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Method for preparing palbociclib intermediate

An intermediate, cyclopentyl technology, applied in the field of pharmaceutical synthesis, can solve the problems of long reaction time, low overall yield, unfavorable health of workers, etc., and achieves the effects of mild reaction conditions and high overall yield

Inactive Publication Date: 2016-09-28
聂红梅 +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method provides a new way for preparing palbociclib, the overall yield of this method is still low, which is mainly due to the third step and N-[5-(1-piperazinyl)-2-pyridine Base] guanidine condensation yield is low, reaction time is long, and this method dehydrogenation reaction has used hypertoxic sodium selenate in addition, is not suitable for large-scale production, and is unfavorable for the health of laborers

Method used

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  • Method for preparing palbociclib intermediate
  • Method for preparing palbociclib intermediate
  • Method for preparing palbociclib intermediate

Examples

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Effect test

Embodiment 1

[0031] A method for preparing palbociclib intermediates, the method comprising the following steps:

[0032] 1) Under the protection of nitrogen, the compound N-cyclopentyl-5-methyl-2-chloro-6-bromopyrido[2,3-d]pyrimidin-7(8H)-one represented by formula (I) 34.3g (100mmol) reacted with 19.6g (200mmol) of trimethylsilyl acetylene in THF at 45-50°C for 3 hours in the presence of 5.7g (40mmol) of cuprous bromide and 16.8g (150mmol) of potassium tert-butoxide, After the reaction, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain the compound N-cyclopentyl-5-methyl-2-chloro-6-ethynylpyrido[2, 3-d] Pyrimidin-7(8H)-one 23.7g, yield 82.4%, purity 99.96% (HPLC area normalization method).

[0033] 2) The compound N-cyclopentyl-5-methyl-2-chloro-6-ethynylpyrido[2,3-d]pyrimidine-7(8H) obtained in step 1) represented by formula (II) Add 10 g of ketone into acidic aqueous solution (10% sulfuric acid aqueous solution) an...

Embodiment 2

[0036] A method for preparing palbociclib intermediates, the method comprising the following steps:

[0037] 1) Under the protection of nitrogen, the compound N-cyclopentyl-5-methyl-2-chloro-6-bromopyrido[2,3-d]pyrimidin-7(8H)-one represented by formula (I) In the presence of 34.3g (100mmol) of cuprous bromide 5g (35mmol) and potassium tert-butoxide 17.9g (160mmol), react with 14.7g (150mmol) of trimethylsilylacetylene in THF at 65°C for 4 hours, after the reaction ends , evaporate the solvent under reduced pressure, wash with water, recrystallize from methanol, and dry to obtain the compound N-cyclopentyl-5-methyl-2-chloro-6-ethynylpyrido[2,3-d ] Pyrimidin-7(8H)-one 23.4g, yield 81.3%, purity 99.95% (HPLC area normalization method).

[0038] 2) The compound N-cyclopentyl-5-methyl-2-chloro-6-ethynylpyrido[2,3-d]pyrimidine-7(8H) obtained in step 1) represented by formula (II) - 10g of ketone was added to acidic aqueous solution (15% sulfuric acid aqueous solution) and hydroly...

Embodiment 3

[0040] A method for preparing palbociclib intermediates, the method comprising the following steps:

[0041] 1) Under the protection of nitrogen, the compound N-cyclopentyl-5-methyl-2-chloro-6-bromopyrido[2,3-d]pyrimidin-7(8H)-one represented by formula (I) In the presence of 7.2g (50mmol) of cuprous bromide (50mmol) and 17.9g (160mmol) of potassium tert-butoxide, 34.3g (100mmol) reacted with 19.6g (200mmol) of trimethylsilyl acetylene in THF at 60°C for 3 hours, and the reaction ended Afterwards, the solvent was evaporated under reduced pressure, washed with water, recrystallized from methanol, and dried to obtain the compound N-cyclopentyl-5-methyl-2-chloro-6-ethynylpyrido[2,3- d] Pyrimidin-7(8H)-one 22.9g, yield 79.6%, purity 99.91% (HPLC area normalization method).

[0042] 2) The compound N-cyclopentyl-5-methyl-2-chloro-6-ethynylpyrido[2,3-d]pyrimidine-7(8H) obtained in step 1) represented by formula (II) - 10g of ketone was added to acidic aqueous solution (10% sulfuric ...

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Abstract

The invention discloses a method for preparing a palbociclib intermediate. The method comprises the following steps: (1) enabling a compound N-cyclopentyl-5-methyl-2-chloro-6-bromine pyridino[2,3-d]pyrimidine-7(8H)-ketone as shown in a formula (I) to react with trimethyl silicon alkyl acetylene to form a compound N-cyclopentyl-5-methyl-2-chloro-6-acetenyl pyridino[2,3-d]pyrimidine-7(8H)-ketone as shown in a formula (II) under the existence of cuprous bromide and potassium tert-butoxide; (2) hydrolyzing the compound N-cyclopentyl-5-methyl-2-chloro-6-acetenyl pyridino[2,3-d]pyrimidine-7(8H)-ketone which is obtained in step (1) and as shown in the formula (II) in an acidic aqueous solution, thus obtaining the palbociclib intermediate N-cyclopentyl-5-methyl-2-chloro-6-acetyl pyridino[2,3-d]pyrimidine-7(8H)-ketone; the formula (I) and the formula (II) are shown in the description. According to the method disclosed by the invention, a new path is developed for preparing the palbociclib intermediate, the conditions are gentle, and the yield is high.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing a palbociclib intermediate. 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. 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 materials to obtain the target product through seven steps. The specific synthetic route is as follows: [0005] [0006] This synthesis method route is long, and wherein the 5th step reaction exists the competitive reaction of Cl an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 王传秀
Owner 聂红梅
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