DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PURIFICATION OF BARNIDIPINE HYDROCHLORIDE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed:
FIELD OF INVENTION

The present invention relates to a process for the purification of Barnidipine hydrochloride of Formula I.

Formula I

BACKGROUND OF THE INVENTION

Bamidipine is an antihypertensive drug belonging to the dihydropyridine (DHP) group of calcium antagonists. The product was developed by Yamanouchi Pharmaceutical and is approved in European Union countries and Japan for the treatment of mild to moderate essential hypertension. Barnidipine contains two chiral centers which have four possible enantiomers. The active component is composed of a single optical isomer (3S, 4S configuration), which is the most potent and longest-acting of the four enantiomers.

Formula I

Several processes are available in the literature for synthesis of Bamidipine hydrochloride. Barnidipine as a racemic compound is first described in Yamanouchi Pharma’s US 4,220,649 A
US ‘649 discloses a chemical process for preparing racemic Barnidipine, which involves the reaction of 1-Benzyl-3-acetoacetyloxypyrrolidine with 3-Nitrobenzaldehyde and Beta-amino-crotonic acid methyl ester to product racemic Barnidipine.

The process is as shown in scheme-I below:

Scheme-I

This patent is silent about the specific isomers preparation or their separation.

EP 0 160 451 B1 of Yamanouchi discloses hydrochloride salt and other salts of Barnidipine. This patent further discloses the preparation of hydrochloride salt of Barnidipine using L-(-)-malate salt of Barnidipine.

The process is shown in the scheme given below:

The major drawback of the above process is cycle time is very high for preparation of (3S, 4S) Barnidipine Malate and quality data is not disclosed.

Journal of Medicinal Chemistry, 29(12), 2504-11, 1986 discloses the preparation of Barnidipine hydrochloride using Barnidipine oxalate and malate salts, which is shown in the scheme given below.

The major drawback of the above process is cycle time for preparation of (3S, 4S) (3S, 4R)-Barnidipine oxalate and (3S, 4S)- Barnidipine Malate is too high and which is not cost effective process and not feasible for manufacturing.

Hence, there is a need for the synthesis of cost effective and commercially viable process which yields optically pure Barnidipine hydrochloride salt with good yield and which involves lesser time durations, and/or easier to handle.

The present invention is directed towards a purification process for the preparation of optically pure Barnidipine hydrochloride salt (I) using seeding technology.

The advantage of the present invention is to provide a simple, cost-effective and industrially viable process for the large scale preparation of Barnidipine Hydrochloride.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a process for the purification of Barnidipine hydrochloride (I) which is industrially viable.

SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a process for the purification of Barnidipine hydrochloride of Formula (I) having purity >99 %,

Formula I

which comprises:
(i) treating Barnidipine free base with a salt forming agent in a solvent to form the solution,
(ii) seeding the step i) solution,
(iii) optionally, isolating the salt of Barnidipine,
(iv) converting the salt of Barnidipine to Barnidipine free base,
(v) optionally, isolating Barnidipine free base,
(vi) treating the Barnidipine free base with an optically active acid in a solvent to obtain an optically active acid addition salt of Barnidipine,
(vii) seeding the above solution,
(viii) optionally, isolating the optically active acid addition salt of Barnidipine,
(ix) converting the optically active acid addition salt of Barnidipine to optically pure Barnidipine hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of present invention is to provide a process for the purification of Barnidipine hydrochloride using seeding technology for the purification.

The process comprises, treating Barnidipine free base with a salt forming agent in a solvent, followed by adding a seed of the salt of Barnidipine to produce a salt of Barnidipine at a temperature range of 15 ± 5?C to 60± 5?C.

In another embodiment of the invention, the salt forming agent selected from an acid comprising the group consisting of hydrochloric acid, hydrobromic acid, oxalic acid, succinic acid, fumaric acid, L-Malic acid, L-Tartaric aid, D-Tartaric acid.

Other embodiment of the invention, the solvent used in the above reaction is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof.

In another embodiment of the invention, the salt of Barnidipine is treated with 0.5% seed of salt of Barnidipine.

After completion of the above reaction the salt of Barnidipine isolated and purified or used as such in the next step.

The salt of Barnidipine is treated with a base in presence of a solvent to produce Barnidipine base.

The base used in the above reaction is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, ammonium hydroxide, sodium bicarbonate, triethylamine, diethylamine, diethyl aminopyridine, pyridine or mixtures thereof.

The solvent used the above reaction is preferably selected from chloroform, methylene dichloride, water, acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof.

Barnidipine free base is isolated and purified or directly used in the next step.

