幸运飞艇正不正规

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幸运飞艇正不正规
从连续流技术看吉利德Remdesivir的合成
来源:东南科仪    发布时间:2020-02-11    阅读:1次
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转自:康宁微反应公众号

JILIDEGONGSIDEGUANGPUKANGBINGDUYAOWURUIDEXIWEI(Remdesivir),ZHENDUI2019XINXINGGUANZHUANGBINGDU(2019-nCoV)XIANSHILEHAODELIAOXIAO。ZHEIYILINGRENZHENFENDEJIEGUOYIJINGBAODAO,JIKEXIYINLEZHONGDUOZHIYAOQIYEDEGUANZHU。


幸运飞艇正不正规KANGNINGFANYINGQIJISHUZUOWEILIANXULIUJISHUDECHANGDAOZHE,CONGLIANXULIUJISHUDEJIAODULAIKANKANJILIDERemdesivirDEHECHENG。

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RemdesivirFENZIJIEGOU


化学名:

(2S)-2-ethylbutyl2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo [2,1f] [1,2,4] triazin-7-yl)-5-cyano-3,4-dihydroxy tetrahydrofuran-2-yl)methoxy) (phenoxy)  phosphoryl) amino)  propanoate


CAS号:1809249-37-3


DANGXIA,GUONEIHENDUOYAOQIYEFENFENJIANGMUGUANGJUJIAODAOLERemdesivir,BUSHAOQIYEHEYANFAJIGOUYIJINGKAISHILIXIANGKAIFACIYAO。SHENZHILIANHUAXUEZHONGJIANTISHANGYEJIARULEZHEIGURECHAO。


合成路线图:


幸运飞艇正不正规RemdesivirHECHENGWEINature2016NIANBAODAODEDIERDAIHECHENGFANGFA,SHIYANSHIKEFANGDAZHIBAIKEJI。GONG6BUFANYING,SHOULVFENBIEWEI40%,85%,86%,90%,70%,69%,ZHONGJIANTI6HECHENGXUYAOLIANGBU,SHOULVFENBIE80%,39%。

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幸运飞艇正不正规RemdesivirHECHENGLUXIANTU

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HUAHEWU3DEHECHENG

化合物3的合成是低温有机强碱加成反应,该步反应收率低,放大困难。而微通道在此类反应展现了很强大的优势,有潜力来解决这类问题。

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HUAHEWU4DEHECHENG

幸运飞艇正不正规HUAHEWU4DEHECHENG,KEYIYONGLIANXULIUDEFANGSHIJINXING。WEICI,GileadZAIZHONGGUOYESHENQINGLEZHUANLI(CN107074902)。GAIQINGJIHUAFANYING,CAIYONGLIANXULIUFANYINGQI,WENDUKONGZHIZAI-40℃,ERFUSHIGONGYIZHONGXUYAOJIANGWENDAO-78℃。

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HUAHEWUNucleosideDEHECHENG

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化合物6的合成

在化合物6的合成中,第一步反应先合成化合物9,该取代反应极易发生二取代而造成选择性降低。连续流可以精准控制反应物料摩尔比及反应温度,在一定程度上提高反应选择性。


ZONGGUANRemdesivirHECHENG,YOUDUOBUFANYINGSHIYONGLEDIWEN。ERDIWENFANYINGZAIGONGYIFANGDAGUOCHENGZHONG,PUBIANCUNZAIZHEKONGZHINAN,SHOULVDIDENGWENTI。


KANGNINGWEITONGDAOFANYINGQI,MOKUAIHUASHEJI,XIANGBIYUCHUANTONGFUSHIFANYING,JUYOU100BEICHUANZHIXIAOLV,1000BEIHUANREMIANJI,JINGQUEKONGZHITINGLIUSHIJIAN。TEBIESHIYONGYUFEIJUNXIANGFANYING、FANGRELIANGDA、JUYOUANQUANFENGXIANYIJIXIAOSHIGONGYIWUFAFANGDADEFANYING。


参考文献:Nature, 2016, Doi:10.1038 /nature 17180 pages381–385

幸运飞艇正不正规WEITONGDAOLIANXULIUJISHUZUOWEIHUAGONGYANFAHESHENGCHANDEYIXIANGJISHUCHUANGXINYUELAIYUESHOUDAOZHONGSHI。TAZAIHENDACHENGDUSHANGGAISHANWULIAODECHUANZHIHEFANYINGDEFANGREQINGKUANG,TIGAOFANYINGDEANQUANXINGJIZHONGJIANTIDEBUWENDINGXING,CONGERZAIFANYINGXUANZEXINGHESHOULVSHANGYUCHUANTONGFUSHIFANYINGXIANGBIJUYOUMINGXIANYOUSHI。


