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药物详细合成路线

Name Talampanel;IDR-53773;GYKI-53773;LY-300164;Kinampa;Ampanel
Chemical Name 7-Acetyl-5-(4-aminophenyl)-8(R)-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine
CAS 161832-65-1
Related CAS
Formula C19H19N3O3
Structure
Formula Weight 337.38158
Stage II 期临床
Company Institute for Drug Research (Originator), Ivax (Originator)
Activity/Mechanism Antiepileptic Drugs, Antispastic Drugs and Drugs for Muscle Spasms, Brain Cancer Therapy, Cerebrovascular Diseases, Treatment of, Extrapyramidal Disorders, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Oncolytic Drugs, Stroke, Treatment of, Tardive Dyskinesia, Treatment of, AMPA Antagonists
Syn. Route 2
Route 1
the reaction of 5-bromo-1,3-benzodioxole (i) with (s)-(-)-propylene oxide (ii) by means of sec-butyllithium in thf gives the (s)-isopropanol derivative (iv) (also obtained by stereoselective reduction of 1-(1,3-benzodioxol-5-yl)-2-propanone (iii) with z. rouxii atcc 14462 in a phosphate buffer). the cyclization of (iv) with 4-nitrobenzaldehyde (v) by means of hcl in hot toluene yields the benzopyran (vi), which is oxidized with air in aqueous naoh affording the carbinol (vii). the reaction of (vii) with acetohydrazide (viii) and hcl in refluxing ethanol gives the acetyl hydrazone (ix), which is mesylated at the secondary oh group with methanesulfonyl chloride and tea in dichloromethane yielding the mesylate (x). the cyclization of (x) by means of naoh in methanol provides the nitro benzodiazepine (xi), which is finally reduced with potassium formate and pd/c in ethanol/water.
List of intermediates No.
4-(acetoxy)-2-cyclopenten-1-yl acetate (i)
n-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalenylidene]-n-methylamine; n-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalenylidene]methanamine (v)
methyl 2,5-diamino-2-(difluoromethyl)pentanoate (iii)
(2s,3s,4e)-2-hexyl-3-hydroxy-5-phenyl-4-pentenoic acid (iv)
(2s,5s,6s)-2-(tert-butyl)-5-hexyl-6-[(e)-2-phenylethenyl]-1,3-dioxan-4-one (vi)
(2s,4r,5s)-2-(tert-butyl)-5-hexyl-6-oxo-1,3-dioxane-4-carbaldehyde (vii)
1-nitroundecane (viii)
(2s,5s,6r)-2-(tert-butyl)-5-hexyl-6-(1-hydroxy-2-nitrododecyl)-1,3-dioxan-4-one (ix)
(2s,5s,6s)-2-(tert-butyl)-5-hexyl-6-[(e)-2-nitro-1-dodecenyl]-1,3-dioxan-4-one (x)
(2s,5s,6s)-2-(tert-butyl)-5-hexyl-6-[2-(hydroxyimino)dodecyl]-1,3-dioxan-4-one (xi)
benzyl (2s,3s)-2-hexyl-3-hydroxy-5-oxopentadecanoate (ii)
Reference 1:
    andrasi, f.; talampanel. drugs fut 2001, 26, 8, 754.
Reference 2:
    anderson, b.a.; et al.; application of a practical biocatalytic reduction to an enantioselective synthesis of the 5h-2, 3-benzodiazepine ly300164. j am chem soc 1995, 117, 49, 12358.
Reference 3:
    andrasi, f.; berzsenyi, p.; botka, p.; farkas, s.; goldschmidt, k.; hamori, t.; korosi, j.; moravcsik, i.; tarnawa, i. (gyogyszerkutato intezet kft.); n-acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. ep 0492485; jp 1993070463; us 5519019; us 5521174; us 5536832; us 5604223; us 5639751 .
Reference 4:
    varie, d.l.; hansen, m.m.; anderson, b.; vicenzi, j.t.; zmijewski, m.j. (eli lilly and company); stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. ep 0699677; us 5665878 .
Reference 5:
    zmijewski, m.j. jr.; varie, d.l.; hansen, m.m.; vicenzi, j.t.; anderson, b.a. (eli lilly and company); physical form of dihidro-2,3-benzodiazepine deriv.. ep 0699676 .
Reference 6:
    hansen, m.m.; vicenzi, j.t.; groleau, e.g.; varie, d.l.; zmijewski, m.j.; anderson, b.a. (eli lilly and company); crystalline form of dihydro-2,3-benzodiazepine deriv.. ep 0699678 .
Reference 7:
    anderson, b.a.; varie, d.l.; vicenzi, j.t.; zmijewski, m.j.; hansen, m.m. (eli lilly and company); stereoselective process for producing dihydro-2,3-benzodiazepine derivs.. us 5919954 .

Route 2
the regioselective reduction of 8-methyl-5-(4-nitrophenyl)-9h-1,3-dioxolo[4,5-h][2,3]benzodiazepine (i) with borane-thf complex catalyzed by (r)-2-amino-3-methyl-1,1-diphenyl-1-butanol (ii) in dichloromethane gives the 8(r)-methyl derivative (iii), which is acetylated with acetic anhydride yielding the 7-acetyl-8(r)-methyl derivative (iv). finally, the nitro group of (iv) is reduced with hydrazine and ni-raney in methanol.
List of intermediates No.
[5-[3-benzoyl-5-[(1r)-2,2-dibromocyclopropyl]-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]-3-(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate (ii)
(2s,5s,6s)-2-(tert-butyl)-5-hexyl-6-[2-(hydroxyimino)dodecyl]-1,3-dioxan-4-one (iv)
(2s,5s,6s)-2-(tert-butyl)-5-hexyl-6-(2-oxododecyl)-1,3-dioxan-4-one (i)
(2s,3s)-2-hexyl-3-hydroxy-5-oxopentadecanoic acid (iii)
Reference 1:
    ling, i.; et al.; asymmetric reduction of a carbon-nitrogen double bond: enantioselective synthesis of 4,5-dihydro-3h-2,3-benzodiazepines. j chem soc - perkins trans i 1995, 11, 1423.
Reference 2:
    ling, i.; hamori, t.; botka, p.; solyom, s.; simay, a.; moravcsik, i. (gyogyszerkutato intezet kft.); optically active 1-(4-nitrophenyl)-4-methyl-7, 8-methylenedioxy-3,4-dihydro-5h-2,3-benzodiazepine and process for preparing same. wo 9501357 .
Reference 3:
    andrasi, f.; berzsenyi, p.; botka, p.; farkas, s.; goldschmidt, k.; hamori, t.; korosi, j.; moravcsik, i.; tarnawa, i. (gyogyszerkutato intezet kft.); n-acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. ep 0492485; jp 1993070463; us 5519019; us 5521174; us 5536832; us 5604223; us 5639751 .
Reference 4:
    berzsenyi, p.; goldschmidt, k.; moravcsik, i.; kór?si, j.; andrási, f.; farkas, s.; hámori, t.; tarnawa, i.; botka, p. (gyogyszerkutato intezet kft.); n-acyl-2,3-benzodiazepine derivs., pharmaceutical compsns. containing them and process for preparing same. us 5459137 .

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他仑帕奈;英文名Talampanel;IDR-53773;GYKI-53773;LY-300164;Kinampa;Ampanel;CAS[161832-65-1]

 
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