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【结 构 式】

【分子编号】50386

【品名】benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate

【CA登记号】

【 分 子 式 】C16H17N3O2

【 分 子 量 】283.33

【元素组成】C 67.83% H 6.05% N 14.83% O 11.29%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(V)

The reaction of 4-cyanobenzyl bromide (I) with NaN3 in DMF gives 4-cyanobenzyl azide (II), which is treated first with HCl and then with ammonia to yield 4-(azidomethyl)benzamidine (III). Protection of the amidino group of (III) with benzyl chloroformate affords the protected compound (IV), which is finally reduced at the azido group with PPh3 in THF to provide 4-(benzyloxycarbonylamidino)benzylamine (V).

1 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155.
2 Antonsson, K.T.; Bylund, R.E.; Gustafsson, N.D.; Nilsson, N.O.I. (AstraZeneca plc); New peptide derivs.. EP 0701568; JP 1996511018; JP 2001322974; US 5602253; US 5723444; WO 9429336 .
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
(II) 50383 4-(azidomethyl)benzonitrile C8H6N4 详情 详情
(III) 50384 4-(azidomethyl)benzenecarboximidamide C8H9N5 详情 详情
(IV) 50385 benzyl [4-(azidomethyl)phenyl](imino)methylcarbamate C16H15N5O2 详情 详情
(V) 50386 benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate C16H17N3O2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

Reduction of the phenyl ring of N-(tert-butoxycarbonyl)-(R)-phenylglycine (VI) with H2 over Rh/Al2O3 in methanol gives the protected (R)-cyclohexylglycine (VII), which is condensed with azetidine (VIII) by means of EDC in acetonitrile to yield the dipeptide (IX). Hydrolysis of the ester group of (IX) affords the carboxylic acid (X), which is condensed with the amino group of the previous intermediate (V) by means of EDC and DMAP in acetonitrile or ethyl acetate/acetonitrile to provide adduct (XI). Cleavage of the Boc-protecting group of (XI) with HCl or methanesulfonic acid gives (XII) with a terminal amino group that is condensed with benzyl 2-(2-nitrophenylsulfonyloxy)acetate (XIII) or benzyl 2-bromoacetate (XIV) by means of K2CO3 in the same solvent to yield the melagatran precursor (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol.

1 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155.
2 Antonsson, K.T.; Bylund, R.E.; Gustafsson, N.D.; Nilsson, N.O.I. (AstraZeneca plc); New peptide derivs.. EP 0701568; JP 1996511018; JP 2001322974; US 5602253; US 5723444; WO 9429336 .
3 Hedstrom, L.; Lundblad, A.; Nagard, S. (AstraZeneca AB); A substantially crystalline form of melagatran. WO 0102426 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 50386 benzyl [4-(aminomethyl)phenyl](imino)methylcarbamate C16H17N3O2 详情 详情
(VI) 22613 (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid 2900-27-8 C13H17NO4 详情 详情
(VII) 35619 (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid C13H23NO4 详情 详情
(VIII) 50387 methyl (2S)-2-azetidinecarboxylate C5H9NO2 详情 详情
(IX) 50388 tert-butyl (1R)-1-cyclohexyl-2-[(2S)-2-[(methylamino)carbonyl]azetidinyl]-2-oxoethylcarbamate C18H31N3O4 详情 详情
(X) 50389 (2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]-2-azetidinecarboxylic acid C17H28N2O5 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
(XIII) 50391 benzyl 2-[[(2-nitrophenyl)sulfonyl]oxy]acetate C15H13NO7S 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

合成路线3

该中间体在本合成路线中的序号:(V)

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