Claims:1) A process for preparation of Glipizide of formula-IV comprising;
a) reacting a mixed anhydride of formula-II,
Formula -II
wherein R is selected from alkyl, aryl or aralkyl group;

with p-(ß-amino-ethyl-)benzene sulphonamide of formula-III;

Formula-III

to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I; and


Formula -I

b) converting the N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I to Glipizide of formula-IV.

2) The process as claimed in claim 1, wherein the alkyl, aryl or aralkyl group ‘R’ is selected from group consisting of n-propyl, iso propyl, n-butyl, iso butyl and tertiary butyl and phenyl.

3) The process as claimed in claim 1, wherein the solvent is selected from aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, esters or ethers either alone or mixtures thereof.

4) The process as claimed in claim 3, wherein the chlorinated hydrocarbon is methylenedichloride, ethylenedichloride, chloroform or carbontetrachloride.

5) The process as claimed in claim 1, wherein the preparation of mixed anhydride of formula-II,

Formula-II

wherein R is alkyl, aryl or aralkyl group;
comprises;
reacting 5-methylpyrazine-2-carboxylic acid with acyl halides of formula R-COX or anhydrides of formula ROCOOR wherein ‘R’ is as defined above and ‘X’ is halide, in presence of a base.

6) The process as claimed in claim 5, wherein the acyl halide is selected from a group consisting of pivaloyl chloride, acetyl chloride, Propanoyl chloride or Benzoyl chloride.

7) The process as claimed in claim 5, wherein the base is selected from a group consisting of triethyl amine, diisopropyl ethylamine, ammonia, pyridine, dimethylaminopyridine and tetrabutylammonium hydroxide.

8) The process as claimed in claim 1, wherein the conversion of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide to Glipizide comprises either;
i) reacting N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I with cyclohexylisocyanate in presence of base to obtain Glipizide; OR
ii) a) reacting N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I with alkylhaloformate to obtain carbamate; and b) reacting the obtained carbamate with cyclohexylamine to obtain Glipizide.

9) A process for preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I,

Formula-I
comprising;
reacting mixed anhydride of formula-II,

Formula -II

wherein R is alkyl, aryl or aralkyl group;

with p-(ß-amino-ethyl-)benzene sulphonamide of formula –III,

formula –III
to obtain desired product.

10) The process as claimed in claim 9, wherein the alkyl, aryl or aralkyl group (R) is n-propyl, iso propyl, n-butyl, iso butyl, tertiary butyl or phenyl.
11) The process as claimed in claim 9, wherein the solvent is halogenated hydrocarbon.

12) The process as claimed in claim 9, wherein the reaction is performed in presence of a base selected from a group consisting of triethyl amine, diisopropyl ethylamine, ammonia, pyridine, dimethylaminopyridine and tetrabutylammonium hydroxide. , Description:Field of the invention:
The present invention relates to an efficient process for preparation of antidiabetic drug Glipizide of formula-IV. More particularly, the invention relates to the preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I, an intermediate useful in the synthesis of Glipizide of formula-IV.

Formula-I

Background of Invention:
Glipizide, chemically known as N-{4-[(5-methylpyrazine-2-carboxamide)ethyl] benzenesulfonyl},N’cyclohexyl urea, is a pharmacologically active hypoglycemic agent that is used in the treatment of diabetes. It belongs to the second generation of class of compounds known as benzenesulfonylureas which are more potent at lowering blood sugar.

Preparation of Glipizide was first disclosed in US3669966 patent. This patent discloses different synthetic routes for preparation of Glipizide. Out of the routes, the route that appears to have commercial significance comprises first reacting 5-methyl pyrazine-2-carboxylic acid with ethylchloroformate in the presence of triethylamine followed by reacting with p-(ß-amino-ethyl-)benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide. The crude product is 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 a base to get Glipizide. This patent also discloses reaction of pyrazine carboxylic acid with thionyl chloride to form corresponding acid chloride followed by reacting it with p-(ß-amino-ethyl-)benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]pyrazine-carboxamide.

However, conversion of the pyrazine carboxylic acid into either it’s acid chloride using thionyl chloride or mixed anhydrides using ethylchloroformate not only leads to formation of a number of impurities during the condensation step, but also the reaction did not proceed to completion thus making the isolation of products difficult, eventually resulting in poor yield but also generates large amounts of effluent.

A Japanese patent JP6279418 discloses a modified process for preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide by dissolving 5-methyl pyrazine-2-carboxylic acid, ethylchloroformate and p-(ß-amino-ethyl-)benzene sulphonamide in ethylene dichloride followed by adding triethylamine to form N-[2-[4-(aminosulfonyl)phenyl]ethyl]pyrazine-carboxamide. However, this process also involves lengthy and tedious work up procedures.

