Question

The initial Mannich reaction can be carried out with methylamine. This gives a more direct route to Prozac, but the Mannich condensation with methylamine is low yielding and produces several by-products. Suggest a reason for this.

Answer 1

Mannich reaction

Mannich reaction can be explained as

The formaldehyde functional group and primary or secondary amine or ammonia will place an acidic proton which is obtained by aminoalkylation, next to the carbonyl group. Here the Mannich base is the final product $\beta$-amino carbonyl compound.

Mannich condensation with methylamine is low yielding and show several by products.

The reason is :

enamine intermediate formed is senstive to hydrolysis. So Separation and Purification is tedious.  Separation process is enhanced by adding ether to the product. Low yield may be due to the loss occurance while separation and purification.

Obviously when the yield of main product is reduced, the formation of byproducts will enchanced.