benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate -Drug Synthesis Database

【结构式】

【分子编号】16585

【品名】benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate

【CA登记号】

【分子式】C₁₇H₁₉NO₃

【分子量】285.3428

【元素组成】C 71.56% H 6.71% N 4.91% O 16.82%

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：(I)

The oxidation of N-(benzyloxycarbonyl)-L-phenylalaninol (I) with oxalyl chloride in DMSO gives the corresponding aldehyde (II), which by dimerization with Zn dust in dichloromethane yields (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexane-3,4-diol (III) [along with the (2S,3S,4S,5S)-isomer]. The reaction of (III) with alpha-acetoxyisobutyryl bromide (IV) in hexane/dichloromethane affords (2S,3R,4R,5S)-2,5-bis(benzyloxycarbonylamino)-4-bromo-1,6-diphenylhexan-3-ol acetate ester (V), which is converted into the corresponding epoxide (VI) with NaOH in dioxane/water. The reduction of the epoxide (VI) with NaBH4 in THF affords (2S,3S,5S)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexan-3-ol (VII), which is deprotected with Ba(OH)2 in refluxing dioxane/water yielding the corresponding diamine (VIII). The cyclization of (VIII) with phenylboronic acid (IX) in refluxing toluene gives (4S,6S)-6-[1(S)-amino-2-phenylethyl]-4-benzyl-2-phenyl-1,3,2-oxaazaborinane (X), which is condensed with (5-thiazolylmethyl)(4-nitrophenyl)carbonate (XI) in THF to afford (2S,3S,5S)-5-amino-1,6-diphenyl-2-(5-thiazolylmethoxycarbonylamino) hexan-3-ol (XII). Finally, this compound is condensed with N-[N-(2-isopropylthiazol-4-ylmethyl)-N-methylaminocarbonyl]-L-valine (XIII) by means of 1-hydroxybenzotriazole (HBT) and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide (DEC) in THF.

参考文献中间体

合成目标

【1】 Graul, A.; Castañer, J.; Ritonavir. Drugs Fut 1996, 21, 7, 700.
【2】 Al-Razzak, L.; Marsh, K.C.; Manning, L.P.; Kaul, D. (Abbott Laboratories Inc.); Pharmaceutical compsns. containing HIV protease inhibitors. EP 0732923; US 5484801; WO 9520384 .
【3】 Kempf, D.J.; Norbeck, D.W.; Sham, H.L.; Zhao, C.; Sowin, T.J.; Reno, D.S.; Haight, A.R.; Cooper, A.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds. EP 0674513; EP 0727419; JP 1996505844; JP 1997118679; JP 1998087639; WO 9414436 .
【4】 Flentge, C.; Kempf, D.; Marsh, K.; et al.; Symmetry-based inhibitors of HIV protease with high oral bioavailability. 207th ACS Natl Meet (March 13-17, San Diego) 1994, Abst MEDI 35.

