Synthesis of 2-alkoxyestradiols

A method of preparing an estradiol represented by the following structural formula:

• ##STR22## wherein R.sub.5 is a lower alkyl group or a substituted lower alkyl group, from a starting compound represented by the following structural formula:
• ##STR23## said method comprising the steps of:
• a) benzylating the starting compound to form a first intermediate represented by the following structural formula:
• ##STR24## wherein R.sub.1 and R.sub.2 are each independently a benzyl or substituted benzyl group;
• b) reacting the first intermediate with reagents consisting essentially of Br.sub.2 and a C1-C5 aliphatic carboxylic acid in an etheral solvent to form a second intermediate represented by the following structural formula:
• ##STR25## c) reacting the second intermediate with an organolithium reagent and a synthetic equivalent of R.sub.4 CO.sup.+, wherein R.sub.4 is selected from the group consisting of --H, a lower alkyl group and substituted lower alkyl group, to form a third intermediate represented by the following structural formula:
• ##STR26## d) reacting the third intermediate with an oxidizing agent capable of oxidizing an aryl alkyl ketone to the corresponding aryl alkonate, to form a fourth intermediate represented by the following structural formula:
• ##STR27## e) cleaving the aryl alkonate group of the fourth intermediate to form a fifth intermediate represented by the following structural formula:
• ##STR28## f) alkylating the free phenol group of the fifth intermediate with an alkylating agent R.sub.5 X, wherein X is a leaving group, to form a sixth intermediate represented by the following structural formula:
• ##STR29## g) debenzylating the sixth intermediate to form the estradiol.

A method of preparing an estradiol represented by the following structural formula:

• ##STR30## wherein R.sub.5 is a lower alkyl group or a substituted lower alkyl group, from a starting compound represented by the following structural formula:
• ##STR31## said method comprising the steps of:
• a) benzylating the starting compound to form a first intermediate represented by the following structural formula:
• ##STR32## wherein R.sub.1 and R.sub.2 are each independently a benzyl or substituted benzyl group;
• b) reacting Br.sub.2 and an aliphatic organic acid with the first intermediate in an etheral solvent to form a second intermediate represented by the following structural formula:
• ##STR33## c) reacting the second intermediate with an alkali metal alkoxide R.sub.5 O.sup.- Y.sup.+, wherein Y.sup.+ is an alkali metal cation, and copper (I) iodide to give a third intermediate represented by the following structural formula:
• ##STR34## d) debenzylating the third intermediate to give the estradiol.