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【结 构 式】 
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【分子编号】27552 【品名】1-bromo-2-(bromomethyl)-4-methoxybenzene 【CA登记号】 |
【 分 子 式 】C8H8Br2O 【 分 子 量 】279.95892 【元素组成】C 34.32% H 2.88% Br 57.08% O 5.71% |
合成路线1
该中间体在本合成路线中的序号：(XI)The intermediate naphthaleneboronic acid (XIX) has been obtained as follows: The bromination of the 3-methylanisole (X) with NBS gives the dibromo compound (XI), which is treated with sodium phenylsulfinate to afford the sulfone (XII). The condensation of (XII) with methyl crotonate (XIII) by means of LDA and KOH gives the butyric acid (XIV), which is cyclized to the tetralone (XV) by means of trifluoroacetic anhydride (TFAA). The aromatization of (XV) by means of t-BuOK or NaOH yields the 5-bromo-8-methoxy-3-methyl-1-naphthol (XVI), which is methylated with dimethyl sulfate to afford the bis(methyl) ether (XVII). The reaction of (XVII) with trimethyl borate and n-BuLi gives the boronic ester (XVIII), which is hydrolyzed with water and ammonium chloride yielding the desired naphthaleneboronic acid (XIX). Alternatively, the naphthaleneboronic acid (XIX) has been obtained as follows: The reaction of 2,4-dibromoanisole (XX) with n-BuLi and cyclohexyl(isopropyl)amine gives the benzyne intermediate (XXI), which, without isolation is cyclized with the lithium enolate of 3-methylcrotonic acid dimethylamide (XXII) to afford the previously described naphthol (XVI), which is purified by chromatography.
| 【1】 Hoye, T.R.; et al.; Total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B. J Org Chem 1999, 64, 19, 7184. |
| 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) | 38309 | 1-methoxy-3-methylbenzene; methyl 3-methylphenyl ether | 100-84-5 | C8H10O | 详情 | 详情 |
| (XI) | 27552 | 1-bromo-2-(bromomethyl)-4-methoxybenzene | C8H8Br2O | 详情 | 详情 | |
| (XII) | 38310 | (2-bromo-5-methoxybenzyl)(dioxo)phenyl-lambda(6)-sulfane; 2-bromo-5-methoxybenzyl phenyl sulfone | C14H13BrO3S | 详情 | 详情 | |
| (XIII) | 26361 | methyl (E)-2-butenoate | 623-43-8 | C5H8O2 | 详情 | 详情 |
| (XIV) | 38311 | 4-(2-bromo-5-methoxyphenyl)-3-methyl-4-(phenylsulfonyl)butyric acid | C18H19BrO5S | 详情 | 详情 | |
| (XV) | 38312 | 5-bromo-8-methoxy-3-methyl-4-(phenylsulfonyl)-3,4-dihydro-1(2H)-naphthalenone | C18H17BrO4S | 详情 | 详情 | |
| (XVI) | 38313 | 5-bromo-8-methoxy-3-methyl-1-naphthol | C12H11BrO2 | 详情 | 详情 | |
| (XVII) | 38314 | 5-bromo-1,8-dimethoxy-3-methylnaphthalene; 4-bromo-8-methoxy-6-methyl-1-naphthyl methyl ether | C13H13BrO2 | 详情 | 详情 | |
| (XVIII) | 38315 | dimethyl 4,5-dimethoxy-7-methyl-1-naphthylboronate | C15H19BO4 | 详情 | 详情 | |
| (XIX) | 38316 | 4,5-dimethoxy-7-methyl-1-naphthylboronic acid | C13H15BO4 | 详情 | 详情 | |
| (XX) | 38317 | 2,4-dibromophenyl methyl ether; 2,4-dibromo-1-methoxybenzene | 21702-84-1 | C7H6Br2O | 详情 | 详情 |
| (XXI) | 38318 | 4-bromo-1,3-cyclohexadien-5-yn-1-yl methyl ether; 1-bromo-4-methoxy-1,3-cyclohexadien-5-yne | C7H5BrO | 详情 | 详情 | |
| (XXII) | 37859 | C8H14LiNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Preparation of the precursor alcohol (XI) is outlined in Scheme 1. Reduction of 2-bromo-5-methoxybenzoic acid (I) with borane-dimethylsulfide complex gave benzylic alcohol (II). After conversion of (II) to the corresponding mesylate, treatment with NaBr provided bromide (III). (1R,2S)-Aminoindanol (IV) was acylated with propionyl chloride to afford amide (V), which was converted to acetonide (VII) with 2-methoxypropene (VI) using pyridinium tosylate as the acid catalyst. Acetonide (VII) was then alkylated with bromide (III) in the presence of lithium hexamethyldisilazide at -35 C to give the chiral intermediate (VIII). Hydrolysis of acetonide at 10 C, followed by amide hydrolysis under reflux furnished a mixture of acid (IX) and methyl ester (X). This mixture was then reduced with LiAlH4 to provide the chiral alcohol (XI).
