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Preparation method of niraparib intermediate (S)-3-(4-bromophenyl) piperidine

A technology of bromophenyl and intermediate, which is applied in the field of preparation of niraparib intermediate-3-piperidine, can solve the problems of expensive preparation cost of raw materials and reagents, poor operation safety and high risk factor, and achieve industrialized amplification The effect of production, overall cost reduction, and safety hazards reduction

Pending Publication Date: 2020-10-23
成都正善达生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] In view of the above-mentioned defects of the prior art, the technical problem to be solved by the present invention is that the preparation method of the existing (S)-3-(4-bromophenyl)piperidine has many steps, is loaded down with trivial details, and the raw materials and reagents are expensive and the preparation cost is high. , the use of dangerous chemicals such as sodium hydride and borane, the use of highly toxic substances such as acrylate and methanesulfonyl chloride, and the use of odorous and irritating reagents have high risk factors and poor operational safety, which is not conducive to industrialization

Method used

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  • Preparation method of niraparib intermediate (S)-3-(4-bromophenyl) piperidine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Embodiment 1, the preparation of compound A-1

[0091] Add 156g of the raw material compound SMB and 780ml of acetonitrile into the reaction vessel, cool down to 0-10°C and add 264g of the raw material compound SMA dropwise, after the addition is completed, heat up to 20-30°C, keep stirring at this temperature for 14-16h; add ethyl acetate to the reaction solution Extract the ester, combine the organic layers, add 1M hydrochloric acid to wash, then add concentrated hydrochloric acid to precipitate a solid, filter with suction, wash the filter cake with ethyl acetate, and dry it with air at 50-60°C for 10-12h to obtain compound A-1 (163g, harvested rate 70%);

[0092] Embodiment 1 On the basis of the above-mentioned experiments, the optimization condition experiment also includes:

[0093] The solvent is the optimized parallel experiment of DMF and THF;

[0094] Optimized parallel experiments with reaction temperatures of 40-50°C and 0-10°C;

[0095] The optimized par...

Embodiment 2

[0096] Embodiment 2, the preparation of compound A-2

[0097] Add 160g of compound A-1, 1.6L of dichloromethane and 147g of the raw material compound SMC into the reaction vessel, cool the reaction solution to 0-10°C, add 69g of triethylamine, then add 144g of condensing agent CDI in batches, and raise the temperature of the reaction solution Stir the reaction at 20-30°C for 10-12h; add water to the reaction liquid to quench, add dilute hydrochloric acid to adjust pH=1-2, remove the water phase, and concentrate the organic phase under reduced pressure to remove the dichloromethane solvent to obtain compound A-2 ( 263g, yield 98%);

[0098] Embodiment 2 On the basis of the above-mentioned experiments, the optimization condition experiment also includes:

[0099]The base is DIPEA, NaHCO 3 Optimized parallel experiments;

[0100] Parallel experiments were optimized for THF as the organic solvent.

Embodiment 3

[0101] Embodiment 3, the preparation of compound A-3

[0102] Add 125g potassium tert-butoxide and 450ml solvent DMF to the reaction vessel, add 220g compound A-2 (solution dissolved in 450ml DMF) after the reaction solution is cooled to 0-10°C, and the reaction solution is heated to 20-30°C and stirred for 10 -12h; After treatment, add water and ethyl acetate to extract, combine the organic layers, wash with water, concentrate under reduced pressure to remove ethyl acetate, add petroleum ether to the residue, stir and filter with suction, and dry the solid at 40-50°C with air blast to obtain compound A-3 (76g , yield 38%) (equivalent to 76% of theoretical yield);

[0103] Embodiment 3 On the basis of the above-mentioned experiments, the optimization condition experiment also includes:

[0104] Solvent is the optimized parallel experiment of THF;

[0105] Optimized parallel experiments with reaction temperatures of 30-40°C and 0-10°C;

[0106] The bases are optimized parall...

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Abstract

The invention discloses a preparation method of a niraparib intermediate that is (S)-3-(4-bromophenyl) piperidine, which comprises the following steps: by using chiral 1-phenylethylamine as a raw material, carrying out alkylation, condensation, cyclization and reduction, and finally removing an amino protection group to obtain the (S)-3-(4-bromophenyl) piperidine. The preparation method of the (S)-3-(4-bromophenyl) piperidine has the advantages of short route, few steps, simple and convenient process operation, avoidance of use of dangerous reagents, highly toxic reagents and irritant malodorous reagents, reduction of potential safety hazards to operators, reduction of the operation safety level of production, environmental protection, and facilitation of industrialization.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for preparing a niraparib intermediate (S)-3-(4-bromophenyl)piperidine. Background technique [0002] The new anticancer drug Niraparib (Niraparib) is a PARP inhibitor, the trade name is Zejula, which was approved by the US FDA in March 2017 for recurrent epithelial ovarian cancer, fallopian tube cancer or primary Maintenance therapy in female patients with acute peritoneal cancer. Niraparib (Niraparib) is the first FDA-approved PARP inhibitor that can be used for treatment without the detection of BRCA mutations or other biomarkers. It can block the enzyme involved in repairing damaged DNA. By blocking this enzyme, cancer The DNA within the cells is not repaired, leading to cell death and possibly slowing or stopping tumor growth. [0003] Compound (S)-3-(4-bromophenyl)piperidine is a key intermediate for the synthesis of niraparib, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/18C07D211/02
CPCC07D211/18C07D211/02
Inventor 庹世川李泽林陶建
Owner 成都正善达生物医药科技有限公司
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