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A kind of preparation method of palbociclib intermediate

A technology of intermediates and compounds, applied in the field of drug synthesis, can solve problems such as unfavorable intermediates industrial production, difficult control of production costs, complex reaction products, etc., to avoid the use of heavy metal palladium catalysts, large implementation value, and reaction yield high effect

Active Publication Date: 2021-02-26
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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  • A kind of 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 drug synthesis, in particular to a preparation method of a palbociclib intermediate. In the preparation method of the present invention, compound I: 2,4-dichloropyrimidine is used as the starting material, replaced by cyclopentylamine, and transesterified with methyl acetoacetate, and then catalyzed by boron trifluoride ether The target compound IV is obtained by ring closure: 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-D]pyrimidinyl-7-one. The synthetic route designed by the invention avoids the use of palladium catalyst, the overall reaction conditions are mild, the reaction yield is high, the production cost is low, it is suitable for industrial production and is environmentally 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...

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Application Information

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Patent Type & Authority Patents(China)
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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