Subsituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes useful for treating hcv infections
A substituent, C1-C2 technology, applied in metallocene, anti-infective drugs, medical preparations containing active ingredients, etc., can solve the problem of lack of high mutation rate of HCV
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Embodiment 1
[0234] Embodiment 1. Synthesis of compound 10
[0235] By [ 2.2] Preparation of compound 10 by bromination of cyclofen. Compounds 1, 2, 6, 8 and 10 are available from commercial sources. Compounds 3 to 7 and 9 were prepared using general synthetic methods known in the art.
Embodiment 2
[0236] Embodiment 2. Synthesis of Compound 11
[0237] 9 (284.2mg), 10 (52.3mg), K in dioxane / water (5.5.mL / 0.55mL) 3 PO 4 (248.1mg) and PdCl 2 dppf CH 2 Cl 2 (7.4 mg) of the deoxygenated (argon) mixture was irradiated in the microwave at 80°C for 2 hours. The resulting mixture was evaporated under reduced pressure and the remaining solid was extracted with DCM. by PTLC (20 cm × 20 cm × 2000 μm glass plate; eluting with 45:50:5 v / v / v DCM:EtOAc:MeOH, R f 0.28) Purification of this crude material afforded 75.3 mg of 11. The purity of 11 was determined by analytical reverse phase HPLC on a Waters AQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column using increasing concentrations of ACN (10% to 90%) in water (with 0.05% formic acid ) at a flow rate of 1.0 mL / min for 3.5 min gradient elution for UV (PDA), ELS and MS (SQ in APCI mode) detection. HPLC: t R 1.57 minutes (98% purity). Calculated MS m / z: C 56 h 64 N8 o 6 ([M]+), 945; Found: 946 ([M+1]+).
Embodiment 3
[0238] Example 3. ((2S, 2'S)-((2S, 2'S, 3aS, 3a'S, 7aS, 7a'S)-2,2'-(5,5'-(tricyclo[8.2 .2.2 4，7 ]Hexadecan-4,6,10,12,13,15-hexene-5,11-diyl)bis(1H-benzo[d]imidazole-5,2-diyl))bis(octahydro- Synthesis of dimethyl 1H-indole-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate (20)
[0239] step 1
[0240]
[0241] To a stirred solution of (2R,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (250 g, 1.0 eq) (12) in THF (3 L) and water (1.5 L) at 0°C Cooled aqueous 2.5M NaOH (1 L) was added dropwise. The reaction mixture was stirred at the same temperature for 15 minutes. Then, di-tert-butyl dicarbonate (1.3 equiv) was added dropwise keeping the temperature at 0°C. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with MTBE (3 times). The aqueous phase was acidified with 1M aqueous citric acid and extracted with ethyl acetate (3 times). The combined organic layers were dried over sodium sulfate and concentra...
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