The problem is that usually you make 2x2 flats for 2x2 images that were taken with different filters (like RGB) than the 1x1 images (usually L). The dusts and other filter related effects will not be corrected correctly if you use flats not made with the same filter and same focus.
So in theory you should make the proper flats with each image configuration (including each filter), on the same night of the image. If you have a flat box and a reasonable control program, this is not very long.
Naturally this depends highly on the quality of image you want to achieve, the time you have and other pragmatic considerations. You may always try to resample the 1x1 master flat made using a geometry/resample or rescale (I do not remember the name) and see if it is very different from the master flats made at 2x2 and if this is acceptable to you. But it is definitely not the same quality as proper flats.
-- bitli