A-53385(anhydrous; free acid), Abbott-53385(anhydrous; free acid), A-56234

合成路线: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.

参考文献标题:A-56234
文献作者:Luther,R.R.; Plattner,J.J.
参考来源:Drugs Fut 1989,14(1),9


合成路线: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.

参考文献标题:Substituted 5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acids: High-ceiling diuretics with uricosuric activity
文献作者:Plattner,J.J.; Fung,A.K.L.; Parks,J.A.; et al.
参考来源:J Med Chem 1984,27(8),1016-26


合成路线: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.

合成路线: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.
参考文献标题:Synthesis and pharmacological evaluation of Abbott (A)-53385: A new high ceiling salidiuretic and uricosuric agent
文献作者:Bunnell,P.R.; Plattner,J.J.; Fung,A.K.L.; et al.
参考来源:Diuretics 1984,374-81