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2024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.
WO2024/8025;(2024);(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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药物Baricitinib(巴瑞克替尼)合成检索总结报告
