FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Barnidipine or its pharmaceutically acceptable salt.

BACK GROUND OF THE INVENTION:

Barnidipine is a useful of mild-to-moderate essential hypertension; it is marketed as hydrochloride salt. It is chemically known as (4S)-1, 4-dihydro-2, 6-dimethyl-4-(3- nitrophenyl)-3, 5-Pyridine dicarboxyiic acid methyl (3S)-1-(phenyl methyl)-3-Pyrroiidinyl ester having the structure of formula I.

US patent 5463064, disclosed Barnidipine and its salts, where in process for the preparation of (S)-1-benzyl-3-hydroxypyrrolidine is reacted with diketene to get (S)-3-acetoacetoxy-1- benzyl pyrrolidine, which is reacted with m-nitrobenzaldehyde and 3-aminocrotonic acid methyl ester to get mixure of diastereomers of barnidipine, separating mixture of diastereomers through column chromatography to get Barnidipine, which is further, converted to Barnidipine hydrochloride by conventional method as shown in scheme-I.

CA127931 patent discloses the process for preparation of Barnidipine, reacting meta nitrobenzaldehyde with tert-butyl acetoacetate to get tert-butyl 2-(m-nitrobenzylidene) acetoacetate, which is reacted with methyl 3-amino crotonate followed by hydrolysis to obtained the compound formula Vila, which is reacted with (S)-1-benzyl-3- hydroxypyrrolidine, purification by column chromatography to obtain the Barnidipine as shown in scheme-II.

Journal of chemical, 2007, 21, 27-29 disclosed the process for the preparation of Barnidipine, acetyl nitro benzaldehyde and methyl acetate as starting material to get carboxylic esters, obtained carboxyllc acid after hydrolysis of racemic carboxylic ester, with pyridine and benzyl alcohol reaction obtained Barnidipine and diastereomeric isomers of mixture, L-malicacid as a resolution agent to get Barnidipine pure product. But L-malicacid as a resolution agent to get optical purity of Barnidipine is not high and not easy to purify, it influence the final product of Barnidipine as shown in scheme-III

CN101643469 patent application is also disclosed the preparation of Barnidipine hydrochloride as shown in scheme-IV.

The above prior art processes are prepared Barnidipine by using column chromatography and resolution step at higher temperatures and reaction time is more to prepared Barnidipine hydrochloride.

Thus there is a need to improve process for the preparation of Barnidipine like reaction time and low temperatures and better yield with pure Barnidipine.

SUMMARY OF THE INVENTION

The present invention relates to process for the preparation of (4S)-1, 4-dihydro-2, 6- dimethyl-4-(3-nitrophenyl)-3,5-Pyridine dicarboxylic acid methyl (3S)-1-(phenylmethyl)-3- Pyrrolidinyl ester of formula I.

One aspect of the present invention is to provide a process for the preparation of Barnidipine of formula I or its salts, which comprises:

a) reacting compound of formula II with optically active compound in the presence of an organic solvent to get compound of formula III,

b) setting free base compound of formula III to get the compound formula IV,

c) halogenating a compound of formula IV to get the compound of formula V in the presence of a halogenating agent and chlorinated solvent,

d) condensing the compound of formula V with hydroxyl protecting compound of the formula Via to get Barnidipine freebase, and

e) optionally converting to pharmaceutically acceptable salt.

Another aspect of the present invention is to provide a process for the preparation of Barnidipine of formula I or its salts, which comprises:

a) reacting compound of formula II with optical active compound in the presence of an organic solvent to get chiral salt of formula III,

b) adding a base to compound of formula III to get the compound formula IV,

c) condensing the compound of formula IV with hydroxyl compound of the formula VI in the presence of dehydrating agent to get Barnidipine freebase, and

d) optionally converting to pharmaceutically acceptable salt.

The entire process for the preparation of Barnidipine hydrochloride is depicted in schemes IV and V below


DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Barnidipine or its pharmaceutically acceptable salt.

In one embodiment, the present invention provides an improved process for the preparation of Barnidipine comprises the steps of;

a) reacting compound of formula II with optically active compound in the presence of an organic solvent to get compound of formula III,

b) setting free base compound of formula III to get the compound formula IV,

c) halogenating a compound of formula IV to get the compound of formula V in the presence of a halogenating agent and chlorinated solvent,

d) condensing the compound of formula V with hydroxy protecting compound of the formula Via to get Barnidipine freebase, and

e) optionally converting to pharmaceutically acceptable salt.

