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Name Pazufloxacin;T-3761;GM-1171;Pasil
Chemical Name (S)-(-)-10-(1-Aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid
CAS 127045-41-4
Related CAS 127046-45-1 (monoHCl), 163680-77-1 (monomethanesulfonate)
Formula C16H15FN2O4
Structure
Formula Weight 318.30735
Stage 上市-2002
Company Toyama (Originator), Mitsubishi Pharma (Codevelopment)
Activity/Mechanism Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones
Syn. Route 3
Route 1
reaction of ethyl 2,3,4,5-tetrafluorobenzoate (i) with the anion of di-tert-butyl malonate followed by in situ decarboxylation with cf3co2h affords ethyl 4-carboxymethyl-2,3,5-trifluorobenzoate (ii), which is esterfied with diphenyldiazomethane to give ethyl 4-(diphenylmethoxycarbonylmethyl)-2,3,5-trifluorobenzoate (iii). compound (iii) is treated with p-formaldehyde in the presence of sodium methoxide to give ethyl 4-[1-(diphenylmethoxycarbonyl)-2-hydroxyethyl]-2,3,5-trifluorobenzoate (iv), which is dehydrated with mesyl chloride and triethylamine to give ethyl 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoate (v). cyclopropanation of (v) with trimethylsulfoxonium iodide affords ethyl 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoate (vii). treatment of (vii) with ethyl chlorocarbonate and sodium azide followed by reaction with benzyl alcohol affords ethyl 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoate (viii), which is hydrolyzed to 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid (ix) on treatment with naoh. reaction of (ix) with magnesium ethoxycarbonylacetate and 1,1-carbonyldiimidazole yields ethyl 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoylacetate (x) , which is then sequentially reacted with n,n-dimethylformamide dimethylacetal and (s)-2-amino-1-propanol to give (s)-ethyl 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)acrylate (xi). cyclization of (xi) with sodium hydride or with k2co3 (2) affords (s)-ethyl 10-[1-(benzyloxycarbonylamino)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (xii), which is hydrolyzed on treatment with sodium hydroxide to give (s)-10-[1-(benzyloxycarbonylamino)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (xiii). deprotection of (xiii) by hydrogenation over pd in acetic acid, followed by treatment with hydrochloric acid, affords the monohydrochloride of t-3761 (xiv), which is finally converted to free t-3761 with potassium hydroxide.
List of intermediates No.
2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoyl chloride (i)
1-(1-acetylcyclopropyl)-2-diazo-1-ethanone (ii)
(4s,5r)-4-(1-methoxy-1-methylethoxy)-5-methyl-2-cyclopenten-1-one (iii)
(2r,3s,3as,4r,7s,7as)-4,7-epoxy-3-(1-methoxy-1-methylethoxy)-2,7-dimethylspiro[perhydroindane-6,1-cyclopropane]-1,5-dione; (2r,3s,3as,4r,7s,7as)-4,7-epoxy-3-(1-methoxy-1-methylethoxy)-2,7-dimethylspiro[perhydroindane-6,1-cyclopropane]-1,5-dione (iv)
(3ar,4r,7s,7as)-4,7-epoxy-2,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1h-spiro[indene-6,1-cyclopropane]-1,5-dione; (3ar,4r,7s,7as)-4,7-epoxy-2,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1h-spiro[indene-6,1-cyclopropane]-1,5-dione (v)
(2r,3r,3ar,4r,7s,7as)-4,7-epoxy-2,3-dihydroxy-2,7-dimethylperhydrospiro[indene-6,1-cyclopropane]-15-dione (vi)
(3ar,5r,8ar)-4,5-dihydroxy-2-methoxy-5,7,8a-trimethyl-3b,4,5,6,8,8a-hexahydro-3ah-spiro[indeno[1,2-d][1,3]dioxole-6,1-cyclopropan]-8-one (vii)
(3ar,5r)-4-acetoxy-5-hydroxy-2,5,7-trimethyl-3a,4,5,6-tetrahydro-1h-spiro[indene-6,1-cyclopropan]-1-one (viii)
6(r)-6-hydroxy-2,4,6-trimethyl-6,7-dihydro-5h-spiro[indene-5,1-cyclopropan]-7-one; 6(r)-6-hydroxy-2,4,6-trimethyl-6,7-dihydro-5h-spiro[indene-5,1-cyclopropan]-7-one (ix)
methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-[[(trifluoromethyl)sulfonyl]oxy]-1-cyclohexene-1-carboxylate (x)
methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-cyclohexene-1-carboxylate (xi)
methyl (1s,3r)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate (xii)
(1s,3r)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid (xiii)
(1s,3r)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxamide (xiv)
(3s,3as,6ar)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1h)-one
Reference 1:
    narita, h.; todo, y.; nitta, j.; takagi, h.; iino, f.; miyajima, m.; fukuoka, y.; saikawa, i. (toyama chemical co., ltd.); pyridonecarboxylic acid derivs. and their salts, process for their preparation as well as antibacterial agent containing them. ch 680793; de 3913245; jp 1993043464; us 4990508 .
