Process for the preparation of enantiomerically pure cycloalkano-indole- and azaindole- and pyrimido 1,2a indole-carboxylic acids and their activated derivatives

摘要

Preparation of (heterocyclyl-methyl)phenylacetic acid compounds of formula (I) and its salts comprises (1) diastereoselective alkylation of a compound of formula CH3-Ar-CH2COOR6 (II) with a compound of formula T-Z (III) in an inert solvent in the presence of a base to give the compound of formula CH3-Ar-CHT(*)COOR6 (IV); (2) halogenation of (IV) to give the compound of formula R7-CH2-Ar-CHT(*)COOR6 (V); (3) reacting (V) with a compound A-H (VI) to give the compound of formula A-CH2-Ar-CHT(*)COOR6 (VII); and (4a) hydrolysis of (VII) to give (I; Q = OH), or (4b) reaction with the appropriate compound to give (I; Q = activated group). Ar = phenylene; A = a group of formula (a) or (b') (N.B., (b') is described as an aza-indole and given everywhere else as a group of formula (b); A', D, E, G, L, M = H or R; R1+R2 complete benzene, pyridine or a ring of formula (c) (all optionally substituted by mono- to tri-substituted by R); R5 = H or 1-4C alkyl; R3+R4 complete benzene, 4-8 membered cycloalkene or 4-8 membered oxocycloalkene group (all optionally mono- to tri-substituted by R); R = halo, CF3, CO2H, OH, 1-6C alkoxy, 1-6C alkoxycarbonyl or 1-6C alkyl (optionally substituted by OH or 1-4C alkoxy); T = 4-12C cycloalkyl or 1-12C alkyl; Q = OH or an activated group; OR6 = a chiral alcohol group; Z = a typical leaving group such as Br, Cl, I, mesyl, tosyl or SO2CF3, preferably I or Br; R7 = halo, such as Cl, Br or I, preferably Br. Also claimed is a method for preparing (I) by resolving (R,S) CH3-Ar-CH2COOH (X) by reaction with (R)- or (S)-phenylethylamine in an inert solvent followed by crystallisation of the resulting phenylethylammonium sa reaction with isobutene in an inert solvent in the presence of an acid to give (XII) of formula (IV; R6 = tert. butyl); and treatment of (XII) as for (IV). The following compounds and their salts are new; (I; A = a group of formula (a1) or (b1); Q = OH or Cl); (IV; R6 = D- or L-menthyl or tert.-butyl and T is not isopropyl (sic)); (V; R6 = D- or L-menthyl or tert.-butyl R7 = Br)); and compounds described as (VII) with R6 = D- or L-menthyl and given the formula (A).