RACEMIC GAMMA-AMINO ACIDS

Field of the Invention:

The invention relates to a process for preparation of enantiomerically enriched and/or racemic γ-amino acids, particularly those useful for preparing γ-amino acids that exhibit binding affinity to the human α ₂ δ calcium channel subunit, including pregabalin and related compounds such as 3-«-propyl-4-aminobutyric acid.

Background of the Invention:

(S)-3-(Aminomethyl)-5-methylhexanoic acid [CAS No. 148553-50-8], which is also called β- isobutyl-γ- aminobutyric acid, isobutyl-GABA, or pregabalin [I] is a potent anticonvulsant. As discussed in U.S. Patent No. 5,563,175, pregabalin exhibits anti-seizure activity and is found to be useful for treatment of various other conditions, like pain, fibromyalgia, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, insomnia, alcoholism and various psychiatric disorders, including mania and bipolar disorder. (U.S. Patent No. 6,242,488; U.S. Patent No. 6,326,374; U.S. Patent No. 6,001,876; U.S. Patent No. 6,194,459; U.S. Patent No. 6, 329, 429; U.S. Patent No. 6, 127,41 8; U.S. Patent No. 6,426, 368; U.S. Patent No. 6,306,910; U.S. Patent No. 6,359,005).

U.S Patent No. 6359169 and Journal of Medicinal Chemistry (1991 , 34, 2295 - 2298) report the anticonvulsant activity for 3-«-propyl-4-aminobutyric acid [CAS No. 90048-40-1, 130912-49-1] [II].

A number of synthetic schemes have been developed for pregabalin. Typically, a racemic mixture of 3-aminomethyl-5-methylhexanoic acid is synthesized and subsequently resolved into (R) and (S) enantiomers. Such methods may employ an azide intermediate, a malonate intermediate or a nitrile intermediate. More details are discussed hereinafter.

US patent No. 5,637,767 disclosed the method for synthesis of (5)-pregabalin. In this process isovaleraldehyde is reacted with diethyl malonate to obtain 2-carboxyethyl-5-methylhex-2- enoic acid ethyl ester, which is further reacted with potassium cyanide to obtain 2- carboxy ethyl 3-cyano-5-methylhexanoic acid ethyl ester. Hydrogenation of 2-carboxyethyl 3-cyano-5-methylhexanoic acid ethyl ester in presence of nickel gives the racemic pregabalin, which is further resolved with (5)-mandelic acid to obtain pregabalin. Although the above method provides the (S) -pregabalin in high optical purity, the overall yield is very poor. Furthermore, the process uses potassium cyanide which is very toxic and hazardous, and to be avoided. Reaction scheme is depicted in Figure 1.

US Patent No. 5,616, 573 disclose the method for synthesis of pregabalin from 3-isobutyl glutaric acid. 3-isobutyl glutaric acid is converted to its corresponding anhydride by refluxing with acetic anhydride. Subsequent reaction with Ν¾ΟΗ produces the glutaric acid mono- amide, which is resolved with (7^-a-phenylethyl amine, yielding the corresponding salt. Decomposition of salt gives the (i? -enantiomer, which on Hoffmann degradation with Br ₂ /NaOH provides ^-pregabalin [I]. The above process, as depicted in Figure 2, involves the use of hazardous chemicals such as bromine, which is not eco-friendly. WO2006/122259 Al has reported a similar type of chemistry as demonstrated in US Patent No. 5,616, 573. Here resolution of glutaric acid mono-amide is via ephedrine or norephedrine yielding the corresponding salt. Decomposition of salt gives the (7?)-enantiomer, which on Hoffmann degradation with Br ₂ NaOH provides (S -pregabalin [I]. Although the above method is providing the (S -pregabalin in high optical purity but overall yield is very poor. Reaction scheme is depicted in Figure 3. The above process involves the use of hazardous chemical such as bromine, which is not eco-friendly.

US patent 5,563,175 discloses the preparation of (S -pregabalin using stoichiometric (+)-4- methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary. The above mentioned process includes the use of pyrophoric and hazardous reagents, such as «-butyl lithium, which leads to number of side reactions and decreases the overall yield. Reaction scheme is depicted in Figure 4. Although the above method provides the (S^-pregabalin in high optical purity, it is not desirable process for synthesis at industrial scale because it uses costly chiral auxiliary ^' · and requires the special cryogenic conditions to reach required operating temperature, which can be as low as -78 °C.

WO 01/55090 Al , reports the asymmetric hydrogenation of a cyano intermediate to produce a cyano precursor of (¾)-aminomethyl 5-methyl hexanoic acid, which is further reduced to obtain (Sj-pregabalin. However, the disclosed method requires the use of carbon monoxide under high pressure, raising serious problem in adapting this process for production scale. The application discloses the use of various C ₂ symmetric bisphosphine ligands, including (R, R) Me-DUPHOS, which is very costly and the "turn over" number is not satisfactory, which creates significant impact on the final cost of the product. Furthermore, the disclosed method requires the use of carcinogenic acrylonitrile and the use of highly toxic carbon monoxide under high pressure. Reaction scheme is depicted in Figure 5.

Process disclosed by G. M. Sammis et al. (J. Am. Chem. Soc, 2003, 125(15) 4442-43) describes an aluminum salen catalyst which is used in the conjugate addition of hydrogen cyanide to α, β -unsaturated imides. This process is also not practical for large scale production due to the use of highly poisonous reagents and also use of aluminum salen catalyst, which is very costly and creates significant impact on the final cost of the product. Reaction scheme is depicted in Figure 6.

WO 2006/1 10783 reports several processes for preparing (S -pregabalin via the following intermediate and its analogues. Reaction scheme is depicted in Figure 7.

US Patent No. 6,924,377 discloses the method for synthesis of pregabalin through reductive amination of mucohalic acid and its derivatives. This process needs special cryogenic equipment to reach required operating temperature, which can be as low as -30 °C. Overall yield is poor and requires column chromatography at most of the stages to obtain pure intermediate or product. Hence it can not be a process for synthesis of pregabalin at industrial scale. Reaction scheme is depicted in Figure 8.

WO 2009053446 A2 discloses the method for synthesis of pregabalin from 2,2'dichloro-3- isobutylcyclobutanone. Reaction scheme is depicted in Figure 9

Desymmetrization of a symmetric anhydride via enantio-selective alcoholysis to generates the corresponding hemiester, a highly functionalized chiral product with one or more stereogenic centers. (Chem. Commun, 1985, 1717-1718; J. Chem. Soc. Perkin Trans 1, 1987,

1053-1058; Chem. Commun, 1988, 632-633; J. Org. Chem 2000, 65, 6984-6990; Org. Synth.

2005, 82, 120-125; JACS 2000, 122, 9542-9543; J. Org. Chem 1998, 63, 1 190-1 197; Chem.

Rev. 2003, 103, 2965-2983; Chem. Rev. 2007, 107, 5683-5712), has been described in the reference cited herein.

Significantly, desymmetrization of glutaric weso-anhydrides with nucleophiles both chiral and achiral such as amines, benzyl amines, alcohols etc. is very well documented (Chem. Rev. 2003, 103, 2965-2983; Chem. Rev. 2007, 107, 5683-5712). Schwartz and Carter (1954) have reported the diastereo-selective process for obtaining 3- phenyl-4-(l -phenyl-ethylcarbamoyl)-butyric acid by reacting 3-phenyl glutaric anhydride with (iS)-phenylethylamine. The product is isolated in 95% yield having 3 :2 diastereomeric ratio (Proc. Natl. Acad. Sci. U.S.A. 1954, 40, 499; Chem. Rev. 2007, 107, 5683-5712)

WO 2007/035890 Al, WO 2007/035789 Al and US Patent Application No. 2008/0306292 have reported the similar chemistry, such as desymmetrization of 3-isobutyl glutaric acid with (5)-phenylethylamine, which are obvious extensions of Schwartz and Carter work and devoid of any inventive merit. Further, there is sufficient teaching, suggestion and motivation in prior art for synthesis of molecule through desymmetrization. This is very similar to the KSR Int'l Co. vs. Teleflex, Inc., 550 U.S. 398 (2007) case in the Supreme Court of the United States concerning the issue of obviousness as applied to patent claims.

