|
【结 构 式】 
|
【分子编号】44771 【品名】phenyl (2S,3R)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxypentanoate 【CA登记号】 |
【 分 子 式 】C24H34O5Si 【 分 子 量 】430.61646 【元素组成】C 66.94% H 7.96% O 18.58% Si 6.52% |
合成路线1
该中间体在本合成路线中的序号：(IV)Condensation of protected ketone (I) with 2-benzyloxy-1-trimethylsilyloxyphenoxyethane (II) by means of Sn(OTf)2 and chiral amine (III) in propionitrile affords aldolic reaction product (IV), which is then dehydroxylated by treatment with thiocarbonyl diimidazole (A) in THF followed by reduction with Bu3SnH in refluxing toluene to provide the protected hydroxyester (V). Reduction of the ester group of (V) with DIBAL in CH2Cl2 followed by Swern oxidation with (COCl)2, DMSO and Et3N in dichloromethane yields aldehyde (VI), which is then condensed with 2-methoxypropene (VII) and 2-methoxyaniline (VIII) in the presence of yterbium triflate (Yb(OTf)3) in THF/H2O to furnish a mixture of diastereoisomers from which anti-(IX) is separated. Derivative anti-(IX) is treated with HF in THF for TBS removal and cyclization is induced by reaction with PPh3 and CBr4 in CH2Cl2, affording piperidine (X). Next, treatment of (X) with cerium ammonium nitrate (CAN) in acetonitrile/H2O allows N-protecting group removal, giving piperidine derivative (XI). Alternatively, (XI) can be obtained as follows: Treatment of aldehyde (VI) with 2-methoxyaniline (VIII) and PMB-protected 2-methoxypropene (XII) in the presence of scandium trisdodecylsulfate (STDS) in THF/H2O yields a mixture of diastereoisomers from which anti-(XIII) is separated. Derivative anti-(XIII) is then converted into (XI) by following the same procedure as for the conversion of anti-(IX) into (XI). Derivative (XI) is then subjected to: (i) N-protection by means of Boc2O; (ii) treatment with lithium hexamethyl disilazide (LHMDS) followed by trimethylsilyl chloride (TMSCl); (iii) oxidation of the silylenol ether by means of MCPBA; and (iv) bromination with PPh3 and CBr4. After all these steps bromo derivative (XIV) is obtained. Finally, coupling of (XIV) with 4-hydroxyquinazoline (XV) using KOH followed by Boc removal by treatment with refluxing HCl furnishes the target compound.
| 【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 |
|---|---|---|---|---|---|---|
| (A) | 11990 | Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole | 6160-65-2 | C7H6N4S | 详情 | 详情 |
| (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) | 44770 | N-[[(2S)-1-methylpyrrolidinyl]methyl]-N-(1-naphthyl)amine; N-[[(2S)-1-methylpyrrolidinyl]methyl]-1-naphthalenamine | 82160-07-4 | C16H20N2 | 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) | 44774 | (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanal | C18H30O3Si | 详情 | 详情 | |
| (VII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VIII) | 25193 | 2-methoxyphenylamine; 2-methoxyaniline | 517-28-2 | C7H9NO | 详情 | 详情 |
| (IX) | 44777 | C27H42NO4Si | 详情 | 详情 | ||
| (X) | 44778 | 1-[(2R,3S)-3-(benzyloxy)-1-(2-methoxyphenyl)piperidinyl]acetone | C22H27NO3 | 详情 | 详情 | |
| (XI) | 44779 | 1-[(2R,3S)-3-(benzyloxy)piperidinyl]acetone | C15H21NO2 | 详情 | 详情 | |
| (XII) | 44780 | 1-methoxy-4-(3-methoxy-3-butenyl)benzene; 4-(3-methoxy-3-butenyl)phenyl methyl ether | C12H16O2 | 详情 | 详情 | |
| (XIII) | 44781 | C35H50NO5Si | 详情 | 详情 | ||
| (XIV) | 44782 | tert-butyl (2R,3S)-3-(benzyloxy)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate | C20H28BrNO4 | 详情 | 详情 | |
| (XV) | 44783 | 4-quinazolinol | C8H6N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |