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Name Grepafloxacin hydrochloride;OPC-17116;Vaxar;Raxar;Lungaskin
Chemical Name (±)-1-Cyclopropyl-6-fluoro-5-methyl-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride
CAS 161967-81-3
Related CAS 119914-60-2 (free base non-specified stereoch.)
Formula C19H23ClFN3O3
Structure
Formula Weight 395.86486
Stage 撤市-1999
Company Otsuka (Originator), GlaxoSmithKline (Licensee)
Activity/Mechanism Antibacterial Drugs, ANTIINFECTIVE THERAPY, DNA Gyrase Inhibitors, Quinolones
Syn. Route 3
Route 1
the methylation of 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (i) with methyl trifluoromethylsulfonate (ii) by means of diisopropylamine and butyllithium in thf gives 2-bromo-3,5,6-trifluoro-4-(trimethylsilyl)toluene (iii), which is carbonated with butyllithium and co2 in ether to yield 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzoic acid (iv). elimination of the silyl group with csf in acetonitrile affords the corresponding benzoic acid (v). the condensation of (v) with malonic acid monoethyl ester (vi) by means of oxalyl chloride and butyllithium in thf affords 3-(3,4,6-trifluoro-2-methylphenyl)-2-oxopropionic acid ethyl ester (vii), which by condensation with triethyl orthoformate in refluxing acetic anhydride is converted into the ethoxymethylene derivative (viii). the cyclization of (viii) with cyclopropylamine (ix) by means of sodium hydride in thf gives 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (x), which is hydrolyzed with refluxing 6n hcl to yield the corresponding free acid (xi) (1). finally, this compound is condensed with 2-methylpiperazine (xii) by means of triethylamine in refluxing acetonitrile.
List of intermediates No.
6-fluoro-8-hydroxy-2,3-dihydro-4h-chromen-4-one (ix)
2-[(e)-4-(1,3-benzodioxol-5-yl)-3-butenyl]-1h-isoindole-1,3(2h)-dione (xii)
(2s)-2-([[(3s,6s,9s,12s)-6-benzyl-12-[(tert-butoxycarbonyl)amino]-9-(1h-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-3-yl]carbonyl]amino)-4-methylpentanoic acid (i)
(2r)-2-[(tert-butoxycarbonyl)amino]-3-([(2s,3r,4s,5r,6r)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2h-pyran-2-yl]sulfanyl)propionic acid (ii)
(2s)-2-([[(3s,6s,9s,12s)-6-benzyl-12-[[(2r)-2-[(tert-butoxycarbonyl)amino]-3-([(2s,3r,4s,5r,6r)-3,4,5-tris(acetoxy)-6-[(acetoxy)methyl]tetrahydro-2h-pyran-2-yl]sulfanyl)propanoyl]amino]-9-(1h-indol-3-ylmethyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-3-yl]carbonyl]amino)-4-methylpentanoic acid (iii)
(2r,3r,4s,5r,6s)-3,5-bis(acetoxy)-2-[(acetoxy)methyl]-6-([[(1s,4s,7s,10s,13r,16s)-4-benzyl-7-(1h-indol-3-ylmethyl)-16-isobutyl-3,6,9,12,15,18,21-heptaoxo-2,5,8,11,14,17,20-heptaazabicyclo[8.8.4]docos-13-yl]methyl]sulfanyl)tetrahydro-2h-pyran-4-yl acetate (iv)
(1s,4s,7s,10s,13r,16s)-4-benzyl-7-(1h-indol-3-ylmethyl)-16-isobutyl-13-([[(2s,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]sulfanyl]methyl)-2,5,8,11,14,17,20-heptaazabicyclo[8.8.4]docosane-3,6,9,12,15,18,21-heptone (v)
ethyl 2-amino-4-nitrobenzoate (vi)
ethyl 2-(acetamido)-4-nitrobenzoate (vii)
ethyl 2-[acetyl(methyl)amino]-4-nitrobenzoate (viii)
4-hydroxy-1-methyl-7-nitro-2-oxo-1,2-dihydro-3-quinolinyl acetate (x)
4-(methoxymethoxy)-1-methyl-7-nitro-2-oxo-1,2-dihydro-3-quinolinyl acetate (xi)
Reference 1:
    ueda, h.; miyamoto, h.; yamashita, h.; tone, h. (otsuka pharmaceutical co., ltd.); benzoheterocyclic cpds. ep 0287951; ep 0565132; jp 1989230558; jp 1995138232; jp 1995165636; us 5563138; us 5591744 .
Reference 2:
    castaner, j.; prous, j.; opc-17116. drugs fut 1992, 17, 4, 286.
Reference 3:
    heifetz, c.l.; johnson, j.; hagen, s.e.; domagala, j.m.; synthesis and biological activity of 5-alkyl-1,7,8-trisubstituted-6-fluoroquinoline-3-carboxylic acids. j med chem 1991, 34, 3, 1155.

