A, protection of mucohalic acid in Step routes. AS depicted in Scheme 2, Route A, mucohalic acid is A provides the hemiacetal 2B. In Step B, Conjugate addition first converted to the O-benzyl acetal 2B. Organocuprate of RRM to 2B, followed by elimination of halide, pro addition provides the conjugate addition product 3B. Hydro vides conjugate addition product 3B. Reductive amination genation and dehalogentation gives rise to 4B. Reductive of 3B in Step C provides lactam 4B, which may undergoes amination under hydrogenation conditions gives rise to hydrolysis in Situ or in a separate Step to provide 3-Substi lactam 5B, which may be hydrolyzed under basic conditions tuted Y amino butyric acid I. In contrast, in Route A, to provide pregabalin. Alternatively, as depicted in Route A reductive amination is the first Step in the Synthetic Sequence of Scheme 2, reductive amination of mucohalic acid in the (Step A), followed by conjugate addition (Step B), hydro first step using benzyl amine (shown) or 1-phenylethyl genation (Step C), and hydrolysis (Step D"). amine provides 2D. Conjugate addition, hydrogenation, and hydrolysis as described for Route A, provides pregabalin.

Scheme 1 Scheme 2 Route A Route A Route A Route A O O O O O O X X X Step A Step A' X X X O is - O --> NR Step A Step A O -a- O --> NCHPh X X X X X X OR OH 2A 1. 2C OCH2Ph OH 2B 1. 2D s B ser B O O s B se B O O X X X X O NR1 Me Me R2 R2 O NCHPh

Me Me R2' OR R2' OCHPh 3A 3C 3B 3D s C s Cl ser C se Cl O O O O

O NR1 Me Me R2 R2 O NCHPh Me Me R OR R OR 4A 4C 4B 4D s D Step D' Step D se D' US 2003/0225149 A1 Dec. 4, 2003

is attached to oxygen. Alkoxy includes, for example, meth -continued oxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Sec-butoxy, O O isobutoxy, tert-butoxu, n-pentoxy, n-heXOXy, n-heptoxy, and the like. Me Step E Me OH --- 0055. The term “alkylcycloalkyl” means a straight or NH2 branched hydrocarbon radical having from 1 to 8 carbon Me Me atoms as defined above attached to cycloalkyl group as 5B I defined above. 0056. The term “alkylalkoxy’, means a straight or 0048 1. Definitions branched hydrocarbon radical having from 1 to 8 carbon 0049. The following definitions are used, unless other atoms as defined above attached to an alkoxy group as wise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, defined above. alkoxy, alkenyl, alkynyl, etc. denote both Straight and 0057 The term “alkylphenyl' means a straight or branched groups, but reference to an individual radical Such branched hydrocarbon radical having from 1 to 8 carbon as “propyl” embraces only the Straight chain radical, a atoms as defined above attached to a phenyl or Substituted branched chain isomer Such as "isopropyl being Specifi phenyl group. cally referred to. 0058. The term “alkyphenoxy' means a straight or 0050 Thus the term “alkyl” means a straight or branched branched hydrocarbon radical having from 1 to 8 carbon hydrocarbon radical having from 1 to 8 carbon atoms and atoms as defined above attached to a phenoxy or Substituted includes, for example, methyl, ethyl, n-propyl, isopropyl, grOup. n-butyl, Sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. 0059. The compounds prepared by the invention process 0051. The term “alkenyl' means a straight or branched may have one or more chiral centers and may exist in and be hydrocarbon radical having from 2 to 7 carbon atoms and used or isolated in optically active and racemic forms. It is includes, for instance, Vinyl, allyl, 1-propenyl, 2-propenyl, to be understood that the processes of the present invention 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, can give rise to any racemic or optically-active forms, or 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2- mixtures thereof. It is to be further understood the products butenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hex of the invention process can be isolated as racemic, enan enyl, 4-hexenyl, 5-hexenyl, 4-methyl-3-pentenyl, 1-hepte tiomeric, or diastereomeric forms, or mixtures thereof. Puri nyl, 2 heptenyl, 3 heptenyl, 2-methyl-1-hexenyl, 2-methyl fication and characterization procedures for Such products 2-hexenyl, 3-methyl-2-hexenyl, 3-methyl-3-hexenyl, are known to those of ordinary skill in the art, and include 3-methyl-1-hexenyl, 4-methyl-1-hexenyl, 5-methyl-1-hex recrystallization techniques, as well as chiral chromato enyl, graphic Separation procedures as well as other methods. 0.052 The term “cycloalkyl” means a hydrocarbon ring 0060 2. 3-Substituted y Amino Butyric Acid Synthesis containing from 3 to 7 carbon atoms, for example, cyclo Via 5-Alkoxy-3,4-dihalo-5H-furan-2-ones (Route A) propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 0061. In Scheme 1, Step A of Route A, mucobromic or cycloctyl, decalinyl, norpinanyl, and adamantyl. Where poS mucochloric acid is converted to the corresponding Sible, the cycloalkyl group may contain double bonds, for 5-alkoxy-3,4-dihalo-5H-furan-2-one 2A upon treatment example, 3-cyclohexen-1-yl. The cycloalkyl ring may be with a C-C alcohol or benzyl or substituted benzyl alcohol unsubstituted or substituted by one or more substituents in the presence of acid. In a typical procedure, a toluene Selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, Solution of 1 equivalent of mucohalic acid is combined with halogen, amino, alkyl and dialkylamino, formyl, carboxyl, 1.5 equivalents of benzylacohol and 0.05 equivalent of CN, -NH-CO-R, -CO-NHR, -COR, -COR, p-toluene Sulfonic acid. The mixture is then heated at reflux wherein R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or for 8 to 24 hours. The product furanone is typically obtained heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined in high yield (85-90 percent). herein. 0062. In Step B of Route A, conjugate addition of an 0053. The term “aryl' means a cyclic or polycyclic organocuprate reagent RRCM to 2A, followed by halide aromatic ring having from 5 to 12 carbon atoms, and being elimination, provides the Substituted furanone 3A. In a unsubstituted or Substituted with one or more of the Sub typical procedure, the organocuprate is generated in Situ in Stituent groups recited above for alkyl, alkenyl, and alkynyl the presence of N-methypyrrolidinone (NMP) from a com groups. Examples of aryl groups include phenyl, 2,6-dichlo mercially available Grignard reagent (e.g., an alkyl-aryl-, or rophenyl, 3-methoxyphenyl, naphthyl, 4-thionaphthyl, alkylmagnesium bromide) and copperiodide. If the requisite tetralinyl, anthracinyl, phenanthrenyl, benzonaphthenyl, Grignard reagent is not commercially available, it can be fluorenyl, 2-acetamidofluoren-9-yl, and 4'-bromobiphenyl. readily preparide from the corresponding organohalide com 0.054 The term “alkoxy' means a straight or branched pound using one of the many methods available to the hydrocarbon radical which has from 1 to 8 carbon atoms and skilled artisan. The furanone is then added to the organo US 2003/0225149 A1 Dec. 4, 2003 cuprate reagent over 5 to 10 minutes at -10 to 0°C., and the and temperatures between 60 and 120° C. resulting mixture is allowed to warm to room temperature.

