The present invention relates to an improved process for the preparation of angiotensin converting enzyme (ACE) inhibitor, Fosinopril Sodium of Formula I.
Fosinopril Sodium of Formula I, the ester prodrug of an angiotensin converting enzyme (ACE) inhibitor, is chemically designated as, L-proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxyl](4-phenylbutyl)phosphinyl]acetyl]-,sodium salt, trans- and is indicated for the treatment of hypertension either alone or in combination with thiazide diuretics. It is also indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics with or without digitalis.
(Formula Removed)
US Patent No. 4,337,201 provides a process for the preparation of phosphinyl alkanoyl proline esters which generically covers fosinopril, which involves reacting a proline derivative with a phosphinylacetic acid, the coupling reaction being accomplished using known amide forming procedures. It also provides a process, which involves alkylation of hydroxy compounds with a halo compound followed by basic hydrolysis.
US Patent No. 4,873,356 provides a process for the preparation of desired isomer of fosinopril, which involves reacting a phosphinyl acetic acid derivative with a haloester in the presence of the organic base to give the corresponding ester which on hydrogenation result a mixture of two diastereomers. The racemic mixture is separated from the other pair by recrystallization from suitable solvents, which is
further resolved by treatment with optically active amines such as L-cinchonidine or other conventional resolving agents to form the resolved salt. The resolved salt is treated with a strong acid to give the desired isomer. The pure desired isomer is reacted with (trans)-4-cyclohexyl-L-proline to give fosinopril, which is converted to the sodium salt by conventional methods.
US Patent No. 5,008,399 (the '399 patent) provides a process for the preparation of fosinopril, which involves reacting a phosphinyl acetic acid derivative with a haloester in the presence of the organic base such as 4-methylmorpholine, diazabicyclooctane, quinuclidine, 1-methylpyrolidine, or cinchonidine in an organic solvent to give the corresponding ester which on hydrogenation result a mixture of two diastereomers. The '399 patent provides the detail that by using the organic bases mentioned therein an increase in the desired diastereoselectivity is achieved.
US Patent No. 4,168,267, US Patent No. 4,384,123, US Patent No. 4,448,772, US Patent No. 4,594,199, US Patent No. 4,602,092, US Patent No. 4,316,905, US Patent No. 4,501,901, US Patent No. 4,588,819, US Patent No. 4,734,508, US Patent No. 4,912,230, US Patent No. 4,912,231, US Patent No. 4,937,355 provides processes for the preparation of intermediates of fosinopril.
US Patent No. 5,162,543 provides a process for the preparation of two polymorphs A and B of fosinopril sodium. It also provides a process for the interconversion of one form into the other.
US Patent Application No. 2004/0225127 provides a process for preparation of fosinopril sodium predominantly in polymorphic form A which involves separation of the four diastereoisomers of fosinopril by reacting with a cesium metal carrier to form a cesium salt of the desired isomer. The cesium salt of the desired isomer is hydrolyzed to give the fosinopril desired isomer which is further converted to fosinopril sodium polymorphic Form A.
US Patent Application No. 2005/0010054 of provides a process for the selective separation of the crystalline polymorphs Form A and Form B of fosinopril sodium.
Journal of Pharmaceutical & Biomedical Analysis, 1993, Vol. 11 pp 1063-1069 provides methods for the preparation of two polymorphic forms, Form A and Form B of fosinopril sodium.
The present inventors have found a cost-effective and convenient method for the synthesis of fosinopril sodium of formula I optionally predominantly in polymorphic Form A.
A first aspect of the invention provides a process for the preparation of fosinopril sodium of formula I, which comprises of,

(Formula Removed)
a) reacting a compound of formula III or its reactive acid derivative

(Formula Removed)
with a compound of formula IV

wherein, R is hydrogen or a protecting group, in an organic solvent or mixtures thereof, to obtain a compound of formula V,
(Formula Removed)
wherein R is as defined as above,
b) deprotecting the compound of formula V to obtain the compound of formula II,
(Formula Removed)
c) reacting compound of formula II with sodium metal carrier in presence of a solvent
or a mixture of solvents to get fosinopril sodium of formula I,
d) optionally converting fosinopril sodium of Formula I, to fosinopril sodium
polymorphic form A which comprises of,
(i) reacting fosinopril sodium of Formula I, with an acid in presence of solvent and water to give compound of formula II,
(ii) mixing together compound of formula II with a sodium metal carrier in presence of a solvent or a mixture of solvents to give fosinopril sodium,
(iii) crystallizing fosinopril sodium of formula I in the same solvent or mixture of solvents to give fosinopril sodium polymorphic Form A.
The compound of Formula IV or its acid salt thereof is taken in an organic solvent and cooled to about 5-10°C. To this, a base is added to form a carboxylic acid salt and the mixture is cooled to about -40°C. The carboxylic group of compound of formula IV can also be protected by the using a silyl compound.
The organic solvent used is selected form the group comprising of methyl acetate, ethyl acetate, butyl acetate, dichloromethane, N,N-dimethyl formamide, tetrahydrofuran, dioxane or mixture thereof.
The carboxylic acid salt of compound of Formula IV can be formed by using bases like diisopropyl ethylamine, N-methyl morpholine, triethyl amine, diazabicycloundecene and mixtures thereof.
The silyl compound used is selected from the group comprising of trimethylsilylchloride, hexamethyldisilazane, N,O bistrimethylsilylacetamide or mixtures thereof.
The compound of Formula III or its salt is dissolved in a solvent or a mixture thereof and cooled to about 0-10°C. To this aqueous potassium hydrogen sulphate is added to adjust the pH to about 2-3. The organic phase is separated, washed and the solvent is evaporated. The residue is dissolved in an organic solvent and evaporated under reduced pressure. The oily mass obtained is taken in an organic solvent. Powdered molecular sieve is added and stirred. The mixture is cooled to about -20°C and a base is added followed by the addition of an acid halide to form a reactive acid derivative. The reaction mass is stirred and cooled to about -40°C.
The organic solvent used is selected form the group comprising of methyl acetate, ethyl acetate, butyl acetate, dichloromethane, N,N-dimethyl formamide, tetrahydrofuran, dioxane or mixture thereof.
The base used is selected form the group comprising of triethylamine, tripropylamine, tributylamine, diisopropyl ethylamine, N-methyl morpholine, pyridine or mixtures thereof.
The compound of Formula V is preferably obtained through the amide bond formation by reacting of the compound of Formula III with compound of Formula IV, after activating the carboxylic function group of compound of Formula III by formation of its mixed anhydride, acid halide, acid ester.
The compound of Formula V is preferably obtained through the amide bond formation by reacting of the compound of Formula III with compound of Formula IV, after activating the carboxylic function group of compound of Formula IV by formation of its carboxylic acid salt or formation of silyl compound.
The compound of Formula V is preferably obtained through the amide bond formation by the condensation of mixed anhydride of compound of Formula III with the compound of Formula IV which is carried out at temperature ranging between -80 to 25°C.
The compound of Formula IV wherein R is hydrogen or a protecting group is added to the compound of Formula III or its acid derivative at about -40°C. The temperature is raised to about 0-5°C and stirred. The reaction mass is filtered and washed. The combined filtrate and the washings are concentrated under reduced pressure and the residue is dissolved in a solvent. The pH of the reaction mass is adjusted to about 1-2 with concentrated acid. Organic phase is separated, washed and the solvent is recovered under reduced pressure to give the compound of Formula II as oil.
The acid used is selected form the group comprising of hydrochloric acid, sulphuric acid, nitric acid, potassium hydrogen sulphate.
The compound of Formula II is dissolved in an organic solvent. To the solution sodium metal carrier in presence of a solvent or a mixture of solvents is added to get
fosinopril sodium of formula I. The fosinopril sodium of formula I obtained is optionally crystallized from an organic solvent.