Moreover, similar type of chemistry is reported in US Patent No. 5,616, 573, where, 3- isobutyl glutaric anhydride is reacted with NH ₄ OH to produces the glutaric acid mono-amide. WO 2007/035890 Al , WO 2007/035789 Al and US Patent Application No. 2008/0306292 have reported the similar chemistry, where, 3-isobutyl glutaric anhydride is reacted with (S)- phenylethylamine to obtain glutaric acid mono-amide, which is obvious extension of US Patent No. 5,616, 573.

WO 2007/035890 Al reports the synthesis of pregabalin via chiral intermediate obtained through Hoffman degradation. This process is also not practical for large scale production due to the use of highly poisonous reagents such as bromine. This process needs the special cryogenic equipment to reach required operating temperature, which can be as low as -60 °C. Reaction scheme is depicted in Figure 10.

WO 2007/035789 Al reports the synthesis of pregabalin via chiral intermediate obtained through Hoffman degradation. This process is also not practical for large scale production due to the use of highly poisonous reagents such as bromine and sodium metal. This process needs the special cryogenic equipment to reach required operating temperature, which can be as low as -60 °C. Reaction scheme is depicted in Figure 1 1.

US Patent Application No. 2008/0306292 reports the synthesis of pregabalin via chiral intermediate through Hoffmann degradation. Further hydrolysis gives the pregabalin. This process is also not practical for large scale production due to the use of highly poisonous reagents such as bromine. Reaction scheme is depicted in Figure 12.

Although compound [III] is described as an impurity in the synthesis of pregabalin, however, spectral data such as IR, NMR or mass of the compound [III] are not provided neither any enablement whatsoever of compound [III] are disclosed. Also, it is very difficult to rationalize the production or generation of compound [III], as an impurity as reported in a disclosed reaction condition for obtaining pregabalin.

Moreover, it must be re-emphasized that the chemistry employed in Figure 12 to produce compound [III] can neither be a synthesis method nor an industrial process.

WO2009/081208A1 discloses the process for preparation of racemic pregabalin. This process is also not practical for large scale production due to the use of highly poisonous reagents such as bromine. Reaction scheme is depicted in Figure 13.

It is evident from prior art that there is a need for an eco-friendly, "green", cost effective, easy-to-operate industrial-scale synthesis of γ-amino acids.

This invention provides that.

Summary of Invention:

The present invention is directed towards the process for preparation of enantiomerically enriched compounds of formula IV

[IV] wherein Ri is H (compound [IVa]) or Ri is CH ₃ (compound [IVb]).

Comprising:

Scheme 1:

a) Reaction of the compound [V] with (S) or (R) - PhCH ₂ (NH ₂ )Ri [VI] to provide compound [VII]. Incidentally, [VII] is a novel class of compound and one of the inventive merits of the application like is in the synthesis of [VIII] from [VII].

R = H, CH ₃

R, = CH ₃ , CH ₂ OH

b) Hydrogenation, catalytic or stoichiometric of compound [VII] to provide compound [VIII]

R = H, CH ₃

Ri = CH ₃ , CH ₂ OH c) Hydrogenolysis, catalytic or stoichiometric of compound [VIII] to provide enantiomerically enriched compound [IV]

R = H, CH ₃

Scheme 2:

Hydrogenation, catalytic or stoichiometric of compound [VII] to compound [IV]

R = H, CH ₃

R, = CH ₃ , CH ₂ OH Scheme 3:

Reaction of the compound [V] with ammonia to provide compound [IX].

IV

R = H, CH ₃ Brief Description of Accompanying Drawings

Figure 1 : Reaction Scheme of US patent No. 5,β1Ί, Ί 61

Figure 2 Reaction scheme of US Patent No. 5,616, 573

Figure 3Reaction Scheme of WO2006/122259

Figure 4 Reaction Scheme of US patent 5,563,175

Figure 5 Reaction Scheme of WO 01/55090

Figure 6 Reaction Scheme G. M. Sammis et al

Figure 7 Reaction Scheme WO 2006/1 10783

Figure 8 Reaction Scheme of US Patent No. 6,924,377

Figure 9 Reaction Scheme of WO 2009053446

Figure 10 Reaction Scheme of WO 2007/035890

Figure 1 1 Reaction Scheme of WO 2007/035789

Figure 12 Reaction Scheme of US 2008/0306292

Figure 13 Reaction Scheme of WO2009/081208A1

Figure 14: Schematic representation of formation of compound Vila including precipitation of compounds Villa and Vlllb

Figure 15 Schematic representation of formation of compound Vllb with precipitation of VHId and VIIIc

Figure 16 Schematic representation of formation of compound VIIc with precipitation of VHIe and VHIf

Figure 17 Schematic representation of formation of compound Vlld with precipitation of VHIh and Vlllg

Figure 18 Schematic representation of formation of compound Vile with precipitation of Villi and Vlllj

Figure 19 Schematic representation of formation of compound Vllf with precipitation of Vlllk and Villi

Figure 20 Schematic representation of formation of compound Vllg with precipitation of Vlllm and VHIn Figure 21 Schematic representation of formation of compound IXa which on hydrogenolysis gives compound II

Figure 22 Schematic representation of formation of compound IXb which on hydrogenolysis gives compound I

Figure 23 Schematic representation of formation of compound Vila and further formation of compound X

Detailed descriptions:

The invention provides method for synthesis of enatiomerically enriched γ-amino acid [IV] according to the following schemes 1 and 2.

Scheme 1:

R = H, CH ₃

R, = CH ₃ , CH ₂ OH

cheme 2:

H, CH ₃ CH ₃ , CH ₂ OH

Scheme 3:

R = H, CH ₃

roposed reaction mechanism is schematically given below

R = H, CH ₃

R, = CH ₃ , CH ₂ OH

According to one aspect, the present invention provides the process for the preparation of γ- amino acid [IV] from compound [V]. In one aspect, compound [V] is reacted with compound [VI] and thereafter the resulting compound [VII] is hydrogenated to obtain compound [VIII]. Further, hydrogenolysis of compound [VIII] produces the enantiomerically enriched γ-amino acid [IV].

According to one aspect, the present invention provides the process for the preparation of γ- amino acid [IV] from compound [V]. In one aspect, compound [V] is reacted with compound [VI] and thereafter the resulting compound [VII] is hydrogenated to produces the enantiomerically enriched γ-amino acid [IV].

According to another aspect, the present invention provides the process for the preparation of γ-amino acid [IV] from compound [V]. In one aspect, compound [V] is reacted with compound [VI] and thereafter the resulting compound [VII] is hydrogenolyzed through catalytic transfer hydrogenation in presence of ammonium formate to produce the γ-amino acid [IV]. According to another aspect, the present invention provides the process for the preparation of racemic γ-amino acid [IV] from compound [V] where compound [V] is reacted with ammonia and thereafter the resulting compound [IX] is hydrogenated to produces the racemic γ-amino acid [IV]. Typically, compound [VII] is synthesized by reacting compound [V] with compound [VI] which is carried out in polar and non-polar solvents. Polar solvents such as, methanol, ethanol, .so-propanol, tetrahydrofuran, di-wopropyl ether etc are used and non-polar solvents such as dichloromethane, toluene are used; preferably, methanol and isopropyl alcohol and more preferably isopropyl alcohol.

According to one of the embodiments, compound [VII] is obtained by reacting compound [V] with compound [VI]. Compound [VI] is chiral or achiral primary amine, preferably with chiral primary amines such as (5)-(-)-or-methyl benzyl amine, ( ?)-(+)-a-methyl benzyl amine, (5)-(+)-phenyI glycinol and ( ?)-(-)-phenyl glycinol.

