Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/38—2-Pyrrolones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the invention relates to a process for preparing highly functionalized ⁇ -butyrolactams and ⁇ -amino acids by reductive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA analog with desirable medicinal activity.
• Pregabalin (3-Aminomethyl-5-methyl-hexanoic acid) is a 3-substituted ⁇ -amino butyric acid (GABA) analog that exhibits an array of useful medicinal properties, as disclosed in WO 93/23383 and U.S. Pat. No. 6,306,910, both of which are assigned to the same assignee as the instant application.
• GABA ⁇ -amino butyric acid
• Synthetic approaches to pregabalin generally commence from a linear precursor.
• WO 93/23383 discloses a route commencing from 5-methyl-hexanoic acid that requires 8 transformations.
• a recently disclosed alternative strategy commences with the enantioselective conjugate addition of S- ⁇ methylbenzyl amine to 2-Methylene-succinic acid dimethyl ester (Michael J. Mayer, Trip Report, Synthetic Pathways 9 th Symposium on the Latest Trends in Organic Synthesis, Albany Molecular Sciences Technical Report Vol. 5, No. 19 (2001), p. 9; also available at http://albmolecular.logical.net/features/tekreps/vol05/no19/last visited Feb. 6, 2003).
• the reaction provides a mixture of diastereomers, which can be separated, and the requsite diastereomer is then converted to pregabalin via 6 additional steps.
• R 1 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (CH 2 ) n -aryl, heterocyclo, (CH 2 ) n -heterocyclo, heteroaryl, or (CH 2 ) n -heteroaryl, wherein n is 0, 1, 2, or 3; and
• R 2 and R 2′ are each independently H, straight or branched (C 1 -C 6 )alkyl, a straight or branched (C 2 -C 7 )alkenyl, (C 3 -C 7 )cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or substituted phenyl;
• M 1 is MgBr, CuBr, or
• M 2 is B(OH) 2 , to 2 to provide 3B, wherein “———” is absent or is a bond;
• R 1 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (CH 2 ) n -aryl, heterocyclo, (CH 2 ) n -heterocyclo, heteroaryl, or (CH 2 ) n -heteroaryl, wherein n is 0, 1, 2, or 3; and
• R 2 and R 2′ are each independently H, straight or branched (C 1 -C 6 )alkyl, a straight or branched (C 2 -C 7 )alkenyl, (C 3 -C 7 )cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or substituted phenyl;
• M 1 is MgBr, CuBr, or
• M 2 is B(OH) 2 , to 2 to provide 3B, wherein “———” is absent or is a bond;
• the invention processes for preparing 3-substituted ⁇ amino butyric acids disclosed herein possess a number of advantages. Firstly, they give rise to 3-substituted ⁇ -amino butyric acids in a minimum number of steps and under mild conditions. Secondly, they make use of generally inexpensive and readily available reagents. Thirdly, they exploit the synthetic potential of mucohalic acid.
• 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 starting materials. Both molecules are characterized by the presence of a carbon-carbon double bond with Z configuration, 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 ⁇ -lactams, and ⁇ -amino acids such as pregabalin.
• biologically active heterocycles such as substituted 1,5-dihydropyrrol-2-ones, pyrrolidines, and ⁇ -lactams, and ⁇ -amino acids such as pregabalin.
• Mucobromic and mucochloric acid surprisingly have not been commonly employed in organic synthesis as C-4 building blocks. Presumably, this is because of the many reactive sites in the molecules, their poor stability under basic conditions, and the perception among those of ordinary skill in the art of the difficulties associated with the selective manipulation of the halogen atoms in the presence of the other functional groups.
• mucohalic acid is the keystone of the invention processes disclosed 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 ⁇ amino butyric acid framework.
• Route A protection of mucohalic acid in Step A provides the hemiacetal 2B.
• Step B Conjugate addition of R 2 R 2′ M to 2B, followed by elimination of halide, provides conjugate addition product 3B.
• Reductive amination of 3B in Step C provides lactam 4B, which may undergoes hydrolysis in situ or in a separate step to provide 3-substituted ⁇ amino butyric acid I.
• reductive amination is the first step in the synthetic sequence (Step A′), followed by conjugate addition (Step B′), hydrogenation (Step C′), and hydrolysis (Step D′).
• Pregabalin is readily prepared by either of these routes.
• Route A mucohalic acid is first converted to the O-benzyl acetal 2B.
• Organocuprate additon provides the conjugate addition product 3B.
• Hydrogenation and dehalogentation gives rise to 4B.
• Reductive amination under hydrogenation conditions gives rise to lactam 5B, which may be hydrolyzed under basic conditions to provide pregabalin.
• Route A′ of Scheme 2D reductive amination of mucohalic acid in the first step using benzyl amine (shown) or 1-phenylethyl amine provides 2D.
• Conjugate addition, hydrogenation, and hydrolysis as described for Route A provides pregabalin.
• halo is fluoro, chloro, bromo, or iodo.
• Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to.
• alkyl means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, and the like.
• alkenyl means a straight or branched hydrocarbon radical having from 2 to 7 carbon atoms and includes, for instance, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 4-methyl-3-pentenyl, 1-heptenyl, 2 heptenyl, 3 heptenyl, 2-methyl-1-hexenyl, 2-methyl-2-hexenyl, 3-methyl-2-hexenyl, 3-methyl-3-hexenyl, 3-methyl-1-hexenyl, 4-methyl-1-hexenyl, 5-methyl-1-hexenyl,
• cycloalkyl means a hydrocarbon ring containing from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, decalinyl, norpinanyl, and adamantyl.
• the cycloalkyl group may contain double bonds, for example, 3-cyclohexen-1-yl.
• the cycloalkyl ring may be unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, alkyl and dialkylamino, formyl, carboxyl, —CN, —NH—CO—R, —CO—NHR, —CO 2 R, —COR, wherein R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein.
• aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms, and being unsubstituted or substituted with one or more of the substituent groups recited above for alkyl, alkenyl, and alkynyl groups.
• aryl groups include phenyl, 2,6-dichlorophenyl, 3-methoxyphenyl, naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl, phenanthrenyl, benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl, and 4′-bromobiphenyl.
• alkoxy means a straight or branched hydrocarbon radical which has from 1 to 8 carbon atoms and is attached to oxygen. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxu, n-pentoxy, n-hexoxy, n-heptoxy, and the like.
• alkylcycloalkyl means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms as defined above attached to cycloalkyl group as defined above.
• alkylalkoxy means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms as defined above attached to an alkoxy group as defined above.
• alkylphenyl means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms as defined above attached to a phenyl or substituted phenyl group.
• alkyphenoxy means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms as defined above attached to a phenoxy or substituted group.
• the compounds prepared by the invention process may have one or more chiral centers and may exist in and be used or isolated in optically active and racemic forms. It is to be understood that the processes of the present invention can give rise to any racemic or optically-active forms, or mixtures thereof. It is to be further understood the products of the invention process can be isolated as racemic, enantiomeric, or diastereomeric forms, or mixtures thereof. Purification and characterization procedures for such products are known to those of ordinary skill in the art, and include recrystallization techniques, as well as chiral chromatographic separation procedures as well as other methods.
• Step A of Route A mucobromic or mucochloric acid is converted to the corresponding 5-alkoxy-3,4-dihalo-5H-furan-2-one 2A upon treatment with a C 1 -C 6 alcohol or benzyl or substituted benzyl alcohol in the presence of acid.
• a toluene solution of 1 equivalent of mucohalic acid is combined with 1.5 equivalents of benzylacohol and 0.05 equivalent of p-toluene sulfonic acid. The mixture is then heated at reflux for 8 to 24 hours.
• the product furanone is typically obtained in high yield (85-90 percent).
• Step B of Route A conjugate addition of an organocuprate reagent R 2 R 2 CM to 2A, followed by halide elimination, provides the substituted furanone 3A.
• the organocuprate is generated in situ in the presence of N-methypyrrolidinone (NMP) from a commercially available Grignard reagent (e.g., an alkyl- aryl-, or alkylmagnesium bromide) and copper iodide. If the requisite Grignard reagent is not commercially available, it can be readily preparide from the corresponding organohalide compound using one of the many methods available to the skilled artisan.
• the furanone is then added to the organocuprate reagent over 5 to 10 minutes at ⁇ 10 to 0° C., and the resulting mixture is allowed to warm to room temperature.
• Step C of Route A hydrogenation of alkylfuranone 3A according to a method readily available to the skilled artisan provides dihydrofuranone 4A.
