G.d. Searle & Company

Pharmacia Corporation

G.d. Searle LLC

Payman N Farid

James R Behling

John R Medich

Sean T Nugent

Pierre-Jean Colson

Richard M Weier

Donald W Hansen, Jr

Ish K Khanna

Barnett S Pitzele

Timothy J Hagen

E Ann Hallinan

Samuel J Tremont

Sofya Tsymbalov

Karen B Peterson

Mark John Pozzo

Srinivasan Babu

Jon P Lawson

Kevin J Koeller

Claire A Przybyla

Mike G Scaros

Kevin A Babiak

James C Peterson

Donald E Korte

Daniel R Pilipauskas

Kevin Babiak

Grace Mary Wagner

Benxin Zhi

Robert Hett

Jay S Trivedi

Lawrence M Miller

Shine Chou

Mike Prunier

Kimberly J Cain-Janicki

Wendel W Doubleday

Mark L Boys

Vlasdislav Orlovski

Christian H Huber

Jung M Park

Glenn L Stahl

Gerald A Weisenburger

Andrew Carpenter

Eduardo K Mar

Vladislav Orlovski

James J Li

Kathleen T McLaughlin

Carl M Knable

Ravindra S Topgi

James Li

Kathleen T Mc Laughlin

Kimberly Jo Cain-Janicki

Mark Laurence Boys

Wendel William Doubleday

Carl Matthew Knable

Joseph Edward Duran

Frank Walter Muellner

Joseph E Duran

Frank W Muellner

Among its several embodiments, the present invention provides an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds.

Method for the preparation of tetrahydrobenzothiepines

The invention herein is directed to a process for the preparation of ethyl 3S-amino-4-pentynoate which involves treating 3-(trimethylsilyl)-2-propynal with L-phenylglycinol in toluene to produce .alpha.S-��3-(trimethylsilyl)-2-propynylidene amino!benzenethanol; reacting .alpha.S-��3-(trimethylsilyl)-2-propynylidene!amino!benzenethanol with BrZnCH.sub.2 CO.sub.2 t-Bu in THF/NMP to produce 1,1-dimethylethyl 3S-�(2-hydroxy-1S-phenylethyl)amino!-5-(trimethylsilyl)-4-pentynoate; reacting the 1,1-dimethylethyl 3S-�(2-hydroxy-1S-phenylethyl)amino!-5-(trimethylsilyl)-4-pentynoate with sodium periodate to form 1,1-dimethylethyl 3S-�(phenylmethylene)amino!-5-(trimethylsilyl)-4-pentynoate; hydrolyzing 1,1-dimethylethyl 3S-�(phenylmethylene)amino!-5-(trimethylsilyl)-4-pentynoate to produce 1,1-dimethylethyl 3S-amino-5-(trimethylsilyl)-4-pentynoate; transesterifying 1,1-dimethyl 3S-amino-5-(trimethylsilyl)-4-pentynoate and desilylating to produce ethyl 3S-amino-4-pentynoate.

Asymmetric synthesis of chiral beta-amiNo acids

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.

A process for the preparation of 1,2-O-(1-methylethylidine)-.alpha.-L-sorbofuranose and 6-(n-substituted amino)-6-deoxy-1,2-O-(1-methylethylidine)-.alpha.-L-sorbofuranose and derivatives of the formula: ##STR1## wherein R' is benzyl or R, wherein R is hydrogen, alkyl of 1 to 13 carbon atoms, and aralkyl wherein alkyl is a lower alkyl of 2 to 6 carbon atoms and aryl is phenyl, unsubstituted or substituted with lower alkyl of 1 to 6 carbon atoms, halo, lower alkoxy of 1 to 4 carbon atoms or thio lower alkyl of 1 to 4 carbon atoms by the steps of: treating L-sorbose with 2,2-dimethoxy propane to yield 1,2:4,6-di-O-(1-methylethylidine)-.alpha.-L-sorbofuranose; treating the compound with sulfuric acid in a solvent to produce 1,2-O-(1-methylethylidine)-.alpha.-L-sorbofuranose; and consecutively treating with sulfonyl chloride and with an amine to yield 6-(substituted amino)-6-deoxy- 1,2-O-(1-methylethylidine)-.alpha.-L-sorbofuranose.

Process for the preparation of

A process for the preparation of 1,5-(alkylimino)-1,5-dideoxy-D-glucitol and derivatives of the formula: ##STR1## wherein R is hydrogen, alkyl of 1 to 13 carbon atoms, and aralkyl wherein alkyl is a lower alkyl of 2 to 6 carbon atoms, and aryl is phenyl, unsubstituted or substituted with lower alkyl of 1 to 6 carbon atoms, halo, lower alkoxy of 1 to 4 carbon atoms or thio lower alkyl of 1 to 4 carbon atoms by the steps of: treating L-sorbose with 2,2-dimethoxypropane to yield 1,2:4,6-di-O-(1-methylethylidene)-.alpha.-L-sorbanose; treating the compound with sulfuric acid in a solvent to produce 1,2-O-(1-methylethylidine)-.alpha.-L-sorbofuranose; consecutively treating with sulfonyl chloride and with an amine to yield 6-(substituted amino)-6-deoxy-1,2-O-(1-methylethylidine)-.alpha.-L-sorbofuranose; adsorbing the compound on an ion exchange resin and hydrogenating to produce compounds of the above formula.

Process for the preparation of 1,5-(alkylimino)-1,5-dideoxy-D-glucitol

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Vernon Hills, IL, United States of America

Payman N Farid