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Title:
PROCESS FOR PREPARATION OF GLIPIZIDE
Document Type and Number:
WIPO Patent Application WO/2018/078657
Kind Code:
A1
Abstract:
The present invention discloses a simple, economic, consistent, commercially viable and industrially applicable process for preparation of Glipizide in high yield and highly pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.

Inventors:
MEHTA, Bharat (5 Avillion, Little Gibbs RoadMaharastra, Mumbai 6, 400006, IN)
UDANI, Kamlesh (4 Dipali Society, KundanGujarat, Bharuch 2, 392002, IN)
UDANI, Moksha (4 Dipali Society, KundanGujarat, Bharuch 2, 392002, IN)
Application Number:
IN2017/050501
Publication Date:
May 03, 2018
Filing Date:
October 27, 2017
Export Citation:
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Assignee:
J.B. CHEMICALS & PHARMACEUTICALS LIMITED (Cnergy IT Park, A2 3rd Floor,Appa Saheb Marathe Marg,Prabhadevi, Maharastra Mumbai 0, 400030, IN)
International Classes:
C07D241/24; A61K31/495; C07C311/59; C07D241/22; C07D241/28; C07D521/00
Foreign References:
IN3265MU2011A
US3669966A1972-06-13
Attorney, Agent or Firm:
KHARKAR, Pallavi et al. (IPRAM Intellectual Property Services, 716 Swastik Disa Corporate Park,L.B.S Marg, Ghatkopar, Maharastra Mumbai 6, 400086, IN)
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Claims:
A process for preparation of N-{4-[2-(5-methylpyrazinyl-2-carboxamido)- ethyl] -benzenesulphonyl } -N'-cyclohexylurea (Glipizide) comprising reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine-2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate to obtain Glipizide.

The process as claimed in claim 1 wherein said alkyl ester of methyl pyrazine-2-carboxylic acid is methyl 5-methylpyrazine-2-carboxylate. The process as claimed in claim 1 wherein said alkali metal alkoxide is selected from group consisting of sodium tert-butoxide, potassium tert- butoxide, potassium methoxide and sodium methoxide.

The process as claimed in claim 1 wherein said alkali metal carbonate is selected from group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, lithium carbonate and lithium bicarbonate.

The process as claimed in claim 1 wherein said reaction is carried out in presence of base, alkali metal alkoxide optionally in a solvent at temperature in the range of 25-100°C for a period of 30 min to 3 hours.

The process as claimed in claim 1 wherein said reaction is carried out in presence of base, alkali metal carbonate and solvent at temperature in the range of 25-100°C for a period of 4 to 40 hours.

The process as claimed in claim 5 and 6 wherein said solvent is selected from toluene, acetonitrile, isopropanol, methanol, dimethylformamide or mixtures thereof.

A process for preparation of Glipizide comprising

i) reacting 4-(2-aminoethyl)benzenesulfonamide and di-tert-butyl dicarbonate in presence of solvent to obtain tert-butyl 4- sulfamoylphenethylcarbamate; ii) reacting tert-butyl 4-sulfamoylphenethylcarbamate with cyclohexylisocyanate in presence of alkali carbonate and solvent to obtain tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate; iii) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide;

iv) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide to obtain Glipizide in high yield; and

v) optionally purifying Glipizide.

9. The process as claimed in any of the preceding claims wherein said alkali metal alkoxide is selected from group consisting of sodium tert-butoxide, potassium tert-butoxide, potassium methoxide, sodium methoxide

10. A purification of Glipizide comprising

a) dissolving Glipizide in first solvent

b) heating the solution

c) optionally treating the solution of step b) with charcoal and filtering the solution

d) adding second solvent to the solution

e) cooling the solution of step d) to obtain pure Glipizide.

11. The process as claimed in claim 10 wherein said first solvent is selected from the group consisting of dimethylformamide, dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidone.

12. The process as claimed in claim 10 wherein said second solvent is alcohol selected from methanol, ethanol, isopropanol, propanol, n-butanol and water, or mixtures thereof.

13. The process as claimed in claim 10 wherein said heating in step b) and adding second solvent in step d) is carried out at 50-100°C to obtain a solution.

