Process for the isolation and purification of ester functionalized imidazole intermediates by selective hydrolysis

A method for the isolation and purification of a compound of the formula (I) from a mixture of compounds of the formula (I) and (II) ##STR8## wherein R.sup.1 is selected from H;

• C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C10alkenyl, or C2-C10 alkynyl;
• C1-C6 alkyl-CO.sub.2 -(C1-C6 alkyl), C1-C6 fluoroalkyl-CO.sub.2 -(C1-C6 alkyl), C2-C10 alkenyl-CO.sub.2 -(C1-C6 alkyl) , or C2-C10 alkynyl-CO.sub.2 -(C1-C6 alkyl);
• C4-C10 cycloalkylalkyl, C3-C6 cycloalkyl, C5-C10 cycloalkylalkenyl, or C5-C10 cycloalkylalkynyl;
• C4-C10 cycloalkylalkyl substituted by 1-13 --F, C3-C6 cycloalkyl substituted by 1-13 --F, C5-C10 cycloalkylalkenyl substituted by 1-13 --F, or C5-C10 cycloalkylalkynyl substituted by 1-13 --F;
• C4-C10 cycloalkylalkyl-CO.sub.2 -(C1-C6 alkyl), C3-C6 cycloalkyl-CO.sub.2 -(C1-C6 alkyl), C5-C10 cycloalkylalkenyl-CO.sub.2 -(C1-C6 alkyl), or C5-C10 cycloalkylalkynyl-CO.sub.2 -(C1-C6 alkyl);
• phenyl, naphthyl, or aryl-(C1-C4 alkyl);
• phenyl substituted with --F, naphthyl substituted with --F, or aryl-(C1-C4 alkyl) substituted with --F;
• phenyl-CO.sub.2 -(C1-C6 alkyl), naphthyl-CO.sub.2 -(C1-C6 alkyl), or aryl-(C1-C4 alkyl)-CO.sub.2 -(C1-C6 alkyl);
• --(CH.sub.2).sub.s O(CH.sub.2).sub.m R.sup.5 ;
• --(CH.sub.2).sub.s O(CH.sub.2).sub.m R.sup.5 substituted with --F;
• --(CH.sub.2).sub.s O(CH.sub.2).sub.m R.sup.5 substituted with --CO.sub.2 -(C1-C6 alkyl);
• benzyl;
• or benzyl substituted with up to 2 groups selected from halo, C1-C4 alkoxy, NO.sub.2, or C1-C4 alkyl;
• R.sup.2 is C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl-(C.sub.1 -C.sub.6)alkyl, phenyl-(C.sub.1 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy-(C.sub.1 -C.sub.6)alkyl, hydroxy-(C.sub.1 -C.sub.6)alkyl, hydroxy-(C.sub.2 -C.sub.6)alkenyl, hydroxy-(C.sub.2 -C.sub.6)alkynyl, aminocarbonylalkyl, carbonylaminoalkyl, halogen;
• R.sup.3 is --CN;
• --CONHR.sup.1 ;
• or --CO.sub.2 R.sup.1 where R.sup.1 as defined above is not H;
• R.sup.5 is H, Br, I, F, CF.sub.3, (C.sub.1 -C.sub.4)alkyl, --C(CF.sub.3).sub.2 OH, --NHSO.sub.2 CH.sub.3, --C(.dbd.O)NHNHSO.sub.2 CF.sub.3, ##STR9## aryl;
• or aryl substituted by R.sup.9 ;
• R.sup.6 is H, halo, NO.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --NHSO.sub.2 CH.sub.3, --NHSO.sub.2 CF.sub.3, --CONHO--(C.sub.1 -C.sub.4)alkyl, tetrazolyl, trityl tetrazolyl, or furyl;
• R.sup.7 is H, halo, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy;
• X is a single bond, --CO--, --CH.sub.2 --, --O--, --CONH--, --NHCO--, --OCH.sub.2 --, --CH.sub.2 O--, --NHSO.sub.2 --, --SO.sub.2 NH--, --CH.dbd.CH--, --CF.dbd.CH--, --CH.dbd.CF--, --CF.dbd.CF--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, or ##STR10## R.sup.8 is H, --NHSO.sub.2 CH.sub.3, --NHSO.sub.2 CF.sub.3, --NHCOCF.sub.3, or --CONHNHSO.sub.2 CF.sub.3 ;
• R.sup.9 is H, C.sub.1 -C.sub.4 alkyl, or phenyl;
• r is 0 to 2;
• m is 1 to 5;
• and
• s is 0 to 5;
• said method comprising the steps of:
• treating a mixture of a compound of formula (I) and its regioisomer of formula (II) in a solvent system, which is:
• a) a solvent or mixture of solvents, selected from a halogenated solvent, an ether solvent, a hydrocarbon solvent, a protic solvent, or an aprotic solvent, said solvent or mixture of solvents forming a single liquid phase;
• or
• b) a solvent mixture of at least two immiscible solvents, selected from the solvent groups defined in a) above, that results in more than one liquid phase, said solvent mixture additionally containing a phase transfer catalyst present in the range of 1-20% mole based upon the mixture of compounds of formula (I) and formula (II);
• with 1-20 molar equivalents of an alkali metal hydroxide, and heating the mixture to solvent reflux for a period of time sufficient to preferentially hydrolyze the compound of formula (II) and separating the compound of formula (I) from the hydrolyzed products of compounds of formula (I) and formula (II).