benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】50376

【品名】benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate

【CA登记号】

【分子式】C₃₃H₄₃N₅O₆

【分子量】605.73452

【元素组成】C 65.44% H 7.16% N 11.56% O 15.85%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XI)

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.

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(XI)

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.

参考文献中间体

合成目标

【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

合成路线3

该中间体在本合成路线中的序号：(I)

Alternatively, the conversion of compound (VII) into bosentan can also be performed by reaction of compound (VII) with ethylene glycol mono tert-butyl ether (IX) by means of NaOH in toluene, yielding the tert-butyl ether derivative (X), which is then treated with formic acid at 85-90 C in toluene to give the 2-(formyloxy)ethoxy derivative (XI). Finally, the formyl group is removed by treatment of (XI) with NaOH in H2O.

参考文献中间体

合成目标

【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Melagatran and Ximelagatran. Drugs Fut 2001, 26, 12, 1155.
【2】 Antonsson, T.; Gustafsson, D.; Hoffmann, K.-J.; Nystrom, J.-E.; Sorensen, H.; Sellen, M. (AstraZeneca plc); Prodrugs of thrombin inhibitors. EP 0995755; JP 2000504313; JP 2001089498; US 5965692; US 6262028; WO 9723499 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	50376	benzyl [4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methylcarbamate	C₃₃H₄₃N₅O₆	详情	详情
(II)	50377	tert-butyl (1R)-2-[(2S)-2-[([4-[amino(imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethylcarbamate	C₂₅H₃₇N₅O₄	详情	详情
(III)	50378	1-[[(4-nitrophenoxy)carbonyl]oxy]ethyl acetate	C₁₁H₁₁NO₇	详情	详情
(IV)	50379	1-[([[[4-([[((2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]azetidinyl)carbonyl]amino]methyl)phenyl](imino)methyl]amino]carbonyl)oxy]ethyl acetate	C₃₀H₄₃N₅O₈	详情	详情
(V)	50380	1-[([[(4-[[([(2S)-1-[(2R)-2-amino-2-cyclohexylethanoyl]azetidinyl]carbonyl)amino]methyl]phenyl)(imino)methyl]amino]carbonyl)oxy]ethyl acetate	C₂₅H₃₅N₅O₆	详情	详情
(VI)	50381	ethyl 2-[[(trifluoromethyl)sulfonyl]oxy]acetate	C₅H₇F₃O₅S	详情	详情
(VII)	50382	ethyl 2-[((1R)-2-[(2S)-2-[([4-[([[1-(acetoxy)ethoxy]carbonyl]amino)(imino)methyl]benzyl]amino)carbonyl]azetidinyl]-1-cyclohexyl-2-oxoethyl)amino]acetate	C₂₉H₄₁N₅O₈	详情	详情

Extended Information