合成路线:The synthesis of 10-EDAM is as follows:3-Methoxyallyl chloride (II) is prepared in situ by treatment of 1-methoxyallene (I) with an equivalent of HCl in ether at low temperature.The dianion of p-n-propylbenzoic acid is generated in THF at 0-5 C by lithium diisopropyl amide and subsequently alkylated with (II).The resulting 4-(p-carboxyphenyl)-1-methoxy-1-hexene (III) is brominated at pH 7-8 to give the alpha-bromoaldehyde acid (IV).Condensation with tetraaminopyrimidine in aqueous AcOH and subsequent in situ oxidation of the resultant dihydropteridine affords crystalline 10-ethyl-10-deaza-4-amino-4-desoxypteroic acid (V).Coupling of (V) with diethyl L-glutamate via the mixed anhydride method using isobutyl chloroformate affords the diethyl ester of 10-EDAM (VI).Following chromatographic purification on silica gel,the diester is saponified with 1N NaOH in methoxyethanol at room temperature to yield 10-EDAM.
参考文献标题:Acid catalyzed ring closure of 1-methoxy or 1-(methylthio)-1-(alpha or beta-hydroxyalkyl)allenes
文献作者:Hoff,S.; Brandsma,L.
参考来源:Recl Trav Chim Pays-Bas 1969,88845
合成路线:A new synthesis for edatrexate has been described:The reaction of 2,4-diamino-6-(bromomethyl)pteridine (I) with tributylphosphine (II) in DMSO gives the corresponding phosphonium salt (III),which is condensed wtih 4-propionylbenzoic acid methyl ester (IV) by means of NaH in DMSO,affording 4-[1-(2,4-diaminopteridin-6-yl)-1-ethylvinyl]benzoic acid methyl ester (V).The hydrogenation of (V) with H2 and PtO2 in acetic acid gives 4-[1-(2,4-diamino-6,7-dihydropteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VI),which,without isolation,is dehydrogenated with H2O2 in the same solvent yielding 4-[1-(2,4-diaminopteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VII).The hydrolysis of (VII) with NaOH in DMSO - water affords the corresponding free acid (VIII),which is condensed with L-glutamic acid diethyl ester (IX) by means of isobutoxycarbonylchloride and triethylamine in DMF,giving edatrexate diethyl ester (X).Finally,this compound is hydrolyzed with NaOH in methanol.
参考文献标题:Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10-dideazaaminopterin and an alternative synthesis of 10-ethyl-10-deazaaminopterin (edatrexate)
文献作者:Piper,J.R.; Johnson,C.A.; Otter,G.M.; Sirotnak,F.M.
参考来源:J Med Chem 1992,35(16),3002
产品链接: CAS No. 80576-83-6››