Tefludazine, Lu-18012, -Drug Synthesis Database

【结构式】

【药物名称】Tefludazine, Lu-18012

【化学名称】trans-4-[3-(4-Fluorophenyl)-2,3-dihydro-6-(trifluoromethyl)-1H-inden-1-yl]-1-piperazineethanol
　　　　　　trans-4-[3-(p-Fluorophenyl)-6-(trifluoromethyl)-1-indanyl]-1-piperazineethanol
　　　　　　trans-1-[4-(2-Hydroxyethyl)-1-piperazinyl]-3-(4-fluorophenyl)-6-(trilfuoromethyl)indan

【CA登记号】80680-06-4

【分子式】C₂₂H₂₄F₄N₂O

【分子量】408.44298

【开发单位】Lundbeck (Originator)

【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS

合成路线1 合成路线2

合成路线1

The Sandmeyer reaction of 4-trifluoromethylanthranilic acid (I) with NaNO2, HBr and Cu2Br2 gives 2-bromo-4-trifluoromethylbenzoic acid (II), which by reaction with SOCl2 is converted into 2-bromo-4-trifluoromethylbenzoyl chloride (III). The Rosemind reduction of (III) with H2 over Pd/BaSO4/S yields 2-bromo-4-trifluoromethylbenzaldehyde (IV), which is condensed with ethyl cyanacetate (V) in refluxing toluene affording ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]propenoate (VI). The addition of 4-fluorophenylmagnesium bromide (VII) to (VI) in toluene ether gives ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoate (VIII), which is hydrolyzed and decarboxylated partially with H2SO4 in refluxing acetic acid water to yield 3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoic acid (IX). Cyclization of (IX) with butyllithium in ether affords 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-one (X), which is reducted with NaBH4 in methanol giving 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-ol (XI). The reaction of (XI) with SOCl2 in hot toluene yields 1-chloro-3-(4-fluorophenyl)-6-(trifluoromethyl)indan (XII).

参考文献中间体

【1】 Castaner, J.; Serradell, M.N.; Tefludazine. Drugs Fut 1984, 9, 5, 346.
【2】 Bogeso, K.P.; Neuroleptic activity and dopamine-uptake inhibition in 1-piperazino-3-phenylindans. J Med Chem 1983, 26, 7, 935-947.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIa)	34137	(1S,3R)-3-(4-fluorophenyl)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol		C₁₆H₁₂F₄O	详情	详情
(XIb)	34138	(1S,3S)-3-(4-fluorophenyl)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol		C₁₆H₁₂F₄O	详情	详情
(XIIa)	34139	(1R,3S)-3-chloro-1-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-indene		C₁₆H₁₁ClF₄	详情	详情
(XIIb)	34140	(1S,3S)-3-chloro-1-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-indene		C₁₆H₁₁ClF₄	详情	详情
(I)	34129	2-amino-4-(trifluoromethyl)benzoic acid		C₈H₆F₃NO₂	详情	详情
(II)	34130	2-bromo-4-(trifluoromethyl)benzoic acid		C₈H₄BrF₃O₂	详情	详情
(III)	34131	2-bromo-4-(trifluoromethyl)benzoyl chloride		C₈H₃BrClF₃O	详情	详情
(IV)	34132	2-bromo-4-(trifluoromethyl)benzaldehyde		C₈H₄BrF₃O	详情	详情
(V)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(VI)	34133	ethyl (Z)-3-[2-bromo-4-(trifluoromethyl)phenyl]-2-cyano-2-propenoate		C₁₃H₉BrF₃NO₂	详情	详情
(VII)	13643	4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide	352-13-6	C₆H₄BrFMg	详情	详情
(VIII)	34134	ethyl 3-[2-bromo-4-(trifluoromethyl)phenyl]-2-cyano-3-(4-fluorophenyl)propanoate		C₁₉H₁₄BrF₄NO₂	详情	详情
(IX)	34135	3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propionic acid		C₁₆H₁₁BrF₄O₂	详情	详情
(X)	34136	3-(4-fluorophenyl)-6-(trifluoromethyl)-1-indanone		C₁₆H₁₀F₄O	详情	详情

合成路线2

Compound (XII) is finally condensed with piperazine-ethanol (XIII) in refluxing butanone. The separation of the trans isomer is performed by precipitation of the oxalate, treatment with dimethyl-amine in water and extraction with ether.

参考文献中间体

【1】 Bogeso, K.P.; Neuroleptic activity and dopamine-uptake inhibition in 1-piperazino-3-phenylindans. J Med Chem 1983, 26, 7, 935-947.
【2】 Castaner, J.; Serradell, M.N.; Tefludazine. Drugs Fut 1984, 9, 5, 346.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIIa)	34139	(1R,3S)-3-chloro-1-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-indene		C₁₆H₁₁ClF₄	详情	详情
(XIIb)	34140	(1S,3S)-3-chloro-1-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-indene		C₁₆H₁₁ClF₄	详情	详情
(XIII)	21893	2-(1-piperazinyl)-1-ethanol; 1-piperazineethanol; 1-(2-Hydroxyethyl)piperazine	103-76-4	C₆H₁₄N₂O	详情	详情
(XIV)	34141	2-[4-[(1S,3S)-3-(4-fluorophenyl)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-1-piperazinyl]-1-ethanol		C₂₂H₂₄F₄N₂O	详情	详情

Extended Information