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【结 构 式】 
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【分子编号】35864 【品名】4-chloro-1-(4-fluorophenyl)-1-butanone 【CA登记号】3874-54-2 |
【 分 子 式 】C10H10ClFO 【 分 子 量 】200.6399032 【元素组成】C 59.86% H 5.02% Cl 17.67% F 9.47% O 7.97% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyleneketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with CuBr2 and NO in THF.
| 【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (IV) | 35865 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C17H24FNO3 | 详情 | 详情 | |
| (V) | 35866 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone | C17H22FNO3 | 详情 | 详情 | |
| (VI) | 35867 | N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine | C9H14BrNSi | 详情 | 详情 | |
| (VII) | 35868 | 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | C21H25FN2O2 | 详情 | 详情 | |
| (VIII) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (IX) | 35869 | C6H5Br2MgN | 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 reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethyleneketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (VIII) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IX). The reaction of (IX) with HCl in methanol yields the corresponding free butanone (X), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (XI). Finally, this compound is treated with Br2 in chloroform.
| 【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 35870 | 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine | 39512-49-7 | C11H14ClNO | 详情 | 详情 |
| (IX) | 35871 | 4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C23H27ClFNO3 | 详情 | 详情 | |
| (X) | 35872 | 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | 52-86-8 | C21H23ClFNO2 | 详情 | 详情 |
| (XI) | 35873 | 1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone | C24H32FNO2Sn | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 1-(4-fluorophenyl)-4-(4-hydroxypiperidin-1-yl)-1-butanone ethyle-neketal (IV). The Oppenauer oxidation of (IV) with 9-fluorenone and potassium tert-butoxide in hot benzene affords the piperidinone (V), which is condensed with 4-bromo-N-(trimethylsilyl)aniline (VI) by means of BuLi in hot hexane to give 4-[4-(4-aminophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone (VII). Finally, this compound is treated with Cu82Br2 and NO in THF.
| 【1】 Vincent, S.H.; et al.; Synthesis of [82Br]bromperidol and preliminary tissue distribution studies in the rat. J Med Chem 1980, 23, 1, 75. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (IV) | 35865 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C17H24FNO3 | 详情 | 详情 | |
| (V) | 35866 | 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinone | C17H22FNO3 | 详情 | 详情 | |
| (VI) | 35867 | N-(4-bromophenyl)(trimethyl)silanamine; N-(4-bromophenyl)-N-(trimethylsilyl)amine | C9H14BrNSi | 详情 | 详情 | |
| (VII) | 35868 | 4-[4-(4-aminophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | C21H25FN2O2 | 详情 | 详情 | |
| (VIII) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (IX) | 35869 | C6H5Br2MgN | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reaction of 4-chloro-1-(4-fluorophenyl)-1-butanone (I) with ethylene glycol and p-toluenesulfonic acid in refluxing benzene gives the corresponding ethylene-ketal (II), which is condensed with 4-(chlorophenyl)-4-hydroxypiperidine (III) by means of K2CO3 in hot DMF yielding 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-1-butanone ethyleneketal (IV). The reaction of (IV) with HCl in methanol yields the corresponding free butanone (V), which is treated with trimethylstannyl sodium in glyme to afford the expected stannyl derivative (VI). Finally, this compound is treated with 75Br2 or 77Br2 and dichloramin T in methanol or H2O2 in acetic acid.
| 【1】 Moerlein, S.M.; Stocklin, G.L.; Synthesis of high specific activity [75Br]- and [77Br]-bromperidol and tissue distribution studies in the rat. J Med Chem 1985, 28, 9, 1319. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| (I) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (II) | 28203 | 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane | 3308-94-9 | C12H14ClFO2 | 详情 | 详情 |
| (III) | 35870 | 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine | 39512-49-7 | C11H14ClNO | 详情 | 详情 |
| (IV) | 35871 | 4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol | C23H27ClFNO3 | 详情 | 详情 | |
| (V) | 35872 | 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone | 52-86-8 | C21H23ClFNO2 | 详情 | 详情 |
| (VI) | 35873 | 1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone | C24H32FNO2Sn | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)A new synthesis for [18F]-labeled BMY-14802 has been reported: The compound can be prepared by two related ways: 1) The fluorination of 4-(cyclopropylcarbonyl)nitrobenzene (I) with [18F]-FK and Kryptofix 2.2.2 gives 4-fluorophenyl cyclopropyl methanone (II), which is treated with HCl in methanol yielding 4-chloro-1-(4-fluorophenyl)-1-butanone (III). The condensation of (III) with 5-fluoro-2-piperazinopyrimidine (IV) affords 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-butan one (V), which is finally reduced with NaBH4 in methanol. 2) The reduction of butanone (III) with NaBH4 in methanol gives 4-chloro-1-(4-fluorophenyl)-1-butanol (VI), which is then condensed with pyrimidine (IV) as before.
