【作者】 陶国建；

【导师】 杨亦文；

【作者基本信息】 浙江大学 ， 制药工程， 2010， 硕士

【摘要】 吡利霉素(pirlimycin, cas:78822-40-9),系法玛西亚-普强公司(Pharmacia& Upjohn Company,现在为辉瑞(Pfizer))创制的林可霉素类抗菌药物。主要用于治疗革兰氏阳性菌所致的牛乳腺炎。本论文主要研究了一种新的可制得高纯度吡利霉素的合成方法。合成路线包括：(a)将4-乙基吡啶经氧化和氰基化反应得到4-乙基-2-氰基吡啶；(b)通过酯化、氢化以及水解反应,由4-乙基-2-氰基吡啶制备得到4-乙基-哌啶-2-甲酸；(c)4-乙基-哌啶-2-甲酸和氯甲酸酯反应得到N-(取代)苄氧羰基-4-乙基-哌啶-2-甲酸；(d)肼解并氯代林可霉素得到7-C1-MTL;(e)将N-(取代)苄氧羰基-4-乙基-哌啶-2-甲酸和7-C1-MTL两者缩合反应制得吡利霉素中间体N-(取代)苄氧羰酰基吡利霉素；(f)钯炭催化下,氢化还原中间体得到目标产物——吡利霉素。本论文的工艺中,以cis-4-乙基-哌啶-2-甲酸作为起始原料计算,可以以总收率为37.3%制得成品纯度在98%左右的成品；可以总收率为26.1%制得成品纯度在99%以上的成品。同时原料成本也更低,更适合产业化的生产。更多还原

【Abstract】 Pirlimycin (CAS No.:78822-40-9) is a lincosamide antibiotic developed by Pharmacia & Upjohn Company (now Pfizer) for the treatment of Gram-positive bacteria-induced bovine mastitis.In this thesis, a novel efficient synthetic method was reported for the preparation of pirlimycin with high purity. The synthetic procedure included the following steps:(a) the preparation of 4-ethyl-2-cyanopyridine from 4-ethyl pyridine via oxidation and cyanation; (b) the synthesis of 4-ethylpiperidine-2-carboxylic acid from 4-ethyl-2-cyanopyridine through esterification, hydrogenation, and hydrolysis reactions; (c) the protection of 4-ethylpiperidine-2-carboxylic acid with chloroformate to produce the N-substituted piperidine-2-carboxylic acid derivative; (d) the formation of 7-chloro-l-methylthio-lincosamine (7-C1-MTL) via the hydrazinolysis of lincomycin and subsequent chlorination; (e) the condensation of N-substituted piperidine-2-carboxylic acid derivatives with 7-Cl-MTL to furnish the pirlimycin intermediate; (f) the Pd/C-catalyzed hydrogenation of the pirlimycin intermediate to obtain the target product---pirlimycin.Based on cis-4-ethyl-piperidine-2-formic acid as starting material, a total yield of 37.3% was obtained with about 98% purity pirlimycin. The total yield was 26.1% when the product purity was 99%. The process has a lower cost of raw materials, more suitable for commercial production.更多还原