0.063. In Step C of Route A, hydrogenation of alkylfura Scheme 3 none 3A according to a method readily available to the O skilled artisan provides dihydrofuranone 4A. In a typical O procedure, the furanone is dissolved in THF, and combined X R" X -R it with a tertiary amine base Such as triethyl amine, and Pd/C. V HOAC N O NHNH s This mixture is hydrogenated in a high pressure reactor until 2N hydrogen uptake ceases. X X 0064. In Step D of Route A, reductive amination of OH dihydrofuranone 4A with ammonium formate or RNH gives rise to lactam 5A, which may be hydrolyzed in Situ or 0071 Other than this reported transformation, however, a isolated and converted to the 3-substituted Y amino butyric manifold for the selective manipulation of the functional acid I in a separate Step. In a typical procedure, dihydro groups present in mucohalic acid is unknown. furanone 4A is combined in methanol with ammonium formate, triethyl amine, and Pd/C. This mixture is hydroge 0072) i. Reagents nated in a high pressure reactor until hydrogen uptake ceases to give rise to a mixture of the lactoam 5A and the desired 0073. The reductive amination process described herein ring-opened material I. Submission of the mixture to accommodates a wide variety of reagents and conditions. hydrolysis conditions known to the skilled artisan (for 0074. Mucohalic Acid: To begin, either mucobromic or example, treatment with aqueous base), as depicted in Step mucochloric acid are Suitable for use in the reductive E, gives rise to I. amination process. 0065 Route A is readily adapted to the synthesis of 0075 Amine: Also, a wide variety of amines may be used pregabalin. Step A remains the Same. Step B requires the use in the reductive amination process, and are represented by of Sec-butyl magnesium bromide to generate the necessary the formula RNH, wherein R is selected from hydrogen or organocuprate. Alternatively, the Sidechain can be attached C-C, alkyl or Substituted C-C, alkyl, C-C cycloalkyl or in a Suzuki-type coupling procedure using Substituted C-C cycloalkyl, C-C heterocycloalkyl or Substituted C-C heterocycloalkyl, aryl or Substituted aryl, Me or heteroaryl or substituted heteroaryl. Y^n, 0076. The primary or secondary alkyl, cycloalkyl, het Me erocycloalkyl, aryl, or heteroaryl amine used in the inven tion can be Substituted with one or more groups Selected from halo, hydroxy, C-C alkoxy, carboxy, C-C alkoxy 0.066 and a palladium catalyst. Steps C, D, and E remain carbonyl, aminocarbonyl, halomethyl, dihalomethyl, triha the same. lomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl, 0067 3.3-Substituted y Amino Butyric Acid Synthesis pentahaloethyl, thiol, (C-C)alkylsulfanyl, (C- Via 3,4-Dihalo-1-Substitued-1,5-dihydro-pyrrol-2-ones C.)alkylsulfinyl, and aminosulfonyl, Examples of Substi (Route A) tuted alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, tribromomethyl, hydroxymethyl, 3-methox 0068. The first step in Route A of Scheme 1 for the ypropyl, 3-carboxypentyl, 3,5-dibromo-6-aminocarbonylde Synthesis of 3-Substituted Y amino butyric acid requires cyl, and 4-ethylsulfinyloctyl. Examples of substituted alk reductive amination of mucohalic acid to provide compound enyl groups include 2-bromoethenyl, 1-amino-2-propen-1- 2C. yl, 3-hydroxypent-2-en-1-yl, 4-methoxycarbonyl-hex-2-en 0069. A. Route A/Step A: Reductive Amination of 1-yl, and 2-nitro-3-bromo-4-iodo-oct-5-en-1-yl. Typical Mucohalic Acid Substituted alkynyl groups include 2-hydroxyethynyl, 3-dimethylamino-heX-5-yn-1-yl, and 2-cyano-hept-3-yn-1- 0070 AS indicated previously, mucobromic and muco yl. chloric acid are not popular C-4 building blocks because of the many reactive Sites in the molecules, their poor Stability 0077. The amine used in the reductive amination process under basic conditions, and the perception among those of may be an amino acid or its corresponding ester. Typical ordinary skill in the art of the difficulties associated with the amino acids include L-lysine, L-alanine, L-arginine L-as Selective manipulation of the halogen atoms in the presence partic acid, N-alpha-benzyloxycarbonyl-L-arginine, L-cit of the other functionality. As an example, although it is rulline, gamma-L-glutamic acid, L-glycine, L-histidine, known that in the presence of acetic acid, mucobromic or L-hydroxproline, L-isoleucine, L-leucine, L-lysine, L-me mucochloric acid may react with hydrazine or arylhydra thionine, L-ornithine, L-phenylalanine, L-proline, L-pyro Zines to form pyridaZinones (Scheme 3), the reaction con glutamic acid, L-serine, L-tryptophan, L-tyrosine, L-Valine. ditions are Severe: acetic acid as the Solvent, a pH of 1 to 2, The amine may also be a carboxy terminal-linked peptide US 2003/0225149 A1 Dec. 4, 2003

