A PROCESS FOR THE PREPARATION OF THE APOPTOSIS PROMOTER ABT-263

    公开(公告)号:NZ589732A

    公开(公告)日:2012-08-31

    申请号:NZ58973209

    申请日:2009-06-18

    Applicant: ABBOTT LAB

    Abstract: Disclosed A process for making ABT-263 (7) an apoptosis promoter having the proper chemical name: N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, comprising: (a) reacting 4,4-dimethylcyclohexanone, an alkyl formate and a first base to provide (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone; (b) reacting the (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone, a second base and a first silyl ether protecting group reagent to provide a first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and isolating or not isolating the first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone; (c) reacting the first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and isolating or not isolating the first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)4,4-dimethylcyclohexanol; and (d) reacting the first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol and a first acid to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)5,5-dimethylcyclohex-1-ene-1-carbaldehyde; (e) reacting 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde, ethyl 4-piperazin-1-ylbenzoate and a first reducing agent and isolating or not isolating the ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate; (f) reacting ethyl 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate and an aqueous third base, and isolating or not isolating the 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid; and (g) reacting 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid, 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide, a first coupling reagent, and, optionally; a first auxiliary coupling reagent and isolating or not isolating the N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1- ((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide.

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