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【结 构 式】 
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【分子编号】68075 【品名】tert-butyl 3-hydroxyazetidine-1-carboxylate 【CA登记号】141699-55-0 |
【 分 子 式 】C8H15NO3 【 分 子 量 】173.21204 【元素组成】C 55.47% H 8.73% N 8.09% O 27.71% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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 |