Process of preparing a peptide epoxyketone immunoproteasome inhibitor, and precursors thereof

A method of preparing (2S,3R)—N-[(2S)-3-(cyclopent-1-en-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[(2S)-2-[2-(morpholin-4-yl)acetamido]propanamido]propanamide (compound “G”)

• comprising:
• (a) admixing a tertiary amine base and a suspension of:
• (i) (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholino-acetamido)propanamido)propanoic acid (compound “E”):
• and
• (ii) (S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-aminium salt (compound “F”):
• wherein X− is a counterion;
• in an aprotic solvent to form a mixture;
• and
• (b) admixing a coupling agent and the mixture of step (a) to form compound G;
• wherein the temperature of each admixing step is maintained at −20° C. to 25° C.