| 【1】 Yevich, J.P.; Frick, M.P.; Shiue, G.G.; Huang, H.; Pleus, R.C.; Shiue, C.-Y.; Bai, L.-Q.; Catt, J.D.; Rysavy, J.A.; Fluorine-18 labeled BMY 14802: Synthesis and anatomical distribution in rodents. J Label Compd Radiopharm 1993, 32, 501. |
| 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) | 11423 | Cyclopropyl(4-nitrophenyl)methanone | C10H9NO3 | 详情 | 详情 | |
| (II) | 11424 | Cyclopropyl(4-fluorophenyl)methanone | C10H9FO | 详情 | 详情 | |
| (II) | 27427 | cyclopropyl(4-fluorophenyl)methanone | 772-31-6 | C10H9FO | 详情 | 详情 |
| (III) | 11425 | 4-Chloro-1-(4-fluorophenyl)-1-butanone | C10H10ClFO | 详情 | 详情 | |
| (III) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (IV) | 11426 | 5-Fluoro-2-piperazinopyrimidine | C8H11FN4 | 详情 | 详情 | |
| (V) | 11427 | 1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)piperazino]-1-butanone | C18H20F2N4O | 详情 | 详情 | |
| (V) | 28204 | 1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanone | C18H20F2N4O | 详情 | 详情 | |
| (VI) | 11428 | 4-Chloro-1-(4-fluorophenyl)-1-butanol | C10H12ClFO | 详情 | 详情 | |
| (VI) | 45061 | 4-chloro-1-(4-fluorophenyl)-1-butanol | C10H12ClFO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)A new synthesis of [18F]-labeled BMY-14802 has been described: The fluorination of 4-(cyclopropylcarbonyl)nitrobenzene (I) with [18F]-CsF in DMSO - 5% water at 180 C gives 4-fluorophenylcyclopropylmethanone (II), which is treated with HCl in methanol, yielding 4-chloro-1-(4-fluorophenyl)-1-butanone (III). The condensation of (III) with 5-fluoro-2-piperazinopyrimidine (VI) affords 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-butan one (V), which is finally reduced with NaBH4 in methanol.
| 【1】 Shea, C.; Taylor, D.P.; Ding, Y.S.; Wolf, A.P.; Logan, J.; Volkow, N.D.; Gatley, S.J.; Fowler, J.S.; Dewey, S.L.; Synthesis and PET studies of fluorine-18-BMY-14802 - A potential antipsychotic drug. J Nucl Med 1993, 34, 2, 246. |
| 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) | 11423 | Cyclopropyl(4-nitrophenyl)methanone | C10H9NO3 | 详情 | 详情 | |
| (II) | 11424 | Cyclopropyl(4-fluorophenyl)methanone | C10H9FO | 详情 | 详情 | |
| (II) | 27427 | cyclopropyl(4-fluorophenyl)methanone | 772-31-6 | C10H9FO | 详情 | 详情 |
| (III) | 11431 | 4-Chloro-1-(4-fluorophenyl)-1-butanone | C10H10ClFO | 详情 | 详情 | |
| (III) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (IV) | 11426 | 5-Fluoro-2-piperazinopyrimidine | C8H11FN4 | 详情 | 详情 | |
| (V) | 11427 | 1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)piperazino]-1-butanone | C18H20F2N4O | 详情 | 详情 | |
| (V) | 28024 | (2S)-2-(chloromethyl)-1-ethylpyrrolidine | C7H14ClN | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)The title compound is prepared by two related methods. N-Benzyl-4-piperidone (I) is condensed with KCN and MeNH2.HCl to produce amino nitrile (II). Partial hydrolysis of nitrile (II) with H2SO4 furnishes amide (III). Condensation of the amino amide (III) with triethyl orthoformate gives rise to the spiro imidazolinone (IV). Catalytic hydrogenation of the imidazoline double bond of (IV) and simultaneous N-benzyl group hydrogenolysis gives rise to 1-methyl-1,3,8-triazaspiro[4,5]decan-4-one (V). This is finally alkylated with 4'-fluoro-4-chlorobutyrophenone (VI) to yield the desired compound (1,2).
