1、 Project Introduction
Trofinetide is a drug jointly developed by Neuren Pharmaceuticals and Acadia Pharmaceuticals for the treatment of rare neurodevelopmental disorders in children. In March 2023, it received FDA approval for use in patients aged 2 years and older with Rett syndrome (including both adults and children).
Retard syndrome is predominantly caused by loss-of-function mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MeCP2). MeCP2 serves as a critical transcriptional regulator and is essential for normal nervous system development. Trifenanide is an orally administered synthetic analog of glycine-proline-glutamate (GPE), which is a N-terminal tripeptide metabolite of insulin-like growth factor-1 (IGF-1). Studies have demonstrated that GPE can partially reverse Retard-like symptoms in mouse models with MeCP2 deficiency, and trifenanide was developed to optimize the pharmacokinetic properties of GPE.
Molecular Formula：C13H21N3O6
Molecular Weight:315.32。
CAS：853400-76-7
Chemical Name：(S)-2-((S)-1-(2-aminoacetyl)-2-methylpyrrolidin-2-carboxamido)glutaric acid
2、Synthetic Route
To date, numerous studies have been published regarding the preparation of trofetide, employing various protective group strategies that are unsuitable for scale-up production due to challenges in reagent selection and column chromatographic purification. Neuren proposes a more feasible synthesis route that utilizes in situ silane protection/deprotection during the amidation step, thereby avoiding product degradation caused by protective group removal.
Step 1: Cbz glycine was activated using hydroxysuccinimide and EDCI; the product precipitated from the reaction mixture with a yield of 84%.
Step 2: First, the carboxylic acid of compound 8.4 was protected by in situ silanization with N-methyl-N-trimethylsilylacetamide; then it was condensed with the activated ester of compound 8.3; finally, the silane ester was deproteected, yielding a yield of 79%.
Step 3: Use ethyl 2-oxymethyl cyanate (Oxyma Pure) and EDCI to activate the carboxylic acid at position 8.6, perform in situ sil烷ation of the carboxylic acid at position 8.7 with N-methyl-N-trimethylsilylacetamide, followed by amide condensation.
Step 4: Use Pd/C and hydrogen to remove the Cbz protecting group; dissolve trufinopeptide in an aqueous phase and obtain the target API via spray drying, with a yield of 90%.
3、 References
[1] Blower, C.; Peterson, M.; Shaw, J. M.; Bonnar, J. A.; Moniotte, E. D. F. P.; Bousmanne, M. B. C.; Betti, C.; Decroos, K. W. L.; Ayoub, M. Compositions of trofinetide. WO 2021026066, 2021.
Special Note: This article does not serve as medical advice for medication use. Specific drug administration should follow physician instructions.
4、Contact Us
Phone: +86-18986204913
Tel: +86-027-83338163
E-Mail: info@cosperpharma.com
