發(fā)布時(shí)間：2018-07-04 10:00

  本文選題：普拉佐米星 + 維奈托克��； 參考：《上海醫(yī)藥工業(yè)研究院》2017年碩士論文

【摘要】：本論文包括兩個(gè)部分,第一部分為氨基糖苷類抗生素普拉佐米星的合成研究。第二部分為首個(gè)Bcl-2蛋白抑制劑維奈托克3個(gè)關(guān)鍵中間體的合成研究。本文第一部分為普拉佐米星的合成研究。普拉佐米星是由Ibis Therapeutics和Achaogen公司合作開(kāi)發(fā)的新型半合成氨基糖苷類抗生素,用于治療細(xì)菌性尿路感染和腎盂腎炎,目前III期臨床實(shí)驗(yàn)已經(jīng)完成,正處于上市申請(qǐng)階段。通過(guò)對(duì)現(xiàn)有合成路線比較和分析,確定了以硫酸西索米星(1)為起始原料,經(jīng)陰離子交換樹(shù)脂游離、6'位氨基用對(duì)硝基芐氧羰基(PNZ)保護(hù)、2',3位氨基用叔丁氧羰基(Boc)保護(hù)、1位氨基用芴甲氧羰基(Fomc)保護(hù)、3"位氨基用Boc保護(hù),然后脫除Fmoc保護(hù)基、酰胺縮合、脫除PNZ保護(hù)基、還原胺化,最后脫除苯甲�；�(Bz)和Boc保護(hù)基得普拉佐米星,并用MS、1H NMR、13C NMR進(jìn)行了結(jié)構(gòu)確證,總收率約為3.8%。本文優(yōu)化了化合物4的后處理?xiàng)l件,收率提高至83.5%;摸索了合成中間體5a的較優(yōu)條件,提高純度,保證了后續(xù)反應(yīng)定量進(jìn)行;革除了微波反應(yīng)和氰基硼氫化物的使用,且所得中間體9a、10未見(jiàn)文獻(xiàn)報(bào)道。改進(jìn)后的制備工藝操作簡(jiǎn)單,條件溫和,為工業(yè)化研究提供了基礎(chǔ)。本文第二部分為維奈托克3個(gè)關(guān)鍵中間體的合成研究。維奈托克是由艾伯維和基因泰克公司聯(lián)合開(kāi)發(fā)的選擇性Bcl-2蛋白抑制劑,用于治療慢性淋巴性白血病,于2016年4月11日被FDA批準(zhǔn)上市。本文在參考文獻(xiàn)的基礎(chǔ)上,合成了3個(gè)關(guān)鍵中間體片段。片段A以5-溴-7-氮雜吲哚(28)為起始原料,氨基經(jīng)叔丁基二甲基硅烷基(TBS)保護(hù)、溴變羥基、親核取代得化合物32。片段B以3,3-二甲基環(huán)己酮(45)為起始原料依次經(jīng)Vilsmerier反應(yīng)、Suzuki偶聯(lián)、還原胺化,脫除Boc保護(hù)基得到化合物44。片段C用4-氯-3-硝基苯磺酰胺(49)親核取代得到化合物51。各中間體經(jīng)MS和1H NMR、13C NMR確證結(jié)構(gòu),其化學(xué)純度經(jīng)HPLC測(cè)定達(dá)99%以上。本文設(shè)計(jì)了一條化合物32的新路線,得到固體狀態(tài)關(guān)鍵中間體30a,有利于純化從而提高了化合物32的反應(yīng)收率。其中29a和30a均為新化合物;篩選了Suzuki反應(yīng)的溶劑及還原胺化反應(yīng)中還原劑用量和重結(jié)晶條件,并優(yōu)化了脫除Boc保護(hù)基方法。這些片段為進(jìn)一步合成維奈托克奠定了基礎(chǔ)。
[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.
【學(xué)位授予單位】：上海醫(yī)藥工業(yè)研究院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914.5

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本文編號(hào)：2095694