Compound [VII] is usually obtained by conducting reaction at temperature of about 25 to 80 °C. Preferably, the temperature maintained during the reaction is about 25 to 30 °C.

After completion of reaction, solvent is distilled out to obtain compound [VII] as yellow oil. Thereafter, the resulting compound [VII] is hydrogenated in alcoholic solvent, in presence of a noble metal catalyst under hydrogen pressure to obtain compound [VIII]. Alcoholic solvent may be selected from methanol, ethanol, so-propanol; preferably methanol and .so-propanol.

Generally, hydrogen pressure is about 1 kg/cm ² to 5 kg/cm ² ; preferably 3 kg/cm ² pressure is used.

Noble metal catalyst can be selected from platinum oxide, palladium on carbon and palladium hydroxide on carbon; preferably the noble metal catalyst is palladium on carbon and palladium hydroxide on carbon. After the completion of reaction, reaction mixture is filtered through filtrate pad to remove the catalyst. Solvent is distilled out to obtain compound [VIII].

Hydrogenolysis of compound [VIII] is carried out in an alcoholic solvent and Bransted acid, in presence of a noble metal catalyst under hydrogen pressure to obtain the corresponding enantiomerically enriched γ-amino acid.

Alcoholic solvent may be selected from methanol, ethanol, z ^' so-propanol; preferably methanol. Generally, hydrogen pressure is about 10 kg/cm ² to 50 kg/cm ² , preferably 40 kg/cm ² pressure.

Noble metal catalyst may be selected from platinum oxide, palladium on carbon, palladium hydroxide on carbon; preferably the noble metal catalyst is palladium on carbon and palladium hydroxide on carbon; more preferably palladium hydroxide on carbon. Bronsted acid can be selected from acetic acid, hydrochloric acid, sulfuric acid and trifluoroacetic acid; preferably acetic acid and trifluoroacetic acid; more preferably trifluoroacetic acid. Compound [Vila] is obtained from reaction of compound [Va] where R=H with (S)- - methyl benzyl amine [Via] and is hydrogenated in presence of noble metal catalyst (Pd/C) under hydrogen pressure in z ^' so-propanol to give the diastereomeric compounds [Villa] and [VHIb] respectively, which get separated during the reaction. Compound [Villa] precipitates out from reaction, leaving compound [VHIb] dissolved in the reaction media. Figure 14 gives the schematic representation.

Compound [Vllb] obtained from reaction of compound [Va] where R=H with ( ?)-a-methyl benzyl amine [VIb] is hydrogenated in presence of noble metal catalyst (Pd/C) under hydrogen pressure in z ^' iO-propanol to give the diastereomeric compounds [VIIIc] & [VHId] respectively, which get separated during the reaction. Compound [VIIIc] precipitates out from reaction, leaving compound [VHId] dissolved in the reaction media. Figure 15 gives the schematic representation.

Compound [VIIc] obtained from reaction of compound [Vb] where R=CH3 with (S)- - methyl benzyl amine [Via] and is hydrogenated in presence of noble metal catalyst (Pd/C) under hydrogen pressure in /so-propanol to give the diastereomeric compounds [VHIe] & [Villi] respectively, as depicted in Figure 16.

Compound [Vlld] is obtained from reaction of compound [Vb] where R=CH ₃ with (R)- - methyl benzyl amine [VIb] and which is hydrogenated in presence of noble metal catalyst (Pd/C) under hydrogen pressure in z ^' so-propanol to give the diastereomeric compounds [VHIg] & [VHIh] respectively, as depicted in Figure 17.

Compound [Vile] obtained from reaction of compound [Va] where R=H with (S)-(+)-phenyl glycinol [Vic] is hydrogenated in presence of noble metal catalyst [Pd(OH) ₂ /C] under hydrogen pressure in methanol to give the diastereomeric compounds [Villi] & [Vlllj] respectively. Figure 18 represents the reaction scheme.

Compound [Vllf] obtained from reaction of compound [Vb] where R=CH ₃ with (S)~(+)- phenyl glycinol [Vic] is hydrogenated in presence of noble metal catalyst [Pd(OH) ₂ /C] under hydrogen pressure in methanol to give the diastereomeric compounds [VHIk] & [Villi] respectively. Figure 19 represents the reaction scheme.

Compound [Vllg] obtained from reaction of compound [Vb] where R=CH ₃ with (R)-(-)- phenyl glycinol [Vld] is hydrogenated in presence of noble metal catalyst [Pd(OH) ₂ /C] under hydrogen pressure in methanol to give the diastereomeric compounds [Vlllm] & [Vllln] respectively. Figure 20 represents the reaction scheme.

Hydrogenolysis of compounds [Villa], [VHIb], [VIIIc], and [VHId] with palladium on carbon under hydrogen gas pressure of 40 kg/cm , in methanol gives the enantiomerically enriched compound [II] having % ee as summarized in Table 1.

Table 1: Hydrogenolysis of Compounds [Villa], [Vlllb], [VIIIc], and [Vllld]

Oxidative debenzylation of compound [Villa], [Vlllb], [VIIIc], and [Vllld] with N- bromosuccinimide in polar solvents such as tert-butanol and dimethyl sulfoxide is done to obtain enantiomerically enriched compound [II] having following % ee, which is summarized in Table 2. Table 2: Oxidative debenzylation of Compounds [Villa], [VHIb], [VIIIc], and [VIHd]

All the above compounds [Villa to d] are diastereomerically pure. Thus, further hydrogenolysis with these compounds as starting materials gives the enantiomerically enriched compound [II] as shown in Table 1 and Table 2.

Hydrogenolysis of the diastereomeric mixture of compounds [Vllle] & [Villi] in presence of palladium on carbon under hydrogen gas pressure of 40 kg/cm ² , in methanol and 10 % acetic acid gives the compound [I] having 60 % ee for (i?)-pregabalin. In this case, hydrogenolysis is monitored by TLC and after about 75 to 80 % conversion; reaction is stopped and monitored by chiral HPLC for % ee.

Hydrogenolysis of the diastereomeric mixture of compounds [Vlllg] & [Vlllh] in presence of palladium on carbon under hydrogen gas pressure of 40 kg/cm ² , in methanol and 10 % acetic acid gives the compound [I] having 60 % ee for (S)-pregabalin. In this case, hydrogenolysis is monitored by TLC and after about 75 to 80 % conversion reaction is stopped and monitored by chiral HPLC for % ee. Hydrogenolysis of the diastereomeric mixture of compounds [VHIk] & [Villi] with palladium hydroxide on carbon under hydrogen gas pressure of 40 kg/cm , in methanol and 10 % trifluoroacetic acid gives the compound [I] having 50 % ee for ( ?)-pregabalin. In this case, hydrogenolysis is monitored by TLC and after about 75 to 80 % conversion reaction is stopped and monitored by chiral HPLC for % ee. Hydrogenolysis of the diastereomeric mixture of compounds [Vlllk] & [Villi] with palladium hydroxide on carbon under hydrogen gas pressure of 40 kg/cm ² , in methanol and 10 % acetic acid gives the racemic compound [I]. The rate of debenzylation of mixture of compounds [VHIk] & [Villi] increases by 2 folds in presence of trifluoroacetic acid as compared to acetic acid.

Hydrogenolysis of compound [VIIc] is carried out in presence of palladium on carbon under hydrogen gas pressure of 40 kg/cm , in methanol and 10 % acetic acid to give the racemic compound [I].

Hydrogenolysis of mixture of compounds [VHIm] and [Vllln] in presence of palladium hydroxide on carbon under hydrogen pressure of 40 kg/cm ² , in methanol and 10 % trifluoroacetic acid gives the racemic compound [I] as seen by chiral HPLC analysis.

Hydrogenolysis of compound [Vllg] in presence of palladium hydroxide on carbon under hydrogen pressure of 40 kg/cm , in methanol and 10 % trifluoroacetic acid gives the racemic compound [I] as seen by chiral HPLC analysis. Catalytic transfer hydrogenation (CTH) of compound [Vllg] with ammonium formate in presence of palladium hydroxide on carbon as a catalyst, in ethanol gives the racemic compound [I], as seen by chiral HPLC analysis.

In principle, if one is able to separate the diastereomers, then enantiomerically enriched γ- amino acid [IV] can be obtained. This has been demonstrated for the diastereomerically pure compounds [Villa to d]; which on further hydrogenolysis give the enantiomerically enriched compound [II] (as shown in Tables 1 and 2).

On the other hand, compounds [VHIe to n] are obtained as diastereomeric mixture, which on further hydrogenolysis give the racemic compound [I]. Since, in the present case, diastereomers are not separated even by using costly chiral amines, hence we thought of replacing these chiral amines with cheap and easily available achiral amines for the preparation of racemic compound [IV] thereby making the process more cost effective, 'green', atom economical and easy to operate at large scale. This postulation is proven true when compound [V] is reacted with simple amine such as ammonia to obtain compound [IX], which on further hydrogenolysis gives the racemic compound [IV].

Compound [IXa] is obtained from reaction of compound [Va] where R=H with ammonia and further hydrogenolysis gives the compound [II]. Figure 21 gives the schematic representation.

Compound [IXb] is obtained from reaction of compound [Vb] where R=CH ₃ with ammonia and further hydrogenolysis gives the compound [I]. Figure 22 gives the schematic representation.

Compound [Vila] is obtained from reaction of compound [Va] where R=H with (S)-a- methyl benzyl amine [Via] and further reduction of compound [Vila] in presence of sodium borohydride gives the compound [X]. Figure 23 gives the schematic representation.

Compound [Villa] is reacted with (S)-(-)-l,l '-bi-2-naphthol to obtain co-crystal having composition 1 : 1 for which, the single crystal analysis details are disclosed in our co-pending patent application entitled "Novel method of resolution of ( ?S)-l, -bi-2-naphthol for obtaining enantiomeric pure i.e. (£)-(-)- l ,l '-bi-2-naphthol and/or (/?)-(+)- l ,l '-bi-2-naphthol via co-crystal formation with optically active derivatives of γ-amino acids".

Nomenclatures used for the compounds mentioned herein are as understood from the CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0.1. Analytical Methods:

The enantiomeric excess (ee) is determined by HPLC using a Shimadzu LC 2010 system equipped with a chiral column (Purosphere star RP-18e (4.6 x 150mm), 5μηι), column oven temperature 25 °C and UV visible detector (UV at 340nm). Mobile phase is buffer: acetonitrile (55 :45) with flow rate 1.0 mL ^"1 , injection volume 20 μΐ. The enantiomeric excess (ee) is determined by derivatized by reacting with Murphy's reagent. NM spectra are obtained at 200 and 400 MHz Bruker instruments, with CDC1 ₃ as solvent. Chemical shifts (S) are given in ppm relative to tetramethylsilane ((5 = 0 ppm). IR spectra are recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and absorption bands are given in cm ^"1 . DSC is recorded on Perkin Elmer model Diamond DSC at the rate of 10 °C/min, and endothermic peak is recorded in ⁰ C and ΔΗ is reported in J/g.

Example 1: Synthesis of 5-hydroxy-4-/i-propyl -5//-furan-2-one [Va] (J. Org. Chem. 1981, 46, 4889-4894)

tt-Heptane (394 mL) and morpholine (127.5 mL) are introduced in a reactor while stirring. The mixture is cooled to 0° C and glyoxylic acid (195 g, 150 mL, 50 wt % in water) is added. The mixture is heated to 20° C during 1 hour and then 77-valeraldehyde (148.8 mL) is added. The reaction mixture is heated at 45° C during 20 hours. After cooling down to 20° C, a 37 % aqueous solution of hydrochloric acid (196.9 mL) is slowly added to the mixture, which is then stirred during 2 hours. After removal of the heptane phase, the aqueous phase is washed three times with heptane. Di- w -propyl ether is added to the aqueous phase. The organic phase is removed and the aqueous phase further extracted with di-z ^' so-propyl ether (2x). The di-wo-propyl ether layers are combined, washed with brine and then dried under reduced pressure. After evaporation of the solvent, 100.0 g of 5-hydroxy-4-«-propyl-5H-furan-2-one are obtained as light brown oil.

FTIR (neat): 3367, 1735 cm ^"1 .

Ή NMR (CDC1 ₃ , 200 MHz): δ 0.93-1.00 (t, 3H), 1.56-1.67 (q, 2H), 2.31-2.43 (q, 2H), 5.81 (s, 1H), 6.02 (s, 1 H).

MS (EI): C ₇ H,o0 ₃ : 142.06; [M+H] ⁺ : 142.93.

Example 2: Synthesis of 5-hydroxy-4-iso-butyl -5//-furan-2-one [Vb] (J. Org. Chem. 1981, -4894)

rc-Heptane (75.0 mL) and morpholine (17.8 g) are introduced in a reactor while stirring. The mixture is cooled to 0° C and glyoxylic acid (29.6 g, 50 wt% in water) is added. The mixture is heated to 20° C during 1 hour and then 4-methyl valeraldehyde (20.0 g) is added. The reaction mixture is heated at 45° C during 20 hours. After cooling down to 20° C, a 37 % aqueous solution of hydrochloric acid (30 mL) is slowly added to the mixture, which is then stirred during 2 hours.

After removal of the ^-heptane phase, the aqueous phase is washed three times with n-heptane. Di-z ^' so-propyl ether is added to the aqueous phase. The organic phase is removed and the aqueous phase further extracted with di-MO-propyl ether (2x). The di-zso-propyl ether layers are combined, washed with brine and then dried under reduced pressure. After evaporation of the solvent, 13.0 g of 5-hydroxy-4-wobutyl-5H-furan-2-one are obtained as light yellow oil.

FTIR (neat): 3371 , 1738 cm ^"1 .

Ή NMR (CDC , 200 MHz): δ 0.87-0.99 (t, 6H), 1.87-2.01 (m, 1H), 2.28-2.32 (d, 2H), 5.82 (s, 1H), 6.1 1 (s, 1H).

MS (EI): C ₈ H ₁₂ 0 ₃ : 156.06; [M-H] ^" : 155.09.

Example 3: Synthesis of 5-hydroxy-l-[(S^-phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyrrol -2- one [Vila]

5-Hydroxy-4-«-propyl-5H-furan-2-one (10.0 g) is dissolved in wo-propanol (100 mL) and (S -a- methyl benzyl amine (8.5 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 : 1 ethyl acetate:hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-l-[(5^-phenyl-ethyl]-4-«-propyl-l ,5-dihydro-pyrrol-2-one as dark yellow oil (16.5 g).

FTIR (neat): 3321 , 1749, 1 165 cm ^"1 .

Ή NMR (CDCI3, 200 MHz): δ 0.86-0.94 (t, 3H), 1.32-1.37 (t, 3H), 1.43-1.57 (m, 2H), 2.12- 2.39 (m, 2H), 4.27-4.30 (d, 1H), 5.15 (s, 1H), 5.70 (s, 1H), 7.25-7.34 (m, 5H).

MS (EI): Ci ₅ H,9N0 ₂ : 245.14; [M+H] ⁺ : 246.15. Example 4: Synthesis of 5-hydroxy-l-[(R -phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyrrol-2- one [VHb]

5-Hydroxy-4-«-propyl-5H-furan-2-one (10.0 g) is dissolved in z ^' so-propanol (100 niL) and (R)-a- methyl benzyl amine (8.5 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 :1 ethyl acetate:hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-l-[(i? -phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyrrol-2-one as dark yellow oil (16.5 g).

FTIR (neat): 3321 , 1749, 1 165 cm ^"1 .

