This application claims priority over this application number 4174/CHE/2012 filed on October 08, 2013.

FIELD OF THE INVENTION

The disclosure relates to Mitiglinide having substantially free of regioisomer.
The present disclosure further relates to an improved process for the preparation of Mitiglinide with recovery of S-benzyl succinic acid, cis-octahydroisoindole from regioisomer.

BACK GROUND

Perhydroisoindole derivative, (S)-Mitiglinide of formula-l is a potassium channel antagonist for the treatment of type 2 diabetes mellitus and is chemically known as (S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionic acid.

It has potent oral hypoglycemic activity and is structurally different from the sulphonylureas, although it stimulates calcium influx by binding to the sulphonylurea receptor on pancreatic p-cells and closing K+ATP channels.
US 5202335 disclose Mitiglinide and its salts, processes for their preparation. This patent discloses preparation of (S)-Mitiglinide by the reaction of (S)-3-benzyloxycarbonyl-4-phenylbutyric acid with cis-hexahydroisoindoline in the presence of N-methylmorpholine and isobutyl chloroformate, followed by debenzylation with palladium on carbon in ethyl acetate to yield (S)-mitiglinide as viscous oil. (S)-Mitiglinide is isolated as its hemi calcium salt using calcium chloride in water which is further recrystallized with diisopropyl ether. Melting point of calcium salt of mitiglinide calcium dihydrate salt is herein reported as 179-185°C. (S)-Mitiglinide prepared by the above process is obtained in low yields, which makes the process is not industrial applicable. The step wise process is as shown in the scheme-l given below.

US 6133454 discloses a process for the preparation of (S)-Mitiglinide by reacting dimethyl succinate with benzaldehyde in methanolic medium, to yield a diacid which is converted to corresponding anhydride and is further reacted with the perhydroisoindole to yield 2-[(cis-perhydroisoindol-2-yl)carbonyl methyl]-3-phenylacrylic acid which is then subjected to catalytic hydrogenation using the complex rhodium/(2S,4S)-N-butoxycarbonyl-4-diphenylphosphino-2-diphenyl-phosphino-ethylpyrrolidine (Rh/(S,S) BPPM) as asymmetric hydrogenation catalyst, followed by conversion to pharmaceutically acceptable salt of (S)-mitiglinide. The above patent utilizes ruthenium complex which is expensive, carcinogenic and toxicity, hence not recommended for industrial scale. The step wise process is as shown in the scheme-ll given below.

CN1324010C discloses the preparation of Mitiglinide by 2-benzyl succinicanhydride with perhydroisoindole; further it treating with calcium chloride in presence of ammonia to gave mitiglinide calcium dihydrate. The crystals of calcium salt are further recrystallized using ethanol. Mitiglinide is prepared by this process consists regioisomer impurity it will not be separated by further purification and it leads to low yield with less purity. The step wise process is as shown in the scheme-Ill given below.

According to prior art processes, there was no disclosure of controlling the regioisomer in Mitiglinide. The present inventors of the invention developed the process to separate the regioisomer to get pure Mitiglinide. The present invention relates to an improved process for the preparation of mitiglinide calcium dihydrate with recovery of S-benzyl succinic acid, Cis-Octahydroisoindole from regioisomer. This process is highly cost effective and industrially feasible in large scale production.

SUMMARY

The present invention provides an improved process for the preparation of Mitiglinide calcium dihydrate and the invention further relates to separation of regioisomer impurity.

First aspect of disclosure relates to provide substantially free of Mitiglinide.

Another aspect relates to a process for the preparation of substantially free of Mitiglinide calcium dihydrate comprising the steps of;

a) reacting (S)-2-benzyl succinic anhydride with cis-octahydroisoindole in aromatic hydrocarbon solvent,
b) heating to get clear solution,
c) cooling the solution to 20-30°C,
d) separating unwanted regioisomer by filtration,
e) adding aqueous alkaline solution to filtrate; separate the aqueous layer,
f) treating aqueous layer with calcium chloride solution, and
g) isolating Mitiglinide calcium dihydrate.

