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【结 构 式】 
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【分子编号】39246 【品名】4-methoxyphenylboronic acid 【CA登记号】5720-07-0 |
【 分 子 式 】C7H9BO3 【 分 子 量 】151.95766 【元素组成】C 55.33% H 5.97% B 7.11% O 31.59% |
合成路线1
该中间体在本合成路线中的序号：(VI)The intermediate 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) has been obtained by several related ways: 1.- The condensation of 4-bromonitrobenzene (I) with piperazine (II) gives 1-(4-nitrophenyl)piperazine (III), which is condensed with 4-bromoanisole (IV) by means of Pdo to yield 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V). Alternatively, (V) can also be obtained by condensation of (III) with 4-methoxyphenylboronic acid (VI) by means of Cu(OAc)2 in DMSO. The demethylation of (V) with HBr yields 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (VII), which is finally reduced with H2 over Pd/C to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). 2.- The condensation of piperazine (II) with 4-bromoanisole (IV) by means of Pdo gives 1-(4-methoxyphenyl)piperazine (IX), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in hot DMSO to yield intermediate 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), already reported. 3.- The condensation of piperazine (II) with 4-(benzyloxy)phenyl bromide (X) by means of Pdo gives 1-(4-benzyloxyphenyl)piperazine (XI), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and TBAI in hot DMSO to yield 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII). The nitro group of (XII) is reduced by means of H2 (50 psi) over Pd/C in wet THF at 50? C to afford 4-[4-(4-benzyloxyphenyl)piperazin-1-yl]aniline (XIII), which is finally debenzylated with H2 (80 psi) over Pd/C in wet THF at 70? C or other drastic conditions to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). Alternatively, 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII) can also be reduced directly to the target intermediate (VIII) with H2 over Pd/C under a variety of drastic conditions.
| 【1】 Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, C.A.; Goodman, A.; Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002, 43, 18, 3359. |
| 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) | 26628 | 1-bromo-4-nitrobenzene | 99-99-0 | C6H4BrNO2 | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (IV) | 63436 | 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether | C7H7BrO | 详情 | 详情 | |
| (V) | 16314 | methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine | C17H19N3O3 | 详情 | 详情 | |
| (VI) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (VII) | 16345 | 4-[4-(4-nitrophenyl)piperazino]phenol | C16H17N3O3 | 详情 | 详情 | |
| (VIII) | 17110 | 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine | 74853-08-0 | C16H19N3O | 详情 | 详情 |
| (IX) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (X) | 43156 | 1-(benzyloxy)-4-bromobenzene; benzyl 4-bromophenyl ether | 6793-92-6 | C13H11BrO | 详情 | 详情 |
| (XI) | 64373 | 1-[4-(benzyloxy)phenyl]piperazine; benzyl 4-(1-piperazinyl)phenyl ether | C17H20N2O | 详情 | 详情 | |
| (XII) | 64372 | benzyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether; 1-[4-(benzyloxy)phenyl]-4-(4-nitrophenyl)piperazine | C23H23N3O3 | 详情 | 详情 | |
| (XIII) | 64371 | 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}aniline; 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}phenylamine | C23H25N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Condensation of 4-bromophenacyl bromide (I) with phenol in the presence of potassium carbonate produced phenoxyacetophenone (II), which was cyclized to benzofuran (III) upon treatment with polyphosphoric acid in refluxing xylene. Suzuki coupling of (III) with 4-methoxybenzeneboronic acid (IV) gave the biphenyl benzofuran (V). The phenolic derivative (VI) was prepared by demethylation of ether (V) with boron tribromide. Lithiation of (VI) with n-butyllithium, followed by addition of N-methoxy-N-methyl benzamide afforded ketone (VII), which was converted to the benzyl benzofuran (VIII) by means of a modified Wolff-Kishner reduction. Coupling of (VIII) with methyl (S)-3-phenyllactate (IX) under Mitsunobu conditions furnished the corresponding ether (X). The methyl ester group of (X) was finally hydrolyzed with NaOH to yield the title carboxylic acid.
| 【1】 Malamas, M.S.; Sredy, J.; Moxham, C.; et al.; Novel benzofuran and benzothiophene biphenyls as inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties. J Med Chem 2000, 43, 7, 1293. |
| 【2】 McDevitt, R.E.; Malamas, M.S.; Adebayo, F.O. (American Home Products Corp.); Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia. WO 9958518 . |
| 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) | 39243 | 2-bromo-1-(4-bromophenyl)-1-ethanone | 99-73-0 | C8H6Br2O | 详情 | 详情 |
| (II) | 39244 | 1-(4-bromophenyl)-2-phenoxy-1-ethanone | C14H11BrO2 | 详情 | 详情 | |
| (III) | 39245 | 3-(4-bromophenyl)-1-benzofuran | C14H9BrO | 详情 | 详情 | |
| (IV) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (V) | 39247 | 4'-(1-benzofuran-3-yl)[1,1'-biphenyl]-4-yl methyl ether; 3-(4'-methoxy[1,1'-biphenyl]-4-yl)-1-benzofuran | C21H16O2 | 详情 | 详情 | |
| (VI) | 39248 | 4'-(1-benzofuran-3-yl)[1,1'-biphenyl]-4-ol | C20H14O2 | 详情 | 详情 | |
| (VII) | 39249 | [3-(4'-hydroxy[1,1'-biphenyl]-4-yl)-1-benzofuran-2-yl](phenyl)methanone | C27H18O3 | 详情 | 详情 | |
| (VIII) | 39250 | 4'-(2-benzyl-1-benzofuran-3-yl)[1,1'-biphenyl]-4-ol | C27H20O2 | 详情 | 详情 | |
| (IX) | 39252 | methyl (2S)-2-hydroxy-3-phenylpropanoate | C10H12O3 | 详情 | 详情 | |
| (X) | 39251 | methyl (2S)-2-[[4'-(2-benzyl-1-benzofuran-3-yl)[1,1'-biphenyl]-4-yl]oxy]-3-phenylpropanoate | C37H30O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Suzuki coupling between 4-methoxyphenylboronic acid (I) and 1-bromo-4-(trifluoromethoxy)benzene (II) gave the biphenyl derivative (III). Methyl ether cleavage in (III) by means of BBr3 provided the biphenyl alcohol (IV), which was condensed with (S)-benzyl glycidyl ether (V) under basic conditions, yielding the chiral glycerol diether (VI). Mitsunobu coupling of alcohol (VI) with the di-Boc-protected hydroxylamine (VII) using DEAD/PPh3 afforded carbamate (VIII). Subsequent catalytic hydrogenolysis of the benzyl ether of (VIII) gave alcohol (IX). Condensation of this alcohol (IX) with 5,5-dimethylhydantoin (X) under Mitsunobu conditions, followed by acidic cleavage of the Boc protecting groups, furnished the hydroxylamine derivative (XI). This was finally N-formylated by treatment with formic acetic anhydride.
