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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information