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【结 构 式】 
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【分子编号】68077 【品名】N-Boc-3-(cyanomethylene)azetidine 【CA登记号】 |
【 分 子 式 】C10H14N2O2 【 分 子 量 】194.23344 【元素组成】C 61.84% H 7.27% N 14.42% O 16.47% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Cyclization of 2-(chloromethyl)oxirane (XI) with benzhydrylamine (XII) in MeOH, followed by reaction of the resulting compound with Na2CO3 in CH2Cl2 yields 1-benzhydrylazetidin-3-ol (XIII). Catalytic hydrogenolysis of azetidine derivative (XIII) over Pd/C, followed by re-protection with Boc2O in THF, yields carbamate (XIV), which is oxidized to N-Boc-3-oxoazetidine (XV) by means of TEMPO in the presence of KBr in EtOAc . Wittig reaction of ketone (XV) with diethyl cyanomethylphosphonate (XVI) by means of t-BuOK or NaH in THF gives N-Boc-3-(cyanomethylene)azetidine (XVII) , which is deprotected with HCl in acetonitrile to produce azetidin-3-ylideneacetonitrile hydrochloride (XVIII). Finally, azetidine derivative (XVIII) is condensed with ethanesulfonyl chloride (XIX) using DIEA in acetonitrile .
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 68070 | 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile | C7H10N2O2S | 详情 | 详情 | |
| (XI) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (XII) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
| (XIII) | 12592 | 1-Benzhydryl-3-azetidinol; 1-Benzhydryl-3-hydroxyazetidine；1-benzhydrylazetidin-3-ol | 18621-17-5 | C16H17NO | 详情 | 详情 |
| (XIV) | 68075 | tert-butyl 3-hydroxyazetidine-1-carboxylate | 141699-55-0 | C8H15NO3 | 详情 | 详情 |
| (XV) | 68076 | tert-butyl 3-oxoazetidine-1-carboxylate | 398489-26-4 | C8H13NO3 | 详情 | 详情 |
| (XVI) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (XVII) | 68077 | N-Boc-3-(cyanomethylene)azetidine | C10H14N2O2 | 详情 | 详情 | |
| (XVIII) | 68078 | C5H6N2.HCl | 详情 | 详情 | ||
| (XIX) | 54065 | Ethanesulfonyl chloride; Ethylsulfonyl chloride | 594-44-5 | C2H5ClO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)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 |