FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A PROCESS FOR THE PREPARATION OF GLIPIZIDE"
2. APPLICANT:
(a) NAME: IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
Act, 1956
(c) ADDRESS: 48, Kandivali Industrial Estate, Charkop, Kandivali (West),
Mumbai-400067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner in which it is to be performed:

Field of the invention:

N-[2-[4-(aminosulfonyl)phenyI]ethyl]-5-methylpyrazine-carboxamide (Formula-I)

The present invention relates to a short, efficient process for preparation of antidiabetic drug Glipizide of formula-IV. More particularly, the invention relates to preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I an intermediate for use in the synthesis of Glipizide of formula-IV.
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 a 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-(P-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 cyclohexylisocyanate in the presence of base to get Glipizide. This patent also discloses

reaction of pyrazine carboxylic acid with thionylchloride to form corresponding acid chloride followed by reacting it with p-((3-amino-ethyl-)benzene sulphonamide to get N-[2-[4-(aminosulfonyl)phenyl]ethyl]pyrazine-carboxamide.
However, conversion of the pyrazine carboxylic acid into either it's acid chlorides using thionylchloride or mixed anhydrides using ethylchloroformate not only leads to formation of a number of impurities during the condensation step 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-(|3-amino-ethyl-)benzene sulphonamide in ethylenedichloride 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-phenylethylamine 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. Overall yield of this route also remains on lower side.
A similar procedure is mentioned in IN 196045 patent starting from 5-methylpyrazine-2-(2-phenylethyl)carboxamide. In this patent the 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 also 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.
Thus the objective of the present invention is to provide a short 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 an ester of formula-II wherein R is alkyl group, with p-(p-amino-ethyl-)benzene sulphonamide of formula-Ill to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I, and


b) converting the N-[2-[4-(aminosulfonyI)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I to Glipizide of formula-IV.
In a preferred embodiment, the N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I is converted to Glipizide by reacting N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-1 with cyclohexylisocyanate in presence of base to get Glipizide.
In an alternative embodiment, the N-[2-[4-(aminosuIfonyl)phenyl]ethyI]-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;

reacting ester of formula-II wherein R is alkyl group, with p-(p-amino-ethyl-)benzene sulphonamide of formula -III to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I.

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 provides a short, 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 provides a process for the preparation of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide having formula-I comprising reacting an ester of formula-II, wherein R is selected from alkyl group such as methyl, ethyl, etc. with p-(P-amino-ethyl-)benzene sulphonamide to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyI]-5-methylpyrazine-carboxamide in good yield and quality as per the scheme-1 mentioned below. Scheme-1:


In a preferred embodiment, the condensation reaction between the ester compound of formula-II and p-(p-amino-ethyl-)benzene sulphonamide of formula-Ill is carried out by refluxing in solvent medium and removing the by- product, alcohol.
The solvent medium includes, but not limited to, aromatic hydrocarbons. Aromatic hydrocarbons preferably selected from benzene, toluene, xylene, ethyl benzene etc. However, preferred solvents are toluene, ethylbenzene and xylene. The volume of the solvent is used in the range of 5 to 15 volumes with respect to the sulphonamide of formula-Ill. However, range of 8-10 volumes is preferred.
The molar ratio of sulfonamide of formula-Ill to ester of formula-II may vary from 0.95 to 1.2 mole (i.e., 0.95 -1.2 mole of formula-Ill per mole of ester of formula-II). However 1 to 1.05 mole of sulfonamide of formula-Ill per mole of ester of formula-II is preferred.
After completion of reaction, the compound of formula I is filtered and washed with solvent, and dried to obtain the product.. The product may be used as such or may be purified either by using suitable solvent or base-acid treatment to get purified product of Formula-I.

According to another aspect, there is provided a process for preparation of Glipizide of formula -IV comprising;
a) reacting ester of formula-II wherein R is as defined above, with p-((3-amino-ethyl-) benzene sulphonamide of formula-Ill

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

b) converting the N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide
having formula-I to Glipizide of formula-IV.
The N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5methylpyrazine-carboxamide of formula-I
obtained as per 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 as per 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, dimethylaecetamide, 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 get purified Glipizide.
The esters of formula-II may be prepared by refluxing 5-methylpyrazine carboxylic acid and corresponding alcohol in the presence of mineral acid catalysts such as HC1 or H2SO4. Starting raw materials of 5-methylpyrazine carboxylic acid and p-(P-amino-ethyl-) benzene sulphonamide are commercially available.
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 present invention further provides a method for the treatment or prevention of diabetes in a subject by administering an effective amount of the compound of Formula

