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A kind of preparation technology of Palbocoxib intermediate 5-bromo-2-chloro-4-cyclopentylaminopyrimidine

A preparation process and intermediate technology, applied in the field of intermediate M1 and palbocoxib, to achieve significant effects, improve the production process, and reduce the generation of substitution impurities

Active Publication Date: 2022-02-15
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the shortcomings of the above-mentioned prior art, that is, the problem of 5-bromo-4-chloro-2-cyclopentylaminopyrimidine impurities in the synthetic route of the compound patent (CN 105008357A), the researchers of the present invention have carried out technical improvements, Aiming at improving the industrial preparation process of intermediate M1 for the synthesis of palbocoxib and intermediate M1 and palbocoxib with higher yield and purity prepared by this process

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  • A kind of preparation technology of Palbocoxib intermediate 5-bromo-2-chloro-4-cyclopentylaminopyrimidine
  • A kind of preparation technology of Palbocoxib intermediate 5-bromo-2-chloro-4-cyclopentylaminopyrimidine
  • A kind of preparation technology of Palbocoxib intermediate 5-bromo-2-chloro-4-cyclopentylaminopyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 2,4-Dichloro-5-bromopyrimidine M0 (200g, 888mmol) and 1.4L dichloromethane were added to the reaction flask, sodium bicarbonate (372g, 4440mmol) was added, and 0.6L dichloromethane was slowly added dropwise at room temperature. Cyclopentylamine (90.7g, 1066mmol) diluted with chloromethane was reacted at room temperature for 13h, the sodium bicarbonate and the resulting inorganic salt were removed by suction filtration, the mother liquor was rotary evaporated to remove dichloromethane, and 1.0L of n-heptane was added for recrystallization to obtain a white solid 236.7g, M1 yield 97.5%, purity >99.8%, impurity 5-bromo-4-chloro-2-cyclopentylaminopyrimidine <0.02%. Melting point: 94-96°C.

[0022] 1H NMR(DMSO-d6)δ(ppm): 8.23(1H,s), 7.35(1H,d), 4.40–4.22(1H,m), 1.98–1.84(2H,m), 1.75–1.66(2H, m), 1.64–1.50 (4H, m).

Embodiment 2

[0024] 2,4-Dichloro-5-bromopyrimidine M0 (100g, 444mmol) and 1.0L methyl tert-butyl ether were added to the reaction flask, potassium bicarbonate (444g, 4440mmol) was added, and at room temperature, slowly added dropwise with 0.3L cyclopentylamine (45.4g, 533mmol) diluted with methyl tert-butyl ether was reacted at room temperature for 12h, the potassium bicarbonate and the resulting inorganic salt were removed by suction filtration, the mother liquor was rotary evaporated to remove the methyl tert-butyl ether, and 0.5L was added. The n-heptane was recrystallized to obtain 117.9 g of white solid, the yield of M1 was 97.1%, the purity was >99.8%, and the impurity 5-bromo-4-chloro-2-cyclopentylaminopyrimidine was less than 0.02%. Melting point: 94-96°C.

[0025] 1H NMR(DMSO)δ(ppm): 8.23(1H,s), 7.35(1H,d), 4.40-4.22(1H,m), 1.98-1.84(2H,m), 1.75-1.66(2H,m) , 1.64–1.50 (4H, m).

Embodiment 3

[0027] 2,4-Dichloro-5-bromopyrimidine M0 (100g, 444mmol) and 1.0L dichloromethane were added to the reaction flask, potassium bicarbonate (444g, 4440mmol) was added, and 0.3L dichloromethane was slowly added dropwise at room temperature. Cyclopentylamine (45.4g, 533mmol) diluted with chloromethane was reacted at room temperature for 15h, the potassium bicarbonate and the resulting inorganic salt were removed by suction filtration, the mother liquor was rotary evaporated to remove dichloromethane, and 0.5L of n-heptane was added for recrystallization to obtain a white solid 117.5g, M1 yield 96.8%, purity >99.8%, impurity 5-bromo-4-chloro-2-cyclopentylaminopyrimidine <0.02%. Melting point: 94-96°C.

[0028] 1H NMR(DMSO)δ(ppm): 8.23(1H,s), 7.35(1H,d), 4.40-4.22(1H,m), 1.98-1.84(2H,m), 1.75-1.66(2H,m) , 1.64–1.50 (4H, m).

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Abstract

The present invention relates to the technical field of medicines, and provides a process for the industrialized preparation of palbocoxib intermediate 5-bromo-2-chloro-4-cyclopentylaminopyrimidine (M1), which comprises the following steps: (1) Under room temperature conditions, select a weakly basic inorganic salt as an acid-binding agent, and use a low-boiling point solvent as a reaction solvent, add cyclopentylamine dropwise to 2,4-dichloro-5-bromopyrimidine (M0), and react for 12-15 hours; (2) Suction filtration to remove inorganic salts, concentrate the mother liquor to dryness, and recrystallize the residue with a less polar solvent to obtain intermediate M1, the reaction formula is as follows. The preparation process provided by the invention has simple operation steps, mild reaction conditions, simpler post-treatment required for the reaction, greatly improved product yield and purity, effectively reduces the generation of 2-substituted impurities, and is better for the promotion and improvement of palbocoxib technology. It is of great significance to be used in clinical patients.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to an improved preparation process for 5-bromo-2-chloro-4-cyclopentylaminopyrimidine (hereinafter referred to as M1), an intermediate for synthesizing palbocoxib, and a preparation process prepared by the process The obtained intermediates M1 and palbocoxib with higher purity and few impurities. Background technique [0002] Palbociclib, chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H- Pyrido[2,3-d]pyrimidine, as shown in structural formula 1, was designed and synthesized by Pfizer, and has strong inhibitory activity against cell cycle-dependent kinase CDK4 / 6 with IC50=11nM, with high selectivity and It is effective orally and has good safety and tolerability. It was approved by the FDA in February 2015 for the treatment of postmenopausal estrogen receptor (ER) positive, human epidermal growth factor receptor 2 ( HER2) negative advanced fem...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 李丹陈超蔡正艳周伟澄张鹏许程诚
Owner SHANGHAI INST OF PHARMA IND CO LTD
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