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Preparation method for intermediate of Ribociclib for treating breast cancers

A technology of ribociclib and intermediates, applied in the field of drug synthesis, can solve the problems of limiting industrial production and application, unsatisfactory, etc., and achieve the effect of increased yield and great application prospects

Active Publication Date: 2017-09-01
上海耀大生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method still does not avoid the coupling reaction using precious Pd metal catalysts. At the same time, although the yield has improved, it is still not ideal, which limits its industrial production application.

Method used

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  • Preparation method for intermediate of Ribociclib for treating breast cancers
  • Preparation method for intermediate of Ribociclib for treating breast cancers
  • Preparation method for intermediate of Ribociclib for treating breast cancers

Examples

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Effect test

preparation example

[0029] Preparation of 2-chloro-4-cyclopentylaminopyrimidine

[0030] In a 500ml round bottom flask, dissolve 75g of 2,4-dichloropyrimidine in 230ml of DMF, then mix 56g of cyclopentylamine and 70g of triethylamine at room temperature, stir overnight at room temperature, pour the reaction solution into water, dichloromethane Extracted and purified by column chromatography to obtain 91.3 g of 2-chloro-4-cyclopentylaminopyrimidine with a yield of 91.7%, MS (ESI) m / z: 198.07 [M+H] + .

Embodiment 1

[0032] Preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine

[0033] Manganese salt 24.1g (Mn(OAc) 3 2H 2 (2, 90mmol), 19.8g (100mmol) of 2-chloro-4-cyclopentylaminopyrimidine, and 16g (130mmol) of 2-bromoacetaldehyde were added to water, stirred at 35°C for contact reaction for 5 hours, and the reaction solution was cooled to room temperature. Extracted with dichloromethane, concentrated under reduced pressure, and recrystallized from petroleum ether to obtain 20.3 g of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine with a yield of 91.7% and a purity of 99.70% (HPLC area normalization method). MS (ESI) m / z: 222.07, [M+H] + , 1 HNMR(d 6 -DMSO, 300MHz) δ1.55-1.68(m,4H),1.71-1.87(m,4H),4.12(m,1H),6.37(m,1H),8.03(d,1H),8.72(s, 1H).

Embodiment 2

[0035] Preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine

[0036] Manganese salt 32.2g (Mn(OAc) 3 2H 2 (2, 120mmol), 19.8g (100mmol) of 2-chloro-4-cyclopentylaminopyrimidine, and 14.8g (120mmol) of 2-bromoacetaldehyde were added to water, stirred at 50°C for contact reaction for 4 hours, and the reaction solution was cooled to room temperature , extracted with dichloromethane, concentrated under reduced pressure, and recrystallized from petroleum ether to obtain 19.8 g of 2-chloro-7-cyclopentyl-7H-pyrrole[2,3-d]pyrimidine, with a yield of 89.5% and a purity of 99.44% ( HPLC area normalization method).

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Abstract

The invention discloses a preparation method of an intermediate of Ribociclib, wherein the preparation method comprises the following steps: 1) in the presence of manganese salt, making 2-chloro-4-cyclopentyl aminopyrimidine and 2-bromoacetaldehyde in a contact reaction to obtain 2-chloro-7-cyclopentyl-7H-pyrrole[2,3-d]pyrimindine; 2) making the product obtained in the step 1) react with formaldehyde and dimethylamine in an ammonium chloride aqueous solution to obtain 2-chloro-7-cyclopentyl-6-(N,N-dimethyl-aminomethyl)-7H-pyrrole[2,3-d] pyrimindine; 3) oxidizing the product obtained in the step 2) to obtain the Ribociclib intermediate, namely 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimindine-6-formamide. The method is readily available in raw materials, and does not use precious metal catalysts and the like, and is further greatly improved in yield and suitable for industrial production, and ensures the supply of the raw materials for Ribociclib preparation and has great application prospects.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing an intermediate of Ribociclib, a drug for treating breast cancer. Background technique [0002] Ribociclib is a highly effective oral anticancer drug developed by Novartis. As a highly specific cell cycle-dependent kinase (CDK4 / 6 dual inhibitor), the drug can significantly inhibit the growth of various neuroblastomas. According to the results of clinical research, the drug is used for the treatment of advanced breast cancer and has significant curative effect. Due to its good drug effect, it has attracted widespread attention. [0003] The chemical name of ribociclib is 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)-piperidin-2-yl]amino}-7H-pyrrole [2,3-d]pyrimidine-6-carboxamide, the specific structure is as follows. [0004] [0005] At present, the preparation of ribociclib is mainly carried out through the key intermediate 2-chloro-7-c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 陈令浩
Owner 上海耀大生物科技有限公司
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