Ή NMR (CDCI ₃ , 200 MHz): δ 0.86-0.94 (t, 3H), 1.32-1.37 (t, 3H), 1.43-1.57 (m, 2H), 2.12- 2.39 (m, 2H), 4.27-4.30 (d, 1H), 5.15 (s, 1H), 5.70 (s, 1H), 7.25-7.34 (m, 5H).

MS (EI): Ci ₅ H,9N0 ₂ : 245.14; [M+H] ⁺ : 246.15.

Example 5: Synthesis of 5-hydroxy-l-[(S^-phenyl-ethyI]-4-«o-butyl-l,5-dihydro-pyrro l-2- one [VIIc]

5-Hydroxy-4-wo-butyl-5H-furan-2-one (10.0 g) is dissolved in wo-propanol (100 niL) and (S)-a- methyl benzyl amine (7.7 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 : 1 ethyl acetate:hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-l -[(5)-phenyl-ethyl]-4- jO-butyl-l ,5-dihydro-pyrrol-2-one as dark yellow oil (15.5 g).

FTIR (neat): 3319, 2959, 1751 , 1 166 cm ^"1 .

Ή NMR (CDCb, 200 MHz): δ 0.86-0.94 (t, 3H), 0.96-0.99 (t, 3H), 1.34-1.38 (d, 2H), 1.49-1.53 (d, 1 H), 1.75-1.85 (m, 1H), 2.24-2.27 (d, 2H), 4.27-4.30 (q, 1H), 5.17 (s, 1H), 5.88 (s, 1H), 7.26- 7.37 (m, 5H).

MS (EI): C, ₆ H ₂ ,N0 ₂ : 259.0; [M+H] ⁺ : 260.30.

Example 6: Synthesis of 5-hydroxy-l-[(R)-phenyl-ethyl]-4-isobutyl-l,5-dihydro-pyrroI -2- one [VHd]

5-Hydroxy-4-/£0-butyl-5H-furan-2-one (10.0 g) is dissolved in zso-propanol (100 mL) and (R)-a- methyl benzyl amine (7.7 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 : 1 ethyl acetate :hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-l -[(/?)-phenyl-ethyl]-4-z ^' 5 ^, o-butyl-l ,5-dihydro-pyrrol-2-one as dark yellow oil (15.5 g). FTIR (neat): 3319, 2959, 1751, 1 166 cm ^"1 .

Ή NMR (CDCb, 200 MHz): δ 0.86-0.94 (t, 3H), 0.96-0.99 (t, 3H), 1.34-1.38 (d, 2H), 1.49-1.53 (d, IH), 1.75-1.85 (m, IH), 2.24-2.27 (d, 2H), 4.27-4.30 (q, IH), 5.17 (s, IH), 5.88 (s, IH), 7.26- 7.37 (m, 5H).

MS (EI): C, ₆ H ₂ ,N0 ₂ : 259.0; [M+H] ⁺ : 260.30.

Example 7: Hydrogenation of 5-hydroxy-l-[(5^-phenyl-ethyl]-4-propyl-l,5-dihydro- pyrrol-2-one [Vila]

5-Hydroxy-l-[(S -phenyl-ethyl]-4-propyl-l,5-dihydro-pyrrol-2-one (16.5 g) is dissolved in MO-propanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped. In the reaction, diastereomers are separated, (S,S)-3-[(l -phenyl ethylamino)- methyl]-hexanoic acid precipitates out from the reaction media and (R,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid remains dissolved in the reaction media.

After completion of reaction, the reaction mixture is filtered and filtrate was concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 6.5 g of (i?,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid as a off-white solid obtained after vacuum filtration. Filtered cake contains Pd/C and (5,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid which is suspended in methanol and stirred for 20 min to dissolve (S,iS)-3-[(l -phenyl ethylamino)- methyl] -hexanoic acid. Pd/C is separated by filtration. Filtrate is concentrated under vacuum to obtain 6.7 g of (S,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid as a white solid.

(S S)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid [Villa] :

FTIR (KBr pellets): 2960, 1623, 1547 cm ^"1 ;

Ή NMR (CDC1 ₃ , 200 MHz): δ 0.84-0.86 (t, 3H), 1.13-1.18 (q, 2H), 1.21-1.26 (q, 2H), 1.69- 1.70 (d, 3H), 2.14-2.18 (d, 2H), 2.51-2.58 (t, 2H), 2.75-2.78 (d, 1H), 4.12-4.17 (q, 1H), 7.35- 7.42 (m, 3H), 7.47-7.51 (m, 2H); ¹³ C NMR (CDCI3, 50 MHz): 14.0, 19.8, 21.2, 32.7, 36.5, 44.2, 51.1 , 57.4, 127.4, 128.6, 129.2, 138.2, 179.3;

MS (EI): Ci ₅ H ₂₃ N0 ₂ : 249.17; [M+H] ⁺ : 250.20

DSC (10 °C/min): Peak at 147.16°C

(R S)-3-[(l-phenyl ethylamino)-methyl] -hexanoic acid [VHIb] :

FTIR (KBr pellets): 2956, 1619, 1549, 1400 cm ^"1 ;

1H NMR (CDCI ₃ , 200 MHz): δ 0.76-0.79 (t, 3H), 1.14-1.23 (m,4H), 1.66-1.68 (d, 3H),-2.26- 2.30 (m, 2H), 2.53-2.59 (t, 2H), 2.77-2.80 (d, 1H), 4.06-4.1 1 (q, 1 H), 7.31-7.57 (m, 5H); ¹³ C NMR (CDCI ₃ , 50 MHz): 14.0, 19.7, 20.5, 33.2, 36.2, 43.7, 51.6, 58.5, 127.5, 128.6, 129.2, 137.8, 179.5;

MS (EI): C, ₅ H ₂₃ N0 ₂ : 249.17; [M+H] ⁺ : 250.05.

DSC (10 °C/min): Peak at 120.1 °C Example 8: Hydrogenation of 5-hydroxy-l-[(R -phenyI-ethyl]-4-propyl-l,5-dihydro- pyrrol-2-one [VHb]

5-Hydroxy-l-[(^-phenyl-ethyl]-4-propyl-l ,5-dihydro-pyrrol-2-one (16.5 g) is dissolved in so-propanol (100 n L) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped. In the reaction, diastereomers are separated, (i?,i?)-3-[(l -phenyl ethylamino)- methyl]-hexanoic acid precipitates out from the reaction media and (S,i?)-3-[(l-phenyl ^; ethylamino)-methyl]-hexanoic acid remains dissolved in the reaction media.

After completion of reaction, the reaction mixture is filtered and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and ' stirred overnight to yield 6.0 g of (S',i?)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid as a off-white solid obtained after vacuum filtration.

Filtered cake contains Pd/C and (i?,i?)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid which is suspended in methanol and stirred for 20 min to dissolve (i?,i?)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid. Pd/C is separated by filtration. Filtrate is concentrated under vacuum to obtain 6.7 g of (R,R)-3-[(\ -phenyl ethylamino)-methyl]-hexanoic acid as white solid.

(R,R)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid [VIIIc] :

FTIR (KBr pellets): 2958, 1621 , 1548, 1397 cm ^"1 . Ή NMR (CDCb, 200 MHz): δ 0.80-0.87 (t, 3H), 1.17-1.22 (m, 4H), 1.67-1.70 (d, 3H), 2.13-2.19 (d, 2H), 2.44-2.61 (t, 2H), 2.74-2.80 (d, IH), 4.1 1-4.20 (q, IH), 7.30-7.54 (m, 5H); ¹³ C NMR (CDCI3, 50 MHz): 14.0, 19.8, 21.2, 32.7, 36.5, 44.2, 51.1 , 57.5, 127.4, 128.6, 129.2, 138.2, 179.2;

MS (EI): C, 5H ₂₃ N0 ₂ : 249.17; [M+H] ⁺ : 250.03.