14. A process for preparing Glipizide having purity more than 99% comprising the steps of a) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide to obtain Glipizide; b) purifying Glipizide by heating a solution of Glipizide in dimethylformamide at 50° to 90°C, treating the solution with charcoal and filtering the solution, adding methanol to the solution and cooling the solution to obtain pure Glipizide.

Description:
PROCESS FOR PREPARATION OF GLIPIZIDE Field of invention

The present invention relates to process for preparation of Glipizide.

Background of invention Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class. The chemical name of Glipizide is l-cyclohexyl-3-[[p-[2-(5-methylpyrazine carboxamido) ethyl]phenyl] sulfonylurea. The molecular formula is C2iH27Ns0 4 S, molecular weight is 445.55; the structural formula is shown below:

Glipizide is commercially marketed as Glucotrol. Glucotrol is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Various patents in the art disclose process for preparation of Glipizide.

US3669966 disclose benzenesulphonylurea compounds and processes of their preparation. The process for preparing Glipizide disclosed in this patent involves reacting 5-methyl pyrazine-2- carboxylic acid with ethyl chloroformate in the presence of triethylamine followed by reacting with p-(4-amino-ethyl) benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine- carboxamide. The crude product is then purified by crystallization from ethanol- water. The purified N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine- carboxamide is further reacted with cyclohexyl isocyanate in the presence of base to obtain Glipizide. Another process disclosed in this patent involves reaction of methyl pyrazine carboxylic acid with thionyl chloride to form corresponding acid chloride followed by reacting the acid chloride with p-(4-amino-ethyl) benzene sulphonamide to obtain N (2-(4-(aminosulfonyl)phenyl) ethyl pyrazine carboxamide. This compound is then treated with cyclohexylisocyanate to obtain Glipizide. When the present inventors followed this process, they noted that the process resulted into formation of a sticky mass due to formation of number of impurities during reaction steps. Therefore, both preparation and isolation of products using the above process was difficult.

Indian patent application 2742/MUM/2013 disclosed preparation of Glipizide comprising a) preparing ester of 5-methylpyrazine-2-carboxylic acid by reacting 5- methylpyrazine-2-carboxylic acid in presence of alcohol and thionyl chloride (SOCb) at temperature 25-40°C; b) reacting ester of 5-methylpyrazine-2- carboxylic acid with 4-(2-aminoethyl)-benzene sulphonamide at 60-80°C to get 5- methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide; c) reacting 5- methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide with cyclohexyl isocyanate in presence of potassium carbonate and mixture of organic solvents to prepare Glipizide. Further it is disclosed that Glipizide is purified using mixture of alcohol and halogenating solvent to get pure Glipizide.

Thus, the above processes involve use of hazardous reagents like thionyl chloride, ethyl chloroformate etc.

CN102993106 disclosed synthesis of Glipizide which comprised of following reaction scheme.

11 \

The process involved use of hazardous reagent like ethychloroformate and expensive reagents like 1-hydroxybenzotriazole (HOBt) and l-ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride.

The present invention provides a simple, consistent, high yielding and industrially viable process for preparation of Glipizide. Object of invention

An object of the invention is to provide new process for preparation of highly pure Glipizide.

Another object of the invention is to provide a simple, economic, consistent process for preparation of highly pure Glipizide with easy work-up procedure.

Yet another object of the invention is to provide a commercially viable and industrially applicable process for preparation of highly pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%. Brief description of drawings

Figure 1: It represents HPLC chromatogram of Blank.

Figure 2: It represents HPLC chromatogram of Glipizide as obtained in Example 5. Figure 3: It represents HPLC chromatogram of pure Glipizide as obtained in Example 10. Summary of invention

In accordance with the above objectives, the present invention provides a simple, economic, consistent, industrially feasible process for the preparation of Glipizide. According to an aspect, the present invention provides a process for preparation of Glipizide in a high yield and high purity for pharmaceutical use.

According to another aspect, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate optionally in a solvent to obtain Glipizide in high yield and high purity.

