E. R. Squibb Sons, Inc.

Bristol-myers Squibb Compnay

Other

Jerome L Moniot

Rita T Fox

Michael A Poss

Jianmei Wei

David J Kucera

Shu-Hui Chen

Ivan D Trifunovich

John K Thottahil

Martin F Haslanger

Peter W Sprague

John J Venit

Sushil K Srivastava

Shankar Swaminathan

John K Thottathil

Ramesh N Patel

Christopher M Cimarusti

Laszlo J Szarka

William John Winter

Amit Banerjee

Venkata B Nanduri

Neal G Anderson

David A Lust

William H Koster

David M Floyd

Paul Alan Jass

James H Simpson

Steven L Goldberg

Shawn K Pack

Robert M Johnston

John L Dillon, Jr

Keith Ramig

Gerard Crispino

Saibaba Racha

Mark D Schwinden

Rajendra P Deshpande

Alan W Fritz

Thomas P Tully

Francis A Sowinski

Chien-Kuang Chen

Steven Brandt

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

Methods for the preparation of sidechain-bearing taxanes, comprising the preparation of an oxazoline compound, coupling the oxazoline compound with a taxane having a hydroxyl group directly bonded at C-13 thereof to form an oxazoline sidechain-bearing taxane, and opening the oxazoline ring of the oxazoline sidechain-bearing taxane so formed. Compounds prepared by the methods of the present invention are also disclosed.

Method for the preparation of novel sidechain-bearing taxanes and intermediates thereof

Disclosed is a process for preparing N-substituted heterocyclic derivatives and its salts using phase transfer catalysis.

Method for preparing N-substituted heterocyclic derivatives using a

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

Novel methods for the preparation of sidechain-bearing taxanes, comprising the preparation of an oxazoline compound, coupling the oxazoline compound with a taxane having a hydroxyl group directly bonded at C-13 thereof to form an oxazoline sidechain-bearing taxane, and opening the oxazoline ring of the oxazoline sidechain-bearing taxane so formed. Novel compounds prepared by the methods of the present invention are also provided.

Methods for the preparation of novel sidechain-bearing taxanes and

Methods for the preparation of novel sidechain-bearing taxanes

Phosphorus bearing taxanes intermediates

A compund having the formula ##STR1## can be prepared by coupling a compound having the formula ##STR2## or a salt thereof, with a compound having the formula ##STR3## to yield a compound having the formula ##STR4## and oxidizing that compound to yield the desired compound; wherein R is hydrogen or an amino protecting group;

Process for the preparation of (3S)-3-[[[2-(protected

A method is provided for preparing phosphinic acid prodrug intermediates which are useful in preparing phosphinic acid angiotensin-converting enzyme inhibitors which method includes the step of coupling a phosphonous acid or its ester of the structure ##STR1## wherein R is H or lower alkyl and R.sup.1 is lower alkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl, with an alkylating agent of the structure ##STR2## wherein Hal is Cl, Br or I, n is 0 or 1, R.sup.2 is H or lower alkyl, and Z is H, lower alkyl, --CO.sub.2 R.sup.3 (wherein R.sup.3 is H or lower alkyl), ##STR3## (wherein R.sup.4 is H, lower alkyl, aryl or arylalkyl), --CN, or ##STR4## (wherein R.sup.5 and R.sup.6 may be the same or different and are selected from the group consisting of H, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkylalkyl and at least one of R.sup.5 and R.sup.6 is other than H, or R.sup.5 and R.sup.6 can be taken with the N-atom to form a 5-, 6- or 7-membered heterocyclic ring which 5-, 6- or 7-membered N-containing ring may or may not contain a CO.sub.2 R.sup.3 group and which 5- or 6-membered N-containing ring may or may not be fused to an aryl ring), in the presence of a silylating agent, to form the phosphinic acid intermediate of the structure ##STR5## wherein R, R.sup.1, R.sup.2, n and Z are as defined above.

Method for making phosphinic acid intermediates

A method is provided for making substituted prolines of the structure ##STR1## wherein X is lower alkyl or aryl, R is H, lower alkyl or an alkali metal and Z is an N-protecting group, which method includes the step of reacting a compound of the structure ##STR2## wherein Z and R are as defined above and Q is Br. tosyloxy or mesylate, with an organic copper lithium compound of the structure

Method for making substituted prolines

Disclosed herein is a process for preparing a compound having the formula ##STR1## which comprises coupling a compound having the formula ##STR2## or a salt thereof, with a compound having the formula ##STR3## to obtain a compound having the formula ##STR4## reacting that compound with 2-aminooxy-2-methylpropanoic acid, or a salt thereof, to obtain a compound having the formula ##STR5## and, if R is an amino protecting group, deprotecting that compound to yield the desired product; wherein

Process for preparing

A method is provided for preparing intermediates for use in prostacyclin syntheses which method includes the steps of aceylating ketopinic acid or its acid halide to form the corresponding ketopinoyl diene ester intermediate, subjecting the diene ester to a Diels-Alder reaction by reacting same with cyclopentendione, subjecting the resulting chiral ester intermediate to a fluorination and reduction to form the corresponding chiral ester diol intermediate, subjecting the diol to solvolysis to form the chiral triol intermediate, hydroxylating the chiral triol to form a pentol intermediate, subjecting the pentol to a ring cleavage to form the difluoro dihydroxy prostacyclin intermediate ##STR1## and subjecting same to a Witting reaction to form the difluoro dihydroxy prostacyclin intermediate ##STR2## All of the above-mentioned intermediates are novel compounds and thus are also provided.

Prostacyclin intermediates

A method is provided for preparing intermediates for use in prostacyclin syntheses which method includes the steps of aceylating ketopinic acid or its acid halide to form the corresponding ketopinoyl diene ester intermediate, subjecting the diene ester to a Diels-Alder reaction by reacting same with cyclopentendione, subjecting the resulting chiral ester intermediate to a fluorination and reduction to form the corresponding chiral ester diol intermediate, subjecting the diol to solvolysis to form the chiral triol intermediate, hydroxylating the chiral triol to form a pentol intermediate, subjecting the pentol to a ring cleavage to form the difluoro dihydroxy prostacyclin intermediate: ##STR1## and subjecting same to a Wittig reaction to form the difluoro dihydroxy prostacyclin intermediate: ##STR2## All of the above-mentioned intermediates are novel compounds and thus are also provided.

6,6-Difluoro-5-hydroxy-4-(3-oxoalk-1-enyl)hexahydro cyclopenta[b]

A method is provided for preparing the optically active isomer [2R-[2.alpha.,3.alpha.,5(R*)]]-2,2'-[[5-[3-[(1,1-dimethylethyl)amino]-2-hy droxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediyl]bis(oxy)]bis-[N,N-dipr opylacetamide] having the structure ##STR1## which is useful as an antiarrhythmic agent.

Method for preparing the optically active isomer of

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Chester, NJ, United States of America

Jerome L Moniot