(a) Ketal reaction: Prepare “16α, 17α-epoxy-4-pregnene-11-one-3,20-diethylene glycol ketal”. In the reaction bottle, add 50g of Platt’s oxide, Mix 100 ml of methylene chloride, 100 ml of ethylene glycol and 80 ml of triethyl orthoformate, stir, add 2 g of boron trifluoride-diethyl ether, stir and react at 20~28°C for more than 8 hours; after the reaction is completed, concentrate under reduced pressure, filter, and use Wash the material with a small amount of methanol, pump it dry, and dry to obtain 60.8g of formula 16α, 17 α-epoxy-4-pregnantene-11-one-3, 20-diethylene glycol ketal;
(b) Reduction reaction: Prepare the formula “11β, 17α-dihydroxy-4-pregnene-3, 20-diethylene glycol ketal”, put it into the reaction bottle and put the formula II 16α, 17α-hydroxy-4-pregnene into the reaction bottle. Stelen-11-one-3,20-dihexanediol ketal 50g, tetrahydrofuran 500ml, methanol 50ml, stir, slowly add 15g lithium aluminum hydride, stir and react at 30~40°C for 4 hours; concentrate under reduced pressure to recover the solvent, add water 1500ml of water was separated, filtered, washed with water until neutral, drained, and dried to obtain 44.8g of formula 11β, 17 α-dihydroxy-4-pregnantene-3, 20-diethylene glycol ketal;
(c) Hydrolysis reaction: Prepare “11β, 17α-dihydroxy-4-pregnene-3,20-dione” and put the formula 11β, 17α-dihydroxy-4-pregnene-3 into the reaction bottle. , 50g of 20-diethylene glycol ketal, 15ml of hydrochloric acid, 200ml of water, stir and react for 2 hours at 20~22°C, add 1500ml of water for precipitation, filter, wash, drain, and dry to obtain formula 11β, 17 α-dihydroxy -4-Pregnene-3,20-dione 38.4g;
(d) Iodine reaction: Prepare “21-iodine-11β,17α-dihydroxy-4-pregnene-3,20-dione”, dissolve 6g of calcium chloride in 60ml of methanol, and take 2/3 The amount is used to dissolve 18g of iodine in the bath, and the remaining 1/3 is put into the reaction bottle, and 20g of formula IV 11β, 17 α-dihydroxy-4-pregnene-3,20-dione and 100ml of chloroform are stirred and dissolved. Add 12g of calcium oxide, adjust the temperature to 0~5℃, add iodine-calcium chloride-methanol solution dropwise, complete the addition, react at 0~5℃ for 2 hours, when the reaction is completed, add 100ml of 20% ammonium chloride aqueous solution (containing chlorine 20g of ammonium chloride), filtered, the water layer was extracted with chlorotetralane, combined, concentrated under reduced pressure to recover the solvent, concentrated to dryness, to obtain 21-iodine-1β, 17 α-dihydroxy-4-pregnene-3, 20 -Diketone 28g;
(e) Acetylation reaction: Prepare hydrocortisone acetate. In the reaction bottle, put 28g of formula V21-iodine-11β, 17 α-dihydroxy-4-pregnantene-3,20-dione and 40ml of DMF into the reaction bottle. 16g of potassium acetate, 2ml of glacial acetic acid, adjust the temperature to reflux for 3 hours. After the reaction is completed, cool to -5°C, filter, wash, drain, and dry to obtain 21.9g of hydrocortisone acetate.