DSC (10 °C/min): Peak at 148.1 1 °C

(S,/?)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid [Vllld]:

FTIR (KBr pellets): 2957, 1620, 1550, 1399 cm- ¹ .

Ή NMR (CDCb, 200 MHz): δ 0.75-0.81 (t, 3H), 1.18-1.41 (m, 4H), 1.65-1.69 (d, 3H), 2.20-2.33 (m, 2H), 2.49-2.60 (t, 2H), 2.76-2.82 (d, IH), 4.07-4.17 (q, IH), 7.32-7.54 (m, 5H). ¹³ C NMR (CDCI ₃ , 50 MHz): 13.9, 19.7, 20.5, 33.2, 36.2, 43.7, 51.5, 58.5, 127.5, 128.6, 129.1 , 137.8, 179.4;

MS (EI): Ci ₅ H ₂₃ N0 ₂ : 249.17; [M+H] ⁺ : 250.50.

DSC (10 °C/min): Peak at 1 19.3°C

Example 9: Hydrogenation of 5-hydroxy-l-[(S -phenyl-ethyl]-4-/sobutyl-l,5-dihydro- pyrrol-2-one [VIIc]

[VHIe] [Villi]

5-Hydroxy-l-[(5J-phenyl-ethyl]-4-wobutyl-l,5-dihydro-pyrr ol-2-one (5.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium- on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1 )]. After complete consumption of starting material, the reaction is stopped.

After completion of reaction, the reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 3.5 g of 3-[(l-(5)-phenylethylamine)- methyl]- 5 -methyl -hexanoic acid as off-white solid obtained after vacuum filtration.

FTIR (KBr): 3435, 2955, 1552, 1399, 702 cm ^-1 .

Ή NMR (CDCb, 200 MHz): δ 0.73-076 (t, 3H), 0.81-0.85 (t, 3H), 0.92-1.06 (m, 2H) 1.46-1.52 (m, 1H), 1.71-1.77 (m, 2H), 2.12-2.39 (m, 2H), 2.45-2.55 (m, 2H), 2.74-2.77 (d, 1H) 4.06-4.10 (q, 1H), 7.31-7.56 (m, 5H); ¹³ C NMR (CDC1 ₃ , 50 MHz): 20.8, 22.2, 22.6, 24.9, 31.4, 43.3, 44.0, 52.1, 58.8, 127.5, 128.5, 129.2, 137.9, 179.5;

MS (EI): C ₁₆ H ₂₅ N0 ₂ : 263.4; [M+H] ⁺ : 264.5.

Example 10: Hydrogenation of 5-hydroxy-l-[(if -phenyl-ethyl]-4-«obutyl-l,5-dihydro- pyrrol-2-one [VHd]

r iiih] 5-Hydroxy-l-[(5 phenyl-ethyl]-4- 5Obutyl-l,5-dihydro-pyrrol-2-one (5.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium- on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped.

After completion of reaction, the reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 3.5 g of 3-[(l-(i?)-phenylethylamine)- methyl]-5-methyl-hexanoic acid as a off-white solid obtained after vacuum filtration.

FTIR (KBr): 3434, 2956, 1546, 1397, 701 cm ^-1 .

1H NMR (CDCb, 200 MHz): δ 0.71-076 (t, 3H), 0.79-0.85 (t, 3H), 0.98-1.00 (d, 2H) 1.44-1.48 (m, 1H), 1.67-1.71 (d, 3H), 2.00-2.24 (m, 2H), 2.42-2.62 (m, 2H), 2.71 -2.77 (d, 1H) 4.09-4.20 (q, 1H), 7.36-7.53 (m, 5H); ¹³ C NMR (CDC1 ₃ , 50 MHz): 20.7, 22.5, 24.9, 31.2, 43.2, 43.9, 51.7, 58.6, 127.5, 128.6, 129.1 , 137.9, 179.5.

MS (EI): Ci ₆ H ₂₅ N0 ₂ : 263.4; [M+H] ⁺ : 264.2.

Example 11: Synthesis of 5-hydroxy-l-(2-hydroxy-l-(S)-phenyI-ethyI)-4- i-propyI-l,5- dihydro-pyrrol-2-one [Vile]

5-Hydroxy-4-«-propyl-5H-furan-2-one (10.0 g) is dissolved in methanol (100 mL) and (S)- phenyl glycinol (9.71 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 : 1 ethyl acetate: hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5- hydroxy- l -(2-hydroxy-l-phenyl-ethyl)-4-«-propyl-l ,5-dihydro-pyrrol-2-one as dark yellow oil

(15.0 g).

FTIR (neat): 3337, 2933, 1740, 1 167, 757 cm ^"1 .

Ή NMR (CDCI3, 200 MHz): δ 0.90-0.98 (m, 3H), 1.47-1.71 (m, 2H), 2.29-2.40 (q, 2H), 3.50- 3.60 (t, 1 H), 3.72-3.74 (d, 1H), 4.31 (s, 1H), 5.77-5.80 (d, 1 H), 5.99 (s, 1 H), 7.30-7.36 (m, 5H). MS (EI): Ci ₅ H, ₉ N0 ₃ : 261 ; [M+H] ⁺ : 262.30.

Example 12: Synthesis of 5-hydroxy-l-(2-hydroxy-l-(S)-phenyl-ethyl)-4-isobutyl-l,5- dihydro-pyrrol-2-one [VHf]

5-Hydroxy-4-wo-butyl-5H-furan-2-one (10.0 g) is dissolved in methanol (100 mL) and (£)-(+) phenylglycinol (8.83 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 : 1 ethyl acetate: hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5- Hydroxy-l-(2-hydroxy-l -phenyl-ethyl)-4-wo-butyl-l ,5-dihydro-pyrrol-2-one as dark yellow oil (14.0 g). FTIR (neat): 3337, 2933, 1740, 1 167, 757 cm ^"1 .

MS (EI): C, ₆ H _{2 l} N0 ₃ : 275.15; [M-H] ^" : 274.30.

Example 13: Synthesis of 5-hydroxy-l-(2-hydroxy-l-(R)-phenyl-ethyl)-4-isobutyl-l,5- dihydro-pyrrol-2-one [Vllg]

5-Hydroxy-4-w0-butyl-5H-furan-2-one (10.0 g) is dissolved in methanol (100 mL) and ( ?)-(-)- phenylglycinol (8.83 g) is added to it at room temperature. The mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 : 1 ethyl acetate: hexane), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5- Hydroxy-l -(2-hydroxy-l -phenyl-ethyl)-4-wo-butyl-l ,5-dihydro-pyrrol-2-one as dark yellow oil (14.0 g).

FTIR (neat): 3337, 2933, 1740, 1 167, 757 cm ^"1

MS (EI): C, ₆ H ₂ |N0 ₃ : 275.15; [M-H] ^" : 274.30.

Example 14: Hydrogenation of 5-hydroxy-l-(2-hydroxy-l-(S)-phenyl-ethyI)-4-n-propyl-l,5- dihydro-pyrrol-2-one [Vile]

5-Hydroxy-l -[(5 -phenyl-ethyl]-4-rt-propyl-l ,5-dihydro-pyrrol-2-one (10.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium- on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1 )]. After complete consumption of starting material, the reaction is stopped.

After completion of reaction, the reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 7.5 g of 3-[(2-hydroxy-l-(S)-phenyl ethyl amino)-methyl]-hexanoic acid as a semi solid material obtained after vacuum filtration.

FTIR (neat): 3584, 2931 , 1568, 732 cm ^"1 ;

l NMR (CDC1 ₃ , 200 MHz): δ 0.75-0.81 (t, 3H), 1.13-1.20 (m, 5H), 2.16-2.28 (m, 1H), 2.45 2.71 (m, 3H), 3.77-3.81 (m, 1H), 4.01 -4.14 (m, 2H), 7.25-7.40 (m, 5H).

