G.d. Searle & Company

G.d. Searle LLC

The University of Texas System

John H Dygos

John S Ng

Kevin A Babiak

Kathleen T McLaughlin

James R Behling

Kalidas Paul

Chi-Huey Wong

Joseph J Wieczorek

Mike G Scaros

William J Hennen

Thomas R Kowar

Michael L Prunier

Yi-Fong Wang

Karlene W Salamon

Gatis Plume

Richard J Salzmann

Keven Anthony Babiak

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

A process for preparing higher order cuprate complexes by reacting an alkyne with zirconocene chloride hydride to produce a zirconium intermediate which is reacted with an alkyllithium and a first copper reagent selected from R.sup.2 Cu(CN)Li or the mixture CuCN and R.sup.2 Li to produce a higher order cuprate complex.

Process for preparing prostaglandin analogs

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

A process for irreversible regio- and stereoselective enzyme catalyzed acylation of alcohols using enol esters as acylating reagents is disclosed. The present invention permits the selective modification of hydroxyl group(s) of chiral and meso alcohols, including sugars, organometallics, and glycosides. The enol freed upon transesterification rapidly tautomerizes to the corresponding volatile aldehyde or ketone thereby preventing the reverse reaction from occurring.

Enantio- and regioselective synthesis of organic compounds using enol

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

A process for preparing a prostaglandin derivative by reacting an alkyne with zirconocene chloride hydride to produce a zirconium intermediate which is reacted with an alkyllithium and a first copper reagent selected from R.sup.2 Cu(CN)Li or the mixture CuCN and R.sup.2 Li to produce a higher order cuprate complex intermediate and reacting the higher order cuprate complex intermediate with a cyclopentenone to produce the prostaglandin derivative.

Process for preparing prostaglandin analogs using organozirconium

Preparation and the antimicrobial and antihypercholesterolemic utility of 20/22/23/24-oxa-7-oxocholesterols and esters thereof are disclosed.

20/22/23/24-Oxa-7-oxocholesterols and esters thereof

Preparation and the antihypercholesterolemic activity of 2,2-dimethyl-2-[(7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[a]phen anthren-3-yl)oxy]ethyl alkanedioates and intermediates thereto are disclosed.

2,2-Dimethyl-2-[(7,15

Preparation and the antihypercholesterolemic activity of 5-(1,2,3,4-tetrahydro-6-methoxy-2-napthyl)-2-hydroxy-1-methylcyclopentanee thanols and esters thereof are disclosed.

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Northbrook, IL, United States of America

John H Dygos