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药物详细合成路线

Name Iloperidone;ILO-522;HP-873;Zomaril
Chemical Name 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone
      1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine
      4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyacetophenone
CAS 133454-47-4
Related CAS
Formula C24H27FN2O4
Structure
Formula Weight 426.49219
Stage 上市-2009
Company Aventis Pharma (Originator), Novartis (Licensee), Titan (Licensee)
Activity/Mechanism Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists, Dopamine D2 Antagonists
Syn. Route 1
Route 1
the reaction of piperidine-4-carboxylic acid (i) with formic acid and acetic anhydride gives 1-formylpiperidine-4-carboxylic acid (ii), which is treated with socl2 and acetic anhydride to yield the corresponding acyl chloride (iii). the friedel-crafts condensation of (iii) with refluxing 1,3-difluorobenzene (iv) by means of alcl3 affords 4-(2,4-difluorobenzoyl)-1-formylpiperidine (v), which is treated with hydroxylamine in refluxing ethanol to give the corresponding oxime (vi). the cyclization of (vi) by means of nah in hot thf/dmf yields 6-fluoro-3-(1-formylpiperidin-4-yl)-1,2-benzisoxazole (vii), which is treated with hcl in refluxing ethanol to afford 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole (viii). finally, this compound is condensed with 4-(3-chloropropoxy)-3-methoxyacetophenone (ix) by means of k2co3 in hot dmf.the intermediate 4-(3-chloropropoxy)-3-methoxyacetophenone (ix) can be obtained by condensation of 4-hydroxy-3-methoxyacetophenone (ix) with 3-chcloropropyl bromide (x) by means of nah or k2co3 in dmf.
List of intermediates No.
ethyl 2-(3,4-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)acetyl]amino]propanoate (xi)
4-ethyl-7-nitro-1,2,3,4-tetrahydroquinoline (iv)
(8s,9s,11r,13s,14s)-11-methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthrene-3,17-diol (i)
2-(4-nitrophenyl)acrylic acid (viii)
methyl (2r,3r,4s)-4-(1,3-benzodioxol-5-yl)-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate (x)
methyl (2s,3r,4s)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methylcyclohexyl)-3-pyrrolidinecarboxylate (ix)
(4r,5r)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone o-methyloxime (ii)
(4s,5r)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone (iii)
(4s,6s,7r)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one (v)
(3r,4r,5s,6s)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol (vi)
benzyl 2-methyl-2-[(4r,5s,6s)-2,2,5-trimethyl-6-[(1s)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4r,5s,6s)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1s)-1-methyl-3-butenyl]-1,3-dioxane (vii)
Reference 1:
    corbett, r.; bordeau, k.j.; helsley, g.c.; szewczak, m.r.; wilmot, c.a.; chiang, y.; hartman, h.b.; conway, p.g.; glamkowski, e.j.; strupczewski, j.t.; 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles as d2/5-ht2 antagonists with potential atypical antipsychotic activity: antipsychotic profile of iloperidone (hp 873). j med chem 1995, 38, 7, 1119-31.
Reference 2:
    strupczewski, j.t.; helsley, g.c.; chiang, y.; bordeau, k.j. (aventis pharmaceuticals, inc.); n-(aryloxyalkyl)heteroarylpiperidines and-heteroarylpiperazines, a process for their preparation and their use as medicaments. ep 0402644; jp 1991063263 .
Reference 3:
    strupczewski, j.t.; helsley, g.c.; chiang, y.; bordeau, k.j.; glamkowski, e.j. (aventis pharmaceuticals, inc.); heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgetics. ep 0542136; ep 0612318; ep 0730452; ep 0957102; ep 0959075; ep 0959076; ep 0963984; jp 1995501055; jp 1997511215; us 5364866; us 5776963; wo 9309102; wo 9511680 .
Reference 4:
    mucke, h.a.m.; castaner, j.; iloperidone. drugs fut 2000, 25, 1, 29.
Reference 5:
    strupczewski, j.t.; allen, r.c.; gardner, b.a. (aventis pharmaceuticals, inc.); 3-(4-piperidyl)-1,2-benzisoxazoles. us 4355037 .

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伊潘立酮;英文名Iloperidone;ILO-522;HP-873;Zomaril;CAS[133454-47-4]

 
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