Another patent, US5516906, discloses reacting 5-methylpyrazine-2-carboxylic acid methyl ester with 2-phenyl ethylamine at 100-200°C to get 5-methylpyrazine-2-(2-phenylethyl)carboxamide. The product is further reacted with chlorosulfonic acid to obtain it’s corresponding sulfonylchloride followed by reaction of the sulfonyl chloride with ammonia to obtain N-[2-[4-(aminosulfonyl) phenyl]ethyl]-5-methyl pyrazine-carboxamide. The said process also results in low yield of carboxamide.

A similar procedure is mentioned in IN196045 starting from 5-methylpyrazine-2-(2-phenylethyl)carboxamide. In this patent 5-methylpyrazine-2-(2-phenylethyl)carboxamide is purified by treating the compound with acid in the presence of charcoal followed by re-precipitating the compound by treating with a base and then subjected for reaction with chlorosulfonic acid followed by treatment with ammonia to obtain N-[2-[4-(aminosulfonyl) phenyl]ethyl]-5-methyl pyrazine-carboxamide.

It is noted that, the processes disclosed in US‘906 and IN‘045 patents suffered low yield of the product, N-[2-[4-(aminosulfonyl) phenyl]ethyl]-5-methyl pyrazine-carboxamide, due to increase in number of steps of chlorosulfonation followed by amidation. The work up procedures also involves large quantities of solvents resulting in yield loss and generating more effluent.

The Indian Application No. 3265/MUM/2011, filed previously by the present applicant have disclosed reaction of 5-methylpyrazine-2-carboxylic acid methyl ester with p-(ß-amino-ethyl-)benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide. This is further reacted with cyclohexylisocyanate in the presence of base to yield Glipizide. However, this process also suffered yield loss.

Yet another Indian Application No. 2742/MUM/2013, discloses a process similar to the process disclosed in 3265/MUM/2011patent application. The process comprises methyl ester preparation in situ in presence of thionyl chloride followed by reaction with p-(ß-amino-ethyl-)benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide. This process involves use of hazardous chemical, thionyl chloride, and due to incomplete reaction, this process is also found to give low yield.

Thus the objective of the present invention is to provide an improved process which involves industrial friendly conditions, eliminating/reducing the solid/liquid effluent generation and improving the yield and quality of final product, Glipizide.

Summary of Invention:
According to one aspect, there is provided a process for preparation of Glipizide of formula- IV comprising;

a) reacting a mixed anhydride of formula-II,

Formula-II
wherein ‘R’ is selected from alkyl, aryl or aralkyl group;

with p-(ß-amino-ethyl-)benzene sulphonamide of formula-III,

Formula -III

to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I; and

Formula-I
b) converting the N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I to Glipizide of formula-IV.

In another aspect, the intermediate N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I is reacted with cyclohexylisocyanate in presence of base to yield Glipizide of formula –IV.

In an alternative aspect, the N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I is converted to Glipizide by i) converting N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazinecarboxamide of formula-I to it’s carbamate derivative followed by reaction with cyclohexylamine to get Glipizide.

According to another aspect, there is provided a process for preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide having formula-I comprising;

Formula -I
reacting mixed anhydride of formula-II;

Formula-II
wherein R is selected from alkyl, aryl or aralkyl group ;

with p-(ß-amino-ethyl-)benzenesulphonamide of formula-III

Formula -III
In an aspect, the alkyl, aryl or aralkyl group (R) of the mixed anhydride of formula –II includes but is not limited to methyl, ethyl, n-propyl, iso propyl, n-butyl, iso butyl, tertiary butyl, phenyl or phenyl acetyl.

Detailed description of the invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.

Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

The present invention relates to an improved and efficient process for the preparation of Glipizide which involves lesser number of steps, is industrial friendly, and employs favorable reaction conditions to obtain the said product of consistent quality and in good yield.

Thus, according to one aspect, the present invention discloses a process for the preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide having formula-I in good yield and purity comprising,

Formula-I

reacting a mixed anhydride of formula-II,

Formula-II

wherein R is selected from alkyl, aryl and aralkyl groups;

with p-(ß-amino-ethyl-)benzene sulphonamide of formula –III

formula -III

The reaction is carried in presence of organic solvents such as halogenated hydrocarbons and in presence of a base selected from a group consisting of triethyl amine, diisopropyl ethylamine, ammonia, pyridine, dimethylaminopyridine or tetrabutylammonium hydroxide.

In an embodiment, the alkyl, aryl or aralkyl group (R) of the mixed anhydride of formula –II includes but is not limited to methyl, ethyl, n-propyl, iso propyl, n-butyl, iso butyl, tertiary butyl, phenyl or phenyl acetyl.

