Synthesis method of Zarustra intermediate

Abstract

The invention discloses a synthesis method of a Zarustra intermediate. The synthesis method of the Zarustra intermediate is characterized in that by comprising the steps of a, adding 5-nitroindole toan organic solvent, slowly adding metal hydride, conducting a reaction for 0.5-2h after bubbles disappear, adding iodomethaneto conduct a reaction for 20-55 DEG C for 1-6 h, and obtaining a compound Bthrough post-treatment after it is tested that raw materials disappear through TLC; b, adding the prepared compound B into dichloromethane (DCM), controlling thesystem temperature at 0-10 DEG C and conducting stirring 1-3 h, adding a catalyst M diethyl aluminium halide dropwise under the protection of a water-free, oxygen-free nitrogen atmosphere, conducting a reaction at 20-40 DEG C for 4-9 h after adding thecatalyst, adding a compound N in batches, conducting a reaction at 20-40 DEG C for 3-7 h after adding the compound N, and obtaining a compound C through post-treatment after it is testedthat raw materials disappear through the TLC. According to the synthesis method of the Zarustra intermediate, the new catalyst diethyl aluminium halide is adopted, thus the yield coefficient reaches91.6%, the reaction cost is low, the operation is simple, the period is short, the usage of a toxic substancedimethyl sulfate is avoided, and the method is environmentally friendly and facilitates theneed satisfaction of the commercial process.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing an intermediate of zafirlukast. Background technique [0002] The chemical name of Zafirlukast is [3-[[2-methoxy-4-[[[(2-methylphenyl)sulfonyl]amino]carbonyl]phenyl]methyl]-1 -Methyl-1H-indol-5-yl]cyclopentyl carbamate. The structure is shown in Scheme1 below: [0003] Zafirlukast is a new generation of leukotriene antagonist developed by AstraZeneca for the treatment of asthma. First launched in Ireland in 1996, it is clinically indicated for mild to moderate asthma. At present, the market price of zafirlukast is relatively expensive, and the preparation process is relatively complicated, which is mainly reflected in the synthesis process of the intermediate of zafirlukast (the structure is shown in Scheme 1 below). Compound C is (3-methoxy-4 -(1-methyl-5-nitroindol-3-ylmethyl)benzoic acid, 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl) Methyl benzoat...

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Problems solved by technology

At present, the market price of zafirlukast is relatively expensive, and the preparation process is relatively complicated, which is mainly reflected in the synthesis process of the intermediate of zafirlukast (the structure is shown in Scheme 1 below). Compound C is (3-methoxy-4 -(1-methyl-5-nitroindol-3-ylmethyl)benzoic acid, 3-methoxy-4-(1-methyl-5-nitroindol-3-ylmethyl) Methyl benzoate, 3-methoxyl-4-(1-methyl-5-nitroindol-3-ylmethyl) tert-butyl benzoate), has low yield, complex post-treatment, and More "three wastes" are more harmful to the environment, which is not conducive to the needs of large-scale industrial production. Therefore, it is of great significance to develop a high-efficiency synthesis method for zafirlukast intermediates. The existing synthetic zafirlukast intermediates There are mainly two routes: Route 1: the intermediate is obtained through Methylation of 5-nitroindole and Friedel-Crafts reaction, a total of 2 steps of reaction, the total yield is 41%, as shown in Scheme 2 below; Route 2 : by 5-nitroindole through Friedel-Crafts reaction, 2-step reaction of methylation makes the intermediate, and the total yield is only 32.4%, as shown in the following Scheme3

Comparing the two routes, it is not difficult to find that there are certain shortcomings, such as low total yield, high cost, and difficult to scale up production.

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