methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】43677

【品名】methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate

【CA登记号】

【分子式】C₈H₁₀N₂O₄

【分子量】198.17848

【元素组成】C 48.49% H 5.09% N 14.14% O 32.29%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XI)

The ethanolysis of 1-benzylpyrrolidin-2-one (I) with HCl in ethanol gives 4-(benzylamino)butyric acid ethyl ester (II), which is alkylated with ethyl bromoacetate (III), yielding the tertiary amine (IV). The cyclization of (IV) by means of sodium ethoxide affords 1-benzyl-3-hydroxy-1,2,5,6-tetrahydropyridine-4-carboxylic acid ethyl ester (V), which by hydrogenolytic debenzylation, followed by reaction with methyl chloroformate (VI), affords the 1,4-dicarboxylate (VII). The reaction of (VII) with ethyleneglycol (VIII) and TsOH gives the cyclic ketal (IX), which is treated with hydroxylamine and NaOMe to yield the carbohydroxamic acid (X). The cyclization of (X) by means of H2SO4 affords 3-hydroxy-4,5,6,7-tetrahydropyrido[4,3-d]oxazole-6-carboxylic acid methyl ester (XI), which is finally decarboxylated by means of HBr and TEA.

参考文献中间体

合成目标

【1】 Krogsgaard-Larsen, P.; Muscimol analogues. II. Synthesis of some bicylic 3-isoxazol zwitterions. Acta Chem Scand 1977, B31, 584-588.
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Paton, D.M.; THIP. Drugs Fut 1980, 5, 5, 257.
【3】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.

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)	43664	1-benzyl-2-pyrrolidinone	5291-77-0	C₁₁H₁₃NO	详情	详情
(II)	43665	ethyl 4-(benzylamino)butanoate		C₁₃H₁₉NO₂	详情	详情
(III)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(IV)	43666	ethyl 4-[benzyl(2-ethoxy-2-oxoethyl)amino]butanoate		C₁₇H₂₅NO₄	详情	详情
(V)	43667	ethyl 1-benzyl-5-hydroxy-1,2,3,6-tetrahydro-4-pyridinecarboxylate		C₁₅H₁₉NO₃	详情	详情
(VI)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(VII)	43668	4-ethyl 1-methyl 5-hydroxy-3,6-dihydro-1,4(2H)-pyridinedicarboxylate		C₁₀H₁₅NO₅	详情	详情
(VIII)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(IX)	43675	10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate		C₁₂H₁₉NO₆	详情	详情
(X)	43676	methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate		C₁₀H₁₆N₂O₆	详情	详情
(XI)	43677	methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate		C₈H₁₀N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The methylation of intermediate 3-hydroxy-4,5,6,7-tetrahydropyrido[4,3-d]oxazole-6-carboxylic acid methyl ester (I) (see intermediate (XI) in the synthesis of scheme 28607501a) with diazomethane gives the methoxy compound (II), which is decarboxylated with KOH to yield 3-methoxy-4,5,6,7-tetrahydropyrido[4,3-d]oxazole (III). The nitrosation of (III) with HNO2 affords 3-methoxy-6-nitroso-4,5,6,7-tetrahydropyrido[4,3-d]oxazole (IV), which is tritiated with 3H2O and TEA to afford the tritiated intermediate (V). Finally, this compound is desmethylated with HBr to provide the target compound.

参考文献中间体

合成目标

【1】 Johansen, J.S.; Falch, E.; Krogsgaard-Larsen, P.; Deuterium labelling of the GABA agonists THIP, piperidine-4-sulphonic acid and the GABA uptake inhibitor THPO. J Label Compd Radiopharm 1982, 19, 689-702.
【2】 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43677	methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate	C₈H₁₀N₂O₄	详情	详情
(II)	43678	methyl 3-methoxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate	C₉H₁₂N₂O₄	详情	详情
(III)	43679	3-methoxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine; methyl 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-yl ether	C₇H₁₀N₂O₂	详情	详情
(IV)	43680	methyl 6-nitroso-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-yl ether; 3-methoxy-6-nitroso-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine	C₇H₉N₃O₃	详情	详情
(V)	43681		C₇H₉N₃O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

The deprotection of 1-benzyl-2-oxopiperidine-3-carboxylic acid ethyl ester (I) by hydrogenation with H2 over Pd/C in aq. ethanol gives 2-oxopiperidine-3-carboxylic acid ethyl ester (II), which is condensed with methyl chloroformate (III) and K2CO3 in water to yield 1-(methoxycarbonyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (IV). The reaction of (IV) with ethyleneglycol (V) and Ts-OH in refluxing benzene affords the ethylene ketal (VI), which is treated with hydroxylamine and KOH in methanol to provide the carbohydroxamic acid (VII). The cyclization of (VII) by means of hot conc. HCl or HClO4 gives 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylic acid methyl ester (VIII), which is finally treated with HBr in refluxing acetic acid and neutralized with TEA to yield the target isoxazolo-pyridine derivative.

参考文献中间体

合成目标

【1】 Krogsgaard-Larsen, P. (H. Lundbeck A/S); Heterocyclic cpds.. EP 0000167; EP 0000338; EP 0027279; EP 0028017; US 4278676; US 4301287 .

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)	57371	ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate		C₁₅H₁₉NO₃	详情	详情
(II)	57372	ethyl 3-oxo-4-piperidinecarboxylate		C₈H₁₃NO₃	详情	详情
(III)	16993	methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate	79-22-1	C₂H₃ClO₂	详情	详情
(IV)	57373	4-ethyl 1-methyl 3-oxo-1,4-piperidinedicarboxylate		C₁₀H₁₅NO₅	详情	详情
(V)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(VI)	43675	10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate		C₁₂H₁₉NO₆	详情	详情
(VII)	43676	methyl 10-[(hydroxyamino)carbonyl]-1,4-dioxa-7-azaspiro[4.5]decane-7-carboxylate		C₁₀H₁₆N₂O₆	详情	详情
(VIII)	43677	methyl 3-hydroxy-4,7-dihydroisoxazolo[5,4-c]pyridine-6(5H)-carboxylate		C₈H₁₀N₂O₄	详情	详情

Extended Information