Ramelteon intermediate and preparation method thereof
A compound and solvent technology, applied in the field of ramelteon intermediates and its preparation, can solve the problems of harsh reaction conditions, unsuitable for industrialization, and long reaction routes, and achieve optimal post-reaction treatment, high optical purity, and shortened synthetic routes. Effect
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Embodiment 1
[0089] Add 9 mL of n-heptane solution of lithium diisopropylamide (2.0mol / L, 18.0 mmol) dropwise into 25 mL of tetrahydrofuran at -60°C, drop the temperature to -70°C ~ -75°C, keep below -70°C and add dropwise Acetonitrile (0.738g, 18.0mmol), after dropping and stirring for 15min, add 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (2g, 6mmol), kept at -70°C for 1 hour. The reaction solution was poured into 50 mL of ice water and stirred for 30 min, extracted three times with 30 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and recrystallized with toluene (18-20 mL) to obtain 1.705 g of solid (Compound III), The yield is 76.2%, the HPLC purity is >99.5%, and the melting point is 174-175°C. MS (ES + ): m / z 396 (M+Na). 1 H-NMR (DMSO-d 6 ):δ2.12~2.20(m,1H); 2.29~2.35(m,1H); 2.81~2.87(m,2H); 2.92~3.08(m,2H); 3.36~3.47(m,2H); 4.64 ~4.69 (m, 2H,); 5.94 (s, 1H).
Embodiment 2
[0091] Drop 18mL lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol / L, 18.0mmol) into 20mL tetrahydrofuran at -60°C, drop the temperature to -70°C ~ -75°C, keep it below -70°C Add acetonitrile (0.738g, 18.0mmol), and after stirring for 30min after dropping, add 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8- Ketone (2g, 6mmol), kept at -70°C for 1 hour. The reaction solution was poured into 50 mL of ice water and stirred for 30 min, extracted 3 times with 30 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and recrystallized with toluene (18-20 mL) to obtain 1.621 g of solid (Compound III), Yield 72.4%, HPLC purity>99.5%, melting point, mass spectrometry and NMR data are the same as in Example 1.
Embodiment 3
[0093] Add 10 mL of n-butyllithium n-hexane solution (2.4mol / L, 24.0 mmol) dropwise into 20 mL of tetrahydrofuran at -60°C, drop the temperature to -70°C to -75°C, and add dropwise acetonitrile (0.984 g, 24.0mmol), after dropping and stirring for 30min, add 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (2g, 6.0 mmol), maintained at -70°C for 2 hours. The reaction solution was poured into 50 mL of ice water and stirred for 30 min, extracted 3 times with 30 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and recrystallized with toluene (18-20 mL) to obtain 1.841 g of solid (Compound III), The yield is 81.9%, the HPLC purity is >99.5%, and the melting point, mass spectrometry and NMR data are the same as in Example 1.
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