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【结 构 式】 
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【分子编号】34722 【品名】2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane 【CA登记号】 |
【 分 子 式 】C10H19NO5 【 分 子 量 】233.2646 【元素组成】C 51.49% H 8.21% N 6% O 34.29% |
合成路线1
该中间体在本合成路线中的序号：(X)Condensation of 4-chloroacetophenone (I) with ethyl diethoxyacetate (II) in the presence of lithium hexamethyldisilazide afforded diketoacetal (III). Formation of pyrazole (V) was accomplished by treatment of (III) with 4-methoxy-phenylhydrazine (IV). Subsequent acid hydrolysis of the diethyl acetal gave aldehyde (VI), which was condensed with carbon tetrabromide using triphenyl phosphine to furnish dibromoethylene compound (VII). Elimination of HBr in (VII) by treatment with tetrabutylammonium fluoride produced bromoacetylene (VIII). After lithium-bromine exchange, addition of acetaldehyde yielded the propargyl alcohol (IX). Further Mitsunobu coupling of (IX) with N,O-bis(tert-butoxycarbonyl)hydroxylamine (X) gave the N,O-bis-protected N-alkyl hydroxylamine (XI). After Boc deprotection of (XI) by means of trifluoroacetic acid, coupling with acetyl chloride provided the O-acetyl hydroxamic acid (XII). Finally, cleavage of the O-acyl group of (XII) with methanolic NaOH furnished the title compound.
| 【1】 Wetter, S.K.; Connolly, P.J.; Beers, K.N.; et al.; N-Hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase. Bioorg Med Chem Lett 1999, 9, 7, 979. |
| 【2】 Chen, R.; Wachter, M.; Connolly, P. (Ortho-McNeil Pharmaceutical, Inc.); Acetylenic 1,5-diarylpyrazoles as antiinflammatory agents. US 5925769 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
| (II) | 25674 | ethyl 2,2-diethoxyacetate | 6065-82-3 | C8H16O4 | 详情 | 详情 |
| (III) | 34716 | 1-(4-chlorophenyl)-4,4-diethoxy-1,3-butanedione | C14H17ClO4 | 详情 | 详情 | |
| (IV) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
| (V) | 34717 | 4-[5-(4-chlorophenyl)-3-(diethoxymethyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(diethoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole | C21H23ClN2O3 | 详情 | 详情 | |
| (VI) | 34718 | 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde | C17H13ClN2O2 | 详情 | 详情 | |
| (VII) | 34719 | 4-[5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1-(4-methoxyphenyl)-1H-pyrazole | C18H13Br2ClN2O | 详情 | 详情 | |
| (VIII) | 34720 | 3-(2-bromoethynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole; 4-[3-(2-bromoethynyl)-5-(4-chlorophenyl)-1H-pyrazol-1-yl]phenyl methyl ether | C18H12BrClN2O | 详情 | 详情 | |
| (IX) | 34721 | 4-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-3-butyn-2-ol | C20H17ClN2O2 | 详情 | 详情 | |
| (X) | 34722 | 2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane | C10H19NO5 | 详情 | 详情 | |
| (XI) | 34723 | 3-(3-[(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino]-1-butynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole | C30H34ClN3O6 | 详情 | 详情 | |
| (XII) | 34724 | 1-((acetoxy)[3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-1-methyl-2-propynyl]amino)-1-ethanone | C24H22ClN3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The reaction of 1,3-dibromopropane (I) with triethyl phosphite (II) at 160 C gives triethyl 3-bromopropylphosphonate (III), which is treated with Tms-Br and water to yield the corresponding phosphonic acid (IV). The reaction of (IV) with PCl3 in refluxing chloroform affords the acyl chloride (V), which is treated with 4-methoxyphenol (VI) and pyridine to provide the expected 4-methoxyphenyl diester (VII). The reaction of (VII) with N,O-bis(tert-butoxycarbonyl)hydroxylamine (VIII) by means of NaH in DMF gives the fully protected hydroxyamino derivative (IX), which by treatment with TFA in dichloromethane yields 3-(hydroxyamino)propylphosphonic acid 4-methoxyphenyl diester (X). Finally, this compound is acylated with Ac-Cl and TEA in ethyl ether to afford the target N-acetylhydroxyamino compound.
| 【1】 Reichenberg, A.; et al.; Diaryl ester prodrugs of FR900098 with improved in vivo antimalarial activity. Bioorg Med Chem Lett 2001, 11, 6, 833. |
| 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) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (II) | 15487 | triethyl phosphite | 122-52-1 | C6H15O3P | 详情 | 详情 |
| (III) | 39080 | diethyl 3-bromopropylphosphonate | C7H16BrO3P | 详情 | 详情 | |
| (IV) | 39105 | 3-bromopropylphosphonic acid | 1190-09-6 | C3H8BrO3P | 详情 | 详情 |
| (V) | 49412 | 3-bromopropylphosphonic dichloride | C3H6BrCl2OP | 详情 | 详情 | |
| (VI) | 32744 | 4-methoxyphenol | 150-76-5 | C7H8O2 | 详情 | 详情 |
| (VII) | 49413 | bis(4-methoxyphenyl) 3-bromopropylphosphonate | C17H20BrO5P | 详情 | 详情 | |
| (VIII) | 34722 | 2-[([[(tert-butoxycarbonyl)amino]oxy]carbonyl)oxy]-2-methylpropane | C10H19NO5 | 详情 | 详情 | |
| (IX) | 49414 | 5-(tert-butoxycarbonyl)-1,1-bis(4-methoxyphenoxy)-9,9-dimethyl-1,7-dioxo-6,8-dioxa-5-aza-1lambda(5)-phosphadecane | C27H38NO10P | 详情 | 详情 | |
| (X) | 49415 | bis(4-methoxyphenyl) 3-(hydroxyamino)propylphosphonate | C17H22NO6P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)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 |