阅读说明：本技术 一种高效合成2,6-二氯-3-氟苯乙酮的方法 (Method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone ) 是由 王贤洵 庄嘉佳 庄佳娥 庄柏润 庄泽林 王贤镔 孙莹 于 2019-05-06 设计创作，主要内容包括：本发明涉及一种高效合成2,6-二氯-3-氟苯乙酮的方法,属于制药领域。本发明提供了一种高效合成2,6-二氯-3-氟苯乙酮的方法,包括如下步骤,以2,4-二氯氟苯和乙酰氯为原料,在氯化物作用下于混合溶剂中发生酰化反应,充分反应后经过分离纯化得到高纯度的目标产物。本发明合成工艺路线简单,后处理方便,适合较大规模工业生产。(The invention relates to a method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone, and belongs to the field of pharmacy. The invention provides a method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone, which comprises the following steps of taking 2, 4-dichloro fluorobenzene and acetyl chloride as raw materials, carrying out acylation reaction in a mixed solvent under the action of chloride, and separating and purifying after full reaction to obtain a high-purity target product. The invention has simple synthetic process route and convenient post-treatment, and is suitable for large-scale industrial production.)

1. A method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone is characterized by comprising the following steps: the method comprises the following steps:

(1) dissolving anhydrous aluminum trichloride in a certain amount of solvent A, fully stirring, and slowly dropwise adding acetyl chloride at room temperature;

(2) dissolving 2, 4-dichlorofluorobenzene in a certain amount of solvent B, slowly dropwise adding the mixed solution into a reaction system, quenching the reaction with ice water after full reaction, extracting the reaction product with ethyl acetate for three times, washing an organic phase with a saturated sodium chloride solution for one time, drying, and removing the solvent to obtain yellow to brown oily mother liquor;

(3) rectifying the obtained mother liquor to obtain a crude product of the 2, 6-dichloro-3-fluoro acetophenone; feeding the 2, 6-dichloro-3-fluoro acetophenone crude product back to the reaction kettle, adding a mixed organic solution with the mass 1.5-3 times of that of the 2, 6-dichloro-3-fluoro acetophenone, stirring for 0.5 hour at 50-65 ℃, cooling to-5-0 ℃, precipitating 2, 6-dichloro-3-fluoro acetophenone crystals again, and centrifuging and filtering; rectifying again, and collecting 29-32 ℃ fractions to obtain a pure product.

2. The method of claim 1, wherein: the solvent A dissolved in the anhydrous aluminum trichloride in the step (1) is a mixed solvent of a polar solvent (such as nitrobenzene, nitromethane and the like) and a neutral solvent (such as dichloromethane, 1, 2-dichloroethane and the like), and when the nitrobenzene and the dichloromethane are used as the solvents, the dosage ratio of the solvents is preferably 0.75: 2.

3. The method of claim 1, wherein: in the step (1) and the step (2), the feeding equivalent ratio of the 2, 4-dichlorofluorobenzene to the anhydrous aluminum trichloride is 1: 3-1: and 8, optimizing to be 1: 4,; the feeding equivalent ratio of the 2, 4-dichlorofluorobenzene to the acetyl chloride is 1: 3-1:5, optimized to 1: 3.5.

4. the method of claim 1, wherein: the solvent B dissolved during the addition of the 2, 4-dichlorofluorobenzene in the step (1) is a neutral solvent, and dichloromethane is preferred.

5. The method of claim 1, wherein: in the step (3), the separation and purification are performed by recrystallization with a mixed solvent of low polarity and high polarity, the lower organic solvent includes but is not limited to dichloromethane, chloroform and the like, the higher organic solvent includes but is not limited to methanol, ethanol, butanol and the like, the volume ratio of the lower organic solvent to the higher organic solvent is 4-9:1-3, and the lower organic solvent is optimized to dichloromethane: ethanol (5: 2).

Technical Field

The invention relates to a method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone, and belongs to the field of pharmacy.

Background

Crizotinib (Crizotinib) is an ATP-competitive multi-target protein kinase inhibitor that inhibits Met/ALK/ROS developed by the company pfeiri. The crizotinib is proved to have obvious clinical curative effect on human bodies in tumor patients with abnormal ALK, ROS and MET kinase activities. The crizotinib is used for treating the non-small cell lung cancer, the curative effect is obviously superior to that of the traditional chemotherapy, the median progression-free survival time (PFS) of a first-line single-drug treatment patient is 10.9 months, the effective rate is up to 74%, and the crizotinib causes the bombing after being marketed in the United states in 2011. The inventor is a Hua-Lu scientist-Tejing Rong, honors the annual award of the inventor in the 38 th United states. 2, 6-dichloro-3-fluoro acetophenone is an important intermediate for synthesizing crizotinib. The purity of the 2, 6-dichloro-3-fluoro acetophenone on the market is too low, the synthesis cost is high, impurities are introduced into the raw material medicines, and the effectiveness, safety and controllability of the final preparation are seriously influenced.

Disclosure of Invention

The invention aims to solve the problems of high pollution, high cost and difficult standard reaching of purity in the existing synthetic purification route of 2, 6-dichloro-3-fluoro acetophenone, and provides a method for efficiently obtaining 2, 6-dichloro-3-fluoro acetophenone, so as to be beneficial to industrial scale production.

The invention provides a method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone, which comprises the following steps:

(1) dissolving anhydrous aluminum trichloride in a certain amount of solvent A, fully stirring, and slowly dropwise adding acetyl chloride at room temperature;

(2) dissolving 2, 4-dichlorofluorobenzene in a certain amount of solvent B, slowly dropwise adding the mixed solution into a reaction system, quenching the reaction with ice water after full reaction, extracting the reaction product with ethyl acetate for three times, washing an organic phase with a saturated sodium chloride solution for one time, drying, and removing the solvent to obtain yellow to brown oily mother liquor;

(3) rectifying the obtained mother liquor to obtain a crude product of the 2, 6-dichloro-3-fluoro acetophenone; feeding the 2, 6-dichloro-3-fluoro acetophenone crude product back to the reaction kettle, adding a mixed organic solution with the mass 1.5-3 times of that of the 2, 6-dichloro-3-fluoro acetophenone, stirring for 0.5 hour at 50-65 ℃, cooling to-5-0 ℃, precipitating 2, 6-dichloro-3-fluoro acetophenone crystals again, and centrifuging and filtering; rectifying again, and collecting 29-32 ℃ fractions to obtain a pure product.

Further, the solvent A dissolved in the anhydrous aluminum trichloride in the step (1) is a mixed solvent of a polar solvent (such as nitrobenzene, nitromethane and the like) and a neutral solvent (such as dichloromethane, 1, 2-dichloroethane and the like), and when nitrobenzene and dichloromethane are used as the solvents, the ratio of the amount of the solvent is preferably 0.75: 2.

Further, the charging equivalent ratio of the 2, 4-dichlorofluorobenzene and the anhydrous aluminum trichloride in the step (1) and the step (2) is 1: 3-1: and 8, optimizing to be 1: 4,; the feeding equivalent ratio of the 2, 4-dichlorofluorobenzene to the acetyl chloride is 1: 3-1:5, optimized to 1: 3.5.

further, the solvent B dissolved in the step (1) during the addition of the 2, 4-dichlorofluorobenzene is a neutral solvent, preferably dichloromethane.

Further, in the separation and purification in the step (3), a mixed solvent of low polarity and high polarity is used for recrystallization, the lower organic solvent includes but is not limited to dichloromethane, chloroform and the like, the higher organic solvent includes but is not limited to methanol, ethanol, butanol and the like, the volume ratio is 4-9:1-3, and dichloromethane is optimized: ethanol (5: 2).

The invention provides a method for efficiently synthesizing 2, 6-dichloro-3-fluoro acetophenone, which has the advantages of simple synthesis process route and convenient post-treatment and is suitable for large-scale industrial production.

Detailed Description

The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.