Novartis Ag

Ciba-geigy Corporation

Novartis Pharma Gmbh

Novartis Pharma Ag

Wen-Chung Shieh

Paul William Manley

Paul Allen Sutton

Raeann Wu

Jörg Brozio

Stéphanie Monnier

Steven Dell

Piotr Henryk Karpinski

Song Xue

Murat Acemoglu

Piotr “Peter” H Karpinski

Mahavir Prashad

Bernhard Erb

Christoph Max Krell

Mark Meisenbach

Stephan Abel

Joseph McKenna

Joseph Sclafani

John Alan Carlson

Mario Emilov Lozanov

Berthold Schenkel

John Joseph Fitt

Francisco Vicente Baños

Noela Marjory Reel

William R Cantrell

Jose Martin Medina

Pedro Garcia Fuentes

Erich Widmer

Joerg Brozio

Jorg Brozio

Joseph Mckenna

Francisco Vicente Banos

Christoph Krell

Plotr H Karpinski

Salts of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide are prepared by various processes.

Salts of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide

The present invention provides a new method of making compounds of formula (I): wherein

Process for the synthesis of 5-(methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine

Crystalline forms of 4-methyl-N-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and salts thereof are prepared by various processes.

Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide

Salts of 4-methyl N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide

Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and salts thereof are prepared by various processes.

Polymorphic forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and salts thereof are prepared by various processes.

Salts of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-Benzamide

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The present invention provides an efficient, safe and cost effective way to prepare 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine which is a key intermediate for the preparation of substituted pyrimidinylaminobenzamides of formula (II): 

Process for the synthesis of organic compounds

The present invention provides an efficient, safe and cost effective way to prepare 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine which is an intermediate for the preparation of substituted pyrimidinylaminobenzamides of formula (II): 

The present invention provides methods for the efficient preparation of indole derivatives of the formula wherein X is methyl or benzyl; and R, R, Rand Rare independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl or heteroaryl; or Rand Rcombined together with the carbon atoms to which they are attached form a fused 6-membered aromatic ring; by reacting indoles of the formula wherein R, R, Rand Rhave meanings as defined for formula I, with dimethyl carbonate when X is methyl, or with dibenzyl carbonate when X is benzyl, in the presence of a catalytic amount of a base at an ambient temperature to afford compounds of formula I wherein X, R, R, Rand Rhave meanings as defined herein above. In particular, the present invention provides methylation and benzylation of the indole nitrogen in nearly quantitative yields using 1,4-diazabicyclo[2.2.2]octane as the base in a catalytic amount under mild conditions, wherein the alkylations may be conducted in the absence or the presence of an ionic liquid, under microwave irradiation or utilizing conventional heat, or combinations thereof.

N-alkylation of indole derivatives

The present invention provides methods for the efficient preparation of indole derivatives of the formulawherein X is methyl or benzyl; and R, R, Rand Rare independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl or heteroaryl; or Rand Rcombined together with the carbon atoms to which they are attached form a fused 6-membered aromatic ring; by reacting indoles of the formulawherein R, R, Rand Rhave meanings as defined for formula I, with dimethyl carbonate when X is methyl, or with dibenzyl carbonate when X is benzyl, in the presence of a catalytic amount of a base at an ambient temperature to afford compounds of formula I wherein X, R, R, Rand Rhave meanings as defined herein above. In particular, the present invention provides methylation and benzylation of the indole nitrogen in nearly quantitative yields using 1,4-diazabicyclo[2.2.2]octane as the base in a catalytic amount under mild conditions, wherein the alkylations may be conducted in the absence or the presence of an ionic liquid, under microwave irradiation or utilizing conventional heat, or combinations thereof.

An accelerated process for preparing an O-methyl phenol comprising reacting a phenol with dimethyl carbonate in the presence of a catalyst selected from 1,8-diazabicyclo&lsqb;5.4.0&rsqb;undec-7-ene; 1,4-diazabicyclo&lsqb;2.2.2&rsqb;octane; and dimethylaminopyridine. According to another aspect, the invention provides an accelerated process for preparing an N-methyl heteroaromatic compound comprising reacting an NH-containing heteroaromatic compound with dimethyl carbonate in the presence of a catalyst selected from 1,8-diazabicyclo&lsqb;5.4.0&rsqb;undec-7-ene; 1,4-diazabicyclo&lsqb;2.2.2&rsqb;octane; and dimethylaminopyridine. According to an additional aspect, the invention provides an accelerated process for preparing a methylated aminophenol comprising reacting an aminophenol having at least one N&mdash;H with dimethyl carbonate in the presence of a catalyst selected from 1,8-diazabicyclo&lsqb;5.4.0&rsqb;undec-7-ene; 1,4-diazabicyclo&lsqb;2.2.2&rsqb;octane; and dimethylaminopyridine. The process of the invention is especially advantageous since the process: (1) utilizes an environmentally friendly methylating reagent, dimethylcarbonate; (2) produces a high yield of the O-methyl phenols, N-methyl aromatic amines, and/or methylated aminophenols, generally 97-100% conversion; and (3) does not require a high-pressure (autoclave) reactor.

Accelerated process for preparing O-methyl phenols, N-methyl heteroaromatic compounds, and methylated aminophenols

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Berkeley Heights, NJ, United States of America

Wen-Chung Shieh