The step wise process of present invention is shown in scheme-IV

Scheme-IV

Still another aspect relates to recovery of S-benzyl succinic acid, cis-octahydroisoindole from regioisomer comprising the steps of;

a) reacting regioisomer in aqueous acid,
b) heating to get clear solution,
c) distilling out the acid, followed by addition of water,
d) adjusting pH and recovering the S-benzyl succinic acid by filtration,
e) basifying the filtrate,
f) adding aromatic hydrocarbon solvent and distilled out completely,
g) adding tetrahydrofuran solvent, h) adjusting pH with an acid, and
i) recovering the cis-octahydroisoindole.
The present invention is shown in scheme- V

DETAILED DESCRIPTION

The present disclosure relates to an improved process for the preparation of Mitiglinide calcium dihydrate by reacting cis-octahydroisoindole with S-benzylsuccinic anhydride in toluene, followed by conversion to acid addition salt and finally to get desired product.

One embodiment of the present disclosure is to provide a process for the preparation of substantially free of Mitiglinide calcium dihydrate comprising the steps of;

a) reacting (S)-2-benzyl succinic anhydride with cis-octahydroisoindole in aromatic hydrocarbon solvent,
b) heating to get clear solution,
c) cooling the solution to 20-30°C,
d) separating unwanted regioisomer by filtration,
e) adding aqueous alkaline solution to filtrate; separate the aqueous layer,
f) treating aqueous layer with calcium chloride solution, and
g) isolating Mitiglinide calcium dihydrate.

According to the present invention, (S)-2-benzyl succinic acid (VI) is treating with acetic anhydride in the presence dichloromethane at reflux temperature. After completion of the reaction, acetic anhydride is distilled out completely under vacuum at 50-60°C. To the resultant mass, diisopropyl ether is added, stirred and filtered to obtain the crystals of S-benzylsuccinic anhydride. Cis-octahydroisoindole) in aromatic hydrocarbon solvent is slowly added to solution of S-benzylsuccinic anhydride in the same solvent at 45-50°C. After completion, the reaction mass is cooled to 25-3CTC and filtered the regioisomer. To the filtrate, alkaline solution is slowly added at 25-30°C to separate the layers; ethanol is added to aqueous layer, followed by calcium chloride solution at 25-30°C.The obtained solid is filtered and washed with water. The crude mitiglinide calcium is recrystallized with 5% aqueous ethanol to get pure Mitiglinide calcium dihydrate.

According to the present invention, the reaction is carried out at reflux temperature in the range of about 30°C to about 60°C, preferably 30°C to about 40°C. The reaction is carried out for a period of about 2 hours to about 6 hours, preferably 3 hours to about 4 hours.

According to the present invention, the aromatic hydrocarbon solvent is selected from toluene, xylene, ethylbenzene or mesitylene; alkaline is selected from sodium hydroxide, potassium hydroxide or calcium hydroxide.

According to the present invention crude mitiglinide calcium dihydrate is purified by recrystallization in alcohol solvent is selected from methanol, ethanol, isopropanol or butanol.

According to the present invention the word "substantially free" is defined as less than 1.0%, preferably less than 0.5%, more preferably less than 0.1% of regioisomer in Mitiglinide or its calcium salt.

Another embodiment of the present invention is to provide substantially pure (S) - Mitiglinide or its calcium salt having regioisomer impurity in an amount of less than about 0.15%.

In yet another embodiment of the present invention provides to recovery of S-benzyl succinic acid, cis-octahydroisoindole from regioisomer comprising the steps of;

a) reacting regioisomer in aqueous acid,
b) heating to get clear solution,
c) distilling out the acid, followed by addition of water,
d) adjusting pH and recovering the S-benzyl succinic acid by filtration,
e) basifying the filtrate,
f) adding aromatic hydrocarbon solvent and distilled out completely,
g) adding tetrahydrofuran solvent, h) adjusting pH with an acid, and
i) recovering the cis-octahydroisoindole.

According to the present invention, regioisomer in aqueous acid is heated to complete the reaction. The reaction mass is cooled and distilled out solvent completely under vacuum at 55-60°C; resultant mass pH 1-2 is adjusts with 6N Hydrochloride (6N HCI), filtered the solid and washed with water; dry the material under vacuum at 50-55°C to obtain S-Benzyl Succinic acid. To the filtrate, sodium hydroxide solution is added, followed by extraction in presence of toluene. The solvent is distilled out completely under vacuum at 50-55°C, added tetrahydrofuran (THF) and stirred. Adjust pH 4-5 with dry HCI gas, filtered the solid and washed with THF; dry the material under vacuum at 40-45°C for 6-10 hours to obtain Cis-Octahydroisoindole hydrochloride.

