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【结 构 式】 
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【分子编号】19370 【品名】methyl 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate 【CA登记号】 |
【 分 子 式 】C15H19NO4 【 分 子 量 】277.3202 【元素组成】C 64.97% H 6.91% N 5.05% O 23.08% |
合成路线1
该中间体在本合成路线中的序号：(V)Benzoxazinone (III) was obtained by the two-step condensation of methyl 3-amino-4-hydroxybenzoate (I) and 2-bromoisobutyryl bromide (II), first with NaHCO3 in H2O-EtOAc to afford the corresponding amide, and then cyclization with K2CO3 in DMF. Subsequent N-alkylation of (III) with 2-iodopropane (IV) in the presence of NaH in DMF at 60 C provided the isopropylated compound (V). Refluxing of (V) with an excess of guanidine (VI) in MeOH yielded the desired acylguanidine, which was finally converted to the mesylate salt upon treatment with methanesulfonic acid in isopropanol.
| 【1】 Yamamoto, T.; Hori, M.; Watanabe, I.; Tsutsui, H.; Harada, K.; Ikeda, S.; Maruo, J.; Morita, T.; Ohtaka, H.; Synthesis and quantitative structure-activity relationships of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidines as Na/H exchange inhibitors. Chem Pharm Bull 1998, 46, 11, 1716. |
| 【2】 Yamamoto, T.; et al.; An acid-catalyzed O,N-acyl migration and application to the synthesis of N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidine methanesulfonate (KB-R9032), a novel Na/H exchange inhibitor. Chem Pharm Bull 1999, 47, 1, 22. |
| 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) | 19366 | methyl 3-amino-4-hydroxybenzoate | 536-25-4 | C8H9NO3 | 详情 | 详情 |
| (II) | 19367 | 2-bromo-2-methylpropanoyl bromide | 20769-85-1 | C4H6Br2O | 详情 | 详情 |
| (III) | 19368 | methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate | C12H13NO4 | 详情 | 详情 | |
| (IV) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (V) | 19370 | methyl 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate | C15H19NO4 | 详情 | 详情 | |
| (VI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 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 alkylation of 3-amino-4-hydroxybenzoic acid methyl ester (I) with isopropyl iodide and NaHCO3 gives 4-hydroxy-3-(isopropylamino)benzoic acid methyl ester (II), which is esterified with 2-bromoisobutyryl bromide (III) and TEA to yield 4-(2-bromoisobutyryloxy)-3-(isopropylamino)benzoic acid methyl ester (IV). The O-N migration of the 2-bromoisobutyryl group of (IV) catalyzed by acetic acid affords the 2-bromoisobutyrylamide (V), which is cyclized by means of K2CO3 to provide 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid methyl ester (VI). Finally, this compound is condensed with guanidine and treated with MeSO3H to give the target mesylate.
| 【1】 Yamamoto, T.; et al.; An acid-catalyzed O,N-acyl migration and application to the synthesis of N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidine methanesulfonate (KB-R9032), a novel Na/H exchange inhibitor. Chem Pharm Bull 1999, 47, 1, 22. |
| 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) | 19366 | methyl 3-amino-4-hydroxybenzoate | 536-25-4 | C8H9NO3 | 详情 | 详情 |
| (II) | 36527 | methyl 4-hydroxy-3-(isopropylamino)benzoate | C11H15NO3 | 详情 | 详情 | |
| (III) | 19367 | 2-bromo-2-methylpropanoyl bromide | 20769-85-1 | C4H6Br2O | 详情 | 详情 |
| (IV) | 36528 | methyl 4-[(2-bromo-2-methylpropanoyl)oxy]-3-(isopropylamino)benzoate | C15H20BrNO4 | 详情 | 详情 | |
| (V) | 36529 | methyl 3-[(2-bromo-2-methylpropanoyl)(isopropyl)amino]-4-hydroxybenzoate | C15H20BrNO4 | 详情 | 详情 | |
| (VI) | 19370 | methyl 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate | C15H19NO4 | 详情 | 详情 | |
| (VII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |