Preparation method of isoxepac

Abstract

The invention relates to a preparation method of isoxepac, belonging to the field of organic matter synthesis. The preparation method sequentially comprises following steps of: 1) condensation: preparing 8-12 parts of p-hydoxyphenylactic acid by weight, 6-12 parts of phthalide by weight and 8-12 parts of sodium methylate, dissolving the p-hydoxyphenylactic acid and the phthalide by using DMAC (dimethylacetamide), adding the sodium methylate, heating the solution to 80-170 DEG C for reaction for 3-10h under pressure of 0.1-10Pa, regulating pH (potential of hydrogen) to 1-5, and conducting crystallization to precipitate 4-(2-carboxybenzyloxy) phenylacetic acid; 2) cyclization: dissolving the 4-(2-carboxybenzyloxy) phenylacetic acid obtained in the step 1 by using glacial acetic acid, adding 3-52 parts of polyphosphoric acid by weight, heating the solution to 30-100 DEG C for reaction for 3-12h under pressure of 0.1-10Pa, and then conducting cooling crystallization to obtain crude isoxepac products; and 3) purification: dissolving the crude isoxepac products by using ethyl acetate and then conducting refining and decolorization to obtain isoxepac products. The preparation method provided by the invention has the advantages of environmental-friendly production, low production cost, high product yield and purity, and short production cycle.

Description

technical field [0001] The invention relates to a preparation method of isoket acid, which belongs to the field of organic compound synthesis. Background technique [0002] Isoket acid is an important intermediate for the synthesis of the new preferred antiallergic drug olopatadine hydrochloride. However, due to the current domestic use of four-step reactions of condensation, hydrolysis, acidification, and cyclization, as well as multiple extraction and recrystallization operations, the traditional process route , the cumbersome traditional process determines the high cost of domestic Isoke acid, and the second hydrolysis reaction of the traditional process is a reversible reaction, resulting in about 8% of unhydrolyzed ester structure impurities will always be brought into the product, and then form impurities Methyl isoketate, the nature of methyl isoketate is very similar to the product, which brings great troubles to the subsequent refining and other post-processing. It ...

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Problems solved by technology

[0006] The process is to carry out the condensation reaction of ethyl o-toluate and ethyl p-hydroxyphenylacetate under the action of potassium carbonate and potassium hydroxide, and then use phosphorus pentoxide as a dehydrating agent to cyclize isoket acid. There are certain defects in the process route, which are mainly reflected in the high cost, which leads to the price of imported isoket acid at about 3,000 yuan / kg, and the use of phosphorus pentoxide, which is harmful to the environment and relatively dangerous, as a dehydrating agent, which will cause A large amount of phosphorus-containing industrial wastes are produced, which does not meet the requirements of energy saving, emission reduction and green and safe production in the new era

[0007] The U.S. literature on olopatadine hydrochloride and its intermediate synthesis process research has a report on the "Journal of Medicinal Chemistry" magazine [Howard B. Lassman, and Jeffrey C.Wilker, 1991]. This process route is complicated and difficult to control

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