According to the present invention, compound of formula II is dissolved in organic solvent at reflux temperature, optically active compound is slowly added to the clear solution at same temperature for 30-90min. optionally seeded the reaction mixture and slowly cooled the mixture to 25-35°C, followed by 10-20°C. The obtained solid is filtered to get compound of formula III. Compound of formula III is treated with aqueous base to get compound of formula IV. This compound is dissolved in a mixture of chlorinated and aprotic polar solvent. The solution is cooled to 0 to -15 °C and slowly added halogenating reagent to get compound of formula V, without isolating to this solution silylated compound of formula Via is added at 0 to -15 °C, temperature is raised to 25-35°C and maintained for 2-5hrs. Water is added to the solution and compound is separated into organic solvent, evaporating the solvent to get Barnidipine freebase. The obtained freebase is purified in ketone solvent.

According to the present invention Barnidipine freebase is suspended in chlorinated solvent. Alcoholic hydrochloric acid is added at ambient temperature, followed by heating 40-50°C to get clear solution and maintained the reaction for about 60min. solvent is evaporated to get crude Barnidipine hydrochloride, This purified in alcohol solvent to get pure Barnidipine hydrochloride.

According to the present invention compound of formula II is dissolved in organic solvent in step a) is selected from methanol, ethanol, isopropyl alcohol, dichloromethane, ethyl acetate, n-butanol or mixture thereof. Optically active compound used for resolution in step a) is selected from L-Norephedrine hydrochloride, D-Norephedrine, L-proline, cinchonidine or quinidine. The base used in step b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate, preferably sodium hydroxide. According to the present invention aprotic polar solvent is selected from dimethylformamide or dimethylsulfoxide.

According to the present invention the halogenating reagent used in step c) is oxalyl chloride, thionyl chloride, phosphorous oxychloride, phosphorous tetrachloride, phosphorous pentachloride or phosphorous bromide, preferably oxalyl chloride.

According to the present invention the Barnidipine freebase is purified in ketone solvent selected from acetone, methylethylketone, methylisobutylketone or mixture thereof. Alcoholic hydrochloride is selected from methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride or butanolic hydrochloric acid. According to the present invention chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride. According to the present invention Barnidipine hydrochloride is purified in alcoholic solvent selected from methanol, ethanol, isopropanol or butanol.

In another embodiment of the present invention which comprises the steps of:

a) reacting compound of formula II with optically active compound in the presence of an organic solvent to get chiral salt of formula III,

b) setting free base compound of formula III to get the compound formula IV,

c) condensing the compound of formula IV with hydroxyl compound of the formula VI in the presence of dehydrating agent to get Barnidipine freebase.

d) optionally converting to pharmaceutically acceptable salt.

According to the present invention, compound of formula II is dissolved in organic solvent at reflux temperature, optically active compound is slowly added to the clear solution at same temperature for 30-90min. optionally seeded the reaction mixture and slowly cooled the mixture to 25-35°C, followed by 10-20°C. The obtained solid is filtered to get compound of formula III. Compound of formula III is treated with aqueous base to get compound of formula IV. This compound is condensed with compound of formula VI in the presence of dehydrating agent in the presence of an acid catalyst to get Barnidipine freebase. The obtained freebase is purified in ketone solvent.

According to the present invention Barnidipine freebase is suspended in chlorinated solvent. Alcoholic hydrochloric acid is added at ambient temperature, followed by heating 40-50°C to get clear solution and maintained the reaction for about 60min. solvent is evaporated to get crude Barnidipine hydrochloride. This purified in alcohol solvent to get pure Barnidipine hydrochloride.

According to the present invention compound of formula II is dissolved in organic solvent in step a) is selected from methanol, ethanol, isopropyl alcohol, dichloromethane, ethyl acetate, n-butanol or mixture thereof. Optically active compound used for resolution in step a) is selected from L-Norephedrine hydrochloride, D-Norephedrine, L-proline, cinchonidine or quinidine. The base used in step b) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate, preferably sodium hydroxide. According to the present invention dehydrating agent is like N, N'- Dicyclohexylcarbodiimide (DCC). Acid catalyst is selected from paratoluenesulfonicacid or perchloric acid.

According to the present invention the Barnidipine freebase is purified in ketone solvent selected from acetone, methylethylketone, methylisobutylketone or mixture thereof. Alcoholic hydrochloride is selected from methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride or butanolic hydrochloric acid. According to the present invention chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride. According to the present invention Barnidipine hydrochloride is purified in alcoholic solvent selected from methanol, ethanol, isopropanol or butanol.

In another embodiment of the present invention provides crystalline Barnidipine hydrochloride characterized by powder X-ray diffraction having peaks at about 6.12, 6.99, 8.99, 9.59, 12.28, 13.17, 13.59, 13.99, 14.72, 15.09, 16.93, 18.08, 18.61, 19.32, 21.08, 21.51, 21.86, 22.57, 23.41, 24.48, 25.17, 27.21, 27.66 , 29.70 , 30.09 and 33.77 ± 0.2 20

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Example 1: Preparation of (R)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3-carboxylic acid.

L-Norephedrine hydrochloride (56.5g 1.0mole) was added to the mixture of purified water and (200ml) n-Butyl alcohol (400ml), portion wise added potassium carbonate to the above solution (41.6g, lOmole) and stir for one hour, separate the aqueous layer and extracted with n-butyl alcohol, combined organic layers and distilled out n-butyl alcohol to get L- Norephedrine free base.

In another flask charged isopropyl alcohol (3800ml) and (±) 5-(methoxycarbonyl)-2, 6- dimethyl- 4-(3-nitrophenyl)-1, 4- dihydropyridine-3-carboxylic acid (100gm, 1.0mole) and raised the temperature to reflux for dissolution. L-Norephedrine was added to the above solution at reflux temperature for 60 minutes and cool the solution to 50-55 °C adds seed material and stirred for 30minutes. Cooled to 30-35 "C in 2-3hours to crystallize the material, further cool to 10-15 °C and stir for 120 minutes. Filtered the solid and wash with chilled isopropyl alcohol (50ml).

Suspended the wet cake (Salt) in purified water (2000ml), stir for 60 minutes at 30-35 °C and adjust pH 11.0 to 11.5 with 2N sodium hydroxide. Charged ethyl acetate (500ml), stir for 30 minutes and separate the layers. The aqueous layer was washed with ethyl acetate (100ml. Adjust pH of aqueous layer to 2.0-2.5 with 6N hydrochloride (~10ml) at 10-15 °C and stir for 120 minutes to crystallize the material. Filtered the solid and wash with chilled purified water (50ml).

Suspended the wet cake in ethanol (700ml) and gradually raised the temperature to reflux and to obtain clear solution. Purified water was added (1400 ml) at reflux temperature. Cooled to 30-35 °C in 30 minutes and further cool 10-15 °C, stir for 120 minutes. Filtered the solid washed with purified water (50ml). The material was dried at 60-65 °C to yield (R)-5- (methoxycarbonyl)-2, 6-dimethyl-4-(3-nitrophenyl)-1, 4- dihydropyridine-3-carboxylic acid.

Example 2: Preparation of (+)-(3'S, 4'S)-1-Benzyl-3-pyrrolidinylmethyl1, 4-dihydro-2, 6- dimethyl-4-(m-nitrophenyl)-3, 5-pyridinedicarboxylate.

Charged (R)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3- carboxylic acid (30gr, 1.0mole) Dichloromethane (150ml) and Dimethyl formamide (28.3g) and cooled to -5 to -10 °C and add slowly oxalylchlohde (57.33g, 1.5mole) under nitrogen atmosphere and maintained for 3- 4 hours to obtain acid chloride. In another flask charge (s)-1-Benzyl-3-pyrrolidinol (16.0g, 1.0mole), Dichloromethane (150ml) and cooled to -10 to -5 °C. Add triethylamine (13.7g, 1.5mole) and slowly trimethyl silyl chloride (14.7g, 1.5mole) under nitrogen atmosphere and raised to 25-30 °C then stir for 2-3 hours. Add this silylated compound to previously prepared acid chloride solution in 2-3 hours at -10 to -5 °C, raised to 25-30 °C and maintained for 3-4 hours. Cooled to 10-15 °C, add purified water (120ml), settled and separate the layers. The organic layer was washed with purified water (100ml) and sodium chloride solution (18.6g dissolved in purified water (60ml)). Organic layer is evaporated the under reduced pressure. Suspended the residue in Acetone (120ml) raised the temperature to 40-45 °C, stir for 60 minutes and cooled 30-35 "C to crystallize the material. Filtered the solid, washed with Acetone (15ml) and dried at 45-50 "C to yield (+)-(3'S, 4'S)-1-Benzyl-3-pyrrolidinylmethyl1, 4-dihydro-2, 6-dimethyl-4-(m-nitro phenyl)-3, 5-pyridinedicarboxylate.

Example-3: Preparation of (+)-(3'S, 4'S)-1-Benzyl-3-pyrrolidinylmethyl-1, 4-dihydro-2, 6-dimethyM-(ni-nitro phenyl)-3, 5-pyridinedicarboxylate hydrochloride.

Charged (+)-(3'S,4'S)-1 -Benzyl-3-pyrrolidinylmethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitro phenyl)-3,5-pyridinedicarboxylate (30g,1.0 mole), Dichloromethane (150ml) and isopropyl alcoholic hydrochloride (13.8g (20-25%w/w) ,1.5mole) at 30-35 °C and heat to 40-45°C to obtain a clear solution and maintain for 60minutes at 40-45 °C. Evaporated the solvents under reduced pressure and suspend the mass in ethanol (120ml) and temperature raised to 40-45 °C and maintain for 30 minutes. Cooled to 25-30 °C to crystallize the material and maintained for 2-3 hours. Filtered, the solid wash with ethanol (15ml) and dried at 50-55 "C to yield (+)-(3'S, 4'S)-1-Benzyl-3-pyrrolidinylmethyl 1, 4-dihydro-2, 6-dimethyl-4-(m-nitro phenyl)-3, 5-pyridine dicarboxylate hydrochloride.

Example-4: Preparation of pure (+)-(3'S, 4'S)-1-Benzyl-3-pyrrolidinylmethyl 1,4- dihydro-2,6-dimethyM-(m-nitro phenyl)-3,5-pyridine dicarboxylate hydrochloride.

(+)- (3'S, 4'S)-1-Benzyl-3-pyrrolidinylmethyl, 4-dihydro-2, 6-dimethyl-4-(m-nitro phenyl)-3,5- pyridinedicarboxylate hydrochloride was suspended in ethanol (300ml) and raised the temperature up to reflux to get clear solution .Then added activated carbon (2g), and stir for 30 minutes, filter the solution. Around 50% of ethanol (75ml) distilled out from the reaction mass under vacuum at below 80°C .The reaction mass cooled to 30-35 "C over a period of 2 hours to crystallize the material and maintained for 2 hours .Further, reaction mass was cool to 9-15 °C over a period of 2hours to crystallized the material and maintain for 2hours. Filtered the solid, wash with ethanol (15ml) and dried under vacuum at 45-50 °C to get pure Barnidipine hydrochloride.

Claims:

1. An improved process for the preparation of Barnidipine of formula I or its pharmaceutically acceptable salts.

Comprising the steps of:

a) reacting compound of formula Il with optically active compound in the presence of an organic solvent to get compound of formula III,

b) setting free base compound of formula 111 in an organic solvent to get the compound formula IV,

c) halogenating a compound of formula IV to get the compound of formula V in the presence of a halogenating agent and chlorinated solvent.

d) condensing the compound of formula V with hydroxyl protecting compound of the formula VIa to get Barnidipine freebase and,


e) Optionally converting to pharmaceutically acceptable salt.

2. An improved process for the preparation of Barnidipine of formula I or its Pharmaceutically acceptable salts.

Which is comprises the steps of:

a) reacting compound of formula II with optically active compound in the presence of an organic solvent to get chiral salt of formula III,

b) setting free base compound of formula III in organic solvent to get the compound formula IV,

c) condensing the compound of formula IV with hydroxyl compound of the formula VI in the presence of dehydrating agent to get Barnidipine freebase.

d) optionally converting to pharmaceutically acceptable salt,

3. The process according to claim 1&2, the said optically active compound in step a) is selected from L-norephedrine, D-Norephedrine, L-proline, cinchonidine, or quinidine.

4. The process according to claim 1&2, the said organic solvent in step a) methanol, ethanol, isopropyl alcohol, dichloromethane, ethyl acetate, n-butanol or mixture thereof.

5. The process according to claim 1&2, the said base is selected from triethylamine, ethylamine, methyl amine and di-isopropyl amine, sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide or ammonia.

6. The process according to claim 1, the said halogenating agent in step c) is selected from oxalyl chloride, thionyl chloride, phosphorous oxychloride, phosphorous tetrachloride, phosphorous pentachloride or phosphorous bromide.

7. The process according to claim 2, the said dehydrating agent is like N, N'- Dicyclohexylcarbodiimide (DCC).

8. According to claim 1, the said silylated group is tertiary butyl diphenyl silyl chloride (TBDPS), tertiary butyl dimethyl silyl chloride (TBDMS), or Trimethyl silyl chloride (TMS), Trimethyl silyl iodide (TMS), Trimethyl silyl Bromide (TMS).

9. According to claim 1 said chlorinated solvent is dichloromethane, dichloroethane, chloroform or carbon tetrachloride.