【结 构 式】 |
【分子编号】45005 【品名】1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone 【CA登记号】 |
【 分 子 式 】C13H10FNO 【 分 子 量 】215.2269432 【元素组成】C 72.55% H 4.68% F 8.83% N 6.51% O 7.43% |
合成路线1
该中间体在本合成路线中的序号:(III)The lithium derivative of 4-picoline (I) was acylated with ethyl 4-fluorobenzoate (II) to afford ketone (III). Condensation of (III) with dimethylformamide dimethylacetal provided enaminone (IV) which was subsequently cyclized with hydroxylamine to give the diaryl isoxazole (V). Isoxazole ring opening in (V) under basic conditions led to keto nitrile (VI). Chlorination of (VI) by means of POCl3, followed by reaction with hydrazine, furnished the amino pyrazole (VII). The diazonium salt (VIII) prepared from amino pyrazole (VII) was then added to the phosphorane aldehyde (IX) to generate the pyrazolotriazine (X). Hydrogenation of the triazine ring of (X) employing NaBH3CN produced the tetrahydro pyrazolotriazine (XI). This was finally acylated by phenylglyoxylic acid (XII) to yield the target alpha-oxo amide.
【1】 Kawai, Y.; Yamazaki, H.; Tanaka, H.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolitriazines with interleukin-1 and tumour necrosis factor inhibitory activity. EP 0686156; JP 1996507056; WO 9419350 . |
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) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
(II) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
(III) | 45005 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
(IV) | 55996 | (Z)-3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridinyl)-2-propen-1-one | C16H15FN2O | 详情 | 详情 | |
(V) | 55997 | 4-[5-(4-fluorophenyl)-4-isoxazolyl]pyridine | C14H9FN2O | 详情 | 详情 | |
(VI) | 55998 | 3-(4-fluorophenyl)-3-oxo-2-(4-pyridinyl)propanenitrile | C14H9FN2O | 详情 | 详情 | |
(VII) | 55999 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-ylamine; 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine | C14H11FN4 | 详情 | 详情 | |
(VIII) | 56000 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-diazonium | C14H9FN5 | 详情 | 详情 | |
(IX) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
(X) | 56001 | 7-(4-fluorophenyl)-8-(4-pyridinyl)pyrazolo[5,1-c][1,2,4]triazine | C16H10FN5 | 详情 | 详情 | |
(XI) | 56002 | 7-(4-fluorophenyl)-8-(4-pyridinyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine | C16H14FN5 | 详情 | 详情 | |
(XII) | 55589 | Benzoylformic acid; Phenylglyoxylic acid | 611-73-4 | C8H6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)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 .
【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 |
合成路线3
该中间体在本合成路线中的序号:(VII)Acylation of the lithium derivative of 4-picoline (VI) with the Weinreb amide of 4-fluorobenzoic acid (V) yielded ketone (VII). The sodium enolate of (VII) was then alkylated with chloro ketone (IV) to afford diketone (VIII). The Paal-Knorr cyclization of diketone (VIII) in the presence of ammonium acetate in boiling HOAc led to pyrrole (IX). Finally, reduction of the benzyloxycarbonyl group of (IX) by means of LiAlH4 furnished the target N-methyl piperidine.
【1】 De Laszlo, S.E.; Mantlo, N.B.; Ponticello, G.S.; Selnick, H.G.; Liverton, N.J. (Merck & Co., Inc.); 2-Substd. aryl pyrroles, compsns. containing such cpds. and methods of use. EP 0863757; JP 1999510510; US 5792778; WO 9705877 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV) | 56084 | benzyl 4-(2-chloroacetyl)-1-piperidinecarboxylate | C15H18ClNO3 | 详情 | 详情 | |
(V) | 29514 | 4-fluoro-N-methoxy-N-methylbenzamide | C9H10FNO2 | 详情 | 详情 | |
(VI) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
(VII) | 45005 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
(VIII) | 56085 | benzyl 4-[4-(4-fluorophenyl)-4-oxo-3-(4-pyridinyl)butanoyl]-1-piperidinecarboxylate | C28H27FN2O4 | 详情 | 详情 | |
(IX) | 56086 | benzyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrrol-2-yl]-1-piperidinecarboxylate | C28H26FN3O2 | 详情 | 详情 |