Barnidipine free base is treated with a seed of an optically active acid salt of Barnidipine and the optically active acid in presence of a solvent at a temperature range of 15 ± 5?C to 60± 5?C.

The optically active acid used in the above reaction is selected from the group consisting of tartaric acid, malic acid, mandelic acid, and camphor-10-sulfonic acid.

The solvent used in the above reaction is selected from a group consisting of acetone, acetophenone, butanone, propanone, cyclopentanone, methyl ethyl ketone, methyl isobutyl ketone, pentanone, methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof .

The seed of optically active acid salt of Barnidipine is ~0.5% and has <0.3% of (3S, 4R)-isomer. The optically active acid salt of Barnidipine is isolated and purified or directly used in next step.
The optically active acid salt of Barnidipine is treated with a base in presence of a solvent to produce Barnidipine base.

The base used in the above reaction is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, ammonium hydroxide, sodium bicarbonate, triethylamine, diethylamine, diethyl aminopyridine, pyridine or mixtures thereof.

The solvent used the above reaction is preferably selected from chloroform, methylene dichloride, water, acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof.

Barnidipine free base is isolated and purified or directly used in the next step.

Barnidipine free base is treated with dilute hydrochloric acid in presence of a solvent to produce optically pure Barnidipine hydrochloride.

The solvent used the above reaction is preferably selected from chloroform, methylene dichloride, water, acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof.

The optical purity of Barnidipine hydrochloride by HPLC is more than 99%. Preferably more than 99.5%. More preferably more than 99.9% consisting of less than of 0.15% of other isomer of Barnidipine hydrochloride.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE-1:

Preparation of (3S,4S) Barnidipine Hydrochloride:
Part-A- (3S,4S) (3S,4R) Barnidipine Oxalate:
(3S)-1-Benzyl-3-pyrrolidinol (59.2 g) was dissolved in methylene chloride (300 ml) under nitrogen atmosphere and triethylamine was added to the above solution at 20-30°C. The reaction mass was cooled to -10°C to 0°C and trimethylsilyl chloride (49 g) was added slowly by maintaining the temperature below 0°C under nitrogen atmosphere. Temperature of the reaction mass was raised to -5°C to 0°C and stirred for 2 h at this temperature. After completion of the reaction (monitored by HPLC), pre-cooled DM water (300 ml) was added to the above reaction mass by maintaining the temperature below 15°C and stirred for 15 minutes. Layers were separated and the aqueous layer was extracted with methylene chloride (120 ml). The combined organic layer was washed with ~10 % w/w aqueous Sodium chloride solution (300 ml) and the organic layer was concentrated under reduced pressure to give TMS protected (3S)-1-Benzyl-3-pyrrolidinol.

2,6-Dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihidropyridine-3 carboxylic acid (100 g) was suspended in methylene chloride (600 ml) and N,N-dimethylformamide (100 ml). The above suspension was cooled to -10°C to 0°C and thionyl chloride (46.6 g) was added slowly under nitrogen atmosphere. The reaction mass was stirred at -10°C to 0°C to give acid chloride of the carboxylic acid.

TMS protected (3S)-1-benzyl-3-pyrrolidinol was dissolved in methylene chloride (200 ml) and was added to the above freshly prepared acid chloride at a temperature below 15°C. Temperature of the reaction mass was raised to 20-30°C and stirred for 4 h at this temperature. After completion of the reaction, cooled to 0-5°C and precooled DM water was added (2000 ml). Temperature was raised to 20-30°C and layers were separated. The upper aqueous layer was extracted with methylene chloride (200 ml). To the combined organic layer, DM water (1000 ml) was added and the pH of the reaction mass was adjusted to ~9.0-10 with aqueous sodium carbonate solution. Layers were separated and the upper aqueous layer was extracted with methylene chloride (200 ml). The combined organic layer was concentrated at a temperature below 45°C under reduced pressure (400-20 mm Hg) till solvent distilled. Ethyl acetate (100 ml) was added to the concentrated mass at 40-45°C and distillation was continued under reduced pressure (400-20 mm of Hg) at below 45°C till the solvent distilled completely. The above concentrated mass was diluted with ethyl acetate (800 ml) at 20-30°C and a solution of oxalic acid dihydrate in 5% v/v aqueous acetone (~210 ml, prepared by dissolving 38 g of oxalic acid dihydrate in 200 ml of acetone and 10 ml DM water) was added at 20-30°C. The contents were heated to 50-60°C and stirred at this temperature for 15±5 min, clear solution results. 0.5% seed of Barnidipine oxalate is charged at 50-60 °C then continued stirring for 2-3 h at 50-60°C to complete the Barnidipine oxalate salt formation, product precipitates out. Reaction mass was slowly cooled the reaction mass to 20-30°C and continue stirring at 20-30°C for 6±1 h to complete the precipitation of the product. The product was and wash it with ethyl acetate (2 x 100 ml, 20-30°C), product kept under suction for ~30 min to squeeze most of the filtrate. The wet filtered mass (~180 g) was dried at 20-30°C for two hours at under vacuum followed by at 50-55°C under reduced pressure (100-20 mm Hg) till ‘Loss on Drying’ is <1% w/w (determined on 1 g at 60°C for 2 h at a pressure not exceeding 20 mm Hg).

