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【结 构 式】

【分子编号】68083

【品名】2-(3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

【CA登记号】 

【 分 子 式 】C20H27N7OSi

【 分 子 量 】409.566

【元素组成】C 58.65% H 6.64% N 23.94% O 3.91% Si 6.86%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXIV)

N-Protection of 4-chloropyrrolo[2,3-d]pyrimidine (I) by means of SEM-Cl in the presence of NaH in DMAc or DMF yields the protected deazapurine (XX) , which is then subjected to Suzuki coupling with pinacol 1-(1-ethoxyethyl)-4-pyrazolylboronate (III) in the presence of K2CO3 and Pd(PPh3)4 in BuOH to give the pyrazol-deazapurine derivative (XXI). Without isolation, compound (XXI) is N-deprotected by acidic hydrolysis to afford the SEM-protected deazapurine (VIII) . Alternatively, intermediate (VIII) can be obtained by Suzuki coupling of N-SEM-4-chloropyrrolo[2,3-d]pyrimidine (XX) with unprotected pyrazolylboronate (XXII) in the presence of K2CO3 and Pd(PPh3)4 in DMF at 125 °C . Coupling of SEM-protected deazapurine (VIII) with N-Boc-3-(cyanomethylene)azetidine (XVII) in the presence of DBU in acetonitrile affords the corresponding acetonitrile derivative (XXIII) , which is then N-deprotected by means of HCl in CH2Cl2 or 1,4-dioxane to provide the azetidine derivative (XXIV) . Finally, condensation of compound (XXIV) with ethanesulfonyl chloride (XIX) using DIEA in THF/EtOAc, followed by N-deprotection of the resulting adduct (IX) with TFA in CH2Cl2 affords baricitinib trifluoroacetate .
Alternatively, N,N-deprotection of intermediate (XXIII) with TFA in CH2Cl2, followed by condensation of the resulting imine (XXVI) with ethanesulfonyl chloride (XIX) using Et3N in THF also results in baricitinib trifluoroacetate .

1 Rodgers, J.D., Shepard, S., Li, Y.-L., Zhou, J., Liu, P., Meloni, D., Xia, M.(Incyte Corp.). Azetidine and cyclobutane derivatives as JAK inhibitors. CN 102026999, EP 2288610, JP 2011514909, KR 2010121657, KR 2012108042, US 2009233903, US 2012077798, US 8158616, US 8420629, US 2013225556, WO 2009114512.
2 Friedman, P.A., Fridman, J.S., Luchi, M.E., Williams, W.V. (Incyte Corp.). Janus kinase inhibitors for treatment of dry eye and other eye related dis-eases. EP 2349260, JP 2012504639, US 201011416, US 2012301464, WO 2010039939.
3 Rodgers, J.D., Shepard, S., Maduskuie, T.P. Jr. et al. (Incyte Corp.). Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors. CA 2632466, EP 1966202, EP 2343298, EP 2343299, EP 2348023, EP 2426129, EP 2455382, EP 2474545, JP 2009519340, KR 2012120462, KR 2012120463, US 2007135461, US 7598257, WO 2007070514.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 60046 4-chloro-7H-pyrrolo[2,3-d]pyrimidine;6-Chloro-7-deazapurine;4-chloropyrrolo[2,3-d]pyrimidine;4-Chloro-1H-pyrrolo[2,3-d]pyrimidine 3680-69-1 C6H4ClN3 详情 详情
(III) 68071 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole   C13H23BN2O3 详情 详情
(VIII) 68072 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine   C15H21N5OSi 详情 详情
(X) 68074 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile   C17H19N7O3S 详情 详情
(XVII) 68077 N-Boc-3-(cyanomethylene)azetidine   C10H14N2O2 详情 详情
(XIX) 54065 Ethanesulfonyl chloride; Ethylsulfonyl chloride 594-44-5 C2H5ClO2S 详情 详情
(XX) 68079 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine   C12H18ClN3OSi 详情 详情
(XXI) 68080 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine   C19H29N5O2Si 详情 详情
(XXII) 68081 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole   C9H15BN2O2 详情 详情
(XXIII) 68082 tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate   C25H35N7O3Si 详情 详情
(XXIV) 68083 2-(3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile   C20H27N7OSi 详情 详情
(XXVI) 68084 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile bis(2,2,2-trifluoroacetate)   C14H13N7.2C2HF3O2 详情 详情
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