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【结 构 式】 
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【分子编号】27490 【品名】1-(bromomethyl)-4-methoxybenzene 【CA登记号】 |
【 分 子 式 】C8H9BrO 【 分 子 量 】201.06286 【元素组成】C 47.79% H 4.51% Br 39.74% O 7.96% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of 2,2-dimethyl-1,3-dioxan-5-one (I) with aminoacetaldehyde dimethyl acetal (II) followed by acetylation with Ac2O/Et3N afforded the amido dioxin (III). Retro Diels-Alder reaction of dioxin (III) in warm benzonitrile generated the amidoacrolein (V), which was trapped in situ with the silyloxydiene (IV) to yield the cycloadduct (VI). Aldol cyclization between the acetamide and aldehyde functionalities of (VI) in the presence of t-BuOK produced the spiro lactam (VII). Subsequent aldol condensation between the acetal and silyl enolate functions of (VII) under acidic conditions furnished the tricyclic hydroxy ketone (VIII). Reduction of the keto group of (VIII) with NaBH(OAc)3 produced the C-4 axial alcohol (IX). Silylation of both hydroxyl groups of (IX) followed by selective cleavage of the C-2 silyl ether provided the C-4 mono silylated derivative (X). The free C-2 hydroxyl group of (X) was then oxidized to the corresponding ketone (XI) under Swern conditions. The potassium enolate of (XI) was stereoselectively alkylated with p-methoxybenzyl bromide (XII) to yield (XIII). Reduction of the keto group of (XIII) with Red-Al gave rise to the alcohol (XIV) in the undesired equatorial configuration. Inversion of the C-2 stereogenic center of (XIV) was achieved via formation of the sulfonate ester (XVI) with 4-nitrobenzenesulfonyl chloride (XV).
| 【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125. |
| 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) | 46538 | 2,2-dimethyl-1,3-dioxan-5-one | C6H10O3 | 详情 | 详情 | |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 48300 | N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide | C12H21NO5 | 详情 | 详情 | |
| (IV) | 48301 | triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether | C13H26OSi | 详情 | 详情 | |
| (V) | 48302 | N-(2,2-dimethoxyethyl)-N-(1-formylvinyl)acetamide | C9H15NO4 | 详情 | 详情 | |
| (VI) | 48303 | N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide | C22H41NO5Si | 详情 | 详情 | |
| (VII) | 48304 | 1-(2,2-dimethoxyethyl)-8-[(triisopropylsilyl)oxy]-1-azaspiro[4.5]deca-3,7-dien-2-one | C22H39NO4Si | 详情 | 详情 | |
| (VIII) | 48305 | (1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione | C11H13NO3 | 详情 | 详情 | |
| (IX) | 48306 | (1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C11H15NO3 | 详情 | 详情 | |
| (X) | 48307 | (1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C17H29NO3Si | 详情 | 详情 | |
| (XI) | 48308 | (1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C17H27NO3Si | 详情 | 详情 | |
| (XII) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (XIII) | 48309 | (1S,6S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C25H35NO4Si | 详情 | 详情 | |
| (XIV) | 48310 | (1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XV) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XVI) | 48311 | (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate | C31H40N2O8SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The condensation of acetonide (I) with 2-aminoacetaldehyde dimethylacetal (II) by means of Ac2O and TEA gives the acetylated enamine (III), which is cyclocondensed with the silylated butadiene (IV) in hot benzonitrile to yield the cycloadduct (V). The cyclization of (V) by means of tBu-OK in ethyl acetate/THF, followed by desilylation with TFA, affords the tricyclic lactam (VI), which is reduced with NaBH(OAc)3 to provide the dihydroxy compound (VII). The silylation of both OH groups of (VII) by means of Tbdms-Cl, followed by selective desilylation of the equatorial silyl ether with TBAF, gives the corresponding alcohol (VIII), which is submitted to a Swern oxidation to yield the ketone (IX). The condensation of (IX) with 4-methoxybenzyl bromide (X) by means of tBu-OK and Red-Al affords the hydroxylated adduct (XI); however, the resulting alcohol presents an unnatural equatorial configuration that is inverted by its esterification with 4-nitrophenylsulfonyl chloride to furnish (XII), followed by acetoxylation of (XII) with rubidium acetate and 18-crown-6, to provide the desired axial acetoxy compound (XIII). The hydrolysis of (XIII) with KOH in methanol gives the corresponding alcohol (XIV), which is silylated with Tes-Otf to yield the bis silyl ether (XV). The reduction of the double bond of (XV) with H2 over PtO2 affords the saturated compound (XVI), which is treated with triethylsilylazide and LDA to provide at the azido compound (XVII). The reduction of lactam and azido groups by means of LiAlH4, followed by protection of the resulting amino group with benzyloxycarbonyl chloride and Na2CO3, gives the benzyl carbamate (XVIII).
| 【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125. |
| 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) | 46538 | 2,2-dimethyl-1,3-dioxan-5-one | C6H10O3 | 详情 | 详情 | |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 48300 | N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide | C12H21NO5 | 详情 | 详情 | |
| (IV) | 48301 | triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether | C13H26OSi | 详情 | 详情 | |
| (V) | 48303 | N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide | C22H41NO5Si | 详情 | 详情 | |
| (VI) | 48305 | (1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione | C11H13NO3 | 详情 | 详情 | |
| (VII) | 48306 | (1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C11H15NO3 | 详情 | 详情 | |
| (VIII) | 48307 | (1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C17H29NO3Si | 详情 | 详情 | |
| (IX) | 48308 | (1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C17H27NO3Si | 详情 | 详情 | |
| (X) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (XI) | 48310 | (1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XII) | 48311 | (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate | C31H40N2O8SSi | 详情 | 详情 | |
| (XIII) | 48313 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl acetate | C27H39NO5Si | 详情 | 详情 | |
| (XIV) | 48314 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XV) | 48315 | (1S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C31H51NO4Si2 | 详情 | 详情 | |
| (XVI) | 48316 | (1R,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one | C31H53NO4Si2 | 详情 | 详情 | |
| (XVII) | 48317 | (1S,3S,6S,7S,8R,9S)-3-azido-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodecan-4-one | C31H52N4O4Si2 | 详情 | 详情 | |
| (XVIII) | 48319 | benzyl (1S,3S,6S,7S,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-ylcarbamate | C33H48N2O5Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Partial hydrolysis of chiral cyclopropanedicarboxylate (I) with 1 equivalent of NaOH in aqueous isopropanol provided monoester (II), which was converted to acid chloride (III) by treatment with SOCl2. Palladium-mediated coupling of (III) with the organozincate from 9-xanthenylmethyl iodide (IV) and Zn-Cu couple afforded (S,S)-ketone (V). Basic hydrolysis of (V) then provided ketoacid (VI), which was transformed into a mixture of diastereomeric hydantoins (VII) under Bucherer-Berg conditions using an excess of KCN and (NH4)2CO3 in water at 55 C. Subsequent reaction of (VII) with 4-methoxybenzyl bromide (VIII) and KHCO3 in DMF produced both N- and O-alkylation to provide a diastereomeric mixture, which was separated by column chromatography. Hydrolysis of isomer (IX) with aqueous Ba(OH)2 in a pressure reactor at 200 C gave the target (S,S,S)-amino acid, which was purified by cation-exchange chromatography.
| 【1】 Kallman, M.J.; Johnson, B.G.; Bleisch, T.J.; Schoepp, D.D.; Tizzano, J.P.; Wright, R.A.; Kennedy, J.H.; Helton, D.R.; Brian Arnold, M.; Ornstein, P.L.; 2-Substituted (2SR)-2-amino-2-(1SR, 2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability. J Med Chem 1998, 41, 3, 358. |
| 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) | 27483 | bis[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] (1S,2S)-1,2-cyclopropanedicarboxylate | C25H42O4 | 详情 | 详情 | |
| (II) | 27484 | (1S,2S)-2-([[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy]carbonyl)cyclopropanecarboxylic acid | C15H24O4 | 详情 | 详情 | |
| (III) | 27485 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-(chlorocarbonyl)cyclopropanecarboxylate | C15H23ClO3 | 详情 | 详情 | |
| (IV) | 27486 | 9-(iodomethyl)-9H-xanthene | C14H11IO | 详情 | 详情 | |
| (V) | 27487 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (1S,2S)-2-[2-(9H-xanthen-9-yl)acetyl]cyclopropanecarboxylate | C29H34O4 | 详情 | 详情 | |
| (VI) | 27488 | (1S,2S)-2-[2-(9H-xanthen-9-yl)acetyl]cyclopropanecarboxylic acid | C19H16O4 | 详情 | 详情 | |
| (VII) | 27489 | (1S,2S)-2-[(4S)-2,5-dioxo-4-(9H-xanthen-9-ylmethyl)imidazolidinyl]cyclopropanecarboxylic acid | C21H18N2O5 | 详情 | 详情 | |
| (VIII) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (IX) | 27491 | 4-methoxybenzyl (1S,2S)-2-[(4S)-1-(4-methoxybenzyl)-2,5-dioxo-4-(9H-xanthen-9-ylmethyl)imidazolidinyl]cyclopropanecarboxylate | C37H34N2O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)Isobutyl N-hydroxycarbamate (IX) was O-alkylated with 4-methoxybenzyl bromide (X) using NaOEt to give (XI). Subsequent N-alkylation with 1,3-dibromopropane (IV) produced bromide (XII), which was condensed with the sodium salt of dibutyl phosphonate (XIII) to furnish adduct (XIV). Acid hydrolysis of (XIV) then gave intermediate (VIII).
| 【1】 Takeno, H.; Hemmi, K.; Hashimoto, M.; Kamiya, T. (Fujisawa Pharmaceutical Co., Ltd.); Hydroxyaminohydrocarbonphosphonic acids. DE 2733658; US 4182758; US 4206156 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (VIII) | 39088 | 3-(hydroxyamino)propylphosphonic acid | C3H10NO4P | 详情 | 详情 | |
| (IX) | 42012 | isobutyl hydroxycarbamate | C5H11NO3 | 详情 | 详情 | |
| (X) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (XI) | 42013 | isobutyl (4-methoxybenzyl)oxycarbamate | C13H19NO4 | 详情 | 详情 | |
| (XII) | 42014 | isobutyl 3-bromopropyl[(4-methoxybenzyl)oxy]carbamate | C16H24BrNO4 | 详情 | 详情 | |
| (XIII) | 39090 | dibutyl phosphonate | 1809-19-4 | C8H19O3P | 详情 | 详情 |
| (XIV) | 42015 | dibutyl 3-[(isobutoxycarbonyl)[(4-methoxybenzyl)oxy]amino]propylphosphonate | C24H42NO7P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Protection of 4-methoxyphenol (I) with methyl chloroformate in the presence of pyridine affords the carbonate ester (II), which is condensed with dichloromethyl methyl ether and TiCl4 to yield alpha-chloro ether (III). Acidic hydrolysis of (III) with HCl furnishes aldehyde (IV), which is converted into the sodium phenoxide (V) by methanolysis of the carbonate ester (IV). Subsequent alkylation of (V) with p-methoxybenzyl bromide (VI) produces the p-methoxybenzyl ether (VII), which is condensed with 3-morpholinopropionitrile (VIII) employing a catalytic amount of NaOMe to give the morpholino acrylonitrile (IX). After conversion of (IX) to the 3-anilino acrylonitrile (X) upon heating with aniline hydrochloride, condensation with guanidine (XI) produces the diaminopyrimidine (XII). The p-methoxybenzyl group of (XII) is then cleaved by treatment with p-toluenesulfonic acid in MeOH, producing phenol (XIII). The sodium salt generated from phenol (XIII) and NaOEt is then alkylated with ethyl 5-bromopentanoate (XIV) to furnish ether (XV). Finally, alkaline hydrolysis of the ethyl ester group of (XV) leads to the title compound.
| 【1】 Rosowsky, A.; Queener, S.F.; Forsch, R.A.; Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity. J Med Chem 2002, 45, 1, 233. |
| 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) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (II) | 59058 | 4-methoxyphenyl methyl carbonate | C9H10O4 | 详情 | 详情 | |
| (III) | 59059 | 3-[chloro(methoxy)methyl]-4-methoxyphenyl methyl carbonate | C11H13ClO5 | 详情 | 详情 | |
| (IV) | 59060 | 3-formyl-4-methoxyphenyl methyl carbonate | C10H10O5 | 详情 | 详情 | |
| (V) | 59061 | sodium 3-formyl-4-methoxybenzenolate | C8H7NaO3 | 详情 | 详情 | |
| (VI) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (VII) | 59062 | 2-methoxy-5-[(4-methoxybenzyl)oxy]benzaldehyde | C16H16O4 | 详情 | 详情 | |
| (VIII) | 31933 | 3-Morpholinopropionitrile; 3-(4-Morpholinyl)propanenitrile | 4542-47-6 | C7H12N2O | 详情 | 详情 |
| (IX) | 59063 | (Z)-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-3-(4-morpholinyl)-2-propenenitrile | C23H26N2O4 | 详情 | 详情 | |
| (X) | 59064 | (Z)-3-anilino-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2-propenenitrile | C25H24N2O3 | 详情 | 详情 | |
| (XI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (XII) | 59065 | 2-amino-5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-4-pyrimidinylamine; 5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2,4-pyrimidinediamine | C20H22N4O3 | 详情 | 详情 | |
| (XIII) | 59066 | 3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenol | C12H14N4O2 | 详情 | 详情 | |
| (XIV) | 37151 | ethyl 5-bromopentanoate | 14660-52-7 | C7H13BrO2 | 详情 | 详情 |
| (XV) | 59067 | ethyl 5-{3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenoxy}pentanoate | C19H26N4O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)4-Methoxybenzyl bromide (I) is condensed with triphenylphosphine in refluxing toluene to produce the phosphonium salt (II). Subsequent Wittig condensation of (II) with 3,5-dimethoxybenzaldehyde (III) gives rise to a mixture of the title Z-stilbene and its E-isomer (IV), which can be separated by means of flash chromatography.
| 【1】 Pettit, G.R.; Grealish, M.P.; Jung, M.K.; Hamel, E.; Pettit, R.K.; Chapuis, J.-C.; Schmidt, J.M.; Antineoplastic agents. 465. Structural modification of resveratrol: Sodium resverastatin phosphate. J Med Chem 2002, 45, 12, 2534. |
| 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) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (II) | 64585 | (4-methoxybenzyl)(triphenyl)phosphonium bromide | C26H24BrOP | 详情 | 详情 | |
| (III) | 21720 | 3,5-dimethoxybenzaldehyde | 7311-34-4 | C9H10O3 | 详情 | 详情 |
| (IV) | 62024 | 4-[(E)-2-(3,5-dimethoxyphenyl)ethenyl]phenyl methyl ether; 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene | C17H18O3 | 详情 | 详情 |