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Niraparib intermediate, preparation method and application thereof, and synthesis method of niraparib

A synthesis method and intermediate technology, which is applied in the preparation of cyanide reaction, chemical instruments and methods, and the preparation of organic compounds, etc., can solve the problems of inability to racemize, recycle and reuse, and improve the overall utilization rate of materials and process safety , The effect of reducing the waste of materials

Active Publication Date: 2020-08-28
宁波人健化学制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009]In the above-mentioned chemical resolution process, the core of the resolution is the piperidine ring, the theoretical yield is only 50%, and the other half of the piperidine enantiomer Neither can be recovered and reused by further racemization

Method used

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  • Niraparib intermediate, preparation method and application thereof, and synthesis method of niraparib
  • Niraparib intermediate, preparation method and application thereof, and synthesis method of niraparib
  • Niraparib intermediate, preparation method and application thereof, and synthesis method of niraparib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] The synthetic method of niraparib key body N-Boc-(3S)-(4-bromophenyl)piperidine, first prepare compound 7 (alpha-(3-aminopropyl)-p-bromophenylacetic acid), synthetic route Such as figure 1 shown, including the following steps:

[0066] (1) Preparation of intermediate compound 3 (N-(3-hydroxypropyl) phthalimide)

[0067] Mix 125.4ml 3-chloropropanol (compound 2), 287.5g phthalamide potassium salt, and 369ml DMF, then keep warm at 120-125°C for reaction, stir for 4-5 hours, check that the reaction is complete, evaporate under reduced pressure to remove most of the Add part of DMF, add 540ml of water, 700ml of EA, stir and separate the layers, back extract the aqueous phase with 150ml of EA once, combine the organic phase, wash with saturated brine 200ml*4, dehydrate the organic phase, evaporate to dryness, add 1200ml of MTBE and heat to reflux to dissolve the crude product After cooling down to room temperature naturally, the ice water was cooled to 0-5 degrees and filt...

Embodiment 2

[0091] The preparation method of new compound 7 (α-(3-aminopropyl)-p-bromophenylacetic acid), and different from Example 1, in step (2), the intermediate compound 4 (N-(3-bromopropyl base) phthalimide) is prepared as follows: 245.3g of compound 3 is mixed in 1141.5ml of DCM, covered with a drying tube, cooled to 0-5 degrees, and slowly added dropwise with 125ml of phosphorus tribromide (FW: 270.7, 2.85 , 1.1eq), remove the ice water after the dropwise addition, stir at room temperature for 1h, TLC detects that the conversion is complete, add 1000ml of semi-saturated brine dropwise, stir for ten minutes to separate the layers, wash the organic phase with 900ml of saturated sodium bicarbonate and the pH of the aqueous phase is not low In 7, dry the organic phase, evaporate to dryness under reduced pressure to obtain the crude product, add 781ml of anhydrous methanol, heat to 58 degrees to dissolve, cool to 0-5 degrees with ice water, stir for half an hour and filter to obtain 211...

Embodiment 3

[0094] The synthesis method of N-Boc-(3S)-(4-bromophenyl)piperidine (compound 1), wherein the nitrogen in compound 7 is realized by introducing dibenzylamine.

[0095] (1) Preparation of intermediate compound (N-(3-hydroxypropyl) dibenzylamine)

[0096] We carried out the synthesis of (N-(3-hydroxypropyl)dibenzylamine) with reference to the method for the first step in Example 1, and the product yield was 81.2%.

[0097] (2) Preparation of intermediate compound (N-(3-bromopropyl) dibenzylamine)

[0098] We carry out bromination with reference to the second step method in Example 1, and the product yield is 82.3%

[0099] (3) Preparation of intermediate compound 7 (methyl p-bromophenylacetate)

[0100] Drop into DMSO 1250ml in the reaction bottle, slowly add potassium tert-butoxide 75.9g, in two dropping funnels, respectively dress embodiment 1 step (3) gained compound 5 144.4g, the DMSO (145ml) solution and embodiment 3 steps (2 ) of the obtained compound N-(3-bromopropyl)dib...

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Abstract

The invention relates to a compound alpha-(3-aminopropyl)-p-bromophenylacetic acid, a preparation method and application thereof, (S)-3-(4-bromophenyl)-piperidine-2-one, a preparation method and application thereof, and synthesis methods of (S)-3-(4-bromophenyl)-piperidine) p-toluenesulfonate, N-Boc-(3S)-(4-bromophenyl)piperidine and niraparib. 4-bromophenylacetate 5 is used as a raw material, a nucleophilic reaction is carried out on the raw material and a nitrogen source reagent 4 under the action of an alkali to generate a compound 6; the compound 6 is subjected to deprotection and hydrolysis to obtain an amino acid compound 7; and the amino acid compound 7 is subjected to chiral column separation or chemical resolution to obtain compounds 8 and 9; and the separated enantiomer 8 can besubjected to racemization and resolution conversion (or chiral column separation) to obtain a compound 9, and the process material cost is greatly reduced. After the compound 9 is obtained, a compound1 can be obtained through conventional condensation reaction ring closing, reduction and BOC loading. Splitting operation is advanced, and the enantiomer 8 is subjected to racemization recovery treatment and is repeatedly applied to different splitting batches to continuously obtain the product 9, so the process material cost is lower.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, relates to a niraparib intermediate and its preparation method and use and a synthesis method of niraparib, in particular to a new compound α-(3-aminopropyl)-p-bromophenylacetic acid and its The preparation method and use also relate to (S)-3-(4-bromophenyl)-piperidin-2-one and its preparation method and use, (S)-3-(4-bromophenyl)-piperidine )) Synthetic method of p-toluenesulfonate, N-Boc-(3S)-(4-bromophenyl)piperidine and niraparib. Background technique [0002] The chemical name of Niraparib (Niraparib, MK-4827) is 2-{4-[(3S)-3-piperidinyl]phenyl}-2H-indazole-7-carboxamide, and its chemical structure is as follows: [0003] [0004] Niraparib is an oral PARP-1 and PARP-2 inhibitor, which was first researched and developed by Merck, and then transferred to Tesaro. The S-configuration compound has better cell activity and BRCA selectivity. Obviously, compound (S)-3 -(...

Claims

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Application Information

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IPC IPC(8): C07C229/36C07C227/18C07D211/76C07D401/10C07D211/18
CPCC07C229/36C07D211/76C07D401/10C07D211/18
Inventor 丁同健葛远东汪卫敏郑飞
Owner 宁波人健化学制药有限公司
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