Held of the Invention:
The invention relates to a process lor preparation of enantiomerically enriched and/or
mcemic y-amino acids. particularly those useful for preparing y-amino acids that exhibit
binding affinin to the human a26 calcium channel subunit. including pregabalin and
related compounds such as 3-/7-propyl-4-aminobutyric acid.
Background of the Invention:
(.S)-3-(Aminomethyl)-5-methylhexanoic acid [CAS No. 148553-50-8]. which is also
called |-J-isobutyl-y- aminobutyric acid. isobutyl-GAHA. or pregabalin |l| is a potent
jnliconuilsant. 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. ph>siological 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
\'o. 6.326.374: U.S. Patent No. 6.001.876: U.S. Patent No. 6.194.45°: l.'.S. Patent No. 6.
329. 429: U.S. Patent No. 6. 127.418: U.S. Patent No. 6.426. 368: l.'.S. Patent No.
6.306.910: l.'.S. Patent No. 6.359.005).

I .S Patent No. 6359169 and Journal of Medicinal Chemistry (1991. 34. 2295 2298)
report the anticomulsani activity for 3-/7-propyl-4-aminobuiyric acid |CAS No. 90048-
40-1. l3()9l2-49-l| |ll|.


A number of symbolic schemes have been developed for pregabalin. Typically, a racemic
mixture o\' 3-amiiu>methyi-5-methyihe.xanoic acid is synthesized and subsequently
resolved into (A'^and (.sy enantiomers. Such methods ma> employ an azidc intermediate,
a malonate intermediate or a nitrile intermediate. More details are discussed hereinafter.
IS patent No. 5.637.767 disclosed the method for synthesis of (.SVpregabalin. In this
process isovaleraldehyde is reacted with diethyl malonate to obtain 2-carboxyelhy 1-5-
methylhex-2-enoic acid ethyl ester, which is further reacted with potassium cyanide to
obtain 2-carboxy ethyl 3-cyano-5-melhyihexanoic acid ethyl ester. I lydrogcnalion of 2-
carbox\ethyl 3-cyano-5-melhylhexanoic acid ethyl ester in presence of nickel gives the
racemic pregabalin. which is further resolved with (.V)-mandelic acid to obtain
pregabalin. Although the above method provides the f.S>pregabalin in high optical
purity. the overall yield is \ery poor. Furthermore, the process uses potassium cyanide
which is \er\ toxic and hazardous, and to be avoided. Reaction scheme is depicted in
figure 1.
I S Patent No. 5.616. 573 disclose the method for synthesis of pregabalin from 3-isobulyl
glutaric acid. 3-isobut>l glutaric acid is converted to its corresponding anhydride b>
relluxing with acetic anhydride. Subsequent reaction with Nll.iOll produces the glutaric
acid mono-amide, which is resolved with fA^-u-phenylethyl amine, yielding the
corresponding salt. Decomposition of salt gi\es the (/^-enanliomer. which on Hoffmann
degradation with Br.- NaOII provides f.sy-pregabalin |l|. The above process, as depicted
in figure 2. invokes 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 l;S
Patent No. 5.616. 57". Here resolution of glutaric acid mono-amide is \iu ephedrine or
norephedrine yielding the corresponding salt. Decomposition of salt gi\es the (Rh
enanliomer. which on Hoffmann degradation with Br> NaOIl provides f.S>pregabalin |1).
.Although the above method is providing the f.S>pregabalin in high optical purity but
o\erall yield is \ery poor. Reaction scheme is depicted in figure 3. I he abo\e process
involves ihe use of hazardous chemical such as bromine, which is not eco-friendly .
I S patent 5.563.175 discloses the preparation otV.S>pregabalin using stoichiometric (■ )-
4-methy l-5-pheny l-2-oxa/olidinonc as a chiral auxiliary. The above mentioned process
includes the use of pyrophoric and hazardous reagents, such as //-butyl lithium, which
leads lo number o\' side reactions and decreases the overall yield. Reaction scheme is
depicted in figure 4. Although the above method provides the ^SV-pregabalin in high
optical purity. il is not desirable process for synthesis at industrial scale because it uses
costly chiral auxiliary and requires the special cryogenic conditions lo reach required
operating temperature, which can be as low as -78 '(.'.
WO i.)l 55090 Al. reports the asymmetric hydrogenalion of a eyano intermediate lo
produce a cyano precursor ofASV-aminomethy I 5-methyl hexanoic acid, which is further
reduced lo obtain f.SV-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 (.'.- symmetric
bisphosphinc ligands. including (A'. R) Me-I)lJfMIOS. 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 aery lonitrile
and the use o\' highly toxic carbon monoxide under high pressure. Reaction scheme is
depicted in figure 5.
Process disclosed by (i. M. Sammis ct ul. (.1. Am. Client. Soc. 2003. 125(15) 4442-43)
describes an aluminum salen catalyst which is used in the conjugate addition of hydrogen
cyanide lo a.^-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 salon
catalyst, which is very costl> and creates significant impact on the final cost of the
product. Reaction scheme is depicted in figure 6.
\\ () 2006 11078} reports several processes for preparing /.SV-pregabalin \ia the following
intermediate and its analogues. Reaction scheme is depicted in figure 7.
IS Patent No. 6.924.377 discloses the method for synthesis of pregabalin through
reductive animation of mucohalic acid and its derivatives. I his process needs special
exogenic equipment to reach required operating temperature, which can be as low as -30
"('. Overall yield is poor and requires column chromatography at most of the stages to
obtain pure intermediate or product. I lence 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*diehloro-
3-isobuly Icyclobutanone. Reaction scheme is depicted in figure 9
Desymmelri/aiion of a symmetric anhydride via enanlio-selective alcohols sis lo
generates the corresponding hemiester. a highly functionalized chiral product with «.>nc or
more stereogenic centers. (C'hem. Commun. lt)85. 1717-1718: J. ("hem. Soc. I'orkin
Irons I. 1987. 1053-1058: Chem. Commun. 1988. 632-633: J. Org. C'hem 2000. 65.
Oi)84-6990; Org. Synth. 2005. 82. 120-125: JACS 2000. 122. 9542-9543: J. Org. Chem
1998. 63. 1190-1 197: Chem. Rev. 2003. 103. 2965-2983: Chem. Rev. 2007. 107. 5683-
5712). has been described in the reference cited heroin.
Significantly. desymnietrizalion of glutaric /77t\SYKinhydrides with nucleophiles both
chiral and achiral such as amines, benzyl aminos, alcohols etc. is \ery well documented
i (hem. Re\. 2003. 103. 2965-2983: Chem. Rev. 2007. 107. 5683-5712).
Schwarl/ and Carter (1954) have reported the diastereo-seleclive process for obtaining 3-
phen\l-4-( l-phenyl-elhylcarbamoyl)-buiyric acid by reacting 3-phenyl glutaric anhydride
with (.SVphenyleihylamine. The product is isolated in 95°o 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 NH4OH 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 (5)-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 2007O357S9 AI reports the synthesis of pregabalin via ehiral intermediate obtained
through Hoffman degradation. This process is also not practical for large scale production
due to the use of highh poisonous reagents such as bromine and sodium metal. This
process neech the special cnogenic equipment to reach required operating temperature,
which can be as low as -60 "C. Reaction scheme is depicted in Figure 1 I.



I S Patent Application No. 2008'0306292 reports the synthesis of pregabalin i/.vchiral
intermediate through Hoffmann degradation, further Indrolysis gives the pregabalin.
I his process is also not practical for large scale production due to the use of highh
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. N'MR or mass of the compound |III| are not pro\ ided
neither am enablement whatsoever of compound |lll| are disclosed. Also, it i>> very
difficult to rationalize the production or generation of compound (Nl|. 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 lo produce
compound jlllj can neither be a synthesis method nor an industrial process.


\V()2()()(M)812()X.\1 discloses the process lor preparation of racemic pregabalin. I his
process is also not practical for large scale production due to the use of highh 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-io-operate industrial-scale synthesis of y-amino acids.
I his invention provides that.
Summary of Invention:
flic present imcniion is directed towards the process for preparation of enanliomerically
enriched compounds of formula IV

wherein Ri is 11 (compound 11Va[) or Ri is CI h(compound |lVb|).
Comprising:
Scheme 1:
a) Reaction of the compound |V| with fSjor (R) I'hCl l:(NI h)R| |YI| to
pro\ ide compound |\'ll|. Incidental!). |VII| is a no\el class o\'

(.■impound and one of the invcnti\e merits of the application like is in
the synthesis of | VIII | from | VII |.

el I hdroLienolysis. catalytic or stoichiometric of compound |VIII| to provide
enantiomerically enriched compound |IV|

bt I Kdrogenalion. catalytic or sioichiomctric of compound |IX| to compound
|IV|

Brief Description of Accompanying Drawings
1 igure 1: Reaction Scheme of US patent No. 5.637.767
figure 2 Reaction scheme of US Patent No. 5.616. 573
figure ."Reaction Scheme of WO2006 122259
figure 4 Reaction Scheme of US patent 5.563.175
Figure 5 Reaction Scheme of WO 01 55000
figure 6 Reaction Scheme (i. M. Sarnmis ci ul
figure 7 Reaction Scheme WO 2006 110783
figure X 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 I 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
V11 Id and VI lie
figure 16 Schematic representation of formation of compound Vile with precipitation of
Vllleand Vlllf

figure 17 Schematic representation of formation of compound Vlld with precipitation of
Vlllh aiul Vlllg
1 ;i yii re 18 Schematic representation of formation of compound Vile with precipitation of
Villi and Villi
figure 1(> Schematic representation of formation of compound VI If with precipitation o\'
\"IIIk and Villi
figure 20 Schematic representation of formation of compound Vllg with precipitation of
Vlllmand VII In
figure 21 Schematic representation of formation of compound IXa which on
hydrogenohsis gi\es compound II
figure 22 Schematic representation of formation of compound IXb which on
hulrogenolysis gives compound I
figure 2? Schematic representation of formation of compound Vila and further
formation oi' compound X
Detailed descriptions:
The invention provides method for synthesis of enatiomerically enriched y-amino acid |IV|
according to the following schemes 1 and 2.

R II.CM;
R: CM;. ('IU)II

According 10 one aspect, the present invention provides the process for the preparation of
/-amino acid |IV| from compound [V|. In one aspect, compound |V| is reacted with
compound |VI| and thereafter the resulting compound |VII| is hydrogenated lo obtain
compound |VIII|. further, hvdrogenolysis of compound |V1II| produces the
enanliomericalK enriched "/-amino acid [IV|.
According to one aspect, the present invention provides the process for the preparation of
y-amino acid |I\'| from compound [\'|. In one aspect, compound |V| is reacted with
compound |\'l| and thereafter the resulting compound |VI1| is hydrogenated to produces
the enanliomericalK enriched y-amino acid [IV].
According to another aspect, the present invention pro\ides the process for the
preparation of/-amino acid |IV| from compound |V|. In one aspect, compound |V| is

reacted v\ i i h compound |\'I| and thereafter the resulting eompound |\'ll| is
h\drogenol\/cd through eatalytie transfer hydrogenation in presence ol" ammonium
formate to produce the y-amino acid |IV|.
According to another aspect, the present imention provides the process for the
preparation of racemic y-amino acid |1V] from compound |V| where compound |Y| is
reacted with ammonia and thereafter the resulting compound |IX| is hulrogcnatcd to
produces the racemic y-amino acid [IV|.
Topically, compound | VII| is s\nthesi/ed by reacting compound \\'\ with compound | VI|
which is carried out in polar and non-polar sohenls. Polar soKents such as. methanol,
eihanol. /v^-propanol. letrahydrofuran. di-/>v;propyl ether etc are used and non-polar
solvents such as dichloromethane. toluene are used: preferably, methanol and isopropyl
alcohol and more preferabh isopropxl alcohol.
According to one of the embodiments, compound |VII| is obtained by reacting compound
|\ | with compound |VI|. Compound |VI| is chiral or achiral primar\ amine. prefcrabK
with chiral priniar> amines such as (.SV(-)-r/-melh>l benzyl amine. (A')-( ■ K/-methyl
ben/yl amine. (.S')-( - )-phen\ I glycinol and (A')-(-)-phen\ I glycinol.
Compound |Y1I| is usually obtained by conducting reaction at temperature of about 25 to
80 "C. Prelerabl\. the temperature maintained during the reaction is about 25 to 30 "C.
After completion of reaction, solvent is distilled out to obtain compound |\'M| as yellow
oil.
Thereafter, the resulting compound |VII| is hydrogenated in alcoholic solxent. in
presence of a noble metal catalyst under hulrogen pressure to obtain compound | VIII |.
Alcoholic sohent may be selected from methanol, ethanol. /w-propanol: prel'erably
methanol and /\<>-propanol.

(ienerally. hydrogen pressure is about I kg cm" to 5 kg cm": preferably 3 kg cm" 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.
Alter the completion of reaction, reaction mixture is filtered through lilt rule pad to
remove the catalyst. SoKent is distilled out to obtain compound | VIII |.
I lydrogenolysis of compound |YIII| is carried out in an alcoholic solvent and Bronsted
acid, in presence of a noble metal catalyst under hydrogen pressure to obtain the
corresponding enantiomerically enriched y-amino acid.
Alcoholic solvent may be selected from methanol, ethanol. /.so-propanol: preferably
methanol.
(ienerally. hydrogen pressure is about 10 kg cm" to 50 kg cm", preferably 40 kg cm"
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
trilluoroacetic acid: preferably acetic acid and irilluoroacetic acid: more preferably
trichloroacetic acid.
Compound |Vlla] is obtained from reaction of compound |Va| where R II with {S)-a
methyl ben/yl amine |Vla| and is hydrogenated in presence of noble metal catalyst
(I'dC) under hydrogen pressure in /.vo-propanol to give the diastereomeric compounds
|VIIIa| and |\'IIIb| respectively, which get separated during the reaction. Compound

|VIIIa| precipitates oi.il from reaclion. leaving compound | VIIIb| dissolved in the reaction
media figure 14 giscs the schematic representation.
Compound |YIIb| obtained from reaction of compound |Ya| where l< II with {tt)-u.
methyl ben/yl amine |Vlb| is hydrogenated in presence of noble metal catalyst (IMC)
under hydrogen pressure in /.w-propanol to give the diastereomeric compounds | YIIIc| &
|\'IIId| respectively, which get separated during the reaclion. Compound |Ylllc|
precipitates out from reaction, leaving compound | VMId) dissolved in the reaction media,
figure 15 gives the schematic representation.
Compound |Yllc| obtained from reaction of compound |Vb| where R -('II; with (.sy«-
methyl ben/yl amine |Vla| and is hydrogenated in presence of noble metal catalyst
(l'd(') under hydrogen pressure in /.«>-propanol to gi\e the diastereomeric compounds
| VIlie| & |\'IIIf| respecti\ely. as depicted in figure 16.
Compound |Vlld| is obtained from reaction of compound |Vb| where R C.'lh with (R)-
-propanol to gi\e the diastereomeric
compounds | VIIIg| & |VllIh| respectively, as depicted in figure 17.
Compound |Vlle| obtained from reaclion of compound |Va| where R II with (.S") ( •■ )-
phenyl glycinol |Ylc| is hydrogenated in presence of noble metal catalyst |1M(()H):'C|
under hydrogen pressure in methanol to give the diastereomeric compounds |Yllli| &
|Ylllj| respectively, figure 18 represents the reaclion scheme.
Compound | YIII'| obtained from reaclion of compound [Vb| where R CII: with {St ■( )-
phenyl glycinol |Yle| is hydrogenated in presence of noble metal catalyst |1M(()1I); C|
under hydrogen pressure in methanol to give the diastereomeric compounds | VII Ik | &
| V1III| respectively, figure ll) represents the reaction scheme.

Compound |Vllg| obtained from reaction of compound |Vb| where R-('lh with (R) (-)-
phen\l gUcinol |VId| is Indrogenaled in presence of noble metal catalyst |1\J(()I I): Cunder h\drogen pressure in methanol to give the diaslereomeric compounds |Vlllm| &
|\'IIIn| respective^, figure 20 represents the reaction scheme.
I Kdrogenohsis of compounds |\'Illa|. |\'lllb|. |YIIIc|. and |VIIId| with palladium on
carbon under hulrogen gas pressure of 40 kg cm", in methanol gi\es the enanliomerically
enriched compound |II| having % tvus summarized in Table 1.

()\idali\e deben/\ lalion of compound | Villa |. |\'lllb|. |VIllc|. and |\'llld| with N-
bromosuccinimide in polar solvents such as /tr/-butanol and dimelhyl sulfoxide is done to
obtain enanliomericalh enriched compound |ll| having following "o cc. which is
summari/ed in fable 2.

All the abo\c compounds [Villa to d| are diaslereomericalk pure. Thus, further
hydrogenolysis with these compounds as starting materials gives the enanliomerically
enriched compound |ll| as shown in fable 1 and fable 2.

I lydrogenolysis ol' the diastcreomeric mixture of compounds |Vlllc| & |Villi] in
presence ol" ptilIcicliinn on carbon under hydrogen gas pressure of 40 kg cm', in methanol
and 10 "o acetic acid gives the compound |l| having 60 % cc for (/O-pregabalin. In this
case. hydrogenolysis is monitored by I LC and after about 75 to 80 "<> conversion:
reaction is slopped and monitored by chiral 111*1.C lor % cc.
I lydrogenolysis ol' the diastcreomeric mixture of compounds [Vlllgl & |\'IIIh| in
presence of palladium on carbon under hydrogen gas pressure of 40 kg cm', in methanol
and 10 "o acetic acid gives the compound |1| having 60 % tv for (.S)-pregabalin. In this
case. hydrogenolysis is monitored by TI.C and after about 75 to 80 % conversion reaction
is slopped and monitored by chiral HPI.C for % cc.
I lydrogenolysi* of the diaslereomeric mixture of compounds |Ylllk| & |YIIII| with
palladium hydroxide on carbon under hydrogen gas pressure of 40 kg cm", in methanol
and 10 "o trichloroacetic acid gives the compound |l| ha\ing 50 % cc for (A')-pregabalin.
In this case, hydrogenolysis is monitored by TI.C and after about 75 to 80 % comersion
reaction is stopped and monitored by chiral HPI.C for % cc.
HydrogenoKsis o\ the diaslereomeric mixture of compounds |VIIIk| & |\'1III| with
palladium hulroxide on carbon under hydrogen gas pressure of 40 kg cm', in methanol
and 10 "o acetic acid gives the raeemic compound |l).
The rale of deben/ylation of mixture of compounds | V111 k | & [ VIIII| increases by 2 folds
in presence of trichloroacetic acid as compared to acetic acid.
I lydrogenolysis ol'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 gi\e the
raeemic compound |l|.
1 lydrogenolysis ol' mixture ol'compounds | V111 in | and |Vllln] in presence oC palladium
hydroxide on carbon under hydrogen pressure oC 40 kg cm', in methanol and 10 %
trichloroacetic acid gi\es the raeemic compound |l| as seen by chiral HPI.C analysis.

I lydrogenoKsis of compound | V'Ilg| in presence of palladium hydroxide on carbon under
Indrogen pressure of 40 kg cm', in methanol and 10 % trifluoroaeelic acid gi\es the
raeemic compound 111 as seen by ehiral 11 PLC analysis.
Catahtic transfer lndrogenation (("I'M) of compound |VlIg| with ammonium formate in
presence ol' palladium hydroxide on carbon as a catalyst, in ethanol gi\es the raeemic
compound |1|. as seen by ehiral IIIM..C analysis.
In principle, if one i.s able to separate the diastereomers. then enantiomericalb enriched y-
amino acid |1V| can he obtained, This has been demonstrated tor the diaslereomerically
pure compounds | Villa to d|: which on further hydrogenolysis gi\e the enaiuiomericalK
enriched compound [ll| (as shown in fables 1 and 2).
On the other hand, compounds | Vllle to n| are obtained as diastereomeric mixture, which
on further hydrogenolysis give the raeemic compound |1|. Since, in the present case,
diastereomers arc not separated e\en by using costly ehiral amines, hence we thought of
replacing these ehiral amines with cheap and easily available achiral amines for the
preparation of raeemic compound |IV| thereby making the process more cost effective,
'green", atom economical and easy to operate at large scale.
1 his postulalion is pro\en true when compound |V| is reacted with simple amine such as
ammonia to obtain compound |IX|. which on further hulrogenolysis gi\es the raeemic
compound | IV |.
Compound |IXa| is obtained from reaction of compound |Va| where R II with ammonia
and further Indrogcnohsis gives the compound |1I|. figure 21 gi\es the schematic
representation.
Compound (IXb| is obtained from reaction of compound |Vb| where 1< CI I: with
ammonia and further hydrogenolysis gives the compound |l|. figure 22 gi\es the
schematic representation.

Compound |Vlla| is obtained from reaction of compound |Va| where K~II with (S)-a
motln 1 hen/\I amine |Vla| and further reduction of compound [VIIa| in presence of
sodium borohxdride gives the compound |X|. figure 23 gi\es the schematic
representation.
Compound |\'IIIa] i> reacted with (.SV(-)-l.l "-bi-2-naphthol to obtain co-cr\stal ha\ing
composition 1:1 for which, the single crjstal analysis details are disclosed in our co-
pending patent application entitled "Novel method of resolution of (/<*>■)-1.1 '-bi-2-
naphthol for obtaining enantiomeric pure i.e. (.SV(-)-l.l'-bi-2-naphthol and or (/{)-{-)-
l.r-bi-2-naphthol via co-crystal formation with optically acli\e derivatives of -/-amino
acids".
Nomenclatures used for the compounds mentioned herein are as understood from the
CambridgeSofi R ChemOffice software ChcmDruw I :ltra version 6.0.1.
Analytical Methods:
I he enantiomeric excess ice) is determined by HPLC using a Shimad/u I.C 2010 system
equipped with a chiral column (Purosphere star RP-l8e (4.6 x 150mm). 5pm). column
oven temperature 25 "C and I'V \isible detector (l:\' at 34()nm). Mobile phase is buffer:
acetonitrile (55:45) with llow rate 1.0 ml."', injection volume 20 JLL 1. The enantiomeric
excess Uv) is determined b\ deri\ati/ed by reacting with Murph\"s reagent. NV1R
X
spectra are obtained at 200 and 400 Mil/ Bruker instruments, with (TX'h as solvent.
Chemical shifts (<■)') are given in ppm relative to tetramethylsilane [<)■ 0 ppm). IR spectra
are recorded on Pork in l-lmor Spectrum (Model: Spectrum 100) and absorption bands are
given in cm"1. DSC is recorded on Perkin F-lmer model Diamond DSC at the rale of 10
"(" min. and endolhermic peak is recorded in "(' and AH is reported in J g.

Kxamplc 1: Synthesis of S-hydroxy-4-u-propyl -5//-furan-2-onc |Va) (J. ()r«. C'hcm.
1981,46,4889-4894)

/7-lleptane (394 ml.) and morpholine (127.5 ml.) arc introduced in a rcaci(>r while stirring.
The mixture is cooled to 0" (.' and glvoxvlic acid (195 g. 150 ml.. 50 wt "n in water) is added.
I he mixture is healed to 20;; (' during 1 hour and then /7-valeraldehydc (I4X.8 ml.) is added.
The reaction mixture is heated at 45" (.' during 20 hours. Alter cooling down to 20; ('. 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.
I)i-/.so-propv I ether is added to the aqueous phase. I'he organic phase is removed and the
aqueous phase further extracted with di-/w-propyl ether (2x). The di-/><;-prop\l ether layers
are combined, washed with brine and then dried under reduced pressure. Alter evaporation of
the solvent. 100.0 g of 5-hvdrox\-4-//-propyl-5//-furan-2-one are obtained as light brown oil.
ri'IK(nvat): 3367. 1735 cm"1.
'II N.MR (( IX lj, 200 MHz): r> 0.93-1.00 (t. 311). 1.56-1.67 (q. 211). 2.31-2.43 (q. 211). 5.81
Is. III). 6.02 (s. 111).
MS (KI): C -I !,.(>:: 142.06: |M :-H|": 142.93.
Kxamplc 2: Synthesis of 5-hydroxy-4-/v«-butyl -5//-furan-2-one |Vb| (.1. Org. C'hem.
1981,46,4889-4894)


//-Heptane (75.0 ml ) and morpholine (17.8 g) are introduced in a reactor while stirring. The
mixture is cooled to 0' C and glyoxvlic acid (2°.6 g. 50 \vi% in water) is added. The mixture
is heated to 20 (.' during 1 hour and then 4-meth\l valeraldehvde (20.0 g) is added. The
reaction mixture is heated at 45c C during 20 hours. Alter cooling down to 20 (.'. a 37 %
aqueous solution of hydrochloric acid (30 ml.) is slowl> added to the mixture, which is then
stirred during 2 hour*.
\lter removal of the //-heptane phase, the aqueous phase is washed three limes with //-
heptane. l)i-/sv>-propy| ether is added to the aqueous phase. The organic phase is removed
and the aqueous phase further extracted with di-/sr'-propyl ether (2\). The di-/s<>-propyl ether
layers are combined, washed with brine and then dried under reduced pressure. Alter
evaporation of the solvent. 13.0 g of 5-hydroxy-4-/.sY4niiyl-5//-furan-2-one are obtained as
light \ellow oil.
I-TIR (neal): 3371. 1738 cm"1.
'H NMR (C'DCIJ, 200 MHz): rf().87-0.99 (t. 611). 1.87-2.01 (m. III). 2.28-2.32 (d. 211). 5.82
(s. III). Ml (s. 111).
MS(FI):Cxlli;();: I 56.06: |M-II|": 155.0".

