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Method for synthesizing palbociclib

A technology of palbociclib and compounds, which is applied in the field of drug synthesis, can solve the problems of low product yield and high production cost, achieve good reaction selectivity, reduce production cost, and be suitable for industrial production

Inactive Publication Date: 2018-03-06
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Purpose of the invention: In order to overcome the defects of low product yield and high production cost in the current method for preparing palbociclib, the present invention provides a method with industrial potential, high yield, high purity and simple preparation of palbociclib

Method used

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  • Method for synthesizing palbociclib
  • Method for synthesizing palbociclib
  • Method for synthesizing palbociclib

Examples

Experimental program
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Effect test

Embodiment 1

[0050] The preparation of embodiment 1,2-acetyl-2,3-dibromobutyric acid methyl ester

[0051] Add 2-acetyl-2-butenoic acid methyl ester (I) (8.52g, 60mmol) and 40mL of dichloromethane in the reaction flask, control the temperature of the reaction flask and add liquid bromine (9.9g, 62mmol) dropwise at 5°C , the dropwise addition was completed, and the reaction temperature was raised to room temperature and stirred for 30 minutes. TLC detects that the reaction is complete. Dry over anhydrous sodium sulfate, distill under reduced pressure to recover the solvent, recrystallize the obtained concentrated solid with ethyl acetate and n-hexane (1:1, V / V), and dry in vacuo to obtain 2-acetyl-2,3-dibromobutane Acid methyl ester (II-1) 17.81 g; yield 99%; purity 99.6% (HPLC area normalization method); mass spectrum (ESI): m / z 300.9 (M+H).

Embodiment 2

[0052] The preparation of embodiment 2,2-acetyl-3-bromo-2-butenoic acid methyl ester

[0053] Add 2-acetyl-2,3-dibromobutanoic acid methyl ester (II-1) (6.04g, 20mmol) and 40mL of methanol into the reaction flask, add sodium methoxide (2.7g, 50mmol) dropwise in 15mL of methanol at room temperature After the solution was dropped, the reaction temperature was kept at 40° C. and stirred for 1 hour. TLC detects that the reaction is complete. Wash 2-3 times with 4% dilute hydrochloric acid aqueous solution to make the reaction solution neutral. The organic phase was dried with anhydrous sodium sulfate, and the solvent was recovered by distillation under reduced pressure. The resulting concentrated solid was recrystallized with ethyl acetate and n-hexane (1:2, V / V), and dried in vacuo to obtain 2-acetyl-3-bromo- 2-butenoic acid methyl ester (III-1) 3.977g; yield 90%; purity 99.8% (HPLC area normalization method); mass spectrum (ESI): m / z 221.98 (M+H).

Embodiment 3

[0054] The preparation of embodiment 3,2-chloro-4-cyclopentylamino-5-bromopyrimidine

[0055] Add 5-bromo-2,4-dichloropyrimidine (IV-1) (11.4g, 50mmol), triethylamine (2.24g, 20mmol) and dichloromethane (150mL) into the reaction flask, stir well and cool to At 0-5°C, cyclopentylamine (V) (4.257g, 50mmol) was slowly added dropwise, and after the dropwise addition, the temperature was raised to 45°C to react for 6 hours, and the reaction was detected by TLC. Add 150 mL of water to quench the reaction, wash the organic phase twice with saturated brine, extract the aqueous phase twice with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and recover the solvent by distillation under reduced pressure. The compound 2-chloro-4-cyclopentylamino-5-bromopyrimidine (VI-1) was separated by column chromatography with ethyl acetate mixed solvent 11.0g; the yield was 80%; the purity was 99.8% (HPLC area normalization method) ; Mass spectrum (ESI): m / z = 275.98 (...

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Abstract

The invention discloses a method for synthesizing palbociclib. The method comprises the following steps: (1) carrying out substitution reaction between a compound of a formula VI and a compound of a formula VII, so as to obtain a compound of a formula VIII; (2) carrying out acylation reaction between the compound of the formula VIII and a compound of a formula III, so as to obtain a compound of aformula IX; (3) carrying out self-coupling on the compound of the formula IX in the presence of a metal catalyst, so as to obtain a compound of a formula X; and (4) carrying out deprotection on the compound of the formula X, so as to obtain a compound of a formula XI, namely the palbociclib. Compared with the prior art, the method has the advantages that a noble metal catalyst or a toxic dehydrogenation reagent or the like is not used, the reaction conditions are mild, the reaction selectivity is good, the total yield is relatively high, the total yield is relatively high, the liquid-phase purity of the product is high, the production cost is substantially lowered, and the method is relatively suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing palbociclib. Background technique [0002] Palbociclib is a new type of highly effective oral anticancer drug developed by Pfizer. It is the world's first marketed CDK4 / 6 kinase inhibitor for the first-line treatment of estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. The global breast cancer drug market can reach tens of billions of dollars each year, and palbociclib has a broad market prospect. [0003] 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: [0004] [0005] At present, there are two main directions for the synthesis of palbociclib, one is the synthesis of the intermediate mother ring A, and the other is the coupling reaction between interme...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 吴学平邢继刚陈耀海威
Owner 安庆奇创药业有限公司
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