合成路线:The key dihydroxy ester intermediate (XIII) was also obtained by asymmetric hydrogenation of hydroxy ketoester (XLIII) in the presence of (S)-BINAP-dichlororuthenium catalyst.The precursor hydroxy ketoester (XLIII) was prepared by two alternative procedures.In one method,the racemic dihydroxy ester (XLII) was selectively oxidized to (XLIII) by means of NaOCl.In another method,the unsaturated keto ester (XLIV) was epoxidized by means of sodium percarbonate,and the resultant epoxide (XLV) was then reduced to the hydroxy ketoester (XLIII) by catalytic hydrogenation over PtO2.
参考文献标题:Method for producing enantiomer-free 6,8-dihydroxyoctanoic acid esters by means of asymmetric,catalytic hydrogenation
文献作者:Gewald,R.(Asta Medica AG)
参考来源:DE 10036516; WO 0210113
合成路线:Both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (LX) were separated employing either (+)- or (-)-alpha-methylbenzylamine.Esterification of the (R)-(-)-enantiomer with HCl-MeOH provided the chloro hydroxy ester (LXI).Further chlorination of (LXI) with SOCl2 and pyridine proceeded with inversion of configuration at C-6 to furnish the (S)-dichloro derivative (LXII).The cyclic disulfide (L) was then prepared by treatment of chloride (LXII) with sulfur and sodium sulfide in boiling EtOH.Basic hydrolysis of the methyl ester group of (LXII) then afforded (R) alpha lipoic acid.The title compound was also obtained from the (S)-(+)-acid (LXIII).Reaction of hydroxy acid (LXIII) with methanesulfonyl chloride produced the chloro mesylate (LXIV),which was then cyclized to the target disulfide in the presence of sulfur and Na2S.
合成路线:The reaction of the chiral dibenzoyloxy-dihydropyran (LXV) with H2SO4 and HgSO4 gives the unsaturated aldehyde (LXVI),which is condensed with the phosphorane (LXVII) to yield the hepatdienoic ester (LXVIII).The hydrogenation of (LXVIII) with H2 over Pd/C affords the heptanoic ester (LXIX),which is treated with Ts-Cl and pyridine to provide the tosyloxy derivative (LXX).The cyclization of (LXX) by means of K2CO3 gives the chiral epoxide (LXXI),which is condensed with vinylmagnesium bromide (LXXII) to yield 6(S)-hydroxy-8-nonenoic acid methyl ester (LXXIII).The oxidation of the terminal double bond of (LXXIII) with ozone affords the carbaldehyde (LXXIV),which is reduced with NaBH4 to provide 6(S),8-dihydroxyoctanoic acid methyl ester (XLVIII).The reaction of (XLVIII) with Ms-Cl and pyridine gives the dimesylate (XLIX),which is treated with Na2S2 to yield the lipoic acid methyl ester (L),which is hydrolyzed to the target acid with KOH in H2O.
参考文献标题:Synthesis of R(+)alpha-lipoic acid
文献作者:Villani,F.; Nardi,A.; Salvi,A.; Falabella,G.
参考来源:WO 0230919
合成路线:Alkylation of the lithio-dianion of propargyl alcohol (XIII) with 6-bromo-1-hexene (XIV),followed by in situ reduction of the resultant disubstituted acetylene with lithium metal gave the allylic alcohol (XV).Asymmetric Sharpless epoxidation of (XV) using tert-butyl hydroperoxide in the presence of L-(+)-diisopropyl tartrate afforded the (S,S)-epoxy alcohol (XVI).This was reduced to the chiral diol (XVII) employing Red-Al?in THF.After formation of the bis-mesylate (XVIII),oxidative cleavage of the terminal double bond by means of NaIO4 in the presence of ruthenium catalyst furnished the carboxylic acid (XIX).The mesylate groups were finally displaced by sodium disulfide to produce the desired cyclic disulfide compound.
