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【结 构 式】 
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【分子编号】36890 【品名】1,2,3-benzotriazin-4(3H)-one 【CA登记号】 |
【 分 子 式 】C7H5N3O 【 分 子 量 】147.13632 【元素组成】C 57.14% H 3.43% N 28.56% O 10.87% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of 1,2,3-benzotriazin-4(3H)-one (I) with ethyl bromoacetate (II) in refluxing butanone afforded the 3-(ethoxycarbonylmethyl) derivative (III). The ethyl ester group of (III) was then converted into the target amide by reaction with N,N-diethylethylenediamine (IV) in hot MeOH
| 【1】 Caliendo, G.; De Nucci, G.; Meli, R.; Mattace Raso, G.; Fiorino, F.; Perissutti, E.; Zanesco, A.; Grieco, P.; Santagada, V.; Preparation and local anaesthetic activity of benzotriazinone and benzoyltriazole derivatives. Eur J Med Chem 1999, 34, 12, 1043. |
| 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) | 36890 | 1,2,3-benzotriazin-4(3H)-one | C7H5N3O | 详情 | 详情 | |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 36891 | ethyl 2-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]acetate | C11H11N3O3 | 详情 | 详情 | |
| (IV) | 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 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Condensation of 1,4-dichloro-2-butene (I) with phenolic derivative (II) in the presence of K2CO3 yields compound (III), which is then converted into acetate (IV) after treatment with ammonium tetrabutyl acetate in acetone. Saponification of (IV) with NaOH in MeOH affords alcohol (V), which is then subjected to Claisen rearrangement by refluxing in ethyl orthoacetate to provide ester (VI). Reduction of (VI) with LiAlH4 in Et2O gives alcohol (VII), which is then condensed with benzotriazine-4-one (VIII) by means of a Mitsunobu reaction with PPh3 and DEAD in THF to furnish compound (IX). Treatment of (IX) with Zn(CN)2 and Pd(PPh3)4 in DMF yields cyano derivative (X), which is then converted into carboxylic acid (XI) either by treatment with NaIO4 and RuCl3 in CCl4:ACN:H2O or by treatment with H5IO6 and RuCl3 followed by reaction with CrO3 and H2SO4. Finally, the target product is obtained by reaction of (XI) with protected hydroxylamine (either benzylhydroxylamine or allyl hydroxylamine) by means of EDC, HOBt, Et3N (or DIEA) in CH2Cl2 and removal of the protecting group (either by hydrogenation over Pd/C or by treatment with Pd(PPh3)2Cl2, Bu3SnH, HOAc in CH2Cl2, respectively).
| 【1】 Tucker, G.C.; Bonnet, J.; Bertrand, M.; Le Diguarher, T.; Chollet, A.-M.; Murray, L.; Atassi, G.; Sabatini, M.; Pierré, A.; Casara, P.; General synthesis of alpha-substituted 3-bisaryloxy propionic acid derivatives as specific MMP inhibitors. Bioorg Med Chem Lett 2001, 11, 3, 295. |
| 【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) | 32186 | (E)-1,4-dichloro-2-butene | 110-57-6 | C4H6Cl2 | 详情 | 详情 |
| (II) | 48853 | 4-(4-Bromophenyl)phenol; 4-(4'-Bromophenyl)phenol; 4-Bromo-4'-hydroxybiphenyl | 29558-77-8 | C12H9BrO | 详情 | 详情 |
| (III) | 48854 | 4-bromo-4'-[[(E)-4-chloro-2-butenyl]oxy]-1,1'-biphenyl; 4'-bromo[1,1'-biphenyl]-4-yl (E)-4-chloro-2-butenyl ether | C16H14BrClO | 详情 | 详情 | |
| (IV) | 48855 | (E)-4-[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]-2-butenyl acetate | C18H17BrO3 | 详情 | 详情 | |
| (V) | 48856 | (E)-4-[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]-2-buten-1-ol | C16H15BrO2 | 详情 | 详情 | |
| (VI) | 48857 | ethyl 3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-pentenoate | C20H21BrO3 | 详情 | 详情 | |
| (VII) | 48858 | 3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-penten-1-ol | C18H19BrO2 | 详情 | 详情 | |
| (VIII) | 36890 | 1,2,3-benzotriazin-4(3H)-one | C7H5N3O | 详情 | 详情 | |
| (IX) | 48859 | 3-(3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-pentenyl)-1,2,3-benzotriazin-4(3H)-one | C25H22BrN3O2 | 详情 | 详情 | |
| (X) | 48860 | 4'-[(2-[2-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]ethyl]-3-butenyl)oxy][1,1'-biphenyl]-4-carbonitrile | C26H22N4O2 | 详情 | 详情 | |
| (XI) | 48861 | 2-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butyric acid | C25H20N4O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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 |