Indian Patents. 217120:'' AN IMPROVED PROCESS FOR THE PREPARATION OF TRIFLUOROMETHANESULFONIC ESTER OF ETHYL (R)-2-HYDROXY -4-PHENYLBUTYRATE-A USEFUL INTERMEDIATE FOR THE PREPARATION OF BENAZEPRIL''

Title of Invention	'' AN IMPROVED PROCESS FOR THE PREPARATION OF TRIFLUOROMETHANESULFONIC ESTER OF ETHYL (R)-2-HYDROXY -4-PHENYLBUTYRATE-A USEFUL INTERMEDIATE FOR THE PREPARATION OF BENAZEPRIL''
Abstract	The present invention relates to an improved process for the preparation of trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate, useful as intermediate for the preparation of ACE (Angiotensin Converting Enzyme) inhibitor, benazepril.

Full Text	The present invention relates to an improved process for the preparation of trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate, referred to here as triflate of structural formula I as shown in the accompanied drawings useful as intermediate for the preparation of ACE (Angiotensin Converting Enzyme) inhibitor, benazepril. Chemically, benazepril is (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbony)-3- phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one of Formula II, as shown in the accompanied drawings. Benazepril is a well known long acting ACE inhibitor primarily for the treatment of hypertension and is known from the U.S. Patent No. 4,410.520. Benazepril and other ACE inhibitors can be prepared by reacting an appropriate ester of (R)-2-hydroxy-4-phenylbutyric acid with an appropriate amine under standard conditions well known in the art. This has been exemplified in a publication by Urbach and Henning (Tetrahedron Lett, 25, 1143 (1984)) wherein the trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate is one of the reactants in the synthesis. The same authors in their Canadian Patent Nos. 1292236 and 1267903 have synthesised triflate of Formula I. The method comprises of the reaction of an a hydroxycarboxylic acid derivative with a trifluromethanesulfonating agent in an inert solvent such as methylene chloride in the presence of a base such as pyridine to afford the triflate of Formula I in 84.3% yield. The triflate prepared by the above method when used in the synthesis of benazepril in the lab does not give the desired yields of benazepril hydrochloride. In fact, a low overall yield of 46% of benazepril hydrochloride was obtained which is not acceptable at a commercial scale. The low yield is attributable to the formation of pyridinium salt, when trifluoromethanesulfonic anhydride and pyridine are combined. To overcome the problem of the formation of pyridinium salts during triflate formation, pyridine has been replaced with sterically hindered bases such as 2,6-di-tert-butyl-4-methyl pyridine and 2,4,6-tri-substituted pyrimidines (Peter J. Stang et al, Synthesis, 1980, p-283; A-Garcia Martinez et al, bid, 1990, p-881). The use of these bases is not practical on commercial scale owing to the high cost involved. Blaser et. al. (US Pat. No. 4,785,089) have emphasized that aromatic p-nitro or halo sulfonic esters of ethyl (R)-2-hydroxy-4-phenylbutyrate give better results than the trifluoromethane sulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate when used in the synthesis of ACE inhibitors like benazepril. The process involves alkylation of benzofused lactam with p-nitro or halo sulfonic ester of (R)-2-hydroxy-4-phenylbutyrate at 75-80°C for about 9 hours and results in an overall yield of benazepril hydrochloride as 83.5%. However, this process is also not completely satisfactory and is disadvantageous at a commercial scale because of low overall yield. It is, therefore, desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation and isolation of triflate of Formula I which process improves the economics by resulting in higher yields of benazepril hydrochloride and less reaction time. The process is easy to handle at commercial scale and removes the excess pyridine and pyridinum salts without any difficulty. Accordingly, the present invention provides a process for preparing trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenyl butyrate of Formula I, as shown in the accompanied drawings, comprising reacting ethyl (R)-2-hydroxy-4-phenyl butyrate of Formula III, as shown in the accompanied drawings, with trifluoromethanesulphonic anhydride of Formula IV, as shown in the accompanied drawings, in an inert solvent in the presence of a base and purifying it by passing through column. The base used to trap the acid formed during the course of the reaction may be selected from an inorganic or organic bases. The inorganic base is selected from potassium carbonate, sodium carbonate or sodium bicarbonate and the organic base is selected from triethylamine or pyridine. Most preferably, pyridine is used. The term 'inert solvent1 includes solvents which cannot react with the trifluoromethane sulfonating agent and the trifluoromethanesulfonating acid derivatives. Solvents used include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and aromatic hydrocarbons such as toluene, benzene or hexane. Most preferably, methylene chloride is used. The reaction is carried out within the temperature range from about -80°C to +80°C, preferably between -80°C to room temperature. Condensation of 3-amino benzofused lactam, namely 1-tert.