Process for the preparation of ethyl 3S-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentyn oate

US5536869A · kind A · utility

Assignee

• G.D. Searle LLC · US

Inventors

• Kevin A. Babiak · Evanston, US
• Srinivasan Babu · San Diego, US
• James R. Behling · Lindenhurst, US
• Mark Laurence Boys · Lyons, US
• Kimberly J. Cain-Janicki · Sleepy Hollow, US
• Wendel W. Doubleday · New Richmond, US
• Payman Farid · Deerfield, US
• Timothy J. Hagen · Gurnee, US
• E. Ann Hallinan · Evanston, US
• Donald W. Hansen, Jr. · Chicago, US
• Donald E. Korte · Mundelein, US
• Kathleen McLaughlin · Arlington Heights, US
• John R. Medich · Highland Park, US
• Sean T. Nugent · Grayslake, US
• Vlasdislav Orlovski · Buffalo Grove, US
• Jung Min Park · San Francisco, US
• Karen B. Peterson · Vernon Hills, US
• Daniel R. Pilipauskas · Glenview, US
• Barnett S. Pitzele · Skokie, US
• Sofya Tsymbalov · Skokie, US
• Glenn L. Stahl · Bradley, US

Key dates

• Filing date: Jul 14, 1995
• Grant date: Jul 16, 1996
• Expiry date: Jul 14, 2015

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07C257/18
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

Abstract

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-pentynoat…