The fosinopril sodium of formula I is optionally converted to fosinopril sodium polymorphic form A by reacting fosinopril sodium of Formula I, with an acid in presence of solvent and water. The organic phase is separated, washed and the solvent is evaporated. The residue is dissolved in an organic solvent and filtered. To the solution sodium metal carrier in presence of a solvent or a mixture of solvents is added and stirred. The solid product obtained is filtered and crystallized from an organic solvent to give fosinopril sodium polymorphic Form A. The crystallization of fosinopril sodium in is carried out at temperature ranging between -20 to 65°C.
The organic solvent used is selected from the group comprising of methanol, ethanol, acetonitrile, ethyl acetate, methyl acetate, tetrahydrofuran toluene, diisopropyl ether, dichloromethane or mixtures thereof.
The sodium metal carrier used is selected from the group comprising of sodium acetate, sodium methoxide, sodium 2-ethyl hexanoate.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
Step I: Preparation of (4S)-4-Cyclohexyl-1-{[(/?)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline
Solution A
(trans)-4-cyclohexyl-L-proline hydrochloride (8.6 g) and powdered molecular sieve 3A° (12.5 g) were taken in tetrahydrofuran (50 ml). The reaction mass was cooled to 5-10°C. Diisopropyl ethyl amine (9.5 g) was added and stirred for 15-20 minutes at 5-10°C. The reaction mass was further cooled to -40°C.
Solution B
[2-methyl-1-(1-oxopropoxy)propoxy(4-phenylbutyl)phosphinyl]acetic acid
cinchonidine salt (25.0 g) was dissolved in mixture of ethyl acetate (150 ml) and water (75 ml) and cooled to 0-5°C. To this aqueous potassium hydrogen sulfate was added slowly till the pH is adjusted to 2.3-2.5. The organic phase was separated and washed twice with water (25 ml). The solvent was evaporated and the residue was redissolved in ethyl acetate (50 ml) and evaporated under reduce pressure. Oily mass was taken in tetrahydrofuran (165 ml) under nitrogen atmosphere. Powdered molecular sieve 3A° (12.5 g) was added and stirred for 5-10 minutes. The reaction mixture was cooled to -20°C, and pyridine (1.46 g) was added. The mixture was stirred for 5 minutes and N-methyl-morpholine (4.10 g) followed by pivaloyl chloride (4.45 g) was added at the same temperature. The reaction mass was stirred for 30 minutes and then cooled to -40°C.
Solution C
Solution B was added to solution A at -40°C. The temperature was raised to 0-5°C and stirred for 2-4 hours. The reaction was monitored by HPLC. The reaction mass was filtered through hyflo and hyflo bed was washed with ethyl acetate (75 ml). The combined filtrate and the washings were concentrated under reduced pressure. The residue was dissolved in ethyl acetate (125 ml) and water (50 ml). The mixture was cooled to 5-10°C and the pH of reaction mass was adjusted to 1.5-1.8 with concentrated hydrochloric acid solution. The organic phase was separated and washed twice with water (50 ml). The solvent was recovered under reduced pressure to give the title compound as oil. Yield: 20.8 g
Step II: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[( 1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenyl butyl)]phosphinyl]acetyl}-L-proline obtained in Step I, was taken in dichloromethane (55 ml and stirred to get clear solution. To this solution was added a solution of sodium-2-ethyl hexanoate [sodium-2-ethyl hexanoate (6.12 g) in ethyl acetate (75
ml)] at 25°C. The mixture was stirred for 30 minutes. Ethyl acetate (135 ml) was
added slowly to the reaction mass and was then stirred for 18-20 hours at same
temperature. The solid product was filtered and washed with ethyl acetate (75 ml) to
give of the title compound as white solid.
