Process for the preparation of nebivolol
By using fungal esterase from Xinyu Shekou Shell for enzymatic hydrolysis and acid-alkali extraction and separation, the problems of multiple steps and low yield in the existing nebivolol synthesis were solved, and efficient and simplified nebivolol preparation was achieved. Improved overall yield and stereoselectivity.
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Embodiment 1
[0098] As described in EP-0687305, recombinant E. coli strains containing the esterase originally expressed in Ulmus chinensis were grown according to techniques well known to those skilled in the art. The cell fraction was lysed by sonication and the lysate was centrifuged to obtain a cell-free supernatant. Mix 1.6 mL of a solution (6800 units / mL) containing esterase (lipase) obtained from Ulmus chinensis (6800 units / mL) and about 25 g of ethyl 6-fluorochroman-2-carboxylate (1) in 25 mL of deionized water with Add 100 μL of the suspension in Tween 80 to 500 mL of 0.1N NaHCO 3 buffer solution (pH 9.7), optionally with 2N NaOH to adjust the pH to 9.7. The mixture thus obtained was stirred slowly.
[0099] The pH was automatically maintained at 9.7 with a controlled addition of 2N NaOH solution.
[0100] The progress of the reaction was controlled by HPLC.
[0101] At the end of the hydrolysis reaction, the mixture was extracted with dichloromethane to obtain the ester in th...
Embodiment 2
[0110] Example 2 Preparation of Acyl Meldrum Derivatives
[0111]
[0112] 28 g of the resolved (R) acid were dissolved in 250 mL of anhydrous dichloromethane; 1.4 equivalents of oxalyl chloride and DMF were added dropwise to the resulting solution. The solution was kept under stirring at room temperature under N 2 Atmospheric conditions; after 1.5 hours, the solvent was evaporated to give an oil which was redissolved in 200 mL of anhydrous dichloromethane. Separately, medrum's acid (1.05 equivalents) and pyridine (2 equivalents) were dissolved in anhydrous dichloromethane (150 mL), and stirred at 0°C for 15 minutes. To this solution was added the previously formed acid chloride. At the end of the addition, the mixture was stirred at 0 °C for 1 hour and at room temperature for an additional 45 minutes. Then, it was diluted with another 500 mL of dichloromethane and washed with H 2 O (2×200mL), 2N HCl (100mL), water and brine washed the organic phase, and 2 SO 4 Dry ...
Embodiment 3
[0113] Example 3 Preparation of β-ketoesters
[0114]
[0115] 40 g of crude acyl medrum derivative (R) were placed under stirring with 110 mL of tert-butanol; the resulting mixture was heated to 80° C. for 1 hour until the control by HPLC showed marked disappearance of the starting product. At the end of the reaction, tert-butanol was evaporated under reduced pressure; it was treated with 500 ml ethyl acetate and washed with saturated NaHCO 3 solution, neutral H 2 O, brine washes organic phase, and it is in Na 2 SO 4 Dry on top. The solvent was then evaporated to obtain 28 g of crude β-ketoester as an oil (HPLC purity = 69%, λ = 280 nm), which was used in subsequent reactions without further purification.
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