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Preparation method of palbociclib

A technology of compound and molar ratio, applied in the field of preparation of antitumor drug Paberkeley, can solve the problems of cumbersome operation, low total product yield, rare raw materials, etc. Effect

Active Publication Date: 2018-02-27
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The reaction synthesis route is long, the operation is cumbersome, the total yield of the product is low, and the highly corrosive reagent bromine which is not friendly to the environment is used
[0009] 2. The synthetic routes reported by the original research company’s PCT patents WO2003062236, WO2008032157, WO2012018540 and WO2012068381 have the problem that the main raw material 2,5,6-trisubstituted pyrimidine ring is rare, even if the synthesis requires multi-step reactions and complex side reactions, At the same time, there is a competing reaction in the subsequent reaction of the synthesis of Pabekley, which affects the overall yield of the product
[0012] Although this route solves the problem of rare raw materials in the prior art and shortening the process route, there is still the problem of low (58.2%) condensation reaction yield of compound IV and compound V in step 3, which will affect the total yield of the final product

Method used

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  • Preparation method of palbociclib
  • Preparation method of palbociclib
  • Preparation method of palbociclib

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Preparation of compound Ⅳ

[0033] Add 20.2 g of compound II, 22 g of compound III, 0.2 mol of sodium ethoxide and 250 ml of absolute ethanol in sequence in a three-neck flask, and stir at 40-50°C for 5 h. The solvent was removed under reduced pressure, the residue was washed with 600ml of distilled water, and then 10% hydrochloric acid was added dropwise to precipitate a solid, which was filtered and vacuum-dried to obtain 32.06g of a solid with a yield of 96.99% and a purity of 99.93%.

Embodiment 2

[0035] Preparation of compound Ⅳ

[0036] Add 20.2 g of compound II, 22 g of compound III, 0.2 mol of sodium methoxide and 250 ml of anhydrous methanol into a three-neck flask in sequence, and stir at 40-50°C for 5 h. The solvent was removed under reduced pressure, the residue was washed with 600ml of distilled water, and then 10% hydrochloric acid was added dropwise to precipitate a solid, which was filtered and vacuum-dried to obtain 31.19g of a solid with a yield of 94.3% and a purity of 99.87%.

Embodiment 3

[0038] Preparation of compound Ⅳ

[0039] Add 20.2 g of compound II, 22 g of compound III, 0.2 mol of sodium hydroxide and 250 ml of absolute ethanol in sequence in a three-neck flask, and stir at 40-50°C for 5 hours. The solvent was removed under reduced pressure, the residue was washed with 600ml of distilled water, and then 10% hydrochloric acid was added dropwise to precipitate a solid, which was filtered and vacuum-dried to obtain 30.86g of a solid with a yield of 93.2% and a purity of 99.77%.

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Abstract

The invention discloses a preparation method of palbociclib. Diethyl acetylmalonate (II) and a compound II are used for performing cyclization reaction to prepare a compound IV, the compound IV undergoes substitution reaction to prepare a compound V, and the compound V undergoes one-pot reaction with ethyl acetoacetate and cyclopentylamine to prepare a final product palbociclib (I). The reaction initial raw material is easy to get, the reaction condition is mild, the operation is simple, the process route is short, the total yield is increased, and the preparation method is suitable for the industrialized production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of the antineoplastic drug Pabekley. Background technique [0002] Palbociclib is a cell cycle-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer, which was granted the "Breakthrough Therapy" qualification by the US FDA in April 2013. Due to its good clinical performance in Phase III, Pfizer submitted a marketing application to the US FDA in August 2014 and obtained priority review qualifications for estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative ( First-line treatment of HER2-) advanced breast cancer. The successful research of this drug will provide another important new option for patients with metastatic breast cancer. [0003] The chemical name of Palbociclib (I) is: 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]pyridine And[2,3-d]pyrimidin-7(8H)-one, its structural formula is: [0004...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘振腾孙逸威徐淑周耿强刘广俄
Owner SHANDONG YUXIN PHARMA CO LTD