Title of Invention

"A PROCESS FOR THE PREPARATION OF AN OPTICALLY ACTIVE ALKYL 4-PHENYL-2-[(TRIFLUOROACETYL) AMINO] BUTANOATE"

Abstract A process for the preparation of an optically active alkyl 4-phenyl-2-[(trifluoroacetyl) amino] butanoate by reacting 4-oxo-4-phenyl-2-(trifluoroacetyl) amino butanoic acid with an alcohol selected from methanol or ethanol in presence of an acid catalyst at temperature in the range of 0 to 60°C for a period of 5 to 45 min, concentrating the reaction mixture to get compound, dissolving this ketoester in an organic solvent and hydrogenating in presence of catalyst selected from 5 to 10% palladium on charcoal at temperature in the range of 20 to 70°C at a pressure in the range of 1-10 atm for a period ranging from 8 to 36 hr, filtering, concentrating and purifying the crude product by conventional methods such as chromatography to obtain optically active alkyl 4-phenyl-2-[(trifluoroacetyl)amino]butanoate.
Full Text This invention relates to a process for the preparation of an optically active alkyl 4-phenyl-2-[(trifluoroacetyl) amino] butanoate with R or S configuration. More particularly it relates to the process for the preparation of the said compound having formula (1) from 4-oxo-4-phenyl-2-(trifluoroacetyl)amino butanoic acid having formula (2). Still more
(Formula Removed)
particularly it relates to the process for the preparation of (S)-ethyl 4-phenyl-2-[(trifluoroacetyl)-amino]butanoate from (S)-4-oxo-4-phenyl-2-(trifluoroacetyl) amino butanoic acid.
(S)-Ethyl 4-phenyl-2-[(trifluoroacetyl)amino] butanoate of the formula (1) wherein R=Et prepared by the present invention is used in the preparation of (S)-homophenylalalnine ethyl ester which is used as an intermediate in the manufacture of various drugs like indolapril, enalalpril, lisinopril, benzepril and/or their analogues with biological activities. It can also be converted into (S)-homophenylalnine which is an industrially important amino acid.
In the prior art ethyl 4-phenyl-2-[(trifluoroacetyl)amino]butanoate is made from ethyl 4-oxo-4-phenyl-2-(trifluoroacetyl)amino botanic acid by esterification with absolute ethanol in acetonitrile in the presence of N,N'-dicyclohexylcarbodiimide and 4-pyrrolidinopyridine followed by reduction with triethyl silane in boron trifluoride etherate (Nordlander J.E., Payne M.J., Njoroge F.G., Vishwanath V.M., Han G.R., Laikos G.D., and Balk M.A., JOC, 1985, 50, 3619) This method cannot be used to get optically active product, as there is racemisation in the esterification step. Also all the reagents used are expensive. (S)-4-Oxo-4-2-trifluoroacetylamino butanoic acid of the formula (2), which is used as starting material in the present invention has been prepared by known method
from L-aspartic acid by reaction with trifluoroacetic anhydride in trifluoroacetic acid to give N-trifluroacetyl-L-aspartic anhydride followed by Friedel-Crafts reaction with benzene (Lindemann U., Wulff-Molder D., and Wessig P., Tetrahedron Asymmetry, 1998, 9, 4459; Steiner A., Ph.D. Thesis, Humboldt-University zu Berlin, 1997).
The inventors of the present invention are reporting for the first time the preparation of optically active alkyt 4-phenyl-2-[(trifluroacetyl)amino] butanoate of the formula (1) from optically active 4-oxo-4-phenyl-2-(trifluroacetyl)amino butanoic acid of the formula (2). The main object of the present invention is therefore to provide a process for the preparation of optically active alkyl 4-phenyl-2-[trifluroacetyl)amino]butanoate. Accordingly, the present invention provides a process for the preparation of an optically active alkyl 4-phenyl-2-[(trifluoroacetyl) amino] butanoate of the formula (1) which comprises reacting 4-oxo-4-phenyl-2-(trifluoroacetyl) amino butanoic acid of the formula (2) with an alcohol selected from methanol or ethanol in presenc
(Formula Removed)
of an acid catalyst at temperature in the range of 0 to 60°C for a period of 5 to 45 min, concentrating the reaction mixture to get compound of formula (3), dissolving this
(Formula Removed)
ketoester in an organic solvent and hydrogenating in presence of catalyst selected from 5 to
10% palladium on charcoal at temperature in the range of 20 to 70°C at a pressure in the
range of 1-10 atm for a period ranging from 8 to 36 hr, filtering, concentrating and purifying
the crude product by conventional methods such as chromatography to obtain optically
active alkyl 4-phenyl-2-[(trifluoroacetyi)amino]butanoate.
