Synthesis of 2-methoxy and 4-methoxy equine estrogens

Abstract

4-Methoxyequilin and 2-methoxyequilin were synthesized from the corresponding 4-bromoequilin and 2-iodoequilin derivatives, respectively, by nucleophilic displacement of halogen with methoxide ion in the presence of copper (II) chloride and 15-crown-5-ether. 4-Bromoequilin was prepared by reacting equilin with one equivalent of N-bromoacetamide. 2-lodoequilin was prepared by reductive dehalogenation of 2,4-diiodoequilin, which in turn was obtained by treatment of equilin with two equivalents of iodine in methanolic ammonium hydroxide solution. 4-Methoxy-equilenin and 2-methoxyequilenin were prepared from the corresponding 4-iodo-and 2-iodo-7ξ,8ξ-epoxyestrone derivatives, respectively. Nucleophilic displacement of iodine with methoxide ion was carried out as described earlier with simultaneous aromatization of the B ring leading to 4- and 2-methoxyequilenin derivatives. Alternatively,4-methoxyequilenin was obtained from 4-methoxyequilin by selenium dioxide oxidation.