药物Baricitinib(巴瑞克替尼)合成检索总结报告

药物Baricitinib（巴瑞克替尼）合成检索总结报告一、Baricitinib（巴瑞克替尼）简介

Baricitinib（巴瑞克替尼）是由礼来公司研发，于2018年5月在美国上市，主要用于治疗成人中度至重度风湿性关节炎。Baricitinib（巴瑞克替尼）是一种BRAF激酶抑制剂，是一种两面神激酶(JAK)抑制剂，可以阻止信号转导转录激活子(STAT)的磷酸化，阻止STAT的激活。

Baricitinib（巴瑞克替尼）不良反应：上呼吸道感染，恶心，单纯性疱疹和带状疱疹。

Baricitinib（巴瑞克替尼）分子结构式如下:

CAS:1187594-09-7英文名称：Baricitinib中文名称：巴瑞克替尼

CAS:1187595-84-1

英文名称：Baricitinibphosphate中文名称：巴瑞克替尼磷酸盐

二、Baricitinib（巴瑞克替尼）合成路线

1三、Baricitinib（巴瑞克替尼）合成检索总结报告(一)Baricitinib（巴瑞克替尼）中间体2的合成

合成方法

操作方法一

实验步骤

Toasolutionof3-hydroxyazetidinehydrochloride1(2.20g)andtriethylamine(4.0mL)inMeOH(20mL)at0°C,

di-tert-butyldicarbonate(3.12g)wasadded.Afterstirringatroomtemperaturefor6h,thesolventwasevaporated.TheresiduewasdilutedwithCH2Cl2,washedwithwaterandtheorganicphasewasevaporatedtodrynesstogivetert-butyl3-hydroxy-l-azetidinecarboxylate2(3.22g,93%)whichwas

2参考文献

WO2007/118830;(2007);(A1)English

操作方法二

操作方法三

操作方法四

usedwithoutpurificationinthenextstep.Toasolutionofazetidin-3-olhydrochloride1(45g,410.75mmol,1eq)inMeOH(1.2L)wasaddedTEA(83.13g,821.51mmol,2eq)anddi-tert-butyldicarbonate(89.65g,410.75mmol,1eq).Themixturewasstirredat25°Cfor16hours.Thenthereactionmixturewasconcentratedinvacuo.Theresiduewasre-dissolvedinEtOAc(1L).ThemixturewaswashedwithH20(3x500mL)andbrine(3x500mL),driedoveranhydrousNa2SO4,filteredandconcentratedinvacuotogivethetitlecompound2(65g,91%)asayellowoil,whichwasuseddirectlyinthenextstep.

Toastirredcold(0°C.)solutionof3-hydroxyazetidinehydrochloride1(75g,0.68mol)inethanol(1300mL)wasaddedtriethylamine(208g/280mL,2.05mol)followedbyBoc2O(164g,0.75mol).Theresultantsolutionwasstirredatambienttemperaturefor16hours.GC/MSanalysisofthereactionmixturerevealedcompletereaction.VolatileswereremovedinvacuoandtheresiduewasdilutedwithEtOAc(1300mL)andwashedwith10%citricacid(700mL),water(700mL)andbrine(700mL).Theorganicsweredriedoversodiumsulfatefiltered,andconcentratedtogivethedesiredproduct2(100.8g,85%yield).

Amixtureof3-azetidinolhydrochloride1(10g,91mmol),di-tert-butyldicarbonate(18.8g,86.3mmol)andsodiumbicarbonate(15.3g,182mmol)indioxane:water(400mL,1:1)wasstirre'datroomtemperaturefor15hours.Theorganicportionwasremovedinvacuoandtheaqueousportionwasextractedwithethylacetatethreetimes.Thecombinedorganicportionwaswashedwith5%aqueousHCl,water,brine,driedoversodiumsulfate,filteredandconcentratedin-vacuotoafford12.8g,74mmol(81%)of1,1-dimethylethyl3-hydroxyazetidine-1-carboxylate2asacolorlessoilwithoutfurtherpurification.

WO2019/8025;(2019);(A1)English

US2012/35122;(2012);(A1)English

WO2007/44515;(2007);(A1);WO2008/76415;(2008);(A1);WO2008/124085;(2008);(A2);ACSMedicinalChemistryLetters;vol.3;nb.5;(2012);p.416-421

(二)Baricitinib（巴瑞克替尼）中间体3的合成

合成方法

实验步骤参考文献

A5L-3-neckflaskequippedwithmechanicalstirrer,thermocouple,additionfunnelandnitrogeninletwasUS2012/35122;chargedwithPy-SO3(277g,1.74mol)andDMSO(900mL)(2012);(A1)andcooledto10°C.inice-bath.TEA(177g/244mL,1.74English;

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