【结 构 式】 |
【分子编号】48857 【品名】ethyl 3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-pentenoate 【CA登记号】 |
【 分 子 式 】C20H21BrO3 【 分 子 量 】389.28894 【元素组成】C 61.71% H 5.44% Br 20.53% O 12.33% |
合成路线1
该中间体在本合成路线中的序号:(VI)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2
该中间体在本合成路线中的序号:(VI)Alternatively, intermediate (VI) can be obtained as follows: 1,4-Dichloro-2-butene (I) is condensed with p-bromophenol (XII) by means of Cs2CO3 in acetonitrile to give compound (XIII), which is then converted into acetate (XIV) after treatment with ammonium tetrabutyl acetate in refluxing acetone. Saponification of (XIV) with NaOH in MeOH affords alcohol (XV), which is then subjected to Claisen rearrangement by refluxing in ethyl orthoacetate in propionic acid to provide ester (XVI). Reduction of (XVI) with LiAlH4 Et2O gives alcohol (XVII), which is finally condensed with 4-bromophenyltributyl tin (XVIII) by means of Pd(PPh3)4 and LiCl in toluene.
【1】 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 |
(VI) | 48857 | ethyl 3-[[(4'-bromo[1,1'-biphenyl]-4-yl)oxy]methyl]-4-pentenoate | C20H21BrO3 | 详情 | 详情 | |
(XII) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
(XIII) | 48862 | 1-bromo-4-[[(E)-4-chloro-2-butenyl]oxy]benzene; 4-bromophenyl (E)-4-chloro-2-butenyl ether | C10H10BrClO | 详情 | 详情 | |
(XIV) | 48863 | (E)-4-(4-bromophenoxy)-2-butenyl acetate | C12H13BrO3 | 详情 | 详情 | |
(XV) | 48864 | (E)-4-(4-bromophenoxy)-2-buten-1-ol | C10H11BrO2 | 详情 | 详情 | |
(XVI) | 48865 | ethyl 3-[(4-bromophenoxy)methyl]-4-pentenoate | C14H17BrO3 | 详情 | 详情 | |
(XVII) | 48866 | 3-[(4-bromophenoxy)methyl]-4-penten-1-ol | C12H15BrO2 | 详情 | 详情 | |
(XVIII) | 48867 | (4-bromophenyl)(tributyl)stannane | C18H31BrSn | 详情 | 详情 |