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【结 构 式】 
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【分子编号】41270 【品名】8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid 【CA登记号】 |
【 分 子 式 】C11H11NO5 【 分 子 量 】237.21208 【元素组成】C 55.7% H 4.67% N 5.9% O 33.72% |
合成路线1
该中间体在本合成路线中的序号：(I)The chlorination of 8-acetamido-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (I) with chlorine in acetic acid gives the 7-chloro derivative (II), which is treated with aqueous NaOH to yield 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (III). The reaction of (III) with carbonyldiimidazole (CDI) affords the activated intermediate (IV), which is finally condensed with 1-(1-butylpiperidin-4-yl)methanol (V) by means of MeLi in THF. The intermediate 1-(1-butylpiperidin-4-yl)methanol (V) has been obtained by condensation of piperidine-4-carboxylic acid ethyl ester (VI) with 1-bromobutane (VII) by means of K2CO3 in methanol, followed by reduction of the ester group with LiAlH4 in THF.
| 【1】 Bulteau, G.; Acher, J.; Thominet, M.; Collignon, C. (Ile de France); Substituted 2,3-alkylenedioxybenzamides. DE 2734270; FR 2360305; GB 1571278; GB 1571447; JP 53018570; US 4186135; US 4248885; US 4255580 . |
| 【2】 Gaster, L.M.; Sanger, G.J.; SB-204070: 5-HT4 receptor antagonists and their potential therapeutic utility. Drugs Fut 1994, 19, 12, 1109. |
| 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) | 41270 | 8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C11H11NO5 | 详情 | 详情 | |
| (II) | 41271 | 8-(acetamido)-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C11H10ClNO5 | 详情 | 详情 | |
| (III) | 41272 | 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid | C9H8ClNO4 | 详情 | 详情 | |
| (IV) | 41273 | (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)(1H-imidazol-1-yl)methanone | C12H10ClN3O3 | 详情 | 详情 | |
| (V) | 41274 | (1-butyl-4-piperidinyl)methanol | C10H21NO | 详情 | 详情 | |
| (VI) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (VII) | 28721 | 1-bromobutane | 109-65-9 | C4H9Br | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)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 |