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【结 构 式】 
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【分子编号】51857 【品名】3-carboxy-2,4-dimethyl-1-pyridiniumolate 【CA登记号】 |
【 分 子 式 】C8H9NO3 【 分 子 量 】167.1644 【元素组成】C 57.48% H 5.43% N 8.38% O 28.71% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Protection of isonipecotic acid (I) as the trifluoroacetamide (II), followed by treatment with thionyl chloride, afforded acid chloride (III). Friedel-Crafts reaction of acid chloride (III) with bromobenzene (IV) gave ketone (V), which was further protected as the ethylene ketal (VI). The trifluoroacetamide group of (VI) was then hydrolyzed to amine (VII) using K2CO3 in MeOH. Condensation of amine (VII) with N-Boc-4-piperidone (VIII) in the presence of titanium isopropoxide, and subsequent addition of diethylaluminum cyanide to the intermediate iminium salt, provided amino nitrile (IX). Treatment of (IX) with methylmagnesium bromide afforded the methyl derivative (X). Acid hydrolysis of the ketal and Boc groups of (X), followed by reprotection with Boc2O, furnished ketone (XI). Oxime formation in (XI) with O-ethyl hydroxylamine produced a 1.5:1 mixture of (E)- and (Z)-isomers, which were separated by silica gel chromatography. Previous equilibration of the mixture under acidic conditions favored the desired (Z)-isomer (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid. The resultant piperidine (XIII) was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XIV) using EDC and HOBt to furnish the title compound.
| 【1】 Palani, A.; et al.; Discovery of 4-[(Z)-(4-bromophenyl)-(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide (SCH 351125). An orally bioavailable human CCR5 antagonist for the treatment of HIV infection. J Med Chem 2001, 44, 21, 3339. |
| 【2】 Palani, A.; et al.; Synthesis, SAR, and biological evaluation of oximino-piperidino-pieperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. J Med Chem 2002, 45, 14, 3143. |
| 【3】 McCombie, S.W.; Clader, J.W.; Baroudy, B.M.; McKittrick, B.A.; Josien, H.B.; Tagat, J.R.; Vice, S.F.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Neustadt, B.R.; Palani, A. (Schering Corp.); Piperidine derivs. useful as CCR5 antagonists. EP 1175402; WO 0066559 . |
| 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) | 17402 | 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid | 498-94-2 | C6H11NO2 | 详情 | 详情 |
| (II) | 51847 | 1-(2,2,2-trifluoroacetyl)-4-piperidinecarboxylic acid | C8H10F3NO3 | 详情 | 详情 | |
| (III) | 51848 | 1-(2,2,2-trifluoroacetyl)-4-piperidinecarbonyl chloride | C8H9ClF3NO2 | 详情 | 详情 | |
| (IV) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (V) | 51849 | 1-[4-(4-bromobenzoyl)-1-piperidinyl]-2,2,2-trifluoro-1-ethanone | C14H13BrF3NO2 | 详情 | 详情 | |
| (VI) | 51850 | 1-[4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]-2,2,2-trifluoro-1-ethanone | C16H17BrF3NO3 | 详情 | 详情 | |
| (VII) | 51851 | 4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]piperidine | C14H18BrNO2 | 详情 | 详情 | |
| (VIII) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (IX) | 51852 | C25H34BrN3O4 | 详情 | 详情 | ||
| (X) | 51853 | C25H37BrN2O4 | 详情 | 详情 | ||
| (XI) | 51854 | C23H33BrN2O3 | 详情 | 详情 | ||
| (XII) | 51855 | C25H38BrN3O3 | 详情 | 详情 | ||
| (XIII) | 51856 | C20H30BrN3O | 详情 | 详情 | ||
| (XIV) | 51857 | 3-carboxy-2,4-dimethyl-1-pyridiniumolate | C8H9NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Enantioselective reduction of 4-trifluoromethylacetophenone (I) with borane-methyl sulfide complex in the presence of the chiral oxaborolidine (II) provided the (R)-alcohol (III) in high enantiomeric excess. Treatment of (III) with methanesulfonyl chloride and Et3N yielded the corresponding mesylate (IV). Displacement of the mesylate group of (IV) with the Boc-protected piperazine (V) produced the desired (S,S)-alpha-methylbenzyl piperazine (VI) as the major isomer. Separation from minor amounts of the (R,S)-diastereomer was effected by flash chromatography. After acid cleavage of the Boc protecting group of (VI), the resultant piperazine (VII) was subjected to a modified Strecker reaction with N-Boc-piperidone (VIII) and diethylaluminum cyanide, yielding amino nitrile (IX). A methyl group was then introduced at the 4-position of the piperidine (IX) by displacement of the cyano group with methylmagnesium bromide to yield (X). Subsequent acidic Boc group cleavage in (X) gave piperidine (XI). This was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XII) to furnish the title compound.
| 【1】 Tagat, J.R.; Steensma, R.W.; McCombie, S.W.; Nazareno, D.V.; Lin, S.-I.; Neustadt, B.R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M.G.; Vantuno, N.; Baroudy, B.M.; Strizki, J.M.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent. J Med Chem 2001, 44, 21, 3343. |
| 【2】 Labroli, M.A.; Smith, E.M.; Baroudy, B.M.; Gilbert, E.; Tagat, J.R.; Josien, H.B.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Clader, J.W.; McKittrick, B.A.; Neustadt, B.R.; Palani, A.; McCombie, S.W.; Vice, S.F. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. EP 1175401; WO 0066558 . |
| 【3】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 6391865 . |
| 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) | 39907 | 1-[4-(trifluoromethyl)phenyl]-1-ethanone | 709-63-7 | C9H7F3O | 详情 | 详情 |
| (II) | 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 |
| (III) | 51861 | (1R)-1-[4-(trifluoromethyl)phenyl]-1-ethanol | C9H9F3O | 详情 | 详情 | |
| (IV) | 51862 | (1R)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate | C10H11F3O3S | 详情 | 详情 | |
| (V) | 51868 | tert-butyl (3S)-3-methyl-1-piperazinecarboxylate | C10H20N2O2 | 详情 | 详情 | |
| (VI) | 51863 | tert-butyl (3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinecarboxylate | C19H27F3N2O2 | 详情 | 详情 | |
| (VII) | 51864 | (2S)-2-methyl-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine | C14H19F3N2 | 详情 | 详情 | |
| (VIII) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (IX) | 51865 | tert-butyl 4-cyano-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate | C25H35F3N4O2 | 详情 | 详情 | |
| (X) | 51866 | tert-butyl 4-methyl-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate | C25H38F3N3O2 | 详情 | 详情 | |
| (XI) | 51867 | (2S)-2-methyl-4-(4-methyl-4-piperidinyl)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine | C20H30F3N3 | 详情 | 详情 | |
| (XII) | 51857 | 3-carboxy-2,4-dimethyl-1-pyridiniumolate | C8H9NO3 | 详情 | 详情 |