Process for the preparation of pyrazinone thrombin inhibitor and its intermediates

1. In a process for the preparation of a compound of formula (I):

wherein 2,2-difluoro-2-(2-pyridyl)ethylamine or its salt is reacted with ethyl 3-chloropyrazin(1H)-2-one-1-acetate to form ethyl 3 -(2,2-difluoro-2-(2-pyridyl)ethylamino)-pyrazin(1H)-2-one- 1-acetate, which is chlorinated to form:

which is further reacted with 2-aminomethyl-3-fluoropyridine or its salt to form 3-fluoro-2-pyridylmethyl-3 -(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one- 1 -acetamide, the compound of formula (I), the improvement comprising:

reducing 2-cyano-3-fluoropyridine with Raney Nickel in the presence of an acid to form 2-aminomethyl-3-fluoropyridine or its salt;

reacting 2,2-difluoro-2-pyridin-2-ylethanol with 4-toluenesulfonyl chloride to form 2,2-difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate, which is converted to 2,2-difluoro-2-(2-pyridyl)ethylamine or its salt by reacting with ammonia; and

optionally purifying the compound of formula (I) by addition of an organic solvent.

2. The process of claim 1 , wherein the salt of 2-aminomethyl-3-fluoropyridine or 2,2-difluoro-2-(2-pyridyl)ethylamine — comprises one or more selected from the group consisting of a hydrochloride, hydrobromide and benzenesulphonate.

3. The process of claim 1 , wherein the acid used in reducing 2-cyano-3-fluoropyridine comprises acetic acid or trifluoroacetic acid.

4. The process of claim 1 , wherein the organic solvent is selected from the group consisting of a ketone, alcohol, ester, ether, hydrocarbon, halogenated solvent and a mixture thereof.

5. The process of claim 4 , wherein the ketone is acetone or butanone.

6. The process of claim 4 , wherein the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, t-butanol, hexanol and isoamyl alcohol.

7. The process of claim 4 , wherein the ester is selected from the group consisting of ethyl acetate, methyl acetate and isopropyl acetate.

8. The process of claim 4 , wherein the ether is diisopropyl ether or methyl t-butyl ether (MTBE).

9. The process of claim 4 , wherein the hydrocarbon is selected from the group consisting of hexane, heptane, cyclohexane, decalin and pentane.

10. The process of claim 4 , wherein the halogenated solvent is dichloromethane (MDC) or 1,2-dichloroethane.

11. The process of claim 4 , wherein the organic solvent is acetone, isopropyl alcohol or a mixture thereof.

12. The compound 2,2-difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate.

13. A process for the preparation of 2,2-difluoro-2-pyridin-2-ylethyl 4-methylbenzenesulfonate, comprising reacting 2,2-difluoro-2-pyridin-2-ylethanol with 4-toluenesulfonyl chloride.