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【结 构 式】 
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【药物名称】A-53385(anhydrous; free acid), Abbott-53385(anhydrous; free acid), A-56234 【化学名称】8-Chloro-3-(2-fluorophenyl)-5,6-dihydrofuro[3,2-f]]-1,2-benzisoxazole-6-carboxylic acid potassium salt monohydrate 【CA登记号】90247-09-9(anhydrous) 【 分 子 式 】C16H10ClFKNO5 【 分 子 量 】389.8152 |
【开发单位】Abbott (Originator) 【药理作用】Diuretics, RENAL-UROLOGIC DRUGS |
合成路线1
Formylation of 1,3-dimethoxybenzene (A) with DMF in the presence of POCl3 gives 2,4-dimethoxybenzaldehyde. Selective ether cleavage of this product with AlCl3 produces the corresponding salicylaldehyde (I), which is alkylated with ethyl chloroacetate to give (II). Ring closure of (II) under phase-transfer conditions leads to a benzofuran derivative from which the corresponding dihydrobenzofuran (III) is obtained by catalytic hydrogenation over Pd/C. Use of excess AlCl3 at room temperature during the Friedel-Crafts acylation step cleaves the methyl ether, and treatment of the crude product with HBr in acetic acid gives (IV) in 93% overall yield. The oximation reaction requires prolonged heating with excess hydroxylamine hydrochloride, but, after esterification of the crude oxime, a 90% yield (V) is obtained. In the cyclization leading to isoxazole (VI), the presence of pyridine increases the reaction rate and reduces formation of an oxazole, isomeric with (VI), which apparently occurs from a Beckman rearrangement with intramolecular capture by the phenol. Treatment of the crude oxime acetate with K2CO3 in DMF at 60 C gives isoxazole (VI) cleanly, in high yield. The remarkable step in the synthesis is the facile chlorination of (VI) with trichloroisocyanuric acid, utilizing all three chlorines from the reagent, leading to the corresponding 8-chloro derivative in nearly quantitative yield. Ester hydrolysis using KOH in water then gives A-56234.
| 【1】 Luther, R.R.; Plattner, J.J.; A-56234. Drugs Fut 1989, 14, 1, 9. |
| 【2】 Bunnell, P.R.; Plattner, J.J.; Fung, A.K.L.; et al.; Synthesis and pharmacological evaluation of Abbott (A)-53385: A new high ceiling salidiuretic and uricosuric agent. Diuretics 1984, 374-81. |
| 【3】 Plattner, J.J.; Fung, A.K.L.; Parks, J.A.; et al.; Substituted 5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acids: High-ceiling diuretics with uricosuric activity. J Med Chem 1984, 27, 8, 1016-26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 19555 | 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione | 87-90-1 | C3Cl3N3O3 | 详情 | 详情 |
| (I) | 19547 | 2-hydroxy-4-methoxybenzaldehyde | 673-22-3 | C8H8O3 | 详情 | 详情 |
| (II) | 19549 | ethyl 2-(2-formyl-5-methoxyphenoxy)acetate | C12H14O5 | 详情 | 详情 | |
| (III) | 19550 | ethyl 6-methoxy-2,3-dihydro-1-benzofuran-2-carboxylate | C12H14O4 | 详情 | 详情 | |
| (IV) | 19552 | 5-(2-fluorobenzoyl)-6-hydroxy-2,3,5,6-tetrahydro-1-benzofuran-2-carboxylic acid | C16H13FO5 | 详情 | 详情 | |
| (V) | 19553 | ethyl 5-[(2-fluorophenyl)(hydroxyimino)methyl]-6-hydroxy-2,3,5,6-tetrahydro-1-benzofuran-2-carboxylate | C18H18FNO5 | 详情 | 详情 | |
| (VI) | 19554 | ethyl 3-(2-fluorophenyl)-5,6-dihydrofuro[3,2-f][1,2]benzisoxazole-6-carboxylate | C18H14FNO4 | 详情 | 详情 | |
| (C) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
合成路线2
Catalytic hydrogenation of banzofuran (I) produces high yields of the dihydrobenzofuran (II) with some contamination of fully saturated material. Use of excess AlCl3 at room temperature during the Friedel Crafts' acylation step cleaves the methyl ether, and treatment of the crude product with HBr in acetic acid gives (III) in 93% overall yield. The oximation reaction requires prolonged heating with excess hydroxylamine hydrochloride, but after esterification of the crude oxime, a 90% yield of (IV) is obtained. In the cyclization leading to isoxazole (V) the presence of pyridine increases the reaction rate and reduces formation of an oxazole, isomeric with (V), which apparently occurs from a Beckmann rearrangement with intramolecular capture by the phenol. Treatment of the crude oxime acetate with K2CO3 in DMF at 60 C gives the isoxazole (V) cleanly, in high yield. The remarkable step in this synthesis is the facile chlorination of (V) with trichloroisocyanuric acid (B), utilizing all three chlorines from the reagent, leading to pure title compound in nearly quantitative yield.
| 【1】 Mannhold, R.; ABBOTT-53385. Drugs Fut 1985, 10, 5, 363. |
| 【2】 Bunnell, P.R.; Plattner, J.J.; Fung, A.K.L.; et al.; Synthesis and pharmacological evaluation of Abbott (A)-53385: A new high ceiling salidiuretic and uricosuric agent. Diuretics 1984, 374-81. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
| (B) | 19555 | 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione | 87-90-1 | C3Cl3N3O3 | 详情 | 详情 |
| (I) | 29156 | ethyl 6-methoxy-1-benzofuran-2-carboxylate | C12H12O4 | 详情 | 详情 | |
| (II) | 19550 | ethyl 6-methoxy-2,3-dihydro-1-benzofuran-2-carboxylate | C12H14O4 | 详情 | 详情 | |
| (III) | 29157 | 5-(2-fluorobenzoyl)-6-hydroxy-2,3-dihydro-1-benzofuran-2-carboxylic acid | C16H11FO5 | 详情 | 详情 | |
| (IV) | 29158 | ethyl 5-[(2-fluorophenyl)(hydroxyimino)methyl]-6-hydroxy-2,3-dihydro-1-benzofuran-2-carboxylate | C18H16FNO5 | 详情 | 详情 | |
| (V) | 19554 | ethyl 3-(2-fluorophenyl)-5,6-dihydrofuro[3,2-f][1,2]benzisoxazole-6-carboxylate | C18H14FNO4 | 详情 | 详情 |