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Synthesis method of (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine and synthesis method of chiral intermediates of niraparib

A chiral intermediate, phenylpiperidine technology, applied in the field of synthesis of chiral intermediates, can solve the problem of high cost of synthesis process

Inactive Publication Date: 2019-05-28
SHANGHAI BIOBOND PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0026] In order to promote the large-scale industrial production of the anticancer drug niraparib and overcome the technical defect that the cost of the existing synthetic process is too high, the present invention mainly aims to provide a new method for synthesizing (S)-3-phenylpiperidine, The method uses commonly used cheap reagents to react, and the reaction conditions are mild, and the yield of each step reaction is high, so that the production cost of the piperidine side chain of niraparib can be effectively controlled; (S)-3-phenylpiperidine Various key chiral intermediates can be further synthesized through simple chemical transformation, therefore, it is beneficial to the production of the anticancer drug niraparib

Method used

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  • Synthesis method of (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine and synthesis method of chiral intermediates of niraparib
  • Synthesis method of (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine and synthesis method of chiral intermediates of niraparib
  • Synthesis method of (R)-3-phenylpiperidine or/and (S)-3-phenylpiperidine and synthesis method of chiral intermediates of niraparib

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1: Synthesis of 3-hydroxyl-3-phenyl-1-benzylpiperidine (3-1)

[0088]

[0089] Phenylmagnesium bromide Grignard reagent (2mol / L in THF, 240mL) and anhydrous tetrahydrofuran (300mL) were added to the reaction flask, protected by nitrogen, cooled to 0°C in an ice-water bath, and N-benzyl-3- Piperidone (2-1, 60.0g, 317.0mmol) was diluted with anhydrous tetrahydrofuran (300mL), added to the dropping funnel, and slowly added dropwise to the reaction flask, the temperature was controlled at 0-5°C, and the dripping was completed in 60 minutes. After the dropwise addition was completed, the stirring reaction was continued for 1 hour. TLC detected that the raw materials had reacted completely. Under stirring, a saturated ammonium chloride aqueous solution (300mL) was added, and then extracted with ethyl acetate (200mL×3). After three extractions, the organic layers were combined and added to An appropriate amount of anhydrous sodium sulfate was dried, filtered, and...

Embodiment 2

[0090] Embodiment 2: Synthesis of 3-hydroxyl-3-phenyl-1-benzylpiperidine (3-1)

[0091]

[0092] Phenylmagnesium bromide Grignard reagent (2mol / L in THF, 240mL) and anhydrous ether (300mL) were added to the reaction flask, protected by nitrogen, cooled to 0°C in an ice-water bath, and N-benzyl-3- Piperidone (2-1, 60.0g, 317.0mmol) was diluted with anhydrous diethyl ether (300mL), added to the dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5°C, and the dripping was completed in 60 minutes. After the dropwise addition was completed, the stirring reaction was continued for 1 hour. TLC detected that the raw materials had reacted completely. Under stirring, a saturated ammonium chloride aqueous solution (300mL) was added, and then extracted with ethyl acetate (200mL×3). After three extractions, the organic layers were combined, and then An appropriate amount of anhydrous sodium sulfate was added to the combined organic layer...

Embodiment 3

[0093] Embodiment 3: Synthesis of 3-hydroxyl-3-phenyl-1-benzylpiperidine (3-1)

[0094]

[0095] Phenylmagnesium chloride Grignard reagent (2mol / L in THF, 240mL) and anhydrous tetrahydrofuran (300mL) were added to the reaction flask, protected by nitrogen, cooled to 0°C in an ice-water bath, and N-benzyl-3-piperidine Ketone (2,60.0g, 317.0mmol) was diluted with anhydrous tetrahydrofuran (300mL), added to the dropping funnel, and slowly added dropwise to the reaction flask, the temperature was controlled at 0-5°C, and the drop was completed after 50 minutes. Continue to stir and react for 1.5 hours, TLC detects that the raw materials have reacted completely, add saturated ammonium chloride aqueous solution (300mL) under stirring, and then extract with ethyl acetate (200mL×3), after extracting three times, combine the organic layers, and then add to the combined organic An appropriate amount of anhydrous sodium sulfate was added to the layer to dry, filtered, and the solvent ...

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Abstract

The invention provides a synthesis method on the first aspect, and by means of the synthesis method, a target product, namely (R)-3-phenylpiperidine or / and (S)-3-phenylpiperidine is / are successfully prepared with N-protected 3-piperidone as a starting material; the invention provides a synthesis method on the second aspect, and by means of the synthesis method, the target product, namely the (R)-3-phenylpiperidine or / and the (S)-3-phenylpiperidine is / are successfully prepared with the same N-protected 3-piperidone as the starting material and by ingeniously utilizing an organic silicon reagent. Chiral intermediates alpha, beta and gamma of niraparib are synthesized from the (S)-3-phenylpiperidine correspondingly according to the third aspect, the fourth aspect and the fifth aspect of the invention. In one word, according to the synthesis method of the (R)-3-phenylpiperidine or / and the (S)-3-phenylpiperidine and the synthesis method of the chiral intermediates alpha, beta and gamma of the niraparib, the production cost is obviously lowered, and large-scale industrial production of niraparib medicines is facilitated.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to the synthesis method of (R)-3-phenylpiperidine or / and (S)-3-phenylpiperidine, and also to the synthesis of chiral intermediates of niraparib method. Background technique [0002] The chemical name of Niraparib (Niraparib, MK-4827) is 2-{4-[(3S)-3-piperidinyl]phenyl}-2H-indazole-7-carboxamide (11), and its chemical The structural formula is as follows: [0003] [0004] As we all know, the anticancer drug Niraparib (Niraparib, MK-4827) developed by Tesaro Biotechnology Company is a new type of oral selective polyadenosine diphosphate-ribose polymerase (PARP) inhibitor. It works by interfering with the DNA repair process in cells, which makes tumors more sensitive to DNA-damaging chemotherapy drugs. The drug is currently undergoing clinical trials in the United States for the treatment of different tumors, including two phase 3 clinical trials for the treatment of ①...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/12C07D211/26C07D211/18
CPCC07B2200/07C07D211/12C07D211/18C07D211/26C07D211/14C07D211/20C07D401/10
Inventor 刘振德高河勇
Owner SHANGHAI BIOBOND PHARMA
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