Efficient synthesis of kainic acid analogues

The present paper deals with an improved synthesis of two molecular hybrids of AMPA and KA, compounds CIP-A and CIP-B, and their transformation into CIOP-A and CIOP-B, the corresponding amido derivatives. Exploiting the continuous-flow technology, a significant improvement in the synthesis of the glutamate agonists CIP-A and CIP-B was accomplished, in terms of overall yield, time, and excess of ethyl chlorooximinoacetate. Moreover, we find out the HPLC conditions suitable to separate, at a preparative level, the three intermediates formed in the 1,3-dipolar cycloaddition step.