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Preparation method for pranlukast

A technology of condensation reaction and phenylbutoxy group, which is applied in the field of preparation of Pronst, can solve the problems of high energy consumption and complicated operation steps, and achieve the effect of low energy consumption and reduction of preparation cost

Inactive Publication Date: 2018-11-30
ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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Problems solved by technology

[0005] The solvent required for the condensation reaction of this preparation method is N, N-dimethylformamide, and the cyclization reaction must be carried out in an alcoholic solvent. The solvent systems required for the two-step reactions are different, so the transition state compound needs to be separated. Purification, and then the cyclization reaction, the operation steps are complicated, and the second step of the cyclization process requires high temperature reflux conditions, and the energy consumption is high

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  • Preparation method for pranlukast
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  • Preparation method for pranlukast

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preparation example Construction

[0027] The present invention provides a kind of preparation method of Prenzast, comprising the following steps:

[0028] Under the protection of nitrogen and the action of an organic base, 3-[4-(4-phenylbutoxy)benzamido]-2-hydroxyacetophenone and ethyl tetrazolecarboxylate were subjected to Claisen condensation reaction in an organic solvent , to obtain a condensation reaction solution; the reaction solution includes a compound having a structure shown in formula I; the organic solvent includes one of N, N-dimethylformamide, dimethylacetamide and N-methylpyrrolidone species or several;

[0029]

[0030] Mixing the condensation reaction solution and the acid solution, the compound having the structure shown in formula I undergoes a cyclization reaction to obtain Prenzast.

[0031] In the present invention, under the protection of nitrogen and the action of an organic base, 3-[4-(4-phenylbutoxy)benzamido]-2-hydroxyacetophenone (structure shown in formula II) and tetrazole fo...

Embodiment 1

[0045]Under nitrogen atmosphere, potassium tert-butoxide (31.36g) was dissolved in DMF (160ml) under stirring, and at room temperature, 3-[4-(4-phenylbutoxy)benzamido]- 2-Hydroxyacetophenone (16.12g) was added to the obtained solution, followed by ethyl tetrazolecarboxylate (7.39g), the reaction temperature rose to 60°C, and the reaction was kept for 5 hours to obtain a condensation reaction solution.

[0046] Then cool the reaction solution to below 10°C, add dilute hydrochloric acid solution (50g concentrated hydrochloric acid + 250g water) in another reaction vessel in advance, add the condensation reaction solution to the dilute hydrochloric acid solution, and perform ring closure reaction at 30°C After 4 hours, after the reaction was completed, the product was filtered, washed with water and dried to obtain Pronstadt (4-oxo-8-[4-(4-phenylbutoxy)benzamido]-2-tetra Azol-5-yl-4H-1-benzopyran hemihydrate), the product quality is 18.5g, the yield is 96%, and the HPLC purity is...

Embodiment 2

[0049] Under a nitrogen atmosphere, potassium methoxide (19.64g) was dissolved in DMF (160ml) with stirring, and 3-[4-(4-phenylbutoxy)benzamido]-2-hydroxyl Acetophenone (16.12 g) was added to the resulting liquid, followed by ethyl tetrazolecarboxylate (7.39 g). The reaction temperature was raised to 60°C, and the reaction was kept for 5 hours to obtain a condensation reaction solution.

[0050] Then the condensation reaction solution was cooled to below 10° C., and a dilute hydrochloric acid solution (50 g of concentrated hydrochloric acid + 250 g of water) was added in advance to another reaction vessel. The condensation reaction solution was added to the dilute hydrochloric acid solution, the temperature was controlled at 30°C, and the cyclization reaction was carried out for 5 hours. After the reaction was completed, the product was filtered, washed with water and dried to obtain Prenzast. The product quality was 16.5 g, and the yield was was 85.8%, and the HPLC purity wa...

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Abstract

The invention provides a preparation method for pranlukast. According to the preparation method, N,N-dimethylformamide, dimethylacetamide or N-methylpyrrolidone is used as a reaction solvent for a Claisen condensation reaction; after the reaction is completed, a condensation reaction solution and an acid solution are directly mixed for a cyclization reaction; the cyclization is carried out in a mixed system of a polar organic solvent (N,N-dimethylformamide, dimethylacetamide or N-methylpyrrolidone) and water; and the mixed system has good product solubility and is favorable for the implementation of the cyclization reaction. The preparation method provided by the invention can carry out a next-step reaction without separating an excess compound, is a one-step method for synthesizing pranlukast, is simple to operation and can improve product yield. Furthermore, the preparation method provided by the invention has a cyclization reaction temperature of only 0 to 40 DEG C, so ring closurecan be achieved at a low temperature; thus, the method has low energy consumption and is reduced in preparation cost.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of Prenmilkast. Background technique [0002] Pronmilt is a new type of anti-asthma drug developed by Ono Company in Japan and launched in the mid-1990s. It has a good effect in the treatment of asthma, and has no serious adverse reactions, no drug interaction problems, and does not affect the metabolism in the body. It is one of the three leukotriene receptor antagonists that are widely paid attention to internationally. [0003] Patent CN1107153 provides the preparation method of Prenzast, wherein with 3-[4-(4-phenylbutoxy) benzamido]-2-hydroxyacetophenone and ethyl tetrazole formate as raw materials, by Condensation reaction to obtain the transition state compound, and then the transition state compound is separated, and then carried out ring closure in the presence of alcohol solvent and acid, and Prenzast is prepared by two-step reaction. The reaction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04
CPCC07D405/04
Inventor 陈文斌盛景新王涛贾春祥
Owner ZHEJIANG SANMEN HYGECON PHARMA CO LTD
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