In one of the embodiments of the present invention, optically active 4-oxo-4-phenyl-2-
(trifluoroacetyl)amino butanoic acid may have R or S configuration.
In another embodiment, the alcohol used for esterification of optically active 4-oxo-4-
phenyl-2-(trifluoroacetyl)amino butanoic acid is selected from methanol and ethanoi.
In yet another embodiment, the acid used as the catalyst for esterification is selected from
gaseous hydrogen chloride, cone. Hydrochloric acid or cone. Sulfuric acid preferably
gaseous hydrogen chloride.
In still another embodiment, the solvent used for hydrogenation is selected from the group
consisting of ethanoi, methanol, ethyl acetate or mixtures thereof, preferably ethanoi.
In yet another embodiment, the catalyst used for hydrogenation is 5 or 10% palladium on
charcoal
In yet another embodiment, the hydrogenation may be carried out at a pressure in the
range of 2 to 5 atmosphere.
The process of the present invention is described by the following examples, which are
illustrative only and should not be construed as limit to the scope of the present invention in
any manner.
Example-1
4-oxo-4-phenyl-2-(S)-N-trifluoroacetyl butanoic acid (1.16 gm, 4 mmol) was taken in 2-necked RB flask equipped with guard tube. Absolute ethanoi (50 ml) was added. Dry hydrogen chloride gas was bubbled for 5 min at room temp (exothermic reaction). TLC (20% acetone in pet ether) indicated completion of reaction. Nitrogen was bubbled through the reaction mixture to remove excess hydrogen chloride and then it was
concentrated Purification over a short silica gel column (eluent -10 %, 20 % acetone in pet ether) afforded desired ketoester (3) (950 mg, 78.5 %); M. P. 82-3°C); [α]D - 3,42" ( c 1 106, met Hanoi). Chiral HPLC showed a single peak. A mixture of this ketoester (870 mg, 2.75 mmol), ethanol (100 ml) and 10 % Pd-C (200 mg) was charged in Parr hydrogenator and hydrogenated at 60°C under 32 kg/cm2 pressure for 12 h. It was then filtered, washed wtth ethanol, concentrated and passed through a short column of silica gel (eluent- 4%, 7% acetone in pet ether) to afford the desired ethyl 4-phenyl-2-(S)-(trifluoroacetyl) amino butanoate (480 mg, 57.62%) [α]D -6.88° ( c 15, MeOll) Chiral HPLC showed it to be optically pure.
Example 2
4-Oxo-4-phenyl-2-(S)-(tntluoroacetyi)amino butanoic acid (5.05g, 175 mmol) was dissolved in dry ethanol (25 ml) taken in R.B. flask equipped with guard tube Dry-hydrogen chloride gas was bubbled at RT for 10 min. Nitrogen was bubbled through the reaction mixture for 10 min and then it was concentrated and purified by passing through short column of silica gel (eluent 10% ethyl acetate in pet ether) to give ethyl 4-oxo-4-phenyl-2-(S)-(trifluoroacetyl)amino butanoate (4.75 gm, 86%), m.p. 83°C [α]25o 3.49° (c 1.035, MeOH). Chiral HPLC showed that it was optically pure This ketoester (634 mg, 2 mmol), ethanol (100 ml) and 10% Pd-C (200 mg) were charged in Pan hydrogenator and hydrogenated at 60"C for 8 hr It was then filtered, concentrated and purified by column chromatography (eluent 10% acetone in pet ether) to yield pure ethyl 4-phenyl-2-(S)-(tntluoroacetyl)-amino butanoate (295 mg, 48.6%), [α]25D -6.730 (c, 1 43, MeOH)
Example 3
4-Oxo-4-phenyl-2~(S)-(trifluoroacetyI)amino butanoic acid (348 nig, 12 mmol) was dissolved in absolute ethanol (6 ml) containing catalytic amount (1 drop) of concentrated sulfuric acid and stirred at RT under nitrogen for 24 hrs. It was then concentrated, diluted with water and extracted with chloroform. Purification by column chromatography on silica gel (eluent 10% acetone in pet ether) afforded pure ethyl 4-oxo-4-phenyl-2-(S)-(tntluoroacetyl)aminobutanoate (309 mg, 81.1%) |α|25D -3.40 (c 1.02, MeOH). This ketoester (158 mg, 0.5 mmol) was dissolved in ethanol (50 ml) and charged in the botlle of Parr hydrogenator. Palladium on charcoal (50 mg) was added, the system was flushed with hydrogen and the mixture was hydrogenated at room temperature under 40 psi pressure for 36 hr It was then filtered, concentrated and purified by column chromatography (eluent 10% acetone in pet ether) to give pure ethyl 4-phenyI-2-(S)-(trffiuoroacetyl)amino butanoate (70 mg, 46%), αD -6.68° (c, 1.6,
methanol)
Advantages of present invention:
1. Industrially important alkyl 4-phenyl-2-trifluoroacetylamino butanoate can be
prepared in optically active form.
2. Starting material is commercially available.
3. The reagents used are cheaper
4. The reaction can be scaled up to get the product in large scale


