普拉佐米星和维奈托克关键中间体的合成研究

发布时间：2018-07-04 10:00

本文选题：普拉佐米星 + 维奈托克　；参考：《上海医药工业研究院》2017年硕士论文

【摘要】：本论文包括两个部分,第一部分为氨基糖苷类抗生素普拉佐米星的合成研究。第二部分为首个Bcl-2蛋白抑制剂维奈托克3个关键中间体的合成研究。本文第一部分为普拉佐米星的合成研究。普拉佐米星是由Ibis Therapeutics和Achaogen公司合作开发的新型半合成氨基糖苷类抗生素,用于治疗细菌性尿路感染和肾盂肾炎,目前III期临床实验已经完成,正处于上市申请阶段。通过对现有合成路线比较和分析,确定了以硫酸西索米星(1)为起始原料,经阴离子交换树脂游离、6'位氨基用对硝基苄氧羰基(PNZ)保护、2',3位氨基用叔丁氧羰基(Boc)保护、1位氨基用芴甲氧羰基(Fomc)保护、3"位氨基用Boc保护,然后脱除Fmoc保护基、酰胺缩合、脱除PNZ保护基、还原胺化,最后脱除苯甲酰基(Bz)和Boc保护基得普拉佐米星,并用MS、1H NMR、13C NMR进行了结构确证,总收率约为3.8%。本文优化了化合物4的后处理条件,收率提高至83.5%;摸索了合成中间体5a的较优条件,提高纯度,保证了后续反应定量进行;革除了微波反应和氰基硼氢化物的使用,且所得中间体9a、10未见文献报道。改进后的制备工艺操作简单,条件温和,为工业化研究提供了基础。本文第二部分为维奈托克3个关键中间体的合成研究。维奈托克是由艾伯维和基因泰克公司联合开发的选择性Bcl-2蛋白抑制剂,用于治疗慢性淋巴性白血病,于2016年4月11日被FDA批准上市。本文在参考文献的基础上,合成了3个关键中间体片段。片段A以5-溴-7-氮杂吲哚(28)为起始原料,氨基经叔丁基二甲基硅烷基(TBS)保护、溴变羟基、亲核取代得化合物32。片段B以3,3-二甲基环己酮(45)为起始原料依次经Vilsmerier反应、Suzuki偶联、还原胺化,脱除Boc保护基得到化合物44。片段C用4-氯-3-硝基苯磺酰胺(49)亲核取代得到化合物51。各中间体经MS和1H NMR、13C NMR确证结构,其化学纯度经HPLC测定达99%以上。本文设计了一条化合物32的新路线,得到固体状态关键中间体30a,有利于纯化从而提高了化合物32的反应收率。其中29a和30a均为新化合物;筛选了Suzuki反应的溶剂及还原胺化反应中还原剂用量和重结晶条件,并优化了脱除Boc保护基方法。这些片段为进一步合成维奈托克奠定了基础。
[Abstract]:This thesis consists of two parts. The first part is the synthesis of the aminoglycoside antibiotic prazomicin. The second part is about the synthesis of three key intermediates of the first Bcl-2 protein inhibitor, Venatodoke. The first part of this paper is about the synthesis of Prazomis. Prazomicin is a new semi-synthetic aminoglycoside antibiotic developed by Ibis Therapeutics and Achaogen for the treatment of bacterial urinary tract infection and pyelonephritis. By comparing and analyzing the existing synthetic routes, it was determined that sisomicin sulfate (1) was used as the starting material. The 6 '-position amino group of anion exchange resin was protected by p-nitrobenzoxy carbonyl group (PNZ). The tert-butoxycarbonyl group (Boc) of 3 position amino group was used to protect 1 amino group. The amino group was protected by fluorene methoxycarbonyl group (Fomc). Then the protection group of FMOC was removed and the amide was condensed. The PNZ protection group was removed, the amination was reduced, and the benzoyl group (Bz) and Boc protected group were finally removed. The structure was confirmed by MSN 1H NMR 13C NMR. The overall yield was about 3.8%. In this paper, the post-treatment conditions of compound 4 were optimized, the yield was increased to 83.5%, the optimum conditions for the synthesis of intermediate 5a were explored, the purity was improved, and the quantitative follow-up reaction was ensured, and the microwave reaction and the use of cyano-borohydride were eliminated. The intermediate 9a10 has not been reported in the literature. The improved preparation process is simple in operation and mild in conditions, which provides a basis for industrial research. The second part of this paper is about the synthesis of three key intermediates. Venetock, a selective Bcl-2 protein inhibitor developed jointly by Albertay and Genentech for the treatment of chronic lymphoblastic leukemia, was approved by the FDA on April 11, 2016. In this paper, three key intermediate fragments were synthesized on the basis of references. Fragment A was prepared from 5-bromo-7-azaindole (28). Amino groups were protected by tertiary Ding Ji dimethylsilyl (Ding Ji), brominated hydroxyl groups and nucleophilic compounds were synthesized. Fragment B was coupled by Vilsmerier reaction and Suzuki reaction, then reduced to amination, and the protective group of Boc was removed to obtain the compound 44 from the starting material of 3 ~ (3) -dimethyl cyclohexanone (45), which was coupled with Suzuki by Vilsmerier reaction in turn. Fragment C was substituted with 4-chloro-3-nitrobenzenesulfonamide (49) to form a nucleophilic compound 51. The structures of the intermediates were confirmed by MS and 1H NMRN ~ (13) C NMR. The chemical purity of the intermediates was over 99% by HPLC. In this paper, a new route of compound 32 has been designed, and the key intermediate of solid state has been obtained for 30 years, which is favorable for purification and thus improves the reaction yield of compound 32. Among them, 29a and 30a were new compounds, the solvent of Suzuki reaction, the amount of reductant and recrystallization conditions in the reduction and amination reaction were screened, and the method of removing the protective group of Boc was optimized. These fragments lay the foundation for the further synthesis of Venetok.
【学位授予单位】：上海医药工业研究院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914.5

【参考文献】