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Ribociclib synthesizing method

A ribociclib and compound technology, applied in the field of drug synthesis, can solve the problems of complex synthesis, high cost, low yield and the like, and achieve the effects of good reaction selectivity, fewer synthesis steps and lower production cost

Active Publication Date: 2018-04-20
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In summary, the synthesis of ribociclib has problems such as low yield, complex synthesis, high cost and no industrial production, so it is still necessary to find a simpler and more efficient new synthesis method

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] (1) Preparation of 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1)

[0052] Add 5-bromo-2,4-dichloropyrimidine (I) (11.4g, 50mmol), triethylamine (2.24g, 20mmol) and dichloromethane (150mL) into the reaction flask, stir well and cool to 0~ At 5°C, cyclopentylamine (II) (4.257g, 50mmol) was slowly added dropwise, and after the dropwise addition, the temperature was raised to 45°C to react for 6 hours, and TLC detected that the reaction was complete. Add 150 mL of water to quench the reaction, wash the organic phase twice with saturated brine, extract the aqueous phase twice with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and recover the solvent by distillation under reduced pressure. The compound 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1) was separated by column chromatography in ethyl acetate mixed solvent 11.0g; the yield was 80%; the purity was 99.8% (HPLC area normalization method) ; Mass spectrum (ESI): m / z = 275....

Embodiment 2

[0064] (1) Preparation of 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1)

[0065] Same as Example 1, except that the molar ratio of compound 5-bromo-2,4-dichloropyrimidine to cyclopentylamine is 1:1; the reaction temperature is 40°C. The base used is pyridine; the molar ratio of the compound 5-bromo-2,4-dichloropyrimidine to the base is 1:0.2; the reaction solvent is dimethylformamide.

[0066] (2) Preparation of 2-chloro-4-cyclopentylamino-5-(propynyl)pyrimidine (V-1)

[0067] Same as Example 1, except that the molar ratio of 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1) to catalyst is 1:0.1. The ligand is selected from triphenylphosphine, and the molar ratio of 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1) to the ligand is 1:0.1. The solvent used was dimethylformamide; the reaction temperature was 50°C.

[0068] Palladium chloride (1.063g, 6mmol) was used as a catalyst, and the final compound 2-chloro-4-cyclopentylamino-5-(propynyl)pyrimidine (V-1) ...

Embodiment 3

[0081] (1) Preparation of 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1)

[0082] Same as Example 1, except that the molar ratio of compound 5-bromo-2,4-dichloropyrimidine to cyclopentylamine is 1:2; the reaction temperature is 100°C. The base used is N-methylmorpholine; the molar ratio of the compound 5-bromo-2,4-dichloropyrimidine to the base is 1:2; the reaction solvent is dimethyl sulfoxide.

[0083] (2) Preparation of 2-chloro-4-cyclopentylamino-5-(propynyl)pyrimidine (V-1)

[0084] Same as Example 1, except that the molar ratio of 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1) to catalyst is 1:0.3. The ligand is selected from tri-tert-butylphosphine. The molar ratio of 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1) to ligand is 1:0.5. The solvent used was dimethylsulfoxide; the reaction temperature was 110°C.

[0085] Cuprous iodide (1.1427g, 6mmol) was used as a catalyst, and the final obtained compound 2-chloro-4-cyclopentylamino-5-(propynyl)py...

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Abstract

The invention discloses a ribociclib synthesizing method which comprises the following steps: (1) performing coupling reaction between compound in a formula III and compound in a formula IV under theaction of a first metal catalyst to obtain compound in a formula V; (2) performing self cyclization reaction on the compound in the formula V to obtain compound in a formula VI; (3) performing oxidization amidation between the compound in the formula VI and dimethylamine under the action of a second metal catalyst to obtain compound in a formula VII; (4) performing substitution reaction between the compound in the formula VII and compound in a formula VIII to obtain compound in a formula IX; (5) removing protection groups of the compound in the formula IX under the acid condition to obtain compound in a formula X, namely ribociclib. Compared with the prior art, the method disclosed by the invention avoids using noble metal catalysts, poisonous sodium cyanide reagents or the like; reactionconditions are moderate, synthesizing steps are small, reaction selectivity is good, total yield is higher, product liquid phase purity is high, production cost is greatly reduced, and the method is more suitable for industrial production. The formulas are shown in the description.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for synthesizing ribociclib. 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 has a significant curative effect for the treatment of advanced breast cancer, so Ribociclib has a broad market prospect. [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, there are two main directions for the synthesis of ribociclib, one is the synthesis of the intermediate parent ring A, and the other is the condensation reaction between intermed...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 吴学平邢继刚储贻结严东洋
Owner 安庆奇创药业有限公司
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