Preparation method for 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride compound

Abstract

The invention specifically relates to a preparation method for a 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride compound, which belongs to the field of synthesis of pharmaceutical chemistry. The preparation method is characterized by comprising the following steps: weighing 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid, the catalyst N,N-dimethyl formamide and ethyl acetate, placing the weighed components in a reaction vessel, slowly adding thionyl chloride drop by drop with temperature controlled to be 30 to 80 DEG C, continuing a reaction for 3 to 4 h after addition is finished, tracking the reaction by using thin-layer chromatography until the reaction is totally completed and carrying out reduced pressure distillation to remove the solvent ethyl acetate and excess thionyl chloride so as to obtain the solid 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride. According to the invention, ethyl acetate is used as the solvent to replace toluene, so reaction temperature and condensation water-bath temperature are reduced, and sublimation loss is avoided; no by product is produced in the process of the reaction, and high yield is realized; product purity is more than 95%, and a next-step reaction for preparation of roflumilast can be directly carried out without purification.

Description

technical field [0001] The invention belongs to the field of medicinal chemical synthesis. Roflumilast is a drug used in the treatment of chronic obstructive pulmonary disease and chronic bronchitis, and 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride is an intermediate of the synthetic drug roflumilast , the present invention relates to a method for preparing the intermediate and a method for synthesizing roflumilast. Background technique [0002] Roflumilast is a drug developed by Nycomed in Switzerland for the treatment of chronic obstructive pulmonary disease and chronic bronchitis. chronic obstructive pulmonary disease (COPD). Trade name: Daliresp, chemical structure formula is IV [0003] [0004] A method for preparing roflumilast is disclosed in WO2004080967, which comprises the following steps: [0005] The first step: by 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (I) Reaction with thionyl chloride to generate 3-cyclopropylmethoxy-4-difluorom...

AI Technical Summary

Problems solved by technology

This method for preparing 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride (II) has the disadvantages of low yield, poor purity and instability, and the product 3-cyclopropylmethoxy- 4-difluoromethoxybenzoyl chloride (II) has the property of sublimation, and the solvent needs to be removed by concentration at 70-90°C to remove the net. When concentrated under reduced pressure, the product (II) will also volatilize with the solvent sublimation

In addition, the product (II) will also decompose at the above high temperature, resulting in a decrease in yield. The yield of this preparation method is 60-80%, and the product purity is about 80-90%.

[0010] Another conventional method suitable for step 1 is to prepare the acid chloride compound by the carboxylic acid compound for using dichloromethane instead of toluene as a solvent, and using oxalyl chloride instead of thionyl chloride as a chlorinating agent. Although this method can reduce the concentration during vacuum concentration temperature, so that the product is not easy to sublimate and decompose, but in this reaction specific to the preparation of roflumilast there is (V) Exist, will react with 3,5-dichloro-4-aminopyridine (III) in step 2 to generate impurity amide (VI), Lead to low yield and poor purity

[0011] The yields of the above preparation methods are all no more than 80%, and the product purity is all lower than 90%.

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