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Name Naratriptan hydrochloride;GG-548;GR-85548A;GR-85548(free base);Amerge;Naramig
Chemical Name N-Methyl-2-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]ethanesulfonamide monohydrochloride
CAS 143388-64-1
Related CAS 121679-13-8 (free base), 121679-19-4 (HCl)
Formula C17H26ClN3O2S
Structure
Formula Weight 371.93267
Stage 上市-1997
Company GlaxoSmithKline (Originator), Sumitomo Pharmaceuticals (Licensee), Schwarz (Comarketer)
Activity/Mechanism Acute Attacks of Migraine, Treatment of, ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT1B Agonists, 5-HT1D Agonists
Syn. Route 1
Route 1
naratriptan can be obtained by several related ways:1) the reaction of 5-bromoindole (i) with 1-methylpiperidin-4-one (ii) by means of koh in methylated spirit (or methanol) at room temperature gives 5-bromo-3-(4-(hydroxy-1-methylpiperidin-4-yl)-1h-indole (iii) (1, 2), which is condensed with n-methylvinylsulfonamide (iv) by means of palladium acetate and tri-p-tolyl phosphine in hot (110 c) dmf to afford (e)-n-methyl-2-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1h-indol-5-yl]vinylsulfonamide (v). finally, this compound is hydrogenated with h2 over pd/c in dmf/water/hcl, dmf/water/methanol/hcl, or water/methanesulfonic acid.2) the reaction of indole (i) with piperidone (ii) or with 4-hydroxy-1-methylpiperidine (vi) by means of koh in refluxing methylated spirit or 1-propanol gives 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1h-indole (vii), which is then condensed with n-methylvinylsufonamide (iv) as before, yielding the substituted sulfonamide (v), already obtained.3) the hydrogenation of the tetrahydropyridine (vii) with h2 over pto2 in methanol/hcl gives 5-bromo-3-(1-methylpiperidin-4-yl)-1h-indole (viii), which is finally condensed with n-methylvinylsulfonamide (iv) as before yielding n-methyl-2-[3-(1-methylpiperidin-4-yl)-1h-indol-5-yl]vinylsulfonamide (xi). finally, this compound is hydrogenated with h2 over pd/c in ethanol/dmf/hcl.4) the reaction of 5-bromoindole (i) with sulfonamide (iv) by means of palladium acetate as before gives 2-(1h-indol-3-yl)-n-methylvinylsulfonamide (ix), which is condensed with piperidone (ii) by means of refluxing koh as before, yielding the substituted tetrahydropyridine (v), already obtained.5) the condensation of sulfonamide (ix) with piperidone (ii), by means of koh at room temperature as before gives n-methyl-2-[3-(4-hydroxy-1-methylpiperidin-4-yl)-1h-indol-3-yl] vinylsulfonamide (x), which is dehydrated to tetrahydropyridine (v) with koh in refluxing methylated spirit.6) the cyclization of 2-(4-hydrazinophenyl)-n-methylethanesulfonamide (xii) with 2-(1-methylpiperidin-4-yl)acetaldehyde (xiii) by means of hcl in water.7) the reaction of 2-(1h-indol-5-yl)-n-methylethanesulfonamide (xiv) with piperidone (ii) by means of koh in refluxing methanol, yielding n-methyl-2-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1h-indol-5-yl] ethylsulfonamide (xv), which is finally hydrogenated with h2 over pd/c in ethanol/dmf.
List of intermediates No.
5-fluoro-1-[6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1h,3h)-pyrimidinedione (ii)
4-(4-hydrazinophenyl)-4h-1,2,4-triazole (i)
(methoxymethyl)(triphenyl)phosphonium bromide (iii)
1-fluoro-3-[(e)-2-methoxyethenyl]benzene; (e)-2-(3-fluorophenyl)ethenyl methyl ether (iv)
3-(3-fluorophenyl)propanal (v)
3-(4-fluorophenyl)-2,5-dimethyl-1-(4-piperidinyl)-1h-indole (vi)
2-[4-[3-(4-fluorophenyl)-2,5-dimethyl-1h-indol-1-yl]-1-piperidinyl]acetonitrile (vii)
2-[4-[3-(4-fluorophenyl)-2,5-dimethyl-1h-indol-1-yl]-1-piperidinyl]-1-ethanamine (viii)
2-[(2-[4-[3-(4-fluorophenyl)-2,5-dimethyl-1h-indol-1-yl]-1-piperidinyl]ethyl)amino]acetonitrile (ix)
n-(2-aminoethyl)-n-(2-[4-[3-(4-fluorophenyl)-2,5-dimethyl-1h-indol-1-yl]-1-piperidinyl]ethyl)amine (x)
indole-3-acetic acid; 2-(1h-indol-3-yl)acetic acid; 3-indoleacetic acid (xi)
2-(1h-indol-3-yl)acetic acid ethyl ester (xii)
ethyl 2-[1-(4-fluorobenzyl)-1h-indol-3-yl]acetate (xiii)
2-[1-(4-fluorobenzyl)-1h-indol-3-yl]acetic acid (xiv)
4-pyridinamine; 4-aminopyridine (xv)
Reference 1:
    mealy, n.; castaner, j.; naratriptan. drugs fut 1996, 21, 5, 476.
Reference 2:
    oxford, a.w.; butina, d.; owen, m.r. (glaxo wellcome plc); indole derivs. au 8820692; ep 0303507; gb 2208646; jp 1989207288; us 4997841 .
Reference 3:
    blatcher, p.; carter, m.; hornby, r.; owen, m.r. (glaxo wellcome plc); process for the preparation of n-methyl-3-(1-methyl-4-piperidinyl)-1h-indole-5-ethanesulfonamide. wo 9509166 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名盐酸那拉曲坦;英文名Naratriptan hydrochloride;GG-548;GR-85548A;GR-85548(free base);Amerge;Naramig;CAS[143388-64-1]

 
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