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【结 构 式】 
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【分子编号】18803 【品名】5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione 【CA登记号】 |
【 分 子 式 】C29H23NO3S 【 分 子 量 】465.57256 【元素组成】C 74.82% H 4.98% N 3.01% O 10.31% S 6.89% |
合成路线1
该中间体在本合成路线中的序号：(V)This compound has been obtained by two related ways: 1) The condensation of 4-acetylbiphenyl oxime (I) with 2-(2-bromoethoxy)tetrahydropyran (II) by means of K2CO3 in hot dimethylacetamide gives the oxime derivative (III), which is treated with TsOH in methanol yielding 4-acetylbiphenyl O-(2-hydroxyethyl)oxime (IV). The condensation of (IV) with 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (V) by means of diethyl azodicarboxylate (DEAD) and PPh3 in THF affords (VI), the trityl derivative of the target compound, which is finally treated with hot aqueous ethanol to eliminate the trityl group. 2) The condensation of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (VIII) with N-(2-hydroxyethoxy)phthalimide (VII) by means DEAD gives the adduct (IX), which is treated with hydrazine to eliminate the phthalimido group yielding the substituted hydroxylamine (X). Finally, this compound is condensed with 4-acetylbiphenyl (XI) by means of TEA.
| 【1】 Yanagisawa, H.; Fujita, T.; Fujimoto, K.; Yoshioka, T.; Wada, K.; Oguchi, M.; Fujiwara, T.; Horikoshi, H. (Sankyo Co., Ltd.); Oxime derivs., their preparation and their therapeutic use. CA 2159938; EP 0708098; JP 1997048779; US 5703096; US 5780490; US 5972959 . |
| 【2】 Isobe, A.; Fujita, S.; Fujiwara, T.; Yanagisawa, H.; Takamura, M.; Yamada, E.; Hagisawa, Y.; Yachi, M.; Novel oximes having 5-benzyl-2,4-thiazolidinedione as antihyperglycemic agents: Synthesis and structure-activity relationship. Bioorg Med Chem Lett 2000, 10, 4, 373. |
| 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) | 36912 | 1-[1,1'-biphenyl]-4-yl-1-ethanone oxime | C14H13NO | 详情 | 详情 | |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 36913 | 1-[1,1'-biphenyl]-4-yl-1-ethanone O-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]oxime | C21H25NO3 | 详情 | 详情 | |
| (IV) | 36914 | 1-[1,1'-biphenyl]-4-yl-1-ethanone O-(2-hydroxyethyl)oxime | C16H17NO2 | 详情 | 详情 | |
| (V) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (VI) | 36915 | 5-[4-[2-([[(E)-1-[1,1'-biphenyl]-4-ylethylidene]amino]oxy)ethoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C45H38N2O4S | 详情 | 详情 | |
| (VII) | 36908 | 2-(2-hydroxyethoxy)-1H-isoindole-1,3(2H)-dione | C10H9NO4 | 详情 | 详情 | |
| (VIII) | 26462 | 5-(4-hydroxybenzyl)-1,3-thiazolidine-2,4-dione | 74772-78-4 | C10H9NO3S | 详情 | 详情 |
| (IX) | 36909 | 2-(2-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]ethoxy)-1H-isoindole-1,3(2H)-dione | C20H16N2O6S | 详情 | 详情 | |
| (X) | 36910 | 5-[4-[2-(aminooxy)ethoxy]benzyl]-1,3-thiazolidine-2,4-dione | C12H14N2O4S | 详情 | 详情 | |
| (XI) | 36916 | 1-[1,1'-biphenyl]-4-yl-1-ethanone | 92-91-1 | C14H12O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)This compound has been obtained by two related ways: 1) The condensation of 3-acetyl-6-phenylpyridine oxime (I) with 2-(2-bromoethoxy)tetrahydropyran (II) by means of K2CO3 in hot dimethylacetamide gives the oxime derivative (III), which is treated with TsOH in methanol yielding 3-acetyl-6-phenylpyridine O-(2-hydroxyethyl)oxime (IV). The condensation of (IV) with 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (V) by means of diethyl azodicarboxylate (DEAD) and PPh3 in THF affords (VI), the trityl derivative of the target compound, which is finally treated with hot aqueous ethanol to eliminate the trityl group. 2) The condensation of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (VIII) with N-(2-hydroxyethoxy)phthalimide (VII) by means DEAD gives the adduct (IX), which is treated with hydrazine to eliminate the phthalimido group yielding the substituted hydroxylamine (X). Finally, this compound is condensed with 3-acetyl-6-phenylpyridine (XI) by means of TEA.
| 【1】 Yanagisawa, H.; Fujita, T.; Fujimoto, K.; Yoshioka, T.; Wada, K.; Oguchi, M.; Fujiwara, T.; Horikoshi, H. (Sankyo Co., Ltd.); Oxime derivs., their preparation and their therapeutic use. CA 2159938; EP 0708098; JP 1997048779; US 5703096; US 5780490; US 5972959 . |
| 【2】 Isobe, A.; Fujita, S.; Fujiwara, T.; Yanagisawa, H.; Takamura, M.; Yamada, E.; Hagisawa, Y.; Yachi, M.; Novel oximes having 5-benzyl-2,4-thiazolidinedione as antihyperglycemic agents: Synthesis and structure-activity relationship. Bioorg Med Chem Lett 2000, 10, 4, 373. |
| 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) | 36904 | 1-(6-phenyl-3-pyridinyl)-1-ethanone oxime | C13H12N2O | 详情 | 详情 | |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 36905 | 1-(6-phenyl-3-pyridinyl)-1-ethanone O-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]oxime | C20H24N2O3 | 详情 | 详情 | |
| (IV) | 36906 | 1-(6-phenyl-3-pyridinyl)-1-ethanone O-(2-hydroxyethyl)oxime | C15H16N2O2 | 详情 | 详情 | |
| (V) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (VI) | 36907 | 5-[4-[2-([[(E)-1-(6-phenyl-3-pyridinyl)ethylidene]amino]oxy)ethoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C44H37N3O4S | 详情 | 详情 | |
| (VII) | 36908 | 2-(2-hydroxyethoxy)-1H-isoindole-1,3(2H)-dione | C10H9NO4 | 详情 | 详情 | |
| (VIII) | 26462 | 5-(4-hydroxybenzyl)-1,3-thiazolidine-2,4-dione | 74772-78-4 | C10H9NO3S | 详情 | 详情 |
| (IX) | 36909 | 2-(2-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]ethoxy)-1H-isoindole-1,3(2H)-dione | C20H16N2O6S | 详情 | 详情 | |
| (X) | 36910 | 5-[4-[2-(aminooxy)ethoxy]benzyl]-1,3-thiazolidine-2,4-dione | C12H14N2O4S | 详情 | 详情 | |
| (XI) | 36911 | 1-(6-phenyl-3-pyridinyl)-1-ethanone | C13H11NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The target compound was obtained by several related ways. Indolylethanol (III) was either prepared by alkylation of indole (I) with methyl bromoacetate, followed by reduction of the resulting indolylacetate (II) with LiAlH4 or by alkylation of (I) with 2-bromoethanol. Alkylation of (III) with 4-fluorobenzaldehyde (IV) in the presence of NaH or condensation with 4-hydroxybenzaldehyde (V) under Mitsunobu conditions provided ether (VII). Alternatively, (VII) was prepared by alkylation of indole (I) with 4-(bromoethoxy)benzaldehyde (VI). Then, Knoevenagel condensation of aldehyde (VII) with 2,4-thiazolidinedione (VIII) in the presence of piperidinium benzoate in refluxing toluene with azeotropic removal of water yielded benzylidene compound (IX). Reduction of the olefinic double bond by either hydrogenation in the presence of an excess of Pd/C or by chemical reduction with Mg in MeOH provided the target benzyl compound. Alternatively, indolylethanol (III) was condensed with hydroxybenzyl compound (X) in the presence of tributyl phosphine and 1,1'-(azodicarbonyl)dipiperidine (ADDP) in benzene to give (XI), which was finally deprotected by hydrogenation in the presence of an excess of Pd/C in dioxan.
| 【1】 Lohray, B.B.; et al.; Novel indole containing thiazolidinedione derivatives as potent euglycemic and hypolipidaemic agents. Bioorg Med Chem Lett 1997, 7, 7, 785. |
| 【2】 Rao, K.N.; Reddy, A.K.; Reddy, P.G.; Vikramadityan, R.K.; Madhavan, G.R.; Bhushan, V.; Rajagopolan, R.; Mamidi, R.N.V.S.; Rajesh, B.M.; Jajoo, H.K.; Rao, B.P.; Murali, N.; Chakrabarti, R.; Subramaniam, S.; Lohray, B.B.; Novel euglycemic and hypolipidemic agent. J Med Chem 1998, 41, 10, 1619. |
| 【3】 Fujita, T.; Fujimoto, K.; Yoshioka, T.; Yanagisawa, H.; Fujiwara, T.; Horikoshi, H.; Oguchi, M.; Wada, K. (Sankyo Co., Ltd.); Heterocyclic cpds. having antidiabetic activity, their preparation and their use. CA 2146701; EP 0676398; JP 1995330728; US 5624935; US 5834501; US 5962470; US 6117893 . |
| 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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (II) | 18795 | methyl 2-(1H-indol-1-yl)acetate | C11H11NO2 | 详情 | 详情 | |
| (III) | 18796 | 2-(1H-indol-1-yl)-1-ethanol | C10H11NO | 详情 | 详情 | |
| (IV) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (V) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VI) | 18799 | 4-(2-bromoethoxy)benzaldehyde | 52191-15-8 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 18800 | 4-[2-(1H-indol-1-yl)ethoxy]benzaldehyde | C17H15NO2 | 详情 | 详情 | |
| (VIII) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (IX) | 18802 | 5-((E)-[4-[2-(1H-indol-1-yl)ethoxy]phenyl]methylidene)-1,3-thiazolidine-2,4-dione | C20H16N2O3S | 详情 | 详情 | |
| (X) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (XI) | 18804 | 5-[4-[2-(1H-indol-1-yl)ethoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C39H32N2O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Alkylation of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione (VII) with methyl bromoacetate (VIII) in the presence of cesium carbonate gave rise to the aryloxy acetate (IX). Subsequent cleavage of the N-trityl protecting group of (IX) was achieved by treatment with HOAc in aqueous dioxan at 80 C. The resulting ester (X) was finally condensed with phenylenediamine (VI) to produce the target benzimidazole.