having 1 to 10 amino acids or an addition Salt thereof. Such 0084. The molar equivalents of each of the reaction peptides may include L-arginyl-L-arginine, N-benzyloxy components (i.e., mucohalic acid, amine, reducing agent, carbonyl-glycyl-L-proline, L-glutaryl-glycyl-arginine, gly and acid catalyst) used in the reductive amination process of cyl-glycine, glycyl-L-phenylalanine, glycyl-L-proline, and the instant application are: L-seryl-L-tyrosine, as well as others. 0085 (a) 1 equivalent of mucohalic acid; 0078. The amine used in the reductive amination process 0086) (b) 1 to 5 equivalents of amine; of the present invention may have one or more chiral centers and may exist in and be used or isolated in optically active 0087 (c) 1 to 10 equivalents of reducing agent; and and racemic forms. It is to be understood that the process of 0088 (d) sufficient acid catalyst to maintain a pH of the present invention can employ any racemic, optically about 2 to about 7. active, polymorphic, geometric, or Stereoisomeric form, or 0089 More preferably, the molar equivalents of each of mixtures thereof, of an amine. It is to be further understood the reaction components (i.e., mucohalic acid, amine, reduc the products of the reductive amination process can be ing agent, and acid catalyst) used in the reductive amination isolated as racemic, optically-active, polymorphic, geomet process if the instant application are: ric, or Stereoisomeric forms, or mixtures thereof. Purifica tion and characterization procedures for Such products are 0090 (a) 1 equivalent of mucohalic acid; known to those of ordinary skill in the art, and include 0.091 (b) 1 to 3 equivalents of amine; recrystallization techniques, as well as chiral chromato graphic Separation procedures as well as other methods. 0092 (c) 1 to 5 equivalents of reducing agent; and 0093 (d) sufficient acid catalyst to maintain a pH of 0079. However, typically, benzyl amine or S-1-phenyl about 3 to about 6. ethyl amine is used. 0094) Most preferably, the molar equivalents of each of 0080 Reducing Agent: A number of reducing agents can the reaction components (i.e., mucohalic acid, amine, reduc be used in the reductive amination process of the present ing agent, and acid catalyst) used in the reductive amination invention. These reducing agents include Sodium triacetoxy process if the instant application are: borohydride, Sodium cyanoborohydride, triethyl silane, Ti(OiPr)/NaBHCN, borohydride exchange resin, Zn/ace 0.095 (a) 1 equivalent of mucohalic acid; tic acid, Sodium borohydride/magnesium perchlorate, or 0096 (b) 1 to 2 equivalents of amine; Zinc borohydride/zinc chloride. Preferably, the reducing agent is Sodium triacetoxyborohydride. 0097 (c) 1 to 3 equivalents of reducing agent; and 0098 (d) sufficient acid catalyst to maintain a pH of 0081. Acid Catalyst: A variety of acid catalysts can be about 4 to about 5. used in the reductive amination process of the present invention. The acid may be a Bronsted, or protic, acid, or a 0099. In the reductive amination process of the present Lewis, or non-protic, acid. Examples of protic acids Suitable invention, the initial concentration of mucohalic acid in the for use in the reductive amination process of the present polar aprotic solvent is typically 0.1 to 0.5M. More pref invention include acetic acid, trichloroacetic acid, trifluoro erably, it is 0.15 to 0.45 M. Most preferably, it is 0.2 to 0.3 acetic acid, or formic acid. Examples of non-protic acids M. Suitable for use in the reductive amination process of the 0100. In the reductive amination process of the present instant application include magnesium chloride, magnesium invention, the temperature is typically from about -25 C. to triflate, boron trifluoride etherate, AlCls, FeCl, ZnCl, about 50 C., with lower temperatures being more suitable AlBr, ZnBr, TiCl, SiCl, and SnCl for mucobromic acid and higher temperatures being more 0082) ii. Procedure and Stochiometry Suitable for mucochloric acid. When mucochloric acid is used, the temperature is more preferably from about about 0. 0.083. In the reductive amination process of the present C. to about 40 C., and most preferably from about 10 C. invention, the mucohalic acid is contacted with the amine, to about 30° C. reducing agent, and acid catalyst. “Contacted” means that the reaction components are typically mixed in a liquid to 0101. In the reductive amination process of the present form a homogeneous or heterogeneous mixture. The liquid invention, reaction times are typically from about 30 min employed in the reductive amination process of the present utes to about 5 days; more preferably, from about 1 hour to invention is Selected from a polar aprotic Solvent. Preferably, 3 days; and most preferably, from about 6 hours to 48 hours. the polar aprotic Solvent is Selected from tetrahydrofuran, 0102) To demonstrate the present invention process, the acetonitrile, nitromethane, chloroform, methylene chloride, reactions of mucobromic or mucochloric acid with aniline or monochloroethane, 1,1, or 1.2 dichloroethane, 1,1,1 or 1,1,2 benzylamine in acetic acid were investigated (Table 4). A tricholoroethane, or 1,1,1,2, or 1,1,2,2 tetrachloroethane. mixture of dichloromethane and acetic acid (1:1 V/v) was More preferred solvents include methylene chloride or chlo chosen as the solvent to maintain the stability and solubility roform. Mixtures of Solvents can also be used. of both starting materials. Sodium triacetoxyborohydride US 2003/0225149 A1 Dec. 4, 2003

was used as the reducing agent and the reactions were conducted at room temperature. Initially Y-lactam 7 was TABLE 4-continued isolated in 46% yield, but a solvent screen illustrated that 7 Reductive amination in different solvents. could be obtained in 65 to 75% yield once the amount of O acetic acid was reduced. Cl

HisNaBH(OAc)3 TABLE 4 O + Solvent Cl Reductive amination in different solvents. 1. OH CH-NH2

6 O O C Cl NaBH(OAc)3 N -e- O + Solvent C Cl 1. 7 OH CH-NH2 6 O entry Solvent Yield (%) C 7 CHNO, 35 8 CHCI 76 'Reaction conditions for entries 1, 2 and 6: 1 equiv of mucochloric acid, C 1.1 equiv. of “aniline, 1.5 equiv of NaBH(OAc), CHCl (cat. HOAc), under N, for 24 h. Reaction conditions for entries 3-5, 7–10: 1 equiv of mucochioric acid, 1.0 equiv. of “aniline, 3.0 equiv of NaBH(OAc), CHCl2:HOAc (5:3 v/v), under N, for 24 h. The reaction time was not optimized. Products were isolated and purified by silica gel chromatogra entry Solvent Yield (%) phy and/or crystallization. Products are estimated to be >95% pure by "H NMR and elemental analysis. All compounds gave satisfactory elemental analysis data. 1. CH.Cl:HOAc 46 (1:1) 0103) The invention process has been further extended to 2 1,4-dioxane 48 anilines, with electron-donating, electron-withdrawing and 3 THF 52 neutral Substituents, as well as an heteroaromatic amine 4 CHCN 49 system (Table 5). Electron-deficient anilines (entries 3, 4 and 5 DCE 68 9) and electron-rich anilines (entries 2, 5 and 7) reacted with 6 CHCI 66 almost equal facility and the heteroaromatic amine (entry 6) also underwent Selective reaction with reasonable yield.

TABLE 5

Reductive amination with different “anilines.

O C NaBH(OAc)3 O + "aniline" - Solvent -- product C OH

Entry “Aniline” Product Yield (%)

1. O 50 C

NH2 C US 2003/0225149 A1 Dec. 4, 2003

TABLE 5-continued

Reductive amination with different “anilines.

O C NaBH(OAc)3 O + "aniline" - Solvent - product C 1. OH

Entry “Aniline” Product Yield (%)

2 MeO OMe O OMe 55 Cl

NH2 Cl OMe

3 Cl O 65 Cl

NH2 Cl C

4 ON O 42 Cl

NH2 Cl NO2

5 HO O 40 Cl

NH2 Cl OH

6 N MeO 55 2N D

NH2 NH2

5 HO O 40 Cl

NH2 Cl OH

6 N Cl O 55 2 N . \ / NH2 Cl US 2003/0225149 A1 Dec. 4, 2003 11

TABLE 5-continued

Reductive amination with different “anilines.

