【结 构 式】 |
【分子编号】12592 【品名】1-Benzhydryl-3-azetidinol; 1-Benzhydryl-3-hydroxyazetidine;1-benzhydrylazetidin-3-ol 【CA登记号】18621-17-5 |
【 分 子 式 】C16H17NO 【 分 子 量 】239.31712 【元素组成】C 80.3% H 7.16% N 5.85% O 6.69% |
合成路线1
该中间体在本合成路线中的序号:(II)The esterification of cyanacetic acid (I) with 1-(diphenylmethyl)azetidin-3-ol (II) by means of dicyclohexylcarbodiimide (DCC) in hot THF gives the corresponding cyanacetic ester (III), which is treated with HCl and then with NH3 to afford amidinoacetic acid (1-diphenylmethyl)azetidin-3-yl ester (IV). Finally, this compound is cyclized with 2-(3-nitrobenzylidene)acetoacetic acid isopropyl ester (V) by means of sodium methoxide in refluxing isopropanol.
【1】 Koike, H.; Yoshimoto, M.; Nishino, H. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Dihydropyridine derivs., their preparation and their use. EP 0266922; EP 0529702; JP 1988253082; US 4772596 . |
【2】 Prous, J.; Castaner, J.; CS-905. Drugs Fut 1990, 15, 7, 1671. |
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) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
(II) | 12592 | 1-Benzhydryl-3-azetidinol; 1-Benzhydryl-3-hydroxyazetidine;1-benzhydrylazetidin-3-ol | 18621-17-5 | C16H17NO | 详情 | 详情 |
(III) | 12593 | 1-benzhydryl-3-azetidinyl 2-cyanoacetate | C19H18N2O2 | 详情 | 详情 | |
(IV) | 12594 | 1-benzhydryl-3-azetidinyl 3-amino-3-iminopropanoate | C19H21N3O2 | 详情 | 详情 | |
(V) | 12595 | isopropyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C14H15NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(V)The deprotection of the benzyloxypyrimidine derivative (I) by treatment wit TFA and thioanisole gives the hydroxypyrimidine (II), which is treated with hot POCl3, yielding the corresponding chloro derivative (III). Finally, the target compound is obtained by condensation of (III) with 3-hydroxyazetidine (IV) in refluxing ethanol. The azetidine (IV) is obtained by deprotection of 1-benzhydryl-3-hydroxyazetidine (V) by hydrogenation with H2 over Pd/C in ethanol/water.
【1】 Naito, H.; Ohsuki, S.; Ejima, A.; Makino, C.; Ohki, H. (Daiichi Pharmaceutical Co., Ltd.); Pyrazole derivs. and salts thereof. EP 1103551; JP 2000169475; WO 0005230 . |
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) | 50359 | 4-(benzyloxy)-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinamine; 4-(benzyloxy)-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinylamine | C28H29F2N7O | 详情 | 详情 | |
(II) | 50360 | 2-amino-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-4-pyrimidinol | C21H23F2N7O | 详情 | 详情 | |
(III) | 50361 | 4-chloro-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinamine; 4-chloro-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-2-pyrimidinylamine | C21H22ClF2N7 | 详情 | 详情 | |
(IV) | 31397 | 3-azetidinol | C3H7NO | 详情 | 详情 | |
(V) | 12592 | 1-Benzhydryl-3-azetidinol; 1-Benzhydryl-3-hydroxyazetidine;1-benzhydrylazetidin-3-ol | 18621-17-5 | C16H17NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XIII)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 |