Niraparib preparation method

A compound and catalyst technology, applied in the field of preparation of niraparib, can solve problems such as unfavorable amplification and high cost of platinum, and achieve the effects of reduced synthesis cost, low synthesis cost and high selectivity

Active Publication Date: 2021-11-12
天津太平洋化学制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This route uses carbon dioxide when reducing the pyridine ring, the cost of platinum is high, and sodium azide is also used as a dangerous reagent, which is not conducive to amplification

Method used

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preparation example Construction

[0031] A preparation method for niraparib, comprising the steps of:

[0032] S1. Dissolve compound 1 and Pd catalyst (0.05eq) in bromobenzene, add potassium formate (1.2eq), and mix to obtain an orange turbid solution;

[0033] Among them, the chemical formula of compound 1 is The Pd catalyst is Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(dppf)Cl 2 , Pd(PPh 3 )2Cl 2 or PdCl 2 any of the

[0034] S2. Irradiating the orange turbid solution and stirring it until HPLC shows that compound 1 has completely reacted;

[0035] Wherein, the light source used for irradiation is visible light or light with a wavelength of 450nm-480nm or light with a wavelength of 500nm-560nm; the reaction temperature is 20°C-60°C;

[0036] S3. After the reaction is finished, post-processing is carried out to obtain compound 2, which is the key intermediate of niraparib;

[0037] Among them, the post-treatment is specifically: using concentrated treatment to remove the solvent, recrystallizin...

Embodiment 1

[0055] Compound 1 (10.0g, 40.0mmol) was mixed with Pd(PPh 3 ) 4 (0.94g, 0.80mmol) was dissolved in bromobenzene (300mL), and potassium formate (4.20g, 50.0mmol) was added to obtain an orange turbid solution; then, under visible light irradiation, heated to 50°C and stirred for 24h, HPLC showed Compound 1 was completely reacted; after the reaction, washed with saturated sodium chloride (300ml), extracted with ethyl acetate (3╳200mL), combined organic phases, dried with anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate), the key intermediate of niraparib was obtained as a white solid (6.97g, 54%), and the melting point was 62.5°C-63.1°C.

Embodiment 2

[0057] Compound 1 (10.0g, 40.0mmol) was mixed with Pd(PPh 3 )2Cl 2 (0.56g, 0.80mmol) was dissolved in bromobenzene (300mL), and potassium formate (4.20g, 50.0mmol) was added to obtain an orange turbid solution; then, under visible light irradiation, heated to 50°C and stirred for 24h, HPLC showed The reaction of the first intermediate is complete; after the reaction, wash with saturated sodium chloride (300ml), extract with ethyl acetate (3╳200mL), combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and use a silica gel column Chromatography (petroleum ether / ethyl acetate) yielded the key intermediate of niraparib as a white solid (5.67g, 44%) with a melting point of 62.5°C-63.1°C.

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Abstract

The invention provides a niraparib preparation method, which comprises: carrying out photocatalysis on a compound 1 and bromobenzene under a Pd catalyst to obtain a niraparib key intermediate; carrying out chiral resolution on the niraparib key intermediate, and coupling the niraparib key intermediate with NBoc-1H-indazole-7-carboxamide under the catalysis of copper bromide to obtain protected niraparib; and removing the protective color of the protected niraparib under the action of methanesulfonic acid, and obtaining the target product niraparib under tetrahydrofuran pulping. The preparation method of niraparib is simple in synthesis process route, high in preparation efficiency, small in damage to human bodies and the environment and low in synthesis cost.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, in particular to a preparation method of niraparib. Background technique [0002] Niraparib is a targeted drug for the treatment of ovarian malignant tumors. It is a polyadenosine diphosphate-ribose polymerase inhibitor and the third PARP inhibitor approved by the FDA after Olaparib. Added new options for the treatment. The role of niraparib is to repair DNA double-strand damage, ensuring that DNA damage in cells is repaired in time to avoid cancer. The patent documents in the existing niraparib synthesis technology include Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly (ADP-ribose) polymerase (PARP) Inhibitor Efficacious in BRCA-1and-2 Mutant Tumors, Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor, etc., disclosed some synthetic routes of niraparib 1-2 . [0003] [0004] The synthetic route uses 3...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/10
CPCC07D401/10C07B2200/07
Inventor 宋香羿杨光
Owner 天津太平洋化学制药有限公司
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