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A kind of preparation method of cdk inhibitor

An inhibitor and catalyst technology, applied in the field of medicine and chemical industry, can solve the problems of poor fluorination reaction effect, high pressure on environmental protection, and multiple waste liquids, and achieve the effects of simple and feasible post-processing, production cost saving, and mild reaction conditions.

Active Publication Date: 2020-10-02
苏州东南药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This route adopts select fluorine reagent to carry out fluorination reaction, because the fluorine reaction effect of intermediate 4 and select fluorine reagent is poor, after the reaction is completed, intermediate 5 accounts for 40%, intermediate 4 accounts for 60%, and the yield of intermediate 5 Only about 30%, during purification, due to the strong adsorption of intermediate 4 and intermediate 5 on silica gel, it is difficult to purify by silica gel column chromatography; in addition, due to the very similar properties of intermediate 5 and intermediate 4 , the solubilities of the two are very close, and recrystallization is difficult to purify. When purifying by recrystallization, when the purity of intermediate 5 is greater than 95%, the total yield is less than 5%, and too much waste liquid is produced. Environmental pressure Larger, which makes industrial production very difficult

Method used

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  • A kind of preparation method of cdk inhibitor
  • A kind of preparation method of cdk inhibitor
  • A kind of preparation method of cdk inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1 N, the preparation of 4-dimethylthiazol-2-amine

[0047] Add 9.01g (100.0mmol) of monomethylthiourea and 9.25g (100.0mmol) of 1-chloroacetone into the reaction flask, add an appropriate amount of methanol (100mL), lower the temperature to 0-30°C, and slowly add 7.91g (100.0mL) of pyridine dropwise. mmol) in methanol solution (20mL), after the dropwise addition, slowly raise the temperature to 20-40°C, continue to stir for 1-24 hours, then drop to -10-0°C, and stir at this temperature for 1-2h, filter, and use cold water to remove the solid washed with ethanol and dried under reduced pressure to obtain 10.3 g of white solid with a yield of 80.5%. 1 H NMR (CDCl 3 -d 3 ,400MHz), 4.6(br,1H), 5.7(s,1H), 2.6(s,3H), 2.1(s,3H); MS(EI)m / e(M+)129.0.

Embodiment 2

[0048] Example 2 Preparation of 5-bromo-N,4-dimethylthiazol-2-amine

[0049] Dissolve 9.0 g (70.0 mmol) of N,4-dimethylthiazol-2-amine in dichloromethane (150 mL), control the temperature at -5 to 5° C., and add 12.5 g (70.0 mmol) of NBS in batches. Keep it at -5~5°C, continue to react at -5~5°C for 0.5-2h after the addition is complete, spin the solvent to dry under reduced pressure, add ethanol (50mL), beat at room temperature for 1-2 hours, filter, and use the solid Ethanol wash. The solid was dried under reduced pressure to obtain 10.7 g (50.2 mmol) of 5-bromo-N,4-dimethylthiazol-2-amine with a yield of 73.8%. 1 H NMR (CDCl 3 -d 3 ,400MHz), 4.9(br,1H), 2.7(s,3H), 2.2(s,3H); MS(EI)m / e(M+)207.0.

Embodiment 3

[0050] The preparation of embodiment 3 key intermediate A

[0051] Under the protection of nitrogen, 2.07g (10.0mmol) of 5-bromo-N,4-dimethylthiazol-2-amine was added to the reaction flask, and then DMSO (15mL), 2.94g (30.0mmol) of potassium acetate, and bis (Pinacolate) diboron 2.55g (10.1mmol) and dppf palladium dichloride 0.22g (0.3mmol) catalyst, then replace the air in the bottle, heat to 65-100°C, and react at this temperature for 3-12 hours , after the reaction is complete, cool down, add water, extract three times with ethyl acetate, combine the extracts, wash with saturated saline solution, then dry with anhydrous magnesium sulfate, spin dry the filtrate under reduced pressure, and then purify with ethanol , filtered, the solid was washed with cold ethanol, and the solid was dried under reduced pressure to obtain 1.89 g of the key intermediate A with a yield of 70.5%. 1 HNMR (CDCl 3 -d 3 ,400MHz), 3.2(s,6H), 2.3(s,3H), 1.3(s,12H); MS(EI)m / e(M+)255.1

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Abstract

The invention discloses a preparation method of a CDK (Cyclin-dependent Kinase) inhibitor. The preparation method comprises the following steps: enabling monomethylthiourea and 1-chloroacetone to react to obtain N,4-dimethylthiazole-2-amine; carrying out bromination reaction to obtain 5-bromo-N,4-dimethylthiazole-2-amine; enabling the 5-bromo-N,4-dimethylthiazole-2-amine and borate to react under the action of a catalyst, so as to obtain an aromatic borate intermediate; enabling the aromatic borate intermediate and 2,4-dichloro-5fluorouracil to be subjected to suzuki coupling reaction under the catalysis of a palladium series catalyst, so as to obtain a coupled product; enabling the coupled product and aromatic amine to be subjected to Buchwald-Hartwig reaction to finally obtain a target product.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a class of CDK inhibitors and a preparation method thereof. Background technique [0002] Tumors are generally considered to be composed of a group of cells that proliferate abnormally. Its basic feature is hyperactivation and continuous cell proliferation, so it can effectively inhibit tumor growth by inducing cell cycle arrest. Cyclin-dependent kinase (CDK) belongs to the serine / threonine protein kinase family and is a key kinase involved in cell cycle regulation. It has been reported that 20 different CDKs combine with cyclins to form active heterodimers and participate in physiological processes such as transcription, metabolism, neural differentiation and development. In tumor cells, the overexpression or overactivation of cyclin, the inhibition of CDKI activity, and the continuous activation of upstream division signals will all cause changes in C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D277/42C07F5/02A61K31/635A61P35/00
CPCC07D277/42C07D417/04C07F5/025
Inventor 吉民胡海燕李锐张影
Owner 苏州东南药业股份有限公司
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