FORM 2
THE PATENTS ACT 1970
As amended by the Patents (Amendment) Act, 2002
COMPLETE SPECIFICATION (SEE SECTION 10, Rule 13)
TITLE
Process for the preparation of anti-diabetic drug N-{4-[2-(5-methyl-pyrazinyl-2-carboxamido)-ethyl]-benzene sulphonyl-N^cyclohexylurea commonly known as glipizide
APPLICANTS
USV Limited, BSD Marg (Govandi Station Road), Govandi, Mumbai - 400088, Maharashtra, India, an Indian company
INVENTORS
Under Section 28(2)
Dr Joshi Shreerang Vidyadhar, 6-Nandadeep, 18 Senapati Bapat Marg, Dadar, Mumbai - 400028, Maharashtra, India, Pawar Milind Parshuram, 501/D-4, Krishna Kaveri Co-op Housing Society, Off Link Road, Andheri, Mumbai 400053, Maharashtra, India and Nawathye Vikas Vasant, B/12, Pavitra Co-op Housing Society, Saptarshi Sankool, Ovari Dahisar, Mumbai - 400068, Maharashtra, India, all Indian nationals
The following specification particularly describes the nature of this
invention and the manner in which it is to be performed:

FIELD OF INVENTION
This invention relates to process for the preparation of anti¬diabetic drag N-{4-[2-(5-methyl-pyrazinyl-2-carboxamido)-etliyl]-benzene sulphonyl-N'-cyclohexylurea commonly known as glipizide.
Glipizide is an important drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM) and is of the formula 1:

Formula I PRIOR ART
us Patent No 3669966 describes preparation of glipizide by condensation of compound of the formula VI with cyclohexyl isocyanate in the presence of an organic solvent and alkali. Crude glipizide is purified by crystallisation from alcohol at reflux temperature. During crystallisation reflux temperature, compound of formula I reacts with alcohol and forms carbamate impurities. This reduces yield and purity of compound of formula 1.

British Patent No 1334471 describes preparation of glipizide by neat condensation of compound of the formula VI with alkali at high temperatures of 14O-160°C under ahydSJus conditions. During condensation at high temperature^ byproducts of compound of the formula I are formed. Therefore, yield and purity of the glipizide are reduced.

I

European Patent No 149592A2 describes preparation of glipizide by reacting compound of the formula VI with N-cyclohexyl uichloroacetamide in the presence of polar aprotic solvent and base under anhydrous conditions and reflux temperature. Purification of crude glipizide is carried out by crystallisation from alcohol at reflux temperature during which carbamate impurities are formed as described above.

In US Patent No 5516906 the compound of formula VI is purified by recrystallisation from dioxane prior to further reaction leading to compound of formula I. Being a volatile solvent presence of residual dioxane in the glipizide is undesirable. Besides, effluents containing dioxane require expensive treatment before being discharged into the environment.

OBJECTS OF INVENTION
An object of the invention is to provide a process for the preparation of glipizide of the formula I injuglryjeld and purity.
Another object of the invention is to provide a process for the v preparation of glipizide of the formula I which is simple and easy to carry out, efficient and economical.


Another object of the invention is to provide a process for the preparation of glipizide of the formula I which is commericaUy viable.

Another object of the invention is to provide a process for the l preparation of glipizide of the formula I which is ecofhendly.
DESCRIPTION OF INVENTION
According to the invention there is provided a process for the preparation of anti-diabetic drug N-{4-[2-(5-methyl-pyrazinyl-2-carboxamido)-ethyl]-benzenesulphonyl}-N'-cyclohexylurea commonly known as Glipizide of the formula 1:


c
H3CT N'
Fomiula I
which comprises
(i) purifying 5-methylpyrazme-2-(2-phenylethyl)carboxaniide of tlie fomiula II
N CONHCH2CH2methylpyrazine carboxamide (250 g; Purity 90%) was treated with sodium ethoxide (85.31 g) at 50 to 60°C for 2 hrs in the presence of N,N-dimethylaeetamide (5.69 L). N,N-Diniethyl acetamide was distilled out partly under reduced pressure and the reaction mass was cooled to room temperature. Clohexyl isocyanate (113.75 g) was added in the reaction mass. The residual solvent in the reaction was distilled out under reduced pressure. Water (5.69 L) was added in the reaction mass. The aqueous solution was filtered and the nitrate was extracted with ethyl acetate (2.84 L). The organic layer was discarded and the aqueous layer was neutralised with sulphuric acid till pH 3.5. Crude Glipizide was filtered and dried (284.3 g).
Glipizide crude (284.3g) was mixed with Isopropanol (2.843 lit) and cooled to 15-20°C. Triethylamine (71.25 g) was added in the above suspension till complete dissolution of Glipizide. The solution was charcoallized and filtered. The filtrate was acidified with acetic acid to pH 4.0 - 5.0 at 15 - 20°C. Glipizide precipitated out was separated by filtration and dried. Yield 250.7 & (67.05 %). PurilyJSo.

Example 2
5-Methylpyrazine-2-(2-phenylethyl)carboxamide (22% purity 90% approximate) was dissolved in 900 ml of methylene chloride. This solution was charged in chlorosulfonic acid (541.5g) at 5°C over a period of 2 hrs. The temperature of the reaction was raised to 30°C and maintained for 1 hr. The reaction mixture was then poured on crush ice and filtered to separate a cake of {N-[2-[4(cMorosidfonyi)phenyiJethyl]-5-niethylpyrazme carboxiamide). The above cake was treated with ammonia solution to obtain N-[2-[4-(Aminosiilfonyl)phenyl]ethyl]-5-meUiylpyrazine carboxamide which was dried at 90°C for 4 hours. N-[2-[4-(Aminosulfonyl)phenyl3efliyl]-5-methylprazine carboxamide was crystallized from 1:4 Dioxane (1200 ml) to obtain pure N-[2-[4-Aniinosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide . Yield 200g. Purity 85%.
N-[2-[4-(Anmosulfonyl)phenyl3ethyl3-5-methylpyrazine carboxamide (200g. Purity 90%) was suspended in acetone (2.2? Lit) and 2N NaOH (484 ml). Cyclohexyl isocyanate (114.6 ml) was added slowly maintaining a temperature of 0 to 5°C. The mixture was stirred for 3 hrs at 20-25°C, and diluted with water (4.5 lit). The undissolved solid was filtered and filtrate was acidified with hydrochloric acid till pH 3.5. Crude Glipizide was filtered and dried (167.0 g). Glipizide crude was crystallized from ethanol (6.0 lit). Glipizide pure was filtered and dried. Yield 122.7g {32.9%). Purity 97.5%.

We Claim:
1) Process for the preparation of anti-diabetic drug N-{4-[2-(5-methyl-pyrazinyl-2-carboxarnido)-ethyl3-benzenesulphonyl}-N'-cyclohexyliirea commonly known as Glipizide of the formula I;

winch comprises (i) purifying 5-methylpyrazine-2-(2-phenylethyl)carboxamide of
the fonmila II

Formula II by treating the confound of the formula II with charcoal in the presence of an acid and filtering out the insoluble impurities followed by extracting the filtrate with an organic solvent and neutralizing the filtrate with a base to pH 5-7 to precipitate purified compound of the formula II;
(ii) chlorosulphonating the purified compound of the formula II

with chlorosulfonic acid in the presence of an organic solvent at 5 to 40°C to obtain {N42-[4-(clUorosulfonyl)phenyl]ethyl]-5-methylpyrazine

(iii) amidating the compound of the formula IX with ammonia solution to obtain N-[2-[4-(aminosuifonyl)phenyl3ethyi]-5-methylpyrazine earboxamide of tJie formula VI:

Formula VI (iv) condensing the compound of the formula VI with cyclohexyl isocyanate in a polar solvent in the presence of a base to give crude N-{4-[2-(5-inethy4-pyrazinyl-2-carboxanudo)-ethyl]-beiizenesulphonyl}-N'-cyclohexylurea of the formula 1 and
(v) purifying the crude compound of the formula I by treating the crude compound of the formula I with charcoal in the presence of an aleohol and an organic base or ammonia at 0-25°C, and filtering out the insoluble impurities followed by acidification of the filtrate with an acid at pH 3 to 6.5 and 0 to 25°C to precipitate out the purified compound of the formula 1.

