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Synthesis method of 4-(4-((2-(4-chlorophenyl)-5,5-dimethyl cyclohexyl-1-polyprolene) methyl) diethylenediamine-1-radical) benzoic acid

A technology of dimethylcyclohexyl and dimethylcyclohexanone, applied in 4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexyl-1-ene) The field of synthesis of methyl)piperazin-1-yl)benzoic acid can solve the problems of high synthesis cost, low yield and complicated operation

Active Publication Date: 2015-07-01
上海药明康德新药开发有限公司
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to improve the route of the important intermediate carboxylic acid fragment of ABT-263, mainly to solve the problems of complex operation, low yield and high synthesis cost in the existing synthesis method

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022]

[0023] 1. (2-Bromo-5,5-dimethylcyclohexyl-1-ene)formaldehyde 2 Synthesis

[0024] Phosphorus tribromide (140 mL) was dropped into a mixed solution of dichloromethane (1.0 L) and N,N-dimethylformamide (130 mL) cooled in an ice bath. The reaction solution was stirred at room temperature for 30 minutes. Cool to 0°C, 4,4-dimethylcyclohexanone 1 (65 g, 0.51 mol) was dissolved in 500 mL of dichloromethane and dropped into the reaction solution. Gradually return to room temperature and stir for 16 hours. After the reaction, the reaction solution was poured into cold saturated aqueous sodium bicarbonate solution, extracted three times with methyl tert-butyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product 2-bromo-5,5 -Dimethylcyclohexyl-1-enecarbaldehyde 2 (Yield: 81%).

[0025] H NMR spectrum 1 H-NMR (CDCl 3 , 400 MHz): δ10.02 (s, 1H), 2.73 (t, J = 5.2 Hz, 2H), 2.08 (s, 2H), 1.53...

Embodiment 2

[0042] Reaction formula sees embodiment 1

[0043] 1. (2-Bromo-5,5-dimethylcyclohexyl-1-ene)formaldehyde 2 Synthesis

[0044] Phosphorus tribromide (140 mL) was dropped into a mixed solution of dichloromethane (1.0 L) and N,N-dimethylformamide (130 mL) cooled in an ice bath. The reaction solution was stirred at room temperature for 30 minutes. Cool to 0°C, 4,4-dimethylcyclohexanone 1 (65 g, 0.51 mol) was dissolved in 500 mL of dichloromethane and dropped into the reaction solution. Gradually return to room temperature and stir for 3 hours. After the reaction, the reaction solution was poured into cold saturated aqueous sodium bicarbonate solution, extracted three times with methyl tert-butyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the product 2-bromo-5,5 -Dimethylcyclohexyl-1-enecarbaldehyde 2 (Yield: 75%).

[0045] H NMR spectrum 1 H-NMR (CDCl 3 , 400 MHz): δ10.02 (s, 1H), 2.73 (t, J = 5.2 ...

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Abstract

The invention relates to an improved synthesis method of the intermediate carboxylic acid segment [4-(4-((2-(4-chlorophenyl)-5,5-dimethyl cyclohexyl-1-polyprolene) methyl) diethylenediamine-1-radical) benzoic acid] of an anticancer compound molecule ABT-263. The synthesis method mainly solves the problems of complicated operation, low yield and high synthesis cost of the existing synthesis method. The synthesis of the intermediate carboxylic acid segment of ABT-263 comprises the following steps: step 1, the reaction takes 4,4-dimethyl cyclohexanone as a raw material to react with phosphorus tribromide, dichloromethane and N,N-dimethylformamide mixed solution, so 2-bromine-5,5-dimethyl cyclohexyl-1-yl-formaldehyde 2 is generated; step 2, reduction reaction: a compound 2 undergoes the reduction reaction under the action of sodium borohydride to generate the corresponding alcoholate; step 3, bromination reaction: the alcoholate undergoes the bromination reaction under the action of phosphorus tribromide to generate the corresponding bromide; and step 4, the reaction is that: the bromide and 4-(diethylenediamine-1-radical) benzoic acid t-butyl ester are subjected to the substitution reaction to generate the intermediate 4-(4-((2-bromine-5,5-dimethyl cyclohexyl-1-alkenyl) diethylenediamine-1-radical) benzoic acid t-butyl ester, and after the Suzuki reaction of a step 5 and the hydrolysis reaction of a step 6, the corresponding carboxylic acid intermediate is generated.

Description

technical field [0001] The present invention relates to an intermediate carboxylic acid fragment [4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohexyl-1-ene)methanol of an anticancer compound molecule ABT-263 Base) improved synthesis of piperazin-1-yl) benzoic acid]. Background technique [0002] ABT-263 is an apoptosis-inducing small molecule Bel-2 inhibitor developed by Abbott Laboratories. Retrosynthetic analysis of Formula 1 shows that the compound can be spliced ​​from three fragments. For the synthesis of the carboxylic acid fragment, the Abbott Pharmaceuticals published patent (US2009 / 318689 A1) and published papers (J. Med. Chem; 2008; 6902-6915) reported the synthetic route formula 2 of the compound, but the route operation Complex, low yield, wherein the yield of reductive amination is only 38%, and most of the intermediates need to be separated by column chromatography, which is not suitable for large-scale preparation. Guangjun Wang et al. reported (Synthesis; 200...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/155
Inventor 张培权肖贻崧张守南吴松亮贺海鹰陈曙辉
Owner 上海药明康德新药开发有限公司
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