O C NaBH(OAc)3 O + "aniline" - Solvent - product C OH

Entry “Aniline” Product Yield (%)

7 MeO O 60 Cl

Cl NH2 OMe

8 O O 68

N w Cl

NH2

9 NC O 75 Cl

Cl NH2 CN

10 O OH O 2O

N Cl OH

NH2

Reaction conditions for entries 1.2 and 6: 1 equiv of mucochloric acid, 1.1 equiv. of "aniline', 1.5 equiv of NaBH(OAc), CHCl (cat. HOAc), under N, for 24 h. Reaction conditions for entries 3-5, 7–10: 1 equiv of mucochloric acid, 1.0 equiv. of “aniline, 3.0 equiv of NaB H(OAc), CH,Cl:HOAc (5:3 v/v), under N, for 24 h. The reaction time was not optimized. Products were isolated and purified by silica gel chromatography and/or crystallization. Products are estimated to be >95% pure by "H NMR and elemental analysis. All compounds gave satis factory elemental analysis data. US 2003/0225149 A1 Dec. 4, 2003

0104 Mucochloric acid (1) can exist as the open or cyclic form (Scheme 6). However, the ultraviolet spectrum in -continued CHCl, indicates 1 exists predominantly in the lactone form. O O Additional spectral data, i.e. vibrational (IR, Raman) and C C others (NMR and NQR) suggest that the lactone is the OH OH dominant form in both the liquid and Solid States. Experi H H mental results further Support these observations. C H' Cl NaBH(OAc)3 11:

Scheme 6 Equilibria of Mucochloric and Mucobromic Acids.

O O X X OH O O He H C X X OH H OH O ay Ho C 1 X = Cl 1 X = Cl 2 X= Br 2X = Br 1. H

0105 The proposed mechanism for the reductive amina tion proceSS is depicted in Scheme 7. Thus, protonation of the aldehyde pushes the equilibrium in favor of the open form aldehyde. Reductive amination of the aldehyde moiety, O O followed by ring closure and loSS of water, provides the C C cyclic lactam. OH OH -HO H E N C C H H HN Scheme 7. Proposed mechanism of reductive amination.

O O C C H O He- OH, -ss O C C C OH OH N

0106. In accordance with this proposed mechanism, reductive amination with dialkyl amines and N-alkyl anilines provided Substituted C.B-unsaturated Y-amino acids. All the attempts were Successful and all products were isolated in acceptable yield. (Table 8). US 2003/0225149 A1 Dec. 4, 2003

TABLE 8

Reductive amination with different amines.

O Cl NaBH(OAc)3 O -- alle ---Solvent product

Cl 1 OH Entry amine product yield (%)

1. O 67 1N, C N C

2 O 2O

C N OH H

C () 3 O 48

C OH

NHCH C

N 1.

4 89 O C

N R

HN R C

5b O O O 50/82 ls Cl C H ONH NH O

Cl C 8 9

6 O O 8O us C ONH O

C US 2003/0225149 A1 Dec. 4, 2003 14

TABLE 8-continued

Reductive amination with different amines.

O Cl NaBH(OAc)3 O -- alle HerSolvent product

Cl 1 OH Entry amine product yield (%) 7 85 O C

N S OH HN s C HO 'Reaction conditions: 1 equiv of mucochioric acid, 1.1 equiv. of amine, 1.5 equiv of NaBH(OAc), CHCl (cat. HOAc), under N, for 24 h. The reaction time was not opti mized. Products were isolated and purified by silica gel chromatography and/or crystalli zation. Products are estimated to be >95% pure by "H NMR and elemental analysis. All compounds gave satisfactory elemental analysis data. This reaction provides a effective method of obtaining substituted Y-butyrolactones.

0107 Interestingly, attempted reductive aminations with crude material was purified by column chromatography on ammonium formate provided not the expected lactam 8, but silica gel eluting with 55, then 10% ethyl acetate in heptane. instead, lactone 9, in 50% yield. When the reaction was repeated without adding ammonium formate, the yield of 9 0115 1.5-Benzyloxy-3,4-dichloro-5H-furan-2-one. Pre increased to 82%. Also, when ammonium acetate was used, pared as provided in Procedure A. 95% yield. "H NMR the reaction gave lactone 9 in 80% yield. (CDC1, 300 MHz) 87.3 (s, 5H), 5.92 (s, 1H), 4.95 (d. 1H), 0108. In summary, Step A of Scheme 1, Route A rep 4.89 (d. 1H). Elemental Analysis Observed (Theroretical) resents a simple, efficient and Selective method to prepare for CHCIO: C, 51.12(50.99); H, 2.92(3.11); N, N-benzyl-3,4-dichloro-1,5-dihydropyrrol-2-one, N-aryl (or <0.05(0.00); C1, 27.19 (27.37). alkyl)-3,4-dichloro-1,5-dihydropyrrol-2-ones and substi tuted Y-amino acids. These products possess a geometrically 0116 2.5-Benzyloxy-3,4-dibromo-5H-furan-2-one. Pre defined tetrasubstituted olefin, two differentiated vinyl pared as provided in Procedure A. 100% yield. H NMR halides and an acidic Sight, and could be used in the (CDC1, 300 MHz) 87.3 (s, 5H), 5.92 (s, 1H), 4.95 (d. 1H), Synthesis of a variety of compounds. 4.89 (d. 1H). Elemental Analysis Observed(Theroretical) for CHBrO: C, 38.62(37.97); H, 2.30(2.32); N, 0109 B. Route A/Steps B, C, and D <0.05(0.00); Br, 44.71 (45.92). 0110 Steps B, C, and D of Route B are as provided for 0117 Step B: 5-Benzyloxy-3-halo-4-isopropyl-5H-fu Steps B, C, and E of Route A. ran-2-one. 0111. The following examples are intended to illustrate various embodiments of the invention and are not intended 0118. Alternative 1: Via Cuprate Addition to restrict the Scope thereof. 0119 5-Benzyloxy-3,4-dihalo-5H-furan-2-one (0.03-0.15 mol, 1 equivalent), 1-methyl-2-2pyrrolidinone EXAMPLES (NMP) (excess), and copper iodide (1 equivalent) were 0112 Route A, Scheme 2 combined and Stirred at room temperature under an inert atmosphere. After about 30 minutes, the resulting tan Sus 0113 Step A: 5-Benzyloxy-3,4-dihalo-5H-furan-2-one. pension was cooled to about -15 to about -20° C., and 0114 Mucohalic acid (0.4–0.6 mol, 1 equivalent), benzyl isobutylmagnesium bromide (1.5 equivalents) was added alcohol (1.5 equivalents), and para-toluenesulfonic acid dropwise as a 2.0 M solution in diethyl ether. The reaction (0.05 equivalent) were combined in 1000 mL toluene and in mixture was then quenched with a Saturated Solution of an apparatus equipped with a Dean Stark Strap. The mixture aqueous ammonium chloride, and extracted with methyl was heated at reflux until water collection in the Dean Stark tertbutyl ether to provide the crude product as an amber oil. Trap had ceased. The mixture was then cooled to room Purification by column chromatography on Silica gel eluting temperature. The toluene was removed in vacuo at 35-40 C. with 10% ethyl acetate in heptane provided the product as a to leave the crude product as a very pale amber oil. The colorless oil. US 2003/0225149 A1 Dec. 4, 2003

0120) 1. 5-Benzyloxy-3-chloro-4-isopropyl-5H-furan-2- 25 C. for 24 hours. The reaction mixture was them one. 70% yield. MS (AP+) 281.0. quenched with water (200 mL) and washed with water (100 mL). The organic layer was dried over magnesium Sulfate 0121 2. 5-Benzyloxy-3-bromo-4-isopropyl-5H-furan-2- and concentrated in vacuo to give 1.28 g of the product one. 70% yield. MS (AP+)325.0. which was further purified by Silica gel column chro 0122) Alternative 2: Via Suzuki Coupling matograpy to provide the lactam (1.59 g, 66% yield. ). 0123 5-Benzyloxy-3,4-dihalo-5H-furan-2-one (1 0.135 Reductive Amination of Mucochloric Acid with equivalent), boronic acid (2 equivalents, cesium fluoride (R)-1-phenylethylamine. (2.5 equivalents, PdCl(PPh3). (0.05 equivalent), and trieth ylbenzyl ammonium chloride (0.05 equivalent) were com 0.136 Following the procedure as provided above, pro bined. To this mixture was added a nitrogen-purged toluene vided an 89% yield of the product lactam after purification. and water Solvent mixture. The reaction mixture was stirred 0.137 All patents, and patent documents are incorporated at room temperature over night and then quenched with 2N by reference herein, as though individually incorporated by acqueous HCl and extracted with 100 mL toluene. The extract reference. The invention has been described with reference was concentrated in vacuo to provide the crude product as a to various Specific and preferred embodiments and tech pale orange oil which was purified by column chromatog niques. However, it should be understood that many varia raphy on Silica gel eluting with 10% ethyl acetate in heptane. tions and modifications may be made while remaining 0.124 2. 5-Benzyloxy-3-bromo-4-isopropyl-5H-furan-2- within the Spirit and Scope of the invention. one. 30% yield. MS (AP+)325.0. 0.125 Step C: 5-Benzyloxy-4-isopropyl-dihydro-furan-2- What is claimed is: OC 1. A process for preparing a compound of formula I 0126. A mixture of 5-Benzyloxy-3-halo-4-isopropyl-5H furan-2-one (5 mmol, 1 equivalent) and triethyl amine (1.2 equivalents) was dissolved in 65 mL THF. The mixture was transferred to a high pressure reactor. Pd/C (0.3 g) was added, and the mixture was hydrogenated with Stirring under 40 pounds per Square inch (psi) of hydrogen. The mixture OH was hydrogenated until hydrogen uptake ceased (about 3 R2 NHR hours). The Pd/C catalyst was filtered out and the solvent was removed in vacuo. The residue was diluted with ethyl acetate, washed with Saturated aqueous ammonium chloride and dried over magnesium Sulfate. The extract was concen trated in vacuo to give the product as a colorleSS oil. wherein: 0127. 1. From 5-Benzyloxy-3-chloro-4-isopropyl-5H-fu R is H., (C-C)alkyl, (C-C7)cycloalkyl, aryl, (CH2)- ran-2-one. 38% yield. MS (AP+) 249.1. aryl, heterocyclo, (CH)-heterocyclo, heteroaryl, or 0128 2. From 5-Benzyloxy-3-bromo-4-isopropyl-5H-fu (CH2)-heteroaryl, wherein n is 0, 1, 2, or 3; and ran-2-one. 83% yield. MS (AP+) 249.1 R and R are each independently H, Straight or branched 0129. Steps D/E: 3-Aminomethyl-4-methyl-pentanoic (C-C)alkyl, a Straight or branched (C-C)alkenyl, Acid (Pregabalin) (C-C7)cycloalkyl, alkylcycloalkyl, alkylalkoxy, alky lphenyl, alkyphenoxy, phenyl or Substituted phenyl, 0.130) 5-Benzyloxy-4-isopropyl-dihydro-furan-2-one was hydrogenated in a high pressure reactor as provided comprising: above in Step C. Thus, 1.3 g of 5-benzyloxy-4-isopropyl dihydro-furan-2-one was combined with 1.7 g of ammonium (a) treating mucochloric or mucobromic acid 1 wherein formate, 0.3 g of 20% Pd/C, 1.7 g of ammonium formate and X is C1 or Br with ROH, wherein R' is (C-C)alkyl, 0.07 g of Ir(COD)Cl] in 25 mL of methanol. The mixture -CH2-phenyl, or -CH2-substituted phenyl in the was hydrogentated at 70° C. and 20 pounds per Square inch presence of acid to provide 2A of pressure until hydrogen uptake ceased (about 7 hours) to provide a mixture of pregabalin (M+160.1) contaminated with 4-isopropyl-pyrrolidin-2-one (M+142.1). O O X X 0131 The mixture may be submitted to base hydrolysis ROH O --> O; to provide exclusively pregabalin. H 0132) Route A, Scheme 1 X X 0.133 Step A. Reductive Amination of Mucohalic Acid OH OR with Benzylamine. 1. 2A 0134 Sodium triacetoxyborohydride (6.4g, 3.0 equiva lents) was added slowly to a mixture of mucohalic acid (1 (b) conjugate addition of RRCMo wherein R and R equivalent) and benzyl amine (1.1 equivalent) in chloroform are as defined above and wherein Mo is MgBr, CuBr, (50 mL). The reaction mixture was stirred at approximately or B(OH), to 2A, to provide 3A US 2003/0225149 A1 Dec. 4, 2003

