Tiflucarbine, TVX-P-4495

合成路线:The reaction of 2-chloro-3,5-dinitrobenzoic acid (I) with thionil chloride,followed by treatment with diethyl ethoxymagnesium malonate gives diethyl 2-chloro-3,5-dinitrobenzoylmalonate (II),which is hydrolyzed and decarboxylated in hot sulfuric acid/propionic acid yielding 2-chloro-3,5-dinitroacetophenone (III).Reaction of (III) with thioglycolic acid by means of NaHCO3 in refluxing isopropanol gives the thioacetic acid compound (IV),which is cyclized in refluxing propionic acid yielding 3-methyl-5,7-dinitrobenzothiophene (V).Partial selective reduction of one of the nitro groups in (V) by means of ammonium sulfide in ethanol leads to 7-amino-3-methyl-5-nitrobenzothiophene (VI),which is diazotied by treatment with NaNO2 in hydrochloric acid.The following reaction with diethylamine in alkaline solution gives the triazene derivative (VII),which is finally fluorinated by reaction with anhydrous HF yielding 7-fluoro-3-methyl-5-nitrobenzothiophene (VIII).Catalytical reduction of (VIII) yields 5-amino-7-fluoro-3-methylbenzothiophene (IX),which is converted to 5-hydrazino-7-fluoro-3-methylbenzothiophene (X) by diazotation and subsequent reduction by means of stannous chloride in hydrochloric acid.The reaction of (X) with N-ethyl-4-piperidone (XI) in refluxing isopropanol gives the corresponding hydrazone,which is cyclized in refluxing isopropanol/HCl yiellding tiflucarbine base.Finally,this compound is converted to the lactate by means of lactic acid in acetone.

参考文献标题:Tiflucarbine
文献作者:Glaser,T.; Seidel,P.-R.
参考来源:Drugs Fut 1987,12(6),562


合成路线:The reaction of 2-chloro-3,5-dinitrobenzoic acid (I) with thionil chloride,followed by treatment with diethyl ethoxymagnesium malonate gives diethyl 2-chloro-3,5-dinitrobenzoylmalonate (II),which is hydrolyzed and decarboxylated in hot sulfuric acid/propionic acid yielding 2-chloro-3,5-dinitroacetophenone (III).Reaction of (III) with thioglycolic acid by means of NaHCO3 in refluxing isopropanol gives the thioacetic acid compound (IV),which is cyclized in refluxing propionic acid yielding 3-methyl-5,7-dinitrobenzothiophene (V).Partial selective reduction of one of the nitro groups in (V) by means of ammonium sulfide in ethanol leads to 7-amino-3-methyl-5-nitrobenzothiophene (VI),which is diazotied by treatment with NaNO2 in hydrochloric acid.The following reaction with diethylamine in alkaline solution gives the triazene derivative (VII),which is finally fluorinated by reaction with anhydrous HF yielding 7-fluoro-3-methyl-5-nitrobenzothiophene (VIII).Catalytical reduction of (VIII) yields 5-amino-7-fluoro-3-methylbenzothiophene (IX),which is converted to 5-hydrazino-7-fluoro-3-methylbenzothiophene (X) by diazotation and subsequent reduction by means of stannous chloride in hydrochloric acid.The reaction of (X) with N-ethyl-4-piperidone (XI) in refluxing isopropanol gives the corresponding hydrazone,which is cyclized in refluxing isopropanol/HCl yiellding tiflucarbine base.Finally,this compound is converted to the lactate by means of lactic acid in acetone.
参考文献标题:
文献作者:Urda,E.; Sahi,J.; Wen,Y.-H.; et al.
参考来源:IXth Intl Symp Med Chem (September 14-18,Berlin) 1986,30(9),977


产品链接: CAS No. 89875-86-5››