1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione -Drug Synthesis Database

【结构式】

【分子编号】19555

【品名】1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione

【CA登记号】87-90-1

【分子式】C₃Cl₃N₃O₃

【分子量】232.40952

【元素组成】C 15.5% Cl 45.76% N 18.08% O 20.65%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(D)

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.

参考文献中间体

合成目标

【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

该中间体在本合成路线中的序号：(B)

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.

参考文献中间体

合成目标

【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

Extended Information