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【结 构 式】 
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【药物名称】Iguratimod, T-614, Careram 【化学名称】3-(Formylamino)-7-(methylsulfonamido)-6-phenoxy-4H-1-benzopyran-4-one 【CA登记号】123663-49-0 【 分 子 式 】C17H14N2O6S 【 分 子 量 】374.37493 |
【开发单位】Toyama (Originator), Dong-A (Licensee), Eisai (Licensee) 【药理作用】Antiarthritic Drugs, Disease-Modifying Drugs, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, NF-kappaB (NFKB) Activation Inhibitors |
合成路线1
The reduction of 3-nitro-4-phenoxyphenol (I) with Fe, aqueous HCl gives 3-amino-4-phenoxyphenol (II), which is acylated with methanesulfonyl chloride by means of pyridine in dichloromethane affording 3-(methylsulfonamido)-4-phenoxyphenol (III). The condensation of (III) with 3-chloropropionic acid (IV) by means of NaOH in water gives 3-[3-(methylsulfonamido)-4-phenoxyphenoxy]propionic acid (V), which is cyclized by means of polyphosphoric acid at 65-70 C yielding 7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one (VI). The bromination of (VI) with Br2 in CHCl3 affords 3-bromo-7-(methylsulfonamido)-6-phenoxy-3,4-dihydro-2H-1-benzopyran-4-one (VII), which is treated with sodium azide in DMF at 70-75 C giving 3-amino-7-(methylsulfonamido)-6-phenoxy-2H-1-benzopyran-4-one (VIII). Finally, this compound is formylated with formic acid in acetic anhydride.
| 【1】 Takano, S.; Yoshida, C.; Inaba, T.; Tanaka, K.; Takeno, R.; Nagaki, H.; Shimotori, T.; Makino, S. (Toyama Chemical Co., Ltd.); 4H-Benzopyran-4-one derivs. and their salts, their processes of production and pharmaceutical compsns. containing them. AU 8823489; CH 679397; FR 2621585; GB 2210879; JP 1995267943; US 4954518 . |
| 【2】 Mealy, N.; Prous, J.; Castaner, J.; T-614. Drugs Fut 1993, 18, 8, 714. |
| 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) | 13517 | 3-Nitro-4-phenoxyphenol | C12H9NO4 | 详情 | 详情 | |
| (II) | 13518 | 3-Amino-4-phenoxyphenol | C12H11NO2 | 详情 | 详情 | |
| (III) | 13519 | N-(5-Hydroxy-2-phenoxyphenyl)methanesulfonamide | C13H13NO4S | 详情 | 详情 | |
| (IV) | 13520 | 3-Chloropropionic acid | 107-94-8 | C3H5ClO2 | 详情 | 详情 |
| (V) | 13521 | 3-[3-[(Methylsulfonyl)amino]-4-phenoxyphenoxy]propionic acid | C16H17NO6S | 详情 | 详情 | |
| (VI) | 13522 | N-(4-Oxo-6-phenoxy-3,4-dihydro-2H-chromen-7-yl)methanesulfonamide | C16H15NO5S | 详情 | 详情 | |
| (VII) | 13523 | N-(3-Bromo-4-oxo-6-phenoxy-3,4-dihydro-2H-chromen-7-yl)methanesulfonamide | C16H14BrNO5S | 详情 | 详情 | |
| (VIII) | 13524 | N-(3-Amino-4-oxo-6-phenoxy-4H-chromen-7-yl)methanesulfonamide | C16H14N2O5S | 详情 | 详情 |
合成路线2
A preparative-scale synthetic route for T-614 has been reported: The reaction of 4-chloro-3-nitroanisole (I) with potassium phenolate in hot DMF gives 4-phenoxy-3-nitroanisole (II), which is reduced to the corresponding 3-amino compound (III) by treatment with Fe and HCl. The reaction of (III) with mesyl chloride in pyridine affords the sulfonamide (IV), which is acylated with 2-aminoacetonitrile (V) and AlCl3 in nitrobenzene/HCl giving the 2-aminoacetophenone (VI). Formylation of (VI) at the NH2 with acetic formic anhydride yields the formamide (VII), which is demethylated with AlCl3 and NaI in acetonitrile affording the phenol (VIII). Finally, this compound is cyclized with dimethylformamide dimethylacetal in DMF.
| 【1】 Yoshida, C.; Tanaka, K.; Nagaki, H.; Takeno, R.; Inaba, T.; Takano, S.; Synthesis and antiinflammatory activities of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models. Chem Pharm Bull 2000, 48, 1, 131. |
| 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) | 24772 | 1-chloro-4-methoxy-2-nitrobenzene | 10298-80-3 | C7H6ClNO3 | 详情 | 详情 |
| (II) | 39674 | 4-methoxy-2-nitrophenyl phenyl ether; 4-methoxy-2-nitro-1-phenoxybenzene | C13H11NO4 | 详情 | 详情 | |
| (III) | 39675 | 5-methoxy-2-phenoxyphenylamine; 5-methoxy-2-phenoxyaniline | C13H13NO2 | 详情 | 详情 | |
| (IV) | 39676 | N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide | C14H15NO4S | 详情 | 详情 | |
| (V) | 39680 | 2-aminoacetonitrile | C2H4N2 | 详情 | 详情 | |
| (VI) | 39677 | N-[4-(2-aminoacetyl)-5-methoxy-2-phenoxyphenyl]methanesulfonamide | C16H18N2O5S | 详情 | 详情 | |
| (VII) | 39678 | N-[4-[2-(formylamino)acetyl]-5-methoxy-2-phenoxyphenyl]methanesulfonamide | C17H18N2O6S | 详情 | 详情 | |
| (VIII) | 39679 | N-[4-[2-(formylamino)acetyl]-5-hydroxy-2-phenoxyphenyl]methanesulfonamide | C16H16N2O6S | 详情 | 详情 | |
| (IX) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |