Bristol-Myers Squibb Compnay

John J Venit

Paul Alan Jass

Keith Ramig

Ramesh N Patel

Mandar V Dali

Ravindra W Tejwani

Sushil K Srivastava

Charles E Dahlheim

Manisha M Dali

Yande Huang

Laszlo J Szarka

Shankar Swaminathan

Wen-sen Li

Ronald L Hanson

Jerome L Moniot

Victor W Rosso

Steven L Goldberg

John L Dillon, Jr

Saibaba Racha

Mark D Schwinden

Atul S Kotnis

David R Kronenthal

Jollie D Godfrey, Jr

William John Winter

Nachimuthu Soundararajan

Amit Banerjee

Venkata B Nanduri

Gerald L Powers

David A Lust

Joseph Nolfo

Mary Jo Donovan

Philip Michael Sher

Shawn K Pack

James H Simpson

Jingyang Zhu

Robert M Johnston

Jason G Chen

Gary D Madding

Ambarish K Singh

Gerard Crispino

Michael E Randazzo

Neal G Anderson

Chien-Kuang Chen

D David Hennings

Thomas P Tully

Robert P Discordia

Glen Young

Imre M Vit Z

Mayra B Reyes

Peter Lee

Maxine Soumellant

Francis J Okuniewicz

Susanne Kiau

Provided herein are novel and useful combretastatin A-4 prodrug salts that increase the solubility of combretastatin A-4, readily regenerate combretastatin A-4 in vivo under normal physiological conditions, and which produce physiologically tolerable products as a result of the regeneration of combretastatin A-4.

Combretastatin A-4 phosphate prodrug mono- and di-organic amine salts, mono- and di-amino acid salts, and mono- and di-amino acid ester salts

Combretastatin A-4 phosphate prodrug mono-and di-organic amine salts, mono-and di-amino acid salts, and mono-and di-amino acid ester salts

Combretastatin A-4 phosphate prodrug mono-and di-organic amine salts, mono-and di-amino acid salts and mono-and di-amino acid ester salts

Provided is a dynamic resolution method of enriching a desired isomer of an alpha-substituted carboxylic acid relative to an undesired isomer, the method comprising: (a) in a solvent, contacting the alpha-substituted carboxylic acid, wherein the alpha substitution is with a leaving group and wherein the alpha carbon is chiral, with a homochiral amine to form a salt that is partially insoluble under selected reaction conditions, wherein the homochiral amine is selected so that the solubility of the amine salt of the undesired alpha-substituted carboxylic acid is greater than that of the amine salt of the desired alpha-substituted carboxylic acid under the selected reaction conditions; (b) reacting under the selected reaction conditions the salt with a nucleophile, wherein the reacting is effective in producing a net increase in the less soluble amine salt of the alpha-substituted carboxylic acid, and wherein the selected conditions are selected to (i) promote nucleophilic substitution of the nucleophile and the leaving group or (ii) to produce the increase in the less soluble amine salt in the absence of a strong base; and (c) maintaining the reaction for a period of time effective to increase the amount of the desired alpha-substituted carboxylic acid isomer.

Dynamic resolution of isomers and resolved isomers

Multiple samples are prepared in slurry form and deposited through a funnel plate by a multiprobe liquid handler into an array of inserts situated in openings in a housing. Each insert has a recess that extends through the insert body and a filter disc situated in the recess to support the sample. The filter is held in place by an annular part which defines a channel providing access to the filter through the lower portion of the recess. A pressure differential is created across each of the filters by attaching a vacuum manifold to the bottom of the housing to simultaneously remove the liquid from each of the samples, leaving the samples in powder form. The housing is then placed in the X-ray diffractometer for sequential analysis of each of the samples, while the samples are situated in the inserts.

High throughput X-ray diffraction filter sample holder

Multiple parallel chemical reactions are performed under pressure in a reactor including a multi-row array of reaction vessels situated between a temperature control base and a fluid flow manifold. The manifold consists of an input portion connected to the fluid supply by a five-way valve and a distribution portion which includes separate parallel distribution channels, one for each row of reaction vessels. A control valve for each distribution channel is interposed between the manifold portions such that the fluid flow to each row of reaction vessels can be independently controlled. An explosion proof transparent shield can be situated between the base and manifold, surrounding the reaction vessels. The interior of the shield can be flooded with inert gas.

High pressure chemistry reactor

Combretastatin A-4 phosphate prodrug mono- and di-organic amine salts, mono- and di- amino acid salts, and mono- and di-amino acid ester salts

The present invention concerns an enzymatic oxidative deamination process of a dipeptide monomer to prepare an intermediate useful to prepare compounds having endopeptidase and angiotensin converting enzyme inhibition activity.

Enzymatic oxidative deamination process

Substituted alkylketo compounds and process

Processes for stereoselective enzymatic conversion of certain keto carboxylic acid derivatives to form the corresponding alkylamino acid compounds are described. The invention also concerns an engineered yeast host cell containing recombinant nucleic acid capable of expressing a phenylalanine dehydrogenase, as well as an engineered host cell containing recombinant nucleic acid capable of expressing a phenylalanine dehydrogenase enzyme and nucleic acid capable of expressing a formate dehydrogenase enzyme.

Stereoselective reductive amination of ketones

Preparation of (S)-2-amino-6,6-dimethoxyhexanoic acid methyl ester via novel dioxolanes

Preparation of (s)-2-amino-6,6-dimethoxyhexanoic acid methyl ester via novel dioxolanes

N-protected-L-homocysteine disulfide of the formula ##STR1## or an activated form thereof is reacted with (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester to give the disulfide intermediate of the formula ##STR2## Cleavage of the disulfide bond followed by acid catalyzed cyclization produces the N-protected lactam of formula III which is useful for preparing the pharmaceutically active compound omapatrilat.

Preparation of

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North Brunswick, NJ, United States of America

John J Venit