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Method for preparing Niraparib of PARP (poly-ADP-ribose polymerase) inhibitor

A benzyl reaction technology, applied in the field of chemical medicine of the present invention, can solve the problems of long synthetic route and high cost

Inactive Publication Date: 2017-05-31
NANJING CORE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Route 3 (such as formula 4) Org.Process Res.Dev.2014,18,215-227 reports: (S)-3-(4-aminophenyl)piperidine is derived from (S)-3-(4-aminophenyl )-2-piperidone is obtained by reduction, and (S)-3-(4-aminophenyl)-2-piperidone is obtained by using specific enzymes through biological fermentation. This method has certain limitations. The enzyme needs to be specially cultivated, and the synthetic route is longer and the cost is higher

Method used

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  • Method for preparing Niraparib of PARP (poly-ADP-ribose polymerase) inhibitor
  • Method for preparing Niraparib of PARP (poly-ADP-ribose polymerase) inhibitor
  • Method for preparing Niraparib of PARP (poly-ADP-ribose polymerase) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0043] Example 1 Under the protection of nitrogen, compound 3 (36.0g, 0.19mol) was dissolved in 190mL of dichloromethane, then diisopropylethylamine (27.0g, 0.21mol) was added, and the temperature was lowered to -60°C, dropwise Add trifluoromethanesulfonic anhydride (59.2g, 0.21mol), and react at this temperature. After the reaction, add water, warm up to room temperature, extract with ethyl acetate, wash with saturated sodium bicarbonate, dry the organic phase, and evaporate under reduced pressure. The solvent was removed to obtain 44.5 g of a mixture of compound 3 as a light yellow solid.

[0044]

example 2

[0045] Example 2 Under the protection of nitrogen, after adding 130mL tetrahydrofuran to the mixture of compound 3 (39.0g, 0.12mol) to dissolve, add p-nitrophenyl borate (31.4g, 0.13mol), tetrakistriphenylphosphopalladium (6.9 g, 6.0mmol), potassium carbonate (33.1g, 0.13mol), and heated to reflux temperature, and reacted at this temperature for 8 hours, after the reaction, the system was lowered to room temperature, and the reaction solution was filtered with diatomaceous earth, and the filtrate Part of the solvent was distilled off under reduced pressure, crystals were precipitated at low temperature, and the mixture of compounds 5 and 6 was obtained by filtration as 37.5 g of a light brown solid.

[0046]

example 3

[0047] Example 3 In an autoclave, 110 mL of methanol was added to the mixture of compounds 5 and 6 (19.0 g, 0.065 mol), 30 mL of acetic acid was added, 1.5 g of palladium hydroxide was added, and then hydrogen gas was introduced, and the reaction was carried out at 12 atmospheres for 24 hours , after the reaction is complete, filter out the solid, and evaporate most of the methanol in the filtrate under reduced pressure, add 1mL sodium hydroxide solution 130mL, stir for 20 minutes, extract twice with ethyl acetate (2*100mL), and use Wash once with saturated citric acid (100 mL), dry the organic phase over anhydrous sodium sulfate, and distill the organic phase under pressure to obtain 9.3 g of a light yellow solid.

[0048]

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Abstract

The invention discloses a method for preparing 2-(4-((3S)-3-piperidyl) phenyl)-2H-indazole-7-formamide of a compound. Benzyl protected-piperidone is generated into piperidone of 3-triflic anhydride under the action of triflic anhydride, the piperidone and nitrobenzoic acid are subjected to Suzuki reaction to obtain a coupled product, 3-(4-aminophenyl) piperidine is obtained under the action of a palladium reagent, (S)-3-(4-halogenated phenyl) piperidine is prepared with a chirality resolution reagent, the (S)-3-(4-halogenated phenyl) piperidine is condensed with 3-formyl-2-methyl nitrobenzoate to form pyrazolone ring under the action of sodium azide, and the Niraparid (with the molecular entity of 2-(4-((3S)-3-piperidyl) phenyl)-2H-indazole-7-formamide) is prepared via aminolysis.

Description

[0001] Technical field: the present invention belongs to the field of chemical medicine, specifically a method for preparing 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide [0002] Background technique: [0003] With the changes of human living environment, living standards and lifestyles and the advancement of medicine, the spectrum of diseases has undergone significant changes, general infectious diseases have been gradually controlled, and malignant tumors have become increasingly common and seriously threaten human life and quality of life. one of the major diseases. At present, in China and even in the world, cancer has become the second leading cause of human death. In recent years, molecular oncology and molecular pharmacology have continuously clarified the nature of tumors. Malignant tumors are diseases in which the body's own cells become uncontrolled proliferation and spread, and are a type of disease in which cells proliferate and differentiate abnormall...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/10
CPCC07D401/10C07B2200/07
Inventor 王雪根何凌云余洋魏超
Owner NANJING CORE TECH CO LTD
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