| 【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 . |
| 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) | 17819 | 2-bromo-5-methoxybenzoic acid | 22921-68-2 | C8H7BrO3 | 详情 | 详情 |
| (II) | 27551 | (2-bromo-5-methoxyphenyl)methanol | C8H9BrO2 | 详情 | 详情 | |
| (III) | 27552 | 1-bromo-2-(bromomethyl)-4-methoxybenzene | C8H8Br2O | 详情 | 详情 | |
| (IV) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (V) | 27553 | N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]propanamide | C12H15NO2 | 详情 | 详情 | |
| (VI) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VII) | 27554 | 1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone | C15H19NO2 | 详情 | 详情 | |
| (VIII) | 27555 | (2S)-1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanone | C23H26BrNO3 | 详情 | 详情 | |
| (IX) | 27556 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropionic acid | C11H13BrO3 | 详情 | 详情 | |
| (X) | 27557 | methyl (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropanoate | C12H15BrO3 | 详情 | 详情 | |
| (XI) | 27558 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol | C11H15BrO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Bromination of 4-bromo-3-methyl anisole derivative (I) by means of NBS and light in CH2Cl2 and (BzO)2 affords derivative (II), which is then treated with protected trifluoroethane derivative (III) in DMF to give (IV). Alternatively, (II) can be converted into (IV) by first treating with 2,2,2-trifluoroethylamine (V) in DMSO followed by N-protection by means of Boc2O in CH2Cl2. Treatment of (IV) with dimethyl itaconate (VII) in the presence of Pd(OAc)2, P(o-tol)3, DIEA and propionitrile yields intermediate (VIII), which is then reduced by hydrogenolysis over Pd/C in EtOAc to afford butanoate (IX). Removal of the Boc protecting group of (IX) by treatment with TFA and anisole provides derivative (X), which is then cyclized by means of tripropylamine in refluxing xylenes to afford benzazepine derivative (XI) in its racemic form. Separation of the two enantiomers of (XI) by chiral HPLC affords (S)-(XII), which is demethylated with BBr3 in CH2Cl2 to yield (XIII). Treatment of N-oxide derivative (XIV) with 3-amino-1-propanol (XV) in tert-amyl alcohol in the presence of NaHCO3 yields derivative (XVI), which is then reacted with phenol derivative (XIII) in a Mitsunobu reaction with PPh3 and DEAD in THF/DMF to give ether derivative (XVII). Reduction of (XVII) with cyclohexene in isopropanol in the presence of Pd/C affords methyl acetate (XVIII), which is finally hydrolyzed by means of aqueous NaOH in dioxane.
| 【1】 Miller, W.H.; Bhatnager, P.K.; Alberts, D.P.; et al.; Discovery of orally active nonpeptide vitronectin receptor antagonists based on a 2-benzazepine gly-asp mimetic. J Med Chem 2000, 43, 1, 22. |
| 【2】 Callahan, J.F.; Cousins, R.D.; Keenan, R.M.; Kwon, C.; Miller, W.H.; Uzinkas, I.N. (SmithKline Beecham plc); Vitronectin receptor antagonists. EP 0957917; WO 9814192 . |
| 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) | 42539 | 4-bromo-3-methylphenyl methyl ether; 1-bromo-4-methoxy-2-methylbenzene | 27060-75-9 | C8H9BrO | 详情 | 详情 |
| (II) | 27552 | 1-bromo-2-(bromomethyl)-4-methoxybenzene | C8H8Br2O | 详情 | 详情 | |
| (III) | 42540 | C7H11F3NNaO2 | 详情 | 详情 | ||
| (IV) | 42541 | tert-butyl 2-bromo-5-methoxybenzyl(2,2,2-trifluoroethyl)carbamate | C15H19BrF3NO3 | 详情 | 详情 | |
| (V) | 42542 | 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine | 753-90-2 | C2H4F3N | 详情 | 详情 |
| (VI) | 42543 | N-(2-bromo-5-methoxybenzyl)-2,2,2-trifluoro-1-ethanamine; N-(2-bromo-5-methoxybenzyl)-N-(2,2,2-trifluoroethyl)amine | C10H11BrF3NO | 详情 | 详情 | |
| (VII) | 21416 | dimethyl 2-methylenesuccinate | 617-52-7 | C7H10O4 | 详情 | 详情 |
| (VIII) | 42544 | dimethyl 2-[(E)-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxyphenyl)methylidene]succinate | C22H28F3NO7 | 详情 | 详情 | |
| (IX) | 42545 | dimethyl 2-(2-[[(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino]methyl]-4-methoxybenzyl)succinate | C22H30F3NO7 | 详情 | 详情 | |
| (X) | 42546 | dimethyl 2-(4-methoxy-2-[[(2,2,2-trifluoroethyl)amino]methyl]benzyl)succinate | C17H22F3NO5 | 详情 | 详情 | |
| (XI) | 42547 | methyl 2-[8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XII) | 42548 | methyl 2-[(4S)-8-methoxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C16H18F3NO4 | 详情 | 详情 | |
| (XIII) | 42549 | methyl 2-[(4S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C15H16F3NO4 | 详情 | 详情 | |
| (XIV) | 34524 | 2-chloro-1-pyridiniumolate | 2402-95-1 | C5H4ClNO | 详情 | 详情 |
| (XV) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (XVI) | 34525 | 2-[(3-hydroxypropyl)amino]-1-pyridiniumolate | C8H12N2O2 | 详情 | 详情 | |
| (XVII) | 42550 | 2-[(3-[[(4S)-4-(2-methoxy-2-oxoethyl)-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]oxy]propyl)amino]-1-pyridiniumolate | C23H26F3N3O5 | 详情 | 详情 | |
| (XVIII) | 42551 | methyl 2-[(4S)-3-oxo-8-[3-(2-pyridinylamino)propoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl]acetate | C23H26F3N3O4 | 详情 | 详情 |