Catalytic Deprotection—DEPRO™ Catalyst Kit/Catalytic Deprotection

Deprotection

Ph.D, Development Manager, Johnson-Matthey Catalysis

In the manufacture of pharmaceuticals and fine chemicals there is often a requirement for a protection strategy to minimize possible side reactions during a synthesis. Small, easily removed protecting groups (PG), available for a range of functional groups, is highly desired. One such easily removed PG is derived from the facile catalytic hydrogenolysis of benzylic groups. An analysis of the published medicinal chemical routes shows that over 1000 drug syntheses currently use this type of protection. The classic functional groups requiring protection are alcohols, acids and amines.

Simple cleavage of these protecting groups is critical. Cleavage by catalytic hydrogenation can be performed with good selectivity under mild conditions using a heterogeneous palladium on carbon (Pd/C) catalyst in the presence of hydrogen gas or a hydrogen transfer agent, e.g. ammonium formate or isopropanol. Efficient removal depends on selection of the most active and selective catalyst, and an optimized set of reaction conditions. This need has led to the development of a range of more active and selective catalysts with reduced metal loadings designed for O-debenzylation of benzyl protected alcohols and acids, N-debenzylation of amines, amides and Cbz (carbamate) type PG of amines.

Model Reactions

Two model reactions were selected and investigated; the debenzylation of 2,3,4,6-tetra-O-benzyl-D-glucopyranose, and the debenzylation of N-benzyl N-α-methylbenzylamine.

Standard reaction conditions for deprotection of the glucopyranose sugar were 25 °C, 3 bar hydrogen pressure using a 5 weight percent catalyst loading based on substrate (for 5% Pd/C catalysts). Standard reaction conditions for deprotection of the amine were 50 °C, 3 bar hydrogen pressure with a 5 weight percent catalyst loading based on substrate (for 5% Pd/C catalysts). Catalysts with higher percent metal loadings were evaluated on an equal metal basis. Screening reactions were carried out in an Argonaut Endeavor™ 8 x 10 mL reactor system. Reactions, products and byproducts were monitored by hydrogen uptake, GC and/or HPLC.

Catalyst Activity and Selectivity

The DEPRO™ 5% Pd/C and 10% Pd/C catalysts were screened under the standard reaction conditions for each reaction along with a current deprotection catalyst standard in the Industry, 20% Pd(OH)₂/C Pearlman’s catalyst. For the O-debenzylation, reactions proceeded with complete conversion to the fully debenzylated product. For the N-debenzylation, hydrogenolysis of the less bulky benzyl group occurred with high selectivity in most cases. The reaction rate/ hydrogen uptake profile for the N-debenzylation reaction is shown in Figure 1. For both the O-debenzylation and N-debenzylation reactions, the DEPRO catalysts were found to be more active and selective than the current Pearlman’s catalyst.

Figure 1.

Solvent Effects

Solvent choice is critical for any deprotection reaction. For amine deprotection, the free amine products are well known to strongly adsorb at active sites, inhibiting or even completely poisoning the catalyst. For each of the O-debenzylation and N-debenzylation reactions a series of commonly employed solvents, THF, ethanol, ethyl acetate, acetic acid, and solvent mixtures were screened under standard reaction conditions using several of the top performing catalysts. Results were in general independent of specific catalyst type.

For the O-debenzylation, reaction rates were fastest in THF, slightly slower in ethanol and acetic acid, and slowest in ethyl acetate. Reaction rates were generally linear with all reactions ultimately producing the completely debenzylated product.

For the N-debenzylation, reaction rates were fastest in ethanol and slowest in THF (Figure 2). The presence of acid served to prevent catalyst inhibition through protonation of the amine product.

Figure 2.

Catalyst Design Effects

The performance of a Pd/C catalyst is affected by the nature of the underlying carbon support, the size and location of the deposited metal particulates, the active metal precursor, the metal oxidation state and the method of catalyst preparation. Metal particulates can be made to distribute preferentially at the exterior surface of the support (an eggshell or surface loaded catalyst) or be evenly dispersed throughout the support structure (a standard or uniform catalyst). Deposited metal may be either in a reduced or unreduced form.

For most O-debenzylation and N-debenzylation reactions, eggshell unreduced, and eggshell reduced catalysts perform better than uniform catalysts. For otherwise equivalent catalysts, the underlying carbon support can have a large effect on both the initial reaction rate and selectivity to the desired product. The DEPRO™ catalysts represent a cross section of these desired properties.

Summary

Facile cleavage of O-benzyl and N-benzyl protecting groups can be achieved by catalytic hydrogenation using heterogeneous Pd/C catalysts at low temperature and pressure, with low catalyst loadings and low catalyst weight percent metal. The structure of the substrate plays an important role in determining the activity and selectivity of any debenzylation catalyst. It is important to investigate a number of catalyst types for each specific application. A variety of solvents, temperatures, pressures, and catalyst loadings should be evaluated to arrive at an optimized set of reaction conditions.