Study On The Synthesis Of DIENOGEST

DIENOGEST is a new contraceptive that was developed by Schering company,and it is used for oral contraception due to its strong ability to inhibit ovulation. Byvirtue of the definite curative effect and low toxicity, DIENOGEST is becoming thefirst choice for the oral contraception.Total synthesis of DIENOGEST was designed and investigated systematicallyin this paper. DIENOGEST was successfully obtained from19-hydroxy-androstene-3,17-dione and estra-4(5),9(10)-diene-3,17-dione,respectively.Route 1: 19-Hydroxy-4-androstene-3,17-dione was converted to DIENOGESTthrough 9 step reactions. The overall yield of DIENOGEST was 16.69% based on19-hydroxy-4-androstene-3,17-dione.Route 2: DIENOGEST was synthesized from 19-hydroxy-4-androstene-3,17-dione by oxidation, decarboxylation, bromination and dehydrohalogenation,3-position ketalation, 17-epoxidation, ring cleavage and 3-position hydrolysisreactions. Collidine reagent was employed for 3-position carbonyl proctection insteadof highly toxic acetone cyanohydrin. The overall yield of DIENOGEST was 15.94%based on 19-hydroxy-4-androstene-3,17-dione. .Route 3: DIENOGEST was obtained from estra-4(5),9(10)-diene-3,17-dione by3-position ketalization, 17-epoxidation, ring cleavage and 3-position hydrolysisreactions. The advantage of this route was the use of a new dehydration reagent notonly avoiding the utilization of highly toxic acetone cyanohydrin, but also theexpensive Collidine reagent,and the yield was raised significantly. The overall yieldof DIENOGEST was 44.16% based on estra-4(5),9(10)-diene-3,17-dione and was19.99% based on 19-hydroxy-4-androstene-3,17-dione.All of the obtained intermediates and target product were characterized byNMR and/or IR, and other necessary analytical methods. Furthermore, the NMRspectra of DIENOGEST was completely assigned and it would be helpful for NMRspectra of this kind of carbon skeleton drugs.The purity of the obtained DIENOGEST was up to 98.9855% by HPLC andcould meet the need of clinic utilization completely and was applied for 3th class newdrug.