# US 8,541,580 B2 · Process for the preparation of pyrazinone thrombin inhibitor and its intermediates

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- Number: US 8,541,580 B2
- Document ID: US8541580B2
- Status: Granted
- Kind: B2
- Application number: 12/938,297
- Filed: 2010-11-02
- Published: 2011-05-05
- Granted: 2013-09-24
- Earliest claimed: 2009-11-03
- Assignees: Diakron Pharmaceuticals, Inc.
- Applicants: Reguri Buchi Reddy; Upparapalli Sampathkumar; Nilam Sahu; Jawaji Karunakara Rao; Gade Brahma Reddy
- Inventors: Reguri Buchi Reddy; Upparapalli Sampathkumar; Nilam Sahu; Jawaji Karunakara Rao; Gade Brahma Reddy
- Web page: https://patentgrep.com/patent/US8541580B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Improved process for the preparation of 3-fluoro-2-pyridylmethyl-3-(2,2-difluoro-2-(2-pyridyl)ethylamino)-6-chloropyrazin-2-one-1-acetamide of formula (I) and its intermediates is provided.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 4)

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

### Claim 6 (depends on 4)

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.

### Claim 7 (depends on 4)

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

### Claim 8 (depends on 4)

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

### Claim 9 (depends on 4)

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

### Claim 10 (depends on 4)

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

### Claim 11 (depends on 4)

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

### Claim 12

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

### Claim 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.