Example 3: Synthesis of 5-hydroxy-l-|(.S>phenyl-ethyl|-4-//-propyl-l,5-dihydro-pyrrol-
2-one|Vlla|

5-Ilydro\v-4-//-propvl-5//-furan-2-one (10.0 g) is dissolved in /vo-propanol (100 ml.) and
(.SW-methyl ben/\| amino (8.5 g) is added to it at room temperature. The mixture is stirred
at room temperature lor 1 hour. After completion of the reaction (monitored by I'l.C 1:1
ethyl aeetale:hexane). the solvent is evaporated under reduced pressure in a rotar> evaporator
lo afford 5-h>dro.\>-l-|(.S>phenyl-ethy||-4-^prop\i-L5-dihydro-p\rn)l-2-one as dark yellow
oil (16.5 ui.
FT1R (neat): 332 1. 1 749. 1165 cm"1.
'H NMR (CIK'IJ, 200 MHz): rf().86-0.94 (l. 311). 1.32-1.37 (t. 3H). 1.43-1.57 (m. 211). 2.12-
2.39 (m. 211). 4.27-4.30 (d. III). 5.15 (s. 111). 5.70 (s. 1II). 7.25-7.34 (m. 511).
MS(KI): C|?ll|.,NO.<: 245.14: |M *-l 11": 246.1 5.
Example 4: Synthesis of 5-hydroxy-l-|(A?>phenyl-ethyl|-4-^propyl-l,5-dihydro-pyrrol-
2-onc |Mlh|
5-1 l\dro\\-4-/7-prop\ l-5/7-furan-2-one (10.0 g) is dissolved in /.so-propanol (100 ml.) and
(A')-tf-nioth>l ben/yl amine (8.5 g) is added lo it at room temperature. The mixture is stirred

ill room temperature lor 1 hour. After completion of the reaction (monitored by ll.(\ 1:1
elhyl acclalc:hexanc). the soKent is evaporated under reduced pressure in a rotary evaporator
to afford 5-hy droxy -1 -| (AV-phenyl-ethyl |-4-/;-propy I-1.5-dihydro-py rrol-2-one as dark
yellow oil (16.5 g).
I-MR (neat): 3321. 174". 1 165 cm"!.
'H NMR (C'IKIJ, 200 MHz): ^0.86-0.94(1. 311). 1..12-1.37 (t. 311). 1.43-1.57 (in. 211). 2.12-
2.39(11!. 211). 4.27-4.30 (d. III). 5.15 (s. IH). 5.70 (s. 111). 7.25-7.34 (m. 511).
MS(KI): C"i?ll|.,N():: 245.14: |M--[I|": 246.15.
Kxample 5: Synthesis of 5-hydroxy-l-|(.S>phcnyl-cthyl|-4-/v/>-butyl-l,5-dihydro-pyrrol-
2-one|Vllc|

5-1 ly droxy-4-/.sv>-huty l-5//-furan-2-one (10.0 g) is dissolved in /w-propanol (100 ml.) and
i .S*)-tf-meihy I ben/yl 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 II.C. 1:1
ethyl acelaie:hexane). the solvent is evaporated under reduced pressure in a rotary evaporator
;o afford 5-hy droxy -1 -|(.SVpheny l-ethy 1 |-4-/.sy>-buly I-1.5-dihydro-py rrol-2-one as dark
yellow oil (15.5 g).
V MR (neat): 33 19. 2959. 1 751. 1166 cm"1.

111 N.V1R (CIK'lj, 200 MHz): tf 0.86-0.94 (t. .111). 0.96-0.99 (I. 311). 1 34-1..18 kl. 211). 1.49-
1.53 ul. 111). 1.75-l.85(m. 1H). 2.24-2.27 (d. 21-1). 4.27-4.30 (q. 111). 5.17 (s. III). 5.88 (s.
III). 7.26-7.37 nil. 511).
MS(KI): C|(.ll;iN():: 259.0: | VI • 11| : 260.30.
Kxample 6: Synthesis of 5-hydroxy-l-|(/^>phcnyl-cthyl|-4-isobutyl-l,5-dihydro-pyrrol-
2-one|Vild|

5-ll\tlri)x\-4-/.s<>-biii\ l-5//-furaii-2-one (10.0 g) is dissohed in /.w-propanol (100 ml.) and
(#)-ff-inctli>l ben/A I amine (7.7 g) is added to il ai room temperature. The mixture is stirred
at room temperature lor 1 hour. Alter completion of the reaction (monitored b\ ll.C. 1:1
ethyl acetale:hexane). the solvent is evaporated under reduced pressure in a rotary ewiporator
lo afford 5-h> drox> -1 -[ (/ft-phenyl-ethyl |-4-/«>-butyl-1.5-dih\dro-p\ rrol-2-one as dark
\ellow oil ( 15.5 g).
FT1R (neat): v319. 2959. I 75 I. II66 cm"1.
'II NMK (CDCIj, 200 MHz): rf0.86-0.94 (t. 3H). 0.96-0.99 (t. 311). 1.34-1.38 (d. 211). 1.49-
1.53 (d. 111). I.75-I.85(m. III). 2.24-2.27 (d. 2H). 4.27-4.30 (q. III). 5.17 (s. 111). 5.88 (s.
111). 7.26-7.37(iii. 511).
MS (Kl): ('|(1ll:iN();: 259.0: |M~H|": 260.30.
Kxample 7: llydrogenation of 5-hydroxy-l-|(»S>phenyl-ethyl|-4-propyl-l,5-dihydro-
pyrrol-2-one |V Ha)


5-llydro\\-l-|(.S>|?hcn\l-cih\'l|-4-propyl-l.5-dih\dro-pyiT()l-2-onL* (16.5 g> is dissolved
in /.vo-propanol (100 ml.) in a I'arr autoclave reactor lb I lowed by addition of 50 "o wet
palladium-on-carhon (I'd (') ui 10 % catalyst loading. Reaclor is purged with hydrogen
gas twice and then 3 kg Indrogen pressure is maintained. Reaction is monitored h\ TI.C
(Chloroform: methanol (9:1 )|. After complete consumption of starting material, the
reaction is slopped. In the reaction, diaslereomers are separated. (.S'..S")-3-|( I-phenyl
eih\iamino)-mcih\ l|-hexanoic acid precipitates DLU from the reaction media and (A'..S")-3-
|( !-phen\l elh\ lamino(-methyl |-hexanoie acid remains dissol\ed in ihe reaction media.
Alter completion of reaction, the reaction mixture is llltered and llltrale was concentrated
under \acuum to obtain a semi solid material, which is suspended in c\clohc\anc (300
ml.) and stirred o\ernighl to \ield 6.5 g of (A'..S")-3-|( I-phenyl eihylamino)-meih>l|-
hexanoic acid as a off-while solid obtained after vacuum filtration.
liliered cake contains I'd (.' and (.S'..S)-3-|( I-phenyl ethv lamino)-mcth\ I |-hexanoic acid
winch is suspended in methanol and stirred for 20 min to dissohe (.S'..S')-3-|( l-phen\l
eihylamino|-meih\ l|-hexanoic acid. Pd (' is separated b\ filtration, lillrate is
concentrated under \acuum to obtain 6.7 g of (.V..S)-3-|( I-pheny I elh\ lamino)-meth\ l|-
hexanoic acid as a white solid.
(.S,.V)-3-|(1-phen\l cthylamino)-methyl|-hcxanoic acid |Yllla|:
FTIK(KBr pellets): 2960. 1623. 1547 cm"1:
'H NMR (CI)C'IJ, 200 MHz): r) 0.84-0.86 (t. 311). 1.13-1.18 U|. 211). 1.21-1.26 ui- 211).
1.69-1.70 id. 311). 2.14-2.18 (d. 211). 2.51-2.58 (t. 2H). 2.75-2.78 (d. III). 4.12-4.17 Ul-

111). 7.35-7.42 mi. 31 h. 7.47-7.51 (m. 211): l3C NMR (C'DCIj, 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(KI): (VII...M)': 249.17: |MHI|: 250.20
DSC (10°(7min): Peak at 147.16-C
(/^.S)-3-|( I-phenyl ethvlamino)-methyl)-hexanoic acid |Ylllb|:
K'i'lK(Klir pellets): 2956. 1619. 1549. 1400 cm"1:
'H NMR (CDCI.,, 200 MHz): rf0.76-0.79 (i. 311). 1.14-1.23 (m.4ll). 1.66-1.68 (d. 311).
2.26-2.30(m. 211). 2.53-2.59(1. 211). 2.77-2.80 (d. 111). 4.06-4.1 1 phenyl-ethyl|-4-propyl-l,5-dihydro-
pyrrol-2-one |\'IIb|

