Process for the Preparation of Pramlintide

Inactive Publication Date: 2010-04-01
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]The present invention provides for an efficient process for making pramlinitide that is high in yield and scalable for commercial production. The process comprises the stepwise synthesis of amino acid segments, and the coupling together of these segments to produce pramlinitide. The present invention provides for four novel intermediate amino acid segments for the preparation of pramlintide. In a preferable embