tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-oxopropyl)carbamate -Drug Synthesis Database

【结构式】

【分子编号】64217

【品名】tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-oxopropyl)carbamate

【CA登记号】

【分子式】C₂₂H₃₄N₂O₅

【分子量】406.52244

【元素组成】C 65% H 8.43% N 6.89% O 19.68%

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：(XXV)

The intermediate aldehyde (XXV) has been prepared by two related procedures. Benzylic bromination of o-tolylacetic acid (XIV) employing NBS and AIBN leads to bromo acid (XV), which is further converted into the tert-butyl ester (XVI) upon treatment with isobutylene and sulfuric acid. Bromide group displacement in (XVI) with NaN3 in hot DMF affords azide (XVII). This is then reduced by catalytic hydrogenation to the corresponding primary amine, which can be isolated as the more stable oxalate salt (XVIII). After protection of amine (XVIII) as the N-Boc derivative (XIX), selective reduction of the ester function employing LiAlH4 in cold Et2O gives rise to alcohol (XX). Further bromination of alcohol (XX) to produce (XXI) is accomplished by treatment with CBr4 and PPh3. Bromide (XXI) is condensed with 3-amino-1-propanol (XXII) yielding amino alcohol (XXIII), which is subsequently protected as the di-Boc derivative (XXIV). Swern oxidation of alcohol (XXIV) generates the required aldehyde intermediate (XXV).

参考文献中间体

合成目标

【1】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	64207	2-(2-methylphenyl)acetic acid		C₉H₁₀O₂	详情	详情
(XV)	64208	2-[2-(bromomethyl)phenyl]acetic acid		C₉H₉BrO₂	详情	详情
(XVI)	64209	tert-butyl 2-[2-(bromomethyl)phenyl]acetate		C₁₃H₁₇BrO₂	详情	详情
(XVII)	64210	tert-butyl 2-[2-(azidomethyl)phenyl]acetate		C₁₃H₁₇N₃O₂	详情	详情
(XVIII)	64211	tert-butyl 2-[2-(aminomethyl)phenyl]acetate		C₁₃H₁₉NO₂	详情	详情
(XIX)	64212	tert-butyl 2-(2-{[(tert-butoxycarbonyl)amino]methyl}phenyl)acetate		C₁₈H₂₇NO₄	详情	详情
(XX)	64213	tert-butyl 2-(2-hydroxyethyl)benzylcarbamate		C₁₄H₂₁NO₃	详情	详情
(XXI)	64214	tert-butyl 2-(2-bromoethyl)benzylcarbamate		C₁₄H₂₀BrNO₂	详情	详情
(XXII)	18522	3-amino-1-propanol	156-87-6	C₃H₉NO	详情	详情
(XXIII)	64215	tert-butyl 2-{2-[(3-hydroxypropyl)amino]ethyl}benzylcarbamate		C₁₇H₂₈N₂O₃	详情	详情
(XXIV)	64216	tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-hydroxypropyl)carbamate		C₂₂H₃₆N₂O₅	详情	详情
(XXV)	64217	tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-oxopropyl)carbamate		C₂₂H₃₄N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXV)

In a related synthesis of (XXV) starting from the mono-protected diamine (XXVI), alkylation with ethyl 3-bromopropionate (XXVII) leads to amino ester (XXVIII), which is further protected as the di-Boc derivative (XXIX). Reduction of ester (XXIX) employing LiAlH4 furnishes alcohol (XXIV), which is further oxidized to aldehyde (XXV) under Swern conditions.

参考文献中间体

合成目标

【1】 Nantermet, P.G.; Barrow, J.C.; Newton, C.L.; Pellicore, J.M.; Young, M.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; McMasters, D.R.; Youwei, Y.; Kuo, L.C.; Vacca, J.P.; Selnick, H.G.; Design and synthesis of potent and selective macrocyclic thrombin inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 168.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIV)	64216	tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-hydroxypropyl)carbamate		C₂₂H₃₆N₂O₅	详情	详情
(XXV)	64217	tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-oxopropyl)carbamate		C₂₂H₃₄N₂O₅	详情	详情
(XXVI)	64218	tert-butyl 2-(2-aminoethyl)benzylcarbamate		C₁₄H₂₂N₂O₂	详情	详情
(XXVII)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(XXVIII)	64219	ethyl 3-[(2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl)amino]propanoate		C₁₉H₃₀N₂O₄	详情	详情
(XXIX)	64220	ethyl 3-[(tert-butoxycarbonyl)(2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl)amino]propanoate		C₂₄H₃₈N₂O₆	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXV)

Reductive condensation between aldehyde (XXV) and amine (XIII) in the presence of NaBH(OAc)3 leads to adduct (XXX). The N-Boc protecting groups of (XXX) are then cleaved under acidic conditions yielding tetra-amine (XXXI). Saponification of the ethyl ester group of (XXXI) with LiOH furnishes amino acid (XXXII). Finally, the title compound is obtained by macrocyclization of (XXXII) employing EDC/HOAt as the coupling reagent (1,2).

参考文献中间体

合成目标

【1】 Nantermet, P.G.; Barrow, J.C.; Newton, C.L.; Pellicore, J.M.; Young, M.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; McMasters, D.R.; Youwei, Y.; Kuo, L.C.; Vacca, J.P.; Selnick, H.G.; Design and synthesis of potent and selective macrocyclic thrombin inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 168.
【2】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIII)	64206	ethyl 2-[3-{[(1S)-2-amino-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₁₇H₂₁ClN₄O₃	详情	详情
(XXV)	64217	tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-oxopropyl)carbamate	C₂₂H₃₄N₂O₅	详情	详情
(XXX)	64221	ethyl 2-[3-{[(1S)-1-benzyl-2-({3-[(tert-butoxycarbonyl)(2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl)amino]propyl}amino)ethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₃₉H₅₅ClN₆O₇	详情	详情
(XXXI)	64222	ethyl 2-[3-({(1S)-2-[(3-{[2-(aminomethyl)phenethyl]amino}propyl)amino]-1-benzylethyl}amino)-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₂₉H₃₉ClN₆O₃	详情	详情
(XXXII)	64223	2-[3-({(1S)-2-[(3-{[2-(aminomethyl)phenethyl]amino}propyl)amino]-1-benzylethyl}amino)-6-chloro-2-oxo-1(2H)-pyrazinyl]acetic acid	C₂₇H₃₅ClN₆O₃	详情	详情

Extended Information