Example 15: Hydrogenation of 5-hydroxy-l-[(S -phenyI-ethyl]-4-«obutyl-l,5-dihydro pyrrol-2-one [Vllf]

S-Hydroxy-l -f^-phenyl-ethylJ^-wobutyl-l ^-dihydro-pyrrol^-one (10.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium- on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by TLC [chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped.

After completion of reaction, the reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 6.0 g of 3-[(2-hydroxy-l -(5 -phenyl- ethylamino) methyl] -5 -methyl hexanoic acid as a semi solid obtained after vacuum filtration.

FTIR (neat): 2926, 1568, 1075 cm ^"1

1H NMR (CDC1 ₃ , 200 MHz): δ 0.72-0.86 (m, 6H), 0.92-0.99 (q, 2H), 1.06-1.24 (m, 1H), 1.32- 1.41 (m, l H), 2.17-2.29 (m, 2H) 2.54-2.73 (m, 2H) 3.83-3.89 (t, 1 H), 4.05-4.15 (d, 2H), 7.32-7,45 (m, 5H).

MS (EI): C _{l 6} H ₂₅ N0 ₃ : 279.03; [M+H] ⁺ = 280.65 Example 16: Hydrogenation of 5-hydroxy-l-[(R)-phenyI-ethyl]-4-/5obutyl-l,5-dihydro- pyrroI-2-one [VHg]

5-Hydroxy-l -[(S)-phenyl-ethyl]-4- 5obutyl-l ,5-dihydro-pyrrol-2-one (10.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium- on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by TLC [chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped. After completion of reaction, the reaction mixture is filtered to separate the Pd/C and filtrate is concentrated under vacuum to obtain a semi solid material, which is suspended in cyclohexane (300 mL) and stirred overnight to yield 6.0 g of 3-[(2-hydroxy-l-(5)-phenyl- ethylamino) methyl] -5 -methyl hexanoic acid as a semi solid obtained after vacuum filtration.

FTIR (neat): 2926, 1568, 1075 cm ^"1

Ή NMR (CDCb, 200 MHz): δ 0.72-0.88 (m, 6H), 0.95-1.05 (q, 2H), 1.23 (s, 2H), 1.43-1.46 (m,lH), 2.16-2.29 (m, 2H) 2.47-2.72 (m, 2H) 3.83-3.87 (m, 1H), 4.01-4.16 (m, 2H), 7.31-7.45 (m, 5H).

MS (EI): C ₁₆ H ₂₅ N0 ₃ : 279.03; [M+H] ⁺ = 279.90

Example 17: Synthesis of 5-hydroxy-4-propyl-l,5-dihydro-pyrrol-2-one [IXa]

5-Hydroxy-4-tt-propyl-5H-furan-2-one (1.9 g) is dissolved in methanol (50 mL) and while stirring ammonia gas is purged for 30 min at room temperature. Further, the reaction mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 9: 1 chloroform: methanol), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-4-propyl-l ,5-dihydro-pyrrol-2-one (2.1 g) as a dark yellow oil.

FTIR (neat): 3244, 2961 , 1749, 1574, 1030 cm ^"1 .

Ή NMR (CDCI ₃ , 200 MHz): δ 0.94-1.04 (m, 3H), 1.58-1.65 (m, 2H), 2.34-2.87 (m, 2H), 5.58- 5.63 (d, 1H), 5.92 (s, 1H).

MS (EI): C ₇ H, ,N0 ₂ : 141.09; [M+H] ⁺ = 141.89. Example 18: Synthesis of 5-hydroxy- -iso-butyl-l,5-dihydro-pyrrol-2-one [IXb]

5-Hydroxy-4- iO-butyl-5H-furan-2-one (1.5 g) is dissolved in methanol (50 mL) and while stirring ammonia gas is purged for 30 min at room temperature. Further, the reaction mixture is stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 9: 1 chloroform: methanol), the solvent is evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-4-/5O-butyl-l,5-dihydro-pyrrol-2-one (1.7 g) as a dark yellow oil. FTIR (neat): 3243, 2957, 1749, 1574, 1030 cm ^"1 .

Ή NMR (CDC , 200 MHz): δ 0.93-1.03 (m, 6H), 1.88-2.00 (m, 1H), 2.18-2.26 (t, 2H), 5.57-

5.64 (d, 1H), 5.98 (s, 1H).

MS (EI): C ₈ H ₁₃ N0 ₂ : 155.09; [M+H] ⁺ = 155.85. Example 19: Synthesis of racemic pregabalin from [VHd]

Compound [VHd] (4.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg/cm hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped.

After completion of reaction, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (1.5 g). Chiral HPLC analysis shows that material is racemic.

FTIR (KBr): 3338, 2956, 1540, 1409 cm ^"1 Ή NMR (CD3OD, 200 MHz): 0.91-0.96 (m, 6H), 1.22-1.23 (q, 2H), 1.64-1.74 (q, 1H), 2.20-2- 48 (m, 3H), 2.79-3.00 (m, 2H).

^,3 C NMR (CDCI3, 50 MHz): 21.4, 21.9, 24.3, 31.6, 40.5, 40.6, 43.5, 181.1.

MS (EI): C ₈ H, ₇ N0 ₂ : 159.13; [M+H] ⁺ = 159.96.

Example 20: Synthesis of pregabalin from diastereomeric mixture of [Vllle] & [Vlllf]

Diastereomeric mixture of [Vllle] and [Vlllfj (2.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After 24 h reaction is stopped, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.7 g). Chiral HPLC analysis shows 60 % ee for (R) -pregabalin Example 21: Synthesis of pregabalin from diastereomeric mixture of [Vlllg] & [VHIh]

Diastereomeric mixture of [VHIg] and [VHIh] (2.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % . catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After 24 h reaction is stopped, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.75 g). Chiral HPLC analysis shows 60 % ee for (S) -pregabalin

Example 22: Synthesis of pregabalin from diastereomeric mixture of [VHIk] and [Villi] Diastereomeric mixture of [VHIk] and [Villi] (2.0 g) is dissolved in methanol (100 mL) and 10 % acetic acid in a Parr autoclave reactor followed by addition of palladium-hydroxide on carbon (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After 24 h reaction is stopped, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.75 g). Chiral HPLC analysis shows ( ?S,) -pregabalin

Example 23: Synthesis of pregabalin from diastereomeric mixture of [ VHIkJ and [Villi] Diastereomeric mixture of [VHIk] and [Villi] (2.0 g) is dissolved in methanol (100 mL) and 10 % trifluoroacetic acid in a Parr autoclave reactor followed by addition of palladium hydroxide on carbon (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After 24 h reaction is stopped, the reaction mixture is filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.6 g). Chiral HPLC analysis shows 60 % ee for (./^-pregabalin

Example 24: Synthesis of pregabalin from diastereomeric mixture of [Vlllm] & [VHIn]

Diastereomeric mixture of [Vlllm] and [VHIn] (3.0 g) is dissolved in methanol (100 mL) and 10% trifluoroacetic acid in a Parr autoclave reactor followed by addition of palladium hydroxide on carbon (20 % catalyst loading).. Reactor is purged with hydrogen gas twice and _; . then 40 kg hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: . methanol (9: 1)]. After 24 h reaction is stopped and chiral HPLC analysis shows racemic pregabalin.

Example 25: Synthesis of racemic pregabalin from [Vllg]

Compound [Vllg] (3.0 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of palladium hydroxide on carbon (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg/cm ² hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9:1)]. After complete consumption of starting material, the reaction is stopped. After completion of reaction, the reaction mixture is filtered and filtrate is concentrated under vacuum to obtain a solid material (1.5 g). Chiral HPLC analysis shows that material is racemic. Example 26: Synthesis of racemic pregabalin from [Vllg]

Compound [Vllg] 3.0 g and ammonium formate is dissolved in ethanol (100 mL) in a glass reactor followed by addition of palladium hydroxide-on-carbon (20 % catalyst loading). Reaction mixture is stirred at 70 °C for 8 h. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped.

