G.d. Searle & Company

Kevin A Babiak

James R Behling

John S Ng

Arthur L Campbell

Donald E Korte

John H Dygos

John R Medich

Donald W Hansen, Jr

Barnett S Pitzele

Timothy J Hagen

E Ann Hallinan

George W Fleet

Sofya Tsymbalov

Karen B Peterson

Srinivasan Babu

Sean T Nugent

Daniel R Pilipauskas

Payman N Farid

Kimberly J Cain-Janicki

Wendel W Doubleday

Mark L Boys

Vlasdislav Orlovski

Jung M Park

Glenn L Stahl

Richard A Mueller

Chi-Huey Wong

Claire A Przybyla

Kathleen T McLaughlin

William J Hennen

Pierre-Jean Colson

Yi-Fong Wang

Lisa M Seaney

Bruce Eric Wise

Kathleen T Mc Laughlin

Sau-hoi N John

A process for producing a lactam of the formula ##STR1## wherein 2-bromo-4 chloro butyryl bromide or 2,4-dibromo butyryl bromide is coupled with 4-aminobenzonitrile to produce 4-(2,4-bromobutyrylamino)-benzonitrile, which is combined with sodium hydroxide, potassium hydroxide or potassium carbonate to produce 4-(3-bromo-2-oxopyrrolidin-1-yl)benzonitrile which is subjected to an excess of ammonium hydroxide to produce compounds of the formula (I).

Process for the preparation of a 2-oxopyrrolidine compound

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.

1,4-Dideoxy-1,4-imino-L-arabinitol is chemically synthesized from D-lyxonolactone by formation of the pyrrolidine ring by joining the nitrogen between C-1 and C-4 and inversion of configuration at both C-2 and C-4, with the C-3 and C-5 hydroxyl groups being protected throughout the synthesis sequence by benzylidenation. The product is preferably isolated as the hydrochloride salt and is useful as an inhibitor of .alpha.-glucosidase and human immunodeficiency virus (HIV).

Synthesis of 1,4-dideoxy-1,4-imino-L-arabinitol

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

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

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

This invention encompasses a process for preparing higher order cuprate complexes which contain a carbanion for the formation of carbon to carbon bonds in reactions such as epoxide addition. The complex is formed by reacting a first cuprate complex with a stannane such that the carbanion to be used to form carbon to carbon bonds is transferred from the stannane to the first cuprate complex to form a different higher order cuprate complex. This process permits the in situ preparation of a higher order cuprate complex having the carbanion desired to be used in a synthetic reaction. Higher order cuprate complexes derived from the reaction of a cuprate complex with 1,2-bis-tri-n-butylstannyl ethylene are particularly useful for the addition to epoxides to form vinyl tin intermediates useful for preparing omega side chains of prostaglandins.

Process for preparing higher order cuprate complexes

This invention relates to a novel cyclopenteneheptenoic acid derivative having the following formula ##STR1## wherein R.sub.1 is hydrogen, --COCH.sub.3, --COCF.sub.3, --CO--phenyl, or a hydroxyl protecting group such as tetrahydropyranyl, tetrahydrofuranyl, or tri-lower alkylsilyl;

Cyclopenteneheptenoic acid derivatives and method of preparation thereof

Novel intermediates and method for the chemical synthesis of N-substituted 1,5-dideoxy-1,5-imino-L-fucitol derivatives are provided. A preferred intermediate is 1,5-dideoxy-1,5-imino-3, 4-O-isopropylidene-L-fucitol which is used to prepare the HIV inhibitor 1,5-dideoxy-1,5-imino-[N-.omega.-methyl caproate]-L-fucitol. These compounds are prepared in a short synthesis from the known compound 2,3-O-isopropylidene-D-lyxono-1,4-lactone or in a multi-step synthesis from D-galactose.

Synthesis of N-substituted 1,5-dideoxy-1,5-imino-L-fucitol derivatives

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Evanston, IL, United States of America

Kevin A Babiak