Merck + Co., Inc.

Ichiro Shinkai

Ralph P Volante

Thomas M Liu

Meyer Sletzinger

Kenneth M Ryan

David G Melillo

David Askin

Thomas R Verhoeven

Joseph E Lynch

Robert A Reamer

William L Laswell

Sander G Mills

Andrew S Thompson

Leonard M Weinstock

Ann E DeCamp

Richard Desmond

Anthony O King

Roger J Tull

Todd K Jones

Lelia M Fuentes

Thomas N Salzmann

Woo-Baeg Choi

David M Tschaen

Guy R Humphrey

Paul J Reider

Ann D Schuda

Daisy Joe

Thomas J Blacklock

James A McCauley

Joseph S Amato

Edward G Corley

Dean R Bender

Robert S Hoerrner

Joel J Friedman

Michael A Wallace

Anthony M De Marco

A process for making a beta methyl carbapenem intermediate is disclosed. A compound of formula I:

Preparation of betamethyl carbapenem intermediates

The present invention is directed to a process of making a Beta-methyl carbapenem intermediate of formula VI from a compound of formula I ##STR1## wherein R and P' are protecting groups R.sup.1 is a methylmalonic acid ester and Nu is a nucleophilic group. Process intermediates are also disclosed.

Preparation of beta-methyl carbapenem intermediates

A process is described for the total synthesis of the macrolide immunosuppressant, FK-506, and important tricarbonyl process intermediates thereof. The tricarbonyl intermediates can be produced by the mild oxidation of 2,3-dihydroxy carboxylate compounds containing olefin moieties.

Process for synthesis of FK-506 and tricarbonyl intermediates

Anti-ulcer agents having a methylsulfinyl bridge between a substituted pyridine moiety and a substituted benzimidazole moiety are prepared by oxidizing the corresponding compounds, having a methylthio bridge, with magnesium monoperoxyphthalate in a suitable solvent. The reaction may be run in an aromatic hydrocarbon solvent, wherein the product may crystallize out of the reaction solution and may be directly isolated by filtration.

Process for the preparation of antiulcer agents

An intermediate, useful in the conversion of FK-506 to FK-525 and analogous 23-membered ring macrolides, of the structure: ##STR1##

FK-506 type macrolide intermediate

The 4-acyloxyazetidin-2-ones, which are intermediates in the production of carbapenems and penems, are produced from nitrogen deprotected 4-furanylazetidin-2-ones.

Nitrogen deprotected 4-acyloxyazetidin-2-ones

An efficient process for stereoselective preparation of a medicinally significant hydroxyamide compound of structural formula: ##STR1## comprises the addition of metalated amide enolates to chiral .alpha.-amino metalated epoxides. The hydroxyamide reaction products are useful as inhibitors of the HIV protease or of renin, or as intermediates in the preparation of inhibitors of the HIV protease or renin.

Stereoselective production of hydroxyamide compounds from chiral

A process for the conversion of FK-506 (I,R=allyl;1) to FK-525 (XV) and analogous 23-membered ring macrolides differing in the C.1-N.7 segment of the molecule (e.g. XVI) and is also applicable to the analogs FK-523 (XVII) and FK-520 (XVIII). The overall process consists of three stages: (a) initial degradation of the primary macrolide to an acyclic fragment containing a selectively protected C.10-C.34 framework with a protected aldehyde function at C.10 and a free hydroxyl function at C.26, (b) reacylation of the C.26 hydroxyl function with an appropriately N-protected alpha-amino acid moiety, and (c) reintroduction of the C.8 and C.9 carbons followed by regeneration of the FK-macrolide system.

Synthetic process for FK-506 type macrolide intermediates

A process is described for the stereocontrolled synthesis of (3R,4R)-3-[(1R)-1-hydroxyethyl]-4-benzoyloxyazetidin-2-ones and their derivatives by cycloaddition involving an imine and a ketone, generated from 3(S)-hydroxybutyrate which are useful intermediates in the synthesis of carbapenem antibiotics.

Stereoselective synthesis of a chiral cis 3-beta hydrogen (3R)

A process is described for the stereochemically controlled synthesis of intermediates useful in producing 1-betamethylcarbapenem antibiotic intermediates involving reacting a beta lactam with a chiral thia- or oxazolidinone enolate to preferentially produce a beta-methyl intermediate which can be transformed into a carbapenem antibiotic.

Enantioselective process for producing 1-beta-methyl carbapenem

The present invention is directed to a process of making tetrahydrofuran of the formula (D) ##STR1## resulting in 2,5-diaryltetrahydrofuran PAF antagonists of pharmaceutically acceptable purity.

Process of making 2,5-diaryl tetrahydrofurans and analogs thereof useful

A process is described for the synthesis of diastereomeric 2-methyl-4-hydroxy-5-protected-hydroxy-hept-6-en-prolinolamides, which are useful as intermediates in the synthesis of the C.sub.10 -C.sub.18 chain of the macrolide structure for the immunosuppressant FK-506. These compounds are also useful as intermediates for preparing lactone ultraviolet radiation absorbers.

Process for synthesis of FK-506 intermediates

A multistep process is described for selectively obtaining 1-.beta.-methylcarbapenem intermediates in high overall yield. The desired 1-.beta.-methyl chirality is obtained through the hydrogenation of certain bicyclic .beta.-lactam ring structures containing an exocyclic methylene double bond alpha to the .beta.-lactam ring, in the presence of a metallic nickel hydrogenation catalyst. The hydrogenation results in a mixture of .alpha.- and .beta.-methyl isomers having a high .beta./.alpha.epimeric molar ratio. New 1-.beta.-methylcarbapenem intermediates containing the exocyclic double bond are also described.

Chiral 1-.beta.-methyl-carbapenem intermediates

A unique process for preparing certain (2R-trans)hexahydroaroquinolizines, especially (2R-trans)-N-[2-(1,3,4,6,7,12b-hexahydro-2'-oxospiro[aro-[2,3-a]-quinolizi ne-2,4'-imidazolidin]-3'-yl) ethyl)-methanesulfonamide from (2R-trans)-N-[2-[(2-cyano-(1,3,4,6,7,12b-hexahydro-aro-[2,3-a]quinolizin-2 -yl)amino]ethyl]methanesulfonamide is described.

Process for certain (2R-trans)hexahydroaroquinolizines

A process is described involving an alkaline rearrangement of FK-506 producing a new decarbonylated 22-membered macrocycle rearrangement derivative of FK-506, i.e. C.9, nor-keto FK-506.

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Westfield, NJ, United States of America

Ichiro Shinkai