药物Letermovir(莱特莫韦)合成检索总结报告

药物Letermovir（莱特莫韦）合成检索总结报告

一、Letermovir（莱特莫韦）简介

Letermovir（莱特莫韦）于2017年11月在美国上市，主要用于治疗接受异基因造血干细胞移植后巨细胞病毒血清呈阳性的成人患者，可预防CMV感染。Letermovir（莱特莫韦）是非核苷CMV抑制剂，常见的不良反应有恶心、腹泻、呕吐、外周水肿、咳嗽、头痛、疲劳和腹痛。

Letermovir（莱特莫韦）分子结构式如下:

CAS:917389-32-3英文名称：Letermovir中文名称：莱特莫韦

本文主要对Letermovir（莱特莫韦）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。

二、Letermovir（莱特莫韦）合成路线

1三、Letermovir（莱特莫韦）合成检索总结报告(一)Letermovir（莱特莫韦）中间体3的合成

合成方法

操作方法一

实验步骤参考文献

Toadegassedsolutionof2-bromo-6-fluoroaniline1(1,99.5g,0.524mol),methylacrylate2(95.0mL,1.05mol),Chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]

palladium(II)(0.537g,1.05mmol)inisopropylacetate(796WO2015/88931;mL),wasaddeddegassedN,N-dicyclohexylmethylamine(2015);(A1)(135mL,0.628mol).TheresultingreactionwasheatedtoEnglish80°Candallowedtostiratthistemperaturefor5hours.Theresultingslurrywascooledto20°Candfiltered.Thefiltratewaswashedwith1Mcitricacidtoprovideasolutionthatcontainedcompound3(99.3g,97%assayyield)inisopropylacrylate,whichwasusedwithoutfurtherpurification.

(二)Letermovir（莱特莫韦）中间体5的合成

合成方法

操作方法一

实验步骤参考文献

Toasolutionofcompound3(48.8g,0.250mol)in683mLofisopropylacetatewasadded244mLofwater,followedbydi-sodiumhydrogenphosphate(53.2g,0.375mol).Totheresultingsolutionwasaddedphenylchloroformate4(39.2mL,0.313mol)dropwiseover30minutes.Theresultingreactionwasheatedto30°CandallowedtostiratthisWO2015/88931;temperaturefor5hoursfor4hoursandthenwasheatedto(2015);(A1)60°Candallowedtostiratthistemperaturefor5hoursforEnglishanadditional2hourstoremoveexcessphenyl

chloroformate.Anadditional293mLofisopropylacetatewasthenaddedandthereactionmixturewasallowedtostir

2操作方法二

atroomtemperatureuntilthesolidscompletelydissolvedintosolution.Theresultingreactionmixturewastransferredtoaseparatoryfunnelandtheorganicphasewaswashedwith98mLofwaterandcollectedtoprovideasolutionofcompound5inisopropylacetate,whichwasusedwithoutfurtherpurification.

Toastirredcrudei-PrOAcsolutionofacrylate3(15.9kg,8.2wt,6.66mol)wasaddedH2O(6.50L)andNa2HPO4(1.42kg,10.0mol)followedbyphenyl

chloroformate4(1.04L,8.33mol)dropwiseover30min.ThereactionmixturewasstirredatRTfor12hbeforebeingheatedto60°Candstirredforafurther2h.Themixturewasthendilutedwithi-PrOAc(7.00L)andheldat60°Cuntilallsolidsweredissolved.TheaqueousphasewasthenseparatedandtheorganicswashedwithH2O(2.60L)beforebeingcooledtoRTtoaffordacrudei-PrOAcslurryofcarbamate5(ca.95%assayyield)whichwasuseddirectlywithout

furtherpurifification.Forthepurposesofcharacterization,asampleofpurecarbamate5wasisolatedbycrystallizationfromasampleofthecrudesolutiondilutedwithheptane.Mp154?158°C.

OrganicProcessResearchandDevelopment;vol.20;nb.6;(2016);p.1097–1103.

(三)Letermovir（莱特莫韦）中间体7的合成方法一

合成方法

操作方法一

操作方法

实验步骤

Asolutionofcompound5(79.0g,0.250mol),2-methoxy-5-(trifluoromethyl)aniline6(52.7g,0.276mol),and

4-dimethylaminopyridine(0.92g,0.0075mol)inisopropylacetate(780mL)washeatedtorefluxandallowedtostiratthistemperaturefor5hours.Theresultingslurrywascooledto20°C,thenallowedtostiratthistemperatureforfortwohoursatthistemperature,thenfiltered.Thecollectedfiltercakewasdriedinvacuotoprovidecompound7(95.0g,0.230mol)asawhitesolid,whichwasusedwithoutfurtherpurification.

Toastirredcrudei-PrOAcsolutionofcarbamate5(<6.66mol)wasadded2-methoxy-5-(triflfluoromethyl)aniline6(1.40kg,7.33mol).Theslurrywasdilutedwithi-PrOAc,heatedto40?45°C,andaconstantvolumedistillationcarriedouttoazeotropicallydrythemixture(KF<400ppm).

3参考文献

WO2015/88931;(2015);(A1)English

OrganicProcessResearchandDevelopment;