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【结 构 式】 
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【分子编号】43797 【品名】ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate 【CA登记号】 |
【 分 子 式 】C18H20N2O3S 【 分 子 量 】344.43448 【元素组成】C 62.77% H 5.85% N 8.13% O 13.94% S 9.31% |
合成路线1
该中间体在本合成路线中的序号：(IX)Reaction of 4-hydroxy-3-nitrobenzaldehyde (I) with hydroxylamine and sodium formate in refluxing formic acid gives 4-hydroxy-3-nitrobenzonitrile (II), which is treated with thioacetamide in hot DMF to yield the corresponding thiobenzamide (III). The cyclization of (III) with 2-chloroacetoacetic acid ethyl ester (IV) in refluxing ethanol affords 2-(4-hydroxy-3-nitrophenyl)-5-methylthiazole-4-carboxylic acid ethyl ester (V), which is alkylated at the phenolic group by means of isobutyl bromide (VI) and K2CO3 in hot DMF, providing the isobutyl ether (VII). The reduction of the NO2 group of (VII) with H2 over Pd/C in ethanol/ethyl acetate gives the expected amino derivative (VIII), which is converted into 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (IX) by diazotation with NaNO2/HCl and treatment with CuCN and KCN. Finally, this compound is hydrolyzed with NaOH in hot THF.
| 【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32. |
| 【2】 Kondo, S.; Fukushima, H.; Hasegawa, M.; Tsuchimoto, M.; Nagata, I.; Osada, Y.; Komoriya, K.; Yamaguchi, H. (Teijin Ltd.); 2-Arylthiazole deriv. and pharmaceutical compsn. containing the same. EP 0513379; JP 1993500083; US 5614520; WO 9209279 . |
| 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) | 18372 | 4-hydroxy-3-nitrobenzaldehyde | 3011-34-5 | C7H5NO4 | 详情 | 详情 |
| (II) | 43792 | 4-hydroxy-3-nitrobenzonitrile | 3272-08-0 | C7H4N2O3 | 详情 | 详情 |
| (III) | 43793 | 4-hydroxy-3-nitrobenzenecarbothioamide | C7H6N2O3S | 详情 | 详情 | |
| (IV) | 21337 | ethyl 2-chloro-3-oxobutanoate | 609-15-4 | C6H9ClO3 | 详情 | 详情 |
| (V) | 43794 | ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate | C13H12N2O5S | 详情 | 详情 | |
| (VI) | 24599 | 1-bromo-2-methylpropane | 78-77-3 | C4H9Br | 详情 | 详情 |
| (VII) | 43795 | ethyl 2-(4-isobutoxy-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate | C17H20N2O5S | 详情 | 详情 | |
| (VIII) | 43796 | ethyl 2-(3-amino-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C17H22N2O3S | 详情 | 详情 | |
| (IX) | 43797 | ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C18H20N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of 4-nitrobenzonitrile (X) with KCN in hot DMSO, followed by treatment with isobutyl bromide (VI) and K2CO3, gives 4-isobutoxybenzene-1,3-dicarbonitrile (XI), which is treated with thioacetamide in hot DMF to yield 3-cyano-4-isobutoxythiobenzamide (XII). Cyclization of (XII) with 2-chloroacetoacetic acid ethyl ester (IV) in refluxing ethanol affords 2-(3-cyano-4-isoutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (IX), which is hydrolyzed with NaOH in hot THF/water.
| 【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32. |
| 【2】 Hasegawa, M.; A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile. Heterocycles 1998, 47, 2, 857. |
| 【3】 Hasegawa, M.; Komoriya, K. (Teijin Ltd.); Cyano cpds. and their preparation method. JP 1994345724 . |
| 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) | 21337 | ethyl 2-chloro-3-oxobutanoate | 609-15-4 | C6H9ClO3 | 详情 | 详情 |
| (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 | |
| (X) | 43798 | 4-nitrobenzonitrile | 619-72-7 | C7H4N2O2 | 详情 | 详情 |
| (XI) | 43799 | 4-isobutoxyisophthalonitrile | C12H12N2O | 详情 | 详情 | |
| (XII) | 43800 | 3-cyano-4-isobutoxybenzenecarbothioamide | C12H14N2OS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)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4
该中间体在本合成路线中的序号：(X)
| 【1】 Feng MS, Cao YP, Han AX, et al.2009. Synthesis of 2-[3-cyano-4-(isobutoxy) phenyl]-4-methyl-5-thiazolecarboxylic acid. Zhongguo Xinyao Zazhi, 18(11): 1066～1069. |
| 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) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 43801 | 4-hydroxybenzenecarbothioamide | 25984-63-8 | C7H7NOS | 详情 | 详情 |
| (IV) | 21337 | ethyl 2-chloro-3-oxobutanoate | 609-15-4 | C6H9ClO3 | 详情 | 详情 |
| (V) | 43803 | ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C13H13NO3S | 详情 | 详情 | |
| (VII) | 67130 | ethyl 2-(4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate | 144060-97-9 | C17H21NO3S | 详情 | 详情 |
| (VIII) | 33491 | Dimethylformamide | 68-12-2 | C3H7NO | 详情 | 详情 |
| (IX) | 43805 | ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C18H21NO4S | 详情 | 详情 | |
| (X) | 43797 | ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C18H20N2O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)
| 【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 |
合成路线6
该中间体在本合成路线中的序号：(VI)
| 【1】 Qi YM, Jie Q, Zhang FM.2009. Preparation of 2-(3-cyanophenyl) thiazole derivatives as xanthine oxidase inhibitors for treatment of hyperuricemia, hyperuricemia-induced gout, arthritis, or heart failure. Farming Zhuanli Shenqing Gongkai Shuomingshu, CN 101386604. |
| 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) | 60542 | ethyl 4-nitrobenzoate | 99-77-4 | C9H9NO4 | 详情 | 详情 |
| (II) | 67135 | ethyl 3-cyano-4-isobutoxybenzoate | C14H17NO3 | 详情 | 详情 | |
| (III) | 67136 | 3-cyano-4-isobutoxybenzamide | C12H14N2O2 | 详情 | 详情 | |
| (IV) | 43800 | 3-cyano-4-isobutoxybenzenecarbothioamide | C12H14N2OS | 详情 | 详情 | |
| (V) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (VI) | 43797 | ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate | C18H20N2O3S | 详情 | 详情 |