合成路线:Befloxatone is obtained by condensation of 1,1,1-trifluoro-4-(tosyloxy)-2(R)-butanol (I) with 3-(4-hydroxyphenyl)-5(R)-(methoxymethyl)oxazolidin-2-one (II) by means of K2CO3 in hot DMF.
合成路线:1) Synthesis of Butanol (I):1a) The reduction of 4,4,4-trifluoro-2-oxobutyric acid ethyl ester (III) with NaBH4 in dichloromethane gives 4,4,4-trifluoro-2-hydroxybutyric acid ethyl ester (IV),which is hydrolyzed with NaOH in ethanol,yielding the corresponding acid (V).The optical resolution of (V) with 1(S)-phenylethylamine in hot ethanol affords the 3(R)-hydroxy enantiomer (VI) (1,3),which is reduced with NaBH4 and BF3 ethearate in THF to provide 4,4,4-trifluorobutane-1,3(R)-diol (VII).Finally,this compound is monotosylated by means of tosyl chloride and DMAP in pyridine to afford intermediate (I).1b) The digestion of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester (IV) with Novozym in a phosphate buffer gives the corresponding (R)-enantiomer (VIII),which is reduced with NaBH4 in ethanol,yielding 4,4,4-trifluorobutane-1,3(R)-diol (VII) (4).Finally,this compound is monotosylated by means of tosyl chloride as before to give butanol (I).
合成路线:2) Synthesis of Oxazolidinone (II):2a) The reaction of 4-benzyloxyaniline (IX) with 1,4-dioxaspiro[4.5]decan-2(S)-ylmethyl methanesulfonate (X) by means of TEA at 140 C gives 3-(4-benzyloxyphenylamino)propane-1,2(R)-diol (XI),which is cyclized with diethyl carbonate and sodium methoxide in refluxing toluene,yielding 3-(4-benzyloxyphenyl)-5(R)-(hydroxymethyl)oxazolidin-2-one (XII).The methylation of (XII) with dimethyl sulfate,NaOH and tetrabutylammonium bisulfate in hot toluene/water affords the corresponding methoxymethyl derivative (XIII).Finally,this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol/dichloromethane to give oxazolidinone (II).2b) The methylation of 4(S)-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (XIV) with dimethyl sulfate and NaOH gives 4(S)-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane (XV),which is hydrolyzed with hot aqueous HCl to 3-methoxypropane-1,2(R)-diol (XVI).The cyclization of (XVI) with diethyl carbonate by means of NaH affords 4(S)-(methoxymethyl)-1,3-dioxolan-2-one (XVII) (2,5).The condensation of (XVII) with N-(4-benzyloxyphenyl)carbamic acid methyl ester (XVIII) (obtained by reaction of 4-benzyloxyaniline (IX) with methyl chloroformate) by means of K2CO3 at 160 C provides the protected oxazolidinone (XIII),which is finally debenzylated as before to give oxazolidinone (II).
参考文献标题:3-Aryl-oxazolidinone derivs.,process for their preparation and their use in therapeutics
文献作者:Jarreau,F.-X.; Koenig,J.-J.; Rovei,V.(Laboratoires Delalande)
参考来源:EP 0511031; FR 2675504; JP 1993112542; US 5264443
合成路线:Befloxatone is obtained by condensation of 1,1,1-trifluoro-4-(tosyloxy)-2(R)-butanol (I) with 3-(4-hydroxyphenyl)-5(R)-(methoxymethyl)oxazolidin-2-one (II) by means of K2CO3 in hot DMF.
合成路线:1) Synthesis of Butanol (I):1a) The reduction of 4,4,4-trifluoro-2-oxobutyric acid ethyl ester (III) with NaBH4 in dichloromethane gives 4,4,4-trifluoro-2-hydroxybutyric acid ethyl ester (IV),which is hydrolyzed with NaOH in ethanol,yielding the corresponding acid (V).The optical resolution of (V) with 1(S)-phenylethylamine in hot ethanol affords the 3(R)-hydroxy enantiomer (VI) (1,3),which is reduced with NaBH4 and BF3 ethearate in THF to provide 4,4,4-trifluorobutane-1,3(R)-diol (VII).Finally,this compound is monotosylated by means of tosyl chloride and DMAP in pyridine to afford intermediate (I).1b) The digestion of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester (IV) with Novozym in a phosphate buffer gives the corresponding (R)-enantiomer (VIII),which is reduced with NaBH4 in ethanol,yielding 4,4,4-trifluorobutane-1,3(R)-diol (VII) (4).Finally,this compound is monotosylated by means of tosyl chloride as before to give butanol (I).
合成路线:2) Synthesis of Oxazolidinone (II):2a) The reaction of 4-benzyloxyaniline (IX) with 1,4-dioxaspiro[4.5]decan-2(S)-ylmethyl methanesulfonate (X) by means of TEA at 140 C gives 3-(4-benzyloxyphenylamino)propane-1,2(R)-diol (XI),which is cyclized with diethyl carbonate and sodium methoxide in refluxing toluene,yielding 3-(4-benzyloxyphenyl)-5(R)-(hydroxymethyl)oxazolidin-2-one (XII).The methylation of (XII) with dimethyl sulfate,NaOH and tetrabutylammonium bisulfate in hot toluene/water affords the corresponding methoxymethyl derivative (XIII).Finally,this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol/dichloromethane to give oxazolidinone (II).2b) The methylation of 4(S)-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (XIV) with dimethyl sulfate and NaOH gives 4(S)-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane (XV),which is hydrolyzed with hot aqueous HCl to 3-methoxypropane-1,2(R)-diol (XVI).The cyclization of (XVI) with diethyl carbonate by means of NaH affords 4(S)-(methoxymethyl)-1,3-dioxolan-2-one (XVII) (2,5).The condensation of (XVII) with N-(4-benzyloxyphenyl)carbamic acid methyl ester (XVIII) (obtained by reaction of 4-benzyloxyaniline (IX) with methyl chloroformate) by means of K2CO3 at 160 C provides the protected oxazolidinone (XIII),which is finally debenzylated as before to give oxazolidinone (II).
参考文献标题:Befloxatone
文献作者:Castar,J.; Sorbera,L.A.; Rabasseda,X.
参考来源:Drugs Fut 1999,24(10),1057
产品链接: CAS No. 134564-82-2››