Process for making a 4-amino-4-oxobutanoyl peptide cyclic analogue, an inhibitor of viral replication, and intermediates thereof

A process of preparing a compound, ACH-0142684, represented by the structure:

• or its pharmaceutically acceptable salt, comprising reacting nonenoic acid (19) with 4-benzyl-2-oxazolidinone to obtain a compound (20);
• wherein the compound (20) is then reacted a strong base and t-butyl haloacetate to obtain a compound (21);
• followed by reacting the compound (21) with hydrogen peroxide in the presence of a base such as LiOH to provide Compound C;
• reacting a compound (29) with the Compound C to obtain a compound (30)
• wherein the Compound C is reacted in the presence of a catalyst to join and merge the vinyl groups with the expulsion of ethylene,
• the t-butyl ester group is converted to a carboxylic acid group;
• and
• the carboxylic acid group is reacted with 3,3-difluoropiperidine;
• thereby forming the compound ACH-0142684.

An intermediate compound of the formula:

• wherein
• R1 is hydroxyl, C1-C 6 alkoxy, aryloxy, benzyloxy, 4-methoxybenzyloxy, C1-C6 acyloxy, halogen, or N-linked 3,3-difluoropiperidinyl;
• R2 is hydroxyl, N-linked cyclopropylsulfonamide, or N-linked benzenesulfonamide in which the benzene ring is further substituted with 0-2nitro groups;
• and
• R4 is hydrogen and R3 is hydroxyl or the heterocyclic group
• R21, in this group, is 1 to 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, —CONH2, —COOH, C1-C4alkyl, C2-C4alkanoyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, C1-C2haloalkyl, and C1-C2haloalkoxy;
• and
• R22 is phenyl, pyridyl, or thiazolyl, each of which is substituted with 0, 1, or 2substituents independently chosen from halogen, hydroxyl, amino, cyano, —COOH, —CONH2, C1-C4alkyl, C1-C4alkoxy, mono- and di-C1-C4alkylamino, trifluoromethyl, and trifluoromethoxy.