DESC:
Background of the invention: Lisinopril dihydrate (I), (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L lysyl]-L-proline dihydrate is an angiotensin-converting enzyme (ACE) inhibitor and it is used to treat high blood pressure, heart failure and acute myocardial infarction. Lisinopril dihydrate is also used in chronic kidney diseases and to treat protein in urine.
.2H2O
(I)
Several processes have been reported in the literature for the preparation of lisinopril dihydrate.

U.S. Pat. No. 5,227,497 describes a process for the preparation of lisinopril by reacting 3-phenylpropionaldehyde and a protected L-lysine derivative in the presence of a cynating agent. The reaction requires an acidic work-up at the end which results in the production of hydrogen cyanide and hence the reaction is not suitable for an industrial scale.

U.S. Pat. No. 4,808,741 describes the process for the preparation of lisinopril by reaction of side chain protected lysine with ethyl 2-halo-4-phenyl butanoate to give corresponding alkyl amino acid derivative as a racemic mixture. The longer reaction time and low diasteromeric ratio makes this process economically unfeasible.

U.S. Pat. No. 4,925,969 describes the process for the preparation of lisinopril by reaction of benzene and maleic anhydride to give trans-[beta]-benzoylacrylic acid as an intermediate. A side product is obtained during the esterification of carboxyl group in alcohol in the presence of an acid up to a ratio of 2:1.

All the above mentioned prior art processes provide lisinopril with low purity. There is still a need for the preparation of lisinopril dihydrate, which produces lisinopril dihydrate in an economic way, in optically pure form and with more yields.

Object of the invention: It is principal object of the present invention to provide an improved process for the preparation of lisinopril dihydrate or its pharmaceutically acceptable salts. It is another object of the present invention to provide a commercially viable and economical process for the preparation of lisinopril dihydrate or its pharmaceutically acceptable salts. The present invention relates to the purification process of lisinopril dihydrate which provides lisinopril dihydrate or its pharmaceutically acceptable salts in high purity. It is still another object of the present invention to provide improved process for the purification of lisinopril dihydrate containing low level of impurities. It is yet another object of the present invention to provide a process for the preparation of lisinopril dihydrate or its pharmaceutically acceptable salts by making use of a metal.

Summary of the invention: The present invention relates to a process for the preparation of the angiotensin-converting enzyme (ACE) inhibitor namely lisinopril dihydrate or its pharmaceutically acceptable salts thereof. According to one aspect of the present invention there is provided a process for the purification of lisinopril dihydrate or its pharmaceutically acceptable salts which yields high purity. The process of purification is cost effective, efficient and industrially feasible which provides lisinopril dihydrate or its pharmaceutically acceptable salts in high yields and purity.

Description of the Invention: The present invention relates to a process for the preparation of the angiotensin-converting enzyme (ACE) inhibitor namely lisinopril dihydrate or its pharmaceutically acceptable salts thereof with low levels of impurities. The impurities in the synthesis of lisinopril dihydrate are:

N2, N6-Bis [(S)-1-Carboxy-3-phenylpropyl]-L-lysyl-L-proline of formula (II),
(II)
2-Amino-4-phenylbutanoic acid of formula (III),
(III)
(S)-2-[(3S,8aR)-3-(4-Aminobutyl)-1,4-dioxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoic acid of formula (IV),
(IV)

(S)-2-[(3S, 8aS)-3-(4-Aminobutyl)-1,4-dioxohexa hydro pyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoic acid (V)
(V)

[(S)-1-Carboxy-3-phenylpropyl]-L-lysine of formula (VI)
(VI)

[(R)-1-Carboxy-3-phenylpropyl]-L-lysyl-L-proline of formula (VII)

(VII)

[(S)-1-Carboxy-3-cyclohexylpropyl]-L-lysyl-L-proline of formula (VIII)
(VIII)

Along with the above listed impurities there are a few unknown impurities formed in the process of lisinopril dihydrate.

In an embodiment, the present invention relates to a process for the purification of lisinopril dihydrate which provides lisinopril dihydrate or its pharmaceutically acceptable salts with purity greater than 99%.

In another embodiment, the present invention relates to a process for the purification of lisinopril dihydrate or its pharmaceutically acceptable salts thereof wherein the process comprises:
(a) providing a solution of lisinopril dihydrate in a solvent,
(b) heating the reaction mixture,
(c) addition of the metal,
(d) optionally hydrogenating the reaction mixture,
(e) isolating lisinopril dihydrate or its pharmaceutically acceptable salts.

In step (a), solvent is selected from the group of water, organic solvent and mixtures thereof. The organic solvent is selected from the group of polar protic solvents such as alcohols, hydrocarbon solvents such as toluene, polar aprotic solvents such as dimethylformamide, ethers such as tetrahydrofuran, non-polar solvents and the like. The polar protic solvents is selected from group of methanol, ethanol, propanol and the like.

In step (b), heating is carried out at a temperature of 40-130°C. Heating in step (b) is carried out preferably at a temperature from 90°C to 100°C.

In step (c), the metal is selected from the group comprising of nickel, zinc, palladium, iridium, ruthenium, rhodium. The preferred metal is nickel, zinc and palladium. Zinc can be used in the presence of acetic acid.

The percentage of the metal used in step (c) is from 2% to 50% preferably 5%.

In step (d), the reaction is carried out at a temperature of -10 to 18°C under hydrogen atmosphere. The reaction is carried for 8 hours to 24 hours, preferably, 10-15 hours.

