Merck + Co., Inc.

Merck Sharp + Dohme Corp.

Michel M Chartrain

Christopher Roberge

Brian Heimbuch

Barbara Ann Krulewicz

Thomas R Verhoeven

David M Tschaen

George M Garrity

John Y Chung

Colleen S Taylor

Chris H Senanayake

Chanyong Brian Lee

Neal C Connors

Jinyou Zhang

Roger C Olewinski, Jr

Laura Kizer Bentley

Barbara A Jackey

Kristin M Listner

Wen-jun Sun

Ralph P Volante

Shieh-Shung T Chen

Paul N Devine

Woo-Baeg Choi

Paul J Reider

David Askin

Gerald F Bills

Dalian Zhao

Peter Emmanuel Maligres

Raymond Cvetovich

Ali Shafiee

Daniel Richard Sidler

James M McNamara

John P Rosazza

Guy H Harris

Norihiro Ikemoto

F Edward Roberts

Joseph D Armstrong, Iii

Steven A King

Shigeko Yamazaki

Michael G Sturr

Jennifer Nielsen-Kahn

Randolph L Greasham

Francis P Gailliot

Lorraine G Katz

Jayanthi Reddy

Hywyn Ro Churchill

Chanyong Lee

Barry C Buckland

Wen-Jun Sun

The present invention relates generally to a method for increasing the yield of plasmid DNA production. The method includes the steps of selecting a highly productive clonal subtype of a strain of, including but not limited to the DH5 strain, harboring a DNA plasmid and cultivating said clonal subtype with fed-batch fermentation in a chemically-defined medium. The plasmid DNA production process described herein can generate record quantities of plasmid DNA when said highly productive clonal subtypes are cultivated on an industrial scale. The disclosed method can be used for the production of pharmaceutical grade DNA for use in polynucleotide vaccination and gene therapy treatment regimens.

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11-hydroxysordarin, biotransformation product of a fermentation with sordarin and Actinomyces spp., (Merck Culture Collection MA7235) ATCC No. 202103 is an antifungal agent. This compound may be useful in the treatment of diseases caused by fungal pathogens such as

11-hydroxysordarin and a process for producing it using actinomyces SSP

This invention relates to crystalline pharmaceutically acceptable salts of an alpha 1a adrenergic receptor antagonist, Compound A, which are useful in the treatment of benign prostatic hyperplasia. Pharmaceutical compositions employing the crystalline salts, and processes for making and using the crystalline salts and pharmaceutical compositions of Compound A are also disclosed. This invention further relates to a process for obtaining enantiomerically pure intermediate useful for the synthesis of end product alpha 1a adrenergic receptor antagonists. The end product compounds are useful for the treatment of benign prostatic hyperplasia and for relaxing lower urinary tract tissue. The invention also relates to a process for preparing a class of dihydropyrimidinone compounds of which Compound A is a member, wherein the process involves deprotonating a dihydropyrimidinone compound and then coupling the deprotonated derivative with a primary amine.

Enzymatic process of making alpha 1a adrenergic receptor antagonists using protease

The invention relates to a class of enantiomerically pure intermediates represented by Formula I, where X is F, Cl, Br, or I, and a novel enantioselective bioreductive process using yeast to form these intermediates, which are useful in the synthesis of endothelin antagonists, and the like. ##STR1##

Enantioselective bioreduction using yeast

A bioconversion process where benzyl acetoacetate is converted to benzyl-(S)-(+)-3-hydroxybutyrate.

Stereospecific bioconversion of benzyl acetoacetate to

The present invention is concerned with a novel process for the preparation of a compound of the formula: ##STR1## This compound is useful as an intermediate in the synthesis of compounds which possess pharmacological activity.

Process for the preparation of (S)-3-carbethoxy-3-benzylpiperidine

The present invention is directed to an improved process for making PDE IV inhibitors. In specific, this application describes a process for making and purifying a chiral bisaryl alcohol, an intermediate compound necessary for the preparation of PDE IV inhibitors such as CDP 840, by asymmetric bioreduction of a pro-chiral ketone. Furthermore, the bioprocess provides for production of each enantiomer of a bisaryl alcohol at elevated optical purity. This invention takes advantage of a microorganism's ability to reduce a pro-chiral bisaryl ketone to the chiral bisaryl alcohol. The alcohol is readily isolated from the media by solvent extraction, crystallography, or other purification method known to the skilled artisan. The chiral alcohol can then be converted to a PDE IV inhibitor, such as CDP 840, by methods well known in the art.

Process for bioreduction of bisaryl ketone to bisaryl alcohol

A method for preparing (1S)-amino-(2R)-indandiol substantially free of its stereoisomers is presented. The method comprises culturing indene with Rhodococcus sp. ATCC 55805, recovering the indandiol and subjecting the indandiol to chiral specific crystallization, treatment with strong acid and reverse ion pair extraction.

Conversion of indene to (1S)-amino-(2R)-indanol free of any steroisomer

A process is disclosed that bioconverts indene to (1S)-amino-(2R)-indanol substantially free of any of its stereoisomers, by the action of a strain of P. putida or Rhodococcus sp., followed by various chemical step(s), e.g., chiral specific crystallization, treatment with strong acid in the presence of acetonitrile.

Conversion of indene to (1S)-amino-(2R)-indanol free of any

A process is disclosed that hydrolyzes, by the action of an epoxide hydrolase of Diplodia gossipina (alternatively named Diplodia gossypina) ATCC 16391 or ATCC 10936, the undesired enantiomer of racemic indene oxide, an epoxide of indan.

Resolution of racemic indene oxide to yield (1S,2R)-indene oxide using

Asymmetric bioreduction of a ketone substrate with yeast produces the corresponding (R)-alcohol of structure: ##STR1## a key intermediate in the synthesis of a .beta..sub.3 -agonist of structure ##STR2##

N-(R)-(2-hydroxy-2-pyridine-3-yl-ethyl)-2-(4-nitro-phenyl)-acetamide

Compound 9 is prepared by a 9-step ##STR1## process in an overall yield of about 35% from 3-acetylpyridine. Compound 10 is prepared by a seven-step ##STR2## process in an overall yield of about 30% from 3-acetyl pyridine. These compounds are key intermediates in the synthesis of Compound 11, an important .beta.-3 agonist useful in the treatment of obesity and diabetes. ##STR3##

Process for

A process is disclosed that quantitatively bioconverts indene to (1S,2R)-indene oxide and (1S,2R)-indandiol, by the action of fungal haloperoxidase followed by various chemical step(s), e.g., adjusting the pH.

Quantitative conversion of indene to (1S,2R) indene oxide and

A biotransformation process for the production of an intermediate used in the chemical synthesis of an antibiotic compound.

Bioconversion of beta keto-ester to (R) hydroxyester

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Westfield, NJ, United States of America

Michel M Chartrain