Synthesis Of Elagolix And N~2-alkylated Guanines

Elagolix was developed by AbbVie in 2008 and approved by the FDA in July 2018.It's the first and the only oral non-peptide small molecule gonadotropin-releasing hormone receptor antagonist,which is used for the treatment of moderate or severe pain associated with endometriosis,such as menstrual pelvic pain,non-menstrual pelvic pain,sexual intercourse pain,etc.In this dissertation,2-fluoro-6-?trifluoromethyl?benzonitrile was used as a starting material and reduced by B₂H₆ to give compound 1,which was followed by substitution and ring-closing to gain the key intermediate 3 in a yield of 59.6%.Then,the compound 3 went through multi-step reactions to obtain the target compound.In particular,the synthetic conditions of compound 3 were carefully screened,so that the content of the isomer by-product was less than 2%.We also optimized reaction conditions of Suzuki coupling and reduced the amount of catalyst to 2.5%,which avoided the formation of the by-product.In this route,elagolix was synthesized in 18%overall yield by 9 steps.Compared with the literatures,this route has the advantages of easy operations,high yields and low cost.Guanine analogues have wide applications in anti-cancer and anti-viral research for decades.So far,the reported synthetic methods for N²-alkylated guanines are not convenient enough.We herein report an improved three-step synthesis of N²-alkylated guanines?yield:63.1%-73.5%?via dual-Boc protection of both N² and N⁹ positions,followed with N²-alkylation and subsequent hydrolysis.The advantages of this procedure included short reaction steps,simple operations and good yields.