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)	16585	benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate		C₁₇H₁₉NO₃	详情	详情
(II)	16586	benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate		C₁₇H₁₇NO₃	详情	详情
(III)	16587	benzyl (1S,2R,3R,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate		C₃₄H₃₆N₂O₆	详情	详情
(IV)	12806	2-bromo-1,1-dimethyl-2-oxoethyl acetate; alpha-Acetoxy-isobutyryl bromide	40635-67-4	C₆H₉BrO₃	详情	详情
(V)	16589	(1R,2R,3S)-3-[[(benzyloxy)carbonyl]amino]-1-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2-bromo-4-phenylbutyl acetate		C₃₆H₃₇BrN₂O₆	详情	详情
(VI)	16590	benzyl (1S)-1-[(2R,3R)-3-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)oxiranyl]-2-phenylethylcarbamate		C₃₄H₃₄N₂O₅	详情	详情
(VII)	16591	benzyl (1S,2S,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2-hydroxy-5-phenylpentylcarbamate		C₃₄H₃₆N₂O₅	详情	详情
(VIII)	16592	(2S,3S,5S)-2,5-diamino-1,6-diphenyl-3-hexanol		C₁₈H₂₄N₂O	详情	详情
(IX)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(X)	16594	(1S)-1-[(4S,6S)-4-benzyl-2-phenyl-1,3,2-oxazaborinan-6-yl]-2-phenylethylamine; (1S)-1-[(4S,6S)-4-benzyl-2-phenyl-1,3,2-oxazaborinan-6-yl]-2-phenyl-1-ethanamine		C₂₄H₂₇BN₂O	详情	详情
(XI)	16595	4-nitrophenyl 1,3-thiazol-5-ylmethyl carbonate	144163-97-3	C₁₁H₈N₂O₅S	详情	详情
(XII)	16596	1,3-thiazol-5-ylmethyl N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]carbamate		C₂₃H₂₇N₃O₃S	详情	详情
(XIII)	16597	(2S)-2-([[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl]amino)-3-methylbutyric acid		C₁₄H₂₃N₃O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

N-Cbz-L-Phenylalaninol (I) was converted to mesylate (II) on treatment with methanesulfonyl chloride and Et3N, and then treated with benzylamine (III) in the presence of NaI to give (IV). Subsequent deprotection of the Cbz group of (IV) with HBr in AcOH afforded diamine (V), which was treated with carbonyl diimidazole to produce the cyclic urea (VI). Finally, condensation with the epoxisulfonamide (VII) in the presence of NaH in DMF provided the target compound.

参考文献中间体

合成目标

【1】 Salituro, F.G.; Baker, C.T.; Court, J.J.; Deininger, D.D.; Kim, E.E.; Li, B.; Novak, P.M.; Rao, B.G.; Pazhanisamy, S.; Porter, M.D.; Schairer, W.C.; Tung, R.D.; Design and synthesis of novel conformationally restricted HIV protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3637.

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)	16585	benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate		C₁₇H₁₉NO₃	详情	详情
(II)	20158	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropyl methanesulfonate		C₁₈H₂₁NO₅S	详情	详情
(III)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(IV)	20160	benzyl (1S)-1-benzyl-2-(benzylamino)ethylcarbamate		C₂₄H₂₆N₂O₂	详情	详情
(V)	20161	(2S)-N(1)-benzyl-3-phenyl-1,2-propanediamine; N-[(2S)-2-amino-3-phenylpropyl]-N-benzylamine		C₁₆H₂₀N₂	详情	详情
(VI)	20162	(4S)-1,4-dibenzyl-2-imidazolidinone		C₁₇H₁₈N₂O	详情	详情
(VII)	20163	N-(cyclopentylmethyl)-4-methoxy-N-[(2R)oxiranylmethyl]benzenesulfonamide		C₁₆H₂₃NO₄S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II). Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity. After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine, (IV) was obtained, then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C. The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI). Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound, which was finally deprotected by treatment with HCl in MeOH-dioxan.

参考文献中间体

合成目标

【1】 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514.
【2】 Trussardi, R.; Karpf, M. (F. Hoffmann-La Roche AG); Process for the preparation of mixed anhydrides. EP 0847994 .

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)	16585	benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate		C₁₇H₁₉NO₃	详情	详情
(II)	16586	benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate		C₁₇H₁₇NO₃	详情	详情
(III)	19678	6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine	1824-81-3	C₆H₈N₂	详情	详情
(IV)	19920	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate		C₄₆H₆₄N₂O₈Si₂	详情	详情
(V)	19921	(1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylamine; (2R,3S,4S,5R)-1,6-diphenyl-3,4-bis[[2-(trimethylsilyl)ethoxy]methoxy]-2,5-hexanediamine		C₃₀H₅₂N₂O₄Si₂	详情	详情
(VI)	19922	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one		C₃₁H₅₀N₂O₅Si₂	详情	详情

Extended Information