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【结 构 式】 
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【分子编号】43518 【品名】(1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate 【CA登记号】 |
【 分 子 式 】C17H14F2O3 【 分 子 量 】304.2931664 【元素组成】C 67.1% H 4.64% F 12.49% O 15.77% |
合成路线1
该中间体在本合成路线中的序号：(XXXXIV)Alternatively, derivative (XXIX) can be obtained in an analogous way as its enantiomer (XIX). Diastereoselective epoxidation of (XXIX) with trimethylsulfoxonium iodide and NaH in DMSO provides oxirane (XXX) (3). THP group removal by means of PPTS in EtOH, followed by reaction with 3,5-dinitrobenzoyl chloride (XXXI) and NaHCO3 in CH2Cl2, yields a diastereomeric mixture from which dinitrobenzoate derivative (2R,3R)-(XXXII) is obtained by recrystallization (1). Hydrolysis of (2R,3R)-(XXXII) in MeOH by treatment with aqueous NaOH gives compound (2R,3R)-(XXXIII), which is converted into ester (2R,3S)-(XXXIV) by Mitsunobu reaction with benzoic acid, Ph3P and DEAD in THF. Subsequent debenzoylation of (2R,3S)-(XXXIV) with NaOMe in MeOH affords oxiranyl ethanol derivative (2R,3R)-(XXXV), which is first converted into its triflate derivative by means of Tf2O and DIEA in CH2Cl2, and then into triazolone derivative (2S,3R)-(XXXVI) by reaction with intermediate (VII) and NaH in CH2Cl2/DMF. Finally, oxirane derivative (2S,3R)-(XXXVI) reacts with triazole (XXVI) and NaH in DMF to furnish the desired product.
| 【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42. |
| 【2】 Tamura, N.; Okonogi, K.; Hayashi, R.; Matsushita, Y.; Kitazaki, T.; Tasaka, A.; Itoh, K.; Optically active antifungal azoles.VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones. Chem Pharm Bull 1996, 44, 2, 314. |
| 【3】 Itoh, K.; Okonogi, K.; Tamura, N. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0567982; US 5371101 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXXIV) | 43518 | (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate | C17H14F2O3 | 详情 | 详情 | |
| (VII) | 43502 | 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C11H9F4N3O2 | 详情 | 详情 | |
| (XXVI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XXIX) | 13102 | (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (XXX) | 13103 | (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-([(1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl]oxy)tetrahydro-2H-pyran | C15H18F2O3 | 详情 | 详情 | |
| (XXXI) | 12053 | 3,5-Dinitrobenzoyl chloride | 99-33-2 | C7H3ClN2O5 | 详情 | 详情 |
| (XXXII) | 27874 | (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate | C17H12F2N2O7 | 详情 | 详情 | |
| (XXXIII) | 27875 | (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol | C10H10F2O2 | 详情 | 详情 | |
| (XXXV) | 27877 | (1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol | C10H10F2O2 | 详情 | 详情 | |
| (XXXVI) | 43519 | 2-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C21H17F6N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXI)2) Propiophenone derivative (XXV) - prepared according to a procedure similar to that described for compound (XIX) - is subjected to a Grignard reaction with (chloromethyl)trimethylsilane (XXVI) and Mg in ether to give the silyl alcohol (XXVII), which by treatment with p-toluenesulfonic acid in MeOH undergoes b-elimination and deprotection to yield the allylic alcohol (XXVIII). Epoxidation of (XXVIII) with tert-butyl hydroperoxide and catalytic oxyvanadium acetylacetonate gives the epoxy-alcohol (XXIX), which is subjected to a Mitsunobu reaction with benzoic acid (XXX) by means of DEAD and PPh3 in THF to provide benzoate (XXXI). Solvolysis of compound (XXXI) in MeOH with catalytic NaOMe yields the epoxyalcohol (XXXII), which is mesylated with methanesulfonyl chloride and triethylamine in CH2Cl2 to afford the protected alcohol (XXXIII). Finally, treatment of compound (XXXIII) with 1H-1,2,4-triazole (XXIV) and NaH in DMF affords the desired intermediate (IX).
| 【1】 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217. |
| 【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 31738 | 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XIV) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XXV) | 43511 | (2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (XXVI) | 59954 | (chloromethyl)(trimethyl)silane | C4H11ClSi | 详情 | 详情 | |
| (XXVII) | 59955 | (3S)-2-(2,4-difluorophenyl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-(trimethylsilyl)-2-butanol | C18H28F2O3Si | 详情 | 详情 | |
| (XXVIII) | 59956 | (2S)-3-(2,4-difluorophenyl)-3-buten-2-ol | C10H10F2O | 详情 | 详情 | |
| (XXIX) | 27877 | (1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol | C10H10F2O2 | 详情 | 详情 | |
| (XXX) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (XXXI) | 43518 | (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate | C17H14F2O3 | 详情 | 详情 | |
| (XXXII) | 27875 | (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol | C10H10F2O2 | 详情 | 详情 | |
| (XXXIII) | 59957 | (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl methanesulfonate | C11H12F2O4S | 详情 | 详情 |