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藥物詳細合成路線

Name Nefopam hydrochloride;Ajan;Acupan
Chemical Name 5-Methyl-1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine hydrochloride
CAS 23327-57-3
Related CAS 13669-70-0 (free base)
Formula C17H20ClNO
Structure
Formula Weight 289.80805
Stage 上市-1983
Company 3M Pharmaceuticals (Not Determined), Biocodex (Not Determined)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics
Syn. Route 4
Route 1
the reaction of 2-benzoylbenzoic acid (i) with socl2 in chcl3, benzene or dmf gives the corresponding acyl chloride (ii), which is condensed with ethanolamine (iii) by means of tea in chcl3 to yield the amide (iv). the reduction of (iv) with lialh4 in thf affords the diol (v), which is cyclized by means of ts-oh in refluxing benzene to provide 1-phenyl-3,4,5,6-tetrahydro-1h-2,5-benzoxazocine (vi). finally, this compound is methylated by means of dimethyl sulfate in refluxing benzene, or by means of formaldehyde in hot dioxane/water.alternatively, the cyclization of n-[2-[1-[2-(chloromethyl)phenyl]-1-phenylmethoxy]ethyl]-n-methylamine (vii) by means of pyridine in refluxing acetonitrile gives also the target benzoxazocine.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate (iii)
Reference 1:
    lazaro porta, a.; process for the preparation of diphenylcarbinol derivs.. es 8100663 .
Reference 2:
    calatayud, j.; luna, m.; process for the preparation of 5-phenyl-1-methyl-1-aza-4-oxa-6,7-benzocyclooctane hydrochloride. es 8605495 .
Reference 3:
    colls alsius, j.; process for the preparation of of a heterocyclic tertiary amine. es 8607261 .

Route 2
the reaction of 3-phenylphthalide (i) with n-methylethanolamine (ii) in refluxing benzene gives n-(2-hydroxyethyl)-2-(1-hydroxy-1-phenylmethyl)-n-methylbenzamide (iii), which is cyclized by means of ts-oh in refluxing toluene to yield 5-methyl-1-phenyl-3,4,5,6-tetrahydro-1h-2,5-benzoxazocin-6-one (iv). finally this compound is reduced with lialh4 in refluxing thf to afford the target benzoxazocine.in an alternative method, the reduction of 2-benzoyl-n-(2-hydroxyethyl)-n-methylbenzamide (v) by means of sodium bis(2-methoxyethoxy)aluminum hydride in refluxing toluene gives the diol (vi), which is then cyclized by means of ts-oh in refluxing toluene, or by means of aq. 48% hbr in hot chloroform to afford the target benzoxazocine.
List of intermediates No.
tert-butyl 4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11h-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxylate (ii)
Reference 1:
    lucero de pablo, m.l.; martin-escudero perez, u.; izquierdo sanjose, m.; process for the preparation of a benzoxazine deriv. and its non-toxic salt. es 8105723 .
Reference 2:
    eberlin, j.w.; process for benz[f]-2,5-oxazocines. us 3978085 .
Reference 3:
    gimbert roura, j.; soler peix, e.; process for the preparation of benzoxazines. ke 8201564 .

Route 3
the reaction of 2-benzoylbenzoic acid (i) with refluxing socl2 gives the corresponding acyl chloride (ii), which is condensed with 2-(methylamino)acetic acid (iii) in benzene to yield the n-(2-benzoylbenzoyl)-n-methylglycine (iv). the reduction of (iv) by means of lialh4 in refluxing thf affords the diol (v), which is finally cyclized by means of ppa at 80 c to provide the target benzoxazocine.
List of intermediates No.
6,7-dichloro-5,8-dimethoxynaphthoquinone (iii)
Reference 1:
    galiano ramos, j.a.; verde casanova, m.j.; fernandez torija, c. (instituto de investigacion y desarrollo quimico biologico sa); process for the preparation of 1-methyl-5-phenyl-aza-4-oxo-6,7-benzocyclooctane. es 8104800 .

Route 4
the reaction of 2-benzoylbenzoic acid (i) with pcl3 in dichloromethane gives the corresponding acyl chloride (ii), which is condensed with n-methylethanolamine (iii) by means of tea in dichloroethane to yield the amide (iv). the reaction of (iv) with pcl3 in dichloroethane affords the 2-chloroethylamide (v), which is reduced with nabh4 and a-oh in dichloromethane to provide the diol (vi). finally, this compound is cyclized by means of aq. hbr in dichloroethane to give the target benzoxazocine.
List of intermediates No.
tert-butyl 4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11h-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxylate (iii)
Reference 1:
    watson, p.g.; process for the preparation of 2-[n-(2-hydroxyethyl)-n-lower alkylaminomethyl]benzhydrols. us 4208349 .
Reference 2:
    watson, p.g.; process for the preparation of 2-[n-(2-hydroxyethyl)-n-lower alkylaminomethyl)benzhydrols. gb 1586578 .

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鹽酸奈福泮;英文名Nefopam hydrochloride;Ajan;Acupan;CAS[23327-57-3]

 
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