"A PROCESS FOR THE PREPARATION OF INTERMEDIATE USEFUL FOR THE PREPARATION OF GLIPIZIDE"
FIELD OF INVENTION
The present invention relates to the single pot process to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyI]pyrazine-2-carboxamide, to the process to prepare Glipizide and to the process to prepare pure Glipizide.
BACKGROUND OF THE INVENTION
Glipizide 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. Glipizide, CAS registry
number [29094-61-9], chemically known as N-[2-[4-
(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-5-methyl-pyrazine-2-carboxamide.
Preparation of Glipizide was first disclosed in US3669966 (assigned to Carlo Erba S.p.A) patent. This patent discloses different synthetic routes for preparation of Glipizide as shown in scheme I.

Scheme I
The preparation of the 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide from 5-methyl-pyrazine-2-carboxylic acid is known in the prior art.
The Starting material 5-methyl-N-[2-(4-sulfamoylphenyl)ethyI]pyrazine-2-carboxamide (sulfonamide, R= -NH2) in '966 is prepared either by

a) Refluxing 5-methyl-pyrazine-2-carboxylic acid with SOCl2 in benzene followed by
reacting acid chloride formed with 4-(2-Aminoethyl)-benzenesulphonamide
OR
b) Reacting 5-methyl-pyrazine-2-carboxylic acid with 4-(2-Aminoethyl)-
benzenesulphonamide in the presence of ethyl chloroformate and triethylamine.
5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide obtained by process taught by US '966 gives lower yield, less than 36%W/W. Further process includes use of single solvent Acetone. The patent teaches a process in which the yield of Glipizide is lowered to less than 20%W/W. Also ethyl chloroformate used is toxic and creates pollution problem.
The Indian Patent INI77976 (USV Ltd) teaches a process to prepare the 5-methyl-N-[2-(4-sulfamoylphenyI)ethyl]pyrazine-2-carboxamide starting from the ester of 5-methylpyrazine-2-carboxylic acid as shown in Scheme II. This ester is treated with 2-phenylethylamine to form the amide. To this amide sulfonyl group is added by chlorosulfonation. Treatment of this compound with ammonia gives the required Sulfonamide. Sulphonamide is obtained in less than 66% yield. The drawback of this invention is large number of steps & lower yield.

A Japanese patent JP3028168B (SUMIKA FINE KEMU) prepared 5-methyl-N-[2-(4-sulfamoyIphenyl)ethyl]pyrazine-2-carboxamide by reacting 5-methylpyrazine-2-carboxylic acid with 4-(2-Aminoethyl)-benzenesulphonamide and ethyl chloroformate in an organic solvent and tert-amine. The yield obtained with this process is good around 90%, however the process is tedious & uses ethyl chloroformate which is toxic and creates pollution problem.

Above mentioned prior arts are silent on the purity of Intermediate 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide & also on the purity of Glipizide.
Indian patent application 3265/MUM/2011 (Ipca Laboratories) disclosed preparation of 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide by reacting ester of 5-methylpyrazine-2-carboxylic acid with 4-(2-Aminoethyl)-benzenesulphonamide in aromatic hydrocarbons (example: xylene) with 74% yield & > 97% HPLC purity. The process required further purification of 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide which resulted in lower yield. Further the ester of 5-methylpyrazine-2-carboxylic acid is prepared separately using Methanol and Sulphuric acid which causes increase in steps of reaction and overall yield of the final product suffers.
Drawbacks and disadvantages such as lower yields, use of toxic and polluting reactants, large number of steps rendering the processes tedious, problem of purity of intermediates and that of Glipizide associated with the processes disclosed in the prior art create an urgent and a strong need for the better process to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide and the process to prepare Glipizide.
Therefore industry needs a simpler process to prepare 4-[2-(5-methylpyrazine-2-carboxamido)ethyl] benzenesulfonamide, useful for the preparation of Glipizide, which is industry friendly, utilizes commercially available materials, employs favorable reaction conditions, avoids use of toxic substances and produces Glipizide of improved purity and better yield with consistent quality.

