Patent ID: 7446129

Claim:
A method for preparing a benzylated PDE4 inhibitor having reduced emetogenic potential relative to the non-benzylated PDE4 inhibitor, wherein the benzylated PDE4 inhibitor has the following formula: wherein Bzl has the formula: wherein each of the numerals 1, 2, 3, 4 and 5 may be carbon or nitrogen, with the proviso that the ring is aromatic and contains at least 3 carbon atoms; n is 5 and R 1 at each occurrence is independently selected from halogen, nitro, R 2 , NR 2 (m) , and OR 2 wherein m=0, 1, 2, or 3 and R 2 at each occurrence is independently selected from H, C 1 -C 8 alkyl, alkoxyalkyl having 3-7 carbons in the alkoxy portion and 2-4 carbons in the alkyl portion, phenoxyalkyl having 2-6 carbons in the alkyl portion, C 3 -C 7 cycloalkyl, C 6 -C 9 polycycloalkyl, alkylcycloalkyl, hydroxyalkyl, carboxyl, alkylcarboxylate, carboxylate, alkyl carboxyl, amide, alkylamide, aryl, heteroaryl, heteroalkyl, heterocycloalkyl, phenylalkyl having 1-8 carbons in the alkyl portion, phenylaminoalkyl having 2-6 carbons in the alkyl portion and the amino may be optionally substituted with C 1 -C 4 alkyl and indanyl; wherein the alkyl portion of an R 2 group may be optionally substituted with one or more fluorine atoms, hydroxyl or C 1 -C 8 alkoxy; and the aryl portion of an group may be optionally substituted with C 1 -C 8 alkyl, C 1 -C 8 alkoxy or halogen, and wherein the method comprises reacting a PDE4 inhibitor having the following formula: where the protecting group is a suitable protecting group for a nitrogen atom; with a benzylating agent having the following formula: wherein n, each R 1 and each numeral 1, 2, 3, 4 and 5 are as defined above for the benzylated PDE4 inhibitor and the leaving group is a halogen or a sulfonate, under basic conditions to form the benzylated PDE4 inhibitor as defined above.