Preparation of pharmaceutical salts of piperazine compounds

This application is a divisional of application Ser. No. 11/326,155 filed Jan. 5, 2006 which in turn claims the benefit of priority from U.S. provisional patent application Serial No. 60/641,910 filed Jan. 6, 2005, each of which is incorporated by reference in its entirety as if set forth fully herein.

This patent application generally discloses a novel process to prepare pharmaceutically useful salts. It specifically discloses a novel process to synthesize pharmaceutically useful salts of piperazine compounds such as piperazine, 4-[4-[(R)-[1-[(cyclopropylsulfonyl)-4-piperidinyl](3-fluorophenyl)methyl]-3(S) -methy 1-piperazinyl]-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-methylpiperidine (Formula 1). It further discloses a process to prepare pharmaceutical salts that are enriched in desired specific rotameric configurations.

4-[4-[(R)-[1-[(Cyclopropylsulfonyl)-4-piperidinyl](3-fluorophenyl)methyl]-3(S) -methyl-1-piperazinyl]-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-methylpiperidine (Formula I) is disclosed U.S. Pat. No. 6,720,325 to Miller, incorporated herein by reference.

U.S. Pat. No. 6,720,325 discloses several novel antagonists of the CCR5 receptor which are useful for the treatment of AIDS and related HIV infections, including the compound of Formula I. CCR5 receptors have also been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.

Generally, pharmaceutical compounds are used as their pharmaceutically acceptable salts. This is true of CCR5 receptor antagonists such as the compound of Formula I too, which makes the preparation of pharmaceutically acceptable salts of such compounds quite important.

The compound of Formula I has two chiral centers and the absolute configurations of the chiral centers are controlled by the chemical synthesis. However, the compound of Formula I exists as a mixture of rotational isomers or rotamers. There are two rotamers (diastereomeric—relationship between the two) resulting from restricted rotation about the amide bond marked “a” in FIG. 1 and in Scheme 1. For present purposes, enantiomers of rotamer 1 are considered inclusively as rotamer 1 and the enantiomers of rotamer 2 are considered inclusively as rotamer 2 which will be apparent from the examples that follow. The two rotamers may be denoted as rotamers 1 and 2, in order of their elution from a HPLC column, rotamer 1 being the one eluting first, and rotamer 2 eluting second.

Scheme 1 illustrates rotation about the amide bond for two example rotamers:

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