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【结 构 式】 
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【分子编号】17819 【品名】2-bromo-5-methoxybenzoic acid 【CA登记号】22921-68-2 |
【 分 子 式 】C8H7BrO3 【 分 子 量 】231.04578 【元素组成】C 41.59% H 3.05% Br 34.58% O 20.77% |
合成路线1
该中间体在本合成路线中的序号：(IX)The condensation of 2-bromo-5-methoxybenzoic acid (IX) with 4-hydroxybenzonitrile (X) by means of K2CO3, Cu and Cu2I2 in n-pentanol gives 2-(4-cyanophenoxy)-5-methoxybenzoic acid (XI), which is cyclized and hydrolyzed with hot H2SO4 to give the starting product (I). Alternatively, compound (XI) can be cyclized and partially hydrolyzed with hot polyphosphoric acid giving 7-methoxy-9-oxoxanthene-2-carboxamide (XII), which is finally hydrolyzed with H2SO4.
| 【1】 Castaner, J.; Blancafort, P.; AH 7725. Drugs Fut 1976, 1, 7, 313. |
| 【2】 Bays, D.E.; Xanthone derivatives.. DE 2058295; FR 2073425; GB 1312620; US 3706768 . |
合成路线2
该中间体在本合成路线中的序号：(I)Reaction of 2-bromo-5-methoxybenzoic acid (I) with hydrazine hydrate gave hydrazinobenzoic acid (II), which was cyclized to indazole (III) on heating with hydrochloric acid. Subsequent alkylation with 2-[4-(chloromethyl)phenoxymethyl]quinoline hydrochloride (IV) in the presence of sodium hydroxide in DMSO provided (V), and treatment of this with HCl in acetone furnished the target dihydrochloride.
| 【1】 Schindler, R.; et al.; 1,5-Disubstituted Indazol-3-ols with Anti-Inflammatlory Activity. Arch Pharm 1998, 331, 1, 13-21. |
| 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) | 17820 | 2-hydrazino-5-methoxybenzoic acid | C8H10N2O3 | 详情 | 详情 | |
| (III) | 17821 | 5-methoxy-1H-indazol-3-ol | C8H8N2O2 | 详情 | 详情 | |
| (IV) | 17822 | 4-(chloromethyl)phenyl 2-quinolinylmethyl ether; 2-[[4-(chloromethyl)phenoxy]methyl]quinoline | C17H14ClNO | 详情 | 详情 | |
| (V) | 17823 | 5-methoxy-1-[4-(2-quinolinylmethoxy)benzyl]-1H-indazol-3-ol | C25H21N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(VII)The intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) has been obtained as follows: the reduction of 2-bromo-5-methoxybenzoic acid (VII) with NaBH4/BF3 gives the expected benzyl alcohol (VIII), which by treatment with SOCl2 is converted into the benzyl chloride (IX). The condensation of (IX) with the chiral auxiliary (X) by means of LIHMDS provides the 2(S)-methylpropionic acid derivative (XI). Elimination of the chiral auxiliary with sulfuric acid gives 3-(2-bromo-5-methoxyphenyl)-2(S)-methylpropionic acid (XII), which is reduced with NaBH4/BF3 to the corresponding alcohol (XIII). Finally, this compound is silylated to afford the intermediate (XIV) with TBDMS-Cl and imidazole.
| 【1】 Song, Z.J.; et al.; Practical asymetric synthesis of an endothelin receptor antagonist. J Org Chem 1999, 64, 26, 9658. |
| 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) | 17819 | 2-bromo-5-methoxybenzoic acid | 22921-68-2 | C8H7BrO3 | 详情 | 详情 |
| (VIII) | 27551 | (2-bromo-5-methoxyphenyl)methanol | C8H9BrO2 | 详情 | 详情 | |
| (IX) | 38553 | 1-bromo-2-(chloromethyl)-4-methoxybenzene; 4-bromo-3-(chloromethyl)phenyl methyl ether | C8H8BrClO | 详情 | 详情 | |
| (X) | 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 | |
| (XI) | 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 | |
| (XII) | 27556 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropionic acid | C11H13BrO3 | 详情 | 详情 | |
| (XIII) | 27558 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol | C11H15BrO2 | 详情 | 详情 | |
| (XIV) | 27567 | 4-bromo-3-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)phenyl methyl ether | C17H29BrO2Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The bromination of 3-methoxybenzoic acid (I) with Br2 in refluxing acetic acid gives 2-bromo-5-methoxybenzoic acid (II), which is condensed with 3-chlorothiophenol (III) by means of cupric acetate in DMF at 150 C yielding the sulfide (IV). The cyclization of (IV) in sulfuric acid affords the thioxanthenone (V), which is condensed with 2-(diethylamino)ethylamine (VI) in pyridine at 115 C giving the corresponding 2-(diethylamino)ethylamino derivative (VII). The hydroxymethylation of (VII) with formaldehyde in hot 5N acetic acid yields the hydroxymethyl derivative (VIII), which is oxidized with MnO2 in hot toluene affording the corresponding aldehyde (IX). Finally, this compound is treated with formamide and formic acid at 170 C.
| 【1】 Perni, R.B.; Wentland, M.P.; Huang, J.I.; Powles, R.G.; Aldous, S.; Klingbeil, K.M.; Peverly, A.D.; Robinson, R.G.; Corbett, T.H.; Jones, J.L.; Mattes, K.C.; Rake, J.B.; Coughlin, S.A.; Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives. J Med Chem 1998, 41, 19, 3645. |
| 【2】 Miller, T.C.; Collins, J.C.; Wentland, M.P.; Perni, R.B.; Corbett, T.H.; Mattes, K.C. (Sanofi-Synthelabo); Thioxanthenone antitumor agents. EP 0518414; EP 0619315; EP 0882723; JP 1993178853; JP 1994340655; US 5346917 . |
| 【3】 Wentland, M.P.; et al.; Anti-solid tumor efficacy and preparation of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thioxanthen-4-yl]methyl]methanesulfonamide (WIN 33377) and related derivatives. Bioorg Med Chem Lett 1994, 4, 4, 609. |
| 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) | 28559 | m-Anisic acid; 3-Methoxybenzoic acid | 586-38-9 | C8H8O3 | 详情 | 详情 |
| (II) | 17819 | 2-bromo-5-methoxybenzoic acid | 22921-68-2 | C8H7BrO3 | 详情 | 详情 |
| (III) | 30443 | 3-chlorophenylhydrosulfide; 3-chlorobenzenethiol | 2037-31-2 | C6H5ClS | 详情 | 详情 |
| (IV) | 30444 | 2-[(3-chlorophenyl)sulfanyl]-5-methoxybenzoic acid | C14H11ClO3S | 详情 | 详情 | |
| (V) | 30445 | 1-chloro-7-methoxy-9H-thioxanthen-9-one | C14H9ClO2S | 详情 | 详情 | |
| (VI) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (VII) | 30446 | 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9H-thioxanthen-9-one | C20H24N2O2S | 详情 | 详情 | |
| (VIII) | 30447 | 1-[[2-(diethylamino)ethyl]amino]-4-(hydroxymethyl)-7-methoxy-9H-thioxanthen-9-one | C21H26N2O3S | 详情 | 详情 | |
| (IX) | 30448 | 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthene-4-carbaldehyde | C21H24N2O3S | 详情 | 详情 |