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【结 构 式】 
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【分子编号】43675 【品名】10-ethyl 7-methyl 1,4-dioxa-7-azaspiro[4.5]decane-7,10-dicarboxylate 【CA登记号】 |
【 分 子 式 】C12H19NO6 【 分 子 量 】273.286 【元素组成】C 52.74% H 7.01% N 5.13% O 35.13% |
合成路线1
该中间体在本合成路线中的序号：(IX)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.
| 【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：(VI)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.
| 【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 |