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A kind of preparation method of pyridopyrimidine derivative

A technology for pyrimidine and cyclopentyl pyridine, which is applied in the field of preparation of pyridopyrimidine derivatives, a key intermediate of palbociclib, can solve the problem of unfavorable green industrial production of intermediate I, cost reduction, and low reaction atom economy. , unstable yield and other problems, to avoid heavy metal residues in the product, high reaction atom economy, and stable yield.

Active Publication Date: 2020-04-28
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The raw material 2,4-dichloro-5-bromo(iodo)pyrimidine used in the above-mentioned preparation route has a higher price and is not easy to obtain. The price of palladium salt catalyst and 3-boronate ethyl crotonate is high, the yield is unstable, and the reaction atom Low economy, not conducive to green industrial production and cost reduction of intermediate Ⅰ

Method used

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  • A kind of preparation method of pyridopyrimidine derivative
  • A kind of preparation method of pyridopyrimidine derivative
  • A kind of preparation method of pyridopyrimidine derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0038]Example 1: Preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydrogen-7-one (I)

[0039] Step (1): Preparation of 2-hydroxy-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydrogen-7-one (Ⅴ)

[0040] In a 500 ml four-neck flask connected with a stirring, thermometer, and distillation device, add 120 g of N,N-dimethylformamide, 17.2 g (0.1 mole) of 3-methyl-2-pentaconate dimethyl , 8.6 g (0.1 mol) cyclopentylamine, 0.2 g DBU, 80 to 85 ° C stirring reaction for 4 hours, 110 to 115 ° C stirring reaction for 4 hours, while distilling off the generated methanol. Cool down to 50-60°C, add 14.3 g (0.12 moles) of N,N-dimethylformamide dimethyl acetal (DMF-DMA), react at 110 to 115°C for 5 hours, cool down to 50-60°C, add 10.0 g (0.17 mole) urea, reacted at 80 to 85°C for 5 hours, recovered part of the solvent (80-85 grams of solvent) by distillation under reduced pressure, lowered to room temperature, added 300 grams of water, filtered, and the fil...

Embodiment 2

[0052] Example 2: Preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydrogen-7-one (I)

[0053] Step (1): Preparation of 2-hydroxy-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydrogen-7-one (Ⅴ)

[0054] In a 500 ml four-necked flask connected with a stirring, thermometer, and distillation device, add 150 g of toluene, 20.0 g (0.1 mole) of 3-methyl-2-pentaconate diethyl ester, 8.6 g (0.1 mole) of cyclic Amylamine, 0.2 g of DBU, reacted with stirring at 80 to 85°C for 4 hours, and at 100 to 105°C for 4 hours, while distilling off the generated ethanol. Cool down to 50-60°C, add 14.3 g (0.12 moles) of N,N-dimethylformamide dimethyl acetal (DMF-DMA), react at 100 to 105°C for 7 hours, cool down to 50-60°C, add 10.0 g (0.17 moles) urea, reacted at 85 to 90°C for 7 hours, recovered the solvent by distillation under reduced pressure, cooled to room temperature, added 300 grams of water, filtered, washed the filter cake with 20 grams of isopropanol, ...

Embodiment 3

[0059] Example 3: Preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydrogen-7-one (I)

[0060] Step (1): Preparation of 2-hydroxy-5-methyl-8-cyclopentylpyridin[2,3-d]pyrimidin-8-hydrogen-7-one (Ⅴ)

[0061] In a 500 ml four-neck flask connected with a stirring, thermometer, and distillation device, add 120 g of N,N-dimethylformamide, 25.5 g (0.1 mole) of 3-methyl-2-pentaconate di-tert-butyl Esters, 8.6 g (0.1 mol) cyclopentylamine, 0.3 g DBU, stirred at 90 to 95° C. for 4 hours, and at 120 to 125° C. for 4 hours, while distilling off the generated tert-butanol alcohol. Cool down to 50-60°C, add 14.3 g (0.12 moles) of N,N-dimethylformamide dimethyl acetal (DMF-DMA), react at 110 to 115°C for 5 hours, cool down to 50-60°C, add 10.0 g (0.17 moles) urea, reacted at 90 to 95°C for 5 hours, recovered part of the solvent (80-85 grams of solvent) by distillation under reduced pressure, lowered to room temperature, added 300 grams of water, filtered, and ...

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Abstract

The invention discloses a preparation method of a pyridine pyrimidine derivative. The preparation method comprises following steps: 3-methyl-2-glutaconate diester and cyclopentamine are subjected to amidation condensation to prepare 1-cyclopentyl-4-methylpyridine-2, 6-(1H, 5H)-dione, and one-pot condensation with methylation reagent (N, N-dimethylformamide acetal) and urea is carried out so as toobtain 2-hydroxyl-5-methyl-8-cyclopentyl pyridine [2, 3-d] pyrimidine-8-hydro-7-one; and then chlorination and bromination reaction are carried out to prepare 2-chlor-5-methyl-6-bromo-8-cyclopentyl pyridine [2, 3-d] pyrimidine-8-hydro-7-one. The preparation method possesses following advantages: using of expensive trihalogen pyrimidine, palladium salt catalyst, and 3-borate substituted ethyl crotonate is avoided; the adopted raw materials are cheap and easily available; operation is convenient; reaction yield is stable; less three wastes are generated; reaction atom economical benefit is high;cost is low; and the preparation method is convenient for green industrialized production.

Description

technical field [0001] The present invention relates to a preparation method for the key intermediate pyridopyrimidine derivatives of palbociclib, in particular to a 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridine[2,3- d] The preparation method of pyrimidin-8-hydrogen-7-one belongs to the technical field of medicinal chemistry. Background technique [0002] Palbociclib (Ⅶ), the trade name is Ibrance, the English name is Palbociclib, and the Chinese name is also called palbociclib or palbociclib. It is a breakthrough breast cancer drug developed by Pfizer. Approved by the US FDA, it is used to selectively inhibit cyclin-dependent kinase 4 and 6 (CDK4 / 6), restore cell cycle control, and block tumor cell proliferation. It is combined with the aromatase inhibitor letrozole for ER+ / HER2 – first-line therapy for postmenopausal metastatic breast cancer. Palbociclib is the world's first marketed CDK4 / 6 inhibitor. The CAS number of Palbociclib is [571190-30-2], and its chemical n...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 戚聿新范岩森刘月盛刘会锋
Owner XINFA PHARMA
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