-butoxycarbonylmethyl-3-S- amino-2,3,4,5-tetrahydro-1H-(1)-benzazepin-2-one of structural Formula V, as shown in the accompanied drawings, with triflate of Formula I as shown in the accompanied drawings, in the presence of a solvent and an acid acceptor, at a temperature from about 0 to 50°C for about 2 to 5 hours followed by a suitable work-up gives the hydrochloride salt of benazepril. 1 -tert.-butoxycarboxylmethyl-3-S-amino-2,3,4,5-tetrahydro-1 H-(1 )-benazepin-2-one of structural formula V is prepared by the method disclosed in European patent application No. 72352. In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, these are not intended in any way to limit the scope of the present invention. EXAMPLE 1 Preparation of (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride salt 5.67gm of ethyl (R)-2-hydroxy-4-phenyl butyrate (99% ee), 2.79gm of pyridine were taken up in methylene chloride and cooled to -20°C. A solution of 10gm of trifluoromethane sulphonic anhydride in methylene chloride was added during 15-20 min. The reaction mixture was then stirred for 30 minutes at -20 to -25°C and monitored by TLC. After the completion of the reaction, the mixture was directly passed through a column of silica gel, (25gm, 60-125 mesh, 1inch diameter column) using methylene chloride as eluant. The fractions were combined and solvent removed to afford ethyl-R-2-(trifluoromethane sulphonyl oxy)-4-phenyl butyrate (triflate) as an oil. The oil was dissolved in 15 ml methylene chloride and added dropwise to a mixture of 5.67gm of 1-tert-butoxycarbonylmethyl-3-S-amino-2,3,4,5-tetrahydro-1H-(1)-benzazepin-2-one and 2.46gm of N-methyl morpholine dissolved in 5ml methylene chloride at 30 to 35°C. The reaction mixture was further stirred for about 2 hours. Completion of reaction was monitored by HPLC. The reaction was quenched by addition of 40ml water and 60 ml methylene chloride. The pH was adjusted to 8.5 with 10% aqueous sodium carbonate solution. The organic portion was separated and washed twice with water. It was then dried over anhydrous sodium sulphate and solvent was distilled off to afford (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one , as an oil. The oil was dissolved in 50ml ethylacetate and dry HCI gas was purged at 8-10°C for few hours to afford benazepril hydrochloride as a fine crystalline slurry. Excess hydrogen chloride was removed by distilling off ethyl acetate in vacuo. The residue was diluted with 45ml acetone and stirred at 5-8°C for 1 hour. The product was filtered and dried to constant weight in vacuo at 45-50°C affording 8.27gm of almost white product with diastereoisomer ratio of SS:SR = 99.36 : 0.18, Yield 91.9%. EXAMPLE 2 Preparation of (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride salt Ethyl-R-2(trifluoromethane sulphonyloxy)-4-phenylbutyrate (triflate) prepared as mentioned in previous example to get an oil. The oil was dissolved in 15 ml methylene chloride and a solution of 5.67 gm of 1-tert-butoxycarbonylmethyl-3-S-amino-2,3,4,5-tetrahydro-1H(1)-benzazepin-2-one and 2.46 gm of N-methyl morpholine in methylene chloride was added dropwise at room temperature. The reaction mixture was stirred for 1 hour. Similar work up as mentioned in previous example afforded benazepril hydrochloride, 8.20gm as almost white powder with diastereoisomer ratio of SS:SR=99.39: 0.15, Yield = 91.8%. WE CLAIM : 1. A process for preparing trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenyl butyrate of Formula I, as shown in the accompanied drawings, comprising reacting ethyl (R)-2-hydroxy-4-phenylbutyrate of Formula III, as shown in the accompanied drawings, with trifluoromethanesulphonic anhydride of Formula IV, as shown in the accompanied drawings, in an inert solvent in the presence of a base and purifying it by passing through packed column and isolating trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenyl butyrate of Formula I. 2. The process of claim 1 wherein the inert solvent is selected from methylene chloride, chloroform, carbon tetrachloride, toluene, benzene or hexane. 3. The process of claim 1 wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine or pyridine. 4. The process of claim 3 wherein the base is pyridine. 5. The process for the preparation of trifluoromethanesulfonic ester of ethyl (R)-2- hydroxy-4-phenyl butyrate of claim 1 for preparation of benazepril hydrohloride of formula II. 6. The process of claim 5, wherein benazepril hydrochloride of Formula II, as shown in the accompanied drawings, is produced by the condensation of 1-tert- butoxycarbonylmethyl-3-S-amino-2,3,4,5-tetrahydro-1 H-(1 )-benzazepin-2-one, of Formula V with trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenyl butyrate of Formula I, in the presence of an organic solvent and an acid acceptor at a temperature from about 0 to 50°C for about 1 to 5 hours followed by a suitable work up. 7. The process for the preparation of trifluoromethanesulfonic ester of ethyl (R)-2- hydroxy-4-phenyl butyrate substantially as herein described and exemplified by the examples.

Full Text

The present invention relates to an improved process for the preparation of trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate, referred to here as triflate of structural formula I as shown in the accompanied drawings useful as intermediate for the preparation of ACE (Angiotensin Converting Enzyme) inhibitor, benazepril.
Chemically, benazepril is (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbony)-3-
phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one of Formula II, as shown in the accompanied drawings. Benazepril is a well known long acting ACE inhibitor primarily for the treatment of hypertension and is known from the U.S. Patent No. 4,410.520.
Benazepril and other ACE inhibitors can be prepared by reacting an appropriate ester of (R)-2-hydroxy-4-phenylbutyric acid with an appropriate amine under standard conditions well known in the art. This has been exemplified in a publication by Urbach and Henning (Tetrahedron Lett, 25, 1143 (1984)) wherein the trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate is one of the reactants in the synthesis.
The same authors in their Canadian Patent Nos. 1292236 and 1267903 have synthesised triflate of Formula I. The method comprises of the reaction of an a hydroxycarboxylic acid derivative with a trifluromethanesulfonating agent in an inert solvent such as methylene chloride in the presence of a base such as pyridine to afford the triflate of Formula I in 84.3% yield. The triflate prepared by the above method when used in the synthesis of benazepril in the lab does not give the desired yields of benazepril hydrochloride. In fact, a low overall yield of 46% of benazepril hydrochloride was obtained which is not acceptable at a commercial scale. The low yield is attributable to the formation of pyridinium salt, when trifluoromethanesulfonic anhydride and pyridine are combined.
To overcome the problem of the formation of pyridinium salts during triflate formation, pyridine has been replaced with sterically hindered bases such as 2,6-di-tert-butyl-4-methyl pyridine and 2,4,6-tri-substituted pyrimidines (Peter J. Stang et al, Synthesis, 1980, p-283; A-Garcia Martinez et al, bid, 1990, p-881). The use of these bases is not practical on commercial scale owing to the high cost involved.

Blaser et. al. (US Pat. No. 4,785,089) have emphasized that aromatic p-nitro or halo sulfonic esters of ethyl (R)-2-hydroxy-4-phenylbutyrate give better results than the trifluoromethane sulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate when used in the synthesis of ACE inhibitors like benazepril. The process involves alkylation of benzofused lactam with p-nitro or halo sulfonic ester of (R)-2-hydroxy-4-phenylbutyrate at 75-80°C for about 9 hours and results in an overall yield of benazepril hydrochloride as 83.5%. However, this process is also not completely satisfactory and is disadvantageous at a commercial scale because of low overall yield.
It is, therefore, desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation and isolation of triflate of Formula I which process improves the economics by resulting in higher yields of benazepril hydrochloride and less reaction time. The process is easy to handle at commercial scale and removes the excess pyridine and pyridinum salts without any difficulty.
Accordingly, the present invention provides a process for preparing trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenyl butyrate of Formula I, as shown in the accompanied drawings, comprising reacting ethyl (R)-2-hydroxy-4-phenyl butyrate of Formula III, as shown in the accompanied drawings, with trifluoromethanesulphonic anhydride of Formula IV, as shown in the accompanied drawings, in an inert solvent in the presence of a base and
purifying it by passing through column.

The base used to trap the acid formed during the course of the reaction may be selected
from
an inorganic or organic bases. The inorganic base is selected from potassium carbonate, sodium carbonate or sodium bicarbonate and the organic base is selected from triethylamine or pyridine. Most preferably, pyridine is used.
The term 'inert solvent1 includes solvents which cannot react with the trifluoromethane sulfonating agent and the trifluoromethanesulfonating acid derivatives. Solvents used include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and aromatic hydrocarbons such as toluene, benzene or hexane. Most preferably, methylene chloride is used.

The reaction is carried out within the temperature range from about -80°C to +80°C, preferably between -80°C to room temperature.
Condensation of 3-amino benzofused lactam, namely 1-tert.-butoxycarbonylmethyl-3-S-
amino-2,3,4,5-tetrahydro-1H-(1)-benzazepin-2-one of structural Formula V, as shown in the
accompanied drawings, with triflate of Formula I as shown in the accompanied drawings, in
the presence of a solvent and an acid acceptor, at a temperature from about 0 to 50°C for
about 2 to 5 hours followed by a suitable work-up gives the hydrochloride salt of benazepril.
1 -tert.-butoxycarboxylmethyl-3-S-amino-2,3,4,5-tetrahydro-1 H-(1 )-benazepin-2-one of
structural formula V is prepared by the method disclosed in European patent application No. 72352.
In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, these are not intended in any way to limit the scope of the present invention.
EXAMPLE 1
Preparation of (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride salt
5.67gm of ethyl (R)-2-hydroxy-4-phenyl butyrate (99% ee), 2.79gm of pyridine were taken up in methylene chloride and cooled to -20°C. A solution of 10gm of trifluoromethane sulphonic anhydride in methylene chloride was added during 15-20 min. The reaction mixture was then stirred for 30 minutes at -20 to -25°C and monitored by TLC. After the completion of the reaction, the mixture was directly passed through a column of silica gel, (25gm, 60-125 mesh, 1inch diameter column) using methylene chloride as eluant. The fractions were combined and solvent removed to afford ethyl-R-2-(trifluoromethane sulphonyl oxy)-4-phenyl butyrate (triflate) as an oil. The oil was dissolved in 15 ml methylene chloride and added dropwise to a mixture of 5.67gm of 1-tert-butoxycarbonylmethyl-3-S-amino-2,3,4,5-tetrahydro-1H-(1)-benzazepin-2-one and 2.46gm of N-methyl morpholine dissolved in 5ml methylene chloride at 30 to 35°C. The reaction mixture was further stirred for about 2 hours. Completion of reaction was monitored by HPLC. The reaction was quenched by addition of 40ml water and 60 ml methylene chloride. The pH was adjusted to 8.5 with 10% aqueous sodium carbonate solution. The organic portion was separated and washed twice with water. It was then dried over anhydrous sodium sulphate and solvent was distilled off to afford (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one , as an oil.
The oil was dissolved in 50ml ethylacetate and dry HCI gas was purged at 8-10°C for few hours to afford benazepril hydrochloride as a fine crystalline slurry. Excess hydrogen chloride was removed by distilling off ethyl acetate in vacuo. The residue was diluted with 45ml acetone and stirred at 5-8°C for 1 hour. The product was filtered and dried to constant weight in vacuo at 45-50°C affording 8.27gm of almost white product with diastereoisomer ratio of SS:SR = 99.36 : 0.18, Yield 91.9%.
EXAMPLE 2
Preparation of (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride salt
Ethyl-R-2(trifluoromethane sulphonyloxy)-4-phenylbutyrate (triflate) prepared as mentioned in previous example to get an oil. The oil was dissolved in 15 ml methylene chloride and a solution of 5.67 gm of 1-tert-butoxycarbonylmethyl-3-S-amino-2,3,4,5-tetrahydro-1H(1)-benzazepin-2-one and 2.46 gm of N-methyl morpholine in methylene chloride was added dropwise at room temperature. The reaction mixture was stirred for 1 hour. Similar work up as mentioned in previous example afforded benazepril hydrochloride, 8.20gm as almost white powder with diastereoisomer ratio of SS:SR=99.39: 0.15, Yield = 91.8%.

