Process for the preparation of N-[2-[4-(aminosulfonyl) phenyl]ethyl]5-methylpyrazinecarboxamide

A process for the preparation of N-[2-[4-(amino-sulfonyl)phenyl]ethyl]-5-methylpyrazinecarboxamide is described which is simple and effective.

BACKGROUND OF THE INVENTION 
This invention relates to a process for the preparation of 
N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the 
formula I: 
##STR1## 
N-[2-[4-aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the 
formula I is immediate or penultimate intermediate for the preparation of 
N-[4-(2-(5-methyl-pyrazine-2-carboxamide)-ethyl]benzene-sulphonyl]-N'cyclo 
hexyl)-urea which is an oral antidiabetic agent. The compound of the 
formula I is known to be prepared by: 
(a) acetylating 2-phenylethylamine of the formula II: 
##STR2## 
with acetic anhydride to protect the amino group and obtain N-acetyl 
(2-phenyl)ethylamine of the formula III: 
##STR3## 
(b) chlorosulfonating the compound of the formula III with chlorosulfonic 
acid to obtain 4-(N-acetylamino) ethyl benzenesulfonyl chloride of the 
formula IV: 
##STR4## 
(c) treating the compound of the formula IV with ammonia to obtain 
4-(2-acetylaminoethyl)benzene sulfonamide of the formula V: 
##STR5## 
(d) hydrolysing the compound of the formula V by treating with sodium 
hydroxide to deprotect the amino group and obtain 4-(2-aminoethyl)benzene 
sulfonamide of the formula VI: 
##STR6## 
(e) treating the compound of the formula VI with hydrochloric acid to 
obtain 4-(2-aminoethyl)benzenesulfonamide hydrochloride of the formula 
VII: 
##STR7## 
(f) purifying the compound of the formula VII by crystallization from 
methanol. 
(g) reprecipitating the 4-(2-aminoethyl) benzene sulfonamide of the formula 
VI by treating the 4-(2-aminoethyl) benzene sulfonamide hydrochloride of 
the formula VII with sodium hydroxide; and 
(h) reacting the 4-(2-aminoethyl) benzenesulfonamide of the formula VI with 
5-methylpyrazine-2-carboxylic acid of the formula VIII: 
##STR8## 
in the presence of ethyl chloroformate and triethylamine to obtain the 
N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5methylpyrazinecarboxamide of the 
formula I. 
Due to protection and deprotection of the amino group in the 
2-phenylethylamine the process involves a large number of steps and is 
lengthy and difficult to carry out. Yield of the process is low (of the 
order of 27%) because of the large number of steps. Ethyl chloroformate is 
toxic and creates pollution problem. 5-Methylpyrazine-2-carboxylic acid is 
difficult to be purified and pure acid is expensive. 
The object of the invention is to provide a simple, easy, environment 
friendly and cheap process for the preparation of 
N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the 
formula I. 
SUMMARY OF THE INVENTION 
The present invention provides a process for the preparation of 
N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of the 
formular I: 
##STR9## 
The process eleminates separate protection and deprotection of amino group 
in the 2-phenyl-ethylamine and is accomplished in a few simple and easy 
steps. 
The process consists of: 
i) treating 5-methylpyrazine-2-carboxylic acid of the formula VIII: 
##STR10## 
with methanol under reflux to obtain 5-methylpyrazine-2-carboxylic acid 
methyl ester of the formula VIII A 
##STR11## 
ii) reacting 5-methylpyrazine-2-carboxylic acid methyl ester of the 
formula VIII A with 2-phenylethylamine of the formula II: 
##STR12## 
at 100.degree. to 200.degree. C. to obtain 5-methylpyrazine 
2-(2-phenylethyl) carboxamide of the formula IX: 
##STR13## 
iii) chlorosulfonating the 5-methylpyrazine-2(2-phenylethyl)carboxamide of 
the formula IX with chlorosulfonic acid at 0.degree.-45.degree. C. to 
obtain [N-[2-[4-Chlorosulfonyl) phenyl]ethyl]-5-methylpyrazine 
carboxamide] of the formula X: 
##STR14## 
iv) and treating the (N-[2-[4-(chlorosulfonyl)phenyl]ethyl]-5-methyl 
pyrazine-carboxamide] of the formula X with ammonia to obtain 
N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the 
formula I. 
DETAILED DESCRIPTION OF THE INVENTION 
According to the invention there is provided a process for the preparation 
of N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine-carboxamide of 
the formula I: 
##STR15## 
consisting of: i) treating 5-methylpyrazine-2-carboxylic acid of the 
formula VIII: 
##STR16## 
with methanol under reflux to obtain 5-methylpyrazine-2-carboxylic acid 
methyl ester of the formula VIII A 
##STR17## 
ii) reacting 5-methylpyrazine-2-carboxylic acid methyl ester of the 
formula VIII A with 2-phenylethylamine of the formula II: 
##STR18## 
at 100.degree. to 200.degree. C. to obtain 5-methylpyrazine 
2-(2-phenylethyl) carboxamide of the formula IX: 
##STR19## 
iii) chlorosulfonating the 5-methylpyrazine-2(2-phenylethyl)carboxamide of 
the formula IX with chlorosulfonic acid at 0.degree.-45.degree. C. to 
obtain [N-[2-[4-Chlorosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide] 
of the formula X: 
##STR20## 
iv) and treating the (N-[2-[4-(chlorosulfonyl)phenyl]ethyl]-5-methyl 
pyrazine-carboxamide] of the formula X with ammonia to obtain 
N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazine carboxamide of the 
formula I. 
According to an embodiment of the invention crude 
5-methylpyrazine-2-carboxylic acid is treated with methanol in step i. 
Preferably the reaction of compounds of the formulae VIIIA and II is 
carried out at 120.degree.-150.degree. C. 
Preferably the compound of the formula IX is chlorosulfonated with 
chlorosulfonic acid at 5.degree.-30.degree. C. 
The process of the invention eliminates separate protection and 
deprotection of amino group in the 2-phenylethylamine and reduces the 
number of steps of the process. It is, therefore, simple and easy to carry 
out. Yield of the process is also increased because of the reduction in 
the number of steps of the process. The process of the invention is 
environment friendly because of the elimination of ethyl chloroformate. In 
the process of the invention crude 5-methylpyrazine-2-carboxylic acid also 
may be used and it is, therefore, cheap. 
The following examples are illustrative of the invention but not limitative 
of the scope thereof:

