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【结 构 式】 
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【药物名称】WAY-141608 【化学名称】1-[6,11-Dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl]-1-[4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)phenyl]methanone 【CA登记号】220602-65-3 【 分 子 式 】C24H18F3N5O 【 分 子 量 】449.43916 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antidiuretics, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Vasopressin V2 Agonists |
合成路线1
Condensation between 1,2-phenylenediamine (I) and 2-chloronicotinic acid (II) in refluxing cyclohexanol generated the tricyclic system (III). Reduction of keto group of (III) with borane-dimethyl sulfide complex afforded 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (IV). Acid chloride (VI), prepared from 4-fluoro-2-(trifluoromethyl)benzoic acid (V), was then condensed with tricyclic amine (IV) to produce amide (VII). Finally, displamecement of the 4-fluoro group of (VII) by the sodium salt of 3-methylpyrazole (VIII) in hot DMF yielded a 5:1 mixture of the title 3-methylpyrazole derivative and its 5-methyl regioisomer (IX), which were separated by column chromatography.
| 【1】 Failli, A.A.; Steffan, R.J.; Sumsky, J.S.; et al.; Pyridobenzodiazepines: Synthesis and structure-activity relationship of a novel class of orally active vasopressin V2 receptor agonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 201. |
| 【2】 Failli, A.A.; Shumsky, J.S.; Steffan, R.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000059; WO 9906403 . |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 38946 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one | C12H9N3O | 详情 | 详情 | |
| (IV) | 38947 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine | C12H11N3 | 详情 | 详情 | |
| (V) | 38951 | 4-fluoro-2-(trifluoromethyl)benzoic acid | 141179-72-8 | C8H4F4O2 | 详情 | 详情 |
| (VI) | 38948 | 4-fluoro-2-(trifluoromethyl)benzoyl chloride | C8H3ClF4O | 详情 | 详情 | |
| (VII) | 38949 | 5,11-dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl[4-fluoro-2-(trifluoromethyl)phenyl]methanone | C20H13F4N3O | 详情 | 详情 | |
| (VIII) | 37998 | 3-methyl-1H-pyrazole | 1453-58-3 | C4H6N2 | 详情 | 详情 |
| (IX) | 38950 | 5,11-dihydro-6H-pyrido[2,3-b][1,5]benzodiazepin-6-yl[4-(5-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)phenyl]methanone | C24H18F3N5O | 详情 | 详情 |
合成路线2
In a modified procedure, 4-fluoro-2-(trifluoromethyl)benzoic acid (V) was converted to acid chloride (VI) and then esterified with methanol to give methyl ester (X). Condensation of (X) with 3-methylpyrazole (VIII) produced a mixture of regioisomeric pyrazoles (XI) and (XII) from which the major 3-methyl isomer (XI) could be isolated by either flash chromatography or by recrystallization from EtOAc-hexane. Basic hydrolysis of the methyl ester of (XI) gave acid (XIII), which was finally coupled with tricyclic amine (IV) via activation as the mixed anhydride with 2,4,6-trichlorobenzoic acid.
| 【1】 Failli, A.A.; Steffan, R.J.; Sumsky, J.S.; et al.; Pyridobenzodiazepines: Synthesis and structure-activity relationship of a novel class of orally active vasopressin V2 receptor agonists. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 201. |
| 【2】 Failli, A.A.; Shumsky, J.S.; Steffan, R.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000059; WO 9906403 . |
| 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) | 38947 | 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine | C12H11N3 | 详情 | 详情 | |
| (V) | 38951 | 4-fluoro-2-(trifluoromethyl)benzoic acid | 141179-72-8 | C8H4F4O2 | 详情 | 详情 |
| (VI) | 38948 | 4-fluoro-2-(trifluoromethyl)benzoyl chloride | C8H3ClF4O | 详情 | 详情 | |
| (VIII) | 37998 | 3-methyl-1H-pyrazole | 1453-58-3 | C4H6N2 | 详情 | 详情 |
| (X) | 38952 | methyl 4-fluoro-2-(trifluoromethyl)benzoate | C9H6F4O2 | 详情 | 详情 | |
| (XI) | 38953 | methyl 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoate | C13H11F3N2O2 | 详情 | 详情 | |
| (XII) | 38954 | methyl 4-(5-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoate | C13H11F3N2O2 | 详情 | 详情 | |
| (XIII) | 38955 | 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoic acid | C12H9F3N2O2 | 详情 | 详情 |
合成路线3
An additional improvement in the ratio of regioisomeric pyrazoles was achieved by displacement of 4-fluoro-2-(trifluoromethyl)benzonitrile (XIV) with 3-methylpyrazole (VIII) in the presence of potassium tert-butoxide to afford a 9:1 mixture of the desired 3-methylpyrazole derivative (XV) and its 5-methyl isomer. Direct recrystallization from EtOH provided pure (XV) that was then hydrolyzed to the carboxylic acid (XIII) by means of NaOH in H2O-EtOH.
| 【1】 Failli, A.A.; Shumsky, J.S.; Steffan, R.J. (American Home Products Corp.); Tricyclic vasopressin agonists. EP 1000059; WO 9906403 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 37998 | 3-methyl-1H-pyrazole | 1453-58-3 | C4H6N2 | 详情 | 详情 |
| (XIII) | 38955 | 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoic acid | C12H9F3N2O2 | 详情 | 详情 | |
| (XIV) | 38956 | 4-fluoro-2-(trifluoromethyl)benzonitrile | C8H3F4N | 详情 | 详情 | |
| (XV) | 38957 | 4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzonitrile | C12H8F3N3 | 详情 | 详情 |