Process for the preparation of plecanatide
Inventors
ADAK, Sandip • BONTE, Manoj • KULKARNI, Chandrakant • SWAMY, Veeranarayana • JOGDAND, Nivrutti • Gadgil, Himanshu
Assignees
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Publication Number
US-12162957-B2
Publication Date
2024-12-10
Expiration Date
Abstract
A process for the preparation of plecanatide. Specifically, an improved process for preparation of plecanatide using a non-linear solid phase peptide synthesis. In particular, the process for preparation of plecanatide involves solid phase synthesis of peptide fragments of five amino acid units using 2-chlorotrityl chloride (2-ClTrt) resin and eleven amino acid unit using Wang resin.
Core Innovation
The invention relates to a process for preparing plecanatide by assembling protected peptide fragments and performing staged cyclization to form the final dicyclic peptide. Fragment A is coupled with a Wang resin bound fragment B to obtain a Wang resin bound protected peptide fragment, which is then cleaved and deprotected to yield a linear chain of formula (I) (SEQ ID NO:8).
The linear chain of formula (I) is monocyclized to obtain a monocyclic peptide of formula (VI) (SEQ ID NO:9), and the monocyclic peptide is further dicyclized to obtain a dicyclic peptide of formula (VII) (SEQ ID NO:1). Monocyclizing is performed with 1% H2O2 and dicyclizing is performed with 2% iodine.
The process includes final purification and desalting of the dicyclic peptide using reverse phase column chromatography to obtain pure plecanatide. The approach is defined using specific protected residues, including Acm-protected cysteines, and uses reverse phase column chromatography to purify the intermediates and the final product.
Claims Coverage
The document provides one independent claim that defines the full plecanatide preparation process, including coupling of specified fragments on resin, cleavage/deprotection to a linear chain, monocyclization and dicyclization, and purification steps. Dependent claims further refine particular process parameters.
Resin-bound fragment coupling to obtain a Wang resin bound protected peptide fragment
Coupling a fragment A with a Wang resin bound fragment B using a coupling reagent to obtain a Wang resin bound protected peptide fragment.
Cleaving and deprotecting to obtain a linear chain of formula (I)
Cleaving and deprotecting the Wang resin bound protected peptide fragment using a mixture of trifluoroacetic acid/triisopropylsilane/DODT/Water to obtain a linear chain of formula (I).
Monocyclizing the linear chain with hydrogen peroxide
Monocyclizing the linear chain of formula (I) with 1% H2O2 to obtain a monocyclic peptide of formula (VI).
Purifying the monocyclic peptide by reverse phase column chromatography
Purifying the monocyclic peptide of formula (VI) using reverse phase column chromatography.
Dicyclizing the monocyclic peptide with iodine and purifying
Dicyclizing the monocyclic peptide of formula (VI) with 2% iodine to obtain a dicyclic peptide of formula (VII), followed by purifying and desalting the dicyclic peptide using reverse phase column chromatography to obtain pure plecanatide.
Overall claim coverage centers on a complete plecanatide process defined by resin-bound coupling to a Wang resin protected intermediate, cleavage/deprotection to a linear chain, monocyclization with H2O2, dicyclization with iodine, and reverse phase column chromatography purification and desalting to obtain pure plecanatide.
Stated Advantages
Simpler process.
Cost-effective.
Scalable.
Improved yield and purity.
Reduced deletion impurities.
Documented Applications
Manufacturing/production of plecanatide using an improved process based on a non-linear solid-phase peptide synthesis “5+11 fragment” strategy.
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