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Palbociclib impurity preparation method

A technology of Sibi and impurities, which is applied in the field of drug synthesis and can solve problems affecting the quality of finished products

Inactive Publication Date: 2016-04-27
北京修正创新药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Since this step reaction needs to hydrolyze two groups in the compound (II), it is unavoidable that one of the groups that is difficult to hydrolyze is incompletely reacted, thus becoming an impurity and remaining, affecting the quality of the finished product

Method used

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  • Palbociclib impurity preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The preparation of embodiment 1 Paboxibi impurity compound (I)

[0024] Add 10g of compound (II), 80ml of methanol, 80ml of purified water, 12g of p-toluenesulfonic acid in a 500ml reaction flask, stir at 60°C for 8 hours, TLC (developing solvent: methanol: ethyl acetate=1:1, rf raw material= 0.1, rf impurity = 0.6, rf Paposi ratio = 0.3) monitor the completion of the reaction, lower the temperature to below 50°C, adjust the pH to 8-9 with ammonia water, filter and dry to obtain 8 g of crude product, and purify by column chromatography (eluent: methanol : ethyl acetate=1:1) to obtain 2 g of compound (I).

[0025] 1HNMR (400MHz, CDCl 3 )δ8.84(s, 1H), δ8.18-8.20(d, 1H), δ8.07-8.07(d, 1H), δ7.27(s, 1H), δ5.86-5.86(m, 1H ), δ3.61-3.63(t, 4H), δ3.12-3.14(t, 4H), δ2.08-2.55(m, 5H), δ2.05-2.08(m, 2H), δ1.87- 1.90(m, 2H), δ1.68-1.71(m, 2H), δ1.64(s, 3H), δ1.49(s, 9H)

[0026] C 29 h 37 N 7 o 4 -MS calculated for Boc+H: 491, found: 491

Embodiment 2

[0027] The detection method of embodiment 2 Palbocepi impurity compound (I)

[0028] When using hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, etc. as protonic acids to synthesize compound (I), samples were taken at different times and detected by HPLC (C18 chromatographic column; mobile phase: A: 0.05% TFA water, B: acetonitrile; Detector: UV357nm; flow rate: 4mL / min; take 10mg sample and dissolve it in 1mL methanol ultrasonically, filter and load the sample), and use the area normalization method to determine the relative content of each compound to understand the state of the hydrolysis reaction.

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Abstract

The present invention discloses a palbociclib critical impurity compound (I) preparation method, according to the method, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid and the like are used as proton acids for synthesis of a compound (I), the reaction is simple in post-treatment and efficient.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing Palbociclib impurities. Background technique [0002] [0003] As above-mentioned structure compound (I) is a kind of key impurity of palbocibil, and its chemical name is: 6-acetyl group-8-cyclopentyl-5-methyl-2-[[5-(piperazine-1- BOC) pyridin-2-yl]amino]-8H-pyrido[2,3-D]pyrimidin-7-one. [0004] The chemical name of Palbocepi is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H-pyridine And[2,3-D]pyrimidin-7-one. It is an oral antineoplastic drug that regulates the cell cycle by inhibiting cyclin-dependent kinases 4 and 6. Mainly by inhibiting CDK4 / 6 activity to prevent cells from G1 phase to S phase and then inhibit DNA synthesis. It first entered people's field of vision at the 2012 San Antonio Breast Cancer Conference (SABCS), and once released, it attracted widespread attention from the industry. The drug is administered...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 王丁泽
Owner 北京修正创新药物研究院有限公司