Patent ID: 9562030
Date: 2017-02-07
CPC Classifications: C07D

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 f. subjecting compound 2 of step (e) to mesylation and dimethyl amination to result in compound 7 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 and treating free base 8 with aqueous HCl to give 1 with E:Z ratio of 1:1.5