Method of synthesizing methanesulfonic acid parzhushaxing intermedinte

Abstract

The invention provides a process for synthesizing pazufloxacin mesylas which comprises, preparing (S)-9,10-difluoro-3-methyl-7-oxy-2,3-dihydro-7H-pyrido[1,2,3-d,e][1,4]benzene oxazine-6-carboxylic acid ethyl ester (difluoro), charging NaOH, cooling down to below 0 deg. C with ice and salt mixture, stirring and charging phase transition catalyst PEG200, ethyl cyanoacetate, stirring and adjusting pH with dilute sulphuric acid, slowly elevating the temperature to 25-60 deg. C, reacting 4-10 hours, cooling down to 2-10 deg. C, stirring 2-5 hours at below 0 deg. C, elevating the temperature to 20-25 deg. C, thermal insulating and reacting 3-8 hours, freezing, evoluting crystal, filtering by suction, finally drying to obtain the product.

Description

technical field [0001] The invention relates to a method for synthesizing an intermediate of pazufloxacin mesylate. Background technique [0002] According to literature reports, the synthesis of (S)-10-(cyanomethyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridine[1,2,3-d, e] [1,4]Benzoxazine-6-carboxylic acid in a two-step process. The first step, the preparation of (S)-10-(cyanoethoxycarbonylmethyl)-9-fluoro-3-methyl-7-oxo 2,3-dihydro-7H-pyrido[1,2,3 -d, e] [1,4] ethyl benzoxazine-6-carboxylate, add its weight 60% NaH64g (1.6mol) in 1250ml DMF at -5-0°C under cooling and stirring with ice salt, 300 ml of ethyl cyanoacetate with a concentration of 99% was added dropwise to the reaction solution at -5°C, and stirred for 60 minutes. (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-d,e][ 1,4] 124 g (0.4 mol) of ethyl benzoxazine-6-carboxylate. Slowly heated to 35°C and reacted for 16 hours, cooled to 25°C, and added 5000ml of ice wate...

AI Technical Summary

Problems solved by technology

[0009] 1. The second type of solvent that should be restricted is used: both dioxane and methylene chloride, the third type of solvent DMF is dimethyl sulfoxide, ethyl acetate that requires restricted use, toxic substances p-toluenesulfonic acid, Dioxane, sodium hydride, a highly dangerous substance, on the one hand brings difficulties to transportation and workers' operation; on the other hand, it brings difficulties to wastewater treatment, causes irreversible damage to the environment, and is extremely dangerous to operators;

[0010] 2. The organic chemical reagents used are expensive, which increases the cost;

[0011] 3. Ethyl acetate is used for extraction. Although it can be reused after re-distillation, the loss in the extraction process is large and the cost is high. It remains in the water phase or volatilizes, which will reduce the purity of the raw material and reduce the yield;

[0012] 4. Use concentrated hydrochloric acid and concentrated sulfuric acid to hydrolyze, the reaction time is long, and there is some pollution to the environment

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