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药物详细合成路线

Name Amisulpride;SL-91.1077;Deniban;Solian;Socian
Chemical Name 4-Amino-N-(1-ethyl-2-pyrrolidinylmethyl)-5-(ethylsulfonyl)-2-methoxybenzamide
CAS 71675-85-9
Related CAS
Formula C17H27N3O4S
Structure
Formula Weight 369.48644
Stage 上市-1986
Company Sanofi-synthélabo (Originator)
Activity/Mechanism Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D2 Antagonists, Dopamine D3 Antagonists
Syn. Route 3
Route 1
acetylation of 5-aminosalicylic acid (i) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (ii), which is methylated with dimethyl sulfate and k2co3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (iii). nitration of (iii) with hno3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (iv), which is deacetylated with h2so4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (v). the diazotation of (v) with nano2-hcl, followed by reaction with sodium ethylmercaptide, oxidation with h2o2 and hydrolysis with naoh in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (vi), which is condensed with n-ethyl-2-aminomethylpyrrolidine (vii) by means of ethyl chloroformate and triethylamine in dioxane affording 2-methoxy-4-nitro-n-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)benzamide (viii). finally, this compound is reduced with h2 over raney-ni in ethanol.
List of intermediates No.
tert-butyl(dimethyl)silyl (2r,4s,6r)-2-[(2s,4e)-5-iodo-2-methoxy-4-pentenyl]-2-methoxy-6-([[(4-methoxybenzyl)oxy]methoxy]methyl)tetrahydro-2h-pyran-4-yl ether; tert-butyl[[(2r,4s,6r)-2-[(2s,4e)-5-iodo-2-methoxy-4-pentenyl]-2-methoxy-6-([[(4-methoxybenzyl)oxy]methoxy]methyl)tetrahydro-2h-pyran-4-yl]oxy]dimethylsilane (i)
(2s,4r)-1-[2-((2s,4s)-6-(benzyloxy)-2,4-bis[[tert-butyl(diphenyl)silyl]oxy]hexyl)-1,3-dithian-2-yl]-4-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-ethoxyethoxy)-2-methyl-2-pentanol (ii)
(2s)-1-[2-((2s,4s)-6-(benzyloxy)-2,4-bis[[tert-butyl(diphenyl)silyl]oxy]hexyl)-1,3-dithian-2-yl]-2-methyl-3-[(2r)oxiranyl]-2-propanol (iii)
(2s,4s)-1-[2-((2s,4s)-6-(benzyloxy)-2,4-bis[[tert-butyl(diphenyl)silyl]oxy]hexyl)-1,3-dithian-2-yl]-2-methyl-6-[(1r)-1-[(2s,3r)-3-methyl-1,5-dioxaspiro[5.5]undec-2-yl]ethyl]-6-heptene-2,4-diol (iv)
(2s,4s,6s,8s,10s)-8-[2-(benzyloxy)ethyl]-4-methyl-2-(2-[(1r)-1-[(2s,3r)-3-methyl-1,5-dioxaspiro[5.5]undec-2-yl]ethyl]-2-propenyl)-1,7-dioxaspiro[5.5]undecane-4,10-diol (v)
2-((2s,4s,6s,8s,10s)-8-[2-[(1r,2s,3r)-2,4-dihydroxy-1,3-dimethylbutyl]-2-propenyl]-4,10-dihydroxy-10-methyl-1,7-dioxaspiro[5.5]undec-2-yl)ethyl 2-methoxyacetate (vi)
2-[(2s,4s,8s,10s)-8-[2-((1r,2s,3r)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-1,3-dimethylbutyl)-2-propenyl]-4,10-dihydroxy-10-methyl-1,7-dioxaspiro[5.5]undec-2-yl]ethyl 2-methoxyacetate (viii)
(2s,4s,6s,8s,10s)-8-(2-[(1r,2s,3s)-2-(acetoxy)-5-[(2s,4s,6s,8r,10s)-10-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-8-([[(4-methoxybenzyl)oxy]methoxy]methyl)-1,7-dioxaspiro[5.5]undec-2-yl]-1,3-dimethyl-4-oxopentyl]-2-propenyl)-10-hydroxy-2-(2-hydrox (vii)
Reference 1:
    acher, j.; monier, j.-c. (societe detudes scientifiques et industrielles de lile de france); nouveaux procédé de préparation de dérivés de 4-amino-5-alkylsulfonyl-o-anisamides et nouveaux dérivés de 4-nitro-5-alkylsulfonyl-o-anisamides utiles comme intermédiaires de synthèse. fr 2460930 .
Reference 2:
    patel, r.; packham, t.w.; germain, a.l.; barras, j.r.; milne, d.j. (glaxosmithkline plc); process of preparing 2,3,5-trihalobenzaldehyde. wo 9507877 .