| 【1】 Metwally, K.A.; Dukat, M.; Egan, C.T.; Smith, C.; Dupre, A.; Gauthier, C.B.; Herrick-Davis, K.; Teitler, M.; Glennon, R.A.; Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 1998, 41, 25, 5084. |
| 【2】 Janssen, P.A.J. (Janssen Pharmaceutica NV); 2,4,8-Triaza-spiro(4,5)dec-2-enes. US 3155669 . |
| 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) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 64576 | 1-benzyl-4-(methylamino)-4-piperidinecarbonitrile | C14H19N3 | 详情 | 详情 | |
| (III) | 22019 | 1-benzyl-4-(methylamino)-4-piperidinecarboxamide | 1024-11-9 | C14H21N3O | 详情 | 详情 |
| (IV) | 64577 | 8-benzyl-1-methyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one | C15H19N3O | 详情 | 详情 | |
| (V) | 64578 | 1-methyl-1,3,8-triazaspiro[4.5]decan-4-one | C8H15N3O | 详情 | 详情 | |
| (VI) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)Similarly, the condensation of N-benzyl-4-piperidone (I) with KCN in the presence of NH4Cl provides amino nitrile (II), which is further hydrolyzed to amide (III) with 95% H2SO4. Cyclization of amino amide (III) with formamide under acidic conditions yields the spiro imidazolinone (IV), which is further reduced to imidazolidinone (V) employing NaBH4 in hot MeOH. Debenzylation of (V) with H2 and Pd/C provides 1,3,8-triazaspiro[4,5]decan-4-one (VI). Then, alkylation of (VI) with 4'-fluoro-4-chlorobutyrophenone (VII) by means of K2CO3 and catalytic KI in methyl isobutyl ketone furnishes (VIII). The imidazolidinone ring of (VIII) is finally methylated with iodomethane and KOH to produce the title compound (2).
| 【1】 Metwally, K.A.; Dukat, M.; Egan, C.T.; Smith, C.; Dupre, A.; Gauthier, C.B.; Herrick-Davis, K.; Teitler, M.; Glennon, R.A.; Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 1998, 41, 25, 5084. |
| 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) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (II) | 64579 | 4-amino-1-benzyl-4-piperidinecarbonitrile | C13H17N3 | 详情 | 详情 | |
| (III) | 64580 | 4-amino-1-benzyl-4-piperidinecarboxamide | C13H19N3O | 详情 | 详情 | |
| (IV) | 64581 | 8-benzyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one | C14H17N3O | 详情 | 详情 | |
| (V) | 64582 | 8-benzyl-1,3,8-triazaspiro[4.5]decan-4-one | C14H19N3O | 详情 | 详情 | |
| (VI) | 64583 | 1,3,8-triazaspiro[4.5]decan-4-one | C7H13N3O | 详情 | 详情 | |
| (VII) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |
| (VIII) | 64584 | 8-[4-(4-fluorophenyl)-4-oxobutyl]-1,3,8-triazaspiro[4.5]decan-4-one | C17H22FN3O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)The reaction of piperidine-4-carboxylic acid (I) with SOCl2 gives the acyl chloride (II), which is treated with methanol to yield the methyl ester (III). Finally, this compound is condensed with 4-chloro-1-(4-fluorophenyl)-1-butanone (IV) by means of K2CO3 in refluxing acetone.
| 【1】 Kar, K.; Pandey, S.K.; Tripathi, R.C.; Saxena, A.K.; Synthesis and SAR studies of 1-substituted-n-(4-alkoxycarbonylpiperidin-1-yl)alkanes as potent antiarrhythmic agents. Bioorg Med Chem Lett 1999, 9, 18, 2693. |
| 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) | 38417 | 4-piperidinecarbonyl chloride | C6H10ClNO | 详情 | 详情 | |
| (III) | 38418 | methyl 4-piperidinecarboxylate; Isonipecotic acid methyl ester; 4-piperidinecarboxylic acid methyl ester | 2971-79-1 | C7H13NO2 | 详情 | 详情 |
| (IV) | 35864 | 4-chloro-1-(4-fluorophenyl)-1-butanone | 3874-54-2 | C10H10ClFO | 详情 | 详情 |