Bridged bicyclic serine protease inhibitors
A cycloalkyl and heterocyclic group technology, which can be applied in the fields of peptide/protein components, medical preparations containing active ingredients, antiviral agents, etc., can solve the problems of unclear prospects for effective anti-HCV vaccines
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Embodiment 1
[0406] Ethyl (1S, 3S, 4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1) (e.g. n=0, m=0; each R 20 =H) see process 1
[0407] To a stirred solution of, for example, 50% ethyl glyoxylate in toluene (23ml, 0.112mol, 1.0eq) in 600ml anhydrous DCM at 0°C was added (R)-methylbenzylamine (15ml, 0.118mol, 1.05eq), the solution contained 27g 4A molecular sieves. The reaction mixture was stirred at 0°C for 1 hour, then cooled to -78°C. The following three reagents were added sequentially with 5 min intervals between each addition: TFA (9.08ml, 0.118mmol, 1.05eq), boron trifluoride etherate (14.93ml, 0.118mol, 1.05eq), and e.g. Diene (16.37ml, 0.146mol, 1.3eq). The reaction mixture was stirred at -78°C for 5 hours and then allowed to warm to room temperature. The molecular sieves were separated and the reaction mixture was carefully washed with saturated aqueous sodium bicarbonate (250ml), brine (250ml) and dried over magnesium sulfate. Concentration and pu...
Embodiment 2
[0409] Ethyl (1S, 3S, 4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (2) (e.g. o=1, m=0; each R 20 =H)
[0410] Aza Diels-Alder adduct 1(23.5g; 0.086mol) was dissolved in 200ml absolute ethanol, for example, Pd-C 10% (600mg) was added. The mixture was stirred under hydrogen (55 psi) at room temperature for 16 hours. Filtration through a Celite pad (or nylon / carbon fiber combination) and concentration gave 14.2 g 2 (97%), a light yellow oil, used directly in the next step. The compound was identified by NMR.
Embodiment 3
[0412] (1S, 3S, 4R)-2-benzoylazabicyclo[2.2.1]heptane-3-carboxylic acid 3 (for example o=1, m=0, each R 20 =H)
[0413] To, for example, a mixture of 1N NaOH (71ml, 0.143mol, 3.5eq) and 71ml of water was added amino ester 2 (3.45g, 0.0204mol, 1.0eq) and stirred at room temperature for 4 hours (TLC monitoring w / EtOAc with 5% TEA mixture). When the saponification is complete, add 100ml of acetone and lower the temperature to 0°C. A solution of benzyl chloroformate (3.5ml, 0.0244mol, 1.2eq) in 40ml of acetone was added slowly and the reaction mixture was stirred at room temperature for 16 hours maintaining the pH at about 9-10 with 1N NaOH. Acetone was removed and 200ml of water was added. The aqueous phase was washed with ether (3 x 200ml) and acidified to pH 2-3 with 2N HCl. The product was extracted with EtOAc (3 x 250ml), dried (Na 2 SO 4 ), concentrated in vacuo to afford 3.85 g (70%) of amino acid 3. This compound was used directly in the next step. The compound was...
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