From Santander N623 to Burgos.
Burgos N620 past Valladolid to Salamanca (nice over-night).
Salamanca N620 to Cuidad Rodrigo, take the C526 south and pick up the N630 to Caceres (Another good over-night, I can recommend the Parador here if you have the dosh!)
Caceras south on N630 towards Sevilla (not as sceneic as the foregoing route but quick enough to cover the ground. You will run into major roads North of Seville and you have a choice of keeping to them (N334) towards Malaga and then West along the coast to Marbella on the N340 or from Seville pick up the C342 and then the C339 cross country and very scenic!
Apart from the Caceres through Merida to Seville N630, I've done most of those roads and they are very scenic. The region of Extramadura down into Andalusia is much under-rated.
Have fun! I'll be doing some of that route again myself in March/April.