| 【1】 Curtin, M.L.; et al.; Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770. Bioorg Med Chem Lett 2001, 11, 12, 1557. |
| 【2】 Dellaria, J.F. Jr.; Gong, J.; Steinman, D.H.; Michaelides, M.R.; Giesler, J.; Davidsen, S.K.; Curtin, M.L.; Florjancic, A.S.; Xu, L.; Guo, Y.; Holms, J.H.; Wada, C.K.; Heyman, H.R. (Abbott Laboratories Inc.); Reverse hydroxamate inhibitors of matrix metalloproteinases. JP 2001523272; WO 9906361 . |
| 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) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (II) | 52466 | 4-Bromophenyl trifluoromethyl ether; 4-(Trifluoromethoxy)bromobenzene; 4-Bromo-(trifluoromethoxy)-benzene; 4-Bromo-alpha,alpha,alpha-trifluoroanisole; 4-Bromotrifluoromethoxybenzene; 1-Bromo-4-(trifluoromethoxy)benzene | 407-14-7 | C7H4BrF3O | 详情 | 详情 |
| (III) | 52467 | 4-(methyloxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl; methyl 4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl ether | C14H11F3O2 | 详情 | 详情 | |
| (IV) | 52468 | 4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-ol | C13H9F3O2 | 详情 | 详情 | |
| (V) | 12350 | Benzyl (2R)oxiranylmethyl ether; (2R)-2-[(Benzyloxy)methyl]oxirane | 14618-80-5 | C10H12O2 | 详情 | 详情 |
| (VI) | 52469 | 1-[(phenylmethyl)oxy]-3-({4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl}oxy)-2-propanol | C23H21F3O4 | 详情 | 详情 | |
| (VII) | 34722 | 2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane | C10H19NO5 | 详情 | 详情 | |
| (VIII) | 52470 | 4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}({[(1,1-dimethylethyl)oxy]carbonyl}oxy)amino]-3-[(phenylmethyl)oxy]propyl}oxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl | C33H38F3NO8 | 详情 | 详情 | |
| (IX) | 52471 | 4-({2-[{[(1,1-dimethylethyl)oxy]carbonyl}({[(1,1-dimethylethyl)oxy]carbonyl}oxy)amino]-3-hydroxypropyl}oxy)-4'-[(trifluoromethyl)oxy]-1,1'-biphenyl | C26H32F3NO8 | 详情 | 详情 | |
| (X) | 32473 | 5,5-dimethyl-2,4-imidazolidinedione | 77-71-4 | C5H8N2O2 | 详情 | 详情 |
| (XI) | 52472 | 3-[2-(hydroxyamino)-3-({4'-[(trifluoromethyl)oxy][1,1'-biphenyl]-4-yl}oxy)propyl]-5,5-dimethyl-2,4-imidazolidinedione | C21H22F3N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Treatment of ketone (IX) with trifluoromethanesulfonic anhydride and pyridine produces the vinyl triflate (X). This is then subjected to Suzuki coupling with 4-methoxyphenylboronic acid (XI) to yield adduct (XII). Finally, regioselective lactam reduction in (XII) with NaBH4 furnishes the title compound.
| 【1】 Thurston, D.E.; Howard, P.W. (University of Portsmouth); Compounds. EP 1109812; WO 0012508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 61276 | (11aS)-7,8-dimethoxy-10-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,1-c][1,4]benzodiazepine-2,5,11(3H,10H,11aH)-trione | C20H28N2O6Si | 详情 | 详情 | |
| (X) | 61277 | (11aS)-7,8-dimethoxy-5,11-dioxo-10-{[2-(trimethylsilyl)ethoxy]methyl}-5,10,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-2-yl trifluoromethanesulfonate | C21H27F3N2O8SSi | 详情 | 详情 | |
| (XI) | 39246 | 4-methoxyphenylboronic acid | 5720-07-0 | C7H9BO3 | 详情 | 详情 |
| (XII) | 61278 | (11aS)-7,8-dimethoxy-2-(4-methoxyphenyl)-10-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione | C27H34N2O6Si | 详情 | 详情 |