Simple and convenient production method of rucaparib

A technology for recapab and compounds, which is applied in the field of simple preparation of recapab, can solve the problems of long reaction process, uncontrolled temperature, unfavorable environmental protection and the like, and achieves the effect of mild process conditions

Active Publication Date: 2019-09-13
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] This route requires nitrification reaction, which is an exothermic reaction, which can easily cause temperature out of control and cause an explosion. Therefore, there are large safety hazards and environmental protection problems in industrial production, and this route uses a large amount of nitric acid, sulfuric acid, and phosphorus oxychloride. , not conducive to environmental protection; the process of compound 17 catalytic hydrogenation to obtain compound 18, the yield is low; and the reaction process of this route is long, the reaction cycle is long, and the overall yield is low

Method used

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  • Simple and convenient production method of rucaparib
  • Simple and convenient production method of rucaparib
  • Simple and convenient production method of rucaparib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: 2-[1-(4-N-methyl-N-benzylaminomethyl)benzoyl-3-p-toluenesulfonate]n-propyl-3-nitro-5 Preparation of -methyl fluorobenzoate (Ⅴ1)

[0068] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser, add 200 gram toluene, 27.0 gram (0.1 mole) 4-(N-methyl-N-benzylaminomethyl) methyl benzoate ( Ⅲ1), 13.5 grams (0.12 moles) of potassium tert-butoxide, heated to 50-55 ° C, dropwise added 22.0 (0.1 moles) 2-methyl-3-nitro-5-fluorobenzoic acid methyl ester (Ⅱ) And 50 grams of toluene mixture, dropwise, 50 ~ 60 ° C stirring reaction for 4 hours. Cool to 0-10°C, pass through 5.0 g of ethylene oxide, and react with stirring at 20-25°C for 4 hours. Add 12 grams of triethylamine, 21.0 (0.11 moles) of p-toluenesulfonyl chloride, and stir for 5 hours at 20-25°C. Add the reaction liquid to 250 g of ice water, adjust the pH value to 6-7 with saturated ammonium chloride solution, separate the layers, and extract the water layer twi...

Embodiment 2

[0069] Example 2: 2-[1-(4-N-methyl-N-benzylaminomethyl)benzoyl-3-benzenesulfonate]n-propyl-3-nitro-5-fluorobenzene Preparation of ethyl formate (Ⅴ1)

[0070] In the 500 milliliter four-neck flask that is connected with stirring, thermometer, reflux condenser, add 200 gram tetrahydrofuran, 28.5 gram (0.1 moles) 4-(N-methyl-N-benzylaminomethyl) ethyl benzoate ( Ⅲ1), 13.5 grams (0.12 moles) of potassium tert-butoxide, heated to 50-55 ° C, dropwise added 23.0 (0.1 moles) ethyl 2-methyl-3-nitro-5-fluorobenzoate (Ⅱ) under stirring And 50 grams of tetrahydrofuran mixture, dropwise, 55 ~ 60 ° C stirring reaction for 4 hours. Cool to 0-10°C, pass through 5.0 g of ethylene oxide, and react with stirring at 20-25°C for 4 hours. Add 12 g of triethylamine and 19.5 g (0.11 mole) of benzenesulfonyl chloride, and stir and react at 20-25° C. for 5 hours. Add the reaction liquid to 200 g of ice water, adjust the pH value to 6-7 with saturated ammonium chloride solution, separate the layers, ...

Embodiment 3

[0071] Example 3: 2-[1-(4-N-methyl-N-benzylaminomethyl)benzoyl-3-methanesulfonate]n-propyl-3-nitro-5-fluorobenzene Preparation of ethyl formate (Ⅴ1)

[0072] In a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 200 g of 2-methyltetrahydrofuran, 28.5 g (0.1 mol) of 4-(N-methyl-N-benzylaminomethyl)benzene Ethyl formate, 8.6 grams (0.13 moles) of sodium ethylate, heated to 60-65 ° C, dropwise added 23.0 grams (0.1 moles) of ethyl 2-methyl-3-nitro-5-fluorobenzoate and 50 grams of 2 -Methyl tetrahydrofuran mixture, after dropping, stir and react at 65-70°C for 2 hours. Cool to 0-10°C, pass through 5.5 g of ethylene oxide, and react with stirring at 20-25°C for 4 hours. Add 12 grams of triethylamine and 15.0 (0.13 moles) of methanesulfonyl chloride, and stir and react at 20-25°C for 4 hours. Add the reaction liquid to 200 g of ice water, adjust the pH value to 6-7 with saturated ammonium chloride solution, separate the layers, and extrac...

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Abstract

The invention relates to a simple and convenient production method of rucaparib. The method comprises the steps of conducting condensation on 5-fluoro-2-methyl-3-nitrobenzoate and 4-(N-methyl-N-PG-aminomethyl)benzoate under the action of an alkaline, subjecting an obtained condensation product and ethylene oxide to a hydroxyethylation reaction, carrying out sulfonyl chloride protection and catalytic hydrogenation indole cyclization to produce 2-(4-methylaminomethyl)phenyl-3-(2-sulphonate)ethyl-6-fluoro-1H-indole-4-formate, and then subjecting the 2-(4-methylaminomethyl)phenyl-3-(2-sulphonate)ethyl-6-fluoro-1H-indole-4-formate and ammonia to an SN2 substitution reaction and an amidation reaction to produce the rucaparib through a one-pot method. The raw materials of the method are cheap andeasy to obtain, and the method is short in technology process, simple and convenient to operate, little in wastewater quantity and environmentally friendly, and benefits industrial production of rucaparib.

Description

technical field [0001] The invention relates to a simple and convenient preparation method of recaprabab, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Recaparib (I), also known as Rucaparib in Chinese, Rucaparib in English, and Rubraca in trade, is a new poly ADP-ribose polymerase (poly ADP-ribose polymerase). Polymerase (PARP) inhibitors, gene mutations that can prevent cancer cells from spreading throughout the body, are used to treat advanced ovarian cancer associated with BRCA gene mutations after two or more lines of chemotherapy. The drug was first discovered by Newcastle University, later acquired by Pfizer, and sold to Clovis in 2011. In April 2015, it was granted the qualification of breakthrough therapy for ovarian cancer by the US Food and Drug Administration (FDA), and in 2016. Accelerated approval for marketing in December, as a monotherapy for patients with refractory advanced ovarian cancer. The chemical na...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/06
CPCC07D487/06
Inventor 戚聿新刘月盛王素平
Owner XINFA PHARMA
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