We claim :
1. A process for the preparation of an optically active alkyl 4-phenyl-2-[(trifluoroacetyl) amino] butanoate of the formula (1) which comprises reacting 4-oxo-4-phenyl-2-(trifluoroacetyl) amino botanic acid of the formula (2) with an alcohol selected from methanol or ethanol in presence
2. (Formula Removed)
3. of an acid catalyst at temperature in the range of 0 to 60°C for a period of 5 to 45 min, concentrating the reaction mixture to get compound of formula (3), dissolving this
4. (Formula Removed)
ketoester in an organic solvent and hydrogenating in presence of catalyst selected from 5 to 10% palladium on charcoal at temperature in the range of 20 to 70°C at a pressure in the range of 1-10 atm for a period ranging from 8 to 36 hr, filtering, concentrating and purifying the crude product by
conventional methods such as chromatography to obtain optically active aikyl 4-phenyl-2-[(trifluoroacetyl)amino]butanoate.
2. A process as claimed in claim 1 wherein the 4-oxo~4-pheny!-2-
(trifluoroacetyl) amino butanoic acid used as starting material has R or S
configuration.
3. A process as claimed in claims 1-2 wherein the acidic catalyst used for
esterification is selected from the group consisting of gaseous hydrogen
chloride, cone, hydrochloric acid and cone, sulfuric acid, preferably
gaseous hydrogen chloride.
4. A process as claimed in claims 1-3 wherein the solvent used for
hydrogenation is selected from the group consisting of ethanol, methanol,
ethyl acetate or mixtures thereof, preferably ethanol.
5. A process as claimed in claims 1-4 wherein the pressure used for
hydrogenation is preferably in the range of 2 to 5 atmosphere.
6. A process for the preparation of an optically active alkyl 4-phenyl-2-
[(trifluoroacetyl)amino] butanoate of the formula (1) as substantially
described herein before with reference to examples 1 to 3.

Documents:

99-del-2001-abstract.pdf

99-del-2001-claims.pdf

99-del-2001-correspondence-others.pdf

99-del-2001-correspondence-po.pdf

99-del-2001-description (complete).pdf

99-del-2001-form-1.pdf

99-del-2001-form-19.pdf

99-del-2001-form-2.pdf


Patent Number 222598
Indian Patent Application Number 0099/DEL/2001
PG Journal Number 36/2008
Publication Date 05-Sep-2008
Grant Date 19-Aug-2008
Date of Filing 31-Jan-2001
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110 001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 RADHIKA DILIP WAKHARKAR NATIONAL CHEMICAL LABORATORY,PUNE 411008,MAHARASTRA,INDIA
2 HANUMANT BAPURAO BORATE NATIONAL CHEMICAL LABORATORY,PUNE 411008,MAHARASTRA,INDIA
3 PRASHANT ANKUSHRAO WASKE NATIONAL CHEMICAL LABORATORY,PUNE 411008,MAHARASTRA,INDIA
4 MUKUND KESHAO GURJAR NATIONAL CHEMICAL LABORATORY,PUNE 411008,MAHARASTRA,INDIA
PCT International Classification Number C12P 7/62
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA