-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】3beta-[4,4-Bis[3-Carboxy-4-(4-carboxybenzyloxy)-5-chlorophenyl]-3-buten-1-yl]cholestane

【CA登记号】

【分子式】C₆₁H₇₂Cl₂O₁₀

【分子量】1036.15399

【开发单位】National Cancer Institute (Originator), Purdue University (Originator), Rega Institute for Medical Research (Originator)

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

合成路线1 合成路线2

合成路线1

The reaction of 3-bromopropanol (I) with TBDMS-Cl, DIEA and DMAP in dichloromethane gives the silyl ether (II), which is treated with PPh3 in refluxing acetonitrile yielding the phosphonium salt (III). The Wittig reaction of (III) with 3-cholestanone (IV) by means of BuLi in DME affords 3-[3-(tert-butyldimethylsilyloxy)propylidene]cholestane (V), which is reduced with H2 over PtO2 in ethyl acetate giving 3beta-[3-(tert-butyldimethylsilyloxy)propyl]cholestane (VI). The reaction of (VI) with TBAF in THF gives the 3-hydroxypropyl derivative (VII), which is treated with CBr4 and PPh3 in dichloromethane yielding the 3-bromopropyl derivative (VIII). The reaction of (VIII) with PPh3 in refluxing chlorobenzene affords the phosphonium salt (IX), which is submitted to a Wittig condensation with 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) by means of NaN(SiMe3)2 in THF giving the expected condensation intermediate (XI). The intermediate 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) has been obtained as follows: The dimerization of 3-chloro-2-hydroxybenzoic acid (XII) with H2CO and H2SO4 in methanol gives 5,5'-methylenebis(3-chloro-2-hydroxybenzoic acid) (XIII), which is fully methylated with SO4Me2 or CO3Me2 and K2CO3 yielding 5,5'-methylenebis(3-chloro-2-methoxybenzoic acid methyl ester) (XIV). Finally, this compound is oxidized with CrO3 in acetic anhydride to afford the desired intermediate (X).

参考文献中间体

【1】 Bader, J.P.; Cushman, M.; Golebiewski, W.M.; Design and synthesis of cosalane, a novel anti-HIV agent. Bioorg Med Chem Lett 1993, 3, 8, 1739.
【2】 Golebiewski, W.M.; McMahon, J.B.; Cushman, M.; et al.; Design, synthesis, and biological evaluation of cosalane, a novel anti-HIV agent which inhibits multiple features of virus reproduction. J Med Chem 1994, 37, 19, 3040.

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)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情
(II)	30994	3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane		C₉H₂₁BrOSi	详情	详情
(III)	30995	(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)(triphenyl)phosphonium bromide		C₂₇H₃₆BrOPSi	详情	详情
(IV)	30996	(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one	15600-08-5	C₂₇H₄₆O	详情	详情
(V)	30997	tert-butyl(3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propyl ether		C₃₆H₆₆OSi	详情	详情
(VI)	30998	tert-butyl(dimethyl)silyl 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl ether; tert-butyl(3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propoxy)dimethylsilane		C₃₆H₆₈OSi	详情	详情
(VII)	30999	3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-propanol		C₃₀H₅₄O	详情	详情
(VIII)	31000	(3R,10S,13R,17R)-3-(3-bromopropyl)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene		C₃₀H₅₃Br	详情	详情
(IX)	31001	(3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl)(trimethyl)phosphonium bromide		C₃₃H₆₂BrP	详情	详情
(X)	26176	methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzoyl]-2-methoxybenzoate		C₁₉H₁₆Cl₂O₇	详情	详情
(XI)	31002	methyl 3-chloro-5-(1-[3-chloro-4-methoxy-5-(methoxycarbonyl)phenyl]-4-[(3S,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-butenyl)-2-methoxybenzoate		C₄₉H₆₈Cl₂O₆	详情	详情
(XII)	31003	3-chloro-2-hydroxybenzoic acid		C₇H₅ClO₃	详情	详情
(XIII)	31004	5-(3-carboxy-5-chloro-4-hydroxybenzyl)-3-chloro-2-hydroxybenzoic acid		C₁₅H₁₀Cl₂O₆	详情	详情
(XIV)	31005	methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzyl]-2-methoxybenzoate		C₁₉H₁₈Cl₂O₆	详情	详情

合成路线2

The demethylation of intermediate (XI) with BBr3 and SMe2 in hot 1,2-dichloroethane gives the phenolic intermediate (cosalane, XV), which is simultaneously alkylated and esterified with 4-(bromomethyl)benzoic acid methyl ester (XVI) by means of K2CO3 in DMF yielding the tetrabenzylated intermediate (XVII). The final hydrolysis of the benzyl ester and methyl ester groups with KCN and K2CO3 in hot ethanol/water affords the target compound.

参考文献中间体

【1】 Cushman, M.; Insaf, S.; Paul, G.; Ruell, J.A.; De Clercq, E.; Schols, D.; Pannecouque, C.; Witvrouw, M.; Schaeffer, C.A.; Turpin, J.A.; Williamson, K.; Rice, W.G.; Extension of the polyanionic cosalane pharmacophore as a strategy for increasing anti-HIV potency. J Med Chem 1999, 42, 10, 1767.
【2】 Bader, J.P.; Cushman, M.; Golebiewski, W.M.; Design and synthesis of cosalane, a novel anti-HIV agent. Bioorg Med Chem Lett 1993, 3, 8, 1739.
【3】 Golebiewski, W.M.; McMahon, J.B.; Cushman, M.; et al.; Design, synthesis, and biological evaluation of cosalane, a novel anti-HIV agent which inhibits multiple features of virus reproduction. J Med Chem 1994, 37, 19, 3040.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	31005	methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzyl]-2-methoxybenzoate		C₁₉H₁₈Cl₂O₆	详情	详情
(XV)	31006	5-(1-(3-carboxy-5-chloro-4-hydroxyphenyl)-4-[(3S,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-butenyl)-3-chloro-2-hydroxybenzoic acid		C₄₅H₆₀Cl₂O₆	详情	详情
(XVI)	14565	methyl 4-(bromomethyl)benzoate	2417-72-3	C₉H₉BrO₂	详情	详情
(XVII)	31007	4-(methoxycarbonyl)benzyl 3-chloro-5-(1-[3-chloro-4-[[4-(methoxycarbonyl)benzyl]oxy]-5-([[4-(methoxycarbonyl)benzyl]oxy]carbonyl)phenyl]-4-[(3S,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-		C₈₁H₉₂Cl₂O₁₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)