After completion of reaction, the reaction mixture is filtered to remove Pd/C and filtrate is concentrated under vacuum to obtain a semi-solid material (1.5 g). Chiral HPLC analysis shows that material is racemic. Example 27: Synthesis of racemic pregabalin from [IXb]

Compound [IXb] (1.7 g) is dissolved in methanol (75 mL) in a Parr autoclave reactor ;·. followed by addition of palladium hydroxide on carbon (10 % catalyst loading). Reactor is purged with hydrogen gas twice and then 5 kg/cm ² hydrogen pressure is maintained. _> Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of · starting material, the reaction is stopped. The reaction mixture is filtered and filtrate is concentrated under vacuum to obtain 1.6 g of compound [I]. Chiral HPLC analysis shows that material is racemic.

Example 28: Synthesis of 3-«-propyl-4-aminobutyric acid from [Villa]

2.0 g of compound [Villa] is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg/cm hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped and filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.8 g). Chiral HPLC analysis shows 64 % ee for (5^-3-«-propyl-4-arninobutyric acid.

FTIR (KBr pellets): 3400, 2958, 1549, 1391 cm ^"1

Ή NMR (D ₂ 0, 200 MHz): 0.94-0.96 (d, 3H), 1.38-1.43 (t, 4H), 2.01 (s, IH), 2.26-2.32 (q, IH), 2.41-2.46 (m, IH), 2.85-2.90 (q, IH), 2.97-3.01 (m, IH);

l ³ C NMR (CDCI ₃ , 50 MHz): 13.0, 19.5, 33.7, 34.6, 41.6, 43.9, 179.3.

MS (EI): C ₇ H| ₅ N0 ₂ : 145.1 1 ; [M+H] ⁺ = 146.03. Example 29: Synthesis of 3-«-propyl-4-aminobutyric acid from [VHIb]

2.0 g of compound [VHIb] is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg/cm ² hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped and filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.65 g). Chiral HPLC analysis shows 34 % ee for (/? -3-«-propyl-4-aminobutyric acid.

Example 30: Synthesis of 3-/i-propyI-4-aminobutyric acid from [VIIIc]

2.0 g of compound [VIIIc] is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg/cm ² hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped and filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.65 g). Chiral HPLC analysis shows 60 % ee for ( ?)-3-«-propyl-4-aminobutyric acid.

Example 31: Synthesis of 3-«-propyl-4-aminobutyric acid from [Vllld]

2.0 g of compound [Vllld] is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (20 % catalyst loading). Reactor is purged with hydrogen gas twice and then 40 kg/cm ² hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped and filtered to remove catalyst (Pd/C) and filtrate is concentrated under vacuum to obtain a solid material (0.65 g). Chiral HPLC analysis shows 64 % ee for (5^-3-«-propyl-4-aminobutyric acid.

Example 32: Synthesis of 3-«-propyl-4-aminobutyric acid from [Villa] by

oxidative debenzylation

1.0 g of compound [Villa] is dissolved in dimethyl sulfoxide (20 mL) in a RB flask, followed by addition of N-bromosuccinimide (0.7 g). The reaction mixture is stirred at room temperature for 2 h or until all the generated bromine gets decolorized. DM water (20 mL) is added to the reaction mixture and stirred for another 20 min. Ethyl acetate (20 mL) is added to the reaction mixture followed by separation of the organic and aqueous phases. The aqueous phase is washed with 10 mL of ethyl acetate and the aqueous phases collected which contain the product (0.5g). Chiral HPLC analysis shows 80 % ee for f -3-rc-propyl-4- aminobutyric acid.

Example 33: Synthesis of 3-«-propyI-4-aminobutyric acid from [Vlllb] by

oxidative debenzylation

1.0 g of compound [Vlllb] is dissolved in dimethyl sulfoxide (20 mL) in a RB flask, followed by addition of N-bromosuccinimide (0.7 g). The reaction mixture is stirred at room temperature for 2 h or until all the generated bromine gets decolorized. DM water (20 mL) is added to the reaction mixture and stirred for another 20 min. Ethyl acetate (20 mL) is added to the reaction mixture followed by separation of the organic and aqueous phases. The aqueous phase is washed with 10 mL of ethyl acetate and the aqueous phases collected which contain the product (0.55g). Chiral HPLC analysis shows 24 % ee for ( ? -3-«-propyl-4- aminobutyric acid.

Example 34: Synthesis of 3-«-propyl-4-aminobutyric acid from [VIIIc] by

oxidative debenzylation 1.0 g of compound [VIIIc] is dissolved in dimethyl sulfoxide (20 mL) in a RB flask, followed by addition of N-bromosuccinimide (0.7 g). The reaction mixture is stirred at room temperature for 2 h or until all the generated bromine gets decolorized. DM water (20 mL) is added to the reaction mixture and stirred for another 20 min. Ethyl acetate (20 mL) is added to the reaction mixture followed by separation of the organic and aqueous phases. The aqueous phase is washed with 10 mL of ethyl acetate and the aqueous phases collected which contain the product (0.47g). Chiral HPLC analysis shows 60 % ee for (7?)-3-n-propyl-4- aminobutyric acid. Example 35: Synthesis of 3-/t-propyl-4-aminobutyric acid from [VHId] by

oxidative debenzylation

1.0 g of compound [Vllld] is dissolved in dimethyl sulfoxide (20 mL) in a RB flask, followed by addition of N-bromosuccinimide (0.7 g). The reaction mixture is stirred at room temperature for 2 h or until all the generated bromine gets decolorized. DM water (20 mL) is added to the reaction mixture and stirred for another 20 min. Ethyl acetate (20 mL) is added . to the reaction mixture followed by separation of the organic and aqueous phases. The aqueous phase is washed with 10 mL of ethyl acetate and the aqueous phases collected which ' contain the product (0.46g). Chiral HPLC analysis shows 64 % ee for fS,)-3-«-propyl-4- aminobutyric acid.

Example 36: Synthesis of 3-/i-propyl-4-aminobutyric acid from [IXa]

Compound [IXa] (2.1 g) is dissolved in methanol (100 mL) in a Parr autoclave reactor followed by addition of palladium hydroxide on carbon (10 % catalyst loading). Reactor is purged with hydrogen gas twice and then 5 kg/cm hydrogen pressure is maintained. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped. The reaction mixture is filtered and filtrate is concentrated under vacuum to obtain 1.9 g of compound [II]. Chiral HPLC analysis shows that material is racemic. Example 37: Synthesis of 3-hydroxymethyl-hex-2-enoic acid ((S)-l-phenyl-ethyl)-amide [X]

5.0 g of compound [Vila] is dissolved in methanol (20 mL) in a RB flask at 0 ^U C and NaBH ₄ (0.9 g) is added in 4 portions. The reaction mixture is stirred at room temperature for 2 h at 0 °C and further 2 h at room temperature. Reaction is monitored by TLC [Chloroform: methanol (9: 1)]. After complete consumption of starting material, the reaction is stopped and poured in 100 mL of water stirred at 40 °C for 6 h. Reaction mixture is then extracted with ethyl acetate (200 mL). Organic phase is washed with brine and solvent evaporated under reduced pressure to obtain 3.0 g of compound [X], as yellow oil.

FTIR (KBr): 3460, 2962, 1681, 1451 cm ^"1

Ή NMR (CDCb, 200 MHz): 0.86-0.93 (t, 3H), 1.41-1.57 (m, 5H), 2.19-2.27 (t, 2H), 3.38-3.48 (d, 1H), 3.72-3.81 (d, 1H), 5.46-5.57 (q, 1H), 5.81 (s, 1H), 7.27-7.34 (m, 5H).

MS (EI): C, 5 H ₂₁ N0 ₂ : 247.16; [M+H] ⁺ = 248.05.