Novartis Ag

Steven Dell

Wen-Chung Shieh

Mario Emilov Lozanov

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.

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Madison, NJ, United States of America

Steven Dell