benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】19920

【品名】benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate

【CA登记号】

【分子式】C₄₆H₆₄N₂O₈Si₂

【分子量】829.19384

【元素组成】C 66.63% H 7.78% N 3.38% O 15.44% Si 6.77%

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：(V)

Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) gave aldehyde (II), which was subjected to a vanadium-mediated pinacol coupling to yield diol (III). Protection of the hydroxyl groups of (III) by reaction with [2-(trimethylsilyl)-ethoxy]methyl chloride (SEMCl) (IV) and DIEA in DMF provided trimethylsilyl)ethoxymethyl ether (V), whose N-benzyloxycarbonyl groups were removed by hydrogenolysis over Pd/C to afford diamine (VI). Finally, cyclization of diamine (VI) with carbonyldiimidazole produced the cyclic urea (VII).

参考文献中间体

合成目标

【3】 Lam, P.Y.; Eyermann, C.J.; Hodge, C.N.; Jadhav, P.K.; DeLucca, G.V. (DuPont Pharmaceuticals Co.); Cyclic ureas and analogues useful as retroviral protease inhibitors. EP 0607334; EP 0686151; EP 0765873; JP 1995500324; JP 1996509700; US 5610294; WO 9307128; WO 9419329 .
【1】 Hodge, C.N.; et al.; Improved cyclic urea inhibitors of the HIV-1 protease: Synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chem Biol 1996, 3, 4, 301.
【2】 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.

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)	27228	benzyl (1R)-1-benzyl-2-hydroxyethylcarbamate		C₁₇H₁₉NO₃	详情	详情
(II)	27884	benzyl (1R)-1-benzyl-2-oxoethylcarbamate		C₁₇H₁₇NO₃	详情	详情
(III)	19618	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate		C₃₄H₃₆N₂O₆	详情	详情
(IV)	27243	[2-(chloromethoxy)ethyl](trimethyl)silane	76513-69-4	C₆H₁₅ClOSi	详情	详情
(V)	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
(VI)	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
(VII)	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

合成路线2

该中间体在本合成路线中的序号：(IV)

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 subsequently deprotected by treatment with HCl in MeOH-dioxan to give (VIII) (1). The stereoselective hydroxyl inversion of the diol was then achieved Swern by oxidation to the ketol (IX), followed by reduction with NaBH4 in EtOH, and purification of the major isomer by column chromatography.

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】 Kaltenbach, R.F. III; Nugiel, D.A.; Lam, P.Y.; Klabe, R.M.; Seitz, S.P.; Stereoisomers of cyclic urea HIV-1 protease inhibitors: Synthesis and binding affinities. J Med Chem 1998, 41, 25, 5113.

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)	16586	benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate		C₁₇H₁₇NO₃	详情	详情
(II)	19618	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate		C₃₄H₃₆N₂O₆	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
(VII)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(VIII)	19924	(4R,5S,6S,7R)-1,3,4,7-tetrabenzyl-5,6-dihydroxy-1,3-diazepan-2-one		C₃₃H₃₄N₂O₃	详情	详情
(IX)	19925	(4R,6S,7R)-1,3,4,7-tetrabenzyl-6-hydroxy-1,3-diazepane-2,5-dione		C₃₃H₃₂N₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

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