METHOD FOR PREPARATION OF ENANTIOMERICALLY ENRICHED AND/OR
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 α2δ 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 b-
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-
carboxyethyl 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 N¾ OH produces the glutaric acid monoamide,
which is resolved with (7^-a-phenylethyl amine, yielding the corresponding salt.
Decomposition of salt gives the (i?j-enantiomer, which on Hoffmann degradation with
Br2/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 Br2 NaOH provides -pregabalin [I]. Although the above
method is providing the -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 -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 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 a,b-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, 1190-1 197; Chem.
Rev. 2003, 103, 2965-2983; Chem. Rev. 2007, 107, 5683-5712), has been described in the
reference cited herein.
Significantly, desymmetrization of glutaric eso-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 ( S)-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 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 (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 11.
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 g-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 i is H (compound [IVa]) or Ri is CH3 (compound [IVb]).
Comprising:
Scheme 1:
a) Reaction of the compound [V] with (S) or (R) - PhCH2(NH2)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, CH3
R, = CH3, CH2OH
b) Hydrogenation, catalytic or stoichiometric of compound [VII] to provide
compound [VIII]
R = H, CH3
Ri = CH3, CH2OH
c) Hydrogenolysis, catalytic or stoichiometric of compound [VIII] to provide
enantiomerically enriched compound [IV]
R = H, CH3
Scheme 2 :
Hydrogenation, catalytic or stoichiometric of compound [VII] to compound [IV]
R = H, CH3
R, = CH3, CH OH
Scheme 3:
Reaction of the compound [V] with ammonia to provide compound [IX].
IV
R = H, CH3
Brief Description of Accompanying Drawings
Figure 1: Reaction Scheme of US patent No. 5,b . ,. 1
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 11 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
V Id and VIIIc
Figure 6 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 V In
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 g-amino acid [IV]
according to the following schemes 1 and 2.
Scheme 1:
R = H, CH3
R, = CH3, CH2OH
cheme 2:
H, CH3
CH3, CH2OH
Scheme 3:
R = H, CH3
roposed reaction mechanism is schematically given below
R = H, CH3
R, = CH3, C 2OH
According to one aspect, the present invention provides the process for the preparation of g-
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 g-amino
acid [IV].
According to one aspect, the present invention provides the process for the preparation of g-
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 g-amino acid [IV].
According to another aspect, the present invention provides the process for the preparation of
g-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 g-amino
acid [IV].
According to another aspect, the present invention provides the process for the preparation of
racemic g-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 g-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, -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, (7?)-(+)-a-methyl benzyl
amine, (5)-(+)-phenyI glycinol and (7?)-(-)-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, -propanol; preferably methanol
and -propanol.
Generally, hydrogen pressure is about 1 kg/cm2 to 5 kg/cm2; preferably 3 kg/cm2 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 g-amino acid.
Alcoholic solvent may be selected from methanol, ethanol, zso-propanol; preferably
methanol.
Generally, hydrogen pressure is about 10 kg/cm2 to 50 kg/cm2, preferably 40 kg/cm2
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 '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 (7?)-a-methyl
benzyl amine [VIb] is hydrogenated in presence of noble metal catalyst (Pd/C) under
hydrogen pressure in z'i O -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 -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=CH3 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=CH3 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=CH3 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 Nbromosuccinimide
in polar solvents such as r t-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/cm2, 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/cm2, 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 (7?)-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/cm2, 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/cm2, 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 g-
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 2 1 gives the schematic
representation.
Compound [IXb] is obtained from reaction of compound [Vb] where R=CH3 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 g-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), 5mhi), 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 m. . 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 CDC13 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 C and DH 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 7-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. Diwo-
propyl ether is added to the aqueous phase. The organic phase is removed and the aqueous
phase further extracted with di-z' -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-5 H-furan-2-one are obtained as light brown oil.
FTIR (neat): 3367, 1735 cm 1 .
NMR (CDC13, 200 MHz): d 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, 1H).
MS (EI): C7H,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' -propyl ether is added to the aqueous phase. The organic phase is removed and the aqueous
phase further extracted with di- O-propyl ether (2x). The di- -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-5 H-furan-2-one are obtained as light yellow oil.
FTIR (neat): 3371, 1738 cm 1 .
NMR (CDC , 200 MHz): d 0.87-0.99 (t, 6H), 1.87-2.01 ( , 1H), 2.28-2.32 (d, 2H), 5.82 (s,
1H), 6.1 1 (s, 1H).
MS (EI): C8H120 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-5 H-furan-2-one (10.0 g) is dissolved in wo-propanol (100 mL) and S - -
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, 1165 cm 1 .
NMR (CDCI3, 200 MHz): d 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): Ci5H,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 so-propanol (100 niL) and (R)-amethyl
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?j-phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyrrol-2-one as dark yellow oil (16.5 g).
FTIR (neat): 3321, 1749, 1165 cm 1.