• the furanone is dissolved in THF, and combined with a tertiary amine base such as triethyl amine, and Pd/C. This mixture is hydrogenated in a high pressure reactor until hydrogen uptake ceases.
• Step D of Route A reductive amination of dihydrofuranone 4A with ammonium formate or R 1 NH 2 gives rise to lactam 5A, which may be hydrolyzed in situ or isolated and converted to the 3-substituted ⁇ amino butyric acid I in a separate step.
• dihydrofuranone 4A is combined in methanol with ammonium formate, triethyl amine, and Pd/C. This mixture is hydrogenated in a high pressure reactor until hydrogen uptake ceases to give rise to a mixture of the lactoam 5A and the desired ring-opened material I.
• Hydrolysis conditions known to the skilled artisan for example, treatment with aqueous base
• Step E gives rise to I.
• Step A is readily adapted to the synthesis of pregabalin. Step A remains the same. Step B requires the use of sec-butyl magnesium bromide to generate the necessary organocuprate. Alternatively, the sidechain can be attached in a Suzuki-type coupling procedure using
• mucobromic and mucochloric acid are not popular C-4 building blocks because of the many reactive sites in the molecules, their poor stability under basic conditions, and the perception among those of ordinary skill in the art of the difficulties associated with the selective manipulation of the halogen atoms in the presence of the other functionality.
• mucobromic or mucochloric acid may react with hydrazine or arylhydrazines to form pyridazinones (Scheme 3), the reaction conditions are severe: acetic acid as the solvent, a pH of 1 to 2, and temperatures between 60 and 120° C.
• Mucohalic Acid To begin, either mucobromic or mucochloric acid are suitable for use in the reductive amination process.
• Amine also, a wide variety of amines may be used in the reductive amination process, and are represented by the formula R 1 NH 2 , wherein R 1 is selected from hydrogen or C 1 -C 7 alkyl or substituted C 1 -C 7 alkyl, C 3 -C 12 cycloalkyl or substituted C 3 -C 12 cycloalkyl, C 3 -C 12 heterocycloalkyl or substituted C 3 -C 12 heterocycloalkyl, aryl or substituted aryl, or heteroaryl or substituted heteroaryl.
• the primary or secondary alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl amine used in the invention can be substituted with one or more groups selected from halo, hydroxy, C 1 -C 6 alkoxy, carboxy, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl, pentahaloethyl, thiol, (C 1 -C 4 )alkylsulfanyl, (C 1 -C 4 )alkylsulfinyl, and aminosulfonyl,
• substituted alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, tribromomethyl, hydroxymethyl, 3-methoxypropyl, 3-carboxypentyl, 3,5-
• substituted alkenyl groups examples include 2-bromoethenyl, 1-amino-2-propen-1-yl, 3-hydroxypent-2-en-1-yl, 4-methoxycarbonyl-hex-2-en-1-yl, and 2-nitro-3-bromo-4-iodo-oct-5-en-1-yl.
• Typical substituted alkynyl groups include 2-hydroxyethynyl, 3-dimethylamino-hex-5-yn-1-yl, and 2-cyano-hept-3-yn-1-yl.
• the amine used in the reductive amination process may be an amino acid or its corresponding ester.
• Typical amino acids include L-lysine, L-alanine, L-arginine L-aspartic acid, N-alpha-benzyloxycarbonyl-L-arginine, L-citrulline, gamma-L-glutamic acid, L-glycine, L-histidine, L-hydroxproline, L-isoleucine, L-leucine, L-lysine, L-methionine, L-ornithine, L-phenylalanine, L-proline, L-pyroglutamic acid, L-serine, L-tryptophan, L-tyrosine, L-valine.
• the amine may also be a carboxy terminal-linked peptide having 1 to 10 amino acids or an addition salt thereof.
• Such peptides may include L-arginyl-L-arginine, N-benzyloxycarbonyl-glycyl-L-proline, L-glutaryl-glycyl-arginine, glycyl-glycine, glycyl-L-phenylalanine, glycyl-L-proline, and L-seryl-L-tyrosine, as well as others.
• the amine used in the reductive amination process of the present invention may have one or more chiral centers and may exist in and be used or isolated in optically active and racemic forms. It is to be understood that the process of the present invention can employ any racemic, optically-active, polymorphic, geometric, or stereoisomeric form, or mixtures thereof, of an amine. It is to be further understood the products of the reductive amination process can be isolated as racemic, optically-active, polymorphic, geometric, or stereoisomeric forms, or mixtures thereof. Purification and characterization procedures for such products are known to those of ordinary skill in the art, and include recrystallization techniques, as well as chiral chromatographic separation procedures as well as other methods.
• Reducing Agent A number of reducing agents can be used in the reductive amination process of the present invention. These reducing agents include sodium triacetoxy borohydride, sodium cyanoborohydride, triethyl silane, Ti(OiPr) 4 /NaBH 3 CN, borohydride exchange resin, Zn/acetic acid, sodium borohydride/magnesium perchlorate, or zinc borohydride/zinc chloride.
• the reducing agent is sodium triacetoxyborohydride.
• Acid Catalyst A variety of acid catalysts can be used in the reductive amination process of the present invention.
• the acid may be a Bronsted, or protic, acid, or a Lewis, or non-protic, acid.
• protic acids suitable for use in the reductive amination process of the present invention include acetic acid, trichloroacetic acid, trifluoroacetic acid, or formic acid.
• non-protic acids suitable for use in the reductive amination process of the instant application include magnesium chloride, magnesium triflate, boron trifluoride etherate, AlCl 3 , FeCl 3 , ZnCl 2 , AlBr 3 , ZnBr 2 , TiCl 4 , SiCl 4 and SnCl 4 .
• the mucohalic acid is contacted with the amine, reducing agent, and acid catalyst.
• Contacted means that the reaction components are typically mixed in a liquid to form a homogeneous or heterogeneous mixture.
• the liquid employed in the reductive amination process of the present invention is selected from a polar aprotic solvent.
• the polar aprotic solvent is selected from tetrahydrofuran, acetonitrile, nitromethane, chloroform, methylene chloride, monochloro ethane, 1,1, or 1,2 dichloroethane, 1,1,1 or 1,1,2 tricholoroethane, or 1,1,1,2, or 1,1,2,2 tetrachloroethane. More preferred solvents include methylene chloride or chloroform. Mixtures of solvents can also be used.
• the molar equivalents of each of the reaction components i.e., mucohalic acid, amine, reducing agent, and acid catalyst used in the reductive amination process if the instant application are:
• the molar equivalents of each of the reaction components i.e., mucohalic acid, amine, reducing agent, and acid catalyst used in the reductive amination process if the instant application are:
• the initial concentration of mucohalic acid in the polar aprotic solvent is typically 0.1 to 0.5 M. More preferably, it is 0.15 to 0.45 M. Most preferably, it is 0.2 to 0.3 M.
• the temperature is typically from about ⁇ 25° C. to about 50° C., with lower temperatures being more suitable for mucobromic acid and higher temperatures being more suitable for mucochloric acid.
• the temperature is more preferably from about about 0° C. to about 40° C., and most preferably from about 10° C. to about 30° C.
• reaction times are typically from about 30 minutes to about 5 days; more preferably, from about 1 hour to 3 days; and most preferably, from about 6 hours to 48 hours.
• Mucochloric acid (1) can exist as the open or cyclic form (Scheme 6). However, the ultraviolet spectrum in CHCl 3 indicates 1 exists predominantly in the lactone form. Additional spectral data, i.e. vibrational (IR, Raman) and others (NMR and NQR) suggest that the lactone is the dominant form in both the liquid and solid states. Experimental results further support these observations.
• Step A′ of Scheme 1, Route A′ represents a simple, efficient and selective method to prepare N-benzyl-3,4-dichloro-1,5-dihydropyrrol-2-one, N-aryl (or alkyl)-3,4-dichloro-1,5-dihydropyrrol-2-ones and substituted ⁇ -amino acids.
• These products possess a geometrically defined tetrasubstituted olefin, two differentiated vinyl halides and an acidic sight, and could be used in the synthesis of a variety of compounds.
• Steps B, C, and D of Route B are as provided for Steps B, C, and E of Route A.
• Step A 5-Benzyloxy-3,4-dihalo-5H-furan-2-one.
• Step B 5-Benzyloxy-3-halo-4-isopropyl-5H-furan-2-one.
• the mixture may be submitted to base hydrolysis to provide exclusively pregabalin.
• Step A′ Reductive Amination of Mucohalic Acid with Benzylamine.

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