6. A process for preparing pregabalin

O O

RRCMo O - He- O; R2 X NH2 OR R2 OR Pregabalin 2A 3A

(c) hydrogenation of 3A to provide 4A comprising: (a) treating mucochloric or mucobromic acid 1 wherein X is C1 or Br with benzyl amine in the presence of O O acid, to provide 2 X H O - - O; and R2 R2 O O X X R2 ORi R2 ORi ROH O --> O; 3A 4A H X X OH OBn (d) reductive amination of 4A under hydrogenation 1. 2 conditions using ammonium formate or RNH2, wherein R is H., (C-C)alkyl, (C-C)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH)-heterocyclo, (b) conjugate addition of heteroaryl, or (CH2)-heteroaryl, wherein n is 0, 1, 2, or 3, followed by hydrolyisis

O H), RNH2 O HCONH4, He R2 Hydrolysis

OR 4A

2. The process of claim 1, step (a) wherein ROH is benzyl alcohol. wherein M is B(OH), to 2 to provide 3B, wherein 3. The process of claim 1, step (b), wherein RRCM is 66 ss is absent or is a bond;

O X

X OBn Me OBn 2 O 3B 4. The process of claim 1, Step (c) using Pd/C as a catalyst Me in the presence of triethyl amine. N- M2 5. The process of claim 1, step (d) wherein the reductive Me amination is effected under hydrogenation conditions using ammonium formate, triethyl amine, and Pd/C. US 2003/0225149 A1 Dec. 4, 2003 17

O O

X X o - I - NR: R1NH2 1s and X X OH 1. 2C OBn OBn 3B 4B

(b) conjugate addition of RRM wherein Mo is MgBr, (d) reductive amination of 4B using ammonium for CuBr, or B(OH), to 2C to provide 3C mate, followed by hydrolyisis O O X X NR All-RoRM NR; R2 H), HCONH4, X He Pregabalin. O Hydroloysis R2 2C 3C

(c) hydrogenation of 3C to provide 4C 7. A process for preparing a compound of formula I O O X H2 NR --> NR1; and R2 R2 OH R2 R2 NHR 3C 4C

(d) hydrolysis of 4C wherein:

R is H., (C-C)alkyl, (C-C7)cycloalkyl, aryl, (CH)- Hydrolysis aryl, heterocyclo, (CH)-heterocyclo, heteroaryl, or NR --> (CH)-heteroaryl, wherein n is 0, 1, 2, or 3; and R and R2 are each independently H, Straight or branched (C-C)alkyl, a straight or branched (C-C)alkenyl, (C-C7)cycloalkyl, alkylcycloalkyl, alkylalkoxy, alky lphenyl, alkyphenoxy, phenyl or Substituted phenyl; 8. The process of step (a) of claim 7, wherein the RNH comprising: is benzylamine or 1-phenylethyl amine. 9. The process of step (a) of claim 7, wherein the reducing (a) reductive amination of mucochloric or mucobromic agent is Selected from Sodium triacetoxy borohydride, acid 1 wherein X is C1 or Br, using a reducing agent sodium cyanoborohydride, triethyl silane, Ti(OiPr)/ in the presence of ammonium formate or RNH, NaBHCN, borohydride exchange resin, Zn/acetic acid, wherein R is (C-C)alkyl, (C-C7)cycloalkyl, aryl, Sodioum borohydride/magnesium perchlorate, or Zinc boro (CH2)-aryl, heterocyclo, (CH2)-heterocyclo, het hydride/zinc chloride. eroaryl, or (CH2)-heteroaryl, wherein n is 0, 1, 2, or 10. The process of step (a) of claim 7, wherein the 3, and an acid catralyst, to provide 2C reducing agent is Sodium triacetoxy borohydride. US 2003/0225149 A1 Dec. 4, 2003

11. The process of step (a) of claim 7, wherein the acid 27. The process of step (b) of claim 7 as provided in claim catalyst is Selected from acetic acid, trichloroacetic acid, 3. trifluoroacetic acid, formic acid, magnesium chloride, mag 28. The process of step (c) of claim 7 as provided in claim nesium triflate, boron trifluoride etherate, AlCls, FeCl, ZnCl, AlBr, ZnBr, TiCl, SiCl, and SnCl. 4. 12. The process of step (a) of claim 7, wherein the acid 29. A process for preparing pregabalin catalyst is acetic acid. 13. The process of step (a) of claim 7, wherein the Stochiometry of the reaction components is: (a) 1 equivalents of mucochloric acid; (b) 1 to 5 equivalents of amine; (c) 1 to 10 equivalents of reducing agent; and NH2 (d) HOAc sufficient to maintain a pH of about 2 to about Pregabalin 7. 14. The process of step (a) of claim 7, wherein the Stochiometry of the reaction components is: comprising: (a) 1 equivalents of mucochloric acid; (b) 1 to 3 equivalents of amine; (a) reductive amination of mucochloric or mucobromic acid 1 wherein X is C1 or Brusing sodium triacetoxy (c) 1 to 5 equivalents of reducing agent; and borohydride in the presence of benzylamine or (d) HOAc sufficient to maintain a pH of about 3 to about 1-phenyl-ethylamine to provide 2D 6. 15. The process of step (a) of claim 7, wherein the Stochiometry of the reaction components is: O O (a) 1 equivalents of mucochloric acid; X X H or Me: H (b) 1 to 2 equivalents of amine; O Benzyl(H) amine or N (c) 1 to 3 equivalents of reducing agent; and X 1-Phenyl-ethylamine X Ph (d) HOAc sufficient to maintain a pH of about 4 to about OH 5. 1. 2D 16. The process of Step (a) of claim 7, wherein contacting comprises mixing in a liquid at a Sufficient concentration and at Sufficient temperatures and for Sufficient times to allow formation of the resulting product. (b) conjugate addition of 17. The process of step (a) of claim 7, wherein the liquid is a polar non protic Solvent and combinations or mixtures thereof. Me Me 18. The process of step (a) of claim 7, wherein the solvent is Selected from tetrahydrofuran, acetonitrile, nitromethane, Sr. O Nes B(OH)2, chloroform, methylene chloride, monochloroethane, 1,1, or Me Me 12 dichloroethane, 1,1,1 or 1,1,2 tricholoroethane, or 1,1, 12, or 1,1,2,2 tetrachloroethane, or combinations or mix tures thereof. 19. The process of step (a) of claim 7, wherein the to provide 3B, wherein “ is absent or is a bond; temperature is from about -25 C. to about 50 C. 20. The process of step (a) of claim 7, wherein the temperature is from about 0° C. to about 40 C. O 21. The process of step (a) of claim 7, wherein the X H or Me temeperature is form about 10 C. to about 30° C. 22. The process of step (a) of claim 7, wherein the N ( Me temperature is from about 12.5 C. to about 27.5 C. X Ph Sr., 23. The process of step (a) of claim 7, wherein the time 2D Me is from about 30 minutes to about 5 days. 24. The process of step (a) of claim 7, wherein the time is from about 1 hour to about 3 days. 25. The process of step (a) of claim 7, wherein the time is from about 6 hours to 48 hours. 26. The process of step (a) of claim 7, wherein the time is from about 12 hours to 36 hours. US 2003/0225149 A1 Dec. 4, 2003 19

(d) base hydrolysis of 4D -continued

Hydrolysis Pregabalin. Me 3D Me 4D

(c) hydrogenationydrog of 3D to pprovide 4D comprising:30. A process for reductively aminating mucohalic acid, (a) contacting mucochloric or mucobromic acid 1 wherein X is Clor Br with sodium triacetoxyborohydride, acetic acid, and RNH, wherein R is H., (C-C)alkyl, (C- C7)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH2)- heterocyclo, heteroaryl, or (CH-)-heteroaryl, wherein n is 0, 1, 2, or 3; to provide 2E

O O X X H O RN. NR X X OH 1. 2E