| 【2】 Fujita, T.; Fujiwara, T.; Izumi, T. (Sankyo Co., Ltd.); Hydrochloride of fused-heterocycle cpd.. EP 1180519; JP 2001039976; US 2002111373; WO 0071540 . |
| 【1】 Fujita, T.; Wada, K.; Oguchi, M.; Yanagisawa, H.; Fujimoto, K.; Fujiwara, T.; Horikoshi, H.; Yoshioka, T. (Sankyo Co., Ltd.); Benzimidazole derivs., their preparation and their therapeutic use. CA 2177858; EP 0745600; JP 1997295970; JP 2000001487; US 5886014 . |
| 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) | 46877 | N-(2-amino-5-methoxyphenyl)-N-methylamine; 4-methoxy-N(2)-methyl-1,2-benzenediamine | C8H12N2O | 详情 | 详情 | |
| (VII) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (VIII) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (IX) | 46878 | methyl 2-[4-[(2,4-dioxo-3-trityl-1,3-thiazolidin-5-yl)methyl]phenoxy]acetate | C32H27NO5S | 详情 | 详情 | |
| (X) | 46879 | methyl 2-[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]acetate | C13H13NO5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Selective substitution of the 2-chloro group of 2,6-dichloro-3-nitropyridine (I) by methylamine gave 6-chloro-2-(methylamino)-3-nitropyridine (II). The 6-chloro group of (II) was then displaced by sodium methoxide to afford methyl ether (III). The nitro group of (III) was reduced by catalytic hydrogenation, and the resulting diamine (IV) was cyclized with glycolic acid to furnish the imidazopyridine (V). Mitsunobu coupling of alcohol (V) with 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione (VI) produced the corresponding ether (VII). The title compound was then obtained by acid deprotection of the trityl group of (VII), followed by conversion to the hydrochloride salt.
| 【2】 Wada, K.; Oguchi, M.; Honma, H.; et al.; Molecular design, synthesis, and hypoglycemic activity of a series of thiazolidine-2,4-diones. J Med Chem 2000, 43, 16, 3052. |
| 【1】 Fujita, T.; Fujimoto, K.; Yoshioka, T.; Yanagisawa, H.; Fujiwara, T.; Horikoshi, H.; Oguchi, M.; Wada, K. (Sankyo Co., Ltd.); Heterocyclic cpds. having antidiabetic activity, their preparation and their use. CA 2146701; EP 0676398; JP 1995330728; US 5624935; US 5834501; US 5962470; US 6117893 . |
| 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) | 13574 | 2,6-Dichloro-3-nitropyridine | 16013-85-7 | C5H2Cl2N2O2 | 详情 | 详情 |
| (II) | 44762 | N-(6-chloro-3-nitro-2-pyridinyl)-N-methylamine; 6-chloro-N-methyl-3-nitro-2-pyridinamine | C6H6ClN3O2 | 详情 | 详情 | |
| (III) | 44763 | 6-methoxy-N-methyl-3-nitro-2-pyridinamine; N-(6-methoxy-3-nitro-2-pyridinyl)-N-methylamine | C7H9N3O3 | 详情 | 详情 | |
| (IV) | 44764 | N-(3-amino-6-methoxy-2-pyridinyl)-N-methylamine; 6-methoxy-N(2)-methyl-2,3-pyridinediamine | C7H11N3O | 详情 | 详情 | |
| (V) | 44765 | (5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)methanol | C9H11N3O2 | 详情 | 详情 | |
| (VI) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (VII) | 44767 | 5-[4-[(5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)methoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C38H32N4O4S | 详情 | 详情 |