Yield: 13.8 g
HPLC purity: 99.64 %
IR (KBr): 2925.37, 2856.46, 1759.39, 1622.94, 1601.02, 1453.41, 1409.45, 1385.39
cm"1
Step III: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(Polymorph A)
Sodium salt of (4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy) propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline, obtained from step II (10.0 g) was taken in ethyl acetate (50 ml) and cooled to 0-5°C. To this aqueous potassium hydrogen sulfate was added slowly till the pH is adjusted to 2.3-2.5. The organic phase was separated and washed twice with water (20 ml). The solvent was evaporated and the residue was redissolved in ethyl acetate (40 ml) and traces of water and ethyl acetate were removed from the solvent to leave oily mass. The residue was redissolved in dichloromethane (22 ml), and filtered through micron filter. To this solution was added a solution of sodium-2-ethyl hexanoate [sodiums-ethyl hexanoate (2.84 g) in ethyl acetate (30 ml)] at 25°C and stirred for 30 minutes. Ethyl acetate (56 ml) was added to the reaction mass and stirred for 18-20 hours at 25-30°C. The solid product was filtered and washed with ethyl acetate (30 ml) and dried under vacuum at 30-35°C to give the title compound as white solid. Yield: 9.62 g HPLC purity: 99.83%.
IR(KBr): 2925.21, 2856.46, 1759.45, 1622.77, 1601.02, 1453.13, 1409.49, 1385.11 cm'1
1H NMR (CD3OD): 8 7.26 - 7.13 (m, 5H, aromatic protons); 6.28 - 6.25 (m, 1H, O-CH -O); 4.42-4.39 (d, 1H J= 8.51 Hz, -CH - COONa);
3.86-3.75 (m, 1H, -NCH-); 3.12 - 2.84 (m, 2H, P-CH2-CO-,) 2.66-2.62 (t, 2H, Ph-CH2); 2.47 - 2.39 (m, 3H); 2.19 - 1.89 (m, 5H); 1.74-1.66 (m, 9H); 1.28 - 0.92 (m, 15H)
EXAMPLE 2
Step I: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline
Solution A
(trans)-4-cyclohexyl-L-proline hydrochloride (8.6 g) and powdered molecular sieve 3A° (12.5 g) was taken in ethyl acetate (50 ml), and cooled to 5-10°C. Diisopropyl ethyl amine (9.5 g) was added and stirred for 15-20 minutes at 5-10CC. The reaction mass was further cooled to -40°C.
Solution B
[2-methyl-1 -(1 -oxopropoxy)propoxy(4-phenylbutyl)phosphinyl]acetic acid
cinchonidine salt (25.0 g) was dissolved in mixture of ethyl acetate (150 ml) and water (75 ml) and cooled to 0-5°C. To this aqueous potassium hydrogen sulfate was added slowly till the pH is adjusted to 2.3-2.5. The organic phase was separated and washed twice with water (25 ml). The solvent was evaporated and the residue was redissolved in ethyl acetate (50 ml) and evaporated under reduce pressure. Oily mass was taken in ethyl acetate (165 ml) under nitrogen atmosphere. Powdered molecular sieve 3A° (12.5 g) was added and stirred for 5-10 minutes. The reaction mixture was cooled to -20°C, and pyridine (1.46 g) was added. The mixture was stirred for 5 minutes and N-methyl-morpholine (4.10 g) followed by pivaloyi chloride (4.45 g) was added at the same temperature. The reaction mass was stirred for 30 minutes and then cooled to -40°C.
Solution C
Solution B was added to solution A at -40°C and further stirred for 2-4 hours at 0 -5°C. The reaction was monitored by HPLC. The reaction mass was filtered through hyflo and the hyflo bed was washed with ethyl acetate (75 ml).
To the combined filtrate, washing water (50 ml) was added and cooled to 5-10°C. The pH of reaction mass was adjusted to 1.5-1.8 with concentrated hydrochloric acid solution. The organic phase was separated and washed twice with water (50 ml). The solvent was recovered under reduced pressure to give the title compound as oil. Yield: 20.5 g
Step II: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenyl
butyl)]phosphinyl]acetyl}-L-proline obtained in Step I was taken in dichloromethane
(55 ml) and stirred to get a clear solution. To this solution was added a solution of
sodium-2-ethyl hexanoate [sodium-2-ethyl hexanoate (6.12 g) in ethyl acetate (75
ml)] at 25°C and stirred for 30 minutes. Ethyl acetate (135 ml) was added to the
reaction mass and then stirred for 18-20 hours at same temperature. The solid
product was filtered and washed with ethyl acetate (75 ml) to give of the title
compound as white solid.