According to yet another aspect, the present invention provides a process for preparation of Glipizide comprising

a) reacting 4-(2-aminoethyl)benzene sulfonamide and di-tert-butyl dicarbonate in presence of solvent to obtain tert-butyl 4-sulfamoylphenethylcarbamate; b) reacting tert-butyl 4-sulfamoylphenethyl carbamate with cyclohexyl isocyanate in presence of alkali carbonate and solvent to obtain tert-butyl 4-(N- (cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate;

c) treating tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethylcarbamate with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N-

(cyclohexylcarbamoyl)benzenesulfonamide;

d) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide with alkyl ester of 5-methyl pyrazine-2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate to obtain Glipizide.

According to one more aspect, the present invention provides a process for purification of Glipizide to obtain Glipizide in purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.

Detailed Description of invention

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

The present invention provides a process for preparation of Glipizide in a high yield and high purity.

The monograph of Glipizide in the United States Pharmacopoeia (USP) mentions specifications for the impurities found in Glipizide. These impurities are determined by liquid chromatography according to the protocol described in the USP. Identified impurities comprise the following impurities: Compound A namely [N-{2-[(4- aminosulfonyl)phenyl]ethyl}-5-methyl-pyrazinecarboxamide], Compound B namely [6-methyl-N-[2-(4-sulfamoyl phenyl) ethyl]pyrazine-2-carboxamide] and Compound C namely [l-cyclohexyl-3-[[4-[2-[[(6-methyl pyrazin-2-yl)carbonyl] amino]ethyl]phenyl] sulfonylurea] .

The levels of the impurities of Glipizide of the present invention as obtained in crude and pure forms are as provided below. Even in crude form, the purity is at least 90 % and preferably above 95%. Table 1

Figures 2 and 3 represent chromatograms of crude and pure Glipizide prepared according to example 5 and example 10 respectively of the present application. The inventors of the present invention have successfully arrived at pure Glipizide having purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%. The total impurities are restricted at less than 1.5 %, preferably less than 1.0% and most preferably less than 0.5%. Thus, Glipizide prepared according to this process comply with both USP and ICH requirements.

According to an embodiment, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of alkali metal alkoxide optionally in a solvent to obtain Glipizide in high yield.

The alkyl ester of 5-methyl pyrazine-2-carboxylic acid is methyl 5-methylpyrazine- 2-carboxylate.

The alkali metal alkoxide is selected from the group consisting of sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide, or mixtures thereof. The solvent used is alcohol for example methanol, ethanol, isopropanol, propanol and n-butanol. A first aspect of the present invention is represented by reaction Scheme 1 as below:

Scheme 1

The process represented in scheme 1 comprises treating 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide with alkyl ester of 5 -methyl pyrazine- 2-carboxylic acid in presence of base selected from alkali metal alkoxide or alkali metal carbonate preferably sodium methoxide. The mixture is stirred and heated at temperature 25-100°C. The reaction is monitored by TLC or HPLC. It takes around 30 mins to 5 hrs for completion. Optionally a second lot of alkyl ester of 5 -methyl pyrazine-2-carboxylic acid and sodium methoxide solution is added to the mixture for the completion of reaction. When two lots of alkyl ester of 5-methyl pyrazine- 2-carboxylic acid and sodium methoxide are used for reaction, ratio of first lot to second lot for sodium methoxide is from at least 10: 1, preferably at least 15: 1 and ratio of first lot to second lot for methyl ester is at least 5: 1. After completion of reaction, water is added to the reaction mass and the reaction mass was acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid Glipizide. According to one embodiment, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of sodium methoxide at temperature in the range of 25-100°C for the period of from 30 min to 5 hours to obtain Glipizide in high yield.

According to another embodiment, the present invention provides a process for preparation of Glipizide comprising heating a mixture of 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and methyl 5-methylpyrazine-2- carboxylate in presence of sodium methoxide solution. Alternatively, powdered sodium methoxide in a solvent can be used. Preferably, the reaction temperature is 50-90°C and reaction time is around 1-2 hr.

Preferably, sodium methoxide is in the form of 25% sodium methoxide solution in methanol.

According to an embodiment, the present invention provides a process for preparation of Glipizide comprising reacting 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine- 2-carboxylic acid in presence of alkali metal carbonate and suitable solvent to obtain Glipizide.

