Research On New Process In Synthesis Of Cortisone Acetate

Cortisone acetate, the chemical name is 17α,21-dihydroxy pregnant steroid-4-ene-3,11,20-trione-21-acetate. It belongs to the adrenal drugs, mainly be used in the treatment of adrenal cortex hypofunction, can also be used in the treatment of autoimmune diseases and allergic diseases.Synthesis of Cortisone acetate more with 21-deoxy cortisone as raw material, halogenated reaction in C-21,then esterification with nucleophilic reagent. Now the current industrial production route of it is iodine generation、esterification route. This paper reference relevant literature, with17α-hydroxypregn-4-ene-3,11,20-trione(Hereinafter referred to as 21-deoxy cortisone) as raw material, through bromine generation、esterification to cortisone acetate. And then optimize the process. Specific work mainly respects in the following respects:(1)The synthesis and optimization of 21-deoxy cortisone to 1-(21-bromo-17-hydroxy-11,20-dioxopregn-4-ene-3-ylidene)pyrrolidinium chloride(Hereinafter referred to as bromide salt), through “one-pot” coupling of C-3 carbonyl protection、salt、bromine generation. Then we check the effects of pyrrolidine and 21- deoxy cortisone molar ratio、bromine and 21- deoxy cortisone molar ratio、brominated reaction time、brominated reaction temperature on product yield through single factor experiment. The suitable reaction conditions are(21-deoxy cortisone quantity in 1 g): pyrrolidine and 21- deoxy cortisone molar ratio 1.3:1, bromine and 21- deoxy cortisone molar ratio 2.2:1, brominated reaction time 6h, brominated reaction temperature 35℃. Quality yield of bromide salt is 76.1% in this condition(based on 21-deoxy cortisone). The route shorten the reaction steps, and the yield has improved compared to the total yield of previous seperate three steps(65.8%).(2) The synthesis and optimization of bromide salt to 21-bromo-17α-hydroxypregn-4-ene-3,11,20-trione(Hereinafter referred to as bromide). We determine potassium carbonate as deprotection reagent through the test of base type. On the basis of this, we check the effects of bromide salt and potassium carbonate molar ratio、reaction temperature、 reaction time、volume ratio of ethanol and water on product yield through single factor experiment. The suitable reaction conditions are(bromide salt quantity in 0.15g): molar ratio of potassium carbonate and bromide salt is 3:1, reaction temperature is 5℃, reaction time is 4h,volume ratio of ethanol and water is 1:11. Quality yield of bromide is 89.5% in this condition(based on bromide salt), yield is greatly enhanced than before(78.5%).(3) The synthesis and optimization of bromide to cortisone acetate. We check the effects of bromide and potassium acetate molar ratio、reaction temperature、reaction time、bromide and acetic anhydride molar ratio on product yield through single factor experiment, and then we check the effects of phase transfer catalyst on reaction. The suitable reaction conditions are(bromide quantity in 0.15g): bromide and potassium acetate molar ratio is 1:5, reaction temperature is 50℃, reaction time is 3h, bromide and acetic anhydride molar ratio is 1:3, TBAB(5%, in terms of bromine quality). Quality yield of cortisone acetate is 90.0% in this condition(based on bromide), yield is greatly enhanced than before(78.9%).(4) We establish the TLC testing condition of products, then characterize the structures of bromine salt、bromide、cortisone acetate through infrared spectrum、nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance spectrum.Synthesis from 21-deoxy cortisone to cortisone acetate through bromine generation、esterification is a novel route, and the line contains three steps to complete. The overall yield was 61.3% in suitable conditions(quality yield, based on 21- deoxy cortisone). This route saves some intermediate product separation, shortens the reaction steps. The yield and reaction conditions are improved through process optimization, so the route has a potential industrial production value.