Yield: 14.10 g
HPLC purity: 99.92 %.
IR(KBr): 2925.61, 2856.28, 1759.44, 1622.60, 1600.77, 1453.34, 1409.44,1384.60
cm"1
Step III: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(Polymorph A)
Sodium salt of (4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy) propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline, obtained from step II (10 g), was taken in ethyl acetate (50 ml) and cooled to 0-5°C. To this aqueous Potassium hydrogen sulfate was added till the pH is adjusted to 2.3-2.5. The organic phase was separated and washed twice with water (20 ml). The solvent was evaporated and residue was redissolved in ethyl acetate (40 ml) and traces of water and ethyl acetate was removed from the solvent to leave oily mass. The residue was redissolved in dichloromethane (22 ml) and filtered through micron filter. To this
solution was added a solution of sodium-2-ethyl hexanoate [sodium-2-ethyl
hexanoate (2.84 g) in ethyl acetate (30 ml)] at 25°C and stirred for 30 minutes. Ethyl
acetate (56 ml) was added to the reaction mass and stirred for 18-20 hours at 25-
30°C. The solid product was filtered, washed with ethyl acetate (30 ml) and dried to
get the title compound as white solid.
Yield: 9.60 g
HPLC purity: 99.95%.
IR(KBr): 2925.58, 2855.96, 1759.26, 1622.89, 1600.77, 1452.92, 1409.32, 1385.39
cm-1
EXAMPLE 3
Step I: Preparation of (4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline
Solution A
(trans)-4-cyclohexyl-L-proline hydrochloride (8.6 g) and powdered molecular sieve 3A° (12.5 g) was taken in ethyl acetate (50 ml), cooled to 5-10°C. To this N-methyl morpholine (7.44 g) was added at same temperature. This was then stirred for 15-20 minutes at 5-10°C and further cooled to -40°C.
Solution B
[2-methyl-1 -(1 -oxopropoxy)propoxy(4-phenylbutyl)phosphinyl]acetic acid
cinchonidine salt (25.0 g) was dissolved in mixture of ethyl acetate and water (75 ml) and cooled to 0-5°C. To this aqueous Potassium hydrogen sulfate was added slowly till the pH is adjusted to 2.3-2.5. The organic phase was separated and washed twice with water (25 ml). The solvent was evaporated and the residue was redissolved in ethyl acetate (50 ml) and evaporated under reduce pressure. Oily mass was taken in ethyl acetate (165 ml) under nitrogen atmosphere. Powdered molecular sieve 3A° (12.50 g) was added followed by stirring for 5-10 minutes. The mixture was cooled to -20°C, pyridine (1.46 g) was added to the reaction mass and stirred for 5 minutes. N-methyl- morpholine (4.10 g) followed by pivaloyl chloride (4.45 g) was added at the same temperature. The reaction mass was stirred for 30 minutes and then cooled to -40°C.