The alkali metal carbonate is selected from the group consisting of potassium carbonate (K2CO3), sodium carbonate (Na 2 C03), potassium bicarbonate (KHCO3) and sodium bicarbonate (NaHC0 3 ).

The solvent used is selected from the group consisting of toluene, acetonitrile, isopropanol, methanol, DMF or mixtures thereof.

The reaction is carried out at temperature in the range of 25-100°C.

The reaction is carried out for 4-40hrs.

Preferably, the reaction of 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide and alkyl ester of 5-methyl pyrazine-2-carboxylic acid is carried out in presence of alkali metal carbonate for example potassium carbonate and solvent for example toluene. The reaction mixture was stirred at refluxed temperature and maintained for 15-20hrs. After completion of reaction the solvent is distilled off from the reaction mixture. The mass is cooled to ambient temperature and water is added to the mass. The pH of reaction mass was brought to below 2.0 using acid for example dilute hydrochloric acid to obtain solid of Glipizide. Glipizide so obtained is then purified to get pure Glipizide.

According to second aspect the present invention provides a process for preparation of Glipizide comprising the steps of 1) reacting methyl 5-methylpyrazine-2-carboxylic acid (8) with acid in presence of solvent to obtain methyl 5-methylpyrazine-2-carboxylate (9);

2) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulphonamide (7) with methyl 5-methylpyrazine-2-carboxylate ester (9) in presence of alkali metal alkoxide or alkali metal carbonate to obtain Glipizide ( 1 ) in high yield;

3) optionally purifying Glipizide.

The acid used in step 1) is sulphuric acid. The solvent used in step 1) is methanol.

The reaction of step 1) is carried at 40-60°C for a period of 1 to 5hrs. Methyl 5-methylpyrazine-2-carboxylate used in step 2) can also be prepared by processes reported in the art.

The alkali metal alkoxide used in step 2) is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, potassium methoxide and sodium methoxide. Preferably sodium methoxide is used. The alkali metal carbonate used in step 2) is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.

The reaction of step 2) is carried out at temperature in the range of 25-100°C optionally in a solvent.

Preferably when alkali metal alkoxide is used as base in step 2) the reaction is carried out for 30min to 5hr. Preferably when alkali metal carbonate is used as base in step 2) the reaction is carried out for 4 to 40 hours. The solvent used is selected from toluene, acetonitrile, isopropanol, methanol, DMF or mixtures thereof.

The second embodiment of the present invention is represented by reaction Scheme 2.

Scheme 2

The process as represented in scheme 2 comprises the following steps:

a) 5-methylpyrazine-2-carboxylic acid in solvent for example methanol is treated with sulphuric acid. The mixture is heated to 50-55°C for 2-3 hrs.

After completion of reaction the mass is cooled to 40-45°C and solvent is distilled out under vacuum to get solid. The solid is treated with a solvent and/or a mixture of solvent for example methylene dichloride (MDC) and water. The mixture is stirred for 20-30 min. The separated organic layer is washed with sodium bicarbonate, treated with activated charcoal at 25° to

35°C and filtered. The solvent is distilled out from the mixture and the mass is treated with another solvent for example cyclohexane at temperature range from 25 °C to 45 °C. The reaction mass is then cooled to 10°C to 15°C to obtain solid of methyl 5-methylpyrazine-2-carboxylate.

b) treating 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate as obtained in step a) in presence of alkali metal alkoxide for example sodium methoxide solution or alkali metal carbonate for example sodium carbonate or potassium carbonate. Optionally the reaction is carried out in presence of solvent. The reaction mixture is stirred and heated at temperature 80-90°C. After completion of reaction, water is added to the reaction mass and the reaction mass is acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid of Glipizide.

According to third aspect, the present invention provides a process for preparation of Glipizide comprising 1) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzenesul fonamide (7);

2) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of alkali metal alkoxide to obtain Glipizide (1) in high yield;

3) optionally purifying Glipizide.

This aspect of the present invention is represented by below reaction Scheme.

(6) CO

Scheme 3

The process as represented in scheme 3 comprises:

a) reacting tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate with suitable acid for example hydrochloric acid in presence of solvent for example methanol. The mixture is heated at 50-70°C with stirring for 2-6 hours. After completion of reaction the solvent is distilled out and water is added to the reaction mass. The reaction mass is then neutralized using alkali for example sodium hydroxide solution to obtain 4- (2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide.

b) treating 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide for example sodium methoxide solution or alkali metal carbonate for example sodium carbonate or potassium carbonate. Optionally the reaction is carried out in presence of solvent. The reaction mixture is stirred and heated at temperature 80-90°C. After completion of reaction, water is added to the reaction mass and the reaction mass is acidified using hydrochloric acid. The mass is stirred for 1-2 hr to obtain solid of Glipizide. c) optionally purifying Glipizide.

Methyl 5-methylpyrazine-2-carboxylate as used in step b) is prepared by the procedures described in one or more embodiment of the present invention or it can be prepared by the processes reported in the art.

According to fourth aspect, the present invention provides a process for preparation of Glipizide comprising

1) reacting tert-butyl 4-sulfamoylphenethylcarbamate (4) with cyclohexylisocyanate (5) in presence of metal carbonate selected from sodium carbonate, cesium carbonate, potassium carbonate and solvent selected from the group consisting of acetone, methyl ethyl ketone and methyl isobutyl ketone to obtain tert-butyl 4-(N- (cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate (6);

2) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide (7);

3) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of alkali metal alkoxide to obtain Glipizide (1) in high yield;

4) optionally purifying Glipizide. This aspect of the present invention is represented by below reaction Scheme 4.

(?)

Scheme 4

The process as represented in scheme 4 comprises the steps of a) treating tert-butyl 4-sulfamoylphenethylcarbamate with potassium carbonate in presence of solvent for example acetone. The reaction mixture is heated to 50-55°C and cyclohexylisocyanate is added to it. The mixture is stirred for 2-6hr. The reaction mass is filtered and washed with solvent for example acetone or water or their mixture. The filtrate is acidified using acid for example hydrochloric acid to give solid of tert-butyl 4-(N-

(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate,

b) tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate obtained in step a) dissolved in solvent for example methanol and the solution is treated with acid for example hydrochloric acid at 50-55°C. After removing solvent from the mixture, the mass is treated with alkali for example sodium hydroxide to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide or tert-butyl 4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate is deprotected by methods known in the prior art;

c) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide as obtained in step b) with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide for example sodium methoxide to obtain Glipizide;

d) optionally purifying Glipizide.

According to fifth aspect, the present invention provides a process for preparation of Glipizide comprising

1) reacting 4-(2-aminoethyl)benzenesulfonamide (2) and di-tert-butyl dicarbonate (3) in presence of solvent selected from the group consisting of dimethylacetamide, dimethylsulfoxide, N-methylpyrollidone and sulfolane to obtain tert-butyl 4-sulfamoylphenethylcarbamate (4);

2) reacting tert-butyl 4-sulfamoylphenethylcarbamate (4) with cyclohexylisocyanate (5) in presence of potassium carbonate and solvent to obtain tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate (6);

3) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with hydrochloric acid followed by alkaline treatment with sodium hydroxide to obtain 4-(2- aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulphonamide (7);

4) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of sodium methoxide to obtain Glipizide (1) in high yield;

5) optionally purifying Glipizide. This aspect of the present invention is represented by below reaction Scheme 5.

<5)

Scheme 5

The process as represented in scheme 5 comprises the steps of a) treating 4-(2-aminoethyl)benzenesulfonamide with di-tert-butyl dicarbonate in presence of solvent for example dimethylformamide for 2- 6hr at ambient temperature. After completion of reaction, water is added to the reaction mass and stirred the mixture for lhr to obtain solid of tert-butyl 4-sulfamoylphenethylcarbamate;

b) treating tert-butyl 4-sulfamoylphenethylcarbamate with potassium carbonate in presence of solvent for example acetone. The reaction mixture is heated to 50-55°C and cyclohexylisocyanate is added to it. The mixture is stirred for 2-4 hr. The reaction mass is filtered and washed with solvent for example acetone. The pH of the filtrate is adjusted between 5 to 6 using acid for example hydrochloric acid to give tert-butyl 4-(N- (cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate;

c) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl) phenethyl carbamate in solvent is treated with acid for example hydrochloric acid at 50-55°C. After removing solvent from the mixture, the mass is treated with alkali for example sodium hydroxide to obtain 4-(2- aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulphonamide and d) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide as obtained in step c) with methyl 5-methylpyrazine-2-carboxylate ester in presence of alkali metal alkoxide for example sodium methoxide to obtain Glipizide.

e) optionally purifying Glipizide.

