1. Reaction bottle was added of catechol and sodium hydroxide solution, stir evenly and dropped of epichlorohydrin at 50 ℃. The dripping process can be finished within 0.5 h. After the completion of dripping, the solution was refluxed at 85 ℃ for 2.5 h, after which the solution turned from dark green to brown oil. It is further extracted with chloroform, and the organic phases are combined, followed by being dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and the residue is cooled to crystallize, filtered. The filter cake is further washed with a small amount of cold carbon tetrachloride and dried at below 50 ℃ to obtain a white solid compound 2.
2. Potassium permanganate and potassium hydroxide solution were added to the reaction flask, and the pyridine solution of Intermediate 2 was added dropwise at 0-10 °C. After the completion of the dropping, the reaction was continued for 24 h at room temperature. The reaction mixture was filtered. The filtrate has its pH adjusted by concentrated ammonia to 7, concentrated to half, added of chloroform after cooling. The concentrated hydrochloric acid was added dropwise of concentrated hydrogen chloride and adjusted to pH = 1. It is then extracted with chloroform. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give Compound 3 as a pale yellow solid.
3. The reaction flask was added with intermediate 3, toluene solution and DMF. The mixture was heated to 50 ° C, stirred and dissolved, and thionyl chloride was added dropwise. The reaction mixture was refluxed for 4 hours. The toluene and the remaining thionyl chloride were distilled off under reduced pressure to give the crude compound 4.
4. Add piperazine, methanol and water to the reaction flask, stir the mixture evenly, add the ethyl acetate solution of Intermediate 4 dropwise at 10-20 ℃, continue the reaction for 2 hours, extract the reaction mixture with methylene chloride. The organic phase was extracted twice with water and the aqueous phase was adjusted to pH 10 with concentrated aqueous ammonia. The organic phase was extracted three times with dichloromethane. The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated of methylene chloride under reduced pressure to give the compound 5 as a pale yellow solid.
5. The reaction flask was added with 2-chloro-4-amino-6, 7-dimethoxyquinazoline, intermediate 5 and n-butanol, stirred and refluxed for 4 hours. After completion of the reaction, the crystals were cooled and washed with n-butanol, and dried to obtain Compound 6 as a white crystalline powder.
6 is placed into the beaker, adjusted to pH = 10 with ammonia; extract it with dichloromethane; remove the water layer; wash the organic phase with water; slowly add methanesulfonic acid and gradually precipitate of white crystals, apply cooling crystallization, filtration and drying to obtain the crude product 1.
7. The crude product is added to the methanol, heated to dissolve all; cool and crystallize it; filter, wash with cold methanol once, dry to obtain the refined product 1.
Figure 1 shows the synthesis route of doxazosin mesylate
