【结 构 式】 |
【分子编号】15149 【品名】alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine 【CA登记号】91-00-9 |
【 分 子 式 】C13H13N 【 分 子 量 】183.25296 【元素组成】C 85.21% H 7.15% N 7.64% |
合成路线1
该中间体在本合成路线中的序号:(XXIIIc)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 3) A study of the influence of different substituents in the cis/trans ratio of the cyclopropanation process has been performed. The general method is as follows: the reaction of benzylamine (XXIII) with acetaldehyde and trichloromethyl chloroformate gives the N-benzyl-N-vinylcarbamoyl chloride (XXIV), which by treatment with alcohol yields the N-vinylcarbamate (XXV). The cyclopropanation of (XXV) with fluorodiiodomethane and diethyl zinc as before preferentially affords the cis-N-(2-fluorocyclopropyl)carbamate (XXVI), which is purified by crystallization. The hydrogenolysis of (XXVI) with H2 over Pd/C in acetic acid gives cis-racemic-2-fluorocyclopropylamine (XXVII), which is submitted to optical resolution with L-menthyl chloroformate to afford pure (1R,2S)-isomer (XXII). Finally, this compound is converted into (III) with tert-butoxycarbonyl anhydride as before.
【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
【2】 Kobayashi, Y.; Hashimoto, M.; Tamura, O.; Terashima, S.; Katoh, T.; Hayakawa, I.; Akiba, T.; Nakatani, K.; Kamada, M.; Synthesis and optical resolution of dl-cis-2-fluorocyclopropylamine, the key component of the new generation of quinolonecarboxylic acid, DU-6859. Tetrahedron Lett 1992, 33, 24, 3483-6. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXIIIa) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
(XXIIIb) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
(XXIIIc) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
(XXIVa) | 15150 | N-benzyl-N-vinylcarbamic chloride | C10H10ClNO | 详情 | 详情 | |
(XXIVb) | 15151 | N-(1-phenylethyl)-N-vinylcarbamic chloride | C11H12ClNO | 详情 | 详情 | |
(XXIVc) | 15152 | N-benzhydryl-N-vinylcarbamic chloride | C16H14ClNO | 详情 | 详情 | |
(XXVa) | 15153 | benzyl N-benzyl-N-vinylcarbamate | C17H17NO2 | 详情 | 详情 | |
(XXVb) | 15154 | benzyl N-(1-phenylethyl)-N-vinylcarbamate | C18H19NO2 | 详情 | 详情 | |
(XXVc) | 15155 | benzyl N-benzhydryl-N-vinylcarbamate | C23H21NO2 | 详情 | 详情 | |
(XXVd) | 15156 | butyl N-benzyl-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
(XXVe) | 15157 | butyl N-(1-phenylethyl)-N-vinylcarbamate | C14H19NO2 | 详情 | 详情 | |
(XXVf) | 15158 | butyl N-benzhydryl-N-vinylcarbamate | C20H23NO2 | 详情 | 详情 | |
(XXVIa) | 15159 | benzyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C18H18FNO2 | 详情 | 详情 | |
(XXVIb) | 15160 | benzyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C19H20FNO2 | 详情 | 详情 | |
(XXVIc) | 15161 | benzyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C24H22FNO2 | 详情 | 详情 | |
(XXVId) | 15162 | butyl N-benzyl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C15H20FNO2 | 详情 | 详情 | |
(XXVIe) | 15163 | butyl N-[(1R,2S)-2-fluorocyclopropyl]-N-(1-phenylethyl)carbamate | C16H22FNO2 | 详情 | 详情 | |
(XXVIf) | 15164 | butyl N-benzhydryl-N-[(1R,2S)-2-fluorocyclopropyl]carbamate | C21H24FNO2 | 详情 | 详情 | |
(III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
(XXII) | 15146 | (1R,2S)-2-Fluorocyclopropanamine; (1R,2S)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 | |
(XXVII) | 63957 | rac-(1R*,2S*)-2-Fluorocyclopropylamine | C3H6FN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(V)Alkylation of tert-butyl (5-hydroxy-2-naphthyl)propionate (I) with methyl bromoacetate (II) in the presence of K2CO3 provided ether (III). Subsequent deprotection of the tert-butyl ester of (III) using trifluoroacetic acid in CH2Cl2 gave carboxylic acid (IV). This was coupled to benzhydrylamine in the presence of EDC and DMAP to afford amide (VI). Finally, ester hydrolysis of (IV) with NaOH yielded the target compound.
