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Synthesis technology of ribociclib

A synthesis process and ribociclib technology, which is applied in the field of ribociclib synthesis process, can solve the problems of excessively long reaction steps, low yield and high cost, and achieve mild conditions, high yield and few reaction steps. Effect

Active Publication Date: 2017-07-07
山东君瑞医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The reaction steps of the method are too long, resulting in lower final product yield and higher cost, which is unfavorable for industrialized production
[0007] In addition, the preparation process of the intermediate 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimidine-6-carboxamide in the above method is cumbersome and the yield is low. Low, and precious metal catalysts are also used in the preparation process, which limits its use in industrial production

Method used

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  • Synthesis technology of ribociclib
  • Synthesis technology of ribociclib

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0025] Preparation of 2-chloro-4-cyclopentylaminopyrimidine

[0026] 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 91.1 g of 2-chloro-4-cyclopentylaminopyrimidine with a yield of 91.5%, MS (ESI) m / z: 198.07 [M+H] + .

preparation example 2

[0028] Preparation of 3-bromo-2-oxo-N,N-dimethylpropionamide

[0029] In a 500ml round bottom flask, at room temperature, dissolve 26.1g (300mmol) of 2-oxopropionic acid, 136.5g (360mmol) of HBTU, and 7.8g (60mmol) of DIEA in 230ml of DMF, stir for 30min, and then drop into dimethyl Amine 16.2g (360mmol), continued to stir at room temperature overnight, the reaction solution was poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The concentrate was dissolved in anhydrous dichloromethane, NBS 100g (600mmol) was added dropwise under ice cooling, stirred for 5 hours, quenched with ice water, the organic phase was separated, washed with sodium thiosulfate, the organic phase was concentrated under reduced pressure, and flash column Chromatography yielded 47.7 g of 3-bromo-2-oxo-N,N-dimethylpropionamide, with a yield of 81.9%, MS (ESI) m / z: 193.97 [M+H] +...

Embodiment 1

[0031] Preparation of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimidine-6-carboxamide

[0032] In a 500ml round bottom flask, add 97.7g (300mmol) of cesium carbonate, 19.8g (100mmol) of 2-chloro-4-cyclopentylaminopyrimidine, 3-bromo-2-oxo-N,N-dimethylpropane Amide 23.3g (120mmol), cuprous iodide 1.5g (8mmol), L-proline 1.2g (10mmol), 220mlTHF, heated up to 40°C and stirred for 4-8 hours, poured into water, extracted with dichloromethane, Recrystallized from n-hexane to obtain 22.6 g of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimidine-6-carboxamide with a yield of 77.2% and a purity of 99.44% (HPLC area normalization method). MS (ESI) m / z: 293.11 [M+H] + , 1 HNMR(d 6 -DMSO, 300MHz) δ1.57-1.68(m,4H),1.72-1.87(m,4H),3.20(s,6H),4.11(m,1H),6.12(m,1H),8.73(s, 1H).

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Abstract

The invention discloses a synthesis technology of ribociclib. The synthesis technology comprises the following steps: 1) in the presence of cesium carbonate, 2-chloro-4-cyclopentylaminopyrimidine and 3-bromo-2-oxo-N,N-dimethylpropionamide react under the co-catalysis of cuprous iodide and L-proline to obtain 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimindine-6-methanamide; and 2) a product obtained in the step 1) and 4-(6-aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester are subjected to a nucleophilic reaction, and then formic acid-tert-butyl ester is removed under the acidic condition so as to obtain ribociclib. The synthesis technology of the medicine ribociclib for treating breast cancer has advantages of less reaction steps, mild condition and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis process of ribociclib. Background technique [0002] Ribociclib is a highly effective oral anticancer drug developed by Novartis. 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. [0003] Ribociclib is a highly specific cell cycle-dependent kinase (CDK4 / 6 dual inhibitor), which can significantly inhibit the growth of various neuroblastomas. As a result of clinical research, the drug has a significant effect on the treatment of advanced breast cancer. It is precisely because of the good effect of ribociclib that researchers in this field have done more research on its structure and its synthesis process. [0004] WO2010020675A discloses a preparation method of ribociclib, which uses 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine as the starting material t...

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 山东君瑞医药科技有限公司
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