According to the present invention, the reaction is carried out at a temperature in the range of about 90°C to about 130°C, preferably 100°C to about 110°C. The reaction is carried out for a period of about 8 hours to about 16 hours, preferably 10 hours to about 12 hours.

According to the present invention, the acid is selected from acetic acid, hydrochloric acid, hydrobromic acid, propanoic acid or paratoluene sulphonic acid.
The following example is provided to illustrate the process of the present invention. However, they are not intended to limit the scope of an invention.

Example-1

Preparation of (S)-2-Benzylsucccinic anhydride

(S)-2-Benzyl Succinic acid (100 gm) was added in dichloromethane (300 ml), followed by acetic anhydride (147 gm) and the resulting mixture were stirred at reflux for 3-4 hours. After completion of reaction, the acetic anhydride was distilled under vacuum at 50-55°C. Diisopropyl ether 100 ml) was added to the resulting mass to remove traces of acetic anhydride by distillation under vacuum at 50-55°C and the resulting mass was recrystallized by diisopropyl ether (300 ml); stirred for 1-2 hours at 25-30°C. The solid was filtered and washed with diisopropyl ether (50 ml) to obtain (S)-2-Benzylsucccinic anhydride. Purity: 99.0%; Wt : 85.0gm

Example-2

Preparation of Mitiglinide calcium dihydrate.

S-Benzylsuccinic anhydride (100 gm) was suspended in toluene (1000ml) were heated to 45-50°C. Toluene (500 ml) solution of Cis-Octahydroisoindole (79 gm) was slowly added to a resultant suspension at 45-50°C for 30-40 min to get a clear solution. After completion, the reaction mass was cooled and stirred for 2 hours at 25-30°C. The obtained regioisomer was separated out by filtration; to the filtrate, slowly added sodium hydroxide solution (19 gm in 500 ml water) at 25-30°C and stir for 10-15 min .Separate the layers and washed the toluene layer with water (100ml). Combined the Aqueous layers, charged ethanol (1000 ml) and then slowly added calcium chloride solution (44 gm in 1400 ml purified water) for a period of 45-60 min at 25-30°C and stirred for 10-12 hours at same temperature. The resultant solid was filtered and washed with purified water and dried at 50-55°C for 10 hours; obtain solid was dissolved in ethanol (1700 ml) at 60°C, filtered through hyflo. The filtrate further heated to reflux temperature, followed by addition of water (100 ml) and maintains at same temperature for 30 min; cooled to ambient temperature and maintained for 2-4 hours The resultant solid was filtered, washed with ethanol and dried at 50-55°C to obtain crude Mitiglinide calcium dihydrate. Purity: 98%; Wt: 85.0gm

Example-3

Preparation of Mitiglinide calcium dihydrate.

Cis-octahydroisoindole hydrochloride (102gm) was dissolved in purified water, followed by addition of toluene. Sodium hydroxide solution (30 g in 300 ml water) was slowly added to the resultant solution in 30 min at 20-25°C to separate the layers; extracted the aqueous layer with toluene (3X200 ml). Combined the toluene layers and distilled off completely under vacuum at 45-50°C to get residue, followed by toluene (500 ml) and stirred for 15 min and kept aside. In another RBF S-Benzylsuccinic anhydride (100 gm) was suspended in toluene (1000ml) were heated to 45-50°C. Above toluene (500 ml) solution of Cis-Octahydroisoindole was slowly added to a resultant suspension at 45-50°C for 30-40 min to get a clear solution. After completion, the reaction mass was cooled and stirred for 2 hours at 25-30°C. The obtained regioisomer was separated out by filtration; to the filtrate, slowly added sodium hydroxide solution (19 gm in 500 ml water) at 25-30°C and stir for 10-15 min .Separate the layers and washed the toluene layer with water (100ml). Combined the Aqueous layers, charged ethanol (1000 ml) and then slowly added calcium chloride solution (44 g in 1400 ml purified water) for a period of 45-60 min at 25-30°C and stirred for 10-12 hours at same temperature.
The resultant solid was filtered and washed with purified water and dried at 50-55°C for 10 hours; obtain solid was dissolved in ethanol (1700 ml) at 60°C, filtered through hyflo. The filtrate further heated to reflux temperature, followed by addition of water (100 ml) and maintains at same temperature for 30 min; cooled to ambient temperature and maintained for 2-4 hours .The resultant solid was filtered, washed with ethanol and dried at 50-55°C to obtain crude Mitiglinide calcium dihydrate. Purity: 98%; Wt: 90.0gm

