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Name Xaliproden hydrochloride;SR-57746A;Xaprila
Chemical Name 1-[2-(2-Naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine hydrochloride
CAS 90494-79-4
Related CAS 135354-02-8 (free base)
Formula C24H23ClF3N
Structure
Formula Weight 417.90581
Stage III 期臨床
Company Sanofi-synthélabo (Orphan Drug), Sanofi-synthélabo (Originator)
Activity/Mechanism Alzheimers Dementia, Treatment of , Amyotrophic Lateral Sclerosis, Agents for, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Multiple Sclerosis, Agents for, Neurodegenerative Diseases, Treatment of, NEUROLOGIC DRUGS, 5-HT1A Receptor Agonists, Neurotrophic Factor Enhancers
Syn. Route 2
Route 1
the condensation of 4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (i) with 2-(2-naphthyl)acetyl chloride (ii) by means of triethylamine in dichloromethane gives 1-[2-(2-naphthyl)acetyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6 tetrahydropyridine (iii), which is finally reduced with lialh4 in ethyl ether.
List of intermediates No.
(4-methoxy-3-methyl-2-pyridinyl)methanol (i)
5-nitro-1h-benzimidazol-2-ylhydrosulfide; 2-mercapto-5-nitrobenzimidazole; 5-nitro-1h-benzimidazole-2-thiol (ii)
5-amino-1h-benzimidazol-2-ylhydrosulfide; 5-amino-1h-benzimidazole-2-thiol (iii)
Reference 1:
    castaner, j.; mucke, h.a.m.; sr-57746a. drugs fut 1998, 23, 6, 616.
Reference 2:
    nisato, d.; frigerio, m.; miranda, g.f. (midy spa; sanofi-synthelabo ); trifluoromethylphenyltetrahydropyridines with anorexigenic activity, a process for their preparation and compsns. ep 0101381 .

Route 2
a synthesis of [14c]-labeled sr-57746a has been described: the iodination of [14c6]-benzene (i) with nitric acid/i2 gives iodobenzene (ii), which is treated with sodium trifluoroacetate and cui yielding trifluoromethylbenzene (iii). the nitration of (iii) with sodium nitrate affords 3-(trifluoromethyl)nitrobenzene (iv), which is reduced with fe/hcl to the corresponding aniline (v). the reaction of (v) with tert-butyl nitrite and cubr2 provides 3-(trifluoromethyl)bromobenzene (vi), which is treated with mg in thf affording the corresponding grignard reagent (vii). the condensation of (vii) with piperidone (viii) gives the piperidol (ix), which is finally dehydrated in acidic medium.in order to aviod radioactive contamination during the purification of compounds iodobenzene (ii) and trifluoromethylbenzene (iii) by liquid chromatography, a safer route using less volatile compounds has been developed: the nitration of [14c6]-benzene (i) with nitric acid gives nitrobenzene (x), which is iodinated with ipy2bf4/cf3so3h yielding 3-iodonitrobenzene (xi). finally, this compound is trifluoromethylated with cf3sime3, cui and kf to provide 3-(trifluoromethyl)nitrobenzene (iv) already reported.
List of intermediates No.
2,3,6-trichloronaphthoquinone (vii)
ethyl 2-[(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate (i)
tert-butyl 2-bromo-2-methylpropanoate (x)
n-([(5s)-3-[3-fluoro-4-(1-oxohexahydro-1lambda(4)-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide (ii)
(5s)-5-(aminomethyl)-3-[3-fluoro-4-(1-oxohexahydro-1lambda(4)-thiopyran-4-yl)phenyl]-1,3-oxazolidin-2-one (iii)
n-[[(5s)-3-(3-fluoro-4-tetrahydro-2h-thiopyran-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide (iv)
tert-butyl (4r)-4-([[(1s)-1-(methoxycarbonyl)-3-(methylsulfanyl)propyl]amino]carbonyl)-5,5-dimethyl-1,3-thiazolidine-3-carboxylate (v)
methyl (2s)-2-([[(4r)-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate (vi)
tert-butyl (1s,2s)-1-[[methoxy(methyl)amino]carbonyl]-2-methylbutylcarbamate (viii)
methyl (2s)-2-[[((4r)-3-[(2s,3s)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]-5,5-dimethyl-1,3-thiazolidin-4-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate (ix)
(2r)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propionic acid (xi)
tert-butyl(dimethyl)silyl (1s)-1-{2-[(4-methoxybenzyl)oxy]ethyl}-3-butenyl ether; tert-butyl[((1s)-1-{2-[(4-methoxybenzyl)oxy]ethyl}-3-butenyl)oxy]dimethylsilane (i)
(3r)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]pentanal (ii)
(1r)-10,10-dimethyl-4-(4-pentenoyl)-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (iii)
(1r)-4-((2s)-2-{(1r,3r)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-hydroxy-5-[(4-methoxybenzyl)oxy]pentyl}-4-pentenoyl)-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (iv)
(1r)-4-{(2s)-2-[(1r,3r)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-1-(methoxymethoxy)pentyl]-4-pentenoyl}-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (v)
(2r)-2-[(1r,3r)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-1-(methoxymethoxy)pentyl]-4-penten-1-ol (vi)
(2r)-2-[(1r,3r)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-1-(methoxymethoxy)pentyl]-4-pentenyl 4-methylbenzenesulfonate (vii)
(5r,7r)-7-{2-[(4-methoxybenzyl)oxy]ethyl}-9,9,10,10-tetramethyl-5-[(1s)-1-methyl-3-butenyl]-2,4,8-trioxa-9-silaundecane; tert-butyl(dimethyl)silyl (1r,3r,4s)-1-{2-[(4-methoxybenzyl)oxy]ethyl}-3-(methoxymethoxy)-4-methyl-6-heptenyl ether (ix)
(3r,5r,6s)-1-[(4-methoxybenzyl)oxy]-5-(methoxymethoxy)-6-methyl-8-nonen-3-ol (x)
Reference 1:
    robic, n.; noel, j.p.; synthesis of [trifluoromethyl-[c-14(6)]-phenyl] sr 57746a. j label compd radiopharm 1999, 42, 2, 109.

今日江苏快3开奖结果走势图 www.xrqodn.com.cn 來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名鹽酸扎利羅登;英文名Xaliproden hydrochloride;SR-57746A;Xaprila;CAS[90494-79-4]

 
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