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Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate

A technology of tert-butyl formate and aminophenyl, which is applied in the field of drug synthesis and can solve problems such as difficult separation, high cost, and inability to split 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl , to achieve the effects of less environmental pollution, easy recycling and good industrial application prospects

Inactive Publication Date: 2017-02-22
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Use 2 times the amount of L-dibenzoyl tartaric acid in this reaction route, the cost is high, and this document further reports simultaneously, use L-dibenzoyl tartaric acid and can not resolve 3-(4-aminophenyl) piperidine- tert-Butyl 1-formate
[0014] In the prior art, another shortcoming of first resolving and then carrying out Boc protection is that the amino group on the benzene ring is also protected, and the content of the double-protected product is between 5-10%, which is comparable to 3-(4-aminophenyl ) tert-butyl piperidine-1-carboxylate has similar properties and is difficult to separate
In the prior art, there is no report on the chemical resolution of the racemate 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester

Method used

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  • Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate
  • Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate
  • Preparation method of niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Dissolve 2.76g (10mmol) of 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester racemate in 85mL of an aqueous ethanol solution (the volume ratio of water to alcohol is 1:16), stir and drop. Add 3.06g of the resolving agent benzenesulfonyl-D-phenylglycine dissolved in 10mL of 50% (v / v) ethanol solution. After the addition is complete, the mixed solution is reacted at 65°C for 2.5 hours, and slowly cooled to 40°C for crystallization 2 After hours, the crystallization was continued at room temperature to obtain (3S)-3-(4-aminophenyl)piperidine-1-carboxylate tert-butyl p-sulfonyl-D-phenylglycinate 2.56 g, with a yield of 90.3%.

[0040] 2.56g (3S)-3-(4-aminophenyl)piperidine-1-carboxylate tert-butyl benzenesulfonyl-D-phenylglycinate was added to 30g ethanol aqueous solution (V water: V ethanol = 1:9 ), heated to 55°C to dissolve, kept for 1.0 hour, stirred and cooled to crystallize to obtain 2.43 g of the product.

[0041] 2.43g (3S)-3-(4-aminophenyl)piperidine-1-car...

Embodiment 2

[0043] Dissolve 2.76g (10mmol) of 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester racemate in 90mL aqueous ethanol solution (water to alcohol volume ratio 1:18), and drop with stirring Add 3.00g of the resolving agent benzenesulfonyl-D-phenylglycine dissolved in 10mL of 50% (v / v) ethanol solution. After the addition is complete, the mixed solution is reacted at 60°C for 3 hours, and slowly cooled to 45°C to crystallize 2 After hours, the crystallization was continued at room temperature to obtain (3S)-3-(4-aminophenyl)piperidine-1-carboxylate tert-butyl benzenesulfonyl-D-phenylglycinate 2.60 g, with a yield of 91.5%.

[0044] Add 2.60g (3S)-3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl benzenesulfonyl-D-phenylglycinate to 36g ethanol aqueous solution (V water: V ethanol = 1:9 ), heated to 60°C to dissolve, kept for 1.5 hours, stirred and cooled to crystallize to obtain 2.40g of the product.

[0045] Suspend 2.40g (3S)-3-(4-aminophenyl)piperidine-1-carboxy...

Embodiment 3

[0047] Dissolve 2.76g (10mmol) of 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester racemate in 78mL of aqueous ethanol solution (volume ratio of water to alcohol is 1:16), stir and drop. Add 3.09g of the resolving agent benzenesulfonyl-D-phenylglycine dissolved in 12mL of 50% (v / v) ethanol solution. After the addition is complete, the mixed solution is reacted at 63°C for 2.5 hours and slowly cooled to 40°C for crystallization 2.0 After hours, the crystallization is continued at room temperature to obtain (3S)-3-(4-aminophenyl)piperidine-1-carboxylate tert-butyl benzenesulfonyl-D-phenylglycinate 2.70g with a yield of 95.1%.

[0048] Add 2.70 g of (3S)-3-(4-aminophenyl)piperidine-1-carboxylate benzenesulfonyl-D-phenylglycinate to 50 g of ethanol aqueous solution (V water: V ethanol = 1:10 ), heated to 58°C for dissolution, kept for 1.0 hour, stirred and cooled to crystallize to obtain 2.54 g of the product.

[0049] (2) Suspend 2.54g (3S)-3-(4-aminophenyl)piperidine-1...

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Abstract

The invention belongs to the field of medicine synthesis, and relates to a preparation method of a niraparib intermediate of (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate. The method is characterized in that a D-phenylglycine derivative is used as a resolving agent; 3-(4-aminophenyl) piperidine-1-tert-butyl formate racemic bodies are used as raw materials; splitting is performed in a solvent; separation is performed to obtain a split salifying product; acid is added into the split salifying product; hydrolysis is performed; the resolving agent is extracted and separated; the pH is regulated to 8 to 10; distillation is performed to obtain the (3S)-3-(4-aminophenyl) piperidine-1-tert-butyl formate. The method has the advantages that the resolving efficiency is high; the product optical purity is high; the resolving agent can be easily recycled and reused; the application cost is low; the preparation method is suitable for large-scale production; the technical support is provided for further preparation of high-purity niraparib.

Description

Technical field [0001] The invention belongs to the field of drug synthesis and relates to a preparation method of (3S)-3-(4-aminophenyl)piperidine-1-carboxylate, which is an anticancer drug niraprab intermediate. Background technique [0002] Niraparib (Niraparib, R&D code MK-4827, CAS: 1038915-60-4) is a PARP inhibitor developed by Merck and later transferred to Tesaro. It is currently in Phase III clinical phase, and its development indications are ovarian cancer, breast cancer, prostate cancer, etc. Its chemical name: 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole- 7-formamide, the chemical structure is shown in the following formula (1): [0003] [0004] Niraparib is a PARP inhibitor. PARPs are one of the important mechanisms for repairing DNA damage. If DNA damage is not repaired, cells may die. Normal cells and some tumor cells will rely on PARP for DNA damage repair. What's interesting is that inhibiting the activity of PARP is unlikely to kill healthy cells, because hea...

Claims

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Application Information

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IPC IPC(8): C07D211/26
CPCC07D211/26
Inventor 陈令浩
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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