Synthesis of anti-Parkinson agent

Patent metadata

Field	Value
Publication number	US-9475757-B2
Application number	US-201414888697-A
Country	US
Kind code	B2
Filing date	May 2, 2014
Priority date	May 3, 2013
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

The present invention relates to an improved process for synthesis of anti-Parkinson compound of formula (I) from commercially available (R)-benzyl glycidyl ether, wherein the compound obtained has enantiopurity greater than >98%. Formula (I) wherein R 1 and R 2 are each independently selected from hydrogen or halogen.

First claim

We claim:

1. A process for preparation of an enantiomer of compound of formula I

wherein R 1 and R 2 are each independently selected from hydrogen or halogen, said process comprising;
a. regio selective reducing an epoxide (R)-compound 2 in presence of a reducing agent to obtain a secondary alcohol (R)-compound 3;

b. mesylating the secondary alcohol (R)-compound 3 of step (a) followed by reacting with NaN 3 to obtain an azido derivative (S)-compound 4;

c. hydrogenating/hydrogenolysis of the azido derivative (S)-compound 4 obtained in step (b) with Pd(OH) 2 catalyst followed by N-nosylation using nosyl chloride under basic conditions to obtain amino alcohol (S)-compound 5;

d. condensing amino alcohol (S)-compound 5 and alkyl iodide compound 9 in presence of a base and a solvent to obtain a coupled product (S)-compound 10;

wherein R 1 and R 2 are each independently selected from hydrogen or halogen;

wherein R 1 and R 2 are each independently selected from hydrogen or halogen;

e. oxidizing the coupled product (S)-compound 10 using TEMPO or bleach conditions to obtain an acid (S)-compound 11;

wherein R 1 and R 2 are each independently selected from hydrogen or halogen

f. reacting the acid (S)-compound 11 of step (e) with ethylchlorofomate in presence of Et 3 N and a solvent followed by reaction with aqueous NH 3 to obtain an amide (S)-compound 12; and

wherein R 1 and R 2 are each independently selected from hydrogen or halogen

g. treating said amide (S)-compound 12 with thiophenol in presence of a base and a solvent to obtain the enantiomer of compound of formula I.

2. The process according to claim 1 , wherein said process further comprises salification of compound of formula I with methane sulphonic acid to obtain a salt of compound of formula I.

3. The process according to claim 1 , wherein the reducing agent is a hydride reducing agent selected from the group consisting of LiAlH 4 , NaBH 4 , Zn(BH 4 ) 2 and borane.

4. The process according to claim 1 , wherein the base used in step (d) and step (g) is an organic base selected from the group consisting of ethylamine, diethylamine and pyridine; or an inorganic base selected from the group consisting of alkali or alkaline metal carbonates or bicarbonates.

5. The process according to claim 1 , wherein the solvent is used in step (d), step (f) and step (g) is a polar aprotic solvent selected from the group consisting of acetonitrile, THF, DCM, ethyl acetate and DMF.

6. The process according to claim 1 , wherein said alkyl iodide compound 9 used in step (d) is prepared by the process comprising;
a. iodinating compound 6 using triphenylphosphine and iodoimidazole generated in situ by iodine and imidazole to obtain a compound 7;

wherein R 1 and R 2 are each independently selected from hydrogen or halogen

wherein R 1 and R 2 are each independently selected from hydrogen or halogen;

b. reacting compound 7 with 4-(hydroxymethyl) phenol under basic condition to obtain an O-alkylated product 8; and

wherein R 1 and R 2 are each independently selected from hydrogen or halogen; Iodinating compound 8 to obtain the alkyl iodide compound 9,

wherein R1 and R2 are each independently selected from hydrogen or halogen.

7. The process according to claim 1 , wherein the compound of formula (I) is safinamide,

8. The process according to claim 1 , wherein the compound of formula (I) is ralfinamide,

9. The process according to claim 1 , wherein the compound obtained has an enantiopurity greater than 98%.

10. The process according to claim 1 , wherein the yield of the enantiomer of compound of formula I is in the range of 85% to 90%.

11. A enantiomer of compound of formula I prepared by the process according to claim 1 for use in treatment of Parkinson's disease.

Assignees

• Council Scient Ind Res

Inventors

• Muthukrishnan Murugan
• Mujahid Mohammad

Classifications

• C07C41/01

  Preparation of ethers · CPC title

• C07C41/18

  by reactions not forming ether-oxygen bonds · CPC title

• C07C231/02 Primary

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07C237/06

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07C17/16

  of hydroxyl groups · CPC title