利福布汀的合成工艺改进

目的:探索利福布汀的最佳合成工艺。方法:以利福霉素S为起始原料,经溴代、硝基化、还原、亚氨基化,最后与侧链环合得到利福布汀;并对合成3-氨基利福霉素S的反应溶剂二氯甲烷的前处理方法(未处理、常压蒸馏、氢化钙干燥、分子筛干燥、氢氧化钾干燥)、合成3-氨基-4-亚氨基利福霉素S的反应温度(25³0、2030、20²5、1525、15²0、1020、10¹5℃)以及侧链N-异丁基哌啶酮的制备工艺进行改进。结果:利福布汀的收率为16.44%,高效液相色谱法检测纯度为99.17%。二氯甲烷的前处理选用氢氧化钾进行干燥;合成3-氨基-4-亚氨基利福霉素S反应温度控制为1515℃)以及侧链N-异丁基哌啶酮的制备工艺进行改进。结果:利福布汀的收率为16.44%,高效液相色谱法检测纯度为99.17%。二氯甲烷的前处理选用氢氧化钾进行干燥;合成3-氨基-4-亚氨基利福霉素S反应温度控制为15²0℃;侧链N-异丁基哌啶酮合成改为以异丁胺和丙烯酸乙酯为原料,其收率为85.2%、气相色谱法检测纯度为98.5%。结论:该改进工艺合成收率和纯度较高,原料易得、反应条件温和、操作简单。

Improvement on the Synthesis Technology of Rifabutin

OBJECTIVE：To explore the optimal synthesis technology of rifabutin. METHODS：Using rifampicin S as starting material,rifabutin was synthesized according to bromination,nitration,reduction,imino,and cyclization with the side chain. The following aspects were all improved,involving pretreatment method of dichloromethane as synthesis solvent of 3-amino-4-imino rifamycin S（untreated,air distillation,calcium hydride drying,molecular sieve drying,potassium hydrate drying）,synthesis temperature of 3-amino-4-imino rifamycin S（25-30 ℃,20-25 ℃,15-20 ℃ and 10-15 ℃） and the preparation technology of side chain N-isobutyl piperidone. RESULTS：The yield of rifabutin was 16.44%,and the purity determinated by HPLC chromatograms was 99.17%. The potassium hydrate drying was chosen as pretreatment method of dichloromethane. The reaction temperatures of3-amino-4-imino rifamycin S were controlled at 15-20 ℃. The yield of the side chain was 85.2% by using isobutylamine and ethyl acrylate as raw material. The purity of side chain was 98.5% determinated by gas chromatography. CONCLUSIONS：The improved technology shows high yield and purity,and raw material is easy to obtain,reaction condition is mild and easy in operation.