2024年3月13日发(作者：)

上市新药lasmiditan（拉米地坦）合成检索总结报告

一、

lasmiditan

（拉米地坦）简介

lasmiditan

（拉米地坦）是礼来公司研发，于

2019

年

10

月在美国

上市，主要用于治疗成人急性偏头痛。

lasmiditan

（拉米地坦）是羟色

胺

1F(5-HT1F)

受体激动剂。不良反应：头晕，疲劳，感觉异常和镇

静。

lasmiditan

（拉米地坦）分子结构式如下：

CAS

：

439239-90-4

英文名称：

lasmiditan

中文名称：拉米地坦、拉司米地坦

二、

lasmiditan

（拉米地坦）合成路线

1

三、

lasmiditan

（拉米地坦）合成检索总结报告

(

一

)lasmiditan

（拉米地坦）中间体

3

的合成

序号

1

实验步骤参考文献

Charge2,6-dibromopyridine1toareactionvessel(1.67

wt,1.4eq,696g)followedbyTHF(7.0vol,6.2wt,2.9

L)andstirat18to25°iPrMgCl/LiCl(Turbo

Grignard;ca.l4%w/wsolutioninTHF,correctedfor

assay,5.7vol,1.54eq,2.4L)maintainingtheinternal

temperatureat18to25°nsewithTHF(1.0vol,

0.9wt,420mL).Stirtheresultingsolutionat18to25°C

untilcompleteby1HNMRanalysis.(Pass

criterion>72%molmetallatedbromopyridine).Charge

N,N-Diethyl-l-methylpiperidine-4-carboxamide2THF

solution(1.0wtcorrected,ca.4vol,417g)tothe

reactionmixtureat18to25°nsewithTHF(1.0

vol,0.9wt,420mL).Stirat18to25°Cuntilcompleteby

HPLCanalysis(passresult<10%areaN-methylamide).

Chargeammoniumchloridesolution(10%w/v,6.0vol,

WO2011/123654;(2011);

2.5L)maintainingtheinternaltemperatureat18to25°C.(A1)English

AdjustthepHofthebiphasiclayerto7.6to7.9targeting

7.6to7.7withcHCl(ca.420mL,ca.1.0voltypically

required)at18to25°Candstirfor20to40minutes

(target35minutes).CheckthepHand,ifnecessary

osettleforatleast60minutes

andremovetheloweraqueousphaseretainingany

THF

(3.0vol,2.7wt,1.2L)totheaqueousphaseat18to

25°hepHand,ifnecessaryadjusttopH7.6to

ratleast20minutesandallowtosettleforat

least60minutesthenseparatethelayersretainingany

THF

(3.0vol,2.7wt,1.2L)totheaqueousphaseat18to

25°hepHand,ifnecessaryadjusttopH7.6to

ratleast20minutesandallowtosettleforat

least60minutesthenseparatethelayersretainingany

2

THF

(3.0vol,2.7wt,1.2L)totheaqueousphaseat18to

25°hepHand,ifnecessaryadjusttopH7.6to

ratleast20minutesandallowtosettleforat

least60minutesthenseparatethelayersretainingany

purified

water(6.0vol,2.5L)tothecombinedorganicphasesat

18to25°heptanes(0.5vol,0.3wt,208mL)to

themixtureat18to25°coneHC1acidtothe

mixtureuntilapH1.0to1.5isreached(ca.1.2L,

expected0.5vol)at18to25°tethelayersat18

to25°ttheorganiclayerwith10%v/v

cHCl/purifiedwater(3.0vol,1.2L)at18to25°C.

Combinetheacidicaqueousextractsandcharge

n-butanol(5.0vol,4.1wt,2.1L)at18to25°

20%w/vsodiumhydroxidesolutiontoadjustthepHto

9.0to10.0(ca.830mL,expectedca.2vol)at18to25°C.

Allowtosettleforatleast20minutesandseparatethe

layersat18to25°ebasicaqueousphasewith

n-butanol(3.0vol,2.4wt,1.2L)at18to25°C.

Concentratethecombinedorganicphasesundervacuum

at20to30°n-butanol(3.0vol,2.4

wt,1.2L)andconcentrateundervacuumtoca.6volat

20to30°inethewatercontentbyKF(AKX

reagent;passcriterion<0.2%w/w).Coolthemixtureto

18to25°Candfilterat18to25°efiltercake

withn-butanol(8.0vol,6.5wt,3.3L)at18to25°C.

Charge48%w/waqueoushydrobromicacidsolution

(0.70vol,1.04wt,292mL)tothecombinedfiltratesat

upto30°Cfollowedbyan-butanol(2.0vol,1.6wt)line

hepHofthemixturewithadamppHstrip

(passcriterionpH<2).y

atmosphericdistillation(expectedtemperature108to

112°C).Determinethewatercontentofafilteredsample

byKF(AKXreagent,passcriterion<0.3%w/wwater).

Coolto18to

25°Can

through

ΙΟΟμιηclothandwashthefiltercakewithn-butanol(2x

1.0vol,2x0.8wt,2x417mL)at18to25°p

to50°Cuntil<0.5%w/wn-butanolby1HNMR.

Expectedyield:50to80%th,92to148%w/w;Isolated

yield:468g(61%th,112%w/w).

(二)lasmiditan（拉米地坦）中间体4的合成

3