【1】 Nagao, Y.; Torisu, K.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); Naphthyloxyacetic acid derivs. and their use as PGE2 agonists and antagonists. EP 0719760; JP 1996239356 . |
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) | 26497 | tert-butyl 3-(5-hydroxy-1-naphthyl)propanoate | C17H20O3 | 详情 | 详情 | |
(II) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
(III) | 26498 | tert-butyl 3-[5-(2-methoxy-2-oxoethoxy)-1-naphthyl]propanoate | C20H24O5 | 详情 | 详情 | |
(IV) | 26499 | 3-[5-(2-methoxy-2-oxoethoxy)-1-naphthyl]propionic acid | C16H16O5 | 详情 | 详情 | |
(V) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
(VI) | 26500 | methyl 2-([5-[3-(benzhydrylamino)-3-oxopropyl]-1-naphthyl]oxy)acetate | C29H27NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(IX)The reaction of 5(S)-methyl-3-phenyl-4,5-dihydro-3H-1,2,3-oxathiazol (VIII) with benzhydrylamine (IX) gives the sulfamic acid (X), which is deprotected by hydrogenation with H2 over Pd/C to yield N-(2(R)-aminopropyl-N-(2-pyridyl)sulfamic acid (XI). The hydrolysis of (XI) with 3N HCl affords N1-(2-pyridyl)propane-1,2(R)-diamine (XII). The cyclization of the intermediate dimesylate (VI) with sulfamic acid (XI) or diamine (XII) by means of K2CO3 and NaI in hot DMF or refluxing acetonitrile provides the disubstituted piperazine (XIII) (1), which is finally condensed with 4-cyanobenzoyl chloride (XIV) by means of K2CO3 in ethyl acetate to give the target benzamide (1,2).
【1】 Kelly, M.G.; Childers, W.E.; Rosenzweig-Lipson, S.J. (Wyeth); Serotonergic agents. US 2002107254; US 6469007; WO 0244142 . |
【2】 Jirkovsky, I.; Zeldis, J.; Chan, A.W.-Y.; Fiegelson, G.B. (Wyeth); Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines. WO 0378396 . |
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) | 64786 | 2-(2,3-dihydro-1,4-benzodioxin-5-yl{2-[(methylsulfonyl)oxy]ethyl}amino)ethyl methanesulfonate | C14H21NO8S2 | 详情 | 详情 | |
(VIII) | 64787 | (5S)-5-methyl-3-(2-pyridinyl)-1,2lambda~6~,3-oxathiazolidine-2,2-dione | C8H10N2O3S | 详情 | 详情 | |
(IX) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
(X) | 64788 | (2R)-2-(benzhydrylamino)propyl(2-pyridinyl)sulfamic acid | C21H23N3O3S | 详情 | 详情 | |
(XI) | 64789 | (2R)-2-aminopropyl(2-pyridinyl)sulfamic acid | C8H13N3O3S | 详情 | 详情 | |
(XII) | 64790 | N-[(2R)-2-aminopropyl]-N-(2-pyridinyl)amine; (2R)-N~1~-(2-pyridinyl)-1,2-propanediamine | C8H13N3 | 详情 | 详情 | |
(XIII) | 64791 | N-{(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl}-2-pyridinamine; N-{(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl}-N-(2-pyridinyl)amine | C20H26N4O2 | 详情 | 详情 | |
(XIV) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(XII)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 |