参考文献标题:Process for the preparation of pure enantiomers of R-(+)-alpha-lipoic acid and S-(-)-alpha-lipoic acid (thioctic acid),and nonene or mesyl derivs.as intermediates thereof
文献作者:Sutherland,I.O.; Page,P.C.B.; Rayner,C.M.(Asta Medica AG)
参考来源:DE 3629116; EP 0261336
合成路线:Both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (LX) were separated employing either (+)- or (-)-alpha-methylbenzylamine.Esterification of the (R)-(-)-enantiomer with HCl-MeOH provided the chloro hydroxy ester (LXI).Further chlorination of (LXI) with SOCl2 and pyridine proceeded with inversion of configuration at C-6 to furnish the (S)-dichloro derivative (LXII).The cyclic disulfide (L) was then prepared by treatment of chloride (LXII) with sulfur and sodium sulfide in boiling EtOH.Basic hydrolysis of the methyl ester group of (LXII) then afforded (R) alpha lipoic acid.The title compound was also obtained from the (S)-(+)-acid (LXIII).Reaction of hydroxy acid (LXIII) with methanesulfonyl chloride produced the chloro mesylate (LXIV),which was then cyclized to the target disulfide in the presence of sulfur and Na2S.
参考文献标题:Preparation and use of the pure enantiomers of 8-chloro-6-sulfonyloxy-octanoic acid and its alkyl esters and of the pure enantiomers of 6,8-dichloro-octanoic acid and its alkyl esters
文献作者:Laban,G.; Beisswenger,T.; Gewald,R.(AWD.pharma GmbH & Co.KG)
参考来源:DE 19533881; EP 0763533; US 5731448
合成路线:Both enantiomers of racemic 8-chloro-6-hydroxyoctanoic acid (LX) were separated employing either (+)- or (-)-alpha-methylbenzylamine.Esterification of the (R)-(-)-enantiomer with HCl-MeOH provided the chloro hydroxy ester (LXI).Further chlorination of (LXI) with SOCl2 and pyridine proceeded with inversion of configuration at C-6 to furnish the (S)-dichloro derivative (LXII).The cyclic disulfide (L) was then prepared by treatment of chloride (LXII) with sulfur and sodium sulfide in boiling EtOH.Basic hydrolysis of the methyl ester group of (LXII) then afforded (R) alpha lipoic acid.The title compound was also obtained from the (S)-(+)-acid (LXIII).Reaction of hydroxy acid (LXIII) with methanesulfonyl chloride produced the chloro mesylate (LXIV),which was then cyclized to the target disulfide in the presence of sulfur and Na2S.
参考文献标题:Preparation and utilisation of pure enantiomers of 8-halogen-6-hydroxyoctanoic acid,their alkyl esters and their salts with pure enantiomers of alpha-methyl-benzylamines
文献作者:Laban,G.; Beisswenger,T.; Gewald,R.(AWD.pharma GmbH & Co.KG)
参考来源:DE 19533882; EP 0763516; US 5869713
合成路线:A synthetic route based on the asymmetric reduction of oxo diesters has been reported.Meldrum's acid (LII) was acylated by methyl adipoyl chloride (LI) in the presence of pyridine to produce the intermediate (LIII) which,upon alcoholysis with isobutanol,led to oxo diester (LIV).Enantioselective reduction of (LIV) by means of baker's yeast furnished the (S)-hydroxy diester (LV).Alternatively,the analogous oxo diester (LVI) was prepared by acylation of methyl acetoacetate with methyl adipoyl chloride (LI),followed by deacetylation in the presence of ammonium hydroxide.Then,asymmetric chemical reduction of (LVI) by hydrogenation in the presence of the chiral catalyst Ru2Cl4[(S)-BINAP]2 provided the (S)-hydroxy diester (LVII).Regioselective reduction of either diester (LV) or (LVII) by means of NaBH4 in refluxing THF furnished dihydroxy ester (XLVIII).After conversion of (XLVIII) to the dimesylate (XLIX),displacement with potassium thioacetate afforded the bis(acetylthio) derivative (LVIII),which was further hydrolyzed with KOH to provide dihydrolipoic acid (LIX).In a related procedure,dihydrolipoic acid (LIX) was prepared by reaction of dimesylate (XLIX) with sodium disulfide,followed by reductive treatment with NaBH4 and NaOH.The title cyclic disulfide was then obtained by oxidation of the dithiol (LIX) using oxygen in the presence of FeCl3.
参考文献标题:Process for the preparation of enantiomerically pure diesters of 3-hydroxyoctandioic acid by asymmetric catalytic hydrogenation
文献作者:Laban,G.; Gewald,R.(Asta Medica AG)
参考来源:DE 19709069; EP 0863125; US 6013833
产品链接: CAS No. 1200-22-2››