Route 2
acetylation of 5-aminosalicylic acid (i) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (ii), which is methylated with dimethyl sulfate and k2co3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (iii). nitration of (iii) with hno3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (iv), which is deacetylated with h2so4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (v). the diazotation of (v) with nano2-hcl, followed by reaction with sodium ethylmercaptide, oxidation with h2o2 and hydrolysis with naoh in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (vi). the reaction of (vi) with refluxing socl2 gives the corresponding acyl chloride (ix), which is then condensed with (vii) in butannne yielding (viii). finally, this compound is reduced with h2 over raney-ni in ethanol.
List of intermediates No.
tert-butyl(dimethyl)silyl (2r,4s,6r)-2-[(2s,4e)-5-iodo-2-methoxy-4-pentenyl]-2-methoxy-6-([[(4-methoxybenzyl)oxy]methoxy]methyl)tetrahydro-2h-pyran-4-yl ether; tert-butyl[[(2r,4s,6r)-2-[(2s,4e)-5-iodo-2-methoxy-4-pentenyl]-2-methoxy-6-([[(4-methoxybenzyl)oxy]methoxy]methyl)tetrahydro-2h-pyran-4-yl]oxy]dimethylsilane (i)
(2s,4r)-1-[2-((2s,4s)-6-(benzyloxy)-2,4-bis[[tert-butyl(diphenyl)silyl]oxy]hexyl)-1,3-dithian-2-yl]-4-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-ethoxyethoxy)-2-methyl-2-pentanol (ii)
(2s)-1-[2-((2s,4s)-6-(benzyloxy)-2,4-bis[[tert-butyl(diphenyl)silyl]oxy]hexyl)-1,3-dithian-2-yl]-2-methyl-3-[(2r)oxiranyl]-2-propanol (iii)
(2s,4s)-1-[2-((2s,4s)-6-(benzyloxy)-2,4-bis[[tert-butyl(diphenyl)silyl]oxy]hexyl)-1,3-dithian-2-yl]-2-methyl-6-[(1r)-1-[(2s,3r)-3-methyl-1,5-dioxaspiro[5.5]undec-2-yl]ethyl]-6-heptene-2,4-diol (iv)
(2s,4s,6s,8s,10s)-8-[2-(benzyloxy)ethyl]-4-methyl-2-(2-[(1r)-1-[(2s,3r)-3-methyl-1,5-dioxaspiro[5.5]undec-2-yl]ethyl]-2-propenyl)-1,7-dioxaspiro[5.5]undecane-4,10-diol (v)
2-((2s,4s,6s,8s,10s)-8-[2-[(1r,2s,3r)-2,4-dihydroxy-1,3-dimethylbutyl]-2-propenyl]-4,10-dihydroxy-10-methyl-1,7-dioxaspiro[5.5]undec-2-yl)ethyl 2-methoxyacetate (vi)
2-[(2s,4s,8s,10s)-8-[2-((1r,2s,3r)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-1,3-dimethylbutyl)-2-propenyl]-4,10-dihydroxy-10-methyl-1,7-dioxaspiro[5.5]undec-2-yl]ethyl 2-methoxyacetate (viii)
2-[(2s,4s,8s,10s)-4-(acetoxy)-8-[2-((1r,2s,3r)-2-(acetoxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethylbutyl)-2-propenyl]-10-hydroxy-10-methyl-1,7-dioxaspiro[5.5]undec-2-yl]ethyl 2-methoxyacetate (ix)
(2s,4s,6s,8s,10s)-8-(2-[(1r,2s,3s)-2-(acetoxy)-5-[(2s,4s,6s,8r,10s)-10-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-8-([[(4-methoxybenzyl)oxy]methoxy]methyl)-1,7-dioxaspiro[5.5]undec-2-yl]-1,3-dimethyl-4-oxopentyl]-2-propenyl)-10-hydroxy-2-(2-hydrox (vii)
Reference 1:
    acher, j.; monier, j.-c. (societe detudes scientifiques et industrielles de lile de france); nouveaux procédé de préparation de dérivés de 4-amino-5-alkylsulfonyl-o-anisamides et nouveaux dérivés de 4-nitro-5-alkylsulfonyl-o-anisamides utiles comme intermédiaires de synthèse. fr 2460930 .
Reference 2:
    patel, r.; packham, t.w.; germain, a.l.; barras, j.r.; milne, d.j. (glaxosmithkline plc); process of preparing 2,3,5-trihalobenzaldehyde. wo 9507877 .

