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Palbociclib preparation method

A technology of compound and structural formula, which is applied in the field of preparation of palbociclib, can solve the problems of difficulty in obtaining raw materials, high toxicity of reaction reagents, poor reaction reproducibility, etc., and achieve low equipment requirements, easy availability of raw materials, and mild reaction conditions Effect

Active Publication Date: 2019-04-05
北京海美桐医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the prior art, there are many synthetic methods for palbociclib, but more or less there are problems such as difficulty in obtaining raw materials, high toxicity of reaction reagents, high price, poor reaction reproducibility, and low reaction yield.

Method used

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preparation example Construction

[0018] The embodiment of the present invention provides a preparation method of palbociclib, which comprises:

[0019] S1. Reaction of compound I with malonic acid diester to obtain compound II.

[0020] Wherein, the structural formula of compound I is The structural formula of compound II is

[0021] In the formula, R is a C1-C4 alkyl group, including but not limited to methyl, ethyl, n-propyl, isopropyl, tert-butyl, etc. Correspondingly, the malonate diester may be dimethyl malonate, diethyl malonate, diisopropyl malonate, di-tert-butyl malonate and the like.

[0022] Further, the molar ratio of compound I to malonate diester is 1:1.8-2.2. Under the above ratio range, the relatively cheap and easy-to-obtain malonate diester can be made in excess to ensure the complete reaction of compound I and improve the reaction yield.

[0023] Further, the reaction between compound I and malonate diester is carried out at -10-0°C, using Lewis acid as an activating reagent, and und...

Embodiment 1

[0044] This embodiment provides a kind of preparation method of compound II, its chemical reaction formula is

[0045]

[0046] Concrete preparation steps are as follows:

[0047] S1. Add 12ml THF into a 100mL three-neck flask, cool down to -10~0℃, add TiCl dropwise 4 Dichloromethane solution (12g / 12g) was added dropwise with a THF solution of a mixture of 3.8g (15.9mmol) of compound I and 5.08g (31.7mmol) of diethyl malonate.

[0048] S2. After the dropwise addition is completed, stir for 5 min, add 6.3 g of pyridine dropwise, and react overnight at room temperature.

[0049] S3. TLC detects that the reaction is complete. It was diluted with water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the concentrate was purified by column chromatography to obtain compound II (5.6 g, yield 93%).

[0050] Compound II is characterized as follows:

[0051] 1 H-NMR (400MHz, DMSO): 1.37(s,6H), 1.61~1.68(m,4H), 1.81~1.89(m,4H), 2.43(s,3H), 2.45(s,...

Embodiment 2

[0053] This embodiment provides a kind of preparation method of compound III, and its chemical reaction formula is

[0054]

[0055] Concrete preparation steps are as follows:

[0056]S1. Dissolve 38.1g (0.1mol) of compound II in 300mL THF, add dropwise 1.1g (0.01mol) potassium tert-butoxide / 10mlTHF solution at room temperature, and stir at room temperature for 5 minutes.

[0057] S2. The completion of the reaction was detected by TLC, and purified by column chromatography to obtain compound III (32.1 g, yield 95.8%).

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Abstract

The invention discloses a palbociclib preparation method, and relates to the field of organic synthesis. The method includes taking a compound I as a starting material; and preforming a five-step reaction to obtain palbociclib. The method has the advantages of simple operation, low requirement on equipment, easily-available raw materials, mild reaction conditions and high yield, so that the methodis suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of palbociclib. Background technique [0002] Palbociclib is a targeted CDK4 / 6 inhibitor, which was first reported by US Patent 6936612. Palbociclib selectively inhibits cyclin-dependent kinases 4 and 6 (CDK4 / 6), restores cell cycle control, and blocks tumor cell proliferation. Palbociclib combined with letrozole for postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer who have not previously received systemic therapy to control advanced disease The initial endocrine basic therapy; combined with fulvestrant for hormone receptor positive (HR+), HER2-advanced or metastatic breast cancer patients whose disease has progressed after receiving endocrine therapy. [0003] In the prior art, there are many synthetic methods for palbociclib, but more or less there ar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 吴滨金帅明张旭刘长茹
Owner 北京海美桐医药科技有限公司
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