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【结 构 式】 
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【分子编号】52642 【品名】1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol 【CA登记号】768-95-6 |
【 分 子 式 】C10H16O 【 分 子 量 】152.23644 【元素组成】C 78.9% H 10.59% O 10.51% |
合成路线1
该中间体在本合成路线中的序号：(II)Friedel-Crafts condensation of 4-bromophenol (I) with 1-adamantanol (II) in the presence of H2SO4 yielded the adamantyl phenol (III). Subsequent alkylation of the sodium phenoxide of (III) with iodomethane produced the methyl ether (IV). The Grignard reagent (V), prepared from aryl bromide (IV), was converted to the organozincate derivative, and then subjected to a nickel-catalyzed cross-coupling with methyl 6-bromo-2-naphthoate (VI) to furnish adduct (VII). The target carboxylic acid was finally obtained by saponification of the methyl ester (VII).
| 【1】 Charpentier, B.; et al.; Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes. J Med Chem 1995, 38, 26, 4993. |
| 【2】 Shroot, B.; Eustache, J.; Bernardon, J.M. (Laboratoires Galderma SA); Benzonaphthalenic acid derivs., process for their preparation and their use in pharmacy and cosmetics. AU 9047961; EP 0199636; US 4717720; US 5098895; US 5183889 . |
| 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) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (II) | 52642 | 1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol | 768-95-6 | C10H16O | 详情 | 详情 |
| (III) | 59536 | 2-(1-adamantyl)-4-bromophenol | C16H19BrO | 详情 | 详情 | |
| (IV) | 59537 | 1-(5-bromo-2-methoxyphenyl)adamantane; 2-(1-adamantyl)-4-bromophenyl methyl ether | C17H21BrO | 详情 | 详情 | |
| (V) | 59538 | [3-(1-adamantyl)-4-methoxyphenyl](bromo)magnesium | C17H21BrMgO | 详情 | 详情 | |
| (VI) | 59539 | 6-Bromo-2-naphthoic acid methyl ester; Methyl 6-bromo-2-naphthoate | 33626-98-1 | C12H9BrO2 | 详情 | 详情 |
| (VII) | 59540 | methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoate | C29H30O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)1-Adamantanol (I) was esterified with 4-nitrobenzoyl chloride (II) in the presence of pyridine, yielding adamantanyl 4-nitrobenzoate (III). After catalytic hydrogenation of the nitro group of (III), the resultant aniline (IV) was condensed with 2,5-dihydroxybenzaldehyde (V) to afford the corresponding Schiff base (VI). Subsequent hydrogenation of the imine double bond of (VI) over Pd/C gave rise to the target amine.
| 【1】 Narayanan, V.L.; Sausville, E.A.; Kaur, G.; Varma, R.K. (US Department of Health & Human Services); Disubstd. lavendustin A analogs and pharmaceutical compsns. comprising the analogs. EP 1060160; WO 9943636 . |
| 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) | 52642 | 1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol | 768-95-6 | C10H16O | 详情 | 详情 |
| (II) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (III) | 52643 | tricyclo[3.3.1.1~3,7~]dec-1-yl 4-nitrobenzoate | C17H19NO4 | 详情 | 详情 | |
| (IV) | 52644 | tricyclo[3.3.1.1~3,7~]dec-1-yl 4-aminobenzoate | C17H21NO2 | 详情 | 详情 | |
| (V) | 52645 | 5-Hydroxysalicylaldehyde; Gentisinaldehyde; 2,5-Dihydroxybenzaldehyde | 1194-98-5 | C7H6O3 | 详情 | 详情 |
| (VI) | 52646 | tricyclo[3.3.1.1~3,7~]dec-1-yl 4-{[(2,5-dihydroxyphenyl)methylidene]amino}benzoate | C24H25NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The title compound is obtained by Friedel-Crafts alkylation of estrone (I) with 1 adamantanol (II) in the presence of boron trifluoride etherate.
