The yield, purity and cost of RGD cyclized pentapeptide as the core starting material of tumor-targeted therapy-related drugs directly determine the feasibility of industrialization. new process of solid phase synthesis solve the traditional process pain points at one stroke, achieve high yield, high purity preparation, proper industrial production optimization scheme!
Focus first: the core value of RGD cyclized pentapeptide
integrin receptor αvβ3 only high expression in tumor cells/tumor neovascularization endothelial cells it is the golden target of tumor targeted therapy.
✅Linear RGD peptide: short plasma half-life, low receptor affinity, poor targeting effect;
✅Cyclization of RGD peptide: more stable structure, greatly improved affinity/targeting, is the preparation of (99m)-HYNIC-PKM-E[L-c(RGDxK)]2 and other radioactive targeting drugs key Starting Materials.
3 major pain points of traditional synthesis process
the existing process is difficult to meet the needs of industrial production, the problem is directly to the point:
1. Liquid phase cyclization process: Polymerization side reactions are easy to occur, the yield is only about 75%, the condensing agent is mixed with the finished product, and the separation is difficult;2. Traditional solid-phase process: using Oall protecting group, the raw material price is high, and the deprotection needs expensive tetrakis (triphenylphosphine) palladium;3. Security risks: the use of palladium reagent is easy to cause heavy metal residues and affect the safety of drugs.
Process core innovation: solid phase ring + preferred OMe protection group
the core idea of the present invention is the side chain carboxyl group of aspartic acid was fixed on CTC resin, and the ring was solidified after step-by-step deprotection. At the same time, optimize the protection group selection, add OMe route, cost, safety, yield all-round upgrade!
Five-step core preparation process (with preferred scheme)
with CTC resin as the carrier, the preparation is completed in 5 steps to provide. OMe, Oall two routes, OMe is preferred for industrialization, the steps are clear and easy to operate!
1. Preparation of intermediate 5: coupling the resin with the carboxyl group on the side chain of Fmoc-aspartic acid (X) to obtain intermediate 5, the resin is CTC resin; X-is the protective group of aspartic acid carboxyl group, is OMe, Oall;
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