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【结 构 式】 
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【分子编号】52236 【品名】methyl 3-amino-4-[3-(benzyloxy)-4-methoxyphenyl]-2-thiophenecarboxylate 【CA登记号】 |
【 分 子 式 】C20H19NO4S 【 分 子 量 】369.4412 【元素组成】C 65.02% H 5.18% N 3.79% O 17.32% S 8.68% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.
| 【1】 McIntyre, J.A.; Castaner, J.; Bayes, M.; Tafenoquine Succinate. Drugs Fut 2003, 28, 9, 859. |
| 【2】 Ugwuegbulam, C.O.; Foy, J.E. (GlaxoSmithKline Inc.; GlaxoSmithKline plc); Process for the preparation of anti-malarial drugs. US 6479660; WO 9713753 . |
| 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) | 52237 | methyl 4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thiophenecarboxylate | C24H21NO4S | 详情 | 详情 | |
| (IV) | 33504 | 3-(trifluoromethyl)phenol | 98-17-9 | C7H5F3O | 详情 | 详情 |
| (VII) | 57243 | 2,6-dimethoxy-4-methyl-8-nitro-5-quinolinyl 3-(trifluoromethyl)phenyl ether; 2,6-dimethoxy-4-methyl-8-nitro-5-[3-(trifluoromethyl)phenoxy]quinoline | C19H15F3N2O5 | 详情 | 详情 | |
| (VIII) | 48081 | 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinamine; 2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinylamine | C19H17F3N2O3 | 详情 | 详情 | |
| (XXI) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (XXII) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (XXIII) | 52236 | methyl 3-amino-4-[3-(benzyloxy)-4-methoxyphenyl]-2-thiophenecarboxylate | C20H19NO4S | 详情 | 详情 | |
| (XXIV) | 52238 | [4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone | C27H26N2O3S | 详情 | 详情 | |
| (XXV) | 57239 | 2,5-dichloro-4-methyl-6-quinolinyl methyl ether; 2,5-dichloro-6-methoxy-4-methylquinoline | C11H9Cl2NO | 详情 | 详情 | |
| (XXVI) | 57240 | 5-chloro-2,6-dimethoxy-4-methylquinoline; 5-chloro-2-methoxy-4-methyl-6-quinolinyl methyl ether | C12H12ClNO2 | 详情 | 详情 | |
| (XXVII) | 57241 | 2-methoxy-4-methyl-6-quinolinyl methyl ether; 2,6-dimethoxy-4-methylquinoline | C12H13NO2 | 详情 | 详情 | |
| (XXVIII) | 57242 | 5-chloro-2,6-dimethoxy-4-methyl-8-nitroquinoline; 5-chloro-2-methoxy-4-methyl-8-nitro-6-quinolinyl methyl ether | C12H11ClN2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)In an alternative procedure, isovanillin (XI) was protected by O-benzylation, giving (XII), and its aldehyde group was subsequently reduced to alcohol (XIII) with NaBH4. The benzylic alcohol (XIII) was chlorinated to (XIV), which was converted to nitrile (XV) by chloride displacement with tetraethylammonium cyanide. Nitrile (XV) was subjected to Claisen condensation with ethyl formate, yielding (XVI), followed by sulfonylation with benzenesulfonyl chloride to afford (XVII), which was cyclized to the amino thiophene (XVIII) by treatment with ethyl thioglycolate (IV) as above. Condensation of (XVIII) with 2,5-dimethoxytetrahydrofuran (VI) produced the corresponding pyrrole derivative (XIX). After conversion of the ester group of (XIX) to amide (XX) upon heating with pyrrolidine (VIII), its cyclization with POCl3 furnished the thienopyrrolizinone (XXI). The O-benzyl protecting group of (XXI) was finally cleaved by treatment with HBr in HOAc.
| 【1】 Lisowski, V.; et al.; Design, synthesis and antiproliferative activity of tripentones: A new series of antitubulin agents. Bioorg Med Chem Lett 2001, 11, 16, 2205. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 12121 | (Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one | C13H15N3O | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XI) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (XII) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (XIII) | 23823 | 5-[4-hydroxy-2-(3-hydroxybutyl)-3,5,6-trimethylphenoxy]-2,2-dimethylpentanoic acid | C20H32O5 | 详情 | 详情 | |
| (XIV) | 52232 | benzyl 5-(chloromethyl)-2-methoxyphenyl ether; 2-(benzyloxy)-4-(chloromethyl)-1-methoxybenzene | C15H15ClO2 | 详情 | 详情 | |
| (XV) | 52233 | (3-Benzyloxy-4-methoxyphenyl)acetonitrile | C16H15NO2 | 详情 | 详情 | |
| (XVI) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XVII) | 52235 | (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyanoethenyl benzenesulfonate | C23H19NO5S | 详情 | 详情 | |
| (XVIII) | 52236 | methyl 3-amino-4-[3-(benzyloxy)-4-methoxyphenyl]-2-thiophenecarboxylate | C20H19NO4S | 详情 | 详情 | |
| (XIX) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XX) | 52238 | [4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone | C27H26N2O3S | 详情 | 详情 | |
| (XXI) | 52239 | 3-[3-(benzyloxy)-4-methoxyphenyl]-8H-thieno[2,3-b]pyrrolizin-8-one | C23H17NO3S | 详情 | 详情 |