Site directed mutagenesis - several different multiple mutations (Jul/11/2008 )

Hello,

does anybody known a good method to introduce several different multiple mutations (up to 7 bases)?
I haven't used completely overlapping primers (as suggested by QuickChange site directed mutagenesis protocol), but primers complementing each other at the 5'-terminus and with at least 8 non overlapping bases at the 3' terminus (as suggested by Zheng et al. 2004) and the PCR doesn't work....
Any suggestions? (The template is 6 kb, the primers Tm is between 70C and 80C, the anealing temperature I use is 52C with Pfu polymerase).

Thanks!

Drosy