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【结 构 式】 
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【分子编号】38925 【品名】1lambda(6)-pyrido[4,3-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione 【CA登记号】 |
【 分 子 式 】C6H5N3O3S 【 分 子 量 】199.19012 【元素组成】C 36.18% H 2.53% N 21.1% O 24.1% S 16.1% |
合成路线1
该中间体在本合成路线中的序号：(XI)The reaction of 4-hydroxypyridine-3-sulfonic acid (VI) with POCl3 and PCl5 gives 4-chloropyridine-3-sulfonyl chloride (VII), which is treated with ammonia at room temperature yielding the sulfonamide (VIII). The resulting sulfonamide (VIII) was heated with ammonia to afford 4-aminopyridine-3-sulfonamide (IX), which is cyclized with urea (X) to provide the pyridothiadiazinone (XI). The reaction of (XI) with P2S5 in pyridine gives the corresponding thione (XII), which is methylated with methyl iodide to furnish the methylsulfanyl compound (XIII). Finally, this compound (XIII) is condensed with the chiral intermediate (R)(-)-1,2-dimethylpropylamine (R)(-)-(I) to afford the chiral (R)(-)-target compound. The condensation of the intermediate methylsulfanyl compound (XIII) with the chiral intermediate (S)(+)-1,2-dimethylpropylamine (S)(+)-(I) to afford the chiral (S)(+)-target compound.
| 【1】 Pirotte, B.; et al.; 3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from rat oancreatic B-cells: a new class of potassium channel openers?. J Med Chem 1993, 36, 21, 3211-13. |
| 【2】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (R)(-)-(I) | 38922 | (1R)-1,2-dimethylpropylamine; (2R)-3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (S)(+)-(I) | 38923 | (1S)-1,2-dimethylpropylamine; (2S)-3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (VI) | 28520 | 4-hydroxy-3-pyridinesulfonic acid | C5H5NO4S | 详情 | 详情 | |
| (VII) | 28521 | 4-chloro-3-pyridinesulfonyl chloride | C5H3Cl2NO2S | 详情 | 详情 | |
| (VIII) | 22151 | 4-chloro-3-pyridinesulfonamide | C5H5ClN2O2S | 详情 | 详情 | |
| (IX) | 38924 | 4-amino-3-pyridinesulfonamide | C5H7N3O2S | 详情 | 详情 | |
| (X) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (XI) | 38925 | 1lambda(6)-pyrido[4,3-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione | C6H5N3O3S | 详情 | 详情 | |
| (XII) | 38926 | 3-thioxo-3,4-dihydro-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(2H)-dione | C6H5N3O2S2 | 详情 | 详情 | |
| (XIII) | 38927 | 3-(methylsulfanyl)-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(4H)-dione | C7H7N3O2S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The reaction of 4-hydroxypyridine-3-sulfonic acid (I) with POCl3 and PCl5 gives 4-chloropyridine-3-sulfonyl chloride (II), which is treated with ammonia at room temperature yielding the sulfonamide (III). The resulting sulfonamide (VIII) was heated with ammonia to afford 4-aminopyridine-3-sulfonamide (IV), which is cyclized with urea (V) to provide the pyridothiadiazinone (VI). The reaction of (XI) with P2S5 in pyridine gives the corresponding thione (VII), which is methylated with methyl iodide to furnish the methylsulfanyl compound (VII) (2). Finally, this compound (VIII) is condensed with the chiral intermediate (R)(-)-1-methylpropylamine (R)(-)-(IX) to afford the chiral (R)(-)-target compound. The condensation of the intermediate methylsulfanyl compound (VIII) with the chiral intermediate (S)(+)-1-methylpropylamine (S)(+)-(IX) to afford the chiral (S)(+)-target compound.
| 【1】 Pirotte, B.; et al.; 3-(Alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides as powerful inhibitors of insulin release from rat oancreatic B-cells: a new class of potassium channel openers?. J Med Chem 1993, 36, 21, 3211-13. |
| 【2】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (R)(-)-(IX) | 38928 | (1R)-1-methylpropylamine; (2R)-2-butanamine | C4H11N | 详情 | 详情 | |
| (S)(+)-(IX) | 38929 | (1S)-1-methylpropylamine; (2S)-2-butanamine | C4H11N | 详情 | 详情 | |
| (I) | 28520 | 4-hydroxy-3-pyridinesulfonic acid | C5H5NO4S | 详情 | 详情 | |
| (II) | 28521 | 4-chloro-3-pyridinesulfonyl chloride | C5H3Cl2NO2S | 详情 | 详情 | |
| (III) | 22151 | 4-chloro-3-pyridinesulfonamide | C5H5ClN2O2S | 详情 | 详情 | |
| (IV) | 38924 | 4-amino-3-pyridinesulfonamide | C5H7N3O2S | 详情 | 详情 | |
| (V) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (VI) | 38925 | 1lambda(6)-pyrido[4,3-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione | C6H5N3O3S | 详情 | 详情 | |
| (VII) | 38926 | 3-thioxo-3,4-dihydro-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(2H)-dione | C6H5N3O2S2 | 详情 | 详情 | |
| (VIII) | 38927 | 3-(methylsulfanyl)-2H-pyrido[4,3-e][1,2,4]thiadiazine-1,1(4H)-dione | C7H7N3O2S2 | 详情 | 详情 |