Simple preparation method of palbociclib

A compound and solvent technology, which is applied in the field of simple preparation of Palbociclib, can solve the problems of difficult industrialized operation, increase synthesis cost and the like, and achieve the effects of low cost, less waste water and waste liquid, and simple steps.

Active Publication Date: 2019-07-16
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The disadvantage of the above synthetic route 2 is that the Heck reaction is used twice, which requires the use of noble metal palladium chloride or palladium acetate, and more expensive ligands, which increases the synthesis cost and is not easy for industrial operation.

Method used

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  • Simple preparation method of palbociclib
  • Simple preparation method of palbociclib
  • Simple preparation method of palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: the preparation of palbociclib (I)

[0053] Step (1): Preparation of 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (Ⅲ)

[0054] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water separator, reflux condenser and dropping funnel, add 220 gram toluene, 0.2 gram methylbenzenesulfonic acid, 26.0 gram (0.2 moles) ethyl acetoacetate, 110 to 115 ° C stirring and reflux dehydration reaction for 5 hours. Cool to 50°C, add 10.0 g (0.12 moles) of cyclopentylamine, stir and react at 90 to 95°C for 4 hours, while distilling off the ethanol generated. The solvent was recovered by distillation under reduced pressure, and the residue was recrystallized with 50 g of methyl tert-butyl ether to obtain 21.7 g of white solid 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H) - diketone, yield 92.5%, liquid phase purity 99.8%.

[0055] Step (2): Preparation of Boc-protected palbociclib (Ⅵ)

[0056] In a 500 ml four-necked...

Embodiment 2

[0063] Embodiment 2: the preparation of palbociclib (I)

[0064] Step (1): Preparation of 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (Ⅲ)

[0065] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water separator, reflux condenser and dropping funnel, add 220 gram toluene, 0.15 gram 98wt% sulfuric acid, 23.2 gram (0.2 moles) methyl acetoacetate, 110 to Stir and reflux dehydration reaction at 115°C for 5 hours. Cool to 50° C., add 10.0 g (0.12 moles) of cyclopentylamine, stir and react at 100 to 105° C. for 3 hours, and simultaneously distill off the generated methanol. The solvent was recovered by distillation under reduced pressure, and the residue was recrystallized with 50 g of methyl tert-butyl ether to obtain 21.3 g of white solid 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H) - diketone, yield 90.6%, liquid phase purity 99.3%.

[0066] Step (2): Preparation of Boc-protected palbociclib (Ⅵ)

[0067] In a 500 ml fo...

Embodiment 3

[0070] Embodiment 3: the preparation of palbociclib (I)

[0071] Step (1): Preparation of 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (Ⅲ)

[0072] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water separator, reflux condenser and dropping funnel, add 220 grams of toluene, 0.25 grams of p-toluenesulfonic acid, 23.2 grams (0.2 moles) of methyl acetoacetate , 110 to 115 ° C stirring reflux dehydration reaction for 5 hours. Cool to 50° C., add 10.0 g (0.12 moles) of cyclopentylamine, stir and react at 100 to 105° C. for 3 hours, and simultaneously distill off the generated methanol. The solvent was recovered by distillation under reduced pressure, and the residue was recrystallized with 50 g of methyl tert-butyl ether to obtain 21.6 g of white solid 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H) - diketone, yield 91.9%, liquid phase purity 99.5%.

[0073] Step (2): Preparation of Boc-protected palbociclib (Ⅵ)

[0074]...

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Abstract

The invention provides a simple preparation method of palbociclib. The method comprises the steps: performing dehydration on an acetacetate under the action of an acid catalyst so as to prepare 2-acetyl-3-methyl-2-pentenediate diester (II), then performing amidation condensation on the 2-acetyl-3-methyl-2-pentenediate diester (II) and cyclopentylamine so as to prepare 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (III), then performing condensation on 3-acetyl-1-cyclopentyl-4-methylpyridine-2,6-(1H,5H)-dione (III) and a methylenation reagent so as to prepare 3-acetyl-1-cyclopentyl-4-methyl-5-dialkylaminomethylenepyridine-2,6-(1H,5H)-dione (IV), then performing a pyrimidine cyclization reaction on the 3-acetyl-1-cyclopentyl-4-methyl-5-dialkylaminomethylenepyridine-2,6-(1H,5H)-dione (IV) and N-[5-(4-tert-butoxycarbonylpiperazin-1-yl)pyridin-2-yl]guanidine (V) so as to obtain Boc-protected palbociclib (VI), and removing a Boc protecting group so as to obtain the palbociclib (I). The method has the advantages of a short process, simple operation, easy realization, low cost, less waste, high product purity and high yield.

Description

technical field [0001] The invention relates to a simple and convenient preparation method of palbociclib, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Palbociclib, the product name is Ibrance, the English name is Palbociclib, and the Chinese name is also called Pabo Saibu or Paboxilin. Palbociclib is a breakthrough drug for the treatment of breast cancer developed by Pfizer, which was approved by the US FDA on February 3, 2015, for the selective inhibition of cyclin-dependent kinase 4 and 6 (CDK4 / 6) , to restore cell cycle control and block tumor cell proliferation, combined with the aromatase inhibitor letrozole for first-line treatment of ER+ / HER2– postmenopausal metastatic breast cancer. Palbociclib is the world's first marketed CDK4 / 6 inhibitor. Compared with the standard treatment drug letrozole (letrozole), the drug has obvious curative effect advantages. The CAS number of Palbociclib is [571190-30-2], and its chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 戚聿新刘月盛刘会锋范岩森
Owner XINFA PHARMA
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