EXAMPLE I 
5-Methylpyrazine-2-carboxylic acid crude (167 gm) was mixed with methanol 
(2 liters) containing con. H.sub.2 SO.sub.4 (2 ml) and refluxed for 2 
hours. Methanol was distilled out. The residue was extracted with water 
(1.5 liters) and filtered. The aqueous layer was extracted three times 
with 500 ml toluene each time and toluene was evaporated. The residue 
containing 5-methylpyrazine-2-carboxylic acid methylester (152 g) was 
heated at 145.degree. C. under stirring with 2-phenylethyl amine (121 g) 
for 4 hours. Methanol was distilled out. The residue was dissolved in 800 
ml of toluene by heating at 80.degree. C. The solution was charcoaled and 
filtered. On cooling the solution to 5.degree. C. 5-methylpyrazine 
(2-phenylethyl) carboxamide (225 g) was obtained and was dissolved in 900 
ml of methylene chloride and added to 541.5 g of chlorosulfonic acid at 5 
.degree. C. over a period of 2 hours. The temperature of the reaction was 
raised to 30.degree. C. and held for 1 more hour. The reaction mixture was 
poured onto 2 kg of ice under stirring, filtered and washed with 100 ml of 
chilled water. The filter cake containing 
N-2-[4-chlorosulfonyl)phenyl]ethyl-5-methylpyrazine carboxamide was 
stirred with 136 g of ammonia liquor and 500 ml of water, filtered, washed 
free of ammonia with water and dried at 90.degree. C. for 4 hours to 
obtain N-[2-[4-aminosulfonyl)phenyl]ethyl]5-methylpyrazine carboxamide. It 
was recrystallized from 4 times the quantity of dioxane to obtain pure 
N-[2-[4-(aminosulfonyl)phenyl]ethyl]-5-methylpyrazinecarboxamide. Yield 
200 g, 66%. MP 190.degree.-200.degree. C. 
EXAMPLE 2 
5-Methylpyrazine-2-carboxylic acid (140 gm) was mixed with methanol (1.55 
liters) containing cone. H.sub.2 SO.sub.4 (2 ml) and refluxed for 3 hours. 
Methanol was distilled out. The residue was extracted with water (1.5 
liters) and filtered. The aqueous layer was extracted three times with 500 
ml toluene each time and toluene was evaporated. The residue containing 
5-methylpyrazine-2-carboxylic acid methyl ester (76 g) was heated at 
130.degree. C. under stirring with 2-phenylethylamine (60.5 g) for 8 
hours. Methanol was distilled out. The residue was dissolved in 300 ml 
isopropanol by heating at 70.degree. C. The solution was charcoaled and 
filtered. On cooling the solution to 0.degree. C. for 4 hours, 
5-methylpyrazine (2-phenylethyl) carboxamide (105 g) was obtained of which 
64.5 g was dissolved in 258 ml methylene chloride and added to 145.6 g of 
chlorosulfonic acid at 0.degree. C. over a period of 1 hour. The 
temperature of the reaction was raised to 40.degree. C. and held for 1 
more hour. The reaction mixture was poured onto 0.5 kg of ice under 
stirring, filtered and washed with 100 ml chilled water. The filter cake 
containing N-[2-[4-chlorosulfonylphenyl]ethyl]-5-methylpyrazine 
carboxamide was stirred with 45 gm ammonia liquor and 200 ml water, 
filtered, washed free of ammonia with water and dried at 90.degree. C. for 
4 hours to obtain N-[2-[4-aminosulfonyl)phenyl]ethyl]5-methylpyrazine 
carboxamide. It was recrystallized from 4 times the quantity of dioxane 
to obtain pure N-[2-[4-[aminosulfonylphenyl]ethyl]-5-methylpyrazine 
carboxamide. Yield 95 gms, 56%, MP 190.degree.-200.degree. C.