2) Process as claimed in claim 1, wherein treatment of compound of the formula II in step (i) is carried out in the presence of an organic acid.
3) Process as claimed in claim 2, wherein the treatment of compound of the formula II is carried out in the presence of acetic acid, oxalic acid or malomc acid.
4) Process as claimed in claim 3, wherein the treatment of compound of the formula II is carried out in the presence of 5 to 90% dilute aqueous solution of acetic acid, oxalic acid or malomc acid.
5) Process as claimed in claim 1, wherein the treatment of compound of the tbrmula II is carried out in the presence of an inorganic acid.
6) Process as claimed in claim 5, wherein the treatment of compound of the formula II is carried out in the presence of sulfuric acid, hydrochloric acid or nitric acid.
7) Process as claimed in 6, wherein the treatment of compound of the formula II is carried out in the presence of 5 to 90% dilute aqueous solution of sulfuric acid, hydrochloric acid or nitric acid.
8) Process as claimed in any one of claims 1 to 7, wherein the filtrate in step (i) is extracted with an organic solvent such as methylene chloride, toluene or ethylene chloride.

9) Process as claimed in claim 8, wherein the filtrate is extracted with 0.5 to 5 volumes of methylene chloride, toluene or ethylene chloride.
10) Process as claimed in any one of claims 1 to 9, wherein neutralization of the filtrate in step (i) is carried out with an inorganic base.
11) Process as claimed in claim 10, wherein neutralisation of the filtrate is carried out with potassium hydroxide, potassium carbonate, sodium hydroxide, sodium bicarbonate or ammonia.
12) Process as claimed in claim 11, wherein neutralisation of the filtrate is carried out with 0.5 to 60% dilute aqueous solution of potassium * hydroxide, potassium carbonate, sodium hydroxide, sodium bicarbonate or ammonia.
13) Process as claimed in anyone of claims 1 to 9, wherein neutralisation of the filtrate in step (i) is carried out with an organic base.
14) Process as claimed in claim 13, wherein neutralization of the filtrate is carried out with primary amine, secondary amine, tertiary amine, pyridine or pipendine.

15) Process as claimed in claim 14, wherein the neutralisation of the filtrate is carried out with 0.5 to 99% dilute aqueous solution of primary amine, secondary amine, tertiary amine, pyridine or piperidine
16) Process as claimed in claim 14, wherein neutralization of the filtrate is carried out with n-butyl amine, N,N'-dimethyl amine or triethyl amine.
17) Process as claimed in claim 16, wherein neutralisation of the filtrate is carried out with 0,5 to 99% dilute aqueous solution of n-butylamine, N,N'-dimethylamine or trimethyl amine.
18) Process as claimed in anyone of claims 1 to 17, wherein neutralisation of the filtrate with base is carried out at pH 6-7.
19) A process as claimed in anyone of claims 1 to 18, wherein the treatment of the crude compound of die formula I in step (v) is carried out in the presence of an alcohol such as ethanol, methanol, isopropanol or amyl alcohol.
20) Process as claimed in anyone of claims 1 to 19, wherein the treatment of the crude compound of the formula I in step (v) is carried out in the presence of an organic base such as primary amine, secondary amine, tertiary amine, cyclic amine, pyridine, piperidine or ammonia.
21) Process as claimed in any one of claims 1 to 20, wherein the treatment of the crude compound of the formula 1 is carried out at 15-20°C.

22) Process as claimed in anyone of claims 1 to 21 wherein acidification
of the filtrate in step (v) is carried out with an organic acid.
23) Process as claiined in claim 22, wherein acidification of the filtrate is
carried out with acetic acid or formic acid.
24) Process as claimed in any one of claims 1 to 21, wherein acidification of the filtrate in step (v) is carried out in with an inorganic acid.
25) Process as claimed in claim 24, wherein acidification of the filtrate is carried out with sulfuric acid or hydrochloric acid.
26) Process as claimed in anyone of claims 1 to 25, wherein acidification of the filtrate in step (v) is carried out at pH 4.0 - 5.0.
27) Process as claimed in anyone of claims 1 to 26, wherein acidification
of the filtrate in step (v) is carried out at 15 - 20^.
28) Process for the preparation of anti-diabetic drug N-{4-[2-(5-methyl-
pyrazmyl-2-carboxamido)-ethyl3-benzenesulphonyl}-N'-cyclohexylurea
commonly known as Glipizide of the formula I:

N. XONHCH2CH2