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【结 构 式】 
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【药物名称】 【化学名称】4-[4-(Trifluoromethylsulfonamido)butyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one dihydrochloride 【CA登记号】 【 分 子 式 】C14H17Cl2F3N4O3S 【 分 子 量 】449.28179 |
【开发单位】Takeda (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Nephritis, Agents for, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, PDGFR Inhibitors |
合成路线1
The chlorination of 5-(hydroxymethyl)imidazo[1,2-a]pyridine (I) with SOCl2 in dichloromethane gives the corresponding chloromethyl derivative (II), which is condensed with 1,4-diaminobutane (III) in refluxing acetonitrile to yield 5-(4-aminobutylaminomethyl)imidazo[1,2-a]pyridine (IV). The sulfonation of (IV) with N-phenyltrifluoromethylsulfonimide (V) and TEA in acetonitrile affords the sulfonamide (VI), which is protected with Boc2O in ethanol to provide the carbamate (VII). The acylation of (VII) with trichloroacetyl chloride and DMAP in refluxing chloroform gives the 3-trichloroacetyl derivative (VIII), which is finally cyclized by means of Tms-I and NaHCO3 in chloroform.
| 【1】 Ikemoto, T.; et al.; A practical synthesis of the chronic renal disease agent, 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives, using regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxy with N-chlorosuccinimide. Tetrahedron 2000, 56, 40, 7915. |
| 【2】 Takatani, M.; Shibouta, Y.; Tomimatsu, K.; Kawamoto, T. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0771319; JP 1996081467; WO 9602542 . |
| 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) | 42068 | imidazo[1,2-a]pyridin-5-ylmethanol | C8H8N2O | 详情 | 详情 | |
| (II) | 42069 | 5-(chloromethyl)imidazo[1,2-a]pyridine | C8H7ClN2 | 详情 | 详情 | |
| (III) | 42070 | 1,4-butanediamine; 4-aminobutylamine | 110-60-1 | C4H12N2 | 详情 | 详情 |
| (IV) | 42071 | N(1)-(imidazo[1,2-a]pyridin-5-ylmethyl)-1,4-butanediamine; N-(4-aminobutyl)-N-(imidazo[1,2-a]pyridin-5-ylmethyl)amine | C12H18N4 | 详情 | 详情 | |
| (V) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |
| (VI) | 42072 | trifluoro-N-[4-[(imidazo[1,2-a]pyridin-5-ylmethyl)amino]butyl]methanesulfonamide | C13H17F3N4O2S | 详情 | 详情 | |
| (VII) | 42073 | tert-butyl imidazo[1,2-a]pyridin-5-ylmethyl(4-[[(trifluoromethyl)sulfonyl]amino]butyl)carbamate | C18H25F3N4O4S | 详情 | 详情 | |
| (VIII) | 42074 | tert-butyl [3-(2,2,2-trichloroacetyl)imidazo[1,2-a]pyridin-5-yl]methyl(4-[[(trifluoromethyl)sulfonyl]amino]butyl)carbamate | C20H24Cl3F3N4O5S | 详情 | 详情 |
合成路线2
The reaction of ethyl chloroacetate (I) with ethyl formate (II) by means of potassium tert-butoxide in diisopropyl ether gives the 2-formylchloroacetate (III), which is cyclized with 6-methylpyridine-2-amine (IV) by means of conc. H2SO4, yielding 5-methylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (V). The chlorination of (V) with NCS in THF affords the chloromethyl derivative (VI), which is condensed with the monoprotected diamine (VII) by means of TEA to provide the adduct (VIII). The cyclization of (VIII) by means of NaOMe, TEA and NaI in DMF gives 4-[4-(benzyloxycarbonylamino)butyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one (IX), which is deprotected with H2 over Pd/C in MeOH, yielding the butylamine derivative (X). Finally, this compound is sulfonated with N-phenyltrifluoromethylsulfonimide (XI) and TEA in DMF.
| 【1】 Ikemoto, T.; et al.; A practical synthesis of the chronic renal disease agent, 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives, using regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxy with N-chlorosuccinimide. Tetrahedron 2000, 56, 40, 7915. |
| 【2】 Takatani, M.; Shibouta, Y.; Tomimatsu, K.; Kawamoto, T. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0771319; JP 1996081467; WO 9602542 . |
| 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) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (II) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (III) | 16600 | ethyl 2-chloro-3-oxopropanoate | C5H7ClO3 | 详情 | 详情 | |
| (IV) | 19678 | 6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine | 1824-81-3 | C6H8N2 | 详情 | 详情 |
| (V) | 42075 | ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate | C11H12N2O2 | 详情 | 详情 | |
| (VI) | 42076 | ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate | C11H11ClN2O2 | 详情 | 详情 | |
| (VII) | 42077 | benzyl 4-aminobutylcarbamate | 62146-62-7 | C12H18N2O2 | 详情 | 详情 |
| (VIII) | 42078 | ethyl 5-[[(4-[[(benzyloxy)carbonyl]amino]butyl)amino]methyl]imidazo[1,2-a]pyridine-3-carboxylate | C23H28N4O4 | 详情 | 详情 | |
| (IX) | 42079 | benzyl 4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-4-yl)butylcarbamate | C21H22N4O3 | 详情 | 详情 | |
| (X) | 42080 | 4-(4-aminobutyl)-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one | C13H16N4O | 详情 | 详情 | |
| (XI) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |