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【结 构 式】 
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【药物名称】Isofebrifugine 【化学名称】3-[(3aS,7aS)-2-Hydroxyperhydrofuro[3,2-b]pyridin-2-ylmethyl]-3,4-dihydroquinazolin-4-one 【CA登记号】32434-44-9 【 分 子 式 】C16H19N3O3 【 分 子 量 】301.34813 |
【开发单位】Okayama University (Originator), University of Tokyo (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antimalarials, Treatment of Protozoal Diseases |
合成路线1
Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (II) | 46170 | 4-(benzyloxy)butanal | C11H14O2 | 详情 | 详情 | |
| (III) | 17778 | ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium | 4301-14-8 | C2HBrMg | 详情 | 详情 |
| (IV) | 47833 | 6-(benzyloxy)-1-hexyn-3-ol | C13H16O2 | 详情 | 详情 | |
| (V) | 47834 | (1S)-1-[3-(benzyloxy)propyl]-2-propynyl acetate | C15H18O3 | 详情 | 详情 | |
| (VI) | 47835 | (3R)-6-(benzyloxy)-1-hexyn-3-ol | C13H16O2 | 详情 | 详情 | |
| (VII) | 47836 | (1S)-1-[3-(benzyloxy)propyl]-2-propenyl acetate | C15H20O3 | 详情 | 详情 | |
| (VIII) | 47837 | (3S)-6-(benzyloxy)-1-hexen-3-ol | C13H18O2 | 详情 | 详情 | |
| (IX) | 47838 | ([(1S)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether | C29H36O2Si | 详情 | 详情 | |
| (X) | 47839 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol | C22H30O2Si | 详情 | 详情 | |
| (XI) | 47840 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate | C23H32O4SSi | 详情 | 详情 | |
| (XII) | 47841 | (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate | C22H30O5SSi | 详情 | 详情 | |
| (XIII) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (XIV) | 47842 | (5S)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate | C21H27NO2Si | 详情 | 详情 | |
| (XV) | 47843 | ((4S)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)methanol | C24H33NO3Si | 详情 | 详情 | |
| (XVI) | 47844 | 3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol | C24H35NO3Si | 详情 | 详情 |
合成路线2
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 trans-piperidine (XXIII) along with the title cis-isomer, which was isolated in the cyclic hemiacetal form.
| 【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) | 47850 | 3-[3-[(2R,3S)-3-hydroxypiperidinyl]-2-oxopropyl]-4(3H)-quinazolinone | C16H19N3O3 | 详情 | 详情 |
合成路线3
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 the target isofebrifugine.
| 【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 |
合成路线4
The enantioselective condensation of the silylated 4-hydroxy-2-butanone (I) with the silylated enol ester (II) by means of Sn(OTf)2 and the chiral pyrrolidine (III) gives the chiral benzylated trihydroxyester (IV), which is partially dehydroxylated with thiocarbonyl diimidazole (TCDI) and tributyltin hydride in refluxing toluene to yield the protected dihydroxy ester (V). The reduction of (V) with DIBAL in dichloromethane affords the corresponding alcohol (VI), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide the aldehyde (VII). The condensation of (VII) with the enol ether (IX) and 2-methoxyaniline (VIII) by means of Yb(OTf)3 in THF/water gives the beta aminoketone (X), which is cyclized by means of HF, PPh3, CBr4 and cerium ammonium nitrate (CAN) in acetonitrile/water to yield the chiral piperidine (XI). The bromination of (XI) with Br2 and HBr in HOAc affords the bromo derivative (XII), which is treated with Boc2O to provide the N-protected piperidine (XIII). The condensation of (XIII) with quinazolin-4(3H)-one (XIV) by means of KOH gives the adduct (XV), which is finally deprotected and cyclized by treatment with refluxing 6N HCl to afford the target isofebrifugine.
| 【1】 Wataya, Y.; Ueno, M.; Suzuki, R.; Kim, H.-S.; Kobayashi, S.; Ishitani, H.; Catalytic asymmetric synthesis of antimalarial alkaloids febrifubine and isofebrifugine and their biological actvity. J Org Chem 1999, 64, 18, 6833. |
| 【2】 Kobayashi, S.; Kim, H.-S.; Wataya, Y. (Japan Science and Technology Corp.); Febrifugine and isofebrifugine and processes for the preparation of both. EP 1076057; WO 0052005 . |
| 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) | 44768 | 4-[[tert-butyl(dimethyl)silyl]oxy]-2-butanone | C10H22O2Si | 详情 | 详情 | |
| (II) | 44769 | benzyl (Z)-2-phenoxy-2-[(trimethylsilyl)oxy]ethenyl ether; [[(Z)-2-(benzyloxy)-1-phenoxyethenyl]oxy](trimethyl)silane | C18H22O3Si | 详情 | 详情 | |
| (III) | 51268 | N-(1-naphthyl)-N-[(2S)pyrrolidinylmethyl]amine; N-[(2S)pyrrolidinylmethyl]-1-naphthalenamine | C15H18N2 | 详情 | 详情 | |
| (IV) | 44771 | phenyl (2S,3R)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxypentanoate | C24H34O5Si | 详情 | 详情 | |
| (V) | 44773 | phenyl (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanoate | C24H34O4Si | 详情 | 详情 | |
| (VI) | 41269 | 2-(2-fluoro-4'-hydroxy[1,1'-biphenyl]-4-yl)acetic acid | C14H11FO3 | 详情 | 详情 | |
| (VII) | 44774 | (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanal | C18H30O3Si | 详情 | 详情 | |
| (VIII) | 25193 | 2-methoxyphenylamine; 2-methoxyaniline | 517-28-2 | C7H9NO | 详情 | 详情 |
| (IX) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (X) | 41270 | 8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C11H11NO5 | 详情 | 详情 | |
| (XI) | 51271 | 1-[(2S,3S)-3-(benzyloxy)piperidinyl]acetone | C15H21NO2 | 详情 | 详情 | |
| (XII) | 51272 | 1-[(2S,3S)-3-(benzyloxy)piperidinyl]-3-bromoacetone | C15H20BrNO2 | 详情 | 详情 | |
| (XIII) | 51273 | tert-butyl (2S,3S)-3-(benzyloxy)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate | C20H28BrNO4 | 详情 | 详情 | |
| (XIV) | 14634 | 4(3H)-quinazolinone | C8H6N2O | 详情 | 详情 | |
| (XV) | 51274 | tert-butyl (2S,3S)-3-(benzyloxy)-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate | C28H33N3O5 | 详情 | 详情 |