According to sixth aspect, the present invention provides a process for preparation of Glipizide comprising i) reacting 4-(2-aminoethyl)benzenesulfonamide (2) and di-tert-butyl decarbonate (3) in presence of solvent to obtain tert-butyl 4- sulfamoylphenethylcarbamate (4);

ii) reacting tert-butyl 4-sulfamoylphenethylcarbamate (4) with cyclohexylisocyanate (5) in presence of alkali carbonate and solvent to obtain tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate (6);

iii) treating solution of tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (6) in solvent with suitable acid followed by alkaline treatment to obtain 4-(2-aminoethyl)-N- (cyclohexylcarbamoyl)benzene sulphonamide (7);

iv) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (7) with methyl 5-methylpyrazine-2-carboxylate (9) in presence of alkali metal alkoxide to obtain Glipizide (1) in high yield; and v) optionally purifying Glipizide.

According to seventh aspect, the present invention provides a process for purification of Glipizide to obtain Glipizide in high purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.

The process for purification of Glipizide according to present invention comprising the steps of a) dissolving Glipizide in first solvent

b) heating the solution

c) optionally treating the solution of step b) with charcoal and filtering the solution

d) adding second solvent to the solution and

e) cooling the solution of step d) to obtain pure Glipizide.

The first solvent is selected from the group selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidone.

The heating is carried out at 50-100°C.

The second solvent is alcohol selected from methanol, ethanol, isopropanol, propanol, n-butanol and water, or mixtures thereof.

In an embodiment, the process of purification of Glipizide involves, dissolving crude Glipizide in first solvent for example dimethylformamide to get a solution.

The solution is heated at 50-70°C and stirred for 10 min. The mixture is treated with activated charcoal and filtered the solution. Second solvent for example methanol. ethanol, isopropanol, n-butanol, preferably methanol is added to the filtrate at 50-

70°C and the mixture is stirred for 1-2 hr at the same temperature. The precipitate obtained is filtered, washed with solvent and dried to afford pure Glipizide.

According to another embodiment the process for purification of Glipizide comprises

a) dissolving Glipizide in dimethylformamide

b) heating the solution at 50° to 70°C c) treating the solution of step b) with charcoal and filtering the solution d) adding methanol to the solution

e) cooling the solution of step d) to obtain pure Glipizide.

Glipizide obtained according to the present invention is having purity more than 99%.

In another embodiment, a process for preparing highly pure Glipizide comprising the steps of a) reacting 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide with methyl 5-methylpyrazine-2-carboxylate in presence of alkali metal alkoxide to obtain Glipizide; b) purifying Glipizide by heating a solution of Glipizide in dimethylformamide at 50° to 90°C, treating the solution with charcoal and filtering the solution, adding methanol to the solution and cooling the solution to obtain pure Glipizide having high purity more than 95%, preferably more than 96%, more preferably more than 98% and most preferably more than 99%.

The advantages of the process of present invention are

1. All the reagents used in the present invention are readily and commercially available and inexpensive, thus the present process is economical.

2. The present process is suitable for scale up production of Glipizide as it involves easy work up procedure and the reaction steps.

3. The present process avoids the use of hazardous reagents like thionyl chloride, ethyl chloroformate.

4. The present process avoids reaction conditions like reactions at low temperature for example below 0°C and high temperature which saves energy.

5. The present process avoids use of expensive coupling reagents like 1- hydroxybenzotriazole, Ν,Ν'-dicyclohexylcarbodimide, 1 -ethyl - (3- dimethylaminopropyl) carbodiimide hydrochloride (EDC HC1).

6. The present process is simple and consistent to achieve Glipizide in high yield and high purity. The following examples are presented for illustrative purpose and not intended to limit the scope of this invention.

Examples

Example 1

Preparation of tert-butyl 4-sulfamoylphenethylcarbamate from 4-(2- aminoethyl)benzenesulfonamide

In a reaction vessel 4-(2-aminoethyl)benzenesulfonamide (50g, 0.24moles) was dissolved in dimethylformamide (200ml) at ambient temperature. Di-tert-butyl dicarbonate (54.5g, 0.24moles) was added slowly to the solution. The reaction mixture was stirred for 4 hr at ambient temperature. After completion of reaction water (600ml) was added to the reaction mass and stirred the mixture for 1 hr. The solid obtained was filtered, washed with water and dried to afford tert-butyl 4- sulfamoylphenethylcarbamate (73g). Yield: 97%

Example 2

Preparation of tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl) phenethyl carbamate

In a reaction vessel, tert-butyl 4-(N-(cyclohexylcarbamoyl) sulfamoyl)phenethyl carbamate (60g, 0.19moles), potassium carbonate (41.4g, 0.29moles) and acetone (250ml) were mixed. The mixture was heated to 50-55°C. Cyclohexylisocyanate (27.5g, 0.21moles) was added slowly to the mixture and the mass was stirred for 3hr at the same temperature. Again, a second lot of cyclohexylisocyanate (0.6moles) and potassium carbonate (0.9moles) was added to the reaction mixture. After completion of reaction, the mixture was cooled to room temperature, water (300 ml) was added and the mass was stirred for 30 min. The mixture was filtered. The undissolved salt was treated with acetone (20ml) and potassium carbonate solution (2.5% solution) in water (60ml) and filtered. The filtrates were combined in a reaction vessel and pH of the mixture was adjusted between 5 to 6 using diluted hydrochloric acid. The mixture was stirred for 1 hr. Solid obtained was filtered, washed with water (2x50ml) and dried to give tert-butyl 4- sulfamoylphenethylcarbamate (84g). Yield: 95% Example 3

Preparation of 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide In a reaction vessel tert-butyl 4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl carbamate (75g, 0.17moles) and methanol (525ml) were charged. Hydrochloric acid (37.5g, 0.34moles) was added slowly to the mixture and the mixture was heated to 50-55°C with stirring for 3hr. After completion of reaction methanol was distilled off under vacuum. The reaction mass was cooled 25°C to 35°C and water (225 ml) was added to the mass. The reaction mass was treated with sodium hydroxide solution (10% solution in water) to adjust the pH between 7 to 7.5. The mass was stirred for 30 min, solid obtained was filtered, washed with water (50ml) and dried to afford 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzene sulfonamide (52.5g). Yield: 93.4%

Example 4

Preparation of Methyl 5-methylpyrazine-2-carboxylate

In a reaction vessel 5-methylpyrazine-2-carboxylic acid (25g, 0.18moles) was dissolved in methanol (250ml). Sulfuric acid (17.74g, 0.18moles) was added at ambient temperature and the mixture was heated to 55°C. The mixture was stirred for 4 hr. After completion of reaction methanol was distilled off under vacuum and charged dichloromethane (250ml) and water (150ml) to the reaction mass. The separated aqueous layer was extracted by dichloromethane (150ml) and then discarded. The combined organic layer was washed with 8% solution of sodium bicarbonate solution (2x125ml) and treated with sodium sulfate. Then activated charcoal (5g) was added to the solution and the mixture was stirred for 30 min. The reaction mass was filtered, washed with dichloromethane (100ml). The organic filtrate was heated to 35°C to 40°C and solvent was distilled out under vacuum. The mass obtained was charged with cyclohexane (100ml) and stir the mass for 5 to 10 min. The solvent was distilled out under vacuum. Again, the mass was charged with cyclohexane (200ml) and the mixture was cooled at 10° to 15°C followed by stirring for 60min. The solid obtained was filtered, washed with cyclohexane (50ml) and dried to afford methyl 5-methylpyrazine-2-carboxylate (22.7g). Yield: 82.7% Example 5

Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide

4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (25g, 0.076 moles) and methyl 5-methylpyrazine-2-carboxylate (12.27g, 0.08moles) were charged and mixed in a reaction vessel. Solution of sodium methoxide in methanol (33.17g, 0.15moles) was added to the vessel. The mixture was stirred at 85°C for lhr and second lot of methyl 5-methylpyrazine-2-carboxylate (1.17g, 0.007moles) and 25% sodium methoxide solution (1.7g, 0.007moles) was added to the mass. After completion of reaction, the reaction mixture was cooled to 25°C to 35°C and water (125ml) was added to it. The mixture was acidified using diluted hydrochloric acid to precipitate out the solid. The solid obtained was filtered, washed with water (2x25ml) and dried to afford Glipizide (29g).

