Method for preparing brexanolone from pregnenolone acetate
A technology of monoenolone acetate and diketone, applied in organic chemistry methods, steroids, organic chemistry, etc., can solve problems such as high reaction cost, difficult separation and purification, and reduced total yield, and achieve stereoselectivity High efficiency, simple and convenient operation, and mild reaction conditions
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Embodiment 15
[0045] Example 1 Preparation of 5α-pregnane-3β-hydroxyl-20-one
[0046]Add 50g of monoenolone acetate, 500g of ethanol, and 2.5g of 5% palladium / carbon into a 1L hydrogenation tank, replace with nitrogen five times, stir and raise the temperature to 50±5°C, control the system temperature at 50±5°C, pressure 0.005 ~ 0.01MPa, hydrogenation reaction 6 ~ 12h, TLC detection reaction end point. Replace with nitrogen three times, filter, rinse with ethanol, add 11.5g of potassium carbonate and 10g of water to the filtrate, heat up to 60±5°C and keep it warm for 2-5 hours, adjust the pH to neutral with 10% dilute hydrochloric acid, concentrate the ethanol to a large amount under reduced pressure Crystallization, cooling to 0±5°C for crystallization for 12-24 hours, filtering, rinsing with ice ethanol, drying the solid in a hot-air oven at 75°C for 6-12 hours, and obtaining white crystals of 5α-pregnane-3β-hydroxy-20-one 42.2 g, yield 95%. 1 H NMR (CDCl 3 ,400MHz):δ3.63-3.57(m,1H),2...
Embodiment 25
[0047] Example 2 Preparation of 5α-pregnane-3,20-dione
[0048] Add 16g of water into a 500mL three-neck flask, add 2g of sodium bicarbonate, 200g of dichloromethane, and 40g of the hydrogenated hydrolyzate of the previous step, 5α-pregnane-3β-hydroxy-20-one under stirring, and then cool down after stirring completely. When the internal temperature of the reaction liquid reached 10°C, 1.2 g of tetramethylpiperidine oxide (TEMPO) was added. Evenly add 150 g of 10% sodium hypochlorite solution dropwise, the dropping time is controlled at 1-2 hours, and the dropping temperature is controlled at 6-15°C. After the dropwise addition, insulate and react at 10-15°C for 2-5 hours, take a sample and analyze the raw materials by TLC. After the reaction, add 30 g of 20% sodium bicarbonate solution to quench the reaction, stir for 10 minutes, and let stand to separate into layers (the emulsified layer is separated into water). phase extraction), the aqueous phase was extracted once with d...
Embodiment 35
[0049] Example 3 Preparation of 5α-pregnane-3α-hydroxy-20-one (Brenolone)
[0050] Inoculate the BL21(DE3) / pET24a-RH strain into a test tube containing 4mL LB medium (yeast extract 5g / L, tryptone 10g / L, sodium chloride 10g / L), cultivate overnight at 37°C, and inoculate the culture medium Erlenmeyer flask filled with 1L TB medium (yeast extract 24g / L, tryptone 12g / L, dipotassium hydrogen phosphate trihydrate 16.4g / L, potassium dihydrogen phosphate 2.3g / L, glycerol 5g / L), 37 When cultured with shaking at °C until OD=3.0, 0.2 mM isopropyl-β-D-thiogalactoside (IPTG) was added for induction, and the temperature was lowered to 25 °C to continue culturing overnight. Centrifuge at 3500 rpm for 20 minutes to collect the precipitate to obtain RH cells, add 3 times the volume of deionized water to the RH cells, and centrifuge at 8000 rpm for 30 minutes after ultrasonic disruption, and take the supernatant to obtain RH enzyme solution. Using the BL21(DE3) / pET24a-GDH strain, the GDH enzym...
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