The mixed anhydrides of formula-II are prepared by reacting acyl halides of formula R-COX or anhydrides of formula ROCOOR wherein R is as mentioned above and X is halogen with 5-methylpyrazine-2-carboxylic acid.

In a preferred embodiment, the present invention discloses a process for the preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide having formula-I in good yield and purity comprising,

Formula-I

reacting a mixed anhydride of formula-II,

Formula-II

wherein R is tertiary butyl

with p-(ß-amino-ethyl-)benzene sulphonamide of formula –III

formula –III

The tertiary butyl anhydride of formula-II may be prepared and reacted with p-(ß-amino-ethyl-)benzene sulphonamide in situ or the tertiary butyl anhydride of formula-II may be isolated and then reacted. However, preparation of the mixed anhydride followed by reaction with p-(ß-amino-ethyl-)benzene sulphonamide in situ is preferred. The in situ process may be carried out in suitable solvent medium, optionally, in presence of a base.

During preparation of mixed anhydride, acyl halides may be used in molar equivalent amount or in excess with respect to 5-methylpyrazine-2-carboxylic acid but preferably in the range of 1.0 -1.5 moles, most preferably 1.05-1.15 moles, relative to mole of 5-methylpyrazine-2-carboxylic acid.

The solvent medium includes, but not limited to, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers etc. Chlorinated hydrocarbons preferably include methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, and aromatic hydrocarbons preferably selected from toluene, xylene, and aliphatic hydrocarbons include hexane, cyclohexane, heptane etc. Esters include ethyl acetate or butyl acetate. Ether includes diisopropyl ether or diethyl ether. Most preferable solvent is methylene dichloride.

The base used in the reaction may be selected appropriately from an organic or inorganic class of compounds. The most preferred organic bases are alkyl amines for example triethyl amine, diisopropyl ethylamine or ammonia, or pyridine or dimethylaminopyridine or tetrabutylammonium hydroxide or the like. Inorganic bases are preferably selected from metal alkoxide, or carbonates, exemplary bases include, but not limited to sodium/potassium hydroxide, sodium/potassium carbonates or bicarbonate or the like. However, most preferred base is triethyl amine.

The base is conveniently used in an amount, although not limited to, equal or greater than molar equivalents relative to the starting 5-methylpyrazine-2-carboxylic acid, preferably in a range between 1.0 -1.5 moles, more preferably between 1.05-1.15 moles.

The reaction may be carried out by adding 5-methylpyrazine-2-carboxylic acid into solvent and then addition of the acyl halide after appropriate cooling preferably at a temperature range between -15 to 25°C. After maintaining the reaction mass for about an hour, base is added followed by addition of p-(ß-amino-ethyl-) benzene sulphonamide. Typically the reaction is maintained at the same temperature for 3–5 hours for completion. After completion of reaction, the product, N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I, may be isolated by filtration.

The obtained intermediate, N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I , may directly be taken for preparation of Glipizide. Alternately, the product may be purified before subjecting for preparation of Glipizide.

According to another aspect, there is provided a process for preparation of Glipizide of formula –IV comprising;

a) reacting a mixed anhydride of formula-II,

Formula-II
wherein ‘R’ is selected from alkyl, aryl or aralkyl group;

with p-(ß-amino-ethyl-)benzene sulphonamide of formula-III,

Formula -III
to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I; and

Formula-I
b) converting the N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I to Glipizide of formula-IV.

In an aspect, the alkyl, aryl or aralkyl group (R) of the mixed anhydride of formula –II includes but is not limited to methyl, ethyl, n-propyl, iso propyl, n-butyl, iso butyl, tertiary butyl, phenyl or phenyl acetyl.

The N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5methylpyrazine-carboxamide of formula-I obtained by the present invention may be converted to Glipizide by the known procedures.

According to one method, the carboxamide of formula-I is converted to it’s carbamate using alkylhaloformate for example ethylchloroformate followed by reacting the so obtained carbamate derivative with cyclohexylamine to get Glipizide.

According to another method which is a preferred embodiment of the invention, the compound of formula-I obtained by the present invention is reacted with cyclohexylisocyanate in polar solvents and in the presence of base.

The polar solvents include ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and/or dimethylformamide, dimethylacetamide, dimethylsulfoxide or the like. However, preferred solvents are dimethylformamide or acetone or mixtures thereof.

The base used in the reaction may be selected from an organic or inorganic class of compounds. The preferred inorganic bases are selected from alkali metal hydroxides or alkali metal carbonates. Exemplary bases include, but not limited to, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate or the like. Most preferred base is potassium carbonate.

On completion of the reaction, the reaction mass is cooled to ambient temperature and filtered to isolate the solid mass. The solid mass is dissolved in water and filtered to separate insolubles. The obtained filtrate is acidified followed by filtration to get crude Glipizide.