5-1 l\clro\y-l-|( A'>-plicii>l-cthyl|-4-propyl-1.5-dih>dro-pyrrol-2-ono (16.5 g) is dissohed
in /.w>-propanol (100 ml.) in a Parr autoclaxe reactor followed b\ addition ol' 50 "<> wot
paHadiimi-on-carbon (I'd C") at 10 % catahst loading. Reactor is purged with Indrogen
gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored In II.C
|Chloroform: methanol (9:l)|. After complete consumption of starting material, the
reaction is stopped. In the reaction, diastereomers are separated. (K.A*)-3-|(1 -phenyl

ethylamino)-metlnl|-hcxanoic acid precipitates out from the reaction media and (.S./0-3-
|( 1 -phon> 1 eth>lammo)-methyl]-hexanoic acid remains dissolved in the reaction media.
Alter completion of reaction, the reaction mixture is filtered and filtrate is concentrated
under wicuum to obtain a semi solid material, which is suspended in cyelohexane (300
ml.) and stirred overnight lo yield 6.0 g of (.S'.Af)-3-|< 1 -phenyl elh>lamino)-methyl|-
hexanoic acid as a off-white solid obtained after vacuum nitration.
filtered cake contains IMC and (A'./<')-3-|( I -phenyl eth\lamino)-meih\l|-hcxanoic acid
which is suspended in methanol and stirred for 20 min to dissohe (A'.A')-5-|( I -phenyl
eil]\lamiiio)-meth\l|-hexanoic acid. I'd ( is separated b> nitration, filtrate is
concentrated under vacuum to obtain 6.7 g of (#./?)-3-|( 1-phenyl ethylamino)-methyl|-
hexanoic acid as white solid.
(/^,/0-3-K 1 -phenvl ethylamino)-methyl|-hexanoic acid |VIIlc|:
FTIR(KBr pellets): 2958. 1621. 1548. 1397 cm'1.
'II NMR (CIK'lj, 200 MHz): r> 0.80-0.87 (t. 311). 1.17-1.22 (m. 411). 1.67-1.70 (d. 311).
2.13-2.19 id. 211). 2.44-2.61 (t. 2H). 2.74-2.80 (d. III). 4.11-4.20 (q. III). 7.30-7.54 (m.
511): IJC NMR (( IKlj, 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 (KI):C|l l:..;N().: 24^.17: |M-ll|": 250.50.
DSC (10 °(/min): Peak al 1 ll).3("

Kxamplc 9: Itydrogcnation of 5-hydroxy-l-|(.S>phenyl-cthyl|-4-/v0but>-|-l,5-dihydn)-
pyrrol-2-onc | \'11c|

5-1 lydroxy-1 -|(.S>phcnyl-cthyl |-4-/sr?but\ I-1.5-dihydro-pyrrol-2-ono (5.0 g) is dissolved
in methanol (100 ml.) in a Parr autoclave reactor followed by addition of 50 (\> wet
palladium-on-carhon (I'd (') at 10 % cataKsl loading. Reactor is purged with hydrogen
gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored by I I.C
|Chloroform: methanol (9:1 )|. After complete consumption of starling material, the
reaction is slopped.
After completion of reaction, the reaction mixture is filtered to separate the I'd C and
llltiate is concentrated under vacuum to obtain a semi solid material, which is suspended
in c\clohe\ane (300 ml.) and stirred overnight to \ield 3.5 g of 3-|(l-(.S>
phen\lethylamine)-melh\l|-5-melhyl-he\anoic acid as off-white solid obtained alter
vacuum nitration.
I NR (KBr): 3435. 2955. 1552. 1399. 702 cm"1.
'H NMR (CDCIJ, 200 MHz): ,) 0.73-076 (l. 311). 0.81-0.85 (I. 311). 0.92-1.06 (m. 211) 1.46-
1.52 (m. III). 1.71-1.77 (m. 211). 2.12-2.39 (m. 211). 2.45-2.55 (m. 211). 2.74-2.77 (d. Ill)
4.06-4.10 phenyl-ethyl|-4-/v«but>l-l,5-dih\dro-
pyrrol-2-one |\'lld|

5-11> dro\> -1 -| (.S>phen> l-ethyl |-4-/.«;biiiyl-1.5-dihydro-pyrrol-2-one (5.0 g) is dissolved
in methanol (100 ml.) in a Parr autoclave reactor followed b> addition of 50 "■«■ wel
palladium-on-carbon (IMC) at 10 % catalyst loading. Reactor is purged with hydrogen
gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored b\ TI.C
|Chloroform: methanol (9:1 )|. After complete consumption oI" starting material, the
reaction is slopped.
After completion of reaction, the reaction mixture is tillered to separate the I'd (' and
llltrate is concentrated under vacuum to obtain a semi solid material, which is suspended
in cyclohexane (300 ml.) and stirred overnight to \ ield 3.5 g o\ 3-|(l-(A>)-
phenyleth\lamine(-methyl|-5-meih\l-hexanoic acid as a off-white solid obtained alter
vacuum nitration.
KTIR (KBr): 3434. 2956. 1546. 1397. 701 cm"1.
'H NMR (CI)CIJ, 200 MHz): rf 0.71-076 (t. 311). 0.79-0.85 (t. 311). 0.98-1.00 (d. 211) 1.44-
1.48 (m. III). 1.67-1.71 (d. 311). 2.00-2.24 (m. 2H). 2.42-2.62 (m. 211). 2.71-2.77 (d. Ill)
4.09-4.20 (q. 111). 7.36-7.53 (ni. 5H): liC N.MR (CIX.'lj, 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 (Kl): (V,l Ij.NOv 263.4: | M ■ llj : 264.2.

Example 11: Synthesis of 5-hydroxy-l-(2-hydroxy-l-(A)-phen>l-cthyl)-4-/i-|)n>pyl-l,5-
dihydro-pyrrol-2-one |V'llc|

5-ll\drox\-4-/7-prop\l-5//-furan-2-one (10.0 g) is dissolved in methanol (100 ml.) and (.S-)-
phenyl ghcinol (9.71 g) is added lo il al room lemperalure. The mixture is stirred at room
temperature for I hour. Alter completion of the reaction (monitored b> I'l.C". 1:1 etlnl
acetate: hexane). the sohenl is evaporated under reduced pressure in a rotar> e\aporalor to
afford 5-h\droxy-l-(2-hydroxy-l-phenyl-ethyl)-4-^prop\l-l.5-dih\dro-p>rrol-2-one as dark
yellow oil (15.0 y).
FTIR (neat): 3337. 2933. 1740. 1 167. 757 em"1.
'II N.MR (CDC'lj, 200 MH/.): rf 0.90-0.98 (m. 311). 1.47-1.71 (m. 211). 2.29-2.40 (q. 2H).
3.50-3.60 (t. 111). 3.72-3.74 (d. III). 4.31 (s. IH). 5.77-5.80 (d. 111). 5.99 (s. III). 7.30-7.36
(m. 511).
MS (El): (.VIINNO;: 261: |M-!1|": 262.30.
Example 12: Synthesis of 5-hydroxy-l-(2-hydroxy-l-(S)-phenyl-ethyl)-4-isobutyl-l,5-
dihydro-pyrroI-2-onc |VIlf|


5-1 Iydri).\y-4-/.s-^-bui\l-5//-luran-2-onc (10.0 g) is dissolved in methanol (100 ml.) and (.S>
l ■ ) phcnvlglvcinol (8.83 g) is added to it at room temperature. The mixture is stirred at room
temperature tor 1 hour. Alter eomplelion of the reaetion (monitored b> TIC. 1:1 ethvl
aeetale: hexane). the solvent is evaporated under reduced pressure in a rotar> evaporator to
afford 5-11> tlrci\\ -1 -(2-h> droxy-1 -phonyl-elh\ l)-4-/'sr>-but\ 1-1.5-dih\ dro-p> n\)l-2-onc as
dark yellow oil ( 14.0 g>.
FTIR (neat): 3337. 2933. 1740. 1167. 757 em"1.
MS(KI): (.V,II:i\();: 275.15: |M-H| : 274.30.
I.xamplc 13: Synthesis of 5-hydroxy-l-(2-h\droxy-1-(/Q-phvnyl-eth\l)-4-isobuty 1-1,5-
dihydro-pyrrol-2-one |VIIg|

