【结 构 式】 |
【分子编号】68070 【品名】2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile 【CA登记号】 |
【 分 子 式 】C7H10N2O2S 【 分 子 量 】186.23468 【元素组成】C 45.15% H 5.41% N 15.04% O 17.18% S 17.22% |
合成路线1
该中间体在本合成路线中的序号:(VI)N-Protection of 4-chloropyrrolo[2,3-d]pyrimidine (I) with POM-Cl by means of NaH in DME yields the POM-protected deazapurine (II), which is then subjected to Suzuki coupling with pinacol 1-(1-ethoxyethyl)-4-pyrazolylboronate (III) using K2CO3 and Pd(PPh3)4 in BuOH at 82 °C to give the protected pyrazolyl-deazapurine derivative (IV). Without isolation, compound (IV) is N-deprotected with HCl in THF, providing the pyrazole-deazapurine (V), which is then condensed with 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile (VI) in the presence of DBU in DMF to produce the 3-[1-(ethylsulfonyl)azetidin-3-yl]pyrazole derivative (VII). Finally, the POM protecting group is removed from precursor (VII) by means of NaOH in MeOH/THF or LiOH·H2O in acetonitrile/i-PrOH .
Coupling of SEM-protected deazapurine (VIII) with azetidine derivative (VI) in the presence of DBU in DMF affords the corresponding ethylsulfonyl derivative (IX), which is then N-deprotected by means of LiBF4 in acetonitrile/water and finally, without isolation, is reacted with NH4OH .
【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. |
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 |
(II) | 69168 | C6H3ClN3.POM | 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 | |
(V) | 69169 | C9H6N5.POM | 详情 | 详情 | ||
(VI) | 68070 | 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile | C7H10N2O2S | 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 | |
(IX) | 68073 | 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile | C22H31N7O3SSi | 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 |
合成路线2
该中间体在本合成路线中的序号:(VI)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 |