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              藥物詳細合成路線

              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 .

              來源:藥化網

              作者:藥化小編

              摘要:本文合成路線介紹的是藥物中文名瑞巴匹特 ;英文名Rebamipide;Pramipide;Proamipide;OPC-12759;Mucosta;CAS[111911-87-6]

               
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