Mozenavir mesilate, DMP-450, XM-412(free base), -Drug Synthesis Database

【结构式】

【药物名称】Mozenavir mesilate, DMP-450, XM-412(free base)

【化学名称】(4R,5S,6S,7R)-1,3-Bis(3-aminobenzyl)-4,7-dibenzyl-5,6-dihydroxyhexahydro-1,3-diazepin-2-one dimethanesulfonate

【CA登记号】153182-59-3 (diHCl), 174391-92-5 (free base)

【分子式】C₃₅H₄₄N₄O₉S₂

【分子量】728.89033

【开发单位】Bristol-Myers Squibb (Originator), Gilead (Licensee)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

Alkylation of diazepinone (VII) with m-nitrobenzyl bromide (VIII) in the presence of NaH gave the bis-nitrobenzyl derivative (IX). The silylethoxymethyl protecting groups of (IX) were then removed by means of HCl in dioxan to afford diol (X). The nitro groups of (X) were finally reduced by catalytic hydrogenation to the target diamino compound, which was finally converted to the bis-methanesulfonate salt.

参考文献中间体

【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
(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
(VIII)	19636	1-(bromomethyl)-3-nitrobenzene	3958-57-4	C₇H₆BrNO₂	详情	详情
(IX)	59259	(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-nitrobenzyl)-5,6-bis{[2-(trimethylsilyl)ethoxy]methoxy}-1,3-diazepan-2-one		C₄₅H₆₀N₄O₉Si₂	详情	详情
(X)	59260	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(3-nitrobenzyl)-1,3-diazepan-2-one		C₃₃H₃₂N₄O₇	详情	详情

合成路线3

In an alternative method, the diamino ketal (XI) was subjected to reductive alkylation with m-nitrobenzaldehyde (XII) using sodium cyanoborohydride, sodium triacetoxyborohydride, or pyridine-borane complex as the reducing reagents to produce the bis-benzylamine (XIII). Cyclization of diamine (XIII) to urea (XIV) was accomplished by means of either phosgene or triphosgene in the presence of diisopropyl ethylamine. Subsequent ketal hydrolysis in (XIV) with methanesulfonic acid in MeOH yielded the dinitro precursor (X), which was finally reduced to the title compound by the same method as above.

参考文献中间体

【1】 Confalone, P.N.; Smyser, T.E. (Bristol-Myers Squibb Co.); Method for preparing N,N'-disubstd. cyclic ureas. WO 9639393 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	59260	(4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(3-nitrobenzyl)-1,3-diazepan-2-one		C₃₃H₃₂N₄O₇	详情	详情
(XI)	18091	(1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine		C₂₁H₂₈N₂O₂	详情	详情
(XII)	12646	3-Nitrobenzaldehyde	99-61-6	C₇H₅NO₃	详情	详情
(XIII)	59261	(1R)-1-((4S,5S)-2,2-dimethyl-5-{(1R)-1-[(3-nitrobenzyl)amino]-2-phenylethyl}-1,3-dioxolan-4-yl)-N-(3-nitrobenzyl)-2-phenyl-1-ethanamine; N-[(1R)-1-((4S,5S)-2,2-dimethyl-5-{(1R)-1-[(3-nitrobenzyl)amino]-2-phenylethyl}-1,3-dioxolan-4-yl)-2-phenylethyl]-N-(3-nitrobenzyl)amine		C₃₅H₃₈N₄O₆	详情	详情
(XIV)	59262	(3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-5,7-bis(3-nitrobenzyl)hexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one		C₃₆H₃₆N₄O₇	详情	详情

Extended Information