Route 3
alkylation of 2-methoxy-4-amino-5-mercaptobenzoic acid (x) with diethyl sulfate acid na2co3 gives 2-methoxy-4-amino-5-ethylthiobenzoic acid (xi), which is oxidized with h2o2 in acetic acid yielding 2-methoxy-4-amino-5-(ethylsulfonyl)benzoic acid (xii). finally, this compound is condensed with (vii) by means of ethyl chloroformate.
List of intermediates No.
2-((2s,4s,6s,8s,10s)-4-(acetoxy)-8-[2-[(1r,2s,3r)-2-(acetoxy)-4-hydroxy-1,3-dimethylbutyl]-2-propenyl]-10-hydroxy-10-methyl-1,7-dioxaspiro[5.5]undec-2-yl)ethyl 2-methoxyacetate (x)
2-((2s,4s,6s,8s,10s)-4-(acetoxy)-8-[2-[(1r,2s,3s)-2-(acetoxy)-1,3-dimethyl-4-oxobutyl]-2-propenyl]-10-hydroxy-10-methyl-1,7-dioxaspiro[5.5]undec-2-yl)ethyl 2-methoxyacetate (xi)
2-((2s,4s,6r,8s,10s)-4-(acetoxy)-8-[(3r,4s,5s,7e,10s)-4-(acetoxy)-11-[(2r,4s,6r)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-6-([[(4-methoxybenzyl)oxy]methoxy]methyl)tetrahydro-2h-pyran-2-yl]-10-methoxy-3,5-dimethyl-2-methylene-6-oxo-7-undeceny (xii)
(2s,4s,6s,8s,10s)-8-(2-[(1r,2s,3s)-2-(acetoxy)-5-[(2s,4s,6s,8r,10s)-10-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-8-([[(4-methoxybenzyl)oxy]methoxy]methyl)-1,7-dioxaspiro[5.5]undec-2-yl]-1,3-dimethyl-4-oxopentyl]-2-propenyl)-10-hydroxy-2-(2-hydrox (vii)
Reference 1:
    acher, j.; thominet, m.; monier, j.-c. (societe detudes scientifiques et industrielles de lile de france); new derivatives of 4-amino-5-alkylsulphonyl-o-anisamides, methods of preparing them and their applications as psychotropic agents. be 0872585; es 476755; fr 2415099; gb 2083458; jp 54145658; us 4294828; us 4401822 .
Reference 2:
    patel, r.; packham, t.w.; germain, a.l.; barras, j.r.; milne, d.j. (glaxosmithkline plc); process of preparing 2,3,5-trihalobenzaldehyde. wo 9507877 .

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阿米舒必利;英文名Amisulpride;SL-91.1077;Deniban;Solian;Socian;CAS[71675-85-9]

 
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