Roxindole mesilate, EMD-62100(free base), EMD-38362(HCl), EMD-49980, -Drug Synthesis Database

【结构式】

【药物名称】Roxindole mesilate, EMD-62100(free base), EMD-38362(HCl), EMD-49980

【化学名称】5-Hydroxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1H-indole methanesulfonate

【CA登记号】119742-13-1, 112192-04-8 (free base), 108050-82-4 (HCl)

【分子式】C₂₄H₃₀N₂O₄S

【分子量】442.5817

【开发单位】Merck KGaA (Originator)

【药理作用】Antidepressants, Antipsychotic Drugs, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors, 5-HT1A Receptor Agonists, Dopamine Autoreceptor Agonists, Prolactin Secretion Inhibitors

合成路线1 合成路线2

合成路线1

By demethylation of 5-methoxy-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1H-indole (I) with diisobutylaluminum hydride (DBH) in hot toluene. The methylated compound (I) can be obtained by two similar ways: a) By condensation of 3-(4-chlorobutyl)-5-methoxy-1H-indole (II), or 3-(4-bromobutyl)-5-methoxy-1H-indole (III) with 4-phenyl-1,2,3,6-tetrahydropyridine (IV) in acetonitrile at room temperature. b) By condensation of 4-(3-indolyl)butyric acid (V) with 4-phenyl-1,2,3,6-tetrahydropyridine (IV) by means of carbonyldiimdazole (CDI) in THF yielding 1-[4-(3-indolyl)butyryl]-4-phenyl-1,2,3,6-tetrahydropyridine (VI), followed by reduction of the carbonyl group of (VI) with LiAlH4 in THF.

参考文献中间体

【1】 Robinson, C.; Castaner, J.; Roxindole Mesylate. Drugs Fut 1995, 20, 12, 1228.
【2】 Hausberg, H.-H.; Bottcher, H.; Seyfried, C.; Bergmann, R. (Merck Patent GmbH); Use of hydroxyindole derivs. for the preparation of an antihypertensive agent. DE 3419935; EP 0166183; JP 1985258117; US 4711893 .
【3】 Hausberg, H.-H.; Koppe, V.; Poetsch, E.; Saiko, O.; Seyfried, C. (Merck Patent GmbH); Indolalkylamines, pharmaceutical compsns. containing them and process for their preparation. EP 0007399 .

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)	12999	5-Methoxy-3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indole; Methyl 3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indol-5-yl ether		C₂₄H₂₈N₂O	详情	详情
(II)	13000	3-(4-Chlorobutyl)-1H-indol-5-yl methyl ether; 3-(4-Chlorobutyl)-5-methoxy-1H-indole		C₁₃H₁₆ClNO	详情	详情
(III)	13001	3-(4-Bromobutyl)-1H-indol-5-yl methyl ether; 3-(4-Bromobutyl)-5-methoxy-1H-indole		C₁₃H₁₆BrNO	详情	详情
(IV)	13002	4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(V)	13003	4-(5-Methoxy-1H-indol-3-yl)butyric acid		C₁₃H₁₅NO₃	详情	详情
(VI)	13004	4-(5-Methoxy-1H-indol-3-yl)-1-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]-1-butanone		C₂₄H₂₆N₂O₂	详情	详情

合成路线2

A new synthesis of roxindole has been described: The condensation of 5-methoxyindole (I) with succinic anhydride (II) by means of methylmagnesium bromide in hot anisole gives the 4-oxobutyric acid derivative (III), which is condensed with the 4-phenyltetrahydropyridine (IV) by means of EDC and DIPEA in DMF yielding the butanedione (V). The reduction of (V) with LiAlH4 in refluxing THF affords intermediate (VI), which is finally demethylated with DIBAH in refluxing toluene.

参考文献中间体

【1】 Lange, J.H.M.; et al.; A straightforward synthetic approach for roxindole. Bioorg Med Chem Lett 1999, 9, 7, 1055.

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)	25902	1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole	1006-94-6	C₉H₉NO	详情	详情
(II)	11291	Dihydro-2,5-furandione; Succinic anhydride	108-30-5	C₄H₄O₃	详情	详情
(III)	30614	4-(5-methoxy-1H-indol-3-yl)-4-oxobutyric acid		C₁₃H₁₃NO₄	详情	详情
(IV)	13002	4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine	10338-69-9	C₁₁H₁₃N	详情	详情
(V)	30615	1-(5-methoxy-1H-indol-3-yl)-4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]-1,4-butanedione		C₂₄H₂₄N₂O₃	详情	详情
(VI)	12999	5-Methoxy-3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indole; Methyl 3-[4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]butyl]-1H-indol-5-yl ether		C₂₄H₂₈N₂O	详情	详情

Extended Information