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【结 构 式】 
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【分子编号】49195 【品名】3-(aminooxy)-1-propene; O-allylhydroxylamine 【CA登记号】 |
【 分 子 式 】C3H7NO 【 分 子 量 】73.09472 【元素组成】C 49.3% H 9.65% N 19.16% O 21.89% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Coupling of N-Boc-L-tert-leucine (I) with (R)-1-phenylethylamine (II) using EDC and HOBt gave amide (III) which, after acid cleavage of the N-Boc group, provided amino amide (IV). Acylation of amine (IV) with (R)-2-allylsuccinic acid 4-tert-butyl ester (V) afforded the diamide (VI). Biphenylyl bromide (IX) was prepared by the Suzuki coupling between 5-bromo-2-iodotoluene (VII) and phenylboronic acid (VIII). The biaryl group was then introduced via Heck reaction of biphenylyl bromide (IX) with olefin (VI), yielding adduct (X). Subsequent hydrogenation of the olefin double bond of (X) over Pd/C afforded (XI). Carboxylic acid (XII) was then obtained by trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI). Conversion of (XII) to the title hydroxamic acid was then achieved by coupling of carboxylic acid (XII) with O-allylhydroxylamine (XIII), followed by O-allyl group cleavage in the presence of ammonium formate and palladium catalyst.
| 【1】 Fray, M.J.; et al.; Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1). 13th Noordwijkerhout-Camerino Symp Trends Drug Res (May 6 2001, Noordwijkerhout) 2001, Abst P8. |
| 【2】 Fray, M.J.; Dickinson, R.P.; Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1). Bioorg Med Chem Lett 2001, 11, 4, 571. |
| 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) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 49186 | tert-butyl (1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propylcarbamate | C19H30N2O3 | 详情 | 详情 | |
| (IV) | 49187 | (2S)-2-amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide | C14H22N2O | 详情 | 详情 | |
| (V) | 49188 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-pentenoic acid | C11H18O4 | 详情 | 详情 | |
| (VI) | 49189 | tert-butyl (3R)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-5-hexenoate | C25H38N2O4 | 详情 | 详情 | |
| (VII) | 49190 | 1-Bromo-4-iodo-5-methylbenzene; 5-Bromo-2-iodotoluene | C7H6BrI | 详情 | 详情 | |
| (VIII) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (IX) | 49191 | 4-bromo-2-methyl-1,1'-biphenyl | C13H11Br | 详情 | 详情 | |
| (X) | 49192 | tert-butyl (3R,5E)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-6-(2-methyl[1,1'-biphenyl]-4-yl)-5-hexenoate | C38H48N2O4 | 详情 | 详情 | |
| (XI) | 49193 | tert-butyl (3R)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-6-(2-methyl[1,1'-biphenyl]-4-yl)hexanoate | C38H50N2O4 | 详情 | 详情 | |
| (XII) | 49194 | (3R)-3-([[(1S)-2,2-dimethyl-1-([[(1R)-1-phenylethyl]amino]carbonyl)propyl]amino]carbonyl)-6-(2-methyl[1,1'-biphenyl]-4-yl)hexanoic acid | C34H42N2O4 | 详情 | 详情 | |
| (XIII) | 49195 | 3-(aminooxy)-1-propene; O-allylhydroxylamine | C3H7NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Itaconic acid mono-tert-butyl ester (IV) was prepared via esterification of itaconic acid (I) with methanol in the presence of an acidic ion exchange resin to form the mono-methyl ester (II), which was further converted to methyl tert-butyl ester (III) upon treatment with isobutylene and sulfuric acid. Subsequent hydrolysis of the methyl ester function of (III) using LiOH furnished mono-ester (IV). Reduction of acid (IV) to the primary alcohol (V) was accomplished using the NaBH4-I2 reagent. Michael addition of p-bromothiophenol (VI) to the unsaturated ester (V) provided the thioether adduct (VII). Mitsunobu coupling of alcohol (VII) with benzo[1,2,3]triazin-4-one (VIII) yielded the 3-substituted triazinone (IX). The biphenyl system (XI) was then obtained by Suzuki coupling of the aryl bromide (IX) with (4-chlorophenyl)tributyltin (X) in the presence of palladium tetrakis(triphenylphosphine) and lithium chloride. Trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI) gave acid (XII), which was subsequently coupled to O-allyl hydroxylamine (XIII) to afford the allyl hydroxamate (XIV). The O-allyl group was finally removed by treatment with tributyltin hydride and a palladium catalyst.
