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【结 构 式】

【药物名称】Febuxostat, TMX-67, TEI-6720

【化学名称】2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid

【CA登记号】144060-53-7

【 分 子 式 】C16H16N2O3S

【 分 子 量 】316.38152

【开发单位】Teijin (Originator), Ipsen (Licensee), TAP (Licensee)

【药理作用】METABOLIC DRUGS, Treatment of Disorders of Purine and Pyrimidine Metabolism, Treatment of Gout, Uricosurics, Xanthine Oxidase Inhibitors

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7

合成路线1

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.

参考文献 中间体
【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

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.

参考文献 中间体
【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

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).

参考文献 中间体
【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

　

参考文献 中间体
【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

　

参考文献 中间体
【1】 Canivet Jerome, Yamaguchi Junichiro, Ben Ikuya, et al. 2009. Nickel-catalyzed biaryl coupling of heteroarenes and aryl halides/triflates. Orangic Letters, 11(8): 1733～1736.
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) 12982 2-Methyl-1-propanol 78-83-1 C4H10O 详情 详情
(II) 67131 2-fluoro-5-iodobenzonitrile 　 C7H3FIN 详情 详情
(III) 67132 5-iodo-2-isobutoxybenzonitrile 　 C11H12INO 详情 详情
(IV) 67133 4-methylthiazole-5-carboxylic acid 20485-41-0 C5H5NO2S 详情 详情
(V) 12982 2-Methyl-1-propanol 78-83-1 C4H10O 详情 详情
(VI) 67134 tert-butyl 4-methylthiazole-5-carboxylate 　 C9H13NO2S 详情 详情

合成路线6

　

参考文献 中间体
【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7

　

参考文献 中间体
【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
Extended Information
Drug NewChemical Entity Original Patent(1)