Preparation method of key intermediate of palbociclib

A palbocicillin and intermediate technology, applied in the field of pharmaceutical preparation, can solve the problems of long synthetic route, inconvenient manufacturers, expensive starting materials, etc., and achieve the effects of short preparation process steps, satisfying use requirements and low cost of raw materials

Inactive Publication Date: 2017-12-19
上海微巨实业有限公司
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Problems solved by technology

[0005] The synthetic route is long, the starting materials are expensive, and dangerous processes such as lithium aluminum hydride reduction are used in the reaction process, which brings inconvenience to the manufacturer.

Method used

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  • Preparation method of key intermediate of palbociclib
  • Preparation method of key intermediate of palbociclib

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Embodiment 1

[0024] A kind of preparation method of palbocillin key intermediate, concrete steps are as follows:

[0025] Step 1, the preparation of 2-methylthio-4-pyrimidinone: take 128g of thiouracil, 500g of dimethyl carbonate, 300g of potassium carbonate, 1g of tetrabutylammonium bromide, heat up to 120 ° C for 8h, after the reaction , cooled to room temperature, filtered, the filtrate was decompressed to recover unreacted dimethyl carbonate, the residue was added with 300 ml of water, extracted with 300 ml of ethyl acetate, dried, filtered, and the filtrate was recrystallized with 100 ml of petroleum ether to obtain 132g of white powder , the yield is 93%;

[0026] Step 2, preparation of 5-bromo-2-methylthio-4-pyrimidinone: Take 142 g of 2-methylthio-4-pyrimidinone, dissolve it in 500 ml of dichloromethane, add 190 g of NBS, reflux for 6 hours, After the reaction, cool to room temperature, filter, wash the filtrate with water, dry the organic phase, and recrystallize in an ice bath t...

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Abstract

The invention discloses a preparation method of a key intermediate of palbociclib, namely 6-bromine-2-methylsulfinyl-8-cyclopentyl-5-methyl pyridino (2,3-d) pyrimidine-7(8H)-ketone. The preparation method comprises the following steps: taking deracil as a starting material, performing methylating, chlorinating and brominating to synthesize 5-bromine-4-chlorine-2-methylthiopyrimidine, then alkylating with cyclopentylamine, conducting a heck reaction with 2-butenoic acid, then conducting an intramolecular acylation reaction to synthesize 2-methylmercapto-8-cyclopentyl-5-methyl pyridino (2,3-d) pyrimidine-7(8H)-ketone, and finally reacting with NBS to prepare the 6-bromine-2-methylsulfinyl-8-cyclopentyl-5-methyl pyridino (2,3-d) pyrimidine-7(8H)-ketone. Steps of the preparation process are short, no dangerous process is used, the operation is simple and convenient, the cost of the raw materials is low, and the use requirement of people is met.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a method for preparing a key intermediate of palbocillin. Background technique [0002] Palbociclib, Palbociclib (PD0332991), the chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H- Pyrido[2,3-d]pyrimidin-7-one is a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor developed by Pfizer, the trade name is Ibrance. In February 2015, the FDA accelerated the approval of palbociclib in combination with letrozole (Letrozole) for the treatment of ER-positive / HER2-negative postmenopausal metastatic breast cancer patients, making it the first FDA-approved CDK4 / 6 inhibitor drug and Approved for listing in the United States. [0003] 6-bromo-2-methylsulfinyl-8-cyclopentyl-5-methylpyrido(2,3-d)pyrimidin-7(8H)-one is used as the key intermediate of palbocillin, and its synthesis The method mainly uses ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘辉
Owner 上海微巨实业有限公司
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