5-llydro\\-4-/.w-butyl-5//-furan-2-one (10.0 g) is dissolved in methanol (100 ml.) and (/0-(-
)-phenvlglvcinol (8.83 g) is added to it at room temperature. The mixture is stirred at room
temperature for I hour. After completion of the reaction (monitored by I I.e. 1:1 ethyl
acetate: hexane). the solvent is evaporated under reduced pressure in a rotary evaporator to
afford 5-11\ droxv -1 -(2-hydroxy-1 -phenyl-ethv 1 )-4-/sv>-butyl-1.5-dihv dro-p> rrol-2-one as
dark yellow oil (14.0 g).
KTIR (neat): 3337. 2933. 1740. 1167. 757 cm"1.
MS (K.I): C|(,II:,N();: 275.1 5: [M-l I j": 274.30.
I.xamplc 14: llydrogenation of 5-hydroxy-l-(2-hydroxy-l-(A)-phenyl-ethyl)-4-/7-propyl-
l,5-dihydro-pyrrol-2-one |VIIe|


5-ll>dro.\\-l-|(.S>phenyl-cth\l|-4-/7-prc)p\]-1.5-dihydro-pyrrol-2-t)ne (10.0 g) is
dissolved in methanol (100 ml.) in a Parr autoclave reactor followed b\ addition of 50 "•<>
wet palladium-on-carbon (Pd ■'(.') at 10 % catalyst loading. Reactor is purged with
hydrogen gas twice and then 3 kg hydrogen pressure is maintained. Reaction is monitored
h\ II.( |('hloroform: methanol (9:1 )|. After complete consumption of starting material,
the reaction is slopped.
\fter completion o\ reaction, the reaction mixture is tillered to separate the I'd (' and
llltrate is concentrated under vacuum to obtain a semi solid material, which i* suspended
in cyclohexanc (300 ml.) and stirred overnight to yield 7.5 g of 3-|(2-h\dro.\\-l-(.V)-
phenyl ethyl amino)-methyl|-hexanoic acid as a semi solid material obtained after
vacuum nitration.
K'l'IR (neat): 3584. 293 1. 1568. 732 cm1:
'll NY1R (CIK.'lj. 200 MHz): rf 0.75-0.81 (t. 311). 1.13-1.20 (m. 511). 2.16-2.28 (m. 111).
2.45-2.71 (m. 311). 3.77-3.81 (m. 111). 4.01-4.14 (m. 211). 7.25-7.40 (m. 511).
F.xamplc 15: llydrogenation of S-liydroxy-1-|(.S>|>hcn>l-elhvl|-4-/w4iul>l-l,5-dihydro-
pyrrol-2-onc |Yllf|


5-llydri>\\-l-|(\fphcn\l-cthyl]-4-/i,^utyl-1.5-dihydro-p\rrol-2-()nc (10.0 g) is dissoKed
in methanol (100 ml.) in a Parr autoclave reactor followed by addition of 50 "o wet
palladium-on-carbon (I'd (.') at 10 % catalyst loading. Reactor is purged with Indrogen
gas twice and then 3 kg hvdrogen pressure is maintained. Reaction is monitored b\ II.C
|chloroform: methanol (9:1 )|. After complete consumption of starting material, the
reaction is slopped.
After completion o\' reaction, the reaction mixture is filtered to separate the I'd (' and
llllrale is concentrated under vacuum to obtain a semi solid material, which is suspended
in c>clohe.\ane (.>()() ml.) and stirred o\ernight to yield 6.0 g of 3-|(2-hydrox>-l-(.sy
phenyl-cthylamino) methyl |-5-methyl hexanoic acid as a semi solid obtained after
\acuum nitration.
FTIR (neat): 2926. 1568. 1075 cm"1
'H N'MR (C I)tl3, 200 MHz): rf 0.72-0.86 (m. 611). 0.92-0.99 (q. 211). 1.06-1.24 (m. 111).
1.32-1.41 (m.lll). 2.17-2.29 (m. 211)2.54-2.73 (m. 211)3.83-3.89(1. 111). 4.05-4.15 (d. 211).
7.32-7.45(m.5ll).
MS (F.I): C|,JI:<\():.: 279.03: | VI—III 280.65
Kxampk- 16: Hydrogenalion of S-hydro\>-l-|(/^>-phciivI-cllivl|-4-A-«l>ut>l-l,5-dihydro-
pyrrol-2-onc |Vllg|


5-llydrox\-l-|(^phcnyl-clhyl|-4-/ls7)but\i-l.5-dihydro-pyrr()l-2-onc (10.0 g) is dissolved
in methanol (100 nil.) in a Parr autoclave reactor followed by addition of 50 % wet
palladium-on-carbon (I'd (') at 10 % catalyst loading. Reactor is purged with hydrogen
gas twice and then 3 kg Indrogen pressure is maintained. Reaction is monitored b\ Tl.C
|chlorolbrm: methanol (9:1 )|. After complete consumption of starting material, the
reaction is stopped.
After completion of reaction, the reaction mixture is tillered to separate the l\l (.' 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-h\drox\-I-(.Si-
phon l-eth>lamino) methyl |-5-methyl hexanoic acid as a semi solid obtained alter
vacuum filtration.
I-TIR (neat): 2926. 1568. 1075 cm"1
'llNMR(( l)(b,200 MHz): r>'0.72-0.88 (m. 611). 0.95-1.05 (q. 2H). 1.23 (s. 211). 1.43-1.46
lm.111). 2.16-2.29 (m. 211) 2.47-2.72 (m. 211) 3.83-3.87 (m. 111). 4.01-4.16 (m. 211). 7.31-
7.45 (m. 511).
MS(KI): CiJKNO.;: 279.03: |V1-I1| 279.90
Example 17: Synthesis of 5-hydroxy-4-propyl-l,5-dihydro-pyrrol-2-onc 11Xn|


5-ll\dro\\-4-//-prop\l-5//-fiirun-2-one (I .9 g) is dissolved in methanol (50 nil.) and while
stirring ammonia gas is purged for 30 min at room temperature, further, the reaction mixture
is stirred at room temperature for I hour. Alter completion of the reaction (monitored by
I I.C. 9:1 chloroform: methanol), the solvent is evaporated under reduced pressure in a rotary
evaporator to afford 5-h>droxv-4-prop>l-1.5-dihvdro-pyrrol-2-one (2.1 g) as a dark yellow
oil.
FTIK(ncat): 3244. 2%1. 1749. 1574. 1030 cm"1.
'H NMR (CIKIJ, 200 MHz): rf 0.94-1.04 (m. 311). 1.58-1.65 (m. 211). 2.34-2.87 (m. 211).
5.58-5.63 (d. III). 5.92 (s. 111).
MS(EI):C-II||N();: 141.09: |M-H| 141.89.
1-xamplc 18: Svnthesis of 5-hydroxy-4-iso-butvl-l,5-dihydro-pyrrol-2-onc |IXb|

5-llydro\\-4-/.sv)-hut>l-5//-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. Alter completion of the reaction (monitored b>
I I.C. 9:1 chloroform: methanol), the solvent is evaporated under reduced pressure in a rotar>
evaporator lo afford 5-h\droxy-4-/sY>-bulyl-1.5-dihydi'o-p\rrol-2-one (1.7 g) as a dark
\ellow nil.
FTIR(neat): 3243. 2957. 1749. 1574. 1030 cm"1.

'II NMR ((IX I.,, 200 MHz): rf 0.93-1.03 (m. 611). 1.88-2.00 (m. 111). 2.18-2.26 (l. 211).
5.57-5.64 (d. 111). 5.98 (s. III).
.YIS(El):Cxll|;N().-: 155.09: |M-I I|'- 155.85.
Example 19: Synthesis of racemic pregabalin from |VIId|
Compound |Vlld| (4.0 g) is dissolved in methanol (100 ml.) in a Parr autoclave reactor
followed h\ addition of 50 % wet palladium-on-carbon (I'd (') (20 % cataKsl loading).
Reactor is purged with hydrogen gas twice and then 40 kg/cnr Indrogen pressure is
maintained. Reaction is monitored by TI.C [Chloroform: methanol (9:1 )|. After complete
consumption of starting material, the reaction is stopped.
After completion of reaction, the reaction mixture is filtered to remo\e calahst (Pd C)
and llltrate is concentrated under \acuum to obtain a solid material (1.5 g). Chiral HP1.C
analysis shows that material is racemic.
I MR (Klir): 3338. 2956. 1540. 1409 cm"1
'11 NMR (C'DjOD. 200 MHz): 0.91-0.96 (m. 611). 1.22-1.23 (q. 211). 1.64-1.74 (q. III).
2.20-2-48(m. 311). 2.79-3.00 (m.2H).
IJC NMR (CIK'lj, 50 MHz): 21.4. 21.9. 24.3. 3 1.6. 40.5. 40.6. 43.5. I 81.1.
MS (El): Cs 11|-N():: 159.13: | M-111 ' - 159.96.
Example 20: Synthesis of pregabalin from diastercomeric mixture of |Vllle| & |VIIIf]
Diastereomeric mixture of | YIIIe| and | VIIIl"| (2.0 g) is dissolved in methanol (100 ml.)
in a Parr aulocla\e reactor followed b\ addition of 50 % wet palladium-on-carbon (Pd'C)
(20 "■<> caiahst loading). Reactor is purged with Indrogen gas twice and then 40 kg
Indrogen pressure is maintained. Reaction is monitored b> TI.C |Chlorolbrm: methanol
(9:1 )|. After 24 h reaction is slopped, the reaction mixture is filtered to rcnunc cataKsl
(Pd C) iind llltraic is eoncentraicd under vacuum to obtain i\ solid material (0.7 g). Chiral
I [PLC anaKsis shows 60 % ee for (A'Apregabalin
Example 21: Synthesis of pregabalin from diastereomeric mixture of |VIIIg| & |Vlllh|