WE CLAIM :
1. A process for preparing trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenyl
butyrate of Formula I, as shown in the accompanied drawings, comprising reacting
ethyl (R)-2-hydroxy-4-phenylbutyrate of Formula III, as shown in the accompanied
drawings, with trifluoromethanesulphonic anhydride of Formula IV, as shown in the
accompanied drawings, in an inert solvent in the presence of a base and purifying it by
passing through packed column and isolating trifluoromethanesulfonic ester of ethyl
(R)-2-hydroxy-4-phenyl butyrate of Formula I.
2. The process of claim 1 wherein the inert solvent is selected from methylene chloride,
chloroform, carbon tetrachloride, toluene, benzene or hexane.
3. The process of claim 1 wherein the base is selected from the group consisting of
potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine or
pyridine.
4. The process of claim 3 wherein the base is pyridine.
5. The process for the preparation of trifluoromethanesulfonic ester of ethyl (R)-2-
hydroxy-4-phenyl butyrate of claim 1 for preparation of benazepril hydrohloride of
formula II.

6. The process of claim 5, wherein benazepril hydrochloride of Formula II, as shown in
the accompanied drawings, is produced by the condensation of 1-tert-
butoxycarbonylmethyl-3-S-amino-2,3,4,5-tetrahydro-1 H-(1 )-benzazepin-2-one, of
Formula V with trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenyl butyrate
of Formula I, in the presence of an organic solvent and an acid acceptor at a
temperature from about 0 to 50°C for about 1 to 5 hours followed by a suitable work
up.
7. The process for the preparation of trifluoromethanesulfonic ester of ethyl (R)-2-
hydroxy-4-phenyl butyrate substantially as herein described and exemplified by the
examples.

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Patent Number

217120

Indian Patent Application Number

374/DEL/2001

PG Journal Number

13/2008

Publication Date

31-Mar-2008

Grant Date

25-Mar-2008

Date of Filing

27-Mar-2001

Name of Patentee

RANBAXY LABORATORIES LIMITED,

Applicant Address

1956 OF 19, NEHRU PLACE, NEW DELHI-110019, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	RAJESH KUMAR THAPER	20, SECTOR -18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001(HARTANA). INDAI.
2	YATENDRA KUMAR	India Delhi India
3	SARIDI MADHA VA DILEEP KUMAR	India Delhi India
4	SHANTANU DE

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA