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【结 构 式】

【分子编号】50394

【品名】1-[amino(hydroxyimino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene

【CA登记号】

【 分 子 式 】C18H27N3O5

【 分 子 量 】365.4296

【元素组成】C 59.16% H 7.45% N 11.5% O 21.89%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XVIII)

Reaction of 4-cyanobenzyl bromide (I) with bis(tert-butoxycarbonyl)imine (XVI) by means of NaH in THF gives the protected benzylamine (XVII), which is treated with hydroxylamine and Na2CO3 in ethanol/water to yield the N-hydroxybenzamidine (XVIII). Reduction of compound (XVIII) with H2 over Pd/C in HOAc/Ac2O affords the protected benzamidine (XIX), which is treated with benzyl chloroformate and NaOH in THF in order to obtain the fully protected compound (XX). Selective deprotection of (XX) with HCl gives 4-(benzyloxycarbonylamidino)benzylamine (V), which is condensed with the protected azetidine-2-carboxylic acid (XXI) to afford the corresponding amide (XXII). Boc-deprotection of (XXII) provides azetidine (XXIII), which is condensed with N-Boc-(R)-cyclohexylglycine (VII) to give the protected dipeptide (XI). Boc-deprotection of (XI) affords intermediate (XII), which is condensed with benzyl 2-bromoacetate (XIV) to give the melagatran precursor (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C as before.

2 Hervé, Y.; Fournier, J.; De Nanteuil, G.; Leborgne, F.; Verbeuren, T.J.; Lila, C.; Gloanec, P.; Cadet, L.; Large scale preparation of protected 4-aminomethylbenzamidine. Application to the synthesis of the thrombin inhibitor melagatran. Synth Commun 1998, 28, 23, 4419.
1 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155.
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) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(V) 50386 benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate C16H17N3O2 详情 详情
(VII) 35619 (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid C13H23NO4 详情 详情
(XI) 50376 benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate C33H43N5O6 详情 详情
(XII) 50390 benzyl (4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methylcarbamate C28H35N5O4 详情 详情
(XIV) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(XV) 50392 benzyl 2-[((1R)-2-[(2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate C37H43N5O6 详情 详情
(XVI) 48447 Di-tert-butyl iminodicarboxylate; Iminodicarboxylic acid di-tert-butyl ester 51779-32-9 C10H19NO4 详情 详情
(XVII) 50393 1-[[bis(tert-butoxycarbonyl)amino]methyl]-4-cyanobenzene C18H24N2O4 详情 详情
(XVIII) 50394 1-[amino(hydroxyimino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene C18H27N3O5 详情 详情
(XIX) 50395 1-[amino(imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene C18H27N3O4 详情 详情
(XX) 50396 1-[[[(benzyloxy)carbonyl]amino](imino)methyl]-4-[[bis(tert-butoxycarbonyl)amino]methyl]benzene C26H33N3O6 详情 详情
(XXI) 26205 (2S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid C9H15NO4 详情 详情
(XXII) 50397 tert-butyl (2S)-2-[([4-[[[(benzyloxy)carbonyl]amino](imino)methyl]benzyl]amino)carbonyl]-1-azetidinecarboxylate C25H30N4O5 详情 详情
(XXIII) 50398 benzyl [4-([[(2S)azetidinylcarbonyl]amino]methyl)phenyl](imino)methylcarbamate C20H22N4O3 详情 详情
Extended Information