Process for the preparation of tetrasubstituted imidazole derivatives and novel crystalline structures thereof

A process for preparing a compound of formula (I)

• wherein
• R1 is selected from the group consisting of phenyl, substituted phenyl, (where the substituents are selected from C1–C5alkyl, halogen or trifluoromethyl);
• R2 is a saturated or unsaturated 6 membered ring with 5 carbon atoms and one nitrogen atom;
• R3 is carbocyclic arylC1–C5alkyl, wherein the aryl group is optionally substituted with substituents selected from C1–C5alkyl, C1–C5alkoxy, halogen, amino, C1–C5alkylamino or di(C1–C5alkyl) amino);
• R4 is
• where
• p is an integer from 0 to 9;
• X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl, (where one or more substituents are selected from fluorine or chlorine), ethynyl, substituted ethynyl (where the substituent is selected from fluorine or chlorine), C1–C5alkyl, substituted C1–C5alkyl (where the alkyl substituents are selected from one or more of C1–C5alkoxy and trihaloalkyl,), and C3–C7cycloalkyl and pharmaceutically acceptable salts thereof;
• comprising
• reacting a compound of formula (VIII), wherein L1 and L2 are independently selected from the group consisting of C1–C4alkyl and C1–C4aralkyl;
• or L1 together with L2 is selected from the group consisting of —CH2—CH2—(optionally substituted with one to four C1–C3 alkyl), and —CH2—CH2—CH2—(optionally substituted with one to six C1–C3 alkyl);
• with a compound of formula (X), to produce the corresponding compound of formula (XI);
• cyclizing the compound of formula (XI), under acid conditions of pH less than about 7, to produce the corresponding compound of formula (XII);
• reacting the compound of formula (XII) with POBr3, PBr5, or a mixture of PBr3 and Br2, to yield the corresponding compound of formula (XIII);
• displacing the bromine on the compound of formula (XIII) by reacting with a compound of formula (XIV), to produce the corresponding compound of formula (I).