Preparation method for palbociclib

A preparation step, acetyl group technology, applied in the field of preparation of the drug palbociclib, can solve the problems of complex synthesis, rare, complex side reactions, etc., and achieve the effect of economical and environmental protection, simple process, and easy-to-obtain raw materials

Active Publication Date: 2015-03-25
铜陵王燕堂生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no matter route one or route two is selected, the synthesis of core core intermediates A and A' is relatively complicated
Its main raw material 2,5,6-trisubstituted pyrimidine ring raw material is very rare, coupled with many reaction steps, complex side reactions and other disadvantages, which greatly limit the industrial production of this drug

Method used

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  • Preparation method for palbociclib
  • Preparation method for palbociclib
  • Preparation method for palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Add 2-acetyl-2-butenoic acid methyl ester (II) (7.1g, 50mmol) and methanol 30mL in the dry reaction bottle, add dropwise 30mL methanol solution of sodium methoxide (5.4g, 100mmol) at room temperature, dropwise , and stirred for 15 minutes. A solution of malononitrile (4.0 g, 60 mmol) in 20 mL of methanol was added dropwise. The temperature was raised to reflux of methanol, and the reaction was continued for 4-5 hours. TLC detected that the reaction was complete. The solvent was recovered under reduced pressure, and the residue was dissolved in water. The pH value of the solution was adjusted to 8.0-9.0 with dilute hydrochloric acid under ice-cooling, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the obtained residue was washed with ethyl acetate and n-hexane (1:1 , V / V) recrystallized and dried in vacuo to give white solid 1,4,5,6-tetrahydro-2-methoxy-4-methyl-5-acetyl-6-oxo-3-pyrid...

Embodiment 2

[0036]Add 1,4,5,6-tetrahydro-2-methoxy-4-methyl-5-acetyl-6-oxo-3-pyridinecarbonitrile (III) (2.1g, 10mmol) into the reaction flask , 0.6g of silicone oil containing 60% sodium hydride and 30mL of N,N-dimethylformamide, heated to 55°C, and stirred for 30 minutes. After cooling down to room temperature, iodocyclopentane (2.9 g, 15 mmol) was added, the temperature was raised to 55°C again, and the reaction was stirred for 30 minutes. TLC detects that the reaction is complete. Quench the reaction with water, extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and a solid precipitates out, the resulting crude product is recrystallized with n-hexane and ethyl acetate (2:1, V / V), and dried in vacuo The off-white solid N-cyclopentyl-1,4,5,6-tetrahydro-2-methoxy-4-methyl-5-acetyl-6-oxo-3-pyridinecarbonitrile (IV) 2.1 g, yield 76.1%; mass spectrum (EI): m / z 277 (M+H).

Embodiment 3

[0038] In a nitrogen atmosphere, add N-cyclopentyl-1,4,5,6-tetrahydro-2-methoxy-4-methyl-5-acetyl-6-oxo-3-pyridylmethyl to the reaction flask Nitrile (IV) (2.8g, 10mmol), N-[5-(1-piperazinyl)-2-piperidinyl]guanidine (V) (4.4g, 20mmol) and xylene 15mL, heated to 150°C, Stir the reaction for 18-20 hours, and TLC detects that the reaction is complete. The solvent was distilled off under reduced pressure, cooled to room temperature, methanol was added, and a solid precipitated out. Filter, wash the filter cake twice with cold methanol, and dry in vacuo to obtain off-white solid 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridine Base]amino]-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (VI) 2.56g, yield 58.2%; mass spectrum (EI): m / z 450 (M +H).

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Abstract

The invention discloses a preparation method for palbociclib (I). The preparation method comprises the following steps: performing cyclization reaction on 2-acetyl-2-butenoic acid methyl ester and malononitrile under an alkaline condition to generate 1,4,5,6-4H-2-methoxyl-4-methyl-5-acetyl-6-oxo-3-pyridine carbonitrile (II); performing substitution reaction on the intermediate (II) and cyclopentane halide (III) under the action of an acid-binding agent to generate N-cyclopentyl-1,4,5,6-4H-2-methoxyl-4-methyl-5-acetyl-6-oxo-3-pyridine carbonitrile (IV); performing condensation reaction on the intermediate (IV) and N-[5-(1-piperazinyl)-2-piperidyl]carbamidine (V)to generate 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-5,6-dihydropyrido[2,3-d]pyrimidine-7(8H)-ketone (VI); performing dehydrogenation reaction on the intermediate (VI) and sodium selenate to generate the palbociclib (I). The preparation method for the palbociclib has the advantages that the raw material is easy to obtain, the process is simple, high efficiency and environmental protection are achieved, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of palbociclib, which may be used to treat breast cancer. Background technique [0002] Palbociclib (Palbociclib) is a cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer, which was granted the "Breakthrough Therapy" qualification by the US FDA in April 2013. Due to its good clinical performance in Phase III, Pfizer submitted a marketing application to the US FDA in August 2014 and obtained priority review qualifications for estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative ( First-line treatment of HER2-) advanced breast cancer. The drug's successful research will provide another important option for patients with metastatic breast cancer. Because the medicine does not yet have a standard Chinese translation, the applica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04A61K31/535A61K31/5395C07B43/04C08K5/03C08K5/34C08K5/3432
Inventor 许学农
Owner 铜陵王燕堂生物科技有限公司
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