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Preparation method of Niraparib intermediate 4-(3S-piperidine-3-yl)aniline

An intermediate, piperidine technology is applied in the field of preparation of anticancer drug Niraparib intermediate 4-aniline, which can solve the problems of high reaction cost, cumbersome processing, poor selectivity, etc., and achieves reduced production cost, fewer steps, and is conducive to scale. production effect

Inactive Publication Date: 2017-02-22
QINGDAO YUNTIAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The object of the present invention is to provide a kind of preparation method of new Niraparib intermediate 4-(3S-piperidin-3-yl) aniline, this method overcomes low yield, poor selectivity and high reaction cost in the existing method, Dealing with cumbersome and other defects

Method used

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  • Preparation method of Niraparib intermediate 4-(3S-piperidine-3-yl)aniline

Examples

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preparation example 1

[0031] The preparation of the compound shown in formula I

[0032] Add 0.35g (1mmol) of (S)-(-)-binaphthol phosphate to ethyl acetate, then add 2.32g (12mmol) of Boc-aniline and 0.82g (10mmol) of 2-cyclopentenone to the above In ethyl acetate at 10-20°C, the reaction time is 2-3 hours, concentrated, poured into water, then extracted with ether, concentrated, recrystallized from petroleum ether, and dried in vacuo to obtain 2.58 g of the compound represented by formula I, with a yield of 93.7%. The ee value is 99.21%, and the reaction process is as follows:

[0033]

preparation example 2

[0035] The preparation of the compound shown in formula I

[0036] Add 5.2g (15mmol) of (S)-(-)-binaphthol phosphate to ethyl acetate, then add 21.3g (110mmol) of Boc-aniline and 8.2g (100mmol) of 2-cyclopentenone to the above In ethyl acetate at 10-20°C, the reaction time is 2-3 hours, concentrated, poured into water, then extracted with ether, concentrated, recrystallized from petroleum ether, and vacuum-dried to obtain 25.9 g of the compound represented by formula I, with a yield of 94.2%. The ee value is 99.41%.

preparation example 3

[0038] The preparation of the compound shown in formula I

[0039] Add 0.17g (0.5mmol) of (S)-(-)-binaphthol phosphate to ethyl acetate, then add 2.13g (11mmol) of Boc-aniline and 0.82g (10mmol) of 2-cyclopentenone In the above ethyl acetate at 10-20°C, the reaction time is 2-3h, concentrated, poured into water, then extracted with ether, concentrated, recrystallized from petroleum ether, and vacuum-dried to obtain 2.55g of the compound represented by formula I, with a yield of 92.6% , ee value 99.17%.

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Abstract

The invention discloses a preparation method of a Niraparib intermediate 4-(3S-piperidine-3-yl)aniline. The preparation method is characterized by comprising the following steps: 1) carrying out a contact reaction on a compound shown as a formula I and hydroxylamine hydrochloride to obtain a compound shown as a formula II; 2) carrying out a catalytic reaction on the compound shown as the formula II in the presence of phenyl dichlorophosphate to obtain a compound shown as a formula III; 3) carrying out a reduction reaction on the compound shown as the formula III to obtain the Niraparib intermediate 4-(3S-piperidine-3-yl)aniline shown as a formula X. A specific reaction process is shown in the description. By adopting the method provided by the invention, the utilization of a metal catalyst and transaminase with a high price is avoided, so that the production cost is lower, and a target product has high yield and stereoselectivity.

Description

technical field [0001] The invention belongs to the field of medicine synthesis and relates to a preparation method of an anticancer drug Niraparib intermediate 4-(3S-piperidin-3-yl)aniline. Background technique [0002] Niraparib (Niraparib) is an oral poly ADP ribose polymerase (PARP) inhibitor, which can inhibit the repair of DNA damage in cells, and its chemical name is 2-[4-((3S)-3-piperidine yl)phenyl]-2H-indazole-7-carboxamide. Nirapabib was developed by Merck and later transferred to Tesaro. It is currently in the third phase of clinical trials. The development indications are ovarian cancer, breast cancer, prostate cancer, etc. Clinical trials have proved that the compound has good chemical properties for the above diseases. The structure is shown in the following formula (1): [0003] [0004] For cancer cells with BRCA gene mutations, if PARP activity is further inhibited, these cells will generate a lot of DNA damage when they divide, leading to the death of...

Claims

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Application Information

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IPC IPC(8): C07D211/26
CPCC07D211/26C07B2200/07
Inventor 王传秀
Owner QINGDAO YUNTIAN BIOTECH
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