Novel synthetic method of Palbociclib

A technology of palbociclib and synthesis method, applied in the direction of organic chemistry, etc., which can solve the problems of unfavorable process amplification, difficult product purification, difficult operation, etc., and achieve the effect of avoiding coupling reaction, simple operation and shortening the reaction steps

Active Publication Date: 2017-04-19
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The process uses methyl 2-acetylbutyrate, malononitrile and guanidine derivatives for one-pot cyclization to obtain the skeleton molecule of the product. Although the reaction steps are shortened, the ring-closing, diazotization, amidoalkyl There are many side reactions in the radicalization and oxidation reactions, not only the scale-up operation is difficult, the reaction yield is low, but also the product purification is difficult, which is not conducive to process scale-up, so it is still necessary to find a new synthesis method that is simpler, more efficient, and lower cost

Method used

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  • Novel synthetic method of Palbociclib
  • Novel synthetic method of Palbociclib
  • Novel synthetic method of Palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055]

[0056]Add 2,4-dichloropyrimidine (14.90g, 100mmol), triethylamine (2.24g, 20mmol) and dichloromethane (149mL) into a three-necked flask, stir evenly, cool to 0-5°C, and slowly drop cyclopentyl Base amine (8.51g), after adding, warm up to room temperature and react for 6-8 hours. After the reaction, 277mL of water is added to quench the reaction. The aqueous phase is extracted 3 times with dichloromethane (75mL), and the combined organic phases are washed with saturated brine (75mL). Once, dried over sodium sulfate, concentrated and separated by column chromatography with a mixed solvent of dichloromethane and ethyl acetate to obtain compound II (15.22 g, 77%). ESI m / z=198.1(M+1).

[0057] Triethylamine in Example 1 can be replaced by diisopropylethylamine, DABCO, DBU, etc.; solvent methylene chloride can be dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran , 1,4-dioxane, acetonitrile or toluene instead.

Embodiment 2

[0059]

[0060] Add 2-chloro-4-(cyclopentylamino)pyrimidine II (19.77g, 100mmol) and 1,2-dichloroethane (99mL) into the three-necked flask, stir well and cool to 0~5℃, add 2mol / L dichloromethane solution of boron trichloride (60mL, 120mmol), after the addition, keep stirring for 30 minutes, add acetonitrile (4.93g, 120mmol) dropwise, heat up to reflux reaction for 20-24 hours after the addition, finish cooling and add 4mol / L hydrochloric acid (75mL, 300mmol) quenched the reaction, and after stirring for 20 minutes, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane (100mL), and the combined organic phase was washed once with saturated sodium bicarbonate (100mL) solution. Washed twice with saturated brine (100 mL), dried over sodium sulfate, concentrated and separated by column chromatography with a mixed solvent of dichloromethane and ethyl acetate to obtain compound III (21.09 g, 88%). ESI m / z=240.2(M+1).

[0061] In embodiment 2,...

Embodiment 3

[0063]

[0064] Add phosphine reagent 4 (33.34g, 110mmol) and dimethylformamide (96mL) into the three-necked flask, stir and dissolve, add potassium tert-butoxide (22.44g, 200mmol), keep warm for 30 minutes after adding, and then drop into the middle Compound III (23.97g, 100mmol) in dimethylformamide (48mL) solution, raised to room temperature after dropwise reaction for 3-4 hours. Add water 240mL to quench the reaction, the aqueous phase is extracted 3 times with ethyl acetate (120mL), the combined organic phase is washed 2 times with saturated brine (120mL), dried over sodium sulfate, and concentrated with petroleum ether ethyl acetate mixed solvent column chromatography Compound 5 (27.41 g, 80%) was isolated. ESI m / z = 342.0, 344.1 (M+1).

[0065] Potassium tert-butoxide can be replaced by sodium hydride, sodium tert-butoxide, lithium hexamethylsilamide, butyllithium or lithium diisopropylamide in embodiment 3; solvent dimethylformamide can be replaced by tetrahydrofur...

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Abstract

The invention provides a novel synthetic method of Palbociclib, comprising the following steps: 1) under the action of alkali and a solvent, an intermediate V and an intermediate B1 undergo a condensation reaction to obtain a compound VI; 2) the compound VI undergoes exchange with a Grignard reagent, and then the exchange reaction product reacts with an acylation reagent to obtain a compound VII; when X is acetyl, the compound VI is the compound VII; 3) the compound VII undergoes deprotection reaction under the action of hydroxyethanesulphonic acid and finally salification is conducted so as to obtain the finished product Palbociclib X. the synthetic method has a simple process route, is low-cost, and is suitable for industrial production. The synthetic route is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new synthesis method for preparing palbociclib. Background technique [0002] Palbocicib (trade name Ibrance) is a new type of high-efficiency oral anticancer drug developed by Pfizer. It is the first CDK4 / 6 kinase inhibitor on the market in the world, which can selectively inhibit cyclin-dependent kinases 4 and 6, and has a remarkable effect in the treatment of advanced breast cancer. The global breast cancer drug market can reach tens of billions of dollars each year, and palbociclib has a broad market prospect. [0003] Palbociclib chemical name: 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2, 3-d] pyrimidin-7-one isethionate, the molecular structure is as follows: [0004] [0005] In the current synthesis methods reported in the literature, the molecular structure skeleton of the product is generally formed by the dockin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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