G.d. Searle & Company

Viiv Healthcare UK Limited

Bristol-myers Squibb Holdings Ireland

Wendel W Doubleday

Donald W Hansen, Jr

Barnett S Pitzele

Timothy J Hagen

E Ann Hallinan

Sofya Tsymbalov

Karen B Peterson

Kevin A Babiak

Donald E Korte

John R Medich

Daniel R Pilipauskas

Payman N Farid

Pierre-Jean Colson

Richard John Fox

Percy Sarwood Manchand

Srinivasan Babu

James R Behling

Anthony J Cocuzza

Sean T Nugent

Kimberly J Cain-Janicki

Mark L Boys

Vlasdislav Orlovski

Chung-Pin H Chen

Jonathan Clive Tripp

Dayne Dustan Fanfair

Mitchell J Schultz

Kathia Levesque

Kathleen T McLaughlin

Denis Favreau

Carl M Knable

Eunhee Choi

Yvonne Lear

Markus Frieser

Glenn L Stahl

Jung M Park

Ravindra S Topgi

Chunyoung Kim

Kathleen T Mc Laughlin

Michel A Couturier

Hyungcheol Kim

Sangsoo Lee

Soonha Yang

Saravanababu Murugesan

Joseph Francis Payack

Joseph E Duran

Frank W Muellner

Shawn A Springfield

The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate and pharmaceutically acceptable acid addition salt thereof.

Process for the preparation of ethyl

The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate and pharmaceutically acceptable acid addition salt thereof which comprises treating (trimethylsilyl)acetylene sequentially with n-butyllithium and 4-formylmorpholine followed by acid hydrolysis to give 3-(trimethylsilyl)-2-propynal; treating 3-(trimethylsilyl)-2-propynal with lithium bis(trimethylsilyl)amide to give in situ N,3-bis(trimethylsilyl)-2-propyn-1-imine; condensation of N,3-bis(trimethylsilyl)-2-propyn-1-imine with lithium t-butyl acetate to give (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; treating (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate- with p-toluenesulfonic acid to give (.+-.)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt, treatment of resulting salt with ethanol in the presence of p-toluenesulfonic acid to give (.+-.)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; desilylation of (.+-.)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate to give in situ (.+-.)ethyl 3-amino-4-pentynoate; resolution of (.+-.)ethyl 3-amino-4-pentynoate using (R)-(-)-mandelic acid and treatment of the resolved product with gaseous hydrochloric acid to give ethyl 3S-amino-4-pentynoate, monohydrochloride; coupling the ethyl 3S-amino-4-pentynoate, monohydrochloride to 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, monohydrochloride in the presence of isobutyl chloroformate and N-methylmorpholine to give ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyno ate, monohydrochloride.

Growing community of inventors

Twin Lakes, WI, United States of America

Wendel W Doubleday