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药物详细合成路线

Name Rebamipide;Pramipide;Proamipide;OPC-12759;Mucosta
Chemical Name (±)-N-(4-Chlorobenzoyl)-3-(2-oxo-1,2-dihydro-4-quinolyl)alanine;(±)-2-(4-Chlorobenzamido)-3-(1,2-dihydro-2-oxo-4-quinolyl)propionic acid
CAS 111911-87-6
Related CAS 90098-04-7 (undefined stereoch.)
Formula C19H15ClN2O4
Structure
Formula Weight 370.7954
Stage 上市-1990
Company Otsuka (Originator)
Activity/Mechanism Antiulcer Drugs, GASTROINTESTINAL DRUGS
Syn. Route 4
Route 1
the synthesis of (r)- and (s)-isomers of opc-12759 has been described:these optical isomers can be obtained in three different ways:1) the reaction of 4-(bromomethyl)quinolin-2(1h)-one (i) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (ii) and 2-chloro-4-(chloromethyl)quinoline (iii), which, without separation, is condensed with 2(s)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (ivs) by means of butyllithium in hexane, yielding (-)-2-chloro-4-[6(s)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(r)-yl methyl]quinoline (vr). the hydrolysis of (vr) with hcl affords 3-(2-chloroquinolin-4-yl)-(r)-alanine methyl ester (vir), which is treated with hcl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(r)-alanine (viir). finally, this compound is acylated with 4-chlorobenzoyl chloride (viii) by means of k2co3 in acetone, affording (r)-opc-12759.
List of intermediates No.
2-methylenecyclopropanecarboxylic acid (i)
(1r)-n-[(1r)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide (ii)
(1s)-n-[(1r)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide (iii)
(1r)-2-methylenecyclopropanecarboxylic acid (ivs)
ethyl (1r)-2-methylenecyclopropanecarboxylate (vr)
ethyl (1s)-2-bromo-2-(bromomethyl)cyclopropanecarboxylate (vir)
[(1s)-2-bromo-2-(bromomethyl)cyclopropyl]methanol (viir)
[(1s)-2-bromo-2-(bromomethyl)cyclopropyl]methyl acetate (viii)
Reference 1:
    morita, s.; yamasaki, k.; shimizu, t.; uchida, m.; otsubo, k.; kanbe, t.; synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1h)-quinolinon-4-yl]propionic acid (rebamipide). chem pharm bull 1991, 39, 11, 2906.

Route 2
2) the same reaction sequence of (i) and (ivr) yields intermediates (vs), (vis) and (viis), and finally (s)-opc-12759.
List of intermediates No.
(1r)-n-[(1r)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide (ii)
(1s)-n-[(1r)-2-hydroxy-1-phenylethyl]-2-methylenecyclopropanecarboxamide (iii)
[(1s)-2-bromo-2-(bromomethyl)cyclopropyl]methyl acetate (viii)
[(1r)-2-[(z)-(6-amino-9h-purin-9-yl)methylidene]cyclopropyl]methyl acetate (ivr)
[(1r)-2-[(e)-(6-amino-9h-purin-9-yl)methylidene]cyclopropyl]methyl acetate (vs)
[(1r)-2-[(e)-(6-amino-9h-purin-9-yl)methylidene]cyclopropyl]methanol (vis)
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-12-[(cyclopropylcarbonyl)oxy]-1,15-dihydroxy-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 (viis)
Reference 1:
    morita, s.; yamasaki, k.; shimizu, t.; uchida, m.; otsubo, k.; kanbe, t.; synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1h)-quinolinon-4-yl]propionic acid (rebamipide). chem pharm bull 1991, 39, 11, 2906.

Route 3
3) the methylation of 3-(2-oxo-1,2-dihydroquinolin-4-yl)-(r,s)-alanine (ix) with socl2 and methanol yields the corresponding methyl ester (x), which is submitted to optical resolution with d-(-)-mandelic acid, affording adducts (xii) and (xiii). the hydrolytic treatment of (xii) and (xiii) with hcl and propylene oxide finally yields isomers (viir) and (viis), already obtained. racemic opc-12759 can also be resolved into its optical isomers by treatment with brucine and fractionated crystallization.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-12-[(cyclopropylcarbonyl)oxy]-1,15-dihydroxy-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 (vii-s)
1-methyl-4-piperidinethiol; 1-methyl-4-piperidinylhydrosulfide (ix)
4-[(3-chloro-4-nitrophenyl)sulfanyl]-1-methylpiperidine; 3-chloro-4-nitrophenyl 1-methyl-4-piperidinyl sulfide (x)
4-[(5-chloro-2-nitrophenyl)sulfanyl]-1-methylpiperidine; 5-chloro-2-nitrophenyl 1-methyl-4-piperidinyl sulfide (xi)
4-chloro-2-[(1-methyl-4-piperidinyl)sulfanyl]phenylamine; 4-chloro-2-[(1-methyl-4-piperidinyl)sulfanyl]aniline (xii)
4-[[5-chloro-2-(1lambda(5)-diazynyl)phenyl]sulfanyl]-1-methylpiperidine; 5-chloro-2-(1lambda(5)-diazynyl)phenyl 1-methyl-4-piperidinyl sulfide (xiii)
4-[(3-chlorophenyl)sulfanyl]-1-methylpiperidine; 3-chlorophenyl 1-methyl-4-piperidinyl sulfide (viir)
Reference 1:
    morita, s.; yamasaki, k.; shimizu, t.; uchida, m.; otsubo, k.; kanbe, t.; synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1h)-quinolinon-4-yl]propionic acid (rebamipide). chem pharm bull 1991, 39, 11, 2906.

Route 4
the condensation of 4-(bromomethyl)quinolin-2(1h)-one (i) with diethyl acetamidomalonate (ii) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (iii), which is submitted to a decarboxylative hydrolysis with refluxing 20% hcl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (iv). finaily this compound is acylated with 4-chlorobenzoyl chloride by means of k2co3 in acetone water.
List of intermediates No.
2-methylenecyclopropanecarboxylic acid (i)
[(1s)-2-bromo-2-(bromomethyl)cyclopropyl]methyl acetate (v)
1-methyl-4-piperidinethiol; 1-methyl-4-piperidinylhydrosulfide (iv)
4-[(4-methoxybenzoyl)amino]butyric acid (ii)
7-fluoro-2-methyl-5,10-dihydro-4h-thieno[2,3-b][1,5]benzodiazepin-4-one (iii)
Reference 1:
    kanbe, t.; nakagawa, k.; morita, s.; uchida, m.; komatsu, m.; tabusa, f.; studies on 2(1h)-quinolinone derivatives as gastri. chem pharm bull 1985, 33, 9, 3775.
Reference 2:
    uchida, m.; komatsu, m.; nakagawa, k. (otsuka pharmaceutical co., ltd.); carbostyril derivs., process for their preparation. de 3324034; us 4578381 .

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瑞巴匹特 ;英文名Rebamipide;Pramipide;Proamipide;OPC-12759;Mucosta;CAS[111911-87-6]

 
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