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药物详细合成路线

Name Sulpiride [L-(-)];Levosulpiride;RV-12309;Levopraid
Chemical Name (S)-5-(Aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide
CAS 23672-07-3
Related CAS 77111-58-1 (HCl)
Formula C15H23N3O4S
Structure
Formula Weight 341.43226
Stage 上市-1987
Company Abbott (Originator), Ravizza (Originator)
Activity/Mechanism Antipsychotic Drugs, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D2 Antagonists
Syn. Route 2
Route 1
this compound is obtained by condensation of 2(s)-(aminomethyl)-1-ethylpyrrolidine (i) with 5-(aminosulfonyl)-2-methoxybenzoyl chloride (ii) by means of k2co3 in acetone. the starting compounds (i) and (ii) are obtained as follows:a) the acylation of 2(s)-(hydroxymethyl)pyrrolidine (iii) with acetic anhydride in refluxing methanol gives 1-acetyl-2(s)-(hydroxymethyl)pyrrolidine (iv), which by reaction with socl2 in chcl3 is converted into 1-acetyl-2(s)-(chloromethyl)pyrrolidine (v). the reaction of (v) with sodium azide in hot dmf affords the corresponding azide (vi), which is reduced with lialh4 in refluxing thf to yield the desired product (i).b) the methylation of 2-hydroxybenzaldehyde (vii) with dimethyl sulfate and k2so3 in refluxing acetone gives 2-methoxybenzaldehyde (viii), which is oxidized with kmno4 in hot aqueous naoh affording 2-methoxybenzoic acid (ix). the sulfonation of (ix) with hot chlorosulfonic acid yields 5-(chlorosulfonyl)-2-methoxybenzoic acid (x), which is finally treated with 28% aqueous naoh to give the desired product (ii).
List of intermediates No.
4-(6-chloro-3-pyridazinyl)morpholine (viii)
(4r)-2-[[(1r)-2-hydroxy-1-phenylethyl]amino]-4-methyloctanenitrile (ix)
butyl 2-[(5s)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate (i)
butyl 2-[(5r)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate (ii)
methyl (2s)-2-[(butoxycarbonyl)amino]-3-([2-[(5s)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)propanoate (iii)
methyl (2s)-2-[(butoxycarbonyl)amino]-3-[[2-((5s)-3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]propanoate (iv)
methyl (2s)-3-[[2-((5s)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[(butoxycarbonyl)amino]propanoate (v)
methyl (3r,4s)-1-benzyl-4-(5-bromo-2-methoxyphenyl)-3-pyrrolidinecarboxylate (vi)
[(3r,4s)-1-benzyl-4-(5-bromo-2-methoxyphenyl)pyrrolidinyl]methanol (vii)
(3ar,9bs)-2-benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile (x)
(3ar,9bs)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile (xi)
Reference 1:
    al-koutayni-rifai, m.; jamet, g.; kerr, r.r.; jung, l.; koffel, j.c.; synthesis of d3-sulpiride and its (r) and (s) isomers. j label compd radiopharm 1989, 27, 7, 811.

Route 2
optically active sulpiride is prepared by converting levo-proline (i) to the correspondig levorotatory acetylproline (ii), followed by reduction, chlorination and amination to afford levorotatory n-ethyl-2-aminomethylpyrrolidine (v), which, upon treatment with an ester of 2-methoxy-5-sulfamoylbenzoic acid (vi), yields n-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulfamoylbenzamide, that is, the levorotatory enantiomer of sulpiride.
List of intermediates No.
1-[4-(4-[[(2s,4r)-2-(2,4-dichlorophenyl)-2-(1h-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]-1-ethanone (i)
butyl 2-[(5s)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate (v)
2-amino-7-methoxy-9h-xanthen-9-one (ii)
7-methoxy-9-oxo-9h-xanthene-2-carboxylic acid (iii)
7-hydroxy-9-oxo-9h-xanthene-2-carboxylic acid (iv)
ethyl 7-hydroxy-9-oxo-9h-xanthene-2-carboxylate (vi)
Reference 1:
    forgione, a.; levosulpiride. drugs fut 1987, 12, 10, 944.

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左旋舒必利;英文名Sulpiride [L-(-)];Levosulpiride;RV-12309;Levopraid;CAS[23672-07-3]

 
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