Your challenge is to make Panama City (the one in Panama) one of the major cities of the New World, with a population of, at least 2 million.
IMO, more likely if the canal is never built, but rather a major rail line is. Then all the goods going over the Isthmus need to be transshipped, and there'll be a lot more jobs and commercial activity there. With a canal, it can all just go straight through, and the ends aren't terribly important.PoD - Simon Bolivar manages to fully unite Gran Colombia, Peru and Upper Peru - and keep it united and stable (a grand federation of sorts). Using the great wealth of Bolivia at the time, this Gran Colombia funds the construction of the Panama Canal - perhaps even naming it after Bolivar to boot. Possibly sooner - bringing in railways earlier and accelerate the growth of Colon and Panama city. (Which might bring the construction of the Canal sooner).
With the commercial benefits granted by the canal, and the significant resources of Gran Colombia to develop the area, the Panama Bay region becomes a major manufacturing hub - with resources from all parts of the country shipped into the region for industrial processing, and then sold on. With the increased flow of capital into the region, I can see Panama City becoming easily twice the size that it is now to the point that the Panama Bay Region becomes its own federal unit within the Federation.