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【结 构 式】 
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【分子编号】56715 【品名】(2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 【CA登记号】 |
【 分 子 式 】C12H14F2N4O 【 分 子 量 】268.2663264 【元素组成】C 53.73% H 5.26% F 14.16% N 20.88% O 5.96% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.
| 【1】 Bartroli, J.; et al.; Aldol condensation of Evans chiral enolates with acetophenones. Its application to the stereoselective synthesis of homochiral antifungal agents. J Org Chem 1995, 60, 10, 3000. |
| 【2】 Bartroli, J.; et al.; New azole antigungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones. J Med Chem 1998, 41, 11, 1869. |
| 【3】 Bartrolí, J.; Turmo, E.; Anguita, M. (J. Uriach & Cía., SA); New pyrimidone derivs. with antifungal activity. EP 0783501; ES 2107376; ES 2120885; JP 1998508317; US 5807854; WO 9705130 . |
| 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) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 47646 | 2-bromo-1-(2,4-difluorophenyl)-1-ethanone | C8H5BrF2O | 详情 | 详情 | |
| (III) | 56711 | (4S)-4-benzyl-3-{(2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoyl}-1,3-oxazolidin-2-one | C21H19F2NO4 | 详情 | 详情 | |
| (IV) | 56712 | (2R)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propanoic acid | C11H10F2O3 | 详情 | 详情 | |
| (V) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (VI) | 56713 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid | C13H13F2N3O3 | 详情 | 详情 | |
| (VII) | 56714 | (4R,5R)-5-(2,4-difluorophenyl)-4-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-oxazolidin-2-one | C13H12F2N4O2 | 详情 | 详情 | |
| (VIII) | 56715 | (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C12H14F2N4O | 详情 | 详情 | |
| (IX) | 52504 | 4-Chloro-2-aminobenzoic acid; 2-Amino-4-chlorobenzoic acid; 2-Carboxy-5-chloroaniline; 3-Amino-4-carboxy-1-chlorobenzene; 4-Chloroanthranilic acid | 89-77-0 | C7H6ClNO2 | 详情 | 详情 |
| (X) | 56716 | 2-amino-4-chloro-N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]benzamide | C19H18ClF2N5O2 | 详情 | 详情 |