Yield: 75-80%.
Purity Ratio by HPLC: (3S,4S) Barnidipine oxalate: 49.79%
(3S,4R) Barnidipine oxalate: 49.62%

Part-B- (3S,4S) (3S,4R) Barnidipine free base from (3S,4S) (3S,4R) Barnidipine Oxalate:

(3S,4S), (3S,4R)-Barnidipine oxalate was suspended in a mixture of methylene chloride (500 ml) and DM water (500 ml) at 20-30°C and stirred for 15±5 min. The pH of the reaction mixture was adjusted to =10 at 20-30°C with ~20% w/w aqueous sodium carbonate solution (500 ml) and stirring was continued at 20-30°C for 20±5 min, Layers were allowed to settle at 20-30°C for 20±5 min. Methylene chloride (200 ml) was added to the upper aqueous layer at 20-30°C, and stirring was continued at 20-30°C for 20±5 min. The layers allowed to settle at 20-30°C for 20±5 min. Concentrated the combined organic layer contains (3’S,4S), (3’S,4R)-Barnidipine free base at a temperature below 45°C under reduced pressure (400-20 mm Hg) till solvent distilled.

Part-C- crude (3S,4S) Barnidipine Malate from (3S,4S) (3S,4R) Barnidipine free base:

Ethyl acetate (100 ml) was added to the concentrated mass obtained from part-B at 40-45°C, and continue distillation under reduced pressure (400-20 mm of Hg) till solvent distilled. The above concentrated mass was diluted with ethyl acetate (600 ml) at 20-30°C and carbon (3 g, 3% w/w) was added to the above solution at 20-30°C. The contents were heated to 40-50°C and stirred for 20±5 min at this temperature. The reaction mass was filtered at 40-50°C through a hyflo pad (prepared in ethyl acetate) to remove the carbon and wash the residue with pre-heated ethyl acetate (200 ml, 40-50°C). The filtrate was heated to 50-60 °C. 0.5% seed of Barnidipine (3S,4S) malate with <0.3% of 3S,4R isomer (0.5 g) was added to reaction mass followed by a solution of L-malic acid in methanol (Prepared by dissolving 23.04 g of L-malic acid in 200 ml methanol) was added at 50-60°C, stirring was continued at this temperature for 2-3 h to complete the Barnidipine malate salt formation. Slowly cooled the reaction mass to 40-45°C in 1 hr and continue stirring at 40-45°C for 4±1 h to complete the precipitation of the product. The product was filtered and washed with ethyl acetate (1 × 100 ml, 20-30°C). The wet filtered mass was dried under vacuum for 2 h at 20-30°C to obtain (3S,4S)-Barnidipine malate crude contains (3S,4R) Barnidipine malate isomer: 3.12%

Yield: 82-85%.
Purity by HPLC: (3S,4S) Barnidipine malate: 96.68%

Part-D- Purification of (3S,4S) Barnidipine Malate:

Barnidipine malate crude was suspended (40 g) in a mixture of methanol (160 ml) and ethanol (160 ml) at 20-30°C, DM water (10 ml, 20-30°C) was added, heated the contents to 60-65°C and continued stirring for 1h±10 min at this temperature. Slowly cooled the contents to 10-15°C in ~1 h. Continued stirring at 10-15°C for 5±1 h at this temperature to complete the precipitation of the product. The product was filtered at 10-15°C and washed with pre-cold ethanol (2 × 40 ml, 10-15°C). The product kept under suction for ~30 min to squeeze most of the filtrate. The wet filtered mass was dried under vacuum for 2 Hrs at 20-30°C followed by 50-55°C under reduced pressure (100-20 mm Hg) for 8 h to obtain (3S,4S) Barnidipine malate contains (3S,4R) Barnidipine malate isomer 0.17%.

Yield: 86-90%.
Purity HPLC: (3S,4S) Barnidipine malate: 99.83%.

