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药物详细合成路线

Name Pariprazole sodium;Rabeprazole sodium;LY-307640;E-3810;Aciphex;Pariet
Chemical Name 2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-ylmethylsulfinyl]benzimidazole 1-sodium salt
CAS 117976-90-6
Related CAS 117976-89-3 (free acid)
Formula C18H20N3NaO3S
Structure
Formula Weight 381.4322
Stage 上市-1997
Company Eisai (Originator), Janssen (Licensee), Janssen-Cilag (Licensee)
Activity/Mechanism Anti-Helicobacter Pylori Agents, Antiulcer Drugs, Esophageal Diseases, Treatment of, Gastroesophageal Reflux Disease, Agents for, GASTROINTESTINAL DRUGS, H+/K+-ATPase Inhibitors
Syn. Route 2
Route 1
the condensation of 4-chloro-2,3-dimethylpyridine n-oxide (i) with 3-methoxypropanol (ii) by means of nah in dmso gives 4-(3-methoxypropoxy)-2,3-dimethylpyridine n-oxide (iii), which is treated with acetic anhydride at 90 c yielding 2-(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (iv). the hydrolysis of (iv) with naoh in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (v), which by treatment with socl2 in dichloromethane is converted into 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (vi). the condensation of (vi) with 2-mercaptobenzimidazole (vii) by means of naoh in ethanol gives 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-ylmethylthio]benzimidazole (viii), which is oxidized with m-chloroperbenzoic acid in ether - dichloromethane to afford 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-ylsulfinyl]benzimidazole (ix). finally, this compound is treated wtih aqueous na2co3.
List of intermediates No.
methyl (3r,6s,8as)-6-amino-5-oxohexahydro-5h-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (i)
phenylmethanesulfonyl chloride (ii)
methyl (3r,6s,8as)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5h-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (iii)
(3r,6s,8as)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5h-[1,3]thiazolo[3,2-a]pyridine-3-carboxylic acid (iv)
tert-butyl (z)-([(3s)-3-[([(3r,6s,8as)-6-[(benzylsulfonyl)amino]-5-oxohexahydro-5h-[1,3]thiazolo[3,2-a]pyridin-3-yl]carbonyl)amino]-4,4-diethoxybutyl]amino)[(tert-butoxycarbonyl)amino]methylidenecarbamate (v)
methyl 3,5-dihydroxybenzoate (vi)
methyl 3,5-bis(benzyloxy)benzoate (vii)
3,5-bis(benzyloxy)benzoic acid (viii)
3,5-bis(benzyloxy)-n-(2-hydroxy-1,1-dimethylethyl)benzamide (ix)
(1s,4r,6r,8s,9s,13s,15r)-13-([[tert-butyl(diphenyl)silyl]oxy]methyl)-6-(4-methoxyphenyl)-5,7,10,12-tetraoxa-11lambda(6)-thiapentacyclo[13.4.1.0(1,9).0(4,9).0(8,13)]icosane-11,11,20-trione
Reference 1:
    souda, s.; ueda, n.; miyazawa, s.; tagami, k.; nomoto, s.; okita, m.; shimomura, n.; kaneko, t.; fujimoto, m.; murakami, m.; oketani, k.; fujisaki, h.; shibata, h.; wakabayashi, t. (eisai co., ltd.); pyridine derivs., pharmaceutical compsns. comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same. au 8781138; ep 0268956; ep 0475456; ep 0654471; ep 0786461; jp 1989006270; jp 1993247035; jp 1995291967; us 5045552; us 5998445 .
Reference 2:
    castaner, j.; prous, j.; e-3810. drugs fut 1991, 16, 1, 19.

Route 2
a synthesis for [14c]-labeled e-3810 has been described:the cyclization of o-phenylenediamine (i) with [14c]-labeled carbon disulfide (ii) by means of aqueous koh gives the potassium salt of [14c]-2-mercaptobenzimidazole (iii), which is treated with acetic acid to obtain the corresponding thiol (iv). the condensation of (iv) with 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (v) by means of naoh in refluxing ethanol yields [14c]-labeled 2-[4-(3-methoxypropoxy)-3-methylpyridin-3-ylmethylthio]benzimidazole (vi). the oxidation of (vi) with m-chloroperbenzoic acid in dichloromethane affords the corresponding sulfoxide (viii), which is finally treated with 0.1 n naoh in ethanol.
List of intermediates No.
methyl 3,5-dihydroxybenzoate (v)
methyl 3,5-bis(benzyloxy)benzoate (iv)
3,5-bis(benzyloxy)benzoic acid (vi)
3,5-bis(benzyloxy)-n-(2-hydroxy-1,1-dimethylethyl)benzamide (vii)
benzyl 3-(benzyloxy)-5-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl ether (i)
2-[2-benzyl-3,5-bis(benzyloxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole (iii)
(2r,4ar,6r,7r,8r,8as)-6-{[(2r,3s,4r,5r,6r)-6-{[(1r,2s,3r,4r,5r)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl methyl ether; (2r,4ar,6r,7r,8r,8as)-6-{[(2r,3s,4r,5r,6r)-6-{[(1r,2s,3r,4r,5r)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-7,8-dimethoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine (iii)
(2r,3s,4s,5r,6r)-6-{[(2r,3s,4r,5r,6r)-6-{[(1r,2s,3r,4r,5r)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-2-(hydroxymethyl)-4,5-dimethoxytetrahydro-2h-pyran-3-ol (iv)
((2r,3s,4s,5r,6r)-6-{[(2r,3s,4r,5r,6r)-6-{[(1r,2s,3r,4r,5r)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-3-hydroxy-4,5-dimethoxytetrahydro-2h-pyran-2-yl)methyl benzoate (vi)
((2r,3s,4r,5r,6r)-3-({(2s,3r,4s,5r,6r)-5-{[(2r,4ar,6r,7r,8s,8ar)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-3,4-bis(benzoyloxy)-6-[(benzoyloxy)methyl]tetrahydro-2h-pyran-2-yl}oxy)-6-{[(2r,3s,4r,5r,6r)-6-{[(1r,2s,3r,4r,5r)-3,4-dimethoxy-6,8-dioxabicyclo[3.2.1]oct-2-yl]oxy}-4,5-dimethoxy-2-(methoxymethyl)tetrahydro-2h-pyran-3-yl]oxy}-4,5-dimethoxytetrahydro-2h-pyran-2-yl)methyl benzoate (vii)
Reference 1:
    sohda, s.; tagami, k.; chiku, s.; synthesis of 14c-labelled sodium pariprazole (e3810). j label compd radiopharm 1993, 33, 9, 849.

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雷贝拉唑钠;英文名Pariprazole sodium;Rabeprazole sodium;LY-307640;E-3810;Aciphex;Pariet;CAS[117976-90-6]

 
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