Preparation method of levosalbutamol hydrochloride
A technology of levosalbutamol hydrochloride and hydrochloric acid, which is applied in the field of medicinal chemistry and can solve the problems of difficult storage of precursor imines, mass production, and difficulty in industrialized mass production.
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Embodiment 1
[0073] Embodiment 1, the preparation of formula VI compound
[0074] Add 200.0g of compound VII, 254.99g of 2,2-dimethoxypropane, 1.55g of p-toluenesulfonic acid, and 1200ml of acetone into a 5L reaction flask in turn, react at 40°C for 2h, add 2400ml of water, precipitate a solid, and lower the temperature to 0 Stir at -5 °C for 1 h, filter; dry the filter cake at 60 °C for 12 h to obtain 215.5 g of compound VI, with a yield of 92.6%.
[0075] Mass Spectrum: ESI-MS (m / z): 243.26[M-H] — ; Molecular formula: C 12 h 13 BrO 3 ;
[0076] Proton NMR spectrum: 1 HNMR (400MHz, DMSO-d 6 )δ7.79-7.88 (m, 2H), 6.93 (m, 1H), 4.94 (s, 2H), 4.82 (s, 2H), 1.51 (s, 6H).
Embodiment 2
[0077] Embodiment 2, the preparation of formula V compound
[0078] 200ml tetrahydrofuran, 35ml R-CBS, 56ml borane dimethyl sulfide were added to a 2L reaction bottle in turn, 200.0g compound VI was dissolved in 800ml tetrahydrofuran, and added dropwise to the above reaction solution at room temperature. Slowly add water and methanol to the reaction solution to quench the reaction, add 1000ml ethyl acetate, extract with 4L purified water, separate the water phase, concentrate the ethyl acetate phase under reduced pressure until no obvious droplets drip out, add 200ml absolute ethanol and 2000ml of n-heptane was heated at 75°C until it dissolved, cooled to 0-5°C, solid precipitated, kept stirring for 1 hour, filtered, and the filter cake was dried at 60°C for 6 hours to obtain 159.8g of compound V with a yield of 79.4% and a purity of 99.2%. Isomer 0.8%.
[0079] Mass Spectrum: ESI-MS (m / z): 284.87[M-H] — ; Molecular formula: C 12 h 15 BrO 3 ;
[0080] Proton NMR spectrum...
Embodiment 3
[0081] Embodiment 3, the preparation of formula III compound
[0082] 130.0g of compound V, 187.7g of anhydrous potassium carbonate, 650ml of isopropanol, reacted at 60°C for 3h, cooled to 0-5°C, kept stirring for 1h, filtered to obtain compound IV, which was directly put into the next reaction.
[0083] The above compound IV, 99.3g of tert-butylamine and 910ml of absolute ethanol were successively added to a 2L reaction flask, reacted at 75°C for 3h, filtered, filtered and concentrated under reduced pressure until no obvious droplets dripped out, and the concentrate was added with 910ml of absolute methanol and 81.1g of D -DBTA, stirred at room temperature, solid precipitated, cooled to 0-5°C, kept stirring for 1h, filtered, and dried the filter cake at 60°C for 6h to obtain 135.6g of compound III, the yield of two-step reaction was 65.4%, the purity was 99.2%, isomer Content 0.02%.
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