NMR (CDCI3, 200 MHz): d 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 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-pyrrol-2-
one [VIIc]
5-Hydroxy-4-wo-butyl-5H-furan-2-one (10.0 g) is dissolved in wo-propanol (100 niL) and (S)-amethyl
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 - -butyl-l,5-dihydro-pyrrol-2-one as dark yellow oil (15.5 g).
FTIR (neat): 3319, 2959, 1751, 1166 cm 1 .
NMR (CDCb, 200 MHz): d 0.86-0.94 (t, 3H), 0.96-0.99 (t, 3H), 1.34-1.38 (d, 2H), 1.49-1.53
(d, 1H), 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,6H2,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 -propanol (100 mL) and (R)-amethyl
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 ,o-butyl-l,5-dihydro-pyrrol-2-one as dark yellow oil (15.5 g).
FTIR (neat): 3319, 2959, 1751, 1166 cm 1.
NMR (CDCb, 200 MHz): d 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 ( , 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,6H2,N0 2: 259.0; [M+H]+: 260.30.
Example 7: Hydrogenation of 5-hydroxy-l-[(5^-phenyl-ethyl]-4-propyl-l,5-dihydropyrrol-
2-one [Vila]
5-Hydroxy-l -[(S)-phenyl-ethyl]-4-propyl-l,5-dihydro-pyrrol-2-one (16.5 g) is dissolved in
-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 yS)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid [Villa]:
FTIR (KBr pellets): 2960, 1623, 1547 cm 1 ;
NMR (CDC13, 200 MHz): d 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); 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): Ci5H2 N0 2: 249.17; [M+H]+: 250.20
DSC (10 °C/min): Peak at 147.16°C
(R yS)-3-[(l-phenyl ethylamino)-methyl] -hexanoic acid [VHIb]:
FTIR (KBr pellets): 2956, 1619, 1549, 1400 cm 1;
1H NMR (CDCI3, 200 MHz): d 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, 1H), 7.31-7.57 (m, 5H); C
NMR (CDCI3, 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,5H23N0 : 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-dihydropyrrol-
2-one [VHb]
5-Hydroxy-l-[(^-phenyl-ethyl]-4-propyl-l,5-dihydro-pyrrol-2-one (16.5 g) is dissolved in
-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.
NMR (CDCb, 200 MHz): d 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);
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,5H23N0 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.
NMR (CDCb, 200 MHz): d 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).
C NMR (CDCI3, 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): Ci5H23N0 2: 249.17; [M+H] +: 250.50.
DSC (10 °C/min): Peak at 119.3°C
Example 9: Hydrogenation of 5-hydroxy-l -[(S )-phenyl-ethyl]-4-/sobutyl-l,5-dihydropyrrol-
2-one [VIIc]
[VHIe] [Villi]
5-Hydroxy-l-[(5J-phenyl-ethyl]-4-wobutyl-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 palladiumon-
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- .
NMR (CDCb, 200 MHz): d 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 ( , 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); C NMR (CDC13, 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): C16 25N0 2: 263.4; [M+H]+: 264.5.
Example 10: Hydrogenation of 5-hydroxy-l-[(if)-phenyl-ethyl]-4-«obutyl-l,5-dihydropyrrol-
2-one [VHd]
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 palladiumon-
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): d 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); 1 C NMR (CDC1 , 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): Ci6H2 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-5 H-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, 1167, 757 cm 1 .
NMR (CDCI3, 200 MHz): d 0.90-0.98 (m, 3H), 1.47-1.71 (m, 2H), 2.29-2.40 (q, 2H), 3.50-
3.60 (t, 1H), 3.72-3.74 (d, 1H), 4.31 (s, 1H), 5.77-5.80 (d, 1H), 5.99 (s, 1H), 7.30-7.36 (m, 5H).
MS (EI): Ci5H,9N0 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-5 H-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, 1167, 757 cm 1.
MS (EI): C,6H2lN0 : 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, 1167, 757 cm
MS (EI): C,6H2 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 palladiumon-
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;
NMR (CDC13, 200 MHz): d 0.75-0.81 (t, 3H), 1.13-1.20 ( , 5H), 2.16-2.28 ( , 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 palladiumon-
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)-phenylethylamino)
methyl] -5-methyl hexanoic acid as a semi solid obtained after vacuum filtration.
FTIR (neat): 2926, 1568, 1075 cm 1
1H NMR (CDC1 , 200 MHz): d 0.72-0.86 (m, 6H), 0.92-0.99 (q, 2H), 1.06-1.24 (m, 1H), 1.32-
1.41 (m,lH), 2.17-2.29 (m, 2H) 2.54-2.73 (m, 2H) 3.83-3.89 (t, 1H), 4.05-4.15 (d, 2H), 7.32-7,45
(m, 5H).
MS (EI): Cl6H2 N0 3: 279.03; [M+H]+ 280.65
Example 16: Hydrogenation of 5-hydroxy-l -[(R )-phenyI-ethyl]-4-/5obutyl-l,5-dihydropyrroI-
2-one [V g]
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 palladiumon-
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)-phenylethylamino)
methyl] -5-methyl hexanoic acid as a semi solid obtained after vacuum filtration.
FTIR (neat): 2926, 1568, 1075 cm 1
NMR (CDCb, 200 MHz): d 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): C16 25N0 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-5 H-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 .
NMR (CDCI3, 200 MHz): d 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 H,,N0 2: 141.09; [M+H]+= 141.89.
Example 18: Synthesis of 5-hydroxy-4-iso-butyl-l,5-dihydro-pyrrol-2-one [IXb]
5-Hydroxy-4- O-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 - -butyl-l,5-dihydro-pyrrol-2-one (1.7 g) as a dark yellow oil.
FTIR (neat): 3243, 2957, 1749, 1574, 1030 cm 1 .
NMR (CDC , 200 MHz): d 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 H 3N0 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
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).
, C NMR (CDCI3, 50 MHz): 21.4, 21.9, 24.3, 31.6, 40.5, 40.6, 43.5, 181.1.
MS (EI): C H, 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 ( ? -pregabalin
Example 23: Synthesis of pregabalin from diastereomeric mixture of [V kJand [Villi]
Diastereomeric mixture of [VHIk] and [Villi] (2.0 g) is dissolved in methanol ( 00 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/cm2 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/cm2 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
NMR (D20 , 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);
C NMR (CDCI 3, 50 MHz): 13.0, 19.5, 33.7, 34.6, 41.6, 43.9, 179.3.
MS (EI): C H 5N0 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 (i?)-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/cm2 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 -3- -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 0 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 S,)-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 C and NaBH4 (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
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 H2 1N0 2: 247.16; [M+H]+= 248.05.
CLAIMS
1. A method of preparation of enantiomerically enriched and/or racemic compound of
formula (IV)
[IVa to b]
which comprises:
i) Preparation of compound [Vila to g] by reaction of compound [Va to b] with
compound [Via to d]
wherein R is H or CH3; Ri is CH3 or CH2OH.
ii) Preparation of compound [Villa to n] through hydrogenation of compound [Vila
to g] in presence of noble metal catalysts under hydrogen gas pressure.
[Villa to n]
wherein R is H or CH ; R is CH or CH2OH.
iii) a) Debenzylation of compound [Villa to n] to obtain compound [IVa to b]
carried out in presence of noble metal catalyst under hydrogen gas pressure in the
presence of Bronsted acid such as acetic acid, trifluoroacetic acid and/or via catalytic
transfer hydrogenation with ammonium formate.
b) Oxidative debenzylation of compound [Villa to n] to obtain compound
[IVa to b] carried out in pressure of N-bromosuccinimide.
2. A method of preparation of racemic compound of formula [IVa to b]; which
comprises:
i) Preparation of compound [Vila to g] by the reaction of compound [Va to b] with
compound [Via to d]
[Vila to g]
wherein R is H or CH3; R, is CH3 or CH2OH.
iii) Hydrogenation of compounds [Vila to g] to obtain compounds [IVa to b] carried
out in presence of noble metal catalyst under hydrogen gas pressure in presence of
Bronsted acid such as acetic acid, trifluoroacetic acid and/or via catalytic transfer
hydrogenation with ammonium formate.
3. A method of preparation of racemic compound of formula [IVa to b]; comprising:
i) Preparation of compound [IXa to b] by the reaction of compound [Va to b] with
ammonia in alcoholic solvent.
[IXa to b]
ii) Hydrogenation of compounds [IXa to b] to obtain compounds [IVa to b] carried '
out in presence of noble metal catalyst under hydrogen gas pressure.
4. The process for preparation of compound [X] comprising the following steps
i) Preparation of 5-hydroxy-l-[(S)-phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyrrol-2-
one [Vila] by the reaction of 5-hydroxy-4-«-propyl -5H-furan-2-one [Va] with (S - -
methyl benzyl amine [Via]
[Vila]
ii) Reduction of compound [Vila] in presence of sodium borohydride to obtain
compound [X].
5. A method of preparation of compound [Vila] according to claim 4 wherein step ii) is
carried out at temperature 0 to 40 °C.
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 to claim 6, organic solvents are alcoholic solvents such as methanol,
ethanol, wo-propanol.
8. The process according to 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 °C.
9. The process according to claim 1, wherein step ii) and iii a) and the process according
to claim 2 wherein step i) and ii) noble metal catalyst 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/cm .
11. The process according to claim 1, wherein step iii a) and the process according to
claim 2 wherein step ii) hydrogen gas pressure is 20 to 50 kg/cm .
12. The process according to claim 1, wherein step iii a) and the process according to
claim 2 wherein step ii) Bronsted acid is selected from hydrochloric acid, acetic acid,
trifluoroacetic acid.
13. Compound of formula [Vila to g]
[Vila to g]
wherein R is H or CH3; Ri is CH3or CH2OH.
14. Compounds of the formula [Villa to n]
[Villa to n]
wherein R is H or CH3; Ri is CH3or CH2OH.
15. Compound of the formula [X]