Yield: 84% Purity: 96.89% Example 6

Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide

4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (5g, 0.015 moles) and methyl 5-methylpyrazine-2-carboxylate (12.27g, 0.017moles) were charged and mixed in a reaction vessel. Solution of sodium methoxide in methanol (4.14g, 0.019 moles) was added to the vessel. The mixture was stirred at 120°C for lhr and second lot of methyl 5-methylpyrazine-2-carboxylate (0.46 g, 0.003 moles) and 25% sodium methoxide solution (0.66 g, 0.003 moles) was added to the mass. After completion of reaction, the reaction mixture was cooled to 25 °C to 35°C and water (25ml) was added to it. The mixture was acidified using diluted hydrochloric acid to precipitate out the solid. The solid obtained was filtered, washed with water (10ml) and dried to afford Glipizide (5.6g).

Yield: 81% Example 7

Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide

In a reaction vessel, 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl) benzene sulfonamide (5g, 0.015moles), methyl 5-methylpyrazine-2-carboxylate (2.33g, 0.015moles) and methanol (10ml) were mixed. Potassium carbonate (4.22g, 0.03moles) and toluene (15ml) were added to the reaction mass and the mixture was stirred. Slowly temperature of the reaction mass was raised to 55°C to 60°C and maintained for 15hrs. After completion of reaction, the solvent was distilled off. The reaction mass was cooled to ambient temperature and water (20ml) was added to it. The pH of reaction mass was brought to below 2.0 using diluted hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford Glipizide (4.2g). Yield: 61%

Example 8

Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide

4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (lOg, 0.03moles), methyl 5-methylpyrazine-2-carboxylate (5.8g, O.038moles), sodium carbonate (5.4g, 0.051moles) and methanol (70ml) were mixed in a reaction vessel. Slowly temperature of reaction mass was raised to 55°C to 60°C and maintained for 40 hrs. After completion of reaction, solvent was distilled off from the reaction mixture. The reaction mass was cooled to ambient temperature and water (60 ml) was added to the reaction mass. The pH of reaction mass was brought to below 2.0 using diluted hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford solid of Glipizide (10.7g).

Yield: 78%

Example 9

Preparation of N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-5- methylpyrazine-2-carboxamide 4-(2-aminoethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide (5g, 0.015 moles), methyl 5-methylpyrazine-2-carboxylate (2.6g, 0.017moles), powder sodium methoxide (4.15g, 0.019moles) and methanol (50ml) were mixed in a reaction vessel. Slowly temperature of reaction mass was raised to 55°C to 60°C and maintained for 26hrs. A second lot of powder sodium methoxide (0.67g, 0.003moles) was charged to the reaction mixture and maintained at 55°C to 60°C for 3hrs. After completion of reaction solvent was distilled off from the reaction mixture. The reaction mass was cooled to ambient temperature and water (20ml) was added to the mass. The pH of reaction mass was brought to below 2.0 using diluted hydrochloric acid. The precipitated solid was filtered, washed with water and dried to afford Glipizide (4.6g). Yield: 67%

Example 10

Purification of Glipizide

Glipizide (55 g) was dissolved in dimethylformamide (250ml). The solution was heated at 55°C and stirred for lOmin. The mixture was treated with activated charcoal (2.75g) and filtered the solution. Methanol (660ml) was added to the filtrate at 55°C and the mixture was stirred for 1 hr at the same temperature. The precipitate obtained was filtered, washed with methanol (50ml) and unloaded.

Further wet cake was treated with methanol (330ml) and heated the mixture at 60 to 65°C. The mixture was stirred for 30 min and cooled to ambient temperature.

The solid was filtered, washed with methanol (70ml) and dried to afford pure

Glipizide (32.5g).

Yield: 59%, Purity: 99.67%