Total Synthesis of Semaglutide Based on a Soluble Hydrophobic-Support-Assisted Liquid-Phase Synthetic Method

Abstract

Considering the high cost of the production of semaglutide, which is currently the most promising antidiabetic drug especially for the treatment of type 2 diabetes mellitus, a new synthetic route of semaglutide production that possesses excellent yield and high purity is of vital importance. Herein, we reported a newly developed synthetic route of semaglutide that is simple and efficient, based on a soluble hydrophobic-support-assisted liquidphase synthetic method by applying Alloc-chemistry to the synthesis of the main chain peptide and side chain peptide of semaglutide. With careful optimization of the reaction conditions and innovative strategy of post-synthetic treatments, the total yield and purity of the crude semaglutide was improved satisfactorily.

A novel synthetic method for backbone-cyclized polypeptide POL7080 with the help of hydrophobic-support materials

“…LPPS is more suitable for synthesizing oligopeptides and peptide fragments, and all organic synthesis methods can be used, which makes it easy to scale up the reaction. 9,10 Kazuhiro Chiba reported synthetic routes for polypeptide drugs assisted by a kind of hydrophobic support (tag) (Fig. 2), the function of which was similar to that of resin materials in SPPS.…”

Liquid-Phase Peptide Synthesis (LPPS): A Third Wave for the Preparation of Peptides

“…Ma and co-workers used PC4 as a tag for the synthesis of semaglutide (31-mer) and TP4 (or Oreoch-2; 25-mer) and its analogues via fragment synthesis (convergent strategy). − During the synthesis, the formation of viscous gel instead of precipitate hindered the purification at each intermediate step. The addition of a moderate amount of diatomite to the viscous precipitate allowed the precipitation of the diatomite-labeled tagged peptide.…”

“…The hydrophobic tagged peptide was easily recovered in the filtrate, which was used directly for the next step. This strategy of diatomite mixing wash, also referred to as “capture and release”, significantly improved the isolation of tagged peptides as fine precipitates. − …”

“…The fragments were then sequentially coupled at a 0.5 mmol scale to obtain the respective protected tagged peptides. Global deprotection using TFA–TIS–H 2 O (95:2.5:2.5) afforded the crude peptides, which were purified by RP-HPLC to render pure semaglutide and TP4. , Following a similar protocol, six distinct analogues of TP4 (12–24 mer) were synthesized (Table SI-PC-A). …”

“…Global deprotection using TFA−TIS−H 2 O (95:2.5:2.5) afforded the crude peptides, which were purified by RP-HPLC to render pure semaglutide and TP4. 142,143 Following a similar protocol, six distinct analogues of TP4 (12−24 mer) were synthesized (Table SI-PC-A). 144 Chiba and co-workers further developed PC5, which turned a distinct green upon acidic treatment.…”