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Preparation process of palbociclib intermediate 5-bromo-2-chloro-4-cyclopentyl aminopyrimidine

A cyclopentylaminopyrimidine, a preparation technology, applied in the field of pharmaceuticals, to achieve the effect of improving the production technology, great significance, and mild reaction conditions

Active Publication Date: 2019-01-15
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • 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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  • Preparation process of palbociclib intermediate 5-bromo-2-chloro-4-cyclopentyl aminopyrimidine
  • Preparation process of palbociclib intermediate 5-bromo-2-chloro-4-cyclopentyl aminopyrimidine
  • Preparation process of palbociclib intermediate 5-bromo-2-chloro-4-cyclopentyl aminopyrimidine

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Experimental program
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Effect test

Embodiment 1

[0021] Add 2,4-dichloro-5-bromopyrimidine M0 (200g, 888mmol) and 1.4L dichloromethane into the reaction flask, add sodium bicarbonate (372g, 4440mmol), and slowly dropwise add 0.6L dichloromethane at room temperature Cyclopentylamine (90.7g, 1066mmol) diluted with methyl chloride, reacted at room temperature for 13h, filtered to remove sodium bicarbonate and the generated inorganic salts, rotary evaporated the mother liquor to remove dichloromethane, added 1.0L n-heptane for recrystallization, and obtained 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 slowly added dropwise at room temperature Cyclopentylamine (45.4g, 533mmol) diluted with 0.3L methyl tert-butyl ether, reacted at room temperature for 12h, removed potassium bicarbonate and the inorganic salts generated by suction filtration, rotary evaporation of the mother liquor removed methyl tert-butyl ether, added 0.5L Recrystallized from n-heptane 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 <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 slowly added dropwise with 0.3L dichloromethane at room temperature Cyclopentylamine (45.4g, 533mmol) diluted with methyl chloride, reacted at room temperature for 15h, removed potassium bicarbonate and generated inorganic salts by suction filtration, removed dichloromethane by rotary evaporation of the mother liquor, added 0.5L n-heptane for recrystallization, and obtained 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

Relating to the technical field of drugs, the invention provides an industrial preparation process of a palbociclib intermediate 5-bromo-2-chloro-4-cyclopentyl aminopyrimidine (M1). The process comprises the steps of: (1) under a room temperature condition, selecting a weak alkaline inorganic salt as an acid-binding agent, adopting a low-boiling point solvent as the reaction solvent, adding cyclopentylamine dropwise into 2, 4-dichloro-5-bromopyrimidine (M0), and carrying out reaction for 12-15h; (2) performing pumping filtration to remove inorganic salt, concentrating mother liquor to dry, andrecrystallizing the residue with a solvent of little polarity to obtain the intermediate M1, with the reaction formula shown as the specification. The preparation process provided by the invention has the advantages of simple operation steps, mild reaction conditions and simpler post-treatment needed by reaction, greatly improves the product yield and purity, effectively reduces the generation of2-substituted impurities, and is of great significance for promotion of palbociclib technology and better application to clinical patients.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to an improved preparation process of an intermediate 5-bromo-2-chloro-4-cyclopentylaminopyrimidine (hereinafter referred to as M1) for synthesizing palbocoxib, and the preparation process Intermediate M1 and palbocoxib with higher purity and few impurities were obtained. 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, is designed and synthesized by Pfizer, and has strong inhibitory activity on cell cycle-dependent kinase CDK4 / 6, with IC50=11nM, which has high selectivity and It is orally effective and has good safety and tolerance. 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 female breast cancer. [0003...

Claims

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Application Information

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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
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