The reduced density matrix is variationally optimized for the two-dimensional Hubbard model. Exploiting all symmetries present in the system, we have been able to study 6 × 6 lattices at various fillings and different values for the on-site repulsion, using the highly accurate but computationally expensive three-index conditions. To reduce the computational cost we study the performance of imposing the three-index constraints on local clusters of 2 × 2 and 3 × 3 sites. We subsequently derive new constraints which extend these cluster constraints to incorporate the open-system nature of a cluster on a larger lattice. The feasibility of implementing these new constraints is demonstrated by performing a proof-of-principle calculation on the 6 × 6 lattice. It is shown that a large portion of the three-index result can be recovered using these extended cluster constraints, at a fraction of the computational cost.