The invention relates to the technical field of
chemical synthesis, and particularly provides a preparation method of a
semaglutide side chain, which comprises the following steps: step S1, carrying out reaction on octadecanedioic acid mono-tert-butyl ester and
trifluoroacetic acid pentafluorophenyl ester to generate a first intermediate; s2, enabling the first intermediate to react with 1-tert-butyl L-
glutamic acid to generate a second intermediate; s3, enabling the second intermediate to react with pentafluorophenyl trifluoroacetate to generate a third intermediate; and S4, carrying out an amidation reaction on the third intermediate and 17-amino-10-oxo-3, 6, 12, 15-tetraoxa-9-aza-heptadecanoic acid, so as to generate a
semaglutide side chain, and carrying out an amidation reaction on the third intermediate and 17-amino-10-oxo-3, 6, 12, 15-tetraoxa-9-aza-heptadecanoic acid. According to the preparation method disclosed by the embodiment of the invention, the pentafluorophenyl trifluoroacetate is used as the condensation
reagent for two times to activate the
carboxylic acid, and the amidation reaction is carried out for two times to construct the amido bond after each activation, so that compared with the traditional
carbodiimide and
urea positive
ion type condensation
reagent, the chiral
racemization in the
condensation process can be effectively avoided, and the yield of the product is improved. The condensation chiral
racemization impurity can be lower than 0.3%.