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Preparation method of palbociclib

The technology of Paboseb and solvent is applied in the field of preparation of Paboseb, which can solve the problems of difficult industrialized operation, increase synthesis cost and the like, and achieve the effects of being beneficial to industrialized production, easy to operate, safe and environmentally friendly in process

Active Publication Date: 2015-04-01
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The disadvantage of the above synthetic route 2 is that the Heck reaction is used twice, which requires the use of noble metal palladium chloride or palladium acetate, and more expensive ligands, which increases the synthesis cost and is not easy for industrial operation.

Method used

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  • Preparation method of palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Preparation of N,N-bis(acetoacetyl)cyclopentylamine (II)

[0058] 250 grams of tetrahydrofuran, 42.6 grams (0.5 moles) of cyclopentylamine, 2.5 grams of ammonium chloride, and 143.2 grams (1.1 moles) of ethyl acetoacetate were successively added to a 500 milliliter flask, and the reaction was maintained at 20 to 25 ° C for 6 hours. Recover tetrahydrofuran under reduced pressure below 40°C, cool to 20°C, add 200 grams of water, 300 grams of toluene, and 10 grams of sodium carbonate, stir for 30 minutes and separate layers, extract the water layer with toluene twice, each time with 50 grams of toluene, and combine the toluene layer, recovered toluene by distillation, and obtained 123.5 g of light yellow viscous liquid N,N-di(acetoacetyl)cyclopentylamine (II), with a yield of 97.6% and a gas phase purity of 98.6%.

Embodiment 2

[0059] Example 2: Preparation of N,N-bis(acetoacetyl)cyclopentylamine (II)

[0060] Replace 143.2 grams (1.1 moles) ethyl acetoacetate of embodiment 1 with 127.5 grams (1.1 moles) of methyl acetoacetate, replace the 2.5 grams of ammonium chloride of embodiment 1 with 3.0 grams of ammonium sulfate, all the other are with embodiment 1, obtain 124.6 g of light yellow viscous liquid N,N-di(acetoacetyl)cyclopentylamine (II), yield 98.4%, gas phase purity 98.5%.

Embodiment 3

[0061] Example 3: Preparation of N,N-bis(acetoacetyl)cyclopentylamine (II)

[0062] Add 250 g of 1,2-dichloroethane, 42.6 g (0.5 mole) of cyclopentylamine, 2.5 g of ammonium chloride, and 92.5 g of diketene into a 500 ml flask in sequence, and keep the reaction at 15 to 20°C for 6 hours. Recover tetrahydrofuran under reduced pressure below 40°C, cool to 20°C, add 200 g of water, 300 g of toluene, and 10 g of sodium carbonate, stir for 30 minutes and then separate into layers, extract the water layer twice with toluene (total 100 g of toluene), and combine the toluene layer, and recovered toluene by distillation to obtain 118.6 g of light yellow viscous liquid N,N-bis(acetoacetyl)cyclopentylamine (II), with a yield of 93.7% and a gas phase purity of 98.9%.

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Abstract

The invention relates to a preparation method of palbociclib. The method comprises the following steps: carrying out N-acetoacetylation reaction by using cyclopentylamine and an acetoacetylation agent to obtain N,N-di(acetoacetyl) cyclopentylamine (II), carrying out intramolecular condensation on N,N-di(acetoacetyl) cyclopentylamine (II) in the presence of an alkaline reagent to obtain N-cyclopentyl-3-acetyl-4-methyl-6-hydroxy-2-pyridone (III), enabling N-cyclopentyl-3-acetyl-4-methyl-6-hydroxy-2-pyridone (III) to react with a formylation reagent to prepare N-cyclopentyl-3-acetyl-4-methyl-5-formyl-6-chlorine-2-pyridone (IV), carrying out pyrimidine ring reaction by using N-cyclopentyl-3-acetyl-4-methyl-5-formyl-6-chlorine-2-pyridone (IV) and N-(5-(4-tert-butoxy carbonyl-1-hexahydropyrazinyl)-2-pyridyl) guanidine sulfate (V), and then hydrolyzing under the alkaline condition to prepare palbociclib. The preparation method of palbociclib is easily available in raw materials, short in process, simple and convenient to operate and safe and environmentally friendly in process.

Description

technical field [0001] The invention relates to a preparation method of palbocyb, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Palbociclib (Palbociclib) is an oral targeted agent newly developed by Pfizer, which is used to selectively inhibit cyclin-dependent kinase 4 and 6 (CDK4 / 6), restore cell cycle control, and block tumor cell proliferation It is mainly used for the treatment of advanced estrogen receptor (ER) positive / human epidermal growth factor receptor 2 (HER2) negative breast cancer in postmenopausal women. Clinical research data show that compared with the standard treatment drug Letrozole (Letrozole) , the combination of Palbociclib and Letrozole has obvious advantages in efficacy, and is expected to be used as a first-line therapy for ER+ / HER2- advanced breast cancer, providing an important new option for patients with metastatic breast cancer. [0003] The CAS number of palbocyb is 571190-30-2, and its chemi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 戚聿新王成威陈军鞠立柱李新发
Owner XINFA PHARMA
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