| 【1】 Le Diguarher, T.; Kucharvzyk, N.; Chollet, A.-M.; et al.; Solid-phase synthesis of alpha-substituted 3-bisarylthio N-hydroxy propionamides as specific MMP inhibitors. Bioorg Med Chem 2002, 10, 3, 531. |
| 【2】 Guilbaud, N.; Atassi, G.; Le Diguarher, T.; Bonnet, J.; Sabatini, M.; Casara, P.; Chollet, A.-M.; Pierre, A.; Tucker, G. (ADIR et Cie.); Carboxylic and hydroxamic acid cpds. inhibiting metalloproteases, method for preparing same and pharmaceutical compsns. containing them. EP 1091937; FR 2780402; WO 0000473 . |
| 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) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (II) | 34820 | 2-(2-methoxy-2-oxoethyl)acrylic acid | 7338-27-4 | C6H8O4 | 详情 | 详情 |
| (III) | 59619 | 1-(tert-butyl) 4-methyl 2-methylenesuccinate | C10H16O4 | 详情 | 详情 | |
| (IV) | 59620 | 3-(tert-butoxycarbonyl)-3-butenoic acid | C9H14O4 | 详情 | 详情 | |
| (V) | 59621 | tert-butyl 2-(2-hydroxyethyl)acrylate | C9H16O3 | 详情 | 详情 | |
| (VI) | 29626 | 4-bromophenylhydrosulfide; 4-bromobenzenethiol | 106-53-6 | C6H5BrS | 详情 | 详情 |
| (VII) | 59622 | tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-hydroxybutanoate | C15H21BrO3S | 详情 | 详情 | |
| (VIII) | 36890 | 1,2,3-benzotriazin-4(3H)-one | C7H5N3O | 详情 | 详情 | |
| (IX) | 59623 | tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate | C22H24BrN3O3S | 详情 | 详情 | |
| (X) | 59624 | tributyl(4-chlorophenyl)stannane | C18H31ClSn | 详情 | 详情 | |
| (XI) | 59625 | tert-butyl 2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate | C28H28ClN3O3S | 详情 | 详情 | |
| (XII) | 59626 | 2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoic acid | C24H20ClN3O3S | 详情 | 详情 | |
| (XIII) | 49195 | 3-(aminooxy)-1-propene; O-allylhydroxylamine | C3H7NO | 详情 | 详情 | |
| (XIV) | 59627 | N-(allyloxy)-2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanamide | C27H25ClN4O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)Claisen condensation between 3,4-dichlorophenylacetic acid (VI) and N-Boc-sarcosine methyl ester (VII), followed by acidic decarboxylation of the intermediate keto acid, furnishes amino ketone (VIII). Alkylation of (VIII) with the silylated bromoethanol (IX) in the presence of NaH and NaI yields adduct (X). Subsequent condensation of ketone (X) with O-allyl hydroxylamine (XI) generates the corresponding oxime (XII). After desilylation of (XII) with tetrabutylammonium fluoride, the resultant primary alcohol (XIII) is oxidized under Swern conditions to furnish aldehyde (XIV)
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (VII) | 60815 | methyl 2-[(tert-butoxycarbonyl)(methyl)amino]acetate | C9H17NO4 | 详情 | 详情 | |
| (VIII) | 60816 | tert-butyl 3-(3,4-dichlorophenyl)-2-oxopropyl(methyl)carbamate | C15H19Cl2NO3 | 详情 | 详情 | |
| (IX) | 55573 | 2-Bromoethoxy-t-butyldimethylsilane | 86864-60-0 | C8H19BrOSi | 详情 | 详情 |
| (X) | 60817 | tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-3-(3,4-dichlorophenyl)-2-oxopentyl(methyl)carbamate | C23H37Cl2NO4Si | 详情 | 详情 | |
| (XI) | 49195 | 3-(aminooxy)-1-propene; O-allylhydroxylamine | C3H7NO | 详情 | 详情 | |
| (XII) | 60818 | tert-butyl 2-[(allyloxy)imino]-5-{[tert-butyl(dimethyl)silyl]oxy}-3-(3,4-dichlorophenyl)pentyl(methyl)carbamate | C26H42Cl2N2O4Si | 详情 | 详情 | |
| (XIII) | 60819 | tert-butyl 2-[(allyloxy)imino]-3-(3,4-dichlorophenyl)-5-hydroxypentyl(methyl)carbamate | C20H28Cl2N2O4 | 详情 | 详情 | |
| (XIV) | 60820 | tert-butyl 2-[(allyloxy)imino]-3-(3,4-dichlorophenyl)-5-oxopentyl(methyl)carbamate | C20H26Cl2N2O4 | 详情 | 详情 |