OBJECT OF THE INVENTION
The object of the present invention is to provide a single pot process to prepare 5-methyl-N-[2-(4-
sulfamoyIphenyl)ethyl]pyrazine-2-carboxamide useful for the preparation of Glipizide.
Another object of the invention is to provide a single pot process to prepare 5-methyl-N-[2-(4-
sulfamoylphenyl)ethyl]pyrazine-2-carboxamide with improved yields.
Yet another object of the invention is to provide the process to prepare Glipizide with improved
yields.
Yet another object of the invention is to provide the process to prepare pure Glipizide.
SUMMARY OF THE INVENTION
The present invention relates to the single pot process to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide, to the process to prepare Glipizide and to the process to prepare pure Glipizide.
It was unexpectedly and surprisingly found that 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide can be prepared in good yield and purity in a single step reaction by reacting 5-methylpyrazine-2-cart>oxylic acid in alcohol with SOCh followed by addition of 4-(2-Aminoethyl)-benzene sulfonamide. Present invention describes this single step reaction process to directly obtain 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide in good yield and to prepare pure Glipizide.
Accordingly, the primary aspect of the present invention is to provide process for preparation of 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV comprising
a) Reacting 5-methylpyrazine-2-carboxylic acid of formula I in alcohol with SOCl2 followed by addition of 4-(2-Aminoethyl)-benzene sulfonamide of formula III to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxaniide of formula IV


Another aspect of the present invention is to provide process for preparation of Glipizide of formula (V), comprising:
a) Reacting 5-methylpyrazine-2-carboxylic acid of formula I in alcohol with SOCI2 followed by addition of 4-(2-Aminoethyl)-benzene sulfonamide of formula III to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV

b) Reacting 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV produced in a) above with cyclohexyl isocyanate in presence of base & mixture of organic solvents to give Glipizide of formula V.

It was surprisingly found that use of mixture of solvents improves the yield of Glipizide.
Another aspect of the present invention is to provide improved process to prepare pure Glipizide
by crystallizing Glipizide in mixture of solvents.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to the single pot process to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide, to the process to prepare Glipizide and to the process to prepare pure Glipizide.
Improved yield of 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide is to be construed as a yield illustrated by examples described in this application. Pure Glipizide as described in this application is to be construed as Glipizide having at least 99.7% purity.

The process disclosed in the present application produces Glipizide yields in the range of 75% to 85% from 5-methylpyrazine-2-carboxylic acid in contrast to lower yield reported in prior art. Inventive step of the present invention is embedded in these higher yields. Inventive step of the invention also resides in the fact that the process disclosed in the present application is a single pot process and hence a simpler process.
Thus, according to the primary aspect, the present invention provides single pot process for preparation of 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV comprising
Step I:
a) Addition of 5-methylpyrazine-2-carboxylic acid of formula I to C1-C4 alcohol to produce reaction mixture,
b) Adding SOCb in catalytic amounts of 0.05 to 0.5 moles, preferably 0.1 moles to the
reaction mixture formed in Step I a) at temperature of 25-40°C, more preferably at 30-35°C and refluxing at 60-80°C, more preferably at 65-75°C to produce ester of the formula II in situ in the refluxed mass,
c) Adding 4-(2-Aminoethyl)-benzene sulfonamide of formula III to refluxed mass and
further refluxing the resulting mixture at 60-80°C, more preferably at 65-75°C to
prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula
IV

Wherein R is Cl-C4alkyl. C1-C4 alcohol is selected from methanol, ethanol, propanol, isopropanol, and butanol. However, more preferred alcohol is methanol or ethanol.
In the single pot reaction disclosed by the present invention, the ester of formula II of 5-methylpyrazine-2-carboxylic acid formed in Step I b) need not be separated and reaction mass can


be subjected to further steps of reaction with 4-(2-Aminoethyl)-benzene sulfonamide of formula III to form carboxamide compound of formula IV.
Wherein R is Cl-C4alkyl
Optionally, the ester of formula II formed in Step I b) from 5-methylpyrazine-2-carboxylic acid during the reaction can be isolated and used directly for further reaction. The ester intermediate of the formula II can be optionally isolated according to routine methods known to the person skilled in the art, for example by removing the solvent and washing the residue.
The ester of formula II in organic solvent is reacted with 4-(2-Aminoethyl)-benzene sulfonamide of formula III to form carboxamide compound of formula IV.
Organic solvent is selected from C1-C4 alcohol selected from methanol, ethanol, propanol, isopropanol, and butanol. However, more preferred alcohol is methanol or ethanol. The reaction mixture after the addition of sulfonamide of formula III is refluxed at 60-80°C, more preferably at 65-75°C. The reaction mixture is then cooled to ambient temperature; the product formed is separated by filtration & dried.
According to another aspect, the present invention provides a process for the preparation of Glipizide of formula V comprising: Step I:
a) Addition of 5-methylpyrazine-2-carboxylic acid of formula I to C1-C4 alcohol to produce reaction mixture,
b) Adding SOCI2 in catalytic amounts of 0.05 to 0.5 moles, preferably 0.1 moles to the
reaction mixture formed in Step a) at temperature of 25-40°C, more preferably at 30-35°C and refluxing at 60-80°C, more preferably at 65-75°C to produce ester of the formula II in situ in the refluxed mass,
c) Adding 4-(2-Aminoethyl)-benzene sulfonamide of the formula III to refluxed mass and
further refluxing the resulting mixture at 60-80°C, more preferably at 65-75°C to prepare 5-methyl-N-[2-(4-suIfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV


Step II:
a) Reacting 5-methyI-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV formed in Step I c) with cyclohexyl isocyanate in presence of base & mixture of organic solvents to prepare Glipizide of formula V

The mixture of organic solvents for Step II is selected from mixtures of ketones and aromatic hydrocarbons. Examples of solvents include, but not limited to, acetone, methyl ethyl ketone, benzene, toluene, xylene, ethyl benzene etc., more preferably acetone and toluene. The base is selected from an organic or inorganic class of compounds. The preferred inorganic bases are selected from alkali metal hydroxides or carbonates or bicarbonates selected from NaOH, KOH, LiOH, Na2C03, K2C03, Li2C03, NaHC03, KHC03r LiHC03; or alkaline earth metal hydroxides or carbonates or bicarbonates selected from Be(OH)2, Mg(OH)2, Ca(OH)2, BaC03, MgC03, CaC03, Mg(HC03)2, Ca(HC03)2 or mixtures thereof. The most preferred base is K2C03.
The reaction mixture is then refluxed at 50-75°C, preferably at 55-70°C, more preferably at 60-65°C. The reaction mixture is then cooled to ambient temperature and filtered to obtain solid mass which is dissolved in water, filtered to remove any undissolved particles & acidified with dil. HC1 followed by filtration to get crude Glipizide.
According to another aspect, there is provided a process to prepare pure glipizide by crystallizing glipizide in mixture of solvents.

Prior art describes purification of Glipizide using alcohol. It was surprisingly found that using mixture of solvents for purification provides Glipizide having at least 99.7% purity. Process comprises dissolving crude Glipizide in mixture of solvents selected form alcoholic and halogenated solvent; refluxing the reaction mixture at 50-75°C, preferably at 55-70°C, more preferably at 60-65°C and then removing the solvent to obtain Glipizide in pure form. Examples of suitable alcoholic solvents include, for example, methanol (MeOH), ethanol, n-propanol, i-propanol, n-butanol, i-butanol or mixtures thereof. Examples of suitable halogenated solvents include methylene dichloride (MDC), ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof. More preferably mixture of MeOH and MDC is used.
The complete process according to the present invention is shown below:

Wherein R is C1-C4 alkyl
The described embodiments of the invention and the disclosed examples are given for the purpose
of illustration only, and are not intended to limit the scope of the invention or appended claims.

WORKING EXAMPLES:
EXAMPLE 1: Preparation of 5-methyl-N-[2-(4-sulfamoyIphenyI)ethyl]pyrazine-2-carboxamide (IV)
lOOgm of 5-methyl-2-carboxylic acid (I) was added to 600ml methanol in a reaction flask. To this, was added 9ml thionyl chloride drop wise at 30-35°C, reaction mixture was then refluxed for 4 hours at 65-70°C. The reaction mixture cooled to 35-40°C, to this, was added 220gm of 4-(2-Aminoethyl)-benzene sulfonamide. The reaction mixture was refluxed for 24 hours. The reaction mixture cooled to 25-30°C, filtered, washed with methanol and dried to give 207gm of 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide (IV) with 89% yield, 190-200°C melting point, 98% purity (HPLC).
EXAMPLE 2: Preparation of Glipizide (V)
lOOgm of 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide (IV) was added to 1000ml acetone in reaction flask. To this, was added 77gm of K2CO3 and the reaction mixture refluxed for 30min at 55-60°C. 78gm of Cyclohexyl isocyanate in 200ml toluene was added to this reaction mixture and reaction mixture further refluxed at 60-65°C for 24 hrs. Reaction mixture cooled to 25-30°C and solid obtained was filtered, washed with 100ml acetone. Wet solid obtained was dissolved in 1500ml water and filtered to remove undissolved solids, filtrate acidified with dil. HC1 at 0-5°C, stirred at 0-5°C for 30min, filtered, washed with water and dried to give crude glipizide 135gm, 97% yield.
EXAMPLE 3; Purification of Glipizide (V)
120gm of crude glipizide added to 840ml methanol followed by 1080ml methylene dichloride. The reaction mixture refluxed at 40-45°C. 5gm of carbon wad added to this reaction mixture and reaction mixture was filtered over hyflo, hyflo bed washed with 120ml methanol and 120ml methylene dichloride. Methylene dichloride from the reaction mixture was then distilled. Reaction mixture cooled at 10-15°C, filtered and washed with methanol to give pure Glipizide 108gm, 90% yield, 200-203°C melting point, 99.7% HPLC purity.

