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Method for synthesizing pyridine propiolic acid ester

A kind of technology of pyridine propiolate and synthesis method, which is applied in the field of pyridine propiolate synthesis, can solve problems such as needing high temperature, and achieves the effect of selecting a reasonable reaction process

Inactive Publication Date: 2010-02-24
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The object of the present invention provides a kind of brand-new synthetic method of pyridyl propiolate, mainly solves the technical problem that needs high temperature in existing synthetic process of pyridyl propiolic acid ester

Method used

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  • Method for synthesizing pyridine propiolic acid ester
  • Method for synthesizing pyridine propiolic acid ester
  • Method for synthesizing pyridine propiolic acid ester

Examples

Experimental program
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Embodiment 1

[0020]

[0021] A dichloromethane solution (500 mL) dissolved with triphenylphosphine (661.0 g, 2.52 mol) was added dropwise to a dichloromethane solution (1000 mL) containing carbon tetrabromide (413 g, 1.26 mol) at 0° C., and the The mixed solution was stirred for 1 hour at 0°C. 2-Pyridinecarbaldehyde (90 g, 0.84 mol) was added dropwise to the reaction solution, and the reaction was continued at 0° C. for 1 hour. TLC (petroleum ether:ethyl acetate volume ratio=10:1) detection showed that the reaction was complete. Water (500ml) was added dropwise. Separate the organic phase and wash with brine. Anhydrous Na 2 SO 4 Drying and concentration gave crude 2-(2,2-dibromo-vinyl)-pyridine (157 g, 68.16%) as a tan oil.

[0022] At -78°C, a THF solution (500 mL) of n-BuLi (2.5 mol / L, 1.255 mol) was slowly added dropwise to crude 2-(2,2-dibromo-vinyl)-pyridine (157 g, 0.6 mol) . Stirring of the reaction was continued at -78°C for 1 hour. Ethyl chloroformate (94.74 g, 0.837 mol...

Embodiment 2

[0024]

[0025] A dichloromethane solution (600 mL) dissolved with triphenylphosphine (733.71 g, 2.80 mol) was added dropwise to a dichloromethane solution (1000 mL) containing carbon tetrabromide (458.43 g, 1.40 mol) at 0° C. The mixed solution was stirred for 1 hour at 0°C. 3-Pyridinecarbaldehyde (100 g, 0.93 mol) was added dropwise to the reaction solution, and the reaction was continued at 0° C. for 1 hour. TLC (petroleum ether:ethyl acetate volume ratio=10:1) detection showed that the reaction was complete. Water (800ml) was added dropwise. Separate the organic phase and wash with brine. Anhydrous Na 2 SO 4 Drying and concentration afforded crude 3-(2,2-dibromo-vinyl)-pyridine (207.61 g, 81.2%) as a tan oil.

[0026] At -78°C, a THF solution (664 mL) of n-BuLi (2.5 mol / L, 1.659 mol) was slowly added dropwise to crude 3-(2,2-dibromo-vinyl)-pyridine (207 g, 0.79 mol) . After continuing to stir the reaction solution at -78°C for 1 hour, ethyl chloroformate (120.02 g...

Embodiment 3

[0028]

[0029] A dichloromethane solution (600 mL) dissolved with triphenylphosphine (733.71 g, 2.80 mol) was added dropwise to a dichloromethane solution (1000 mL) containing carbon tetrabromide (458.43 g, 1.40 mol) at 0° C. The mixed solution was stirred for 1 hour at 0°C. 4-Pyridinecarbaldehyde (100 g, 0.93 mol) was added dropwise to the reaction solution, and the reaction was continued at 0° C. for 1 hour. TLC (petroleum ether:ethyl acetate volume ratio=10:1) detection showed that the reaction was complete. Water (800ml) was added dropwise. The organic phase was separated and washed with brine, anhydrous Na 2 SO 4 Drying and concentration afforded crude 4-(2,2-dibromo-vinyl)-pyridine (115.05 g, 44.5%) as a black oil.

[0030] At -78°C, a THF solution (370 mL) of n-BuLi (2.5 mol / L, 0.924 mol) was slowly added dropwise to crude 4-(2,2-dibromo-vinyl)-pyridine (115 g, 0.44 mol) . The reaction solution was stirred at -78°C for 1 hour, and ethyl chloroformate (66.84 g, ...

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Abstract

The invention relates to a method for preparing pyridine propiolic acid ester and mainly solves the technical problem of high temperature requirement in the prior process for synthesizing the pyridinepropiolic acid ester. In the method, pyridylaldehyde serving as a readily available and large-scale production material undergoes a witting reaction, and the resulting product undergoes an addition-elimination reaction with chloroformate to obtain the corresponding pyridine propiolic acid ester. The chemical reaction formula is shown as above. The invention provides the method for synthesizing the pyridine propiolic acid ester, which has the advantages that: the raw materials are low in price and readily available, the total yield is 50 to 60 percent, and the intermediate is unnecessarily purified.

Description

Technical field: [0001] The invention relates to a new synthetic method of pyridine propiolate. Background technique: [0002] 3-pyridine propiolate is a useful drug intermediate. Three synthetic methods have been reported in the literature. Phosphine reaction, followed by high-temperature rearrangement to obtain 3-pyridine propiolate (J.of Heterocyclic Chemistry.1981, 519-523). This route requires a high temperature of 250°C, and the reaction is easy to carbonize, resulting in low yield. Another method is to start from 3-acetylpyridine, first synthesize ethyl 3-acetylpyridinepyruvate, then enolize it into triflate, and react with triphenylphosphine oxide to obtain the target product (US20020169200A1). The third method is to take 3-iodopyridine as raw material, and the coupling reaction of ethyl propiolate with different substituents under different palladium catalyzed to prepare 3-pyridine propiolate (Synthesis, 1992,746-748; Synthesis Communications, 2007, 1301-1311). ...

Claims

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Application Information

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IPC IPC(8): C07D213/55
Inventor 李进飞陈东东钱占山施一峰马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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