Diastereomeric mixture of |VIIIg| and |VIIIh| (2.0 g) is dissolved in methanol (100 ml.)
in a Pair autoclave reactor followed by addition of 50 l)/<> wet palladium-on-carbon (I'dC)
(20 % calahsl loading). Reactor is purged with hydrogen gas twice and then 40 kg
hvdrogen pressure is maintained. Reaction is monitored bv TI.C |('hloroform: methanol
(^:1 )|. .After 24 h reaction is slopped, the reaction mixture is filtered to remove catalyst
(PdC) and nitrate is concentrated under vacuum to obtain a solid material (0.75 g).
C'hiral I IPI.C anahsis shows 60 % ee for (.S>pregabalin
Kxamplc 22: Synthesis of pregahalin from diastereomeric mixture of |V IllkJ and
| V 1111)
Diastereomeric mixture ol" | VIIIk| and |VI1II| (2.0 g) is dissolved in methanol (100 ml.)
and 10 "o acetic acid in a Parr autoclave reactor followed by addition of palladium-
hvdroxide on carbon (20 "•<> catalyst loading). Reactor is purged with hvdrogen gas twice
and then 40 kg hvdrogen pressure is maintained. Reaction is monitored b> TI.C
|Chloroform: methanol (^:1)|. After 24 h reaction is stopped, the reaction mixture is
filtered to remove catalyst (I'd.C) and filtrate is concentrated under vacuum to obtain a
solid material (0.75 g). C'hiral IIP1..C analysis shows (/£S>pregabalin
Kxamplc 23: Synthesis of pregahalin from diastereomeric mixture of |Vlllk| and
|VII1I|
Diastereomeric mixture of |Vlllk| and |VIIII| (2.0 g) is dissolved in methanol (100 ml.)
and 10 "(i trilluoroacetic acid in a Parr autoclave reactor followed bv addition of
palladium hulroxide on carbon (20 % catalyst loading). Reactor is purged with hvdrogen
gas twice and then 40 kg hvdrogen pressure is maintained. Reaction is monitored bv I LC
IChloroform: methanol (9:1)|. After 24 h reaction is slopped, the reaction mixture is
tillered to remove catalyst (Pd'C) and filtrate is concentrated under vacuum to obtain a
M)lid material (0.6 g). C'hiral 1 IPI.C analysis shows 60 % cc for (AVpregabalin
Kxamplc 24: Synthesis of pregabalin from diastereomeric mixture of | V111 m | & (VIIIn|

Diastereomeric mixture ol'|VHIm| and [\'llln| (3.0 g) is dissolved in methanol (100 ml.)
and l()"o iritluoroacetic 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 b> TIC"
IChlorol'orm: methanol (9:1 )|. .After 24 h reaction is stopped and chiral IIPI.C analysis
shows racemic pregabalin.
Kxample 25: Synthesis of racemic pregabalin from |Vllg|
Compound |VIIg| (3.0 g) is dissohed in methanol (100 ml.) in a I'arr autoclave reactor
followed by addition of palladium hydroxide on carbon (20 % catalyst loading). Reactor-
is purged with hydrogen gas twice and then 40 kg.cnr hydrogen pressure is maintained.
Reaction is monitored by TI.C [Chloroform: methanol (9:l)|. After complete
consumption of starling material, the reaction is stopped.
After completion of reaction, the reaction mixture is tillered and filtrate is concentrated
under \acuum to obtain a solid material (1.5 g). Chiral IIPI.C analysis shows that
material is racemic.
Kxample 26: Synthesis of racemic pregabalin from (Yilg|
Compound |YIIg| 3.0 g and ammonium formate is dissolved in elhanol (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 TI.C
IChlorol'orm: methanol (l):l)|. After complete consumption of starling material, the
reaction is slopped.
After completion of reaction, the reaction mixture is filtered to remove Pd C and llllrate
is concentrated under vacuum to obtain a semi-solid material (1.5 g). Chiral IIPI.C
analysis *IIOWN that material is racemic.

r.xamplv 27: Synthesis ofracemic prcgabalin from |IXb|
Compound |IXb| (1.7 g) is dissolved in methanol (.75 ml.) in a Parr autoclave reactor
followed h> addition of palladium hvdroxide on carbon (10 "<> catahsl loading). Reactor
is purged with hvdrogen gas twice and then 5 kg cm" hydrogen pressure is maintained.
Reaction is monitored bv II.C |Chloroform: methanol (9:1)|. After complete
consumption of starting material, the reaction is stopped. The reaction mixture is filtered
and llltrale is concentrated under \acuum to obtain 1.6 g of compound (1|. Cliiral IIPI.C
analysis shows that material is racemic.
I.xamplc 2S: Synthesis of 3-ff-propyl-4-aminobutvric acid from |Vllla|
2.0 g of compound |Vllla| is dissolved in methanol (100 ml.) in a Parr autoclave reactor-
followed b\ addition of 50 % wet palladium-on-carbon (Pd C) (20 % catalvsi loading).
Reactor is purged with hydrogen gas twice and then 40 kg cm" hydrogen pressure is
maintained. Reaction is monitored by TI.C |C'hloroform: methanol (9:l)|. After complete
consumption of starling 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). C'hiral
I IP1.C" analysis shows 64 % cc for (.S>3-//-propyl-4-aminobutyric acid.
I MR(KBr pellets): 3400.2958. 1549. 1391 cm"1
'H NMR (IM>, 200 MHz): 0.94-0.96 (d. 311). 1.38-1.43 (t. 411). 2.01 (s. III). 2.26-2.32 (q.
III). 2.4l-2.46(m. III). 2.85-2.90 (q. I H). 2.97-3.01 (m. Ill):
,JC N.Y1R (CIX'lj, 50 MHz): 13.0. 19.5. 33.7. 34.6. 41.6. 43.9. 179.3.
MS(KI):C'-HiA'(>.: 145.1 I: |MHI|'= 146.03.
Kxample 29: Synthesis of 3-#*-propyl-4-aminobutyric acid from |\'lllb|
2.0 g of compound | YIIIb| is dissolved in methanol (100 ml.) in a Parr autoclave reactor
followed bv addition of 50 '■■<> wel palladium-on-carbon (Pd (.') (20 °» catalyst loading).
Reactor is purged with hvdrogen gas twice and then 40 kg cm" hydrogen pressure is
maintained. Reaction is monitored bv TI.C |Chloroform: methanol (9:1 )|. Alter complete
consumption o\' starting material, the reaction is slopped and filtered to remove catalyst

(PdC) and llltraie is concentraied under vacuum to obtain a solid material (0.65 g).
Crural I IPI.C anaKsis shows 34 % ft*for (/?>3-/?-propyl-4-aminobulyric acid.
Kxamplc30: Synthesis of 3-/f-propyl-4-aminobutyric acid from |VIIIc|
2.0 g orcompound |\'lllc| is dissolved in methanol (100 ml.) in a I'arr autoclave reactor
followed by addition of 50 % wet palladium-on-carbon (1N.1 C) (20 % catalyst loading).
Reactor is purged with hydrogen gas twice and then 40 kg cm" Indrogen pressure is
maintained. Reaction is monitored by I'].(' |Chloroform: methanol (l):l )|. After complete
consumption of starting material, the reaction is stopped and filtered to remo\e catalyst
(I'dCi and llllrate is concentrated under vacuum to obtain a solid material (0.65 g).
Crural IIPI.C anaKsis shows 60 % t-f for (A^w/-propyl-4-aminobul\ric acid.
Kxamplc31: Synthesis of 3-/f-propyl-4-aminobutyric acid from |VIIId|
2.0 g of compound |Vllld| is dissohed in methanol (100 ml.) in a I'arr autocla\e reactor
followed b> addition of 50 % wet palladium-on-carbon (I'd C) (20 "h cataKsl loading).
Reactor is purged with hydrogen gas twice and then 40 kg cm" Indrogen pressure is
maintained. Reaction is monitored by II.C |Chloroform: methanol (9:1 )|. Alter complete
consumption of starling material, the reaction is slopped and filtered to remo\e catalyst
(I'dC) and filtraie is concentraied under vacuum to obtain a solid material (0.65 g).
Chiral HIM.C analysis shows 64 % ce for (.Vf.V/7-propy|-4-aminobut>ric acid.
Kxamplc 32: Synthesis of 3-#*-propyl-4-aminobutyric acid from | V111 a | In
oxidative deben/.ylation
1.0 g of compound |VIIIa| is dissolved in dimethyl sulfoxide (20 ml.) in a RB llask.
followed b> 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. l-llnl acetate (20
ml.) is added lo the reaction mixture followed b> separation of the organic and aqueous
phases. I he aqueous phase is washed with 10 ml. of elhyl acetate and the aqueous phases

