The patent badge is an abbreviated version of the USPTO patent document. The patent badge does contain a link to the full patent document.
The patent badge is an abbreviated version of the USPTO patent document. The patent badge covers the following: Patent number, Date patent was issued, Date patent was filed, Title of the patent, Applicant, Inventor, Assignee, Attorney firm, Primary examiner, Assistant examiner, CPCs, and Abstract. The patent badge does contain a link to the full patent document (in Adobe Acrobat format, aka pdf). To download or print any patent click here.
Patent No.:
Date of Patent:
Jul. 16, 1996
Filed:
Jul. 14, 1995
Kevin A Babiak, Evanston, IL (US);
Srinivasan Babu, San Diego, CA (US);
James R Behling, Lindenhurst, IL (US);
Mark L Boys, Buffalo Grove, IL (US);
Kimberly J Cain-Janicki, Sleepy Hallow, IL (US);
Wendel W Doubleday, Twin Lakes, WI (US);
Payman Farid, Vernon Hills, IL (US);
Timothy J Hagen, Gurnee, IL (US);
E Ann Hallinan, Evanston, IL (US);
Donald W Hansen, Jr, Skokie, IL (US);
Donald E Korte, Mundelein, IL (US);
Kathleen T McLaughlin, Arlington Heights, IL (US);
John R Medich, Gurnee, IL (US);
Sean T Nugent, Grayslake, IL (US);
Vlasdislav Orlovski, Buffalo Grove, IL (US);
Jung M Park, Glenview, IL (US);
Karen B Peterson, Vernon Hills, IL (US);
Daniel R Pilipauskas, Glenview, IL (US);
Barnett S Pitzele, Skokie, IL (US);
Sofya Tsymbalov, Skokie, IL (US);
Glenn L Stahl, Buffalo Grove, IL (US);
G. D. Searle & Co., Chicago, IL (US);
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-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.