Claims:1) A process for the preparation of Gliclazide of Formula (I)

(I)
comprising the steps of:
a. reacting the Hexahydrocyclopenta[c]pyrrol-2(1H)-amine compound of Formula III or a salt thereof
(III)
with a 4-Methylbenzenesulfonyl isocyanate compound of Formula II or a salt thereof
(II)
optionally in the presence of base and optionally in an organic solvent at temperature between 10°C – 100°C to afford Gliclazide (I);
b. subjecting Gliclazide of step (a) to purification in a suitable organic solvent to obtain pure Gliclazide (I).

2) A process for the preparation of Gliclazide (I), according to claim 1, wherein the acid used for the salt of compound of Formula III selected from hydrochloride, sulphuric acid and phosphoric acid.

3) A process for the preparation of Gliclazide (I), according to claim 1, wherein the base selected from inorganic base as sodium hydroxide, sodium carbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, sodium ethoxide and triethyl amine.

4) A process for the preparation of Gliclazide (I), according to claim 1, wherein the organic solvent selected from aromatic solvents as toluene, xylene or alcohol solvents as methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or amide solvents as N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide or chlorinated solvents as dichloromethane, monochloromethane, trichloromethane, tetrachloromethane, dichloroethane or ketone solvents as ethyl methyl ketone, methyl isobutyl ketone, acetone or pyrrolidine solvents as dimethylpyrrolidine (DMP), N-methylpyrrolidine (NMP) or water and mixtures thereof.

5) A process for the preparation of Gliclazide (I), according to claim 1, where in step b of purifying Gliclazide comprising the steps of:
a) providing Gliclazide in a solvent or a mixture of solvents;
b) optionally heating the reaction mixture obtained in step a at a temperature
30°C - reflux temperature;
c) cooling the reaction mass at temperature 0-10°C;
d) separating pure Gliclazide (I).

6) A process for the preparation of Gliclazide (I), according to claim 5, wherein organic solvent selected from alcohol solvents as methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or water and mixtures thereof.

7) A process for the preparation of Gliclazide (I) according to claim 1, wherein Gliclazide (I) having HPLC purity of atleast 99.9 %
, Description:FIELD OF THE INVENTION
The present invention relates to improved process for the preparation of Gliclazide of formula I.

(I)
Gliclazide (I) is useful in the treatment of diabetic.

BACKGROUND OF THE INVENTION
Gliclazide of formula I, is chemically known as N-(hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamoyl)-4-methylbenzenesulfonamide. The molecular formula is C15H21N3O3S and the molecular weight for the drug substance is 323.42.

(I)

Gliclazide is an anti-diabetic medication used to treat diabetic mellitus type 2. The trademark name is Diamicron. Gliclazide is a white or almost white powder.

Yan Liu et.al in the patent CN 100591667C discloses process for the preparation of Gliclazide and its intermediates as per below scheme:

Scheme I
Jiang Aiping et.al in the patent CN102584677B discloses process for the preparation Gliclazide using 8-12 parts of tetrahydrofuran and copper-zinc oxide catalyst is about 0.1 parts and reaction carried at very high temperature 200-205°C. Further, the obtained intermediate was treated with bis(trichloromethyl)carbonate to obtain a isocyanate intermediate compound. The obtained intermediate was condensed with methylbenzenesufonamide to give Gliclazide. The scheme was disclosed as below:

Scheme II

Fan Xingshan et.al in the patent CN102850257B discloses process for the preparation of Gliclazide at very lowtemperature treating cyclohexane a-bromo-formamide with alcohols and alcohol sodium salt wherein the obtained intermediate was reduced with LiAlH4 and the obtained compound was treated with sodium nitrate and further reduced with Zn as catalyst. The obtained intermediate was condensed with p-toluenesulfonylurea to obtain Gliclazide. The scheme was disclosed as below:

Scheme III

Che Daqing Du Xiaohua in the patent CN102993080B discloses process for the preparation of Gliclazide using 1,2-dibromomethyl cyclopentane and N-[(4-methylphenyl)
sulfonyl]-hydrazide carboxamide in the presence of base. The scheme was disclosed as below:

Scheme IV

Various procedures were reported by varying substances utilizing p-toluene sulfonamide and cyclopentapyrrole as key materials. There is a need to have alternate procedures which are industrially feasible. The inventors of this application have developed an alternate process using lesser amount of the solvent. The process of this invention provides Gliclazide in substantially pure form. Thus, present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of Gliclazide, which provides high overall yield and purity.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of Gliclazide (I). Gliclazide obtained by the process of the present invention was found to substantially pure and stable.