| 【1】 Covey, D.F. (Washington University); Modified, hydroxy-substd. aromatic structures having cytoprotective activity. WO 0236605 . |
合成路线4
该中间体在本合成路线中的序号：(II)Coupling between 4-bromophenol (I) and 1-adamantanol (II) in the presence of H2SO4 affords the adamantanyl phenol (III), which is further protected as the silyl ether (IV) by means of t-butyldimethylsilyl chloride and DMAP. Addition of triisopropyl borate to the organolithium derivative of (IV) gives rise, after aqueous quenching, to the boronic acid (V). Then, Suzuki coupling of boronic acid (V) with 6-bromopyridine-3-carbaldehyde (VI) furnishes the phenylpyridine adduct (VII). Desilylation of (VII) to provide phenol (VIII) is accomplished by treatment with tetrabutylammonium fluoride in THF. Finally, condensation of pyridine aldehyde (VIII) with 2,4-thiazolidinedione (IX) under Knoevenagel conditions provides the target compound
| 【1】 Spruce, L.W.; Pfahl, M.; Fanjul, A.; Tachdjian, C.; Al-Shamma, H.A.; Pleynet, D.P.M.; Wiemann, T.R.; Ibarra, J.B. (Maxia Pharmaceuticals, Inc.); Heterocyclic derivs. for the treatment of cancer and other proliferative diseases. WO 02/072009 . |
| 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) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (II) | 52642 | 1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol | 768-95-6 | C10H16O | 详情 | 详情 |
| (III) | 59536 | 2-(1-adamantyl)-4-bromophenol | C16H19BrO | 详情 | 详情 | |
| (IV) | 59537 | 1-(5-bromo-2-methoxyphenyl)adamantane; 2-(1-adamantyl)-4-bromophenyl methyl ether | C17H21BrO | 详情 | 详情 | |
| (V) | 61340 | 3-(1-adamantyl)-4-{[tert-butyl(dimethyl)silyl]oxy}phenylboronic acid | C22H35BO3Si | 详情 | 详情 | |
| (VI) | 61343 | 6-bromonicotinaldehyde | C6H4BrNO | 详情 | 详情 | |
| (VII) | 61341 | 6-(3-(1-adamantyl)-4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)nicotinaldehyde | C28H37NO2Si | 详情 | 详情 | |
| (VIII) | 61342 | 6-[3-(1-adamantyl)-4-hydroxyphenyl]nicotinaldehyde | C22H23NO2 | 详情 | 详情 | |
| (IX) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Friedel-Crafts condensation of 4'-bromobiphenyl-4-ol (I) with 1-adamantanol (II) affords the adamantanylbiphenyl derivative (III). This is then subjected to Heck coupling with methyl acrylate (IV) to produce the biphenylyl acrylate (V). Finally, basic hydrolysis of ester (V) leads to the title carboxylic acid.
| 【1】 Cincinelli, R.; Dallavalle, S.; Merlini, L.; Penco, S.; Pisano, C.; Carminati, P.; Giannini, G.; Vesci, L.; Gaetano, C.; Illy, B.; Zuco, V.; Supino, R.; Zunino, F.; A novel atypical retinoid endowed with proapoptotic and antitumor activity. J Med Chem 2003, 46, 6, 909. |
| 【2】 Penco, S.; Merlini, L.; Giannini, G.; Vesci, L.; Pisano, C.; Dallavalle, S. (Sigma-Tau Industrie Farmaceutiche Riunite SpA); Retinoid derivs. with antiangiogenic, antitumoral and proapoptotic activities. WO 0311808 . |
| 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) | 48853 | 4-(4-Bromophenyl)phenol; 4-(4'-Bromophenyl)phenol; 4-Bromo-4'-hydroxybiphenyl | 29558-77-8 | C12H9BrO | 详情 | 详情 |
| (II) | 52642 | 1-Adamantanol; 1-Hydroxyadamantane; Tricyclo[3.3.1.1]decan-1-ol | 768-95-6 | C10H16O | 详情 | 详情 |
| (III) | 63330 | 4'-bromo-3-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-ol | C22H23BrO | 详情 | 详情 | |
| (IV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (V) | 63331 | methyl 3-(4'-hydroxy-3'-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-yl)-2-propenoate | C26H28O3 | 详情 | 详情 |