Part-E- Preparation of (3S,4S) Barnidipine Hydrochloride

(3’S,4S)-Barnidipine malate (100 g) was suspended in a mixture of methylene chloride (500 ml) and DM water (500 ml) at 20-30°C and stirred for 15±5 min. The pH was adjusted to = 10 at 20-30°C with ~20% w/v aqueous sodium carbonate solution (~500 ml). Layers were allowed to settle at 20-30°C for 20±5 min. To the upper aqueous layer at 20-30°C, methylene chloride (200 ml) was added and continued stirring at 20-30°C for 20±5 min, layers were allowed to settle at 20-30°C for 20±5 min. Dilute hydrochloric acid (~230 ml, prepared by dissolving 33.3 g of conc. Hydrochloric acid in 200 ml of DM water) was added to the combined organic layer at 20-30°C and continued stirring at 20-30°C for 20±5 min, the layers were separated. Dilute hydrochloric acid (~230 ml, prepared by dissolving 33.3 g of conc. Hydrochloric acid in 200 ml of DM water) was added to the organic layer at 20-30°C, continued stirring at 20-30°C for 20±5 min, organic layers were concentrated at a temperature below 45°C under reduced pressure (400-20 mm Hg) till solvent distilled. Ethanol (absolute alcohol, 200 ml) was added to the above concentrated mass at 40-45°C, and continued distillation under reduced pressure (400-20 mm of Hg) till solvent distilled. To the above concentrated mass ethanol (absolute alcohol, 1500 ml) was added at 20-30°C. The suspension was heated to reflux (75-80°C) and continued stirring at this temperature for 1h±10 min. The above solution was cooled to 50-60°C. Slowly further cooled to 0-5°C, continued stirring at 0-5°C for 4±1 h to complete the precipitation of the product. The product was filtered and washed with ethanol (2 x 100 ml, 0-5 °C). The wet filtered mass was dried under vacuum for 2 h at 20-30°C followed by 50-55°C under reduced pressure (100-20 mm Hg) to obtain (3S,4S) Barnidipine hydrochloride contains (3S,4R) Barnidipine hydrochloride isomer 0.11%.

Yield: 88-90%.
Purity HPLC: (3S,4S) Barnidipine hydrochloride: 99.86% ,CLAIMS:WE CLAIM:
1. A process for the preparation of optically pure Barnidipine hydrochloride of Formula (I),

Formula I

which comprises:
(i) treating Barnidipine free base with a salt forming agent in a solvent to form the solution,
(ii) seeding the step i) solution,
(iii) optionally, isolating the salt of Barnidipine,
(iv) converting the salt of Barnidipine to Barnidipine free base,
(v) optionally, isolating Barnidipine free base,
(vi) treating the Barnidipine free base with an optically active acid in a solvent to obtain an optically active acid addition salt of Barnidipine,
(vii) seeding the above solution,
(viii) optionally, isolating the optically active acid addition salt of Barnidipine,
(ix) converting the optically active acid addition salt of Barnidipine to optically pure Barnidipine hydrochloride.

2. The process as claimed in claim 1, wherein the salt forming agent of step-i) is selected from hydrochloric acid, hydrobromic acid, oxalic acid, succinic acid, fumaric acid, L-Malic acid, L-Tartaric aid and D-Tartaric acid; wherein, the seed of salt of Barnidipine is 0.5%.

3. The process as claimed in claim 1, wherein the solvent used in step-i) is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof.

4. The process as claimed in claim 1, wherein step-iv) is carried out by treating the salt of Barnidipine with a base in the presence of a solvent to produce Barnidipine base.

5. The process as claimed in claim 4, wherein the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, ammonia hydroxide, sodium bicarbonate, triethylamine, diethylamine, diethyl aminopyridine, pyridine or mixtures thereof.

6. The process as claimed in claim 4, wherein the solvent is selected from chloroform, methylene dichloride, water, acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof.

7. The process as claimed in claim 1, wherein the optically active acid used in step-vi) is selected from tartaric acid, malic acid, mandelic acid, and camphor-10-sulfonic acid; wherein the seed is ~0.5% and has <0.3% of (3S, 4R)-isomer.

8. The process as claimed in claim 1, wherein the solvent used in step-vi) is selected from acetone, acetophenone, butanone, propanone, cyclopentanone, methyl ethyl ketone, methyl isobutyl ketone, pentanone, methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF, DMSO or mixture thereof .

9. The process as claimed in claim 1, wherein the step-ix) is carried out by treating optically active acid salt of Barnidipine with a base in presence of a solvent to produce Barnidipine base which is treated with hydrochloric acid in a solvent to produce optically pure Barnidipine hydrochloride.

10. The process as claimed in claim 9, wherein the optically pure Barnidipine hydrochloride is having purity >99 % by HPLC.