Levonantradol hydrochloride, NSC-331615, CP-50556-1

左南曲朵 Chemical Name: Acetic acid (-)-(6S,6aR,9R,10aR)-9-hydroxy-6-methyl-3-[1(R)-1-methyl-4-phenylbutoxy]-5,6,6a,7,8,9,10,10a-octahydrophenanthridin-1-yl ester hydrochloride
CAS No. 70222-86-5, 71048-87-8 (free base)
项目整合开发状态: Biological Testing
项目研究机构:
合成路线:Synthesis of intermediate (XI): The reaction of 3,5-dimethoxyaniline (I) with ethyl acetoacetate (II) by means of acetic acid in refluxing benzene gives ethyl 3-(3,5-dimethoxyanilino)-2-butenoate (III),which is reduced with NaBH4 in methanol or with H2 over Pt in acetic acid affording ethyl 3-(3,5-dimethoxyanilino)butyrate (IV).The reaction of (IV) with ethyl chloroformate (V) in pyridine yields ethyl 3-(3,5-dimethoxy-N-ethoxycarbonylanilino)butyrate (VI),which is hydrolyzed with diluted NaOH in ethanol giving 3-(3,5-dimethoxy-N-ethoxycarbonylanilino)butyric acid (VII).The cyclization of (VII) with polyphosphoric acid in hot CHCl3 affords 1-ethoxycarbonyl-5,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (VIII),which is hydrolyzed with refluxing 48% aqueous HBr to give 5,7-dihydroxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (XI).The tetrahydroquinolone (XI) can also be obtained by condensation-cyclization of 3,5-dimethoxyaniline (I) with crotonic acid (IX) or its methyl ester (X) by means of acetic acid or pyridine,followed by a treatment with aqueous HBr to hydrolyze the methoxy groups.

合成路线:The condensation of (XI) with 5-phenyl-2-pentanol (XII) by means of triethylamine in THF yields 5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline (XIII),which is formylated with ethyl formate by means of NaH affording 1-formyl-5-hydroxy-3-hydroxymethylen-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-1,2,3,4-tetrahydroquinoline (XIV).The reaction of (XIV) with methyl vinyl ketone (XV) by means of triethylamine in methanol yields 1,3-diformyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3(3-oxobutyl-1,2,3,4-tetrahydroquinoline (XVI),which by treatment with K2CO3 in ether is converted into 1-formyl-5-hydroxy-2-methyl-7-(5-phenyl-2-pentyloxy)-4-oxo-3(3-oxobutyl-1,2,3,4-tetrahydroquinoline (XVII).The cyclization of (XVII) with KOH in refluxing methanol gives 5,6,6a,7-tetrahydro-1-5-hydroxy-6beta-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinoline-9(8H)-one (XVIII),which is treated first with Li in liquid NH3,and then with acetic anhydride to afford 5,6,6a,7,10,10a-hexahydro-1-acetoxy-6beta-methyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinoline-9(8H)-one (XIX).Finally this compound is reduced with NaBH4 in ethanol.