药物Ertugliflozin(埃格列净)合成检索总结报告

药物Ertugliflozin（埃格列净）合成检索总结报告

一、Ertugliflozin（埃格列净）简介

Ertugliflozin（埃格列净）于2017年12月在美国上市，主要适用于通过运动和饮食控制仍血糖不佳的2型糖尿病患者。Ertugliflozin（埃格列净）常见的不良反应有鼻咽炎、体质量下降、口干等等。

Ertugliflozin（埃格列净）分子结构式如下:

CAS:1210344-57-2英文名称：Ertugliflozin中文名称：埃格列净

CAS:1210344-83-4

英文名称：ErtugliflozinL-pyroglutamicacid

中文名称：埃格列净L-焦谷氨酸盐

本文主要对Ertugliflozin（埃格列净）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、Ertugliflozin（埃格列净）合成路线

1三、Ertugliflozin（埃格列净）合成检索总结报告(一)Ertugliflozin（埃格列净）中间体2的合成

合成方法

操作方法一

操作方法二

操作方法三

实验步骤

Dissolve50gofcompound(1)in285mLofDMSOandthenintoit190mLofaceticanhydridewasaddedandallowedtoreactatroomtemperatureovernight.Thereactionsolutionwaspouredintocoldwater,extractedwithethylacetate,andwashedwithsaturatedsodiumhydrogencarbonatesolution.Washwithpolyester,saturatedsodiumchloridesolution,Dryoveranhydroussodiumsulfate.Evaporationonasilicagelcolumnunderreducedpressuretogiveacolorlessoil(2)44g,yield89%.

4gfreshlyactivatedmolecularsieve4?and3.3gN-methylmorpholine-N-oxideareaddedtoasolutionof10.0g2,3,4,6-tetra-O-benzyl-α-D-glucopyranose1in140mldichloromethane.Thesolutionisstirredfor20minatambienttemperature,beforeadding0.3gof

tetrapropylammoniumperruthenate.After2hstirringatambienttemperaturethesolutionisdilutedwith

dichloromethaneandfilteredthroughCelite.Thefiltrateiswashedwithaqueoussodiumthiosulfatesolutionandwaterandthendriedoversodiumsulfate.Afterthesolventis

removedtheresidue2ischromatographedthroughsilicagel(cyclohexane/ethylacetate4:1).Yield:8.2g(82%oftheory)Toasolutionof2,3,4,6-tetra-O-benzyl-D-glucopyranoside1(5g,9.25mmol)inDMSO(25mL)wasaddedaceticacidanhydride(15mL).Themixturewasstirredovernightbeforedilutedwithwater(200mL),thenextractedwithethylacetatefor5times.Thecombinedorganicphasewere

washedwithsaturatedNaClsolution,driedwithanhydrousNa2SO4,filtrated,andconcentratedunderreducedpressure.Theresiduewaspurifiedbycolumnchromatography(petroleumether/ethylacetate=8/1)togivecompound2

2参考文献

CN105085494;(2019);(B)Chinese

US2006/189548;(2006);(A1)English;

US2006/234953;(2006);(A1)English;

US2007/4648;(2007);(A1)English;

US2007/27092;(2007);(A1)English

BioorganicandMedicinalChemistry

Letters;vol.22;nb.1;(2012);p.642-644

操作方法四

操作方法五

(4.63g,93%)asacolorlessoil.Toasolutionofoxalylchloride(2.4mL,27.74mmol)indichloromethane(100mL)coolto-78oCwasaddedDMSO(2.6mL,37.00mmol)andtheresultingsolutionstirredfor15minutes.Asolutionof2,3,4,6-tetra-O-benzyl-β-D-glucopyranose1(6g,11.10mmol)indichloromethane(10mL)wasaddedviasyringeandtheresultingmixturewasstirredfor1hourat-78oC.Finally,triethylamine(6.4mL,46.24mmol)wasaddedandthemixturewasstirredfor1hourallowingtowarmtoroomtemperature.Dilutedwithethylacetate(200mL)andwashedwith0.5MHCl(2×75mL),water(1×75mL)andbrine(1×75mL).Theorganicsweredriedovermagnesiumsulfate,filtered,and

concentrated.Thecrudeproduct2wasusedwithoutfurtherpurification.

Asolutionof2,3,4,6-tetra-O-benzyl-D-glucopyranose1(25.0g)indimethylsulfoxide(100mL,4L/kg)wasstirredat20?25°Cfor30minunderanitrogenatmosphere.Aceticanhydride(75mL,3L/kg)wasaddedatarateof5mL/min(～15min)at15?25°C.Aftercompleteaddition,thereactionmixturewasstirredfor18?24hat20?25°C.AftercompletereactionwasconfirmedbyUHPLC/MSanalysis,thereactionmixturewasdilutedwithtoluene(225mL,9L/kg)anda3.3NaqueoussolutionofHCl(225mL,9L/kg)wasslowlyaddedtoquenchtheexcessaceticanhydride.Thereactionmixturewasstirredfor20minat20?25°Ctocompletethisquench.Thephaseswereseparated,theaqueouslayerwasdiscarded,andtheorganiclayerwaswashedwitha2Maqueousphosphatebuffer(pH7,225mL,9L/kg).Afterstirringfor20minat20?25°C,thephaseswereseparated,andtheorganiclayerwasdriedoversodiumsulfate(as

needed)andfiltered.Analysisofthefiltrateindicated26.9goflactone2waspresent(924mg/gpotency,94.6%purity).

WO2006/138163;(2006);(A2)English

OrganicProcessResearchandDevelopment;vol.18;nb.1;(2014);p.66–81.

(二)Ertugliflozin（埃格列净）中间体3的合成

合成方法实验步骤

Asolutionoftetra-O-benzylgluconolactone2(14.7wt/wt%,50g)intoluene(340gtotalsolutionmass)wasstirredat

3参考文献