tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】54624

【品名】tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate

【CA登记号】

【分子式】C₁₄H₂₁NO₃

【分子量】251.32568

【元素组成】C 66.91% H 8.42% N 5.57% O 19.1%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XIV)

The reduction of N-Boc-L-phenylalanine (XIII) with B2H6 in THF gives the expected alcohol (XIV), which is oxidized with SO3/pyridine to yield the corresponding aldehyde (XV). The cyclization of (XV) with 2-sulfanylethylamine (XVI) affords the thiazolidine (XVII), which is dehydrogenated by means of MnO2 to afford the thiazole derivative (XVIII). Finally, the amino group of (XVIII) is deprotected with HCl to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XIX).

参考文献中间体

合成目标

【1】 Tomioka, K.; et al.; An expeditious synthesis of dolastatin 10. Tetrahedron 1991, 32, 21, 2395.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XIV)	54624	tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate		C₁₄H₂₁NO₃	详情	详情
(XV)	23452	tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate		C₁₄H₁₉NO₃	详情	详情
(XVI)	13186	2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine	60-23-1	C₂H₇NS	详情	详情
(XVII)	54625	tert-butyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate		C₁₆H₂₄N₂O₂S	详情	详情
(XVIII)	54626	tert-butyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate		C₁₆H₂₀N₂O₂S	详情	详情
(XIX)	54607	(1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine		C₁₁H₁₂N₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

The reduction of N-Boc-L-phenylalanine (XVI) with diborane in THF gives N-Boc-L-phenylalaninol (XVII), which is oxidized with SO3/pyridine in DMSO to yield N-Boc-L-phenylalaninal (XVIII). The cyclization of (XVIII) with 2-sulfanylethylamine (XIX) affords the thiazolidine (XX), which is dehydrogenated by means of MnO2 to provide the thiazole derivative (XXI). Finally, compound (XXI) is N-deprotected by a treatment with TFA to provide the 2-phenyl-1(S)-(2-thiazolyl)ethylamine intermediate (XXII).

参考文献中间体

合成目标

【1】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63.
【2】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463.
【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XVII)	54624	tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate		C₁₄H₂₁NO₃	详情	详情
(XVIII)	23452	tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate		C₁₄H₁₉NO₃	详情	详情
(XIX)	13186	2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine	60-23-1	C₂H₇NS	详情	详情
(XX)	54625	tert-butyl (1S)-2-phenyl-1-(1,3-thiazolidin-2-yl)ethylcarbamate		C₁₆H₂₄N₂O₂S	详情	详情
(XXI)	54626	tert-butyl (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylcarbamate		C₁₆H₂₀N₂O₂S	详情	详情
(XXII)	54607	(1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine		C₁₁H₁₂N₂S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

The reaction of N-(2(S)-benzyl-3-hydroxypropyl)carbamic acid tert-butyl ester (VIII), with sodium azide and PPh3 gives the corresponding 3-azido derivative (IX), which is deprotected to afford 3-azido-2(S)-benzylpropylamine (X). The condensation of (X) with the intermediate bromopyrazinone (VII) by means of TEA in hot ethanol provides the secondary amine (XI), which is chlorinated with NCS in hot dichloroethane to give the chloropyrazinone (XII). The reduction of the azido group of (XII) by means of SnCl2 in methanol/THF yields the primary amine (XIII), which is condensed with the Boc protected 2-(5-bromopentyloxy)-5-chlorobenzylamine (XIV) by means of triethylamine in DMF to afford the linear precursor (XV). The deprotection of the NH2 group of (XV) by means of HCl provides the benzylamine derivative (XVI), which is treated with LiOH in THF to furnish the aminoacid precursor (XVII). Finally this compound is cyclized by means of EDC and HOAt to obtain the target macrolactam (1, 2).

参考文献中间体

合成目标

【1】 Nantermet, P.G.; Selnick, H.G.; Potent thrombin inhibitors via a 20-membered ring olefin metathesis macrocyclization. Tetrahedron Lett 2003, 44, 11, 2401.
【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
(VII)	63820	propyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate	C₉H₁₁BrN₂O₃	详情	详情
(VIII)	54624	tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate	C₁₄H₂₁NO₃	详情	详情
(IX)	63851	tert-butyl (1S)-2-azido-1-benzylethylcarbamate	C₁₄H₂₀N₄O₂	详情	详情
(X)	63852	(1S)-2-azido-1-benzylethylamine; (2S)-1-azido-3-phenyl-2-propanamine	C₉H₁₂N₄	详情	详情
(XI)	63853	propyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-2-oxo-1(2H)-pyrazinyl]acetate	C₁₈H₂₂N₆O₃	详情	详情
(XII)	63854	propyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₁₈H₂₁ClN₆O₃	详情	详情
(XIII)	63855	propyl 2-[3-{[(1S)-2-amino-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₁₈H₂₃ClN₄O₃	详情	详情
(XIV)	63856	tert-butyl 2-[(5-bromopentyl)oxy]-5-chlorobenzylcarbamate	C₁₇H₂₅BrClNO₃	详情	详情
(XV)	63857	ethyl 2-[3-[((1S)-1-benzyl-2-{[4-(2-{[(tert-butoxycarbonyl)amino]methyl}-4-chlorophenoxy)butyl]amino}ethyl)amino]-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₃₃H₄₃Cl₂N₅O₆	详情	详情
(XVI)	63858	methyl (3aR,4R,5S,5aR,10bR,13aR)-4-(acetyloxy)-3a-ethyl-9-{(5S,7R,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-7-({[(4-methylphenyl)sulfonyl]oxy}methyl)-3-[(4-nitrophenyl)sulfonyl]-1,2,3,4,5,6,7,8,9,10-decahydroazacycloundecino[5,4-b]indol-9-yl}-5-hydr; ethyl 2-[3-{[(1S)-2-({4-[2-(aminomethyl)-4-chlorophenoxy]butyl}amino)-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₅₉H₆₉N₅O₁₆S₂	详情	详情
(XVII)	63859	2-[3-{[(1S)-2-({4-[2-(aminomethyl)-4-chlorophenoxy]butyl}amino)-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetic acid	C₂₆H₃₁Cl₂N₅O₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

Mitsunobu coupling of N-Boc-L-phenylglycinol (VIII) with hydrazoic acid affords azide (IX). Subsequent acidic cleavage of the N-Boc protecting group of (IX) furnishes amino azide (X). This is then condensed with the bromopyrazinone (VII) upon heating at 110 C in a pressure vessel to furnish adduct (XI). Treatment of (XI) with N-chlorosuccinimide in hot dichloroethane gives rise to the chloropyrazinone (XII). The azido group of (XII) is then reduced to the corresponding amine (XIII) employing SnCl2 in MeOH/THF (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
(VII)	63219	ethyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate	C₈H₉BrN₂O₃	详情	详情
(VIII)	54624	tert-butyl (1S)-1-benzyl-2-hydroxyethylcarbamate	C₁₄H₂₁NO₃	详情	详情
(IX)	63851	tert-butyl (1S)-2-azido-1-benzylethylcarbamate	C₁₄H₂₀N₄O₂	详情	详情
(X)	63852	(1S)-2-azido-1-benzylethylamine; (2S)-1-azido-3-phenyl-2-propanamine	C₉H₁₂N₄	详情	详情
(XI)	64204	ethyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-2-oxo-1(2H)-pyrazinyl]acetate	C₁₇H₂₀N₆O₃	详情	详情
(XII)	64205	ethyl 2-[3-{[(1S)-2-azido-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₁₇H₁₉ClN₆O₃	详情	详情
(XIII)	64206	ethyl 2-[3-{[(1S)-2-amino-1-benzylethyl]amino}-6-chloro-2-oxo-1(2H)-pyrazinyl]acetate	C₁₇H₂₁ClN₄O₃	详情	详情

Extended Information