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【结 构 式】

【分子编号】43666

【品名】ethyl 4-[benzyl(2-ethoxy-2-oxoethyl)amino]butanoate

【CA登记号】

【 分 子 式 】C17H25NO4

【 分 子 量 】307.38984

【元素组成】C 66.43% H 8.2% N 4.56% O 20.82%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

The alcoholysis of 1-benzyl-2-pyrrolidinone (I) with HCl in ethanol gives 4-(benzylamino)butyric acid ethyl ester (II), which is condensed with ethyl 2-bromoacetate (III) to yield the tertiary amine (IV). The cyclization of (IV) by means of NaOEt 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 reduction of (VII) with H2 over Ni gives the cis-3-hydroxy-1,4-dicarboxylate (VIII), which is hydrolyzed and selectively decarboxylated with HCl, yielding cis-3-hydroxypiperidine-4-carboxylic acid (IX). Finally, this compound is dehydrated by means of HBr and TEA.

1 Christensen, V.; Krogsgaard-Larsen, P.; Falch, E.; Chemistry and pharmacology of the GABA agonists THIP (Gabodaxol) and isoguvacine. Drugs Fut 1984, 9, 8, 597.
2 Johnston, G.A.R.; Krogsgaard-Larsen, P.; Structure-activity studies on the inhibition of GABA binding to rat brain membranes by muscinol and related compounds. J Neurochem 1978, 30, 1377-1382.
3 Krogsgaard-Larsen, P.; Christensen, T.R.; GABA agonists. Synthesis and structure-activity studies on analogues of isoguvacine and THIP. Eur J Med Chem 1979, 14, 157-164.
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) 43669 4-ethyl 1-methyl (3S,4S)-3-hydroxy-1,4-piperidinedicarboxylate C10H17NO5 详情 详情
(IX) 43670 (3S,4S)-3-hydroxy-4-piperidinecarboxylic acid C6H11NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

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
Extended Information