In step (e), isolation is performed by conventional means known in the prior art which includes but not limited to filtration, distillation, crystallization, acid-base treatment, seeding and the like, preferably filtration.

In yet another embodiment, the present invention relates to a process for the purification of lisinopril dihydrate or its pharmaceutically acceptable salts thereof wherein the process comprises:
(a) providing a solution of lisinopril dihydrate in a solvent,
(b) heating the reaction mixture,
(c) addition of the metal and
(d) isolating lisinopril dihydrate or its pharmaceutically acceptable salts.

In step (a), solvent is selected from the group of water, organic solvent and mixtures thereof. The organic solvent is selected from the group of polar protic solvents such as alcohols, hydrocarbon solvents such as toluene, polar aprotic solvents such as dimethylformamide, ethers such as tetrahydrofuran, non-polar solvents and the like. The polar protic solvents is selected from group of methanol, ethanol, propanol and the like.

In step (b), heating is carried out at a temperature of 40-130°C. Heating in step (b) is carried out preferably at a temperature from 90°C to 100°C.

In step (c), the metal is selected is zinc. The reaction is carried in the presence of acetic acid.

The percentage of the metal used in step (c) is from 2% to 50%.

In step (d), isolation is performed by conventional means known in the prior art which includes but not limited to filtration, distillation, crystallization, acid-base treatment, seeding and the like, preferably filtration.

It is of utmost importance to control the impurities during the synthesis of lisinopril dihydrate. The lisinopril dihydrate or its pharmaceutically acceptable salts obtained by the process of the present invention has purity greater that 99%. The yield of lisinopril dihydrate obtained by the process of the present invention has yields greater than 90%.

The analytical method used for the determination of the impurities in the synthesis of lisinopril dihydrate or pharmaceutically acceptable salt thereof is the HPLC method. The impurities in the lisinopril dihydrate were determined by HPLC method. The instrument used is HPLC with UV-Vis detector column heater and suitable data processor. The column used is C8, 4.6 x 250 mm, 5 microns. The impurities were determined by HPLC method with mobile phase and phosphate solution and flow rate of 1.0 ml/min. The mobile phase is phosphate solution (pH 5.0) and acetonitrile in the volume of 960 ml: 40ml.

The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples. The invention, which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.

Examples:
Example 1: Crude lisinopril dihydrate (100 gm) was added to water (600 ml) and heated to 80°C. The reaction mixture was stirred till dissolution. The reaction mass was cooled and Raney Nickel (5 gm) was added. The reaction mixture was hydrogenated for 15 hrs at 20°C with pressure at 3.5-4.5 Kg/cm2. The reaction mixture was filtered. The filtrate was heated to 40-45°C. The reaction mixture was charcolized and concentrated. Ethanol (22 ml) was added to the mixture and seeded with lisinopril dihydrate. The reaction mass was stirred, cooled and filtered.
Yield: 90.5%
Purity: 99.6%

Example 2: Crude lisinopril dihydrate (120 gm) was dissolved in water (790 ml) at 80°C and cooled to 20-30°C. The solution was treated with zinc metal (12 gm) and acetic acid (22.1 gm) for 10 hours. The reaction mixture is filtered. The filtrate is charcolized and concentrated. Ethanol is added to the reaction mixture and seeded with lisinopril to crystallize the material. The mass was stirred at 45-50°C for 12-24 hours and cooled. Ethanol was added and stirred. The reaction mixture was filtered, washed with ethanol and dried.

Example 3: Crude lisinopril dihydrate (50 gm) was dissolved in water (332 ml) at 80°C. The reaction mixture was cooled to 20-30°C. The solution was hydrogenated using Palladium on carbon (10 gm) for 5 hours. The palladium on carbon is separated by filtration. The reaction filtrate is charcolized. Ethanol is added to the filtrate and seeded with Lisinopril to crystallize. The mass is stirred at 45-50°C for 24 hours. The reaction mass is cooled to 15-18°C. Ethanol is added, the reaction mixture is filtered and washed with ethanol and dried.
,CLAIMS:Claim 1: A process for purification of lisinopril dihydrate (I) or its pharmaceutically acceptable salt comprising,
(a) providing a solution of lisinopril dihydrate in a solvent,
(b) heating the reaction mixture,
(c) addition of the metal,
(d) optionally hydrogenating the reaction mixture,
(e) isolating lisinopril dihydrate or its pharmaceutically acceptable salts.

Claim 2: A process according to claim 1, wherein solvent is selected from the group of water, organic solvents, or mixtures thereof.

Claim 3: A process according to claim 2, wherein the organic solvent is selected from the group of polar protic solvents such as alcohols, hydrocarbon solvents such as toluene, polar aprotic solvents such as dimethylformamide, ethers such as tetrahydrofuran, non-polar solvents or mixtures thereof.

Claim 4: A process according to claim 3, wherein the alcohols are selected from group of methanol, ethanol, propanol and mixtures thereof.

Claim 5: A process according to claim 1, wherein heating is carried out at a temperature of 40-130°C.

Claim 6: A process according to claim 1, wherein the metal is selected from the group of nickel, zinc, palladium, iridium, ruthenium, rhodium.

Claim 7: The process according to claim 8, wherein zinc is used in the presence of acetic acid.

Claim 8: The process according to claim 7, wherein the percentage of the metal is from 2% to 50%.

Claim 9: A process according to claim 1 step (d), wherein hydrogenation is carried out at a temperature of -10 to 18°C.

Claim 10: Lisinopril dihydrate obtained by the process of claim 1, wherein purity of lisinopril dihydrate is greater than 99%.