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【结 构 式】 
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【分子编号】43806 【品名】ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate 【CA登记号】 |
【 分 子 式 】C14H12N2O3S 【 分 子 量 】288.32696 【元素组成】C 58.32% H 4.19% N 9.72% O 16.65% S 11.12% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Cyclization of 4-hydroxythiobenzamide (XIII) with 2-bromoacetoacetic acid ethyl ester (XIV) in refluxing ethanol provides 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XV), which is formylated by reaction with hexamethylenetetramine (HMTA) and polyphosphoric acid (PPA) in hot HOAc/water to afford 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI). Alkylation af (XVI) with isobutyl bromide (VI), K2CO3 and KI in DMF gives 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVII), which is treated with formic acid, sodium formate and hydroxylamine hydrochloride to give the already reported 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-catboxylic acid ethyl ester (IX). Finally, this compound is hydrolyzed with NaOH in THF/EtOH. Alternatively, 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVI) can also be treated first with formic acid, sodium formate and hydroxylamine hydrochloride to provide 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (XVIII), which is then alkylated with isobutyl bromide (VI), K2CO3 and KI in DMF to give the already reported 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (IX).
| 【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32. |
| 【2】 Miller, B. (American Cyanamid Co.); Thiazolylphenyl phosphates. US 3518279 . |
| 【3】 Watanabe, K.; Fujii, T.; Tanaka, T.; Kondo, S. (Teijin Ltd.); Preparation method of 2-(4-alkoxy-3-cyanophenyl)thiazol derivs., and novel intermediates for the synthesis of them. JP 1994329647 . |
| 【4】 Watanabe, K.; Yarino, T.; Hiramatsu, T. (Teijin Ltd.); Preparation method of 2-(4-alkoxy-3-cyanophenyl)thiazole derivs.. JP 1998045733 . |
| 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) | 24599 | 1-bromo-2-methylpropane | 78-77-3 | C4H9Br | 详情 | 详情 |
| (IX) | 43797 | ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C18H20N2O3S | 详情 | 详情 | |
| (XIII) | 43801 | 4-hydroxybenzenecarbothioamide | 25984-63-8 | C7H7NOS | 详情 | 详情 |
| (XIV) | 43802 | ethyl 2-bromo-3-oxobutanoate | C6H9BrO3 | 详情 | 详情 | |
| (XV) | 43803 | ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C13H13NO3S | 详情 | 详情 | |
| (XVI) | 43804 | ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C14H13NO4S | 详情 | 详情 | |
| (XVII) | 43805 | ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C18H21NO4S | 详情 | 详情 | |
| (XVIII) | 43806 | ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C14H12N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)
| 【1】 Zhang ZX,Xue MX, Zhao Y, et al. 2010.Synthesis of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. Shengyan Yaoke Daxue Xuebao, 27(5): 365～368. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 43804 | ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C14H13NO4S | 详情 | 详情 | |
| (I) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 21337 | ethyl 2-chloro-3-oxobutanoate | 609-15-4 | C6H9ClO3 | 详情 | 详情 |
| (IV) | 43803 | ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C13H13NO3S | 详情 | 详情 | |
| (VI) | 43806 | ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C14H12N2O3S | 详情 | 详情 | |
| (VII) | 24599 | 1-bromo-2-methylpropane | 78-77-3 | C4H9Br | 详情 | 详情 |
| (VIII) | 43797 | ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C18H20N2O3S | 详情 | 详情 |