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US 12,162,957 B2Granted
Process for the preparation of plecanatide
AssigneeEnzene Biosciences Limited
InventorsSandip Adak, Manoj Bonte, Chandrakant Kulkarni, Veeranarayana Swamy, Nivrutti Jogdand, Himanshu Gadgil
Life of this patent
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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.
Claims9
A process for preparing plecanatide comprising the steps of:
- (a) coupling a fragment A, wherein fragment A is selected from the group consisting of:
- Fmoc-Asn(Trt)-Asp(OtBu)-Glu(OtBu)-Cys(Trt)-Glu(OtBu)-OH (SEQ ID NO:
- 3) and Boc-Asn(Trt)-Asp(OtBu)-Glu(OtBu)-Cys(Trt)-Glu(OtBu)-OH (SEQ ID NO:
- 4), with Wang resin bound fragment B:
- H2N-Leu-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(OtBu)-Gly-Cys(Acm)-Leu-O-Wang resin (SEQ ID NO:5) using a coupling reagent to obtain a Wang resin bound protected peptide fragment:
- Fmoc-Asn(Trt)-Asp(OtBu)-Glu(OtBu)-Cys(Trt)-Glu(OtBu)-Leu-Cys(Acm)-Val-Asn(Trt)-Val-Ala-Cys(Trt)-Thr(OtBu)-Gly-Cys(Acm)-Leu-O-Wang resin (SEQ ID NO:6);
- (b) cleaving and deprotecting the Wang resin bound protected peptide fragment obtained in a step (a) using a mixture of trifluoroacetic acid/triisopropylsilane/DODT/Water to obtain a linear chain of formula (I);
- H2N-Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys(Acm)7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Glyl4-Cys(Acm)15-Leu16-OH (SEQ ID NO:8);
- (c) monocyclizing the linear chain of formula (I), H2N-Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys(Acm)7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Glyl4-Cys(Acm)15-Leu16-OH (SEQ ID NO:8) with 1% H2O2 to obtain a monocyclic peptide of formula (VI):
- (d) purifying the monocyclic peptide of formula (VI) (SEQ ID NO:9) obtained in step (c) using reverse phase column chromatography,
- (e) dicyclizing the monocyclic peptide of formula (VI) (SEQ ID NO:9) obtained in step (d) with 2% iodine to obtain a dicyclic peptide of formula (VII):
- and
- (f) purifying and desalting the dicyclic peptide of formula (VII) (SEQ ID NO:1) obtained in step (e) using reverse phase column chromatography to obtain pure plecanatide.
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Dependencies are inferred from the claim text.