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Preparation method of palbociclib intermediate

A technology for intermediates and compounds, applied in the field of pharmaceutical synthesis, can solve problems such as unfavorable industrialized production of intermediates, difficult control of production costs, complicated reaction products, etc., and achieves avoiding the use of heavy metal palladium catalysts, increasing implementation value, and reaction yield. high effect

Active Publication Date: 2020-07-17
TIANJIN PHARMACN MEDICAL TECH
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Problems solved by technology

[0009] In the synthetic route of compound IV, the Heck coupling reaction catalyzed by palladium is used. Due to the extremely harsh reaction conditions of this coupling reaction, it generally needs to be carried out under the protection of anhydrous, oxygen-free and inert gas, and the reaction product is complicated, and the product yield The rate is low; in addition, the palladium catalyst used in this route not only has certain toxicity but also is expensive, making the production cost difficult to control, which is generally unfavorable for the industrial production of the intermediate

Method used

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

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Embodiment 1

[0030] 1) Preparation of compound II:

[0031] The ratio of compound I: 2,4-dichloropyrimidine, cyclopentylamine and triethylamine is =1:1:1.2

[0032] Add (1490g, 10.0mol) 2,4-dichloropyrimidine and 3L ethanol to a 10L four-neck flask, control the temperature in an ice-water bath to not exceed 25°C, add (851g, 9.99mol) cyclopentylamine and (1215g, 12.0mol) dropwise ) a mixed solution of triethylamine, after the dropwise addition was completed, stir at room temperature for 1 h. After the reaction was detected by HPLC, 3 L of water was added, stirred at room temperature for 1 hour to precipitate a white solid, filtered, washed with water, and dried to obtain compound II: 1680 g of 2-chloro-N-cyclopentylpyrimidin-4-amine, yield: 85.0%, MS: m / z 199 (M+H) +

[0033] The hydrogen spectrum characterization of compound II: 1 H NMR (400MHz, CDCI 3 , δppm): 1.46-1.56 (m, 4H), 1.58-1.83 (m, 4H), 2.64 (m, 1H), 6.14 (d, 1H), 7.59 (s, 1H), 7.73 (d, 1H).

[0034] 2) Preparation of Com...

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Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of a palbociclib intermediate. According to the preparation method, a compound I, namely 2,4-dichloropyrimidine is used as an initial raw material, and is subjected to substitution by cyclopentylamine, amine ester exchange with methyl acetoacetate and catalytic cyclization by boron trifluoride diethyl ether so as to obtain a target compound IV, namely 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-D]pyrimidinyl-7-one. The synthesis route designed by the invention avoids the use of a palladium catalyst, has the advantages of mild overall reaction conditions, high reaction yield and low production cost, is suitable for industrial production, and is green and environment-friendly.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a palbociclib intermediate. Background technique [0002] Palbociclib (Palbociclib) is a highly selective cyclin-dependent kinase (CDK4 / 6) inhibitor developed by Pfizer. It is suitable for estrogen receptor (ER)-positive in combination with letrozole. Treatment of postmenopausal women with human epidermal growth factor receptor (HER2)-negative, advanced breast cancer. Palbociclib can act on the key nodes of cell mitosis and play a decisive role in inhibiting the crazy proliferation of cancer cells. [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 structure is as follows: [0004] [0005] In the current synthesis method of palbociclib reported in the literature, the key lies in how to efficiently construct the key intermediate mother ring molecule: 2...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 田东奎何磊李国伟
Owner TIANJIN PHARMACN MEDICAL TECH
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