Solution C
Solution B was added to solution A at -40°C and further stirred for 2-4 hours at 0-5°C. The reaction was monitored by HPLC. The reaction mass was filtered through hyflo and the hyflo bed was washed with ethyl acetate (75 ml). To the combined filtrate, washing water (50 ml) was added and cooled to 5-10°C. The pH of reaction mass was adjusted to 1.5-1.8 with concentrated hydrochloric acid solution. The organic phase was separated and washed twice with water (50 ml). The solvent was recovered under reduced pressure to the title compound as oil. Yield: 20.5 g
Step II: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenyl butyl)]phosphinyl]acetyl}-L-proline obtained in Step I was taken in dichloromethane (55 ml) and stirred to get clear solution. To this, a solution of sodium-2-ethyl hexanoate [sodium-2-ethyl hexanoate (6.12g) in ethyl acetate (75ml)] was added at 25°C and stirred for 30 minutes. Ethyl acetate (135 ml) was added to the reaction mass and stirred for 18-20 hours at same temperature. The solid product was filtered and washed with ethyl acetate (75 ml) to give the title compound as white solid. Yield: 14.16 g HPLC purity: 99.62%. IR(KBr): 2924.9, 2856.20, 1759.3, 1622.6, 1600.2, 1452.10, 1409.10,1384.60 cm"1
Step III: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(Polymorph A)
Sodium salt of (4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxoprppoxy) propoxy)(4-phenyl butyl)]phosphinyl]acetyl}-L-proline, obtained in step II (10 g) was taken in ethyl acetate (50 ml) and cooled to 0-5°C. To this aqueous Potassium hydrogen sulfate was added till the pH is adjusted to 2.3-2.5. The organic phase was separated and washed twice with water (20 ml). The solvent was evaporated from the organic phase and the residue was redissolved in ethyl acetate (40 ml) and
traces of water and ethyl acetate were removed from the solvent to leave oily mass. The residue was redissolved in dichloromethane (22 ml), and filtered through micron filter. To this solution was added a solution of sodium-2-ethyl hexanoate [sodiums-ethyl hexanoate (2.84 g) in ethyl acetate (30 ml)] at 25°C and stirred for 30 minutes. Ethyl acetate (56 ml) was added to the reaction mass and stirred for 18-20 hours at 25-30°C. The solid product was filtered, washed with ethyl acetate (30 ml) and dried under reduced pressure at 30-35°C to give the title compound as white solid. Yield: 9.57 g HPLC purity: 99.70%.
IR(KBr): 2925.37, 2856.46, 1759.39, 1622.94, 1601.02, 1453.41, 1409.45, 1385.39 cm-1
EXAMPLE 4
Step I: Preparation of (4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline Solution A
(trans)-4-cyclohexyl-L-proline hydrochloride (8.60 g) was taken in tetrahydrofuran (50 ml) at 25-30°C. Hexamethyldisilazane (11.90 g) was added at 25-30°C and stirred for 5 hours at 25-30°C. The reaction mass was cooled to -40°C.
Solution B
[2-methyl-1 -(1 -oxopropoxy)propoxy(4-phenylbutyl)phosphinyl]acetic acid
cinchonidine salt (25.0 g) was dissolved in mixture of ethyl acetate (150 ml) and water (75 ml), cooled to 0-5°C. To this aqueous Potassium hydrogen sulfate was added slowly till the pH is adjusted to 2.3 -2.5. The organic phase was separated and washed twice with water (25 ml). The solvent was evaporated and the residue was redissolved in ethyl acetate (50 ml) and evaporated under reduced pressure. Oily mass was taken in tetrahydrofuran (165 ml) under nitrogen atmosphere. Powdered molecular sieve 3A° (12.5 g) was added and stirred for 5-10 minutes. The reaction mixture was cooled to -20°C and pyridine (1.46 g) was added. The mixture was stirred for 5 minutes and N-methyl-morpholine (4.10 g) followed by pivaloyl chloride (4.45 g) were added at the same temperature. The reaction mass was stirred for 30 minutes and then cooled to -40°C.
Solution C
Solution B was added in solution A at -40°C and further stirred for 2-4 hours at 0 -5°C. The reaction was monitored by HPLC. The reaction mass was filtered through hyflo and the hyflo bed was washed with ethyl acetate (75 ml). The combined filtrate and the washings were concentrated under reduced pressure. The residue was dissolved in ethyl acetate (125 ml) and water (50 ml). The mixture was cooled to 5-10°C and the pH of reaction mass was adjusted to 1.5-1.8 with concentrated hydrochloric acid solution. The organic phase was separated and washed twice with water (50 ml). The solvent was recovered under reduced pressure to give of title compound as oil. Yield: 20.80 g
Step II: Preparation of (4S)- 4-Cyclohexyl-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenyl butyl)]phosphinyl]acetyl}-L-proline obtained in Step I was taken in dichloromethane (55 ml) and stirred to get a clear solution. To this solution was added a solution of sodium-2-ethyl hexanoate [sodium-2-ethyl hexanoate (6.12g) in ethyl acetate (75ml)] at 25°C. The mixture was stirred for 30 minutes. Ethyl acetate (135 ml) was added slowly to the reaction mass and was stirred for 18-20 hours at same temperature. The solid product was filtered and washed with ethyl acetate (75 ml) to give the title compound as white solid. Yield: 14.76 g HPLC purity: 99.72% IR(KBr): 2925.46, 2856.53, 1759.45, 1622.95, 1601.02, 1453.43, 1409.50 cm-1.
Step III: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(Polymorph A)
Sodium salt of (4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy) propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline, obtained from step II (10 g) was taken in ethyl acetate (50 ml) and cooled to 0-5°C. To this aqueous Potassium hydrogen sulfate was added till the pH is adjusted to 2.3-2.5. The organic phase was
separated and washed twice with water (20 ml). The solvent was evaporated and the residue was redissolved in ethyl acetate (40 ml) and traces of water and ethyl acetate were removed from the solvent to leave oily mass. The residue was redissolved in dichloromethane (22 ml), filtered through micron filter. To this solution was added a solution of sodium-2-ethyl hexanoate [sodium-2-ethyl hexanoate (2.84 g) in ethyl acetate (30 ml)] at 25°C and stirred for 30 minutes. Ethyl acetate (56 ml) was added to the reaction mass and stirred for 18-20 hours at 25-30°C. The solid product was filtered and washed with ethyl acetate (30 ml) and dried under vacuum at 30-35°C to give the title compound as white solid. Yield: 9.60 g HPLC purity: 99.86%. IR(KBr): 2925.42, 2856.50, 1759.44, 1622.83, 1600.98, 1453.35, 1409.51 cm-1.
EXAMPLE 5
Step I: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline
Solution A
(trans)-4-cyclohexyl-L-proline hydrochloride (17.20 g) was taken in dichloromethane (200 ml) at ambient temperature. Hexamethyldisilazane (23.78 g) was added and stirred for 4 hours at 30-35°C. This reaction mass was cooled to 0-5°C.
Solution B
[2-methyl-1 -(1 -oxopropoxy)propoxy(4-phenylbutyl)phosphinyl]acetic acid
cinchonidine salt (50.0 g) was dissolved in mixture of dichloromethane (300 ml) and water (150 ml) and cooled to 0-5°C. To this aqueous Potassium hydrogen sulfate was added slowly till the pH is adjusted to 2.3-2.5. The organic phase was separated and washed twice with water (100 ml). The solvent was evaporated and the residue was redissolved in dichloromethane (100 ml) and evaporated under reduce pressure.
Oily mass was taken in dichloromethane (300 ml) under nitrogen atmosphere and stirred for 5-10 minutes. The mixture was cooled to -20°C and pyridine (2.92 g) was added to the reaction mass. The mixture was stirred for 5 minutes and N-methyl morpholine (8.18 g) followed by pivaloyl chloride (9.07 g) were added at the same temperature. The reaction mass was stirred for 30 minutes and then cooled to -70°C.