The isolated crude Glipizide may be purified either by using suitable solvent or base-acid treatment to yield purified Glipizide.

The process for preparation of intermediate N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I starting and subsequently to Glipizide of formula –IV is shown in Scheme-I below:

Scheme I
The Glipizide obtained by the process of the present invention may be formulated into a suitable dosage form such as tablets, capsules, etc., by combining with one or more pharmaceutically acceptable excipients using known techniques. The dosage form may include a suitable amount of the active ingredient and other pharmaceutical agents.

The following examples, which include preferred embodiments, are intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Experimental:
The starting raw material 5-methylpyrazine carboxylic acid and p-(ß-amino-ethyl)benzene sulphonamide which are commercially available are directly used in the present invention.

Example 1:
Stage-I: 5-Methyl Pyrazine-2-carboxylic acid (MPC) to N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide (MPS)

To a clean and dry round bottom flask with Nitrogen atmosphere was charged Methylene dichloride (500 ml) and Pivaloyl chloride (92 gm). The mixture was cooled to 0to(-5)°C and added 5-Methyl Pyrazine-2-carboxylic acid (MPC) (100 gm) dissolved in 50 ml of methylene dichloride. Stirred the mass for 0.5 to 1 hr and then added 78 gm of triethylamine drop-wise into the reaction mass and maintained the reaction for 0.5 hr. Then charged 145 gm of 4-(2-Aminoethyl)benzene sulfonamide (ABS) dissolved in 50 ml methylene dichloride and raised the temperature to 30-35°C and maintained the reaction at 30-35°C till completion of reaction. The reaction mass was filtered and the cake was washed with 100 ml of methylene dichloride. The wet was suck dried and charged into 1050 ml methanol and refluxed for 1.0 hr and then cooled to temperature of 30-35°C to obtain slurry. The slurry was filtered and washed with 150 ml methanol. Dried the cake at 80°C to obtain purified N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide( MPS).

Yield = 88.41 %, HPLC Purity >96.00%

Stage-II: MPS to Glipizide (crude)
To a clean and dry round bottom flask, was charged acetone (900 ml), N,N-dimethyl formamide (100 ml), MPS (100 gm) and dry potassium carbonate (49 gm) and heated to reflux under nitrogen atmosphere and maintained for 1.0 hr. After refluxing for 1 hr was added cyclohexyl isocyanate (CHI) (38 gm,1st lot) drop wise and maintained the reflux for 3.0 hrs. The second lot of cyclohexyl isocyanate (CHI) (10 gm, 2nd lot) was further charged and the mixture was maintained at reflux for another 3.0 hrs. Later, added (8 gm, 3rd lot) of CHI and maintained at reflux for 3.0 hrs till completion of reaction. After completion of reaction, the reaction mass was cooled to room temperature filtered and washed with 2 x150 ml of acetone. The cake was suck dried, and the wet cake was slurried in 2500 ml of DM water, stirred for 1/2 hr, filtered and washed with 2x200 ml DM water. The filtrate was treated with 3.0 gm of carbon BW280, filtered on hyflo and washed with 400 ml of DM water. The carbon treated filtrate was taken in RB Flask and adjusted the pH to about 5-6 with aq.HCl solution (100 ml HCl + 300 ml DM water) and then cooled to 0-5°C, maintained for 1.0 hr, filtered and washed with DM water till neutral pH. Dried the cake at 80°C.

Yield of Glipizide = 93.37 %; HPLC Purity = 98.0%

Stage-III : Glipizide (crude) to Glipizide (Pure)
Glipizide crude (100 gm) was added into methanol (1000 ml), refluxed for 2.0 hrs and cooled to 30-35°C for 30 min to obtain crystals, filtered and washed with 200 ml methanol. Dried the cake at 60-65°C.

Yield Glipizide = 93 %; HPLC Purity >99.00%

Table 1: Details depicting the reaction conditions for Preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide (MPS) from 5-Methyl Pyrazine-2-carboxylic acid (MPC) using other acyl chlorides in methylene dichloride as solvent,
Reagent Conditions Duration for completion of reaction Yield % Analysis
Propanoyl chloride Addition of propanoyl chloride at -5 to 0°C and raising the temperature reaction to30-35°C Reaction completed in 6-8 hrs 60 purity-95.98%
Benzoyl chloride Addition of benzoyl chloride at-5 to 0°C and raising the temperature reaction to 30-35°C Reaction completed in 4-6 hrs 83 purity-89.37%
Acetyl chloride Addition of acetyl chloride at -5 to 0°C and raising the temperature reaction to30-35°C Reaction completed in 4-6 hr 75 -