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An Improved and commercially viable process for preparation of (4S,5R)-5- [3,5-bis(trifluoromethyl)phenyl] -3-{ [4'-fluoro-2'-methoxy-5'-(propan-2-yl)-4-(trifluorome-thyl) [1,1'-biphenyl] -2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one and its intermediates

IP.com Disclosure Number: IPCOM000250318D
Publication Date: 2017-Jun-28
Document File: 3 page(s) / 155K

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The IP.com Prior Art Database

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An Improved and commercially viable process for preparation of (4S,5R)-5- [3,5-

bis(trifluoromethyl)phenyl] -3-{ [4'-fluoro-2'-methoxy-5'-(propan-2-yl)-4-

(trifluorome-thyl) [1,1'-biphenyl] -2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one and

its intermediates.

Introduction

(4S,5R)-5- [3,5-bis(trifluoromethyl)phenyl] -3-{ [4'-fluoro-2'-methoxy-5'-(propan-

2-yl)-4-(trifluorome-thyl) [1,1'-biphenyl] -2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one is a

cholesteryl ester transfer protein (CETP) inhibitor, for the prevention of atherosclerosis,

and treatment of hypercholesterolemia.

Provided the process for synthesis of (4S,5R)-5- [3,5-bis(trifluoromethyl)-

phenyl] -3-{ [4'-fluoro-2'-methoxy-5'-(propan-2-yl)-4-(trifluoromethyl) [1,1'-biphenyl] -2-yl]

methyl}-4-methyl-1,3-oxazolidin-2-one and its intermediate.

(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid is reacted with 2-Chloro-

5-(trifluoromethyl)benzyl alcohol in presence of suitable palladium metal catalyst,

suitable base like sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium

acetate, potassium acetate, potassium carbonate, sodium carbonate, cesium

carbonate, potassium pivalate or sodium pivalate most preferable potassium carbonate

and suitable solvent like DME, 2-methyl THF, THF, DMF, Toluene, 1,4-Dioxane,

acetonitrile, dimethylacetamide, cyclopentyl methyl ether, acetone, isopropanol, ethanol,

butanol, ethyl acetate, isopropyl acetate, water and mixture thereof, most preferable

solvent for this condensation is toluene, water and mixture thereof at suitable

temperature varies from 10 to 80°C to obtain 4'-Fluoro-2'-methoxy-5'-isopropyl-4-

trifluoromethyl-1,1'-biphenyl-2-methanol. The palladium content was controlled by

suitable technique viz. hydrochloric acid wash or by activated charcoal or suitable resin

or palladium metal scavenger and passed through solka floks or celite bed.

The obtained 4'-Fluoro-2'-methoxy-5'-isopropyl-4-trifluoromethyl-1,1'-biphenyl-

2-methanol is halogenated using suitable halogenated reagent to obtain 2'-

(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1'-biphenyl or 2'-

(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1'-biphenyl or 2'-

(iodomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1'-biphenyl more

preferable 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1'-

biphenyl for further synthesis.

The 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)-1,1'-

biphenyl has been condensed with (4S,5R)-5-(3,5bis(trifluoromethyl)phenyl-4-

methyloxazolidin-2-one in suitable base like sodium hydroxide, potassium hydroxide,

cesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate,

potassium phosphate, dipotassium phosphate, barium hydroxide, DBU, potassium tert

butoxide, sodium hydride, sodium HMDS, LiHMDS, KHMDS, more preferably potassium

carbonate in suitable solvent like DMF, DMSO, DMA, DMAc, acetonitrile, acetone and

combination thereof at suita...