Example -4

Purification of Mitiglinide calcium dihydrate

Crude mitiglinide calcium (100 g) was dissolved in ethanol (1700 ml) at 65°C. The reaction mass was filtered through hyflo bed; followed by micron filter at 60-65°C and washed with ethanol (200 ml). The filtrate further heated to reflux temperature, followed by addition of water (100 ml) and maintained at same temperature for 30 min; cooled to ambient temperature and maintained for 2-4 hours. The resultant solid was filtered, washed with ethanol, and dried under vacuum at 50-55°C to obtain mitiglinide calcium dihydrate. Purity: 99.8 %; Wt: 92.0gm

Example-5

Recovery of S-Benzyl succinic acid and cis-octahydroisoindole hydrochloride from S-

Mitiglinide regioisomer

Method-a)

S-Regioisomer (10gm) was suspended in acetic acid and water (60 ml and 150 ml) were heated to 100-110°C and stirred for 6-8 hours. After completion, the reaction mass was cooled to 25-30°C and distilled out solvent completely under vacuum at 55-60°C; water (100 ml) was added to the resultant mass and adjust pH 1-2 with 6N HCI solution. The solid was filtered, washed with purified water (20ml) and dried under vacuum at 50-55°Cto obtain S-benzyl succinic acid. To the filtrate, sodium hydroxide solution (7.6gm in 76 ml water) was slowly added at 20-25°C; followed by extraction with toluene (4x50 ml). The solvent was distilled out completely under vacuum at 50-55°C, added tetrahydrofuron (30 ml) and stirred for 10 min. The reaction mass pH 4-5 was adjusted with dry HCI gas, filtered the resultant solid under nitrogen atmosphere and washed with tetrahydrofuron (5ml); dry the material under vacuum at 40-45X for 8 hours to obtain cis-octahydroisoindole hydrochloride. Cis-octahydroisoindole hydrochloride - Wt:

2.5gm S-benzylsuccinic acid - Wt: 5.3gm

Method-b)

S-Regioisomer (10gm) was suspended in hydrobromic acid (40%) and water (50 ml and 100 ml) were heated to 100-110°C and stirred for 10-15 hours. After completion, the reaction mass was cooled to 25-30°C and distilled out solvent completely under vacuum at 55-60°C. Water (100 ml) was added to the resultant mass and adjusts pH 1-2 with 6N HCI solution. The solid was filtered, washed with purified water (20ml) and dried under vacuum at 50-55°Cto obtain S-Benzyl Succinic acid.

To the filtrate, sodium hydroxide solution (7.6 gm in 76 ml water) was slowly added at 20-25°C; followed by extraction with toluene (4x50 ml). The solvent was distilled out completely under vacuum at 50-55°C, added tetrahydrofuron (30 ml) and stirred for 10 min. The reaction mass pH 4-5 was adjusted with dry HCI gas, filtered the resultant solid under nitrogen atmosphere and washed with THF (5 ml); dry the material under vacuum at 40-45°C for 8 hours to obtain Cis-

Octahydroisoindole hydrochloride
Cis-Octahydroisoindole hydrochloride - Wt: 2.5gm
S-Benzylsuccinic acid - Wt: 4.5gm

Method-c)

S-Regioisomer (10gm) was suspended in hydrochloric acid (36%) and water (50 ml and 100 ml) were heated to 100-110°C and stirred for 12 hours. After completion, the reaction mass was cooled to 25-30°C and distilled out solvent completely under vacuum at 55-60°C. Water (100 ml) was added to the resultant mass and adjusts pH 1-2 with 6N HCI solution. The solid was filtered, washed with purified water (20ml) and dried under vacuum at 50-55°Cto obtain S-benzyl succinic acid.

