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【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%

与该中间体有关的原料药合成路线共 4 条

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
Extended Information