collected which contain the product (0.5g). C'hiral IIIM.C' analysis shows 80 "o cc lor (Sh
w/-prop\ l-4-aniinobut\rie acid.
Ixample 33: Synthesis of 3-i?-propyl-4-aminobuty ric acid from |VIIIb| by
oxidative deben/ylation
1.0 g of compound |VIIlb| is dissolved in dimethyl sulfoxide (20 ml.) in a KB flask,
followed h> addition of N-bromosuecinimide (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 nil.) is added to the reaction mixture and stirred for another 20 min. l-.tlnl acetate (20
ml.) is added to the reaction mixture followed by separation of the organic and aqueous
phases. I he aqueous phase is washed with 10 ml. of ethyl acetate and the aqueous phases
collected which contain the product (0.55g). C'hiral IIIM.C analysis shows 24 "<> cc for
r7^>3-/j-propyl-4-iiminobul> ric acid.
I'.xamplc 34: Synthesis of 3-fr-propyl-4-aminobutyric acid from |Vlllc| by
oxidatix c deben/ylation
1.0 g of compound |V'llIc| is dissolved in dimethyl sulfoxide (20 ml.) in a KB llask.
followed b> 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. I it In I acetate (20
ml.) is added to the reaction mixture followed b\ 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). C'hiral IIIM.C" analysis shows 60 "» cc for
th'j-?>-ii-prop\ l-4-aminobutyric acid.
Kxample 35: Synthesis of 3-u-propyl-4-aminobutyric acid from |VIIId| by
oxidative deben/ylation
1.0 g of compound |V'llld| is dissolved in dimethyl sulfoxide (20 mil in a KB llask.
followed b> 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. lain I acetate (20
nil. I 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). C'hiral I1P1.C analysis shows 64 "o cc for
f.S>3-/7-prop> l-4-aminobutyric acid.
K\amplv 36: S\nthcsis of 3-u-propyl-4-aminobutyric acid from |IXa|
Compound |IXa| (2.1 g) is dissolved in methanol (100 ml.) in a Parr autoclave reactor
followed h\ addition of palladium hydroxide on carbon (10 % caiakst loading). Reactor
is purged with hulrogen gas twice and then 5 kg cm' hydrogen pressure is maintained.
Reaction i.*> monitored by II.(.' |Chloroform: methanol (°:l)|. After complete
consumption of starting material, the reaction is stopped. The reaction mixture is filtered
and tlltrate is concentrated under vacuum to obtain 1.9 g of compound |ll|. C'hiral 111M.C
analysis shows that material is racemic.
I xample 37: Synthesis of 3-hydroxymcthyl-hex-2-enoic acid ((S)-l-phenyl-ethyl)-amide

5.0 g of compound |VIIa| is dissolved in methanol (20 ml.) in a RB flask at 0 "C and NaHl \.(0.9 g) is added in 4 portions. I he reaction mixture is stirred at room temperature for 2 h at 0
'(' anil further 2 h at room temperature. Reaction is monitored b> TIC |Chloroform:
methanol (9:1 )|. After complete consumption of starting material, the reaction is Mopped and
poured in 100 ml. of water stirred at 40 'C for 6 h. Reaction mixture is then extracted with

cih\l aceiale (200 ml.). Organic phase is washed with brine and soheni exaporaied under
reduced pressure 10 obtain 3.0 g of compound |X|. as \ellow oil.
KTIK(KBr): 3460. 2%2. 1681. 1451 cm"1
'H NMR (C'lKI.,, 200 MHz): 0.86-0.93 (t. 311). 1.41-1.57 (m. 511). 2.19-2.27 (i. 211). 3.38-
3.48 (d. 111). 3.72-3.81 (d. 111). 5.46-5.57 (q. HI). 5.81 (s. 111). 7.27-7.34 (m. 511).
.VIS(KI):(.|,ll:-|\Ov 247.16: |M-H| 248.05.

We claim:
I. A method of preparation of enanliomerically enriched and or racemie compound
of formula (IV)

which comprises:
i) Preparation of compound [Vila to g| by reaction of compound |Va to h| with
compound [ Via to d|

wherein R is II or CH-,: R, is CH3or CH2OH.
ii) Preparation of compound |\'llla to n| through hydrogenation of compound
|\'lla 10 g| in presence of noble metal catalysts under hydrogen gas pressure.

wherein R is 11 or CH3: R, is CH3, or CH2OH.

iii) a) Debenzylation of compound [VIlla 10 n] to obtain compound [IVa to b]
carried out in presence of noble metal catalyst under hydrogen gas pressure in the
presence of lironsled acid such as acetic acid, trifluoroacelic acid and or vin
cataktic transfer hydrogenation with ammonium formate.
b) Oxidative dcbcnzylation of compound [ Villa to n] to obtain compound
[ IVa to b] carried out in pressure of N-bromosuccinimide.
2. A method of preparation of racemie compound of formula |IVa to b|: which
comprises:
i) Preparation of compound |Ylla to g| by the reaction of compound |\'a to b|
with compound |\'Ia lo d|

wherein R is 11 or CH3: R1 is CH3 or CH2OH.
iii) Hydrogenation of compounds [VIla to g| lo obtain compounds [lVa to b]
carried out in presence of noble metal catalyst under hydrogen gas pressure in
presence of lironsted acid such as acetic acid, trifluoroacclic acid and or via
eatalwic transl'er hydrogenation with ammonium formate.
3. A method of preparation of racemie compound of formula [IVa lo b|: comprising:
i) Preparation of compound |IXa lo b| by the reaction of compound |Va lo b|
with ammonia in alcoholic solvent.


ii) Hydrogenalion of compounds [IXa to b] to obtain compounds IVa to b|
carried out in presence of noble metal catalyst under hvdrogen gas pressure.
4. The process for preparation of compound [X] comprising the following steps
i) Preparation of 5-hydroxy-1 -[(S)-phcnyl-ethyl ]-4-n-propyl 1-1,5-dihydro-pyrrol-
2-one |Vlla| by the reaction of 5-hydroxy-4-n-propyl 5H-furan-2-onc |Va| with
(.S*)-u-melhy| benzyl amine |Vla|

ii) Reduction of compound |VIla] in presence of sodium borolndridc to obtain
compound |X|.
5. A method of preparation of compound | VIIa] according to claim 4 wherein step ii)
is carried out at temperature 0 to 40 oC
6. The process according to claim 1. wherein in step i). ii) and iii a), the process
according to claim 2. wherein in step i). the process according to claim 3. wherein
step i) and ii) and the process according to claim 4. wherein step i) and ii) is
carried out in organic solvents.

7. According lo claim 6. organic solvents are alcoholic solvents such as methanol,
elhanol. iso-propanol.
8. The process according lo claim 1. wherein step i). ii) and iii a) and the process
according to claim 2 wherein step i) and ii) is carried out at temperature 25- 80
9. The process according to claim I. wherein step ii) and iii a) and the process
according lo claim 2 wherein step i) and ii) noble metal catalst is selected from
palladium on carbon and palladium hydroxide on carbon.
10. The process according to claim 1. wherein step ii) and the process according to
cliam 3. wherein step ii) hydrogen gas pressure is 3 to 5 kg cm2.
11. The process according to claim 1. wherein step iii a) and the process according to
claim 2 wherein step ii) Indrogen gas pressure is 20 to 50 kg/cm2.
12. I he process according to claim 1. wherein step iii a) and the process according to
claim 2 wherein step ii) Bronsled acid is selected from hydrochloric acid, acetic
acid, trilluoroacetic acid.
13. Compound of formula |VlIa to g|


14. Compounds ot'lhc formula | Villa lo n|

15. Compound of the formula |X|

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 Α2Δ calcium channel subunit, including pregabalin and related compounds
such as 3-n-propyl-4-aminobutyric acid.