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Name Flumazepil;Flumazenil;RO-151788;Romazicon;Mazicon;Anexate
Chemical Name Ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
CAS 78755-81-4
Related CAS
Formula C15H14FN3O3
Structure
Formula Weight 303.29553
Stage 上市-1987
Company Roche (Originator), Yamanouchi (Licensee)
Activity/Mechanism Antagonists to Benzodiazepines, Specific Antidotes, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, GABA(A) BZ Site Receptor Antagonists
Syn. Route 3
Route 1
the oxidation of 2-nitro-5-fluorotoluene (i) with kmno4 in water gives 2-nitro-5-fluorobenzoic acid (ii), which by reduction with h2 over pd/c in methanol - aqueous hcl yields 2-amino-5-fluorobenzoic acid (iii). the reaction of (iii) with phosgene in thf aqueous hcl affords 5-fluoroisatoic acid anhydride (iv), which by cyclization with n-methylglycine (v) in oms at 100 c affords 7-fluoro-4-methyl-3,4-dihydro-2h-1,4-benzodiazepin-2,5(1h)-dione (vi). finally, this compound is cyclized again with ethyl isocyanacetate (vii) by means of potassium tert-butylate and diethyl chlorophosphate in dmf.
List of intermediates No.
6,7-dichloro-5,8-dimethoxynaphthoquinone (v)
ethyl (3r)-3-hydroxy-5-(trimethylsilyl)-4-pentynoate (vii)
4-nitrobenzyl (2s,4s)-2-[[(3s,4s)-3,4-dihydroxypyrrolidinyl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate (i)
(3s)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-penten-3-ol (ii)
(5s)-5-isopropenyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (1s)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-2-propenyl ether (iii)
(3s)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-pentanone (iv)
diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate (vi)
Reference 1:
    haefely, w.; hunkeler, w.; kyburz, e.; mohler, h.; pieri, l.; polc, p.; gerecke, m. (f. hoffmann-la roche ag); imidazodiazepine derivatives. ep 0027214; gb 2060632; jp 1156968; us 4316839; us 4346033 .
Reference 2:
    blancafort, p.; castaner, j.; hillier, k.; serradell, m.n.; ro-15-1788. drugs fut 1982, 7, 6, 402.

Route 2
the cyclization of anhydride (iv) with n-(2,4-dimethoxybenzyl)glycine (viii) as before gives 7-fluoro-4-(2,4dimethoxybenzyl)-3,4-dihydro-2h-1,4-benzodiazepin-2,5(1h)-dione (ix), which by a new cyclization with (vii) as before is converted into ethyl-8-fluoro-5-(2,4dimethoxybenzyl)-5,6-dihydro-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (x). the deprotection of (x) with trifluoroacetic acid yields ethyl-8-fluoro-5,6-dihydro-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (xi), which is finally methylated with methyl iodide and nah in dmf.
List of intermediates No.
ethyl (3r)-3-hydroxy-5-(trimethylsilyl)-4-pentynoate (vii)
(3s)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-pentanone (iv)
tert-butyl(dimethyl)silyl (1s,2e)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((e,3s)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole (viii)
4-((1e,3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1s)-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether (ix)
(1s)-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate (x)
(4s,7r,8s,9s,16s)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione (xi)
Reference 1:
    haefely, w.; hunkeler, w.; kyburz, e.; mohler, h.; pieri, l.; polc, p.; gerecke, m. (f. hoffmann-la roche ag); imidazodiazepine derivatives. ep 0027214; gb 2060632; jp 1156968; us 4316839; us 4346033 .
Reference 2:
    blancafort, p.; castaner, j.; hillier, k.; serradell, m.n.; ro-15-1788. drugs fut 1982, 7, 6, 402.

Route 3
the reaction of 7-fluoro-4-methyl-2,3,4,5-tetrahydro-1h-1,4-benzodiazepine-2,5-dione (i) with pocl3 and n,n-dimethyl-p-toluidine in hot toluene gives 2-chloro-7-fluoro-4-methyl-4,5-dihydro-3h-1,4-benzodiazepin-5 one (ii), which is condensed with n-(dimethylaminomethylene)glycine ethyl ester (iii) (obtained by condensation of glycine ethyl ester (iv) with dimethylformamide (v) and tea in dichloromethane) to yield a mixture of intermediates (vi) and (vii). finally, these compounds are cyclized in refluxing acoh to provide the target flumazenil.
List of intermediates No.
1-methoxy-2-naphthaldehyde (iv)
diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate (i)
(2r,3r,4s,5r,6r)-2-(hydroxymethyl)-6-[(2-tetradecylhexadecyl)oxy]tetrahydro-2h-pyran-3,4,5-triol (v)
Reference 1:
    rogers-evans, m.; spurr, p.; hennig, m.; the isolation and use of a benzodiazepine iminochloride for the efficient construction of flumazenil. tetrahedron lett 2003, 44, 11, 2425.

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氟馬西尼;英文名Flumazepil;Flumazenil;RO-151788;Romazicon;Mazicon;Anexate;CAS[78755-81-4]

 
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