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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information