| Quetiapine hemifumarate, chemically called11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine hemifumarate, was developed by Zeneca in Britain. It is a kind of effective atypical antipsychotic agent and widely used in clinical. However, there exists some limitation, such as high cost of the starting material, environmentally unfriendly substance phenyl chloroformate with low utilization, a significant excess of polyphosphoric acid during the cyclization process. Therefore, it is of great significance to improve the synthesis processes of quetiapine hemifumarate.Synthesis of quetiapine hemifumarate was improved on the basis of literature reviews. Quetiapine hemifumarate was prepared using2-nitroaniline as material. Firstly,2,2’-thiodianiline was prepared from diazotization, vulcanization-reduction on one-pot. Secondly,2-amino diphenylsulfide was prepared from salification, acetylation, single diazotization, denitrification and neutralization. Then,2-amino diphenylsulfide reacted with triphosgene to gain (2-isocyanatophenyl)(phenyl)sulfane. Followed by cyclization, chlorination and condensation with2-(2-(piperazin-1-yl)ethoxy)ethanol to gain quetiapine. Finally, the target product quetiapine hemifumarate was gained through salification with fumaric acid, with the yield of33.6%from2-nitroaniline. The reaction conditions of each step are as follows:(1) From the starting material2-nitroaniline, diazonium salt was prepared with sodium nitrite and hydrochloric acid at the temperature of5-10℃; followed by vulcanization-reduction on one-pot, that was, vulcanization reaction was operated at the temperature of45-50℃for4hours, then raised the temperature to80℃and continued reduction for4hours to gain2,2’-thiodianiline; then2,2’-thiodianiline reacted with the same mole hydrochloric acid and acetic anhydride respectively at the temperature of30℃for1.5h, and then reacted with sodium nitrite and hydrochloric acid at the temperature of5-10℃to gain diazonium salt; finally, diazonium salt was removed nitrogen at the temperature of50-55℃for2hours with the ethanol as reducing agent, and neutralized by aqueous NaOH to gain2-amino diphenylsulfide with the total yield of55.6%.(2)(2-Isocyanatophenyl)(phenyl)sulfane was prepared by the reaction of2-amino diphenylsulfide and triphosgene at the temperature of60℃for2hours with the toluene as solvent. The proper mole ratio of the materials was2-amino diphenylsulfide:triphosgene=1:0.37. Then,(2-isocyanatophenyl)(phenyl)sulfane was cyclizated at the temperature of100℃for5hours to gain the key intermediate dibenzo[b,f][1,4]thiazepin-11(10H)-one under the polyphosphoric acid and S-strong acid as catalyst, with the yield of88.1%. The proper mass ratio of the materials was (2-isocyanatophenyl)(phenyl)sulfane:polyphosphoric acid:S-strong acid=2:8:1. Compared with the traditional method without S-strong acid, the amount of polyphosphoric acid has been reduced by70%.(3)2-(2-(Piperazin-1-yl)ethoxy)ethanol was firstly prepared by the reaction of piperazine and2-(2-chloroethoxy)ethanol at the temperature of100℃for3hours. The proper mole ratio of the materials was piperazine:2-(2-chloroethoxy)ethanol=1.5:1. Then,11-chlorodibenzo[b,f][1,4]thiazepine was gained through chlorination between dibenzo[b,fJ[1,4]thiazepin-11(10H)-one and POCl3at the temperature of105℃for4hours. The proper mole ratio of the materials was dibenzo[b,f][1,4]thiazepin-11(10H)-one:POCl3=1:6. Followed,11-chlorodibenzo[b,f][1,4]thiazepine was condensated with2-(2-(piperazin-1-yl)ethoxy)ethanol to gain quetiapine at the temperature of100℃for8hours with Nal as catalyst, with the yield of76.8%from dibenzo[b,f][1,4]thiazepin-11(10H)-one. Finally, quetiapine hemifumarate was gained through salification between quetiapine and fumaric acid at the temperature of80℃for1hours with ethanol as solvent, with the yield of89.4%. The proper mole ratio of the materials was quetiapine:fumaric acid=2:1.The structure of the target product and key intermediates were confirmed by1H-NMR,13C-NMR, MS and IR.In this thesis, the following improvements were proposed. (1)2-Amino diphenylsulfide was prepared from the starting material2-nitroaniline, by diazotization, vulcanization-reduction on one-pot, salification, acetylation, single diazotization, denitrification and neutralization in turn. This avoided using the odoriferous and high-price starting material thiophenol, and simplified the process operations.(2) During the cyclization, high-efficient catalyst S-strong acid was introduced, which made the amount of polyphosphoric acid reduce by70%and saved the cost. Moreover, it also reduced wastewater discharge. |
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