Preparation method of 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate

Abstract

The invention discloses a preparation method of 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate, which comprises the following steps: by taking 4-hydroxyaniline as a raw material, carrying out ring closing on the 4-hydroxyaniline and dichloroethylamine hydrochloride to synthesize 1-(4-hydroxyphenyl) piperazine with the purity of 95A% and the correction yield of 80%; 4-nitrochlorobenzene and the prepared 1-(4-hydroxyphenyl) piperazine are coupled to synthesize 4-(4-(4-nitrophenyl)-1-piperazinyl) phenol, the purity is 93 A%, and the correction yield is 88%; then carrying out nitro reduction to synthesize 1-(4-aminophenyl)-4-(4-hydroxyphenyl) piperazine with the purity of 98A% and the correction yield of 77%; and finally, synthesizing 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate with the purity of 98.7%, the content of 98.5 wt% and the correction yield of 83% by using phenyl chloroformate to protect phenolic hydroxyl groups. According to the invention, the high-purity target product 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate can be obtained through easily available raw materials and simple process steps.

Description

technical field [0001] The invention relates to a preparation method of phenyl 4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]carbamate, which belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Posaconazole is suitable for fungemia caused by fungi of the genus Candida and Cryptococcus, respiratory, gastrointestinal, urinary tract mycosis, peritonitis, meningitis, etc. It is also clinically used for the treatment of aspergillosis, zygomycosis, fusarium disease, and some Candida infections. Studies have shown that posaconazole can widely and effectively treat phaeohyphomycosis and improve the survival rate of patients infected with exophthias dermatitis. As a second-line drug, the effective rate for invasive aspergillosis resistant to amphotericin B or itraconazole is 44% to 78%, and the effective rate for zygomycete infection is 71%. [0003] While the new crown epidemic is becoming more and more serious in India, mucormyc...

AI Technical Summary

Problems solved by technology

Although the use of precious metals is avoided, to a certain extent, in order to reduce costs, Rany Ni is extremely flammable, and the reaction needs to be carried out under hydrogen pressure. Special hydrogenation equipment is required, and the reduction energy of nitro groups is very large. It is difficult to effectively control the reaction process, so the reaction risk is also high

The most important thing is that patent CN108003118A uses 4-hydroxyaniline as raw material to synthesize 1-(4-aminophenyl)-4-(4-hydroxyphenyl) piperazine, and does not involve 4-[4-[4-(4- Hydroxyphenyl) piperazin-1-yl] phenyl] phenyl carbamate is synthetic, but just synthesized this premise patent and just used four-step reaction, used a large amount of hydrobromic acid and Boron trifluoride diethyl ether, carried out under high temperature conditions of 110 ℃ for more than 16h (even some literature 1 mentions that the reaction process lasts for several days), the reaction efficiency is very low and a large amount of waste acid waste water is produced.

[0007] In addition, the quality of the commercially available intermediates in the market is uneven. They exist in various forms such as hydrochloride salts and sodium salts. Can reach about 95%

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