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【结 构 式】 
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【药物名称】Rogletimide, Pyridoglutethimide, PG 【化学名称】(±)-3-Ethyl-3-(4-pyridyl)piperidine-2,6-dione 【CA登记号】121840-95-7, 92788-10-8 (undefined stereoch.) 【 分 子 式 】C12H14N2O2 【 分 子 量 】218.25758 |
【开发单位】Institute of Cancer Research (Originator), BTG (Licensee) 【药理作用】ONCOLYTIC DRUGS, Aromatase Inhibitors |
合成路线1
1) The reaction of 4-(chloromethyl)pyridine (I) with KCN in refluxing methanol gives 2-(4-pyridyl)acetonitrile (II), which is alkylated with ethyl iodide and sodium hydride in DMF, yielding 2-(4-pyridyl)butyronitrile (III). The condensation of (III) with acrylonitrile (IV) by means of Triton B in tert-butanol affords 2-cyano-2-(4-pyridyl)hexanenitrile (V), which is finally cyclized with concentrated H2SO4 in refluxing acetic acid. 2) The alkylation of 2-(4-pyridyl)acetic acid ethyl ester (VI) with ethyl iodide and potassium tert-butoxide gives 2-(4-pyridyl)butanoic acid ethyl ester (VII), which is condensed with acrylamide (VIII) by means of potassium tert-butoxide, yielding 4-carbamoyl-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (IX). Finally, this compound is cyclized in the presence of potassium tert-butoxide. 3) The condensation of ester (VI) with acrylonitrile (IV) in the presence of Triton B gives 4-cyano-2-(4-pyridyl)butanoic acid ethyl ester (X), which is alkylated with ethyl iodide and lithium diisopropylamide yielding 4-cyano-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (XI). Finally, this compound is cyclized with concentrated H2SO4 in refluxing acetic acid.
| 【1】 Foster, A.B.; Jarman, M.; Taylor, G.N.; Kwan, C.-S. (Institute of Cancer Research); 2,6-Dioxopiperidine derivs., their preparation and pharmaceutical compsns. containing them. EP 0147121; GB 2151226; JP 1986500613; US 5071857; WO 8502618 . |
| 【2】 Markson, A.J.; Boss, A.M.; Clissold, D.W.; Thickitt, C.P.; Mann, J.; A concise synthesis of racemic pyridoglutethimide and its resolution using chiral stationary phase HPLC. Tetrahedron 1989, 45, 18, 6011. |
| 【3】 Jarman, M.; Griggs, L.J.; Wilman, D.E.V.; Rowlands, M.G.; Foster, A.B.; Leung, C.-S.; Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as selective inhibitors of aromatase: Derivatives with variable 1-alkyl and 3-alkyl substituents. J Med Chem 1987, 30, 9, 1550. |
| 【4】 Sampson, P.; Taylor, G.N.; Leung, C.-S.; Rowlands, M.G.; Plevey, R.G.; Jarman, M.; Foster, A.B.; Analogues of animoglutethimide: Selective inhibition of aromatase. J Med Chem 1989, 28, 2, 200. |
| 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) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (II) | 10845 | 2-(4-Pyridinyl)acetonitrile | C7H6N2 | 详情 | 详情 | |
| (III) | 10846 | 2-(4-Pyridinyl)butanenitrile | C9H10N2 | 详情 | 详情 | |
| (IV) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (V) | 10848 | 2-Ethyl-2-(4-pyridinyl)pentanedinitrile | C12H13N3 | 详情 | 详情 | |
| (VI) | 10849 | ethyl 2-(4-pyridinyl)acetate; Ethyl 4-pyridylacetate | 54401-85-3 | C9H11NO2 | 详情 | 详情 |
| (VII) | 10850 | ethyl 2-(4-pyridinyl)butanoate | C11H15NO2 | 详情 | 详情 | |
| (VIII) | 10851 | Acrylamide | 79-06-1 | C3H5NO | 详情 | 详情 |
| (IX) | 10852 | ethyl 5-amino-2-ethyl-5-oxo-2-(4-pyridinyl)pentanoate | C14H20N2O3 | 详情 | 详情 | |
| (X) | 10853 | ethyl 4-cyano-2-(4-pyridinyl)butanoate | C12H14N2O2 | 详情 | 详情 | |
| (XI) | 10854 | ethyl 4-cyano-2-ethyl-2-(4-pyridinyl)butanoate | C14H18N2O2 | 详情 | 详情 |
合成路线2
4) The (R)- and (S)-enantiomers of title product are obtained as follows: the trans-esterification of 2-(4-pyridyl)acetic acid methyl ester (XII) with the chiral alcohol (Oppolzer's camphor) (XIII) by means of butyllithium in THF gives the corresponding ester (XIV), which is alkylated with ethyl iodide and potassium hydride in THF yielding a mixture of the corresponding alkylated esters (XVR) and (XVS). The condensation of this mixture with acrylonitrile (IV) by means of potassium tert-butoxide in tert-butanol affords a mixture of the two diastereomeric nitriles (XVIR) and (XVIS), which are easily separable by column chromatography in silica gel. Both isolated compounds are then cyclized with sulfuric acid in refluxing acetic acid.
| 【1】 Webster, G.; Thickitt, C.P.; Rowlands, M.G.; Neidle, S.; Jarman, M.; Clissold, D.W.; McCague, R.; Mann, J.; Synthesis of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione and its enantiomers. J Chem Soc - Perkins Trans I 1989, 196. |
| 【2】 Prous, J.; Castaner, J.; Rogletimide. Drugs Fut 1992, 17, 9, 791. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV-S) | 10858 | 1-[[(dicyclohexylamino)sulfonyl]methyl]-7,7-dimethylbicyclo[2.2.1]hept-2-yl (2S)-2-(4-pyridinyl)butanoate | C31H48N2O4S | 详情 | 详情 | |
| (XV-R) | 10859 | 1-[[(dicyclohexylamino)sulfonyl]methyl]-7,7-dimethylbicyclo[2.2.1]hept-2-yl (2R)-2-(4-pyridinyl)butanoate | C31H48N2O4S | 详情 | 详情 | |
| (XVI-S) | 10860 | 1-[[(dicyclohexylamino)sulfonyl]methyl]-7,7-dimethylbicyclo[2.2.1]hept-2-yl (2R)-4-cyano-2-ethyl-2-(4-pyridinyl)butanoate | C34H51N3O4S | 详情 | 详情 | |
| (XVI-R) | 10861 | 1-[[(dicyclohexylamino)sulfonyl]methyl]-7,7-dimethylbicyclo[2.2.1]hept-2-yl (2R)-4-cyano-2-ethyl-2-(4-pyridinyl)butanoate | C34H51N3O4S | 详情 | 详情 | |
| (IV) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (XII) | 10855 | methyl 2-(4-pyridinyl)acetate | C8H9NO2 | 详情 | 详情 | |
| (XIII) | 10856 | N,N-Dicyclohexyl(2-hydroxy-7,7-dimethylbicyclo[2.2.1]hept-1-yl)methanesulfonamide; (-)-10-Dicyclohexylsulfamoyl-d-isoborneol | C22H39NO3S | 详情 | 详情 | |
| (XIV) | 10857 | 1-[[(dicyclohexylamino)sulfonyl]methyl]-7,7-dimethylbicyclo[2.2.1]hept-2-yl 2-(4-pyridinyl)acetate | C29H44N2O4S | 详情 | 详情 |