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【结 构 式】 
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【分子编号】38272 【品名】3-[[(3aS,7aS)-2-hydroxyoctahydrofuro[3,2-b]pyridin-2-yl]methyl]-4(3H)-quinazolinone 【CA登记号】 |
【 分 子 式 】C16H19N3O3 【 分 子 量 】301.34528 【元素组成】C 63.77% H 6.36% N 13.94% O 15.93% |
合成路线1
该中间体在本合成路线中的序号：(II)The isomerization of febrifugine (I) by means of HCl in methanol gives isofebrifugine (II), which is then cyclized with acetone over SiO2.
| 【1】 Takaya, Y.; Takeshita, M.; Kim, H.-S.; Wataya, Y.; Uwai, K.; Oshima, Y.; Tasaka, H.; Chiba, T.; Miura, M.; Tanitsu, M.-a.; New type of febrifugine analogues, bearing a quinolizidine moiety, show potent antimalarial activity against Plasmodium malaria parasite. J Med Chem 1999, 42, 16, 3163. |
合成路线2
该中间体在本合成路线中的序号：(XXIII)After protection of (XVI) as the N-Boc derivative (XVII), the diol function was cyclized to epoxide (XIX) by treatment with N-tosyl imidazole (XVIII) in the presence of NaH. Epoxide (XIX) opening with the potassium salt of 4-quinazolinone (XX) gave alcohol (XXI). Subsequent Dess-Martin oxidation of (XXI) yielded the epimeric mixture of ketones (XXII). Acid hydrolysis of this mixture furnished the title trans-piperidine along with the cis-isomer, which was isolated in the cyclic hemiacetal form (XXIII). The title compound was also obtained by isomerization of (XXIII) in refluxing MeOH).
| 【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 47844 | 3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol | C24H35NO3Si | 详情 | 详情 | |
| (XVII) | 47845 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2,3-dihydroxypropyl)-1-piperidinecarboxylate | C19H39NO5Si | 详情 | 详情 | |
| (XVIII) | 47846 | 1-[(4-methylphenyl)sulfonyl]-1H-imidazole | 2232-08-8 | C10H10N2O2S | 详情 | 详情 |
| (XIX) | 47847 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(2-oxiranylmethyl)-1-piperidinecarboxylate | C19H37NO4Si | 详情 | 详情 | |
| (XX) | 14634 | 4(3H)-quinazolinone | C8H6N2O | 详情 | 详情 | |
| (XXI) | 47848 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-hydroxy-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C27H43N3O5Si | 详情 | 详情 | |
| (XXII) | 47849 | tert-butyl (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C27H41N3O5Si | 详情 | 详情 | |
| (XXIII) | 38272 | 3-[[(3aS,7aS)-2-hydroxyoctahydrofuro[3,2-b]pyridin-2-yl]methyl]-4(3H)-quinazolinone | C16H19N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The enantioselective reduction of 2-allyl-1-(benzyloxycarbonyl)piperidin-3-one (I) by means of Baker's yeast and sucrose in ethanol/water gives a mixture of unreacted (R)-piperidinone (II) and the desired (2S,3S)-piperidinol (III), which are easily separated by chromatography. The bromination of (III) with NBS in acetonitrile yields the furo piperidine (IV), which is treated with potassium tert-butoxide and NBS in methanol to afford the methoxy compound (V). The condensation of (V) with quinazolinone (VI) by means of K2CO3 in DMF provides the adduct (VII), which is deprotected by hydrogenation with H2 over Pd/C in methanol to give isofebrifugine (VIII). Finally, this compound is converted into the target febrifugine by treatment with water at 80 C.
| 【1】 Takeuchi, Y.; et al.; Asymmetric synthesis of (+)-febrifugine and (+)-isofebrifugine using yeast reduction. Tetrahedron 2001, 57, 7, 1213. |
| 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) | 51238 | benzyl 2-allyl-3-oxo-1-piperidinecarboxylate | C16H19NO3 | 详情 | 详情 | |
| (II) | 51239 | benzyl (2R)-2-allyl-3-oxo-1-piperidinecarboxylate | C16H19NO3 | 详情 | 详情 | |
| (III) | 51240 | benzyl (2S,3S)-2-allyl-3-hydroxy-1-piperidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (IV) | 51241 | benzyl (3aS,7aS)-2-(bromomethyl)hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate | C16H20BrNO3 | 详情 | 详情 | |
| (V) | 51242 | benzyl (3aS,7aS)-2-(bromomethyl)-2-methoxyhexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate | C17H22BrNO4 | 详情 | 详情 | |
| (VI) | 14634 | 4(3H)-quinazolinone | C8H6N2O | 详情 | 详情 | |
| (VII) | 51243 | benzyl (3aS,7aS)-2-hydroxy-2-[[4-oxo-3(4H)-quinazolinyl]methyl]hexahydrofuro[3,2-b]pyridine-4(2H)-carboxylate | C24H25N3O5 | 详情 | 详情 | |
| (VIII) | 38272 | 3-[[(3aS,7aS)-2-hydroxyoctahydrofuro[3,2-b]pyridin-2-yl]methyl]-4(3H)-quinazolinone | C16H19N3O3 | 详情 | 详情 |