Process for the synthesis of olopatadine

Patent metadata

Field	Value
Publication number	US-9562030-B2
Application number	US-201414778311-A
Country	US
Kind code	B2
Filing date	Mar 19, 2014
Priority date	Mar 19, 2013
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention provides a process for the synthesis of olopatadine. Further, the invention discloses a process that results in improved yield of the desired Z isomer.

First claim

We claim:

1. An improved process for synthesis of olopatadine comprising the steps of:
a. treating Isoxepac (5), 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid with thionyl chloride in the ratio ranging between 2 to 4 in the presence of an alcohol at room temperature in the range of 15 to 30° C. for period in the range of 12 to 24 hours to yield the corresponding ester;

b. treating the ester of step (a) with allyl bromide using Zn in a solvent conducting Barbier reaction to obtain the allylic alcohol 4;

c. Hydroborating the allyl alcohol (4) as obtained in step (b) using 9-BBN (9-Borabicyclo(3.3.1)nonane)/diborane quenched by sodium hydroxide and hydrogen peroxide to obtain diol 6;

d. treating diol 6 as obtained in step (c) with catalytic p-toluenesulfonic acid to form a spiro tetrahydrofuran ring 3 in almost quantitative yield;

e. treating compound 3 as obtained in step (d) with AlCl 3 as Lewis acid in dichloromethane to yield olefin 2 and satisfactory E/Z ratio of 1 to 1.5;

f. subjecting compound 2 of step (e) to mesylation and dimethyl amination to result in compound 7

in the range of 55 to 60%;

g. treating compound 7 as obtained in step (f) with aqueous NaOH to yield the corresponding carboxylic acid, treating the acid with p-toluenesulfonic acid to yield the corresponding p-toluenesulfonate, crystallizing the p-toluenesulfonate to isolate the Z-isomer of the p-toluenesulfonate, treating the Z-isomer of the p-toluenesulfonate with NaHCO 3 to yield the free base 8

and treating free base 8 with aqueous HCl to give 1 with E:Z ratio of 1:1.5

2. The process according to claim 1 , wherein the alcohol used in step (a) is methanol.

3. The process according to claim 1 , wherein the solvent used in step (b) is dimethyl formamide (DMF).

Assignees

• Council Scient Ind Res

Inventors

• Chavan Subhash Prataprao
• Lasonkar Pradeep Bhaskarrao

Classifications

• C07D313/12 Primary

  [b,e]-condensed · CPC title