Solution C
Solution A was added to solution B at -70°C and stirred for 1-2 hours at -40 to 35°C. The reaction was monitored by HPLC. Water (250 ml) was charged to the reaction mixture and the temperature was raised to 5-10°C. The pH of reaction mass was adjusted to 1.5-1.8 with concentrated hydrochloric acid solution. The organic phase was separated and washed twice with water (250 ml). The solvent recovered under reduced pressure to give title compound as oil. Yield: 61.0 g
Step II: Preparation of (4S)-4-Cyclohexy 1-1-{[(R)-[(1S)-2-methy 1-1-(1-oxopropoxy)propoxy)(4-phenylbutyl)]phosphinyl]acetyl}-L-proline sodium salt
(4S)-4-Cyclohexyl-1-{[(R)-[(1S)-2-methyl-1-(1-oxopropoxy)propoxy)(4-phenyl butyl)]phosphinyl]acetyl}-L-proline obtained in Step I was taken in dichloromethane (110 ml) and stirred to get a clear solution. To this solution was added a solution of sodium-2-ethyl hexanoate [sodium-2-ethyl hexanoate (12.23g) in ethyl acetate (150ml)] at 25°C and stirred for 30 minutes. Ethyl acetate (270 ml) was added slowly to the reaction mass and stirred for 18-20 hours at same temperature. The solid product was filtered and washed with ethyl acetate (150 ml) to give the title compound as white solid. Yield: 33.58 g HPLC purity: 99.90% IR(KBr): 2925.46, 2856.53, 1759.45, 1622.95, 1601.02, 1453.43, 1409.50 cm-1.

WE CLAIM:
1. A process for the preparation of fosinopril sodium of formula I, which comprises of,
(Formula Removed)
a) reacting a compound of formula III or its reactive acid derivative,

with a compound of formula IV
(Formula Removed)
wherein, R is hydrogen or a protecting group, in an organic solvent or mixtures thereof, to obtain a compound of formula V,

(Formula Removed)
wherein R is as defined as above,
b) deprotecting the compound of formula V to obtain the compound of formula II,
(Formula Removed)
c) reacting compound of formula II with sodium metal carrier in presence of a solvent
or a mixture of solvents to get fosinopril sodium of formula I,
d) optionally converting fosinopril sodium of Formula I, to fosinopril sodium
polymorphic form A which comprises of,
(i) reacting fosinopril sodium of Formula I, with an acid in presence of solvent and
water to give compound of formula II,
(ii) mixing together compound of formula II with a sodium metal carrier in presence of
a solvent or a mixture of solvents to give fosinopril sodium,
(iii) crystallizing fosinopril sodium of formula I in the same solvent or mixture of
solvents to give fosinopril sodium polymorphic Form A.
2. A process according to claim 1, wherein the reactive acid derivative of compound of formula III is mixed anhydride, acid halides, acid ester.
3. A process according to claim 1, wherein the protecting group of compound of formula IV is a carboxylic acid salt or a silyl protecting group.
4. A process according to claim 3, wherein the carboxylic acid salt employed, is
formed by using bases like diisopropyl ethylamine, N-methyl morpholine, triethyl
amine, diazabicycloundecene and mixtures thereof.
5. A process according to claim 3, wherein the silyl-protecting compound employed,
is formed by using silyl compounds selected from trimethylsilylcholride,
hexamethyldisilazane, N.O-bistrimethylsilylacetamide and mixtures thereof.
5. A process according to claim 1, wherein the solvent used in step a) is selected from the group comprising of methyl acetate, ethyl acetate, butyl acetate, dichloromethane, N,N-dimethyl formamide, tetrahydrofuran, dioxane and mixture thereof.
6. A process according to claim 1, wherein step a) condensation of mixed anhydride of compound of Formula III with the compound of Formula IV is carried out at temperature ranging -80 to 25°C.
7. A process according to claim 1, wherein the deprotection in step b) is carried out in acidic medium.
8. A process according to claim 1, wherein the sodium metal carrier used in step c) and step d) is selected from the group comprising of sodium acetate, sodium methoxide, sodium 2-ethyl hexanoate.
9. A process according to claim 1, wherein the solvent used in step c) and step d) is selected from the group comprising of methanol, ethanol, acetonitrile, ethyl acetate, methyl acetate, tetrahydrofuran toluene, diisopropyl ether, dichloromethane or mixtures thereof.
10. A process according to claim 1, wherein the process of claim 1 wherein crystallization of fosinopril sodium in step d) is carried out at temperature ranging between -20 to 65°C.