Process for the preparation of aniline-derived thyroid receptor ligands

A process for synthesizing a compound of formula I

• wherein
• R1 represents halogen, trifluoromethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 7 carbons;
• R2 and R5 are the same or different and represent hydrogen, halogen, an alkyl group of 1 to 4 carbons, or a cycloalkyl group of 3 to 6 carbons, at least one of R2 and R3 being other than, hydrogen;
• R4 represents hydrogen or a lower alkyl group;
• R5 represents a carboxylic acid or an alkyl ester thereof;
• and
• Y represents —(CH2)n—where n is an integer from 1 to 5, or a cis- or trans-ethylene group —CH=CH—;
• and all stereoisomers thereof;
• said process comprising the steps of:
• a) reacting a compound of formula III with a phenol of formula A, wherein R1, R2, R3, and R4 are as defined above and G is a protecting group, in the presence of a base to produce a compound of formula IV;
• b) deprotecting and reducing the compound of formula IV to form a compound of formula VI;
• c) reacting the compound of formula VI with a compound of the formula XC(O)YR5, wherein X represents OH or a halogen and R5 is a carboxylic acid alkyl ester, in the presence of a base, to produce a compound of formula I wherein R5 is a carboxylic acid alkyl ester;
• and
• (d) optionally de-esterifying the compound of formula I wherein R5 is a carboxylic acid alkyl ester to produce a compound of formula I wherein R5 is a carboxylic acid;
• wherein the compound of Formula III is produced by reacting a compound of formula II
• wherein L is a leaving group;
• R2 and R3 are the same or different and represent hydrogen, halogen, an alkyl group of 1 to 4 carbons, or a cycloalkyl group of 3 to 6 carbons, at least one of R2 and R3 being other than hydrogen;
• and
• R4 alkyl group;
• with an iodinating agent.