本文選題：GS-7977 + D-甘油醛縮丙酮　； 參考：《河北科技大學(xué)》2014年碩士論文

【摘要】：丙型肝炎是1989年發(fā)現(xiàn)的一種嚴(yán)重危害人類健康的病毒傳染性疾病,全球范圍內(nèi)HCV感染率約為3%。GS-7977是一種新型核苷酸丙肝口服藥物,于2013年12月FDA批準(zhǔn)在美國(guó)上市,預(yù)計(jì)2018年銷售額50億美元。本文主要對(duì)其手性中間體(2’R)-2'-脫氧-2'-氟-2’-甲基脲苷的合成進(jìn)行研究。論文通過(guò)實(shí)驗(yàn)確定了以D-甘露醇為起始原料,經(jīng)丙酮縮合保護(hù)、高碘酸鈉氧化,制備獲得D-甘油醛縮丙酮；然后經(jīng)Wittig反應(yīng)、氧化反應(yīng)制備中間體(2S,3R)-3-((R)-2,2-二甲基-[1,3]二氧戊環(huán)-4-基)-2,3-二羥基-2-甲基丙酸乙基酯。將文獻(xiàn)Wittig反應(yīng)操作溫度由-78℃提高到-10℃,以蒸餾法代替文獻(xiàn)柱層析法,簡(jiǎn)化操作,提高了反應(yīng)收率。經(jīng)雙鍵高錳酸鈉氧化反應(yīng)、鄰二醇與二氯亞砜的亞硫酸酯化、次氯酸鈉氧化、Et3N·HF氟代、脫除丙酮保護(hù)基、分子內(nèi)環(huán)合反應(yīng)、羥基苯甲�；@得3-苯甲酰氧基-5-(4-苯甲酰氨基-2-氧-2H-嘧啶-1-基)-4-氟4.甲基-四氫-呋喃-2-基甲基酯。經(jīng)羰基還原、羥基磺�；4-苯甲�；奏さ挠H核取代反應(yīng)、脫苯甲酰保護(hù)基得到目標(biāo)產(chǎn)物—(2'R)-2'-脫氧-2'-氟-2'-甲基脲苷。以羥基甲磺�；瘉�(lái)代替羥基鹵代反應(yīng),通過(guò)提高離去基團(tuán)反應(yīng)活性,提高反應(yīng)收率。(2'R)-2'-脫氧-2'-氟-2’-甲基脲苷經(jīng)14步反應(yīng)以總收率4.6%獲得,結(jié)構(gòu)及其中間體的化學(xué)結(jié)構(gòu)由核磁共振(1H NMR、13C NMR)、紅外光譜(IR)確證,光學(xué)純度由旋光測(cè)定儀測(cè)定。
[Abstract]:Hepatitis C is a serious infectious disease of human health discovered in 1989. The worldwide infection rate of HCV is about 3%.GS-7977, which is a new oral drug of nucleotide hepatitis C, which was approved by FDA in December 2013 in the United States.Sales are expected to be $5 billion in 2018.In this paper, the synthesis of its chiral intermediate, 2C ~ (2 +) -R ~ (2 +) -O _ (2) O _ (2) O _ (2) F _ (2) O _ (2) -methylurethroside was studied.In this paper, D- glyceraldehyde acetone was prepared from D- mannitol by acetone condensation protection, sodium periodate oxidation and Wittig reaction.The intermediate 2SN 3RN-3-rn-2n-2-dimethyl-[1] dioxopentyl ring-4-4-butadiene-2-dihydroxy-2-methyl propionate was prepared by oxidation reaction in the presence of 2-dioxomethyl-2-dimethylidene-2-dimethyl propionic acid ethyl ester.The operating temperature of Wittig reaction in literature was raised from -78 鈩，

本文編號(hào)：1740706