Synthesis And Process Of Steroid Intermediates With Androstenedione As Feedstock

Due to the shortage of dioscorea zingiberensis resources and the environmental pollution in the traditional saponin production,the production of saponin has been greatly restricted in recent years,thus results its price remain high.Sterol is an ideal substitute resource for saponin,and almost all steroid hormone intermediates can be synthesized by sterol as substrate and androstenedione?4AD?obtained after microbial treatment.With the development of microbiological technology,the price of androstenedione will be greatly reduced.Epiandrosterone and methyltestosterone are two important steroid hormone intermediates mainly prepared with saponin as raw material,which has high production cost and no obvious competitive advantage in the market.Therefore,it is urgent to develop new processes to improve their competitiveness.Epiandrosterone and methyltestosterone were synthesized as raw material of androstenedione and their production processes were studied.This study can provide theoretical basis and technical support for the synthesis of epiandrosterone and methyltestosterone as raw material of androstenedione in terms of reducing cost and increasing yield.The specific research contents and results are as follows:1.Epiandrosterone was synthesized as raw material of androstenedione.Choose acetic anhydride to protect reagent for 3-carbonyl protection product protected by ene esterification and ethylene glycol to ene esterification product 17-carbonyl protection of ketal protection products,and then after alkaline hydrolysis,not directly with palladium carbon reduction after post-processing,hydrolysis,reduction in a pot,and finally in the alcohol acid solution for hydrolysis product target therapy.The intermediate and the target compound were characterized by melting point,¹H NMR,¹³C NMR and IR,and the structure of the products at each step were confirmed.The reaction mechanism of each step was discussed.2.The synthesis process of epiandrosterone was optimized.Optimum process conditions are as follows:?1?Ene esterification reaction:dichloromethane was selected as the solvent of the reaction system,and acetyl chloride was added as the dehydrating agent,the dosage was 10m L,and p-toluene sulfonic acid was selected as the catalyst,the optimal dosage of p-toluene sulfonic acid was 0.08g,the temperature was 50?,the mole ratio was 1:21.2,the yield was 66.6%.?2?Ketal protection reaction:glycol was selected as the ketal protection reagent,and the optimal dosage was 8m L.8m L trimethyl orthoformate was added in 4 times,each time added 2m L,material ratio was1:10.temperature was 40?,the yield was 93.0%.?3?Alkaline hydrolysis and reduction reaction:potassium hydroxide as an alkaline hydrolysis reagent.Reduction of stress and palladium carbon dosage is 1Mpa and 0.6g,respectively,50?as the temperature of the hydrogenation,the yield was 89.8%.?4?Acid hydrolysis reaction:choose hydrochloric acid as the acid hydrolysis reagent,with 15m L of hydrochloric acid added amount,acid hydrolys was 80?,the yield was 91.7%.The optimized yield was 51.0%.3.Methyltestosterone was synthesized as raw material of androstenedione.Triethyl orthoformate was used to selectively protect 3-carbonyl group,methyl iodide was used as halogenated alkanes and magnesium filings to prepare griggott's reagent,iodine particles were used as preformed initiator,and then reacted with 17-carbonyl group,methyl was introduced,finally hydrolyzed under acidic conditions,and the enetherified protective group of 3-carbonyl group was removed to obtain methyl testosterone.The intermediate and the target compound were characterized by melting point,¹H NMR and IR,and the structure of each step product were confirmed.The reaction mechanism of each step was discussed.4.The synthesis process of testosterone was optimized.Optimum process conditions are as follows:?1?Dilute alcohol ether reaction:catalyst for p-toluene sulfonic acid,temperature is was 10?,n androstenedione:n triethyl orthoformate=1:9,the yield was 85.8%.?2?The graves and hydrolysis reaction:anhydrous tetrahydrofuran as solvent,methyl iodide as halogenated reagents,temperature was 60?,n _{magnesium scrap}:n _{methyl iodide}:n _{etherified product}=1:40:1,hydrolysis reagent for dilute hydrochloric acid,hydrolysis temperature was 60?,the yield was 82.3%.The optimized yield was 70.6%.