(I)
In one aspect of the present invention, it relates to process for the preparation of Gliclazide (I) comprising the steps of:
a. reacting the Hexahydrocyclopenta[c]pyrrol-2(1H)-amine compound of Formula III or a salt thereof
(III)
with a 4-Methylbenzenesulfonyl isocyanate compound of Formula II or a salt thereof
(II)
optionally in the presence of base and in an organic solvent at temperature between 10°C – 100°C to afford Gliclazide (I);
b. subjecting Gliclazide of step (a) to purification in a suitable organic solvent to obtain pure Gliclazide (I).
In another aspect of the present invention relates to isolating Gliclazide (I) comprising
the steps of:
a) providing Gliclazide in a suitable organic solvent or a mixture of solvents;
b) optionally heating the reaction mixture obtained in step a at a temperature 30°C - reflux temperature;
c) cooling the reaction mass at temperature 0-10°C;
d) separating pure Gliclazide (I).

In a further aspect of the present application also relates to a pharmaceutical composition comprising Gliclazide of the present application and atleast one or more pharmaceutically acceptable excipients.

In another aspect of the present invention relates to substantially pure Gliclazide (I) having HPLC purity of atleast 99.9%.

Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide an efficient process for the preparation of Gliclazide (I). Gliclazide (I) obtained by the process of the present invention is found to be substantially pure.

In another embodiment according to present application, it provides a process for the preparation of Gliclazide (I), comprising the steps of:
a. reacting the Hexahydrocyclopenta[c]pyrrol-2(1H)-amine compound of Formula III or a salt thereof
(III)
with a 4-Methylbenzenesulfonyl isocyanate compound of Formula II or a salt thereof
(II)
optionally in the presence of base and in an organic solvent at temperature between 10°C – 150°C to afford Gliclazide (I);
b. subjecting Gliclazide of step (a) to purification in a suitable organic solvent to obtain pure Gliclazide (I).

Individual steps of the embodiments are detailed herein below.

In process step of reacting Hexahydrocyclopenta[c]pyrrol-2(1H)-amine compound of Formula III or a salt with 4-Methylbenzenesulfonyl isocyanate compound of Formula II in a solvent selected from group consisting of aromatic solvents as toluene, xylene or alcohol solvents as methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or amide solvents as N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide or chlorinated solvents as dichloromethane, monochloromethane, trichloromethane, tetrachloromethane, dichloroethane or ketone solvents as ethyl methyl ketone, methyl isobutyl ketone, acetone or pyrrolidine solvents as dimethylpyrrolidine (DMP), N-methylpyrrolidine (NMP) or water and mixtures thereof. Further, the salt of the Hexahydrocyclopenta[c]pyrrol-2(1H)-amine compound of Formula III can be selected from the group consisting of hydrochloride, sulphuric acid and phosphoric acid and base selected from the group consisting of inorganic base as sodium hydroxide, sodium carbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, sodium ethoxide, triethyl amine. The reaction was performed at a temperature ranging between 10°C – 100°C for 1-10 hours.

In one of the particular embodiment according to present invention in step a, salt of Hexahydrocyclopenta[c]pyrrol-2(1H)-amine was Hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride salt.

In one of the particular embodiment according to present invention in step a, solvents were selected from Ethyl acetate, Toluene, Xylene, Chloroform, Dimethylformamide (DMF), N-methylpyrrolidone (NMP), Acetone.

In one of the particular embodiment according to present application in step a, reaction was performed at 25-45°C for 1-10 hours.

In one of the particular embodiment according to present invention in step a, reaction was performed at 25-45°C for 8 hours.

In one of the particular embodiment according to present invention in step a, reaction was performed using sodium methoxide and potassium carbonate.

In one of the particular embodiment according to present invention in step a, reaction was performed without using any base.

In process step b of purification of Gliclazide (I) of the present invention comprising the steps of:
a) providing Gliclazide in a solvent or a mixture of solvents;
b) optionally heating the reaction mixture obtained in step a at a temperature 30°C - reflux temperature;
c) cooling the reaction mass at temperature 0-10°C;
d) separating pure Gliclazide (I).