CLAIMS:
We claim,
1) A single pot process to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV comprising Step I:
a) Addition of 5-methylpyrazine-2-carboxylic acid of formula I to C1-C4 alcohol to produce reaction mixture,
b) Adding SOCI2 in catalytic amounts of 0.05 to 0.5 moles, preferably 0.1 moles to the
reaction mixture formed in Step a) at temperature of 25-40°C, more preferably at 30-35°C and refluxing at 60-80°C, more preferably at 65-75°C to produce ester of the formula II in situ in the refluxed mass,
c) Adding 4-(2-Aminoethyl)-benzene sulfonamide of the formula III to refluxed mass and
further refluxing the resulting mixture at 60-80°C, more preferably at 65-75°C to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV

2) The process as claimed in claim 1 a), wherein C1-C4 alcohol is selected from the group consisting of methanol, ethanol, propanol, iso-propyl alcohol, butanol, preferably methanol.
3) The process as claimed in claim 1, comprising an optional separation of ester compound of the formula (II) formed in Step I b) in situ and its treatment with 4-(2-Aminoethyl)-benzene sulfonamide to produce compound of formula IV.
4) A process to prepare Glipizide of formula V comprising
Step I: a) Addition of 5-methylpyrazine-2-carboxylic acid of formula I to C1-C4 alcohol to produce reaction mixture,

b) Adding SOCI2 in catalytic amounts of .0.05 to 0.5 moles, preferably 0.1 moles to the
reaction mixture formed in a) at temperature of 25-40°C, more preferably at 30-35°C and refluxing at 60-80°C, more preferably at 65-75°C to produce ester of the formula II in situ in the refluxed mass,
c) Adding 4-(2-Aminoethyl)-benzene sulfonamide of the formula III to refluxed mass and
further refluxing the resulting mixture at 60-80°C, more preferably at 65-75°C to prepare 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV

Step II:
a) Reacting 5-methyl-N-[2-(4-sulfamoylphenyl)ethyl]pyrazine-2-carboxamide of formula IV formed in Step I c) with cyclohexyl isocyanate in presence of base & mixture of organic solvents to prepare Glipizide of formula V

5) The process as claimed in claim 4 Step I a), wherein C1-C4 alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol, preferably methanol.
6) The process as claimed in claim 4 comprising an optional separation of ester that is formed in Step I b) in situ and its treatment with 4-(2-Aminoethyl)-benzene sulfonamide to produce compound of formula IV.
7) The process as claimed in claim 4 Step II a), wherein mixture of organic solvents is selected from mixtures of ketones and aromatic hydrocarbons.

8) The process as claimed in claim 7, wherein said mixture of organic solvents is selected form mixtures of acetone methyl ethyl ketone, benzene, toluene, xylene, ethyl benzene, more preferably acetone and toluene.
9) The process as claimed m claim 4 Step II a), wherein base is selected form the group consisting of organic and inorganic bases or mixture thereof.
10) The process as claimed in claim 9, wherein the "inorganic "base is selected irom the group comprising alkali metal hydroxides or carbonates or bicarbonates, or alkaline earth metal hydroxides or carbonate or bicarbonates or mixtures thereof.
11) The process as claimed in claim 10, wherein alkali metal hydroxides or carbonates or bicarbonates is selected from NaOH, KOH, LiOH, Na2C03, K2C03, Li2C03, NaHCOs, KHCO3, LiHC03 ; or alkaline earth metal hydroxides or carbonate or bicarbonates selected from Be(OH)2, Mg(OH)2, Ca(OH)2, BaC03, MgC03, CaC03, Mg(HC03)2, Ca(HC03)2 or mixtures thereof, more preferably K2C03.
12) A process to prepare pure Glipizide comprising crystallizing glipizide in mixture of solvents
selected from alcoholic and halogenated solvent wherein the alcoholic solvents include
methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol or mixtures thereof and
halogenated solvers include methylene dichloride, ethylene dichloride, chloroform, carbon
tetrachloride or mixtures thereof.