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Method for synthesizing palbociclib intermediate

A synthetic method and intermediate technology, applied in the field of organic preparation, can solve the problems of high cost, expensive reagents, and many process steps, and achieve the effect of easy control and less impurities

Inactive Publication Date: 2016-09-28
HUAIHAI INST OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The technical problem to be solved by this invention is to overcome the existing reports of preparing formula (I) compound 2-chloro-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine There are many process steps in the technology of -7-ketone, expensive reagents, easy to produce impurities, low yield, high cost, and the defects of being unfavorable for industrialized large-scale production, providing a one-step effective preparation of 2-chloro-6-bromo -A method for 8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, the method has short steps, high yield and few impurities, and is suitable for industrial production

Method used

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  • Method for synthesizing palbociclib intermediate

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Embodiment 2

[0019] The preparation of embodiment 2 formula (III) compound 2-chloro-6-bromo-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0020] Add 10mmol 4-amino-2-chloro-5-pyrimidineethanone, 18mmol ethyl bromoacetate, 20mmol triethylamine and 30mL dry tetrahydrofuran into the reaction flask, stir and mix well. Stir the reaction under reflux for 7 h, stop heating, distill off the solvent under reduced pressure, add 20 mL of 1N HCl to the residue, stir for 1 h and let stand, filter the precipitated solid with suction, dry and recrystallize with isopropanol to obtain formula (III) Compound, yield 74%.

Embodiment 3

[0021] The preparation of embodiment 3 formula (I) compound 2-chloro-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

[0022] With 10mmol formula (III) compound 2-chloro-6-bromo-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, 0.6mmol sodium acetate, 15mmol chlorocyclopentane and 30mL Anhydrous ethanol was added into the reaction flask, stirred and mixed evenly, and reacted at room temperature for 7 hours. The solvent was distilled off under reduced pressure, and 50 mL of petroleum ether and 20 mL of 1N HCl were added to the residue. A white solid was precipitated, filtered by suction, dried and recrystallized with isopropanol to obtain the compound of formula (I) with a yield of 88%.

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Abstract

The invention discloses a method for synthesizing a palbociclib intermediate 2-chloro-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one. The method comprises the following steps of 1) preparing 2-chloro-6-bromo-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one by means of performing cyclization on 4-amino-2-chloro-5-pyrimidine ethanone and ethyl bromoacetate under the effect of alkali; 2) preparing a target product by means of performing amine alkylation reaction on the 2-chloro-6-bromo-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one and chlorinated cyclopentane. The method for synthesizing an important palbociclib intermediate 2-chloro-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one provided by the invention has the advantages that the steps are few, the reaction condition is mild, the operation is easy and convenient, the synthesis efficiency is high, impurities are few, the method is suitable for industrialized production, and a new approach is provided for the preparation of palbociclib and the palbociclib intermediate. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of organic preparation, in particular to a palbociclib intermediate 2-chloro-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidine A new method for the synthesis of -7-ketones. Background technique [0002] Palbociclib, chemical name 2-[(4-piperidinyl)benzyl]-6-acetyl-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidine-7 (8H)-ketone, whose English name is Palbociclib, was developed by Pfizer, and it was approved by the US Food and Drug Administration for the first time in February 2015. Palbociclib is an oral chemically synthesized selective inhibitor of cyclin-dependent kinases CDK4 and CDK6, which mainly prevents cells from G1 phase to S phase by regulating the cell cycle and inhibiting the activity of CDK4 and CDK6. Synthesis of DNA; it is mainly used clinically to treat patients with advanced (metastatic) breast cancer. [0003] Compound 2-chloro-6-bromo-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 程青芳王启发张颖李重阳陈璐
Owner HUAIHAI INST OF TECH
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