To the filtrate, sodium hydroxide solution (7.6 g in 76 ml water) was slowly added at 20-25°C; followed by extraction with toluene (4x50 ml). The solvent was distilled out completely under vacuum at 50-55°C, added tetrahydrofuron (30 ml) and stirred for 10 min. The reaction mass pH 4-5 was adjusted with dry HCI gas, filtered the resultant solid under nitrogen atmosphere and washed with tetrahydrofuron (5 ml); dry the material under vacuum at 40-45X for 8 hours to obtain cis-octahydroisoindole hydrochloride. Cis-Octahydroisoindole hydrochloride - Wt: 2.0gm S-benzylsuccinic acid - Wt: 4.5gm

Method-d)

S-Regioisomer (10gm) was suspended in paratoluene sulphonic acid and water (27gm and 100 ml) were heated to 100-110°C and stirred for 10-12 hours. After completion, the reaction mass was cooled to 25-30°C and distilled out solvent completely under vacuum at 55-60°C. Water (100 ml) was added to the resultant mass and adjusts pH 1-2 with 6N HCI solution. The solid was filtered, washed with purified water (20ml) and dried under vacuum at 50-55°Cto obtain S-benzyl succinic acid.

To the filtrate, sodium hydroxide solution (7.6 gm in 76 ml water) was slowly added at 20-25°C; followed by extraction with toluene (4x50 ml). The solvent was distilled out completely under vacuum at 50-55°C, added tetrahydrofuron (30 ml) and stirred for 10 min. The reaction mass pH 4-5 was adjusted with dry HCI gas, filtered the resultant solid under nitrogen atmosphere and washed with tetrahydrofuron (5 ml); dry the material under vacuum at 40-45cC for 8 hours to obtain cis-octahydroisoindole hydrochloride Cis-octahydroisoindole hydrochloride - Wt: 2.3gm S-Benzylsuccinic acid -Wt: 5.1gm

Method-e)

S-Regioisomer (10gm) was suspended in acetic acid (50 ml) were heated to 100-110°C and stirred for 10-12 hours. After completion, the reaction mass was cooled to 25-30°C and distilled out solvent completely under vacuum at 55-60°C; water (100 ml) was added to the resultant mass and adjusts pH 1-2 with 6N HCI solution. The solid was filtered, washed with purified water (20ml) and dried under vacuum at 50-55°Cto obtain S-benzyl succinic acid.

To the filtrate, sodium hydroxide solution (7.6 gm in 76 ml water) was slowly added at 20-25°C; followed by extraction with toluene (4x50 ml). The solvent was distilled out completely under vacuum at 50-55°C, added tetrahydrofuron (30 ml) and stirred for 10 min. The reaction mass pH 4-5 was adjusted with dry HCI gas, filtered the resultant solid under nitrogen atmosphere and washed with tetrahydrofuron (5 ml); dry the material under vacuum at 40-45°C for 8 hours to obtain cis-octahydroisoindole hydrochloride. Cis-Octahydroisoindole hydrochloride - Wt : 1.8gm S-benzylsuccinic acid - Wt: 4.0gm

We claim:

1. A process for the preparation of mitiglinide calcium dihydrate comprising the steps of;

a) reacting (S)-2-benzyl succinic anhydride with cis-octahydroisoindole in aromatic hydrocarbon solvent,
b) heating to get clear solution at 45-50°C,
c) cooling the solution to 20-30°C,
d) separating unwanted regioisomer by filtration,
e) adding aqueous alkaline solution to filtrate; separate the aqueous layer,
f) treating aqueous layer with calcium chloride solution, and
g) isolating Mitiglinide calcium dihydrate.

2. The process according to claim 1, wherein alkaline is selected from sodium hydroxide, potassium hydroxide or calcium hydroxide.

3. The process according to claim 1, wherein crude mitiglinide calcium dihydrate is purified by recrystallization in alcohol solvent is selected from methanol, ethanol, isopropanol or butanol

4. A process for the recovery of S-benzyl succinic acid, cis-octahydroisoindole from regioisomer comprising the steps of;

a) reacting regioisomer in aqueous acid,
b) heating to get clear solution,
c) distilling out the acid, followed by addition of water,
d) adjusting pH and recovering the S-benzyl succinic acid by filtration,
e) basifying the filtrate,
f) adding aromatic hydrocarbon solvent and distilled out completely,
g) adding tetrahydrofuran solvent,
h) adjusting pH with an acid, and
i) recovering the cis-octahydroisoindole.

5. The process according to claim 4, wherein the pH is adjusted to 1-2 with 6N Hydrochloride.

6. The process according to claim 1 and 4, wherein the aromatic hydrocarbon solvent is selected from toluene, xylene, ethyl benzene or mesitylene.

7. The process according to claim 4, wherein the acid is selected from acetic acid, hydrochloric acid, hydrobromic acid, propanoic acid or paratoluene sulphonic acid.

8. The process according to the claim 4, wherein the regioisomer of the compound of formula (VIII) is