Schering Corporation

Merck Sharp + Dohme Corp.

Timothy L McAllister

Xiaoyong Fu

Tiruvettipuram K Thiruvengadam

Chou-Hong Tann

Jianguo Yin

Shuyi Zhang

Anantha R Sudhakar

Agnes S Kim-Meade

Jason L Winters

Doris P Schumacher

John S Chiu

Junning Lee

Cesar Colon

Wenxue Wu

David R Andrews

Dinesh Gala

Hongbiao Liao

Gary M Lee

Martin Lawrence Schwartz

T K Thiruvengadam

Chou-Hang Tann

Donal Maloney

Arthur G Taveras

Michael J Green

Michael P Dwyer

Younong Yu

Ronald C Breslow

Derek H Barton

Kevin Joseph Klopfer

Michael R Reeder

Mengwei Hu

Kelvin Yong

Kenneth Stanley Matthews

David J Tsai

Gerald Werne

David J S Tsai

Mathew Thomas Maust

Frank Bruno Guenter

Timothy D Cutarelli

Thiruvengadam K Thiruvettipuram

This application discloses a novel process for the preparation of 1,2-substituted 3,4-dioxo-1-cyclobutene compounds, which have utility, for example, in the treatment of CXC chemokine-mediated diseases, and intermediates useful in the synthesis thereof.

Process and intermediates for the synthesis of 1,2-substituted 3,4-dioxo-1-cyclobutene compounds

A process is provided for preparing azetidinones useful as intermediates in the synthesis of penems and as hypocholesterolemic agents, comprising reacting a &#x3b2;-(substituted-amino)amide, a &#x3b2;-(substituted-amino)acid ester, or a &#x3b2;-(substituted-amino)thiolcarbonic acid ester with a silylating agent and a cyclizing agent selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof, or the reaction product of: (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl.

Process for the synthesis of azetidinones

The present invention relates to four distinct crystalline polymorphs of a monohydrate of Compound A having the following chemical structure:  These four polymorphic forms, herein referred to as Forms I, II, III and IV are active as a CXC-chemokine receptor ligands. The invention is further directed to formulations, methods of treatment, and processes of synthesis of these polymorphic forms.

Crystalline polymorphs of a CXC-chemokine receptor ligand

This application discloses a novel process to synthesize 2-(Quinolin-5yo)-4,5-Disubstituted-Azole derivatives, which may be used, for example, as PDE IV inhibitor compounds in pharmaceutical preparations.

Process and intermediates for the synthesis of 2-(quinolin-5-yl)-4,5 disubstituted-azole derivatives

Disclosed is a process for making the compound of formula I: using the compounds of formulas II, Q, and XI or XII: wherein A is selected from the group consisting of Br, Cl and I (with Br being preferred); and R represents (C-C)alkyl. Also disclosed are intermediate compounds that are made in the disclosed process.

Synthesis of 2-Hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide

In an illustrative embodiment, the present invention describes the synthesis of the following compound and similar compounds, in high stereochemical purity by a novel stereoselective alkylation process: 

Stereoselective alkylation of chiral 2-methyl-4-protected piperazines

Synthesis of 2-hydroxy-n,n-dimethyl-3-[[2-[[1(r)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide

Disclosed is a process for making the compound of formula I: using the compounds of formulas II, Q, and XI or XII: wherein A is selected from the group consisting of Br, Cl and I (with Br being preferred); and R represents (C&#x2013;C)alkyl. Also disclosed are intermediate compounds that are made in the disclosed process.

Synthesis of 2-hydroxy-N,N-dimethyl-3-[ [2-[1 (R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]aminobenzamide

In an illustrative embodiment, the present invention describes the synthesis of the following compound and similar compounds, in high stereochemical purity by a novel stereoselective alkylation process:

Enantioselective synthesis of azetidinone intermediate compounds

This invention provides a process for preparing the hypocholesterolemic compound

This invention provides an improved process for producing azetidinones. More particularly, this invention provides the steps of producing an trans-azetidinone represented by the formula ##STR1## from a carboxylic acid R.sup.2 --D--CH.sub.2 COOH, an aldehyde R.sup.1 --A--CHO and an amine RNH.sub.2, by the steps of: (a1) converting a carboxylic acid to the corresponding acid chloride; (b1) deprotonating a chiral oxazolidinone and treating the resulting anion with the product of step (a1); (c1) enolizing the product of step (b1) and condensing with the aldehyde; (d1) hydrolyzing the product of step (c1); (e1) condensing the product of step (d1) with the amine; and (f1) cyclizing the product of step (e1). Alternatively, the process comprises (a2) enolizing the product of step (b1) and condensing, in the presence of a Lewis acid, with a Schiff's base prepared from the aldehyde and the amine; and (b2) cyclizing the product of step (a2).

Process for the stereospecific synthesis of azetidinones

This invention provides an improved process for producing azetidinones. More particularly, this invention provides the steps of producing an azetidinone represented by the formula I ##STR1## from a carboxylic acid R.sup.2 --D--CH.sub.2 COOH, an aldehyde R.sup.1 --A--CHO and an amine RNH.sub.2, by the steps of: (a) converting a carboxylic acid to the corresponding acid chloride; (b) deprotonating a chiral oxazolidinone and treating the resulting anion with the product of step (a); (c) enolizing the product of step (b) and condensing with an imine; and (d) cyclizing the product of step (c). Steps (c) and (d) of this process are as shown in the following reaction scheme. ##STR2##

This invention provides an improved process for producing azetidinones. More particularly, this invention provides the steps of producing an trans-azetidinone represented by the formula ##STR1## from a carboxylic acid R.sup.2 -D-CH.sub.2 -COOH, an aldehyde R.sup.1 -A-CHO and an amine RNH.sub.2, by the steps of: (a1) converting a carboxylic acid to the corresponding acid chloride; (b1) deprotonating a chiral oxazolidinone and treating the resulting anion with the product of step (a1); (c1) enolizing the product of step (b1) and condensing with the aldehyde; (d1) hydrolyzing the product of step (c1); (e1) condensing the product of step (d1) with the amine; and (f1) cyclizing the product of step (e1). Alternatively, the process comprises (a2) enolizing the product of step (b1) and condensing, in the presence of a Lewis acid, with a Schiff's base prepared from the aldehyde and the amine; and (b2) cyclizing the product of step (a2).

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Westfield, NJ, United States of America

Timothy L McAllister