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A kind of preparation method of high-purity palbociclib

A technology of acetoacetate and reaction solution, which is applied in the field of preparation of high-purity palbociclib, can solve the problems of difficult industrial operation and increased synthesis cost, and achieves simple operation, high product yield and purity, and short process flow Effect

Active Publication Date: 2018-06-19
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of preparation method of high-purity palbociclib
  • A kind of preparation method of high-purity palbociclib
  • A kind of preparation method of high-purity palbociclib

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Experimental program
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Effect test

Embodiment 1

[0044] Embodiment 1: the preparation of palbociclib (Ⅰ)

[0045]In the 500 milliliter four-necked flasks that are connected with stirring, thermometer, water separator, reflux condenser and dropping funnel, add 200 gram toluene, 0.2 gram toluenesulfonic acid, 26.0 gram (0.2 moles) ethyl acetoacetate, 110 to 115 ° C stirring and reflux dehydration reaction for 5 hours. Cool to 20° C., add 11.1 g (0.11 mol) of trimethyl orthoformate, and react with stirring at 30 to 35° C. for 4 hours. Add 20.0 grams of 28% sodium methoxide methanol solution, and add 34.3 grams (0.105 moles) of N-(5-(4-tert-butoxycarbonyl-1-hexahydropyrazinyl) 2-pyridine in batches between 30 and 40°C Base) guanidine hemisulfate, after the addition, stir and react at 60 to 65°C for 3 hours, add 9.4 grams (0.11 moles) of cyclopentylamine at 60 to 65°C, and react at 70 to 75°C for 3 hours. Cool to 20°C, add 50 grams of water, stir at 20°C for 3 hours, filter, and recrystallize the filter cake with 250 grams of i...

Embodiment 2

[0049] Embodiment 2: the preparation of palbociclib (I)

[0050] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water trap, reflux condenser and dropping funnel, add 200 gram toluene, 0.18 gram methanesulfonic acid, 26.0 gram (0.2 moles) ethyl acetoacetate, 110 Stir and reflux dehydration reaction at 115°C for 5 hours. Cool to 20° C., add 11.1 g (0.11 mol) of trimethyl orthoformate, and react with stirring at 30 to 35° C. for 4 hours. Add 20.0 grams of 28% sodium methoxide methanol solution, and add 34.3 grams (0.105 moles) of N-(5-(4-tert-butoxycarbonyl-1-hexahydropyrazinyl) 2-pyridine in batches between 30 and 40°C Base) guanidine hemisulfate, after the addition, stir and react at 60 to 65°C for 3 hours, add 9.4 grams (0.11 moles) of cyclopentylamine at 60 to 65°C, and react at 70 to 75°C for 3 hours. Cool to 20°C, add 50 grams of water, stir at 20°C for 3 hours, filter, and recrystallize the filter cake with 250 grams of isopropanol ...

Embodiment 3

[0051] Embodiment 3: the preparation of palbociclib (I)

[0052] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water trap, reflux condenser and dropping funnel, add 200 gram toluene, 0.2 gram 98% concentrated sulfuric acid, 26.0 gram (0.2 mole) ethyl acetoacetate, 110 Stir and reflux dehydration reaction at 115°C for 5 hours. Cool to 20° C., add 11.1 g (0.11 mol) of trimethyl orthoformate, and stir and react at 30 to 35° C. for 4 hours. Add 20.0 grams of 28% sodium methoxide methanol solution, and add 34.3 grams (0.105 moles) of N-(5-(4-tert-butoxycarbonyl-1-hexahydropyrazinyl) 2-pyridine in batches between 30 and 40°C Base) guanidine hemisulfate, after the addition, stir and react at 60 to 65°C for 3 hours, add 9.4 grams (0.11 moles) of cyclopentylamine at 60 to 65°C, and react at 70 to 75°C for 3 hours. Cool to 20°C, add 50 grams of water, stir at 20°C for 3 hours, filter, and recrystallize the filter cake with 250 grams of isopropan...

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Abstract

The invention relates to a preparation method of high-purity palbociclib. The method comprises using acetoacetate for reflux dehydration in the function of an acid catalyst to prepare 2-acetyl-3-methyl-2-diethyl (methyl) glutaconate (III), condensing the compound (III) and trimethyl orthoformate for methanol removal to obtain 2-acetyl-3-methyl-4-methoxymethylene-2-diethyl (methyl) glutaconate (IV), cyclizing the compound (IV) and N-(5-(4-tertbutoxycarbonyl-1-hexahydropiperazinyl)-2-pyridyl) guanidine (V) with pyrimidine to obtain 2-acetyl-3-[[5-(4-tertbutoxycarbonylpiperazinyl-1-yl) pyridine-2-yl] amino]-3H-4-one-dihydropiperazinyl-2-ethyl (methyl) butenyl ester (VI), and finally cyclizing the compound (VI) and cyclopentylamine to remove Boc protecting groups, thereby obtaining palbociclib. The preparation method is cheap and available in raw materials, short in technical process, simple and convenient to operate, good in reaction selectivity, and high in product yield and purity and is green and eco-friendly.

Description

technical field [0001] The invention relates to a preparation method of high-purity 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 breast cancer drug 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), recovery Cell cycle control, blocking tumor cell proliferation, used in combination 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, the drug has obvious curative effect advantages. The CAS number of Palbociclib is [571190-30-2], and its chemical name is: 6-acetyl-8-cyclopent...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCY02P20/55
Inventor 戚聿新鞠立柱陈军李新发
Owner XINFA PHARMA