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【结 构 式】 
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【分子编号】51994 【品名】1-ethyl-1-methyl-4-oxopiperidinium iodide 【CA登记号】 |
【 分 子 式 】C8H16INO 【 分 子 量 】269.12565 【元素组成】C 35.7% H 5.99% I 47.15% N 5.2% O 5.94% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The Stobbe-type condensation of tetralone (I) with diethyl succinate (II) by means of potassium tert-butoxide in tert butanol and subsequent hydrolysis/decarboxylation in HOAc/HCl gives the propionic acid (III), which is asymmetrically reduced with H2 over a chiral ruthenium catalyst in methanol to afford (S)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)propionic acid (S)-(IV). The cyclization of (IV) by means of PPA at 130 C provides the hexahydrophenalen-1-one (V), which by reaction with hydroxylamine is converted into the oxime (VI). The reduction of (VI) with H2 over Raney Ni in methanol yields the corresponding amine (VII), which is condensed with the piperidinium iodide (VIII) by means of K2CO3 in refluxing ethanol to afford a diastereomeric mixture from which the desired enantiomer (IX) is separated by column chromatography. A Strecker reaction of (IX) with aniline and Tms-CN in HOAc gives the anilino nitrile (X), which is finally cyclized by reaction with formic acid, Ac2O and formamide at 200 C to yield the target spiro compound. Alternatively, the anilino nitrile (X) is hydrolyzed with formic acid/Ac2O to give the formylated carboxamide (XI), which is finally cyclized with refluxing triethyl orthoformate, followed by reduction with NaBH4 in methanol.
| 【1】 Hennig, M.; Adam, G.; Wichmann, J.; Cesura, A.M.; Dautzenberg, F.M.; Scalone, M.; Jenck, F.; Rover, S.; Synthesis of (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic properties. Eur J Med Chem 2000, 35, 9, 839. |
| 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) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (II) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (III) | 51989 | 3-(3,4-Dihydronaphthalen-1-yl)propionic acid | C13H14O2 | 详情 | 详情 | |
| (IV) | 51990 | 3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]propionic acid | C13H16O2 | 详情 | 详情 | |
| (V) | 51991 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one | C13H14O | 详情 | 详情 | |
| (VI) | 51992 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-one oxime | C13H15NO | 详情 | 详情 | |
| (VII) | 51993 | (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-amine; (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-ylamine | C13H17N | 详情 | 详情 | |
| (VIII) | 51994 | 1-ethyl-1-methyl-4-oxopiperidinium iodide | C8H16INO | 详情 | 详情 | |
| (IX) | 51995 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-piperidinone | C18H23NO | 详情 | 详情 | |
| (X) | 51996 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-anilino-4-piperidinecarbonitrile | C25H29N3 | 详情 | 详情 | |
| (XI) | 51997 | 1-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-4-(formylanilino)-4-piperidinecarboxamide | C26H31N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)Quaternization of 1-ethyl-4-piperidone (XIV) with methyl iodide provides the ammonium salt (XV) which, upon treatment with tert-butylamine and NaHCO3, gives rise to 1-tert-butyl-4-piperidone (XVI). The reaction of 1-tert-butyl-4-piperidone (XVI) firstly with LiN(SiMe3)2 and subsequently with N-(5-chloro-2-pyridyl) trifluoromethanesulfonimide [(Tf)2NPyr] in THF provides the enol triflate (XVII). Reaction of triflate (XVII) with hexamethylditin in the presence of palladium catalyst furnishes 1-tert-butyl-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine (XVIII). Stille coupling between the quinazolinyl triflate (XIII) and the stannyl tetrahydropyridine (XVIII) produces adduct (XIX). Finally, hydrogenation of the tetrahydropyridine double bond of (XIX) using PtO2 as the catalyst leads to the target piperidinyl compound.
| 【1】 Stelmach, J.E.; Liu, L.; Patel, S.B.; Pivnichny, J.V.; Scapin, G.; Singh, S.; Hop, C.E.C.A.; Wang, Z.; Strauss, J.R.; Cameron, P.M.; Nichols, E.A.; O'Keefe, S.J.; O'Neill, E.A.; Schmatz, D.M.; Schwartz, C.D.; Thompson, C.M.; Zaller, D.M.; Doherty, J.B.; Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett 2003, 13, 2, 277. |
| 【2】 Doherty, J.B.; Rupprecht, K.M.; Goulet, J.L.; Chen, M.-H.; Bao, J.; Liu, L.; Miao, S.; Hunt, J.A.; Hong, X.; Stelmach, J.E.; Ruzek, R.D.; Wisnoski, D.D.; Natarajan, S.R. (Merck & Co., Inc.); (Halo-benzo carbonyl)heterocyclic fused phenyl p38 kinase inhibiting agents. EP 1345603; WO 0258695 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 63190 | 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydro-7-quinazolinyl trifluoromethanesulfonate | C21H11Cl3F4N2O4S | 详情 | 详情 | |
| (XIV) | 28868 | 1-ethyl-4-piperidinone; N-ethyl-4-piperidinone | 3612-18-8 | C7H13NO | 详情 | 详情 |
| (XV) | 51994 | 1-ethyl-1-methyl-4-oxopiperidinium iodide | C8H16INO | 详情 | 详情 | |
| (XVI) | 24875 | 1-(tert-butyl)-4-piperidinone; N-(tert-butyl)-4-piperidinone | C9H17NO | 详情 | 详情 | |
| (XVII) | 63191 | 1-(tert-butyl)-1,2,3,6-tetrahydro-4-pyridinyl trifluoromethanesulfonate | C10H16F3NO3S | 详情 | 详情 | |
| (XVIII) | 63192 | 1-(tert-butyl)-4-(trimethylstannyl)-1,2,3,6-tetrahydropyridine | C12H25NSn | 详情 | 详情 | |
| (XIX) | 63193 | 7-[1-(tert-butyl)-1,2,3,6-tetrahydro-4-pyridinyl]-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-2(1H)-quinazolinone | C29H27Cl3FN3O | 详情 | 详情 |