Bristol-myers Squibb Compnay

Britsol-myers Squibb Company

Robert P Discordia

John J Venit

Chiajen Lai

Victor W Rosso

Jingyang Zhu

David Kenneth Leahy

Lori Ann Spangler

Gary D Madding

Jason G Chen

Jaan A Pesti

Francis S Gibson

Michael E Randazzo

Gerard Crispino

John E Thornton

Atul S Kotnis

Paul C Lobben

Gerard A Crispino

D David Hennings

Zhongmin Xu

Francis J Okuniewicz

Mourad Hamedi

Susanne Kiau

Thomas L LaPorte

Jale Muslehiddinoglu

Thomas L Laporte

David K Leahy

The invention relates to an improved process for preparing [(1R), 2S]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester of the formula:  Compound I has been shown to be useful for the treatment of certain types of cancer.

Process for the preparation of [(1R), 2S]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2, 1-F][1,2,4]triazin-6-yloxy]-1-methylethyl ester

Provided is a dynamic resolution method of enriching a desired isomer of an alpha-substituted carboxylic acid relative to an undesired isomer, the method comprising: (a) in a solvent, contacting the alpha-substituted carboxylic acid, wherein the alpha substitution is with a leaving group and wherein the alpha carbon is chiral, with a homochiral amine to form a salt that is partially insoluble under selected reaction conditions, wherein the homochiral amine is selected so that the solubility of the amine salt of the undesired alpha-substituted carboxylic acid is greater than that of the amine salt of the desired alpha-substituted carboxylic acid under the selected reaction conditions; (b) reacting under the selected reaction conditions the salt with a nucleophile, wherein the reacting is effective in producing a net increase in the less soluble amine salt of the alpha-substituted carboxylic acid, and wherein the selected conditions are selected to (i) promote nucleophilic substitution of the nucleophile and the leaving group or (ii) to produce the increase in the less soluble amine salt in the absence of a strong base; and (c) maintaining the reaction for a period of time effective to increase the amount of the desired alpha-substituted carboxylic acid isomer.

Dynamic resolution of isomers and resolved isomers

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Pennington, NJ, United States of America

Robert P Discordia