【药物名称】Tiflucarbine, TVX-P-4495
化学结构式(Chemical Structure):
参考文献No.687
标题:7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, a process for their preparation and medicaments containing them
作者:Sch鰈lnhammer, G.; Seidel, P.-R. (Troponwerke GmbH & Co KG)
来源:EP 0120439; US 4816461
合成路线图解说明:

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No.58314
标题:Tiflucarbine
作者:Glaser, T.; Seidel, P.-R.
来源:Drugs Fut 1987,12(6),562
合成路线图解说明:

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No.700521
标题:
作者:Urda, E.; Sahi, J.; Wen, Y.-H.; et al.
来源:IXth Intl Symp Med Chem (September 14-18, Berlin) 1986,30(9),977
合成路线图解说明:

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.

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