I am doing a coupling reaction using naphthyridine dicarboxylic acid and 2-aminomethylpyridine using EDC HCl, HOBt, DMAP and DMF. Do I need to add base to neutralize the HCl salt before, during or after the reaction, or is that not necessary? I am worried that the acidic conditions will protonate my starting materials and cause problems during workup.
You can use 2 equiv DMAP, which will take care of neutralisation in the reaction mass itself. No need seperate neutralisation prior to the reaction.
Charge neutralization by EDC/ethanolamine in excess is another option (Chau Y, Tan FE, Langer R. Synthesis and characterization of dextran-peptide-methotrexate conjugates for tumor targeting via mediation by matrix metalloproteinase II and matrix metalloproteinase IX. Bioconjugate Chem 2004; 15: 931-41).
Please appreciate also the publication Polymer-drug conjugates: Progress in polymeric prodrugs Jayant Khandare & Tamara Minko. Prog. Polym. Sci. 31 (2006) 359-397.
You probably do not need the HOBt, which is usually added to protect the sterochemical integrity in alpha-amino acid couplings. DMAP is usually added only catalytically, but I do not think it's necessary here. I think you would want to have a real base such as DIEA thrown in there. EDC-HCl/DIEA/DMF should work. Just mix the acid with the EDC/DIEA and then add the amine.
Thanks to everyone for the answers ! My amide product is actually a bit heat sensitive-I am therefore thinking about using a lower-boiling base like TEA. Let's see how that works !
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