G.d. Searle & Company

Kathleen T McLaughlin

John R Medich

John H Dygos

John Jeffrey Talley

John S Ng

Edward E Yonan

Henry T Gaud

Kalidas Paul

Donald W Hansen, Jr

Barnett S Pitzele

Timothy J Hagen

E Ann Hallinan

Sofya Tsymbalov

Karen B Peterson

Robert J Chorvat

Joseph J Wieczorek

Srinivasan Babu

James R Behling

Mike G Scaros

Sean T Nugent

Kevin A Babiak

Donald E Korte

Daniel R Pilipauskas

Payman N Farid

Thomas R Kowar

Michael L Prunier

Kathleen A Prodan

Gatis Plume

Kimberly J Cain-Janicki

Wendel W Doubleday

Mark L Boys

Vlasdislav Orlovski

Jung M Park

Glenn L Stahl

Richard J Salzmann

A stable crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide is described. This crystal structure, designated Form B, is more stable, has favorable handling properties and is characterized by its melting point, x-ray and other physical characterizations.

Crystalline form of 4-[5-methyl-3-phenylisoxazol-4-yl] benzenesulfonamide

A stable crystalline form of 4-&lsqb;5-methyl-3-phenylisoxazol-4-yl&rsqb;benzenesulfonamide is described. This crystal structure, designated Form B, is more stable, has favorable handling properties and is characterized by its melting point, x-ray and other physical characterizations.

Crystalline form of 4-&lsqb;5-methyl-3-phenylisoxazol-4-yl&rsqb; benzenesulfonamide

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.

Process for the preparation of ethyl

The present invention relates to a novel process for the preparation of heterocyclic alkylamide derivatives having the following formula: ##STR1## and the pharmaceutically acceptable acid addition salt thereof wherein X represents halo, alkyl having 1 to 6 carbon atoms, hydrido, trifluoromethyl, phenyl, or lower alkoxy having 1 to 6 carbon atoms; Y represents the group --CN or --CONH.sub.2 ; R.sub.2 represents alkyl having 1 to 6 carbon atoms; R.sub.3 represents acetyl, benzoyl, phenacetyl or trifluoroacetyl; m is the integer 1 or 2 and n is an integer from 1 to 3 inclusive; which comprises alkylating an aminoalkanol using a benzaldehyde/aminoalkanol/ketone mixture in the presence of a platinum catalyst to give an alkyl substituted phenylmethylaminoalkanol; halogenating the alkanol using a halogenating agent to give a haloalkyl alkylbenzenemethanamine salt; treating the salt with substituted phenyl piperidinealkanenitrile or substituted phenyl pyrrolidinealkanenitrile in the presence of base and dimethyl sulfoxide to give a substituted phenyl substituted aminoalkyl piperidinealkanenitrile or substituted aminoalkyl pyrrolidinealkanenitrile; hydration of the nitrile to give the corresponding amide; and N-debenzylation of the amide followed by acetylation to give the compounds of formula I wherein Y is --CONH.sub.2.

Process for the preparation of heterocyclic alkylamide derivatives

Disclosed is a process for the preparation of 3-aryl-3-aminoalkyl-2,6-dioxohexahydropridines and particularly the compound 3-[3-(dimethylamino)propyl]3-(3 methoxyphenyl)-4, 4-dimethyl-2,6-piperidinedione, monohydrochloride, which is useful as an antidepressant. The process of the present invention comprises the condensation of a sterically hindered nitrile with a sterically hindered .alpha.,.beta.-unsaturated diester to produce a nitrile diester. These compounds can then undergo acid catalyzed cyclization and decarboalkoxylation in a one step process to provide the desired 3-aryl-3-aminoalkyl-2,6 -dioxohexahydropyridine.

Process for the preparation of diethyl

Disclosed is a process for the preparation of 3-aryl-3-aminoalkyl-2,6-dioxohexahydropridines and particularly the compounds 3-[3-(dimethylamino)propyl]-3-(3-methoxyphenyl)-4, 4-dimethyl-2,6-piperidinedione, monohydrochloride, which is useful as an antidepressant. the process of the present invention comprises the condensation of a sterically hindered nitrile with a sterically hindered .alpha., .beta.-unsaturated diester to produce a nitrile diester. These compounds can then undergo acid catalyzed cyclization and decarboalkoxylation in a one step process to provide the desired 3-aryl-3-aminoalkyl-2,6-dioxohexahydropyridine.

Process for the preparation of

This invention relates to a process for preparing useful antiarrhythmic 1,3-diazabicyclo[4.4.0]dec-2-en-4-ones from 1-acyl-.alpha.-[2-[bis(1-methylethyl)amino]ethyl]-.alpha.-phenyl-2-piperid ineacetamides. This invention also relates to the 1-acyl-.alpha.-[2-[bis(1-methylethyl)amino]ethyl]-.alpha.-phenyl-2-piperid ineacetamides employed in this process.

Process for antiarrhythmic 1,3-diazabicyclo[4.4.0]dec-2-en-4-ones

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Arlington Heights, IL, United States of America

Kathleen T McLaughlin