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【结 构 式】 
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【药物名称】Tiazofurin, Tiazofurine, Cpd-5825, ICN-4221, CI-909, TCAR, NSC-286193, Tiazole 【化学名称】2-(beta-D-Ribofuranosyl)thiazole-4-carboxamide 【CA登记号】60084-10-8 【 分 子 式 】C9H12N2O5S 【 分 子 量 】260.27039 |
【开发单位】Valeant (Orphan Drug), Valeant (Originator) 【药理作用】Leukemia Therapy, Multiple Myeloma Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Antimetabolites, Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitors |
合成路线1
A new synthesis of thiazofurin has been described: The reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (I) with trimethylsilyl cyanide and SnCl4 in dichloromethane gives 2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl cyanide (II), which is treated with H2S gas and dimethylaminopyridine (DMAP) in ethanol yielding the corresponding thioamide (III). The carefully controlled cyclization of (III) with 3-bromopyruvic acid ethyl ester (IV) by means of NaHCO3 in dimethoxyethane, followed by treatment with trifluoroacetic anhydride and 2,6-lutidine in the same solvent affords 2-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)thiazole-4-carboxylic acid ethyl ester (V). Elimination of the benzoyl protecting groups of (V) with NaOEt in ethanol gives 2-(beta-D-ribofuranosyl)thiazole-4-carboxylic acid ethyl ester (VI). Which is finally treated with dry ammonia in methanol to afford the target amide.
| 【1】 Garcia-Munoz, G.; Stud, M.; Fuertes, M.; Synthesis of C-glycocyl thiazoles. J Org Chem 1976, 41, 4074. |
| 【2】 Ramasamy, K.S.; Averett, D.; A modified synthesis of tiazofurin. Nucleosides Nucleotides 1999, 18, 11-12, 2425. |
| 【3】 Eastland, G.; Tiazofurine. Drugs Fut 1985, 10, 4, 304. |
| 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) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (II) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (III) | 29144 | (2R,3S,4R,5R)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C27H23NO7S | 详情 | 详情 | |
| (IV) | 25183 | ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate | 70-23-5 | C5H7BrO3 | 详情 | 详情 |
| (V) | 29145 | ethyl 2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,3-thiazole-4-carboxylate | C11H15NO6S | 详情 | 详情 | |
| (VI) | 34062 | ethyl 2-[(2R,3S,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl]-1,3-thiazole-4-carboxylate | C32H27NO9S | 详情 | 详情 |
合成路线2
A new synthesis of tiazofurin has been reported: The cyclization of 5-O-benzoyl-2,3-O-isopropylidene-beta-D-ribofuranosyl-1-carbonitrile (I) with cysteine ethyl ester (II) by means of TEA in dichloromethane gives the thiazoline derivative (III), which is dehydrogenated with MnO2 in the same solvent to yield the corresponding thiazole derivative (IV). Removal of the isopropylidene protecting group of (IV) with TFA in THF/water affords 2-(5'-O-benzoyl-beta-D-ribofuranosyl)thiazole-4-carboxylic acid ethyl ester (V), which is finally debenzoylated and amidated by reaction with ammonia in methanol.
| 【1】 Ramasamy, K.S.; Bandaru, R.; Alverett, D.; A new synthetic methodology for tiazofurin. J Org Chem 2000, 65, 18, 5849. |
| 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) | 46544 | [(3aR,4R,6S,6aS)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl benzoate | C16H17NO5 | 详情 | 详情 | |
| (II) | 46545 | ethyl 2-amino-3-sulfanylpropanoate | C5H11NO2S | 详情 | 详情 | |
| (III) | 46546 | ethyl 2-[(3aS,4R,6R,6aR)-6-[(benzoyloxy)methyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-4,5-dihydro-1,3-thiazole-4-carboxylate | C21H25NO7S | 详情 | 详情 | |
| (IV) | 46547 | ethyl 2-[(3aS,4R,6R,6aR)-6-[(benzoyloxy)methyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-1,3-thiazole-4-carboxylate | C21H23NO7S | 详情 | 详情 | |
| (V) | 46548 | ethyl 2-[(2R,3R,4S,5R)-5-[(benzoyloxy)methyl]-3,4-dihydroxytetrahydro-2-furanyl]-1,3-thiazole-4-carboxylate | C18H19NO7S | 详情 | 详情 |
合成路线3
The reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (I) with Tms-CN and SnCl4 in dichloromethane gives the carbonitrile (II), which is cyclized with L-cysteine methyl ester (III) by means of TEA in dichloromethane to yield the thiazoline carboxylate (IV). The dehydrogenation of (IV) by means of BrCCl3 and DBU in the same solvent affords the thiazole carboxylate (V), which is finally treated with ammonia in methanol to hydrolyze the benzoate groups and form the carboxamide residue of the target tiazofurin.
| 【1】 Brown, R.S.; et al.; A concise route to tiazofurin. Tetrahedron Lett 2002, 43, 37, 6561. |
| 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) | 61497 | (2S,3R,4R,5R)-2-(acetyloxy)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (II) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (III) | 27413 | methyl (2R)-2-amino-3-sulfanylpropanoate | C4H9NO2S | 详情 | 详情 | |
| (IV) | 61498 | methyl 2-{(2R,3S,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl}-4,5-dihydro-1,3-thiazole-4-carboxylate | C31H27NO9S | 详情 | 详情 | |
| (V) | 61499 | methyl 2-{(2R,3S,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl}-1,3-thiazole-4-carboxylate | C31H25NO9S | 详情 | 详情 |