Intermediates and processes for the preparation of 4- (acetylamino) ) -3- [ (4-chloro-phenyl) thio] -2-methyl-1h-indole-1-acetic acid

Abstract

The invention relates to compounds of formula (X), and salts thereof, and their use as intermediates in improved manufacturing processes for the synthesis of pharmaceutical compound of formula (I): X is =0, =N-0H or =N-OC(O)Me; Y is hydrogen, PhS- or p-chlorophenylsulfanyl; Z is hydrogen or -CH2COOR1 wherein R1 is selected from hydrogen, optionally substituted hydrocarbyl and optionally substituted heterocyclyl.

Description

technical field [0001] The present invention relates to the technical field related to the large-scale preparation of pharmaceutical compounds. Background technique [0002] International patent application PCT / SE2004 / 000808 (WO2004 / 106302) relates to substituted indoles useful as pharmaceutical compounds for the treatment of respiratory disorders, medicaments containing them and processes for their preparation. More specifically, page 25 of WO2004 / 106302 discloses 4-(acetylamino)-3-[(4-chloro-phenyl)thio]-2-methyl-1H-indole as Example 1 -1-Acetic acid (hereinafter referred to as the compound of formula (I)). [0003] [0004] The routes disclosed on pages 25 and 26 of WO2004 / 106302 for the preparation of compounds of formula (I) are shown in Scheme (I) below. [0005] [0006] Program (I) [0007] The synthesis of compounds of formula (I) disclosed in WO2004 / 106302 has some potential disadvantages. [0008] For example, prior art methods involve the use of very lo...

AI Technical Summary

Problems solved by technology

Another known method for the synthesis of 2-methyl-4-nitroindole requires conditions that are not ideal for large-scale synthesis, as it involves the use of an air atmosphere in the presence of organic solvents, which presents control and safety difficulties (Tetrahedron Letters, 1999, 40, 5395; and Tetrahedron, 2004, 60, 347)

It has actually been found that 2-methyl-4-nitroindole itself is a high-energy molecule (positive results at 2 mm in the Koenen tube test), a clear obstacle to its large-scale use

Also, 2-methyl-4-nitroindole has been found to be relatively expensive as a starting material due in part to the large solvent volumes required and the need for multiple crystallizations to remove by-products

Thus, for prior art methods of synthesizing compounds of formula (I) from 2-methyl-4-nitroindole, the "cost of goods" is potentially disadvantageously high

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