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Method for preparing heteroaryl cyanide through cyanation reaction on palbociclib intermediate

A cyanation reaction, the technology of Palbocoxib, which is applied in the field of preparing heteroaryl cyanide by cyanation reaction of Palbocoxib intermediates, can solve the problems of high reaction cost, low yield, harmfulness to human body and environment, etc. , to achieve the effect of low raw material cost, high yield and mild reaction conditions

Inactive Publication Date: 2019-07-02
上海贤鼎生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In order to overcome the problems that the existing palbocoxib intermediate cyanation reaction has high cost, low yield, and harmful cyanide ions to the human body and the environment, the present invention provides a palbocoxib intermediate cyanation reaction The method for preparing heteroaryl cyanide by reaction is cheap and environmentally friendly, the reaction conditions are milder, the yield is higher, and the post-reaction treatment process will not produce cyanide ions harmful to the human body and the environment. important to the development of industrial

Method used

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  • Method for preparing heteroaryl cyanide through cyanation reaction on palbociclib intermediate
  • Method for preparing heteroaryl cyanide through cyanation reaction on palbociclib intermediate
  • Method for preparing heteroaryl cyanide through cyanation reaction on palbociclib intermediate

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Experimental program
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Effect test

Embodiment 1

[0028] According to the following chemical reaction equation, the cyanation of 6-bromo-8-cyclopentyl-5-methyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one prepared 6-cyano- 8-Cyclopentyl-5-methyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one:

[0029]

[0030] Under the protection of inert gas, 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanylpyrido[2,3-d]pyrimidin-7-one (4,500mg, 1.41 mmol), potassium hexacyanoferrite trihydrate (298 mg, 0.71 mmol), bis[2-(diphenylphosphino)phenyl]ether palladium chloride (303 mg, 0.42 mmol), potassium acetate (69.3 mg, 0.71 mmol), N,N-dimethylformamide (5 mL) and water (0.5 mL), the reaction flask was sealed with a rubber stopper and heated and stirred at 100° C. for 7 hours. After the reaction solution was cooled, ethyl acetate was added, and then washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The light yellow solid obtained after the crude product was subjected to column...

Embodiment 2

[0033] According to the following chemical reaction equation, 6-cyano-8-cyclopentyl was prepared by cyanation of 6-bromo-8-cyclopentyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one -2-Methylthiopyrido[2,3-d]pyrimidin-7-one:

[0034]

[0035] Under the protection of inert gas, 6-bromo-8-cyclopentyl-2-methylthiopyrido[2,3-d]pyrimidin-7-one (4a, 680.5 mg, 2 mmol) was added to a 25 mL reaction flask, Potassium hexacyanoferrite trihydrate (422.4 mg, 1 mmol), bis[2-(diphenylphosphino)phenyl]ether palladium chloride (429.5 mg, 0.6 mmol), potassium acetate (98.1 mg, 1 mmol) ), N,N-dimethylformamide (7 mL) and water (0.7 mL), the reaction flask was sealed with a rubber stopper and heated and stirred at 100° C. for 7 hours. After the reaction solution was cooled, ethyl acetate was added, and then washed with saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The light yellow solid obtained after the crude product was subjected to...

Embodiment 3

[0038] According to the following chemical reaction equation, 4-(6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 -ylamino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester cyanation to prepare 4-(6-(6-cyano-8-cyclopentyl-5-methyl-7-oxo) -7,8-Dihydropyrido[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester:

[0039]

[0040] Under the protection of inert gas, 4-(6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3] was added to a 25 mL reaction flask. -d] pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate tert-butyl ester (4b, 584.5 mg, 1 mmol), potassium hexacyanoferrite trihydrate (211.2 mg, 0.5 mmol) ), bis[2-(diphenylphosphino)phenyl]ether palladium chloride (214.8 mg, 0.3 mmol), potassium acetate (49.1 mg, 0.5 mmol), N,N-dimethylformamide (4 mL) and water (0.4 mL), the reaction vial was sealed with a rubber stopper and heated and stirred at 100°C for 7 hours. After the reaction so...

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Abstract

The invention relates to the technical field of organic synthesis. In order to solve the problems that an existing palbociclib intermediate, especially a compound with a pyrido[2,3-d]pyrimidine-7-oneskeleton structure, is high in 6-site cyanation reaction cost and low in yield, and cyanide ions harmful to human bodies and the environment can be generated, the invention provides a method for preparing heteroaryl cyanide through the cyanation reaction of the compound. According to the method, a non-toxic cyanation reagent, potassium hexacyanoferrate (K4[Fe(CN)6]), is used as a cyanogen source,and efficient conversion is realized under the catalytic action of bis[2-(diphenylphosphinyl)phenyl]ether palladium chloride (PdCl2(DPEPhos)). The method has the advantages of low cost, greenness, environmental protection, milder reaction conditions and higher yield. Cyanide ions harmful to the human body and the environment are not generated in the post-treatment process of the reaction, so thatthe method has important significance for research and industrial development in pharmacy and related fields.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing heteroaryl cyanide by cyanation reaction of a palbocoxib intermediate. Background technique [0002] Palbociclib is a highly potent CDK4 / 6 inhibitor with broad-spectrum anti-cancer activity. It is the world's first blockbuster new drug in the field of CDK inhibitors. Palbocoxib is the first highly selective inhibitor of CDK4 / 6 with a completely different mechanism from the previous anti-tumor drugs. In addition to advanced metastatic breast cancer, it targets various other malignant tumors such as lymphoma, lung cancer and melanoma. in the corresponding clinical trial stage. [0003] [0004] In the early chemical synthesis research of Palbocoxib, it mainly involved the synthesis and modification of its core skeleton pyrido[2,3-d]pyrimidin-7-one compound. Compounds 2, 3 and 4 in the reaction scheme I are all Important intermediates involved i...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 何皓蒋昌盛董海平
Owner 上海贤鼎生物科技有限公司