IV, prepared by the process of instant invention, along with one or more suitable pharmaceutical agents.
The following examples, which include preferred embodiments, is 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.
Example 1: Preparation of 5-Methyl -2-pyrazine carboxylic acid methyl ester (Formula II)
To a mixture of lOOgm of 5-methyl -2-pyrazine carboxylic acid in 600ml of methanol, 8.1 ml of H2SO4 is added under stirring. The reaction mass is heated to reflux till completion of reaction. The reaction mass is then concentrated and product is extracted with toluene. The toluene layer is washed with sodium bicarbonate solution and concentrated the toluene layer to get the product. Yield = 92%. HPLC Purity: >99 %
Example 2: Preparation of N-(2-[4-Aminosulphonyl) phenyI]ethyl]-5-methyl pyrazine carboxamide ( Formula I)
To a round bottom flask, xylene (1 lit), 5-Methyl -2-pyrazine carboxylic acid methyl ester (lOlg) and p-(β-amino-ethyl-)benzene sulphonamide (139.5g) are charged. Reaction mass is refluxed till completion of reaction. Reaction mass is cooled to room temperature and filtered, washed with 200 ml xylene to obtain crude product which is purified by dissolving in sodium hydroxide solution and acidifying with hydrochloric acid to get pure N-(2-[4-Aminosulphonyl) phenyl]ethyl]-5-methyl pyrazine carboxamide. Yield = 74 %, HPLC Purity >97%.
Example 3: Preparation of Glipizide of formula -IV
To a mixture of 50 gm N-(2-[4-Aminosulphonyl) phenyl]ethyl]-5-methyl pyrazine carboxamide, 450ml of acetone and 50ml of dimethylformamide, 44.2 gm of anhydrous potassium carbonate is charged under nitrogen. The reaction mass is heated to reflux. To the reaction mixture, 78.12 gm of cyclohexyl isocyanate in 10 ml acetone is added drop

wise and further refluxed for 4 hrs. After completion of reaction, reaction mass is cooled to room temperature, solid filtered and washed the cake with 150 ml acetone. The cake is transferred to round bottom flask and stirred for 30 minutes with 1250 ml water. Insoluble mass is filtered, filtrate acidified with 1:1 HC1 to obtain slurry. The slurry is further stirred for 1 hr at 0-5 C. Solid is filtered and washed with water till neutral pH. Suck dried and dried under vacuum at 80 C to obtain Glipizide. Glipizide is purified by dissolving in sodium hydroxide solution and acidifying with hydrochloric acid to get pure product. Yield = 80-81% HPLC Purity: >99.5%.

We claim,
1) A process for preparation of Glipizide of formula-IV comprising; a) reacting ester of formula-II wherein R is alkyl group, with p-(β-amino-ethyl)benzene sulphonamide of formula-Ill in a solvent medium to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I; and

b) converting the N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I to Glipizide.
2) The process as claimed in claim 1, wherein the R is methyl or ethyl.
3) The process as claimed in claim 1, wherein the solvent is selected from aromatic hydrocarbons or mixtures thereof.
4) The process as claimed in claim 3, wherein the aromatic hydrocarbon is benzene, toluene, xylene, ethylbenzene or mixtures thereof.
5) The process as claimed in claim 1, wherein the sulphonamide of formula-Ill is used in the range of 0.95 to 1.2 mole per mole of ester of formula-II.

6) The process as claimed in claim 1, wherein, conversion of N-[2-[4-
(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide to Glipizide comprises
either;
reacting N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I with cyclohexylisocyanate in presence of base to obtain Glipizide; OR 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 form Glipizide.
7) A process for preparation of N-[2-[4-(aminosulfonyl)phenyl]emyl]-5-methylpyrazine-
carboxamide having formula-I comprising;
reacting ester of formula-II wherein R is alkyl group, with p-(P-amino-ethyl)benzene sulphonamide of formula-Ill in a solvent medium to obtain N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of formula-I.

8) The process as claimed in claim 7, wherein the R is methyl or ethyl.
9) The process as claimed in claim 7, wherein the solvent is selected from aromatic hydrocarbons or mixtures thereof.
10) The process as claimed in claim 9, wherein the aromatic hydrocarbon is benzene,
toluene, xylene, ethylbenzene or mixtures thereof.

11) The process as claimed in claim 7, wherein the sulphonamide of formula-Ill is used in the range of 0.95 to 1.2 mole per mole of ester of formula-II