Isoguvacine, -Drug Synthesis Database

【结构式】

【药物名称】Isoguvacine

【化学名称】1,2,3,6-Tetrahydropyridine-4-carboxylic acid

【CA登记号】64603-90-3

【分子式】C₆H₉NO₂

【分子量】127.14413

【开发单位】University of Arizona (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, GABA(A) Receptor Agonists

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【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

The methylation of pyridine-4-carboxylic acid (X) gives the pyridinium iodide (XI), which is reduced with NaBH4 to yield 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester (XII). The desmethylation of (XII) with ethyl chloroformate (XIII) affords 1,23,6-tetrahydropyridine-1,4-dicarboxylic acid diethyl ester (XIV), which is finally hydrolyzed and monodecarboxylated with HCl and TEA.

参考文献中间体

【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)	43671	ethyl isonicotinate	1570-45-2	C₈H₉NO₂	详情	详情
(II)	43672	4-(ethoxycarbonyl)-1-methylpyridinium iodide		C₉H₁₂INO₂	详情	详情
(III)	43673	ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate		C₉H₁₅NO₂	详情	详情
(IV)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(V)	43674	diethyl 3,6-dihydro-1,4(2H)-pyridinedicarboxylate		C₁₁H₁₇NO₄	详情	详情

合成路线3

The reaction of pyridine-4-carboxylic acid ethyl ester (I) with methyl iodide gives the pyridinium iodide (II), which is reduced with tritiated NaB3H4, yielding the tritiated tetrahydropyridine (III). The desmethylation of (III) with ethyl chloroformate (IV), followed by a treatment with HBr, affords the tritiated target compound.

参考文献中间体

【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】 Krogsgaard-Larsen, P.; Christensen, S.B.; Preparations of deuterium labeled guvacine and isoguvacine. J Label Compd Radiopharm 1980, 17, 191-202.

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)	43671	ethyl isonicotinate	1570-45-2	C₈H₉NO₂	详情	详情
(II)	43672	4-(ethoxycarbonyl)-1-methylpyridinium iodide		C₉H₁₂INO₂	详情	详情
(III)	43673	ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate		C₉H₁₅NO₂	详情	详情
(IV)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情

Extended Information