benzyl (1R)-1-benzyl-2-oxoethylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】27884

【品名】benzyl (1R)-1-benzyl-2-oxoethylcarbamate

【CA登记号】

【分子式】C₁₇H₁₇NO₃

【分子量】283.32692

【元素组成】C 72.07% H 6.05% N 4.94% O 16.94%

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：(II)

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：(II)

The synthesis of DMP-851 has been performed as follows: The oxidation of N-(benzyloxycarbonyl)-D-phenylalaninol (I) with NaOCl catalized by 2,2,6,6-tetramethyl-1-piperidinyloxyl free radical (TEMPO) and NaBr in water gives the corresponding aldehyde (II), which is dimerized by means of the Coulton's reagent (VCl3/Zn/THF) to the pinacol (III). The silylation of (III) with triethylsilyl chloride and imidazole in DMF yields the silylated diol (IV), which is submitted to hydrogenolysis with H2 over Pd/C in toluene affording the free diamine (V). The cyclization of (V) with carbonyldiimidazole (CDI) in toluene followed by desilylation with 1N HCl gives (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one (VI), which is treated with 2,2-dimethoxypropane (VII) and p-toluenesulfonic acid in DMF yielding the corresponding acetonide (VIII) [Pierce, M.E. et al. J Org Chem 1996, 61(2): 444]. The methylation of (VIII) with methyl triflate in refluxing dichloroethane affords the cyclic isourea (IX), which is alkylated with butyl iodide/NaH in DMF giving the N-monobutyl derivative (X). A new alkylation of (X) with 3-cyano-4-fluorobenzyl bromide (XI) in refluxing acetonitrile yields the disubstituted cyclic urea (XII), which is finally treated with hydrazine in refluxing butanol to generate the indazole ring, and treated with HCl in methanol to eliminate the acetonide group.

参考文献中间体

合成目标

【1】 Rodgers, J.D.; Lam, P.Y.S.; Johnson, B.L.; Wang, H.; Li, R.; Ru, Y.; Ko, S.S.; Seitz, S.P.; Trainor, G.L.; Anderson, P.S.; Klabe, R.M.; Bacheler, L.T.; Cordova, B.; Garber, S.; Reid, C.; Wright, M.R.; Chang, C.-H.; Erickson-Viitanen, S.; Design and selection of DMP 850 and DMP 851: The next generation of cyclic urea HIV protease inhibitors. Chem Biol 1998, 5, 10, 597.

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)	27221	benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylcarbamate		C₄₆H₆₄N₂O₆Si₂	详情	详情
(V)	27222	(1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylamine		C₃₀H₅₂N₂O₂Si₂	详情	详情
(VI)	27223	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one		C₁₉H₂₂N₂O₃	详情	详情
(VII)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(VIII)	27049	(3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethylhexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one		C₂₂H₂₆N₂O₃	详情	详情
(IX)	27224	(3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether		C₂₃H₂₈N₂O₃	详情	详情
(X)	27885	(3aS,4R,8R,8aS)-4,8-dibenzyl-5-butyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether		C₂₇H₃₆N₂O₃	详情	详情
(XI)	27225	5-(bromomethyl)-2-fluorobenzonitrile		C₈H₅BrFN	详情	详情
(XII)	27886	5-[[(3aS,4R,8R,8aS)-4,8-dibenzyl-7-butyl-2,2-dimethyl-6-oxohexahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile		C₃₄H₃₈FN₃O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

The chiral bicyclic alcohol (I) was converted to the benzyl ether (II) using benzyl bromide and NaH. Subsequent reduction of the ester group of (III) with LiBH4 provided primary alcohol (III), and further Swern oxidation yielded aldehyde (IV). Pinacol coupling of (IV) with D-phenylalaninal (V) by means of VCl3 - (THF)3 and Zn furnished diol (VI) with 85% diastereoselectivity. This was protected as the acetonide (VIII) upon treatment with 2,2-dimethoxypropane (VII) and camphorsulfonic acid. Selective removal of the two N-benzyloxycarbonyl groups of (VIII) by hydrogenation in the presence of Pd/C and NH3 gave diamine (IX), which was cyclized to the urea (X) employing carbonyldiimidazole and pyridine.

参考文献中间体

合成目标

【1】 Han, W.; Pelletier, J.C.; Hodge, C.N.; Tricyclic ureas: A new class of HIV-1 protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3615.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(I)	29582	7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate		C₁₉H₂₅NO₅	详情	详情
(II)	29583	7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate		C₂₆H₃₁NO₅	详情	详情
(III)	29584	benzyl (1S,3R,4R)-3-(benzyloxy)-1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate		C₂₂H₂₅NO₄	详情	详情
(IV)	29585	benzyl (1S,3R,4R)-3-(benzyloxy)-1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate		C₂₂H₂₃NO₄	详情	详情
(V)	27884	benzyl (1R)-1-benzyl-2-oxoethylcarbamate		C₁₇H₁₇NO₃	详情	详情
(VI)	29586	benzyl (1S,3R,4R)-3-(benzyloxy)-1-((1R,2R,3R)-3-[[(benzyloxy)carbonyl]amino]-1,2-dihydroxy-4-phenylbutyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate		C₃₉H₄₂N₂O₇	详情	详情
(VII)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(VIII)	29587	benzyl (1S,3R,4R)-3-(benzyloxy)-1-[(4R,5R)-5-((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]heptane-7-carboxylate		C₄₂H₄₆N₂O₇	详情	详情
(IX)	29588	(1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine		C₂₆H₃₄N₂O₃	详情	详情
(X)	29589	(1S,2R,6R,7R,11R,12R)-7-benzyl-12-(benzyloxy)-4,4-dimethyl-3,5-dioxa-8,10-diazatetracyclo[9.2.2.0(1,10).0(2,6)]pentadecan-9-one		C₂₇H₃₂N₂O₄	详情	详情

Extended Information