DANGJINXINGYOUJIJINSHULEIHUAXUEFANYINGSHI,TONGCHANGYOULIANGZHONGGUOCHENGJILIRUXIATU1SUOSHI。KONGZHIYOUJILIZHONGJIANTIDEWENDINGXINGZUOWEINEIWENHANSHU (IT)HETINGLIUSHIJIAN(τ)

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图1. 反应进程和准绝热的温度分布


DIYIZHONGJILICONGSHANGTU1ZHONGa)QUXIANKEYIKANCHUZAIFANYINGJINCHENGZHONGZAIQINDIANSHIJICUMIEQIANZENGJIAFANGJILIZHONGJIANTIDEBANSHUAIQILAIYANZHANGTINGLIUSHIJIAN(ZUIDUOFENZHONG)。ZAIZHEIZHONGQINGKUANGXIA,HUNHEXIAOLVQICIYAOZUOYONG。TINGLIUSHIJIAN(FANYING)KEYIBEIHENHAODIYOUHUA,ZUIDAHUADIZHUANHUANFANGJILUHUAWUWEIXIANGYINGDEFANGJILIZHONGJIANTI。ZHEILEIFANYINGTONGCHANGKEYIZAIFANYINGQIZHONGZAI-78°CJINXINGFANGREDELUSUHELIDEJIAOHUAN,RANHOUYONGQINDIANSHIJIZAI-78°CXIAOUHE。


DIERZHONGJILISHIDUIYUJIKUAISUFANYING(FANYINGSHIJIANXIAOYU1MIAO),RUTU1ZHONGb)QUXIANSUOSHI,XIANGFANCEZHONGYUSHUNSHI、GAOXIAOHUNHEHETINGLIUSHIJIANJIAODUANDEFANYING。ZAIZHEIZHONGQINGKUANGXIA,FANYINGSHIJIANSHIYOUZHUNJUERETIAOJIANXIADEHUNHESHIJIANHEXIANGBIANTIAOJIANLAIJUEDING。ZHEIZHONGLEIXINGDECAOZUOTONGCHANGZAIWEIFANYINGQIZHONGJINXING,TONGGUOKUAISUBUHUOBUWENDINGFANGJILIWUZHONGBIMIANQIFENJIE。


YOUGEZHONGWENXIANBAODAODELIZIXIANSHIZAIFANYINGSHIJIANXIAOYU1MIAOCHIDUSHANGHUAXUEHECHENG,RUBUWENDINGFANGJILIZHONGJIANTIDESHENGCHENGYUJUYOUGONGNENGXINGQINDIANSHIJIJIEHESHENGCHENGXINQI,LINGRENYINXIANGSHENKEDEXINXINGHUAXUEPIN。DUIYUJINSHUYOUJILEIXINGDEFANYING,WEITONGDAOLIANXULIUFANYINGQIKEYIZAIDIWENXIAHENHAODIKONGZHIFANYINGWENDUJIYOUJILISHIJIJIDIWUDEHUNHE。


JIYUWEIFANYINGQIGAOXIAOHUNHEJIJINGZHUNKONGZHIFANYINGWENDUDEYOUDIAN,KEYIZAIYAOWUYANJIUDEBUTONGJIEDUANKUAISUTIGONGSHAOLIANGHUOPILIANGDECHANPIN。


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幸运飞艇正不正规LIRUTU2SUOSHI,BIANHUANBUTONGDEDIWU,KEYIKUAISUHECHENGBUTONGDEPENGSUANYOUJIWU。

 

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ZAIRUTU3SUOSHI,BIANHUANBUTONGDEQINDIANSHIJIHEDIWU,KEYIDEDAOBUTONGDEOUHECHANWU。


WEITONGDAOFANYINGQIKEYIZUOWEIYIGEYAOWUKAIFAHEPILIANGSHENGCHANDEQIANGYOULIDEGONGJU,YINWEIQIDUTEDEHUNHEHEHUANREJIWENDUJINGZHUNKONGZHIDEGONGNENG,WEIXINQIYAOWUDEKAIFADAKAILEYIGEXINDECHUANGKOU。


康宁研发型反应器平台开发的工艺到康宁工业化生产无放大效应,可以更快、更好地应对市场的需求。康宁公司不仅对低温有机强碱反应经验丰富,对其他类型反应也有很好的经验。比如Remdesivir合成的最后的一步(水解反应),康宁在其类似底物的反应中展现了很大的优势,收率得到了大幅度的提升。如您想了解更多成功案例,欢迎来康宁反应器技术有限公司深度交流。


参考文献:Org. Lett. 2016, 18, 3630−3633


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