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Preparation method of palbociclib for treating breast cancer

A breast cancer and compound technology, applied in the field of drug synthesis, can solve the problems of long reaction time, low product yield, harsh conditions, etc., and achieve the effect of simple operation steps, increased yield, and mild reaction conditions

Inactive Publication Date: 2016-08-31
QINGDAO MUNICIPAL HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to overcome defects such as cumbersome steps, low product yield, harsh conditions, and long reaction time in the existing method for preparing palbociclib, and provide a simple, mild condition, high yield, and short reaction time. The method for the preparation of palbociclib

Method used

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  • Preparation method of palbociclib for treating breast cancer
  • Preparation method of palbociclib for treating breast cancer
  • Preparation method of palbociclib for treating breast cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] A preparation method for palbociclib for treating breast cancer, comprising the following steps:

[0032] 1) Under the protection of nitrogen, the compound N-cyclopentyl-2-methoxy-3-cyano-4-methyl-5-acetyl-6-oxopiperidine-2 shown in formula (I) -ene 27.6g (100mmol), compound N-[5-(1-piperazinyl)-2-pyridyl]guanidine represented by formula (II) 35.2g (160mmol), compound 20.5 represented by formula (M) g (60mmol) was added to 300ml 1,4-dioxane for 6 hours of contact reaction, the temperature of the contact reaction was 95°C, after the reaction was completed, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain Compound 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-5,6- Dihydropyrido[2,3-d]pyrimidin-7(8H)-one 37.6g, yield 83.7%, purity 99.82% (HPLC area normalization method).

[0033] 2) Under nitrogen protection, the 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]...

Embodiment 2

[0036] A preparation method for palbociclib for treating breast cancer, comprising the following steps:

[0037]1) Under the protection of nitrogen, the compound N-cyclopentyl-2-methoxy-3-cyano-4-methyl-5-acetyl-6-oxopiperidine-2 shown in formula (I) -ene 27.6g (100mmol), compound N-[5-(1-piperazinyl)-2-pyridyl]guanidine represented by formula (II) 41.1g (200mmol), compound 27.3 represented by formula (M) g (80mmol) was added to 300ml 1,4-dioxane for 6 hours of contact reaction, the temperature of the contact reaction was 90°C, after the reaction was completed, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain Compound 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-5,6- Dihydropyrido[2,3-d]pyrimidin-7(8H)-one 37.5g, yield 83.5%, purity 99.82% (HPLC area normalization method).

[0038] 2) Under nitrogen protection, the 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]a...

Embodiment 3

[0041] A preparation method for palbociclib for treating breast cancer, comprising the following steps:

[0042] 1) Under the protection of nitrogen, the compound N-cyclopentyl-2-methoxy-3-cyano-4-methyl-5-acetyl-6-oxopiperidine-2 shown in formula (I) -ene 27.6g (100mmol), compound N-[5-(1-piperazinyl)-2-pyridyl]guanidine represented by formula (II) 39.7g (180mmol), compound represented by formula (M) 17g (50mmol) was added into 300ml 1,4-dioxane and carried out contact reaction for 7.5 hours. The temperature of the contact reaction was 85°C. After the reaction was completed, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain the formula The compound shown in (III) 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-5,6-di Hydropyrido[2,3-d]pyrimidin-7(8H)-one 37.3g, yield 82.9%, purity 99.82% (HPLC area normalization method).

[0043] 2) Under nitrogen protection, the 6-acetyl-8-cyclopen...

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Abstract

The invention discloses a preparation method of palbociclib for treating breast cancer. The method comprises the following steps: 1) enabling N-cyclopentyl-2-methoxyl-3-cyan-4-methyl-5-acetyl-6-oxopiperidine-2-alkene and N-[5-(1-piperazinyl)-2-pyridyl] guanidine in the presence of N, N-Mes imidazolium salt to carry out a contact reaction to obtain 6-acetyl-8-cyclopentyl5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-5,6-dihydropyridino-[2,3-d]pyrimidine-7(8H)-ketone, wherein the temperature of the contact reaction is 85-100 DEG C; and (2) enabling 6-acetyl-8-cyclopentyl5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-5,6-dihydropyridino-[2,3-d]pyrimidine-7(8H)-ketone obtained in step 1) to carry out a dehydrogenation reaction in the presence of a dehydrogenation accelerant to generate palbociclib. The method is simple, is mild in condition and is capable of improving the yield and shortening the reaction time.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of palbociclib for treating breast cancer. Background technique [0002] Palbociclib, a cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer, is used for estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2 -) First-line treatment of advanced breast cancer. It has been clinically shown that palbociclib can double the progression-free survival of breast cancer compared with letrozole. It is a new hope for breast cancer patients and has achieved a breakthrough in efficacy. The chemical name of palbociclib is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyrido[2, 3-d] pyrimidin-7(8H)-one, the specific structure is as follows: [0003] [0004] WO2008032157 discloses a synthetic method of palbociclib, which uses 2,4-dichloro-5-bromo and cyclopentylamine as starting mater...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
CPCC07D471/04
Inventor 王传秀
Owner QINGDAO MUNICIPAL HOSPITAL
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