Route 2
the syntheses of the metabolites of grepafloxacin, 7-(2-aminoethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro quinoline-3-carboxylic acid (iii), 7-(2-aminopropylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (v), 7-amino-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid (viii), 7-(carboxymethylamino)-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydr oquinoline-3-carboxylic acid (xi), 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-7-(3-methylpiperazin-1-yl)-4-o xo-1,4-dihydroquinoline-3-carboxylic acid (xviii) and 7-amino-1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydroquino line-3-carboxylic acid (xx) have been reported:1) compound (iii): by condensation of 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid diacetoxyborane ester (i) with 2-(tert-butoxycarbonylamino)ethylamine (ii) by heating at 110 c followed by a treatment with hcl in ethanol/water.2) compound (v): by condensation of quinolone (i) with 2-(tert-butoxycarbonylamino)ethylamine (iv) by heating at 110 c, followed by hydrolysis with hcl as before.3) compound (viii): the condensation of quinolone (i) with 4-methoxybenzylamine (vii) by heating at 110 c gives 1-cyclopropyl-6-fluoro-7-(4-methoxybenzylamino)-5-methyl-4-oxo-1,4-dihy droquinoline-3-carboxylic acid (vii), which is then debenzylated by treatment with a mixture of trifluoroacetic acid and concentrated sulfuric acid.4) compound (xi): the condensation of quinolone (i) with glycine ethyl ester (ix) by heating at 110 c gives 1-cyclopropyl-7-(ethoxycarbonylmethylamino)-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (x), which is then saponified with naoh in refluxing ethanol.
List of intermediates No.
1-methoxy-2-naphthaldehyde (ix)
methyl 4-(4-[[5-(4-methylphenyl)-1h-1,2,4-triazol-3-yl]methyl]-1-piperazinyl)phenyl ether; 1-(4-methoxyphenyl)-4-[[5-(4-methylphenyl)-1h-1,2,4-triazol-3-yl]methyl]piperazine (ii)
3-(heptyloxy)-4-(methoxymethoxy)-1-methyl-7-nitro-2(1h)-quinolinone (i)
7-amino-3-(heptyloxy)-4-hydroxy-1-methyl-2(1h)-quinolinone (iii)
4-[(e)-3-chloro-3-oxo-1-propenyl]-2,6-dimethoxyphenyl acetate (iv)
4-((e)-3-[[3-(heptyloxy)-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-7-quinolinyl]amino]-3-oxo-1-propenyl)-2,6-dimethoxyphenyl acetate (v)
(3s,5r,8r,9s,10s,13r,17r)-17-(3-furyl)-10,13-dimethylhexadecahydro-14h-cyclopenta[a]phenanthrene-3,14-diol (vi)
(3s,5r,8r,9s,10s,13r,17r)-3-(2,2-diethoxyethoxy)-17-(3-furyl)-10,13-dimethylhexadecahydro-14h-cyclopenta[a]phenanthren-14-ol (vii)
2-[[(3s,5r,8r,9s,10s,13r,14s,17r)-17-(3-furyl)-14-hydroxy-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]acetaldehyde (viii)
2-(2-[[(3s,5r,8r,9s,10s,13r,14s,17r)-17-(3-furyl)-14-hydroxy-10,13-dimethylhexadecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]ethyl)-1h-isoindole-1,3(2h)-dione (x)
(3s,5r,8r,9s,10s,13r,17r)-3-(2-aminoethoxy)-17-(3-furyl)-10,13-dimethylhexadecahydro-14h-cyclopenta[a]phenanthren-14-ol (xi)
Reference 1:
    otsubo, k.; kawano, y.; ohguro, k.; uchida, m.; ohtani, t.; ohmori, k.; matsubara, j.; morita, s.; synthesis of possible metabolites of 1-cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (grepafloxacin, opc-17116). chem pharm bull 1995, 43, 12, 2246.

Route 3
5) compound (xviii): the esterification of 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid (xii) with socl2/methanol gives the corresponding methyl ester (xiii), which is brominated with n-bromosuccinimide (nbs) and benzoyl peroxide (bpo) in refluxing ccl4 yielding the corresponding bromomethyl derivative (xiv). the reaction of (xiv) with sodium acetate in hot dmf affords the expected acetoxymethyl derivative (xv), which is saponified with k2co3 in methanol/water to give 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydroquinoline-3-c arboxylic acid (xvi). finally, this compound is condensed with 2-methylpiperazine (xvii) by heating at 110 c.6) compound (xx): the condensation of the hydroxymethylquinolone (xvi) with the benzylamine (vi) as before gives 6-fluoro-5-(hydroxymethyl)-4-(4-methoxybenzylamino)-4-oxo-1,4-dihydroqu inoline-3-carboxylic acid (xix), which is then debenzylated with trifluoroacetic acid an h2so4 as before.
List of intermediates No.
2-[(e)-4-(1,3-benzodioxol-5-yl)-3-butenyl]-1h-isoindole-1,3(2h)-dione (xvii)
(3s,5r,8r,9s,10s,13r,17r)-17-(3-furyl)-10,13-dimethylhexadecahydro-14h-cyclopenta[a]phenanthrene-3,14-diol (vi)
3-(3-pyridinyl)-beta-alanine (xii)
n-(2-phenylacetyl)-3-(3-pyridinyl)-beta-alanine (xiii)
(3s)-3-[(2-phenylacetyl)amino]-3-(3-pyridinyl)propionic acid (xiv)
(3s)-3-amino-3-(3-pyridinyl)propionic acid (xv)
methyl (3s)-3-amino-3-(3-pyridinyl)propanoate (xvi)
tert-butyl (3r)-3-([[(1s)-3-methoxy-3-oxo-1-(3-pyridinyl)propyl]amino]carbonyl)-1-piperidinecarboxylate (xviii)
methyl (3s)-3-[[(3r)piperidinylcarbonyl]amino]-3-(3-pyridinyl)propanoate (xix)
1-boc-piperidin-4-ylpropionic acid; 3-[1-(tert-butoxycarbonyl)-4-piperidinyl]propionic acid (xx)
Reference 1:
    otsubo, k.; kawano, y.; ohguro, k.; uchida, m.; ohtani, t.; ohmori, k.; matsubara, j.; morita, s.; synthesis of possible metabolites of 1-cyclopropyl-1,4-dihydro-6-fluoro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (grepafloxacin, opc-17116). chem pharm bull 1995, 43, 12, 2246.

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格帕沙星;英文名Grepafloxacin hydrochloride;OPC-17116;Vaxar;Raxar;Lungaskin;CAS[161967-81-3]

 
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