In process step b of purification of Gliclazide (I) of the present invention, slurrying Gliclazide using the solvents selected from the group consisting of alcohol solvents as methanol, ethanol, isopropanol, n-propanol, butanol, or ester solvents as ethyl acetate, isopropyl acetate, butyl acetate or water and mixtures thereof. The solution obtained is heated to 30°C to a reflux temperature and separating the wet Gliclazide (I) by performing various conventional methods like distillations, filtering, drying, centrifugation etc. to obtain pure Gliclazide (I).

In one of the particular embodiment according to present invention, in the process step (b) solvents are Ethyl acetate, mixture of Ethyl acetate and Water.

In one of the embodiment according to present invention, step c is performed at temperature ranging between 0-10°C.
In particular embodiment according to present invention, step c is performed at temperature ranging between 0-5°C.

Substantially pure Gliclazide (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% and preferably greater than 99.9%.

The purity of the Gliclazide samples was measured using Chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

The invention was further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Example-1:
p-Toluene Sulfonyl isocyanate (9.09.0g, 0.0522 mole) charged in Ethyl acetate (25mL). Add lot wise Hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride (HCP) or 3-Amino-3-Azabicyclo octane hydrochloride (5.0g, 0.0307mole) at 25-35°C. Heat the reaction mass to 40-45°C and maintain 2 hours for reaction completion. After reaction completion, cool to 25-35°C and add 25 ml of water. Cool the reaction mass to 0-5°C and filter the solid to get pure gliclazide.
Yield: 80.5%
Purity: 98.4% (by HPLC)

Example-2:
p-Toluene Sulfonyl isocyanate (8.02g, 0.0461 mole) charged in Chloroform (25mL). Add lot wise Hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride (HCP) or 3-Amino-3-Azabicyclo octane hydrochloride (5.0g, 0.0307mole) at 25-35°C. Maintain the reaction mass 2 hour for reaction completion at 25-35°C. After reaction completion wash the organic layer with water twice (2x25ml). Extract the product from aq. Layer with chloroform 10 ml. Combined organic layer was concentrated and to obtain crude product.
Yield: 88.0%
Purity: 98.2% (by HPLC)

Example-3:
p-Toluene Sulfonyl isocyanate (8.02g, 0.0461 mole) charged in Dichloromethane (25mL). Add lot wise Hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride (HCP) or 3-Amino-3-Azabicyclo octane hydrochloride (5.0g, 0.0307mole) at 25-35°C. Maintain the reaction mass 2 hour for reaction completion at 25-35°C. After reaction completion wash the organic layer with water twice (2x25ml). Extract the product from aq. Layer with dichloromethane 10 ml. Combined organic layer was concentrated to obtain crude product. Crude product was slurried in Ethyl acetate (25 mL) and water (25 mL) mixture at room temperature and heat to 45-50°C and maintain for 30-60 minutes. Cool the mass to 0-5°C and maintain for 1-2 hours filter to get pure product.
Yield: 85%
Purity: 99.5% (by HPLC)

Example-4:
p-Toluene Sulfonyl isocyanate (6.67g, 0.03375 mole), Hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride (HCP) or 3-Amino-3-Azabicyclo octane hydrochloride (5g, 0.03075 mole), and Sodium methoxide (1.99g, 0.0369 mole) charged in Ethyl acetate (25mL). Heat the reaction mass to reflux and maintain 8 hour for reaction completion. After reaction completion cool to 0-5°C, the precipitated solid was filtered to get crude product. Crude product was slurried in Ethyl acetate (25 mL) and water (25 mL) mixture at room temperature and heat to 45-50°C and maintain for 30-60 minutes. Cool the mass to 0-5°C and maintain for 1-2 hours filter to get pure product.
Yield: 64.5%
Purity: 99.8% (by HPLC)

Example-5:
p-Toluene Sulfonyl isocyanate (6.67g, 0.03375 mole), Hexahydrocyclopenta[c]pyrrol-2(1H)-amine hydrochloride (HCP) or 3-Amino-3-Azabicyclo octane hydrochloride (5g, 0.03075 mole), and Sodium methoxide (1.99g, 0.0369 mole) charged in Acetone (25mL). Heat the reaction mass to reflux and maintain 8 hour for reaction completion. After reaction completion cool to room temperature wash the organic layer twice with water 2x25 ml followed and extract the product with Dichloromethane 10 ml from aq. layer, Distill out the combined organic layer and crude product was slurried in Ethyl acetate(25 mL) and water (25 mL) mixture at room temperature and heat to 45-50°C and maintain for 30-60 minutes. Cool the mass to 0-5°C and maintain for 1-2 hours filter to get pure product.
Yield: 70.0%
Purity: 99.9% (by HPLC)

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.