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药物详细合成路线

Name Midazolam maleate;Ro-21-3981/003(HCl);Ro-21-3981/001;Versed;Hypnovel;Dormicum
Chemical Name 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine maleate
CAS 59467-94-6
Related CAS 59467-70-8 (free base), 59467-96-8 (HCl)
Formula C22H17ClFN3O4
Structure
Formula Weight 441.84989
Stage 上市-1982
Company Roche (Originator), Yamanouchi (Not Determined)
Activity/Mechanism PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, Benzodiazepines, GABA(A) BZ Site Receptor Agonists
Syn. Route 2
Route 1
the reaction of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2h-1,4-benzodiazepin-2-one (i) with methylamine by means of ticl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-methylamino-3h-1,4-benzodiazepine (ii), which by reaction with nano2 in acetic acid is converted into its n-nitroso derivative (iii). the treatment of (iii) with nitromethane and potassium tert-butoxide in dmf affords 7-chloro-5-(2-fluorophenyl)-2-nitromethylene-2h-1,4-benzodiazepine (iv), which is reduced with h2 over raney-ni in thf affording the 2-aminomethyl derivative (v).the acetylation of (v) with acetic anhydride in ch2cl2 gives the acetamide (vi), which is cyclized with polyphosphoric acid at 150 c yielding 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine (vii). the deshydrogenation of (vii) with mno2 in refluxing toluene affords 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine (viii), which is finally treated with maleic acid (a) in hot ethanol.
List of intermediates No.
methyl 1-methyl-5-nitro-1h-imidazol-2-yl sulfide; 1-methyl-2-(methylsulfanyl)-5-nitro-1h-imidazole (a)
methyl 2-(3-methyl-4-pyridinyl)acetate (i)
2-(aminomethyl)-5,6-dimethyl-2-indanamine; (2-amino-5,6-dimethyl-2,3-dihydro-1h-inden-2-yl)methylamine (ii)
(iii)
(iv)
(v)
n-(9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6-oxo-6,9-dihydro-1h-purin-2-yl)acetamide (vi)
4-(chloromethyl)-1,3-dioxolane (vii)
[2-(acetoxy)-1-(chloromethyl)ethoxy]methyl acetate (viii)
Reference 1:
    fryer, r.i.; walser, a.; benzo or heterocyclic fused imidazodiazepines and pharmaceutical compositions containing them. be 0833248; de 2540522; fr 2303016; gb 1527131; jp 51125099 .
Reference 2:
    dhaon, m.k. (abbott laboratories inc.); process for the preparation of midazolam. wo 0170744 .
Reference 3:
    thorpe, p.; castaner, j.; midazolam maleate. drugs fut 1978, 3, 11, 822.

Route 2
the reaction of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-one (i) with methylamine by means of ticl4 in refluxing benzene gives 7-chloro-5-(2-fluorophenyl)-2-(methylamino)-3h-1,4-benzodiazepine (ii), which is treated with nano2 and hoac to yield the nitroso derivative (iii). the condensation of (iii) with dimethyl malonate (iv) by means of potassium tert-butoxide in dmf affords 2-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1h-1,4-benzodiazepin-2-ylidene]malonic acid dimethyl ester (v), which is monodecarboxylated with koh in refluxing methanol, providing the corresponding acetate (vi). the reaction of (vi) with nano2 and hoac gives the hydroxyimino derivative (vii), which is reduced with h2 over rani in hot methanol to provide the expected amino derivative (viii). the cyclization of (viii) with triethyl orthoacetate (ix) and hcl in refluxing ethanol affords 8-chloro-6-(2-fluorophenyl)-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester (x), which is hydrolyzed with koh in refluxing methanol/water to provide the corresponding free acid (xi). finally, this compound is decarboxylated by heating in refluxing ethyleneglycol to give the target compound along with some 6h-isomer that is separated by chromatography.alternatively, the decarboxylation of (xi) can also be performed in mineral oil at 230 c to obtain a better yield of the target compound.
List of intermediates No.
1,3-bis(trimethylsilyl)-2,4(1h,3h)-pyrimidinedione (ix)
[(1r,2r)-7-chloro-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepin-2-yl]methanol (iv)
methyl 2-(3-methyl-4-pyridinyl)acetate (i)
2-(aminomethyl)-5,6-dimethyl-2-indanamine; (2-amino-5,6-dimethyl-2,3-dihydro-1h-inden-2-yl)methylamine (ii)
(iii)
methyl (2r)-2-[(3,5-dimethylbenzoyl)amino]-3-(4-nitrophenyl)propanoate (v)
methyl (2r)-2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-(4-nitrophenyl)propanoate (vi)
methyl (2r)-3-(4-aminophenyl)-2-[(3,5-dimethylbenzoyl)(methyl)amino]propanoate (vii)
methyl (2r)-2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(1h-pyrrol-1-yl)phenyl]propanoate (viii)
(2r)-2-[(3,5-dimethylbenzoyl)(methyl)amino]-3-[4-(1h-pyrrol-1-yl)phenyl]propanoic acid (x)
(2r)-2-amino-3-(4-nitrophenyl)propanoic acid (xi)
Reference 1:
    bhatia, a.v.; dhaon, m.k.; davis, d.a.; esser, g.l. (abbott laboratories inc.); process for the preparation of midazolam. wo 0102402 .
Reference 2:
    walser, a.; fryer, r.i. (f. hoffmann-la roche ag); process for the preparation of diazepine derivs.. de 2609486; gb 1549836 .

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马来酸咪达唑仑;英文名Midazolam maleate;Ro-21-3981/003(HCl);Ro-21-3981/001;Versed;Hypnovel;Dormicum;CAS[59467-94-6]

 
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