Synthesis of Saquinavir

Original Synthesis

Reduction of 1 to 3 and 4 is acomplished in a 3:1 ration. Crystallization is used to separate the two. In the original synthesis of saquinavir 6a is a key intermediate. It is prepared from phenylalanine-derived mixed anhydride by treatment with diazomethane and acidolysis. 6 and 7 are derivatives of 3 and 4 after potassium hydroxide is added. A test for the stereochemistry is done on sample by an HNMR. The results should show that 11a and 12a are acheived.

Retrosynthesis

In determining were to start the synthesis of saquinavir 5 was determined to be a fixed part. This is because a good way to make 5 was already in use. The main objective was to create a new way to make electrophile 13. Five approaches were used. The first three started with phenylalanine and required a one-carbon homologation. The next started with material that had the chirll center already. In this case dimethyl D-tartrate. Finally, generate both chirals with Sharpless epoxidation. It is important to keep in mind that a slightly protected nitrogen that is part of an amino acid aldehyde and ketone analogue react in chelation-controlled fashion.

During the reaction19 could not be used for two reasons. One the shape of the molecule was slightly off, and two because the reagent that was needed is toxic. The reaction of 21b through carbonyldiimidazole activation leads to 23b. This was a 3:1 mixture with 23b. Crystallization separated the two. 23a, b ends up as 25 a,b through hydrolysis of the ester. A loss of the protection group in 26 a,b to 27a,b was a nessesity in the change of the acids to their acid chlorides. Here 27b is easily removed by titration with a petroleum ether.

The formation of 9 required multiple steps. Phthaloyl protection was chosen over the benzyloxycarbonyl group due to the rigorous reactions that occure throughout the synthesis. No purification steps were nessecary in going from 30 to 32. DMF was the solvent used to carry out the reaction of 5 and 33 and were carried out at 120oC. Sequential treatment with ethanolic methylamine and hydrogen chloride lead to another key intermediate, 9.