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

A chiral intermediate, phenylpiperidine technology, applied in the field of synthesis of chiral intermediates, can solve the problems of high reaction yield, high synthesis process cost, mild reaction conditions, etc., and achieves high reaction yield and reduced production. Cost, mild effect of reaction conditions

Inactive Publication Date: 2018-06-26
SHANGHAI BIOBOND PHARMA
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Problems solved by technology

[0028] In order to promote the large-scale industrial production of niraparib and overcome the technical defects of the high cost of the existing synthetic process, the present invention aims to provide a new method for synthesizing (S)-3-phenylpiperidine, which uses Commonly used cheap reagents react, and the reaction conditions are mild, and the yield of each step reaction is higher, so that the production cost of the piperidine side chain of niraparib can be effectively controlled; and (S)-3-phenylpiperidine can be passed through A simple chemical transformation affords Boc-protected (S)-3-p-aminophenylpiperidine 13 and Boc-protected (S)-3-p-bromophenylpiperidine 23, respectively

Method used

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

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Experimental program
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Effect test

Embodiment 1

[0075] Embodiment 1: Synthesis of 3-hydroxyl-3-phenyl-1-benzylpiperidine (3)

[0076] Scheme 10:

[0077]

[0078] 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 (2,60.0g, 317.0mmol) was diluted with anhydrous tetrahydrofuran (300mL), added to the dropping funnel, slowly added dropwise to the reaction flask, and the temperature was controlled at 0-5°C. After completion, continue to stir and react for 1 hour. TLC detects that the raw materials have reacted completely. Add saturated ammonium chloride aqueous solution (300mL) while stirring, and then extract with ethyl acetate (200mL×3). After three extractions, combine the organic layers and add an appropriate amount of Dry over sodium sulfate, filter, and spin dry the solvent to obtain 76.5 g of the crude product (3-hydroxy-3-phenyl-1-benzylpiperidine ...

Embodiment 2

[0079] Embodiment 2: Synthesis of 3-hydroxyl-3-phenyl-1-benzylpiperidine (3)

[0080] Scheme 11:

[0081]

[0082] 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 (2,60.0g, 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. After 60min, dropwise added After completion, continue to stir and react for 1 hour. 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 An appropriate amount of anhydrous sodium sulfate was added to the organic layer to dry, filtered, and the solvent was spin-dried to ...

Embodiment 3

[0083] Embodiment 3: Synthesis of 3-hydroxyl-3-phenyl-1-benzylpiperidine (3)

[0084] Scheme 12:

[0085]

[0086] 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, filtere...

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Abstract

The invention belongs to the technical field of organic synthesis. The synthesis method firstly provided by the invention takes benzyl-4-oxopiperidine as a starting material, and the starting materialis subjected to Grignard reaction, elimination reaction, hydrogenation reduction reaction and chiral resolution in sequence to successfully obtain a target product (R)-3-phenylpiperidine or/ and (S)-3-phenylpiperidine. The synthesis method sencondly provided by the invention takes the same starting raw material for Grignard reaction, organic silicon reagent is used for removing a hydroxide radical, and benzyl is removed by catalytic hydrogenation reaction; finally, the chiral resolution is carried out to obtain a target product. The (S)-3-phenylpiperidine can be synthesized according to the synthesis method. (S)-3-p-aminosalicylic phenylpiperidine can be synthesized according to the third aspect; or according to the fourth aspect, (S)-3-p-bromophenyl piperidine is synthesized to serve asthe key intermediate for preparing the niraparib. According to the synthesis method for (R)-3-phenylpiperidine or/ and (S)-3-phenylpiperidine and the synthesis method for chiral intermediate of niraparib, production cost is obviously lowered, and the synthesis methods are favorable for the large-scale industrial production of a niraparib medicine.

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 刘振德崔效源高河勇
Owner SHANGHAI BIOBOND PHARMA
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