The racemic mixture containing the (R)-enantiomer BAY X 1005 (IV) can be prepared according to the following scheme: 4-Hydroxyphenylacetic acid methyl ester (I) is coupled with 2-chloromethylquinoline and potassium carbonate in DMF. The resulting product (II) is alkylated with cyclopentylbromide and sodium hydride in DMF to give product (III). Final saponification is undertaken with sodium hydroxide in methanol leading to the racemic carboxylic acid (IV).
Separation of the Enantiomer: The enantiomers are separated from the racemic carboxylic acid (IV). After activation of the carboxylic acid group as imidazolide (V), this compound reacts with L-phenylglycinol and toluene sulfonic acid in DMF forming the diastereomeric mixture of L-phenylglycinolamides. These diastereomers can be separated by fractionated crystallization using ethanol (diastereomer VI) or a mixture of diethylether and isopropanol (diastereomer VII) as solvents. The release of enantiomerically pure carboxylic acids (VIII) and (IX) takes place by cleavage of the amide bond with sulfuric acid, neutralization and recrystallization from ethanol. The (R)-(-)-enantiomer is the active leukotriene synthesis inhibitor BAY X 1005.
Stereoselective Synthesis of BAY X 1005: To prepare larger amounts of BAY X 1005 a second order stereoselective synthesis was elaborated: The starting material [4-(2-quinolinylmethoxy)phenyl]acetic acid (X) is esterified with D-menthol and toluene sulfonic acid in boiling toluene. Following alkylation with cyclopentylbromide and excess potassium tert-butylate in DMF leads to a diastereomeric mixture. Under the reaction conditions the diastereomer (XII) precipitates, whereas the remaining soluble diastereomer undergoes continuous epimerization. After crystallization a yield of > 85% of the desired diastereomer (XII) results with a de > 99%. Acidic cleavage with sulfuric acid yields the (R)-(-)-enantiomer BAY X 1005.