4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine -Drug Synthesis Database

【结构式】

【分子编号】33798

【品名】4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine

【CA登记号】

【分子式】C₁₄H₁₀FN₃

【分子量】239.2520232

【元素组成】C 70.28% H 4.21% F 7.94% N 17.56%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

Selenium dioxide oxidation of diaryl ethanone (I) afforded diketone (II), which was cyclized to the imidazole (III) by reaction with hexamethylenetetramine and ammonium acetate in hot AcOH. Alkylation of (III) with 1-bromo-3-phenylpropane (IV) in the presence of NaH gave rise to a mixture of regioisomeric imidazoles (V) and (VI) that were separated by column chromatography. After deprotonation of the desired isomer (V) with LDA, treatment with iodine produced iodoimidazole (VII). Then, palladium-catalyzed coupling of (VII) with 3-butyn-1-ol (VIII) yielded the title compound.

参考文献中间体

合成目标

【1】 Malloy, E.; Wachter, M.P.; Wu, W.; Beers, S.A. (Ortho-McNeil Pharmaceutical, Inc.); Substd. imidazoles useful in the treatment of inflammatory diseases. EP 1028954; US 5965583; WO 9847892 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	37912	2-(4-fluorophenyl)-1-(4-pyridinyl)-1-ethanone		C₁₃H₁₀FNO	详情	详情
(II)	37913	1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanedione		C₁₃H₈FNO₂	详情	详情
(III)	33798	4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine		C₁₄H₁₀FN₃	详情	详情
(IV)	20884	1-(3-bromopropyl)benzene	637-59-2	C₉H₁₁Br	详情	详情
(V)	37914	4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-1H-imidazol-5-yl]pyridine		C₂₃H₂₀FN₃	详情	详情
(VI)	37915	4-[5-(4-fluorophenyl)-1-(3-phenylpropyl)-1H-imidazol-4-yl]pyridine		C₂₃H₂₀FN₃	详情	详情
(VII)	37916	4-[4-(4-fluorophenyl)-2-iodo-1-(3-phenylpropyl)-1H-imidazol-5-yl]pyridine		C₂₃H₁₉FIN₃	详情	详情
(VIII)	32507	3-butyn-1-ol	927-74-2	C₄H₆O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The known diarylimidazole (I) was protected as the N-[2-(trimethylsilyl)ethoxy]methyl derivative (II) by treatment with 2-(trimethylsilyl)ethoxymethyl chloride and NaH. Lithiation of (II) with BuLi at -78 C, followed by quenching with N-formylmorpholine (III) provided aldehyde (IV). This was converted to the dimethyl acetal (V) upon treatment with trimethyl orthoformate and p-toluenesulfonic acid. Further condensation of (V) with methyl 2,2-bis(hydroxymethyl)propionate (VI) produced the dioxane derivative (VII) as a mixture of cis and trans isomers. Basic hydrolysis of the methyl ester group of (VII) afforded the corresponding carboxylic acid. The desired trans isomer (VIII) was then isolated by selective precipitation of the acidified methanolic solution. Finally, coupling of (VIII) with morpholine (IX) using EDC and HOBt furnished the title amide.

参考文献中间体

合成目标

【1】 McLay, I.M.; Halley, F.; Souness, J.E.; et al.; The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-anthritic efficacy. Bioorg Med Chem 2001, 9, 2, 537.
【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	33798	4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine		C₁₄H₁₀FN₃	详情	详情
(II)	33799	[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine		C₂₀H₂₄FN₃OSi	详情	详情
(III)	33800	4-morpholinecarbaldehyde	4394-85-8	C₅H₉NO₂	详情	详情
(IV)	33801	4-(4-fluorophenyl)-5-(4-pyridinyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-carbaldehyde		C₂₁H₂₄FN₃O₂Si	详情	详情
(V)	33802	[2-(dimethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(2-(dimethoxymethyl)-4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine		C₂₃H₃₀FN₃O₃Si	详情	详情
(VI)	33803	methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate		C₆H₁₂O₄	详情	详情
(VII)	33804	methyl 2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylate		C₂₁H₂₀FN₃O₄	详情	详情
(VIII)	33805	2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylic acid		C₂₀H₁₈FN₃O₄	详情	详情
(IX)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

1-(4-Fluorophenyl)-2-(4-pyridyl)ethanone (I) was brominated in HOAc to yield bromoketone (II). Reaction of (II) with ammonium oxalate in formamide at 200 C produced a 1:1 mixture of imidazole (III) and oxazole (IV). After isolation of the desired oxazole (IV), its lithiation with n-butyllithium followed by addition to N-methyl-4-piperidinone (V) furnished the corresponding carbinol .

参考文献中间体

合成目标

【1】 Zimmerlin, A.G.; Di Padova, F.E.; Revesz, L.; Manning, U.; Gram, H.; Hiestand, P.; Buhl, T.; Feifel, R.; SAR of 4-hydroxypiperidine and hydroxyalkyl substituted heterocycles as novel p38 MAP kinase inhibitors. Bioorg Med Chem Lett 2000, 10, 11, 1261.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	45005	1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone		C₁₃H₁₀FNO	详情	详情
(II)	45006	2-bromo-1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone	4736-60-1	C₁₃H₉BrFNO	详情	详情
(III)	45007	4-[4-(4-fluorophenyl)-1,3-oxazol-5-yl]pyridine		C₁₄H₉FN₂O	详情	详情
(IV)	33798	4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine		C₁₄H₁₀FN₃	详情	详情
(V)	10919	1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one	1445-73-4	C₆H₁₁NO	详情	详情

Extended Information