Reference 2:
    takakura, i.; yamakawa, t.; kitayama, i.; fujishima, t. (toyama chemical co., ltd.); dissolution method for quinolonecarboxylic acids or their salts. jp 1990264724 .
Reference 3:
    prous, j.; mealy, n.; castaner, j.; t-3761. drugs fut 1993, 18, 8, 717.

Route 2
a new synthesis of t-3761 has been described:the esterification of 2,3,4,5-tetrafluorobenzoic acid (i) with ethyl bromide and k2co3 in dmso gives the corresponding ethyl ester (ii), which is condensed with tert-butyl cyanoacetate (iii) by means of k2co3, yielding 4-(cyanomethyl)-2,3,5-trifluorobenzoic acid ethyl ester (v) through the intermediate (iv). the cyclopropanation of (v) with 1,2-dibromoethane and benzyltriethylammonium chloride and naoh in water/dichloromethane affords 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoic acid, which by treatment with h2o2 and naoh is converted to 4-(1-carbamoylcyclopropyl)-2,3,5-trifluorobenzoic acid (vii). degradation of amide (vii) with cl2 and naoh gives the corresponding 4-aminocyclopropyl derivative (viii), which is acetylated with acetic anhydride to the acetamide (ix). the reaction of (ix) with socl2 yields the acid chloride (x), which is condensed with malonic acid monoethyl ester potassium salt (xi) by means of triethylamine to afford 2-[4-(1-acetamidocyclopropyl)-2,3,5-trifluorobenzoyl]acetic acid ethyl ester (xii). the consecutive reaction of (xii) first with dimethylformamide dimethylacetal (xiii) in acetic acid and then with 2(s)-aminopropanol (xiv) gives the benzoylacrylic intermediate (xv), which, without isolation, is treated with k2co3 in dmso at 100 c to afford the ethyl ester of the acetylated t-3761 (xvi). finally, this compound is deprotected by successive treatment first with ethanolic naoh and then with hot 6n hcl.
List of intermediates No.
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl]acetyl chloride (xiii)
2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoic acid (ii)
d-methionine (i)
benzyl (2r)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate (iii)
[(3r)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide (iv)
benzyl (3r)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate (v)
benzyl (3r)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate (vi)
benzyl (3r)-2-hydroxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate (vii)
benzyl (3r)-2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate (viii)
1-ethoxy-3-methyl-1-(triisopropylsilyloxy)-1-butene (ix)
benzyl (2s,3r)-2-[(1s)-1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate (x)
benzyl (2s,3r)-3-amino-2-[(1s)-1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate (xi)
benzyl (3ar,6s)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2h)-carboxylate (xii)
(3s,3as,6ar)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1h)-one (xiv)
(e)-4-(1-piperidinyl)-2-butenoic acid (xv)
(2r)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid (xvi)
Reference 1:
    iino, f.; momonoi, k.; hayashi, k.; todo, y.; kuroda, h.; takagi, h.; narita, h.; takata, m.; practical synthesis of t-3761, (s)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7h-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. chem pharm bull 1994, 42, 12, 2629.

Route 3
a new synthesis for t-3761 has been described:the esterification of 2,3,4,5-tetrafluorobenzoic acid (i) with socl2 and ethanol gives ethyl 2,3,4,5-tetrafluorobenzoate (ii), which is condensed with di-tert-butyl malonate (iii) by means of nah in dmf and decarboxylated with hcl/trifluoroacetic acid to 4-(carboxymethyl)-2,3,5-trifluorobenzoic acid ethyl ester (iv). esterification of (iv) with diphenyldiazomethane in ether affords the corresponding ester (v), which is methylenated with bis(dimethylamino)methane (vi) and acetic anhydride in dmso to give 4-[1-(diphenylmethoxycarbonyl)vinyl]-2,3,5-trifluorobenzoic acid ethyl ester (vii). the cyclopropanation of (vii) with trimethylsulfoxonium iodide and potassium tert-butoxide [(ch3)2so=ch2] yields the cyclopropane compound (viii), which is selectively hydrolyzed with trifluoroacetic acid to 4-(1-carboxycyclopropyl)-2,3,5-trifluorobenzoic acid ethyl ester (ix). the decarboxylative amination of (ix) with ethyl chloroformate, sodium azide and benzyl alcohol gives 4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoic acid ethyl ester (x), which is saponified with naoh in dioxane/ethanol to the corresponding acid (xi). the condensation of (xi) with the magnesium salt of malonic acid mono-tert-butyl ester (xii) by means of carbonyldiimidazole (im2co) in thf affords the benzoylacetic ester (xiii), which is treated first with dimethylformamide dimethylacetal (xiv) in refluxing benzene and then with 2-amino-1-propanol (xv) to yield 2-[4-[1-(benzyloxycarbonylamino)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)-2-propenoic acid ethyl ester (xvi). the cyclization of (xvi) by means of k2co3 in hot dmf gives the pyridobenzoxazine (xvii), which is saponified with naoh in ethanol/dioxane to the corresponding free acid (xviii). finally, the amino group of (xviii) is deprotected by hydrogenation with h2 over pd/c
List of intermediates No.
2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl]acetyl chloride (xiv)
2-chloro-4-[(5-fluoro-2-methylbenzoyl)amino]benzoic acid (ii)
1-(1-acetylcyclopropyl)-2-diazo-1-ethanone (iv)
(4s,5r)-4-(1-methoxy-1-methylethoxy)-5-methyl-2-cyclopenten-1-one (v)
(3ar,4r,7s,7as)-4,7-epoxy-2,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1h-spiro[indene-6,1-cyclopropane]-1,5-dione; (3ar,4r,7s,7as)-4,7-epoxy-2,7-dimethyl-3a,4,5,6,7,7a-hexahydro-1h-spiro[indene-6,1-cyclopropane]-1,5-dione (vii)
(2r,3r,3ar,4r,7s,7as)-4,7-epoxy-2,3-dihydroxy-2,7-dimethylperhydrospiro[indene-6,1-cyclopropane]-15-dione (viii)
(3ar,5r,8ar)-4,5-dihydroxy-2-methoxy-5,7,8a-trimethyl-3b,4,5,6,8,8a-hexahydro-3ah-spiro[indeno[1,2-d][1,3]dioxole-6,1-cyclopropan]-8-one (ix)
6(r)-6-hydroxy-2,4,6-trimethyl-6,7-dihydro-5h-spiro[indene-5,1-cyclopropan]-7-one; 6(r)-6-hydroxy-2,4,6-trimethyl-6,7-dihydro-5h-spiro[indene-5,1-cyclopropan]-7-one (xi)
methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-[[(trifluoromethyl)sulfonyl]oxy]-1-cyclohexene-1-carboxylate (xiii)
d-methionine (i)
1-azepanecarbonyl chloride (iii)
(2s)-2-amino-3-[4-(benzyloxy)phenyl]propionic acid (vi)
2-azido-1-phenyl-1-ethanone (x)
(z)-2-azido-1-phenylethenyl 3-cyclopentylpropanoate (xii)
1-(3-nitrophenyl)piperazine (xv)
2-[4-[4-(3-nitrophenyl)-1-piperazinyl]butyl]tetrahydro-1h-pyrrolo[1,2-c]imidazole-1,3(2h)-dione (xvi)
2-[4-[4-(3-aminophenyl)-1-piperazinyl]butyl]tetrahydro-1h-pyrrolo[1,2-c]imidazole-1,3(2h)-dione (xvii)
2-diazo-2-phenylacetic acid methyl ester (xviii)
Reference 1:
    fukuoka, y.; nitta, j.; todo, y.; nishida, n.; saikawa, i.; narita, h.; miyajima, m.; yamashiro, y.; pyridonecarboxylic acids as antibacterial agents. viii. synthesis and structure-activity relationship of 7-(1-aminocyclopropyl)-4-oxo-1,8-naphthyridine-3-carboxylic acids and 7-(1-aminocyclopropyl)-4-oxoquinoline-3-carboxylic acids. chem pharm bull 1994, 42, 10, 2063.

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帕珠沙星;英文名Pazufloxacin;T-3761;GM-1171;Pasil;CAS[127045-41-4]

 
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