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Preparation method of ribociclib and product and use thereof

A technology of ribociclib and aminopyridine, applied in the field of preparation of ribociclib, can solve the problems of high preparation difficulty, industrialization difficulty, separation and purification difficulty of SM2, etc., and is suitable for large-scale industrial application, low adsorption cost, high purity effect

Inactive Publication Date: 2019-03-01
CHONGQING SANSHENG IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The preparation of SM2 in this route is relatively difficult, and the reaction is an ultra-low temperature reaction. The preparation of intermediate A1 requires column chromatography purification, separation and purification are difficult, and industrialization is difficult.

Method used

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  • Preparation method of ribociclib and product and use thereof
  • Preparation method of ribociclib and product and use thereof
  • Preparation method of ribociclib and product and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)aminopyridin-3-yl) Piperazine-1-carboxylic acid tert-butyl ester) (formula 3) preparation, reaction formula is as follows:

[0033]

[0034] In a 2L four-neck round bottom flask, add 100g of 2-chloro-4-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimidine-6-carboxamide (Formula 2), 104.6g4-(6-aminopyridin-3-yl)piperazine-1-carboxylate tert-butyl ester (formula 1), 155.8g cesium carbonate, after nitrogen replacement three times, add 800g4-methyl-2-pentanone, 1.534 g palladium acetate, 6.38g BINAP. After the feeding was completed, the temperature was raised to 90-100° C. under nitrogen protection environment, and the reaction was carried out for 3 hours. Cool down to 65°C, add 800g of water, 270g of n-heptane, 10ml of propylenediamine, cool down to room temperature, filter, soak the filter cake in 500g of water once, and use 160g of 4-methyl-2-pentanone / 270g of n-heptane mixed solvent ...

Embodiment 2

[0035] The preparation of embodiment two Ribociclib hydrochloride

[0036] Add 20g of 4-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)aminopyridine- 3-base) piperazine-1-carboxylate tert-butyl ester) (formula 3), 100g n-hexane, stirred and dissolved, added dropwise 100g3mol / L hydrochloric acid at room temperature, reacted for 1 hour, separated liquids, took the water layer, and poured it into the water layer Add 200 g of acetone. Raise the temperature to reflux, then lower the temperature to below 10°C to crystallize, stir for 3 hours, and filter to obtain Ribociclib hydrochloride.

Embodiment 3

[0037] The preparation of embodiment three Ribociclib (formula 4)

[0038] Dissolve Ribociclib hydrochloride in 200g of water, add 1g of activated carbon, 0.5g of 100-200 mesh column chromatography silica gel, stir for adsorption and decolorization, filter, add saturated aqueous sodium bicarbonate solution to the filtrate to adjust the pH to 9-10, and precipitate solid, cooled to 10°C and stirred. After filtration, the filter cake was dried at 60° C., 14 g of Ribociclib (Formula 4) was obtained, and the yield was 85.0%.

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Abstract

A preparation method of ribociclib comprises the following steps: 1) utilizing 4-(6-aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester and 2-chloro-4-cyclopentyl-N,N-dimethyl-7H-pyrrole[2,3-d]pyrimidine-6-formamide as raw materials and conducting reaction in a protective atmosphere with palladium acetate / BINAP as a catalyst, cesium carbonate as an acid absorber and 4-methyl-2-pentanone as a solvent to obtain 4-(6-(7-cyclopentyl-6-(dimethylaminoformyl)-7H-pyrrolo[2,3-d]pyrimidine-2-yl)aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester); 2) dissolving the4-(6-(7-cyclopentyl-6-(dimethylaminoformyl)-7H-pyrrolo[2,3-d]pyrimidine-2-yl)aminopyridine-3-yl)piperazine-1-carboxylic acid tert-butyl ester) obtained in step 1) in an organic solvent, adding acid dropwise at the room temperature to remove tert-butyl formate, conducting liquid separation, adding a water-soluble organic solvent to an aqueous layer, separating solids and filtering to obtain ribociclib acid salt; 3) adding water to the ribociclib acid salt for dissolving, adding an adsorbent, filtering and adding alkali to the filtrate to obtain the ribociclib.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of Ribociclib and its product and application. Background technique [0002] Ribociclib is a novel drug developed by Swiss Novartis that selectively inhibits CDK4 / 6, restores cell cycle control, blocks tumor cell proliferation, and thus achieves the treatment of breast cancer. In March 2017, it was approved for marketing by the US FDA. Its trade name is Kisqali, and its chemical name is 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo [2,3-d]pyrimidine-6-carboxylic acid dimethylamide. The chemical structural formula of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide is as follows The formula shows: [0003] [0004] The invention patent WO2010020675 discloses the synthesis method of this compound, and the reaction process is shown in the following route: [0005] [0006] In this...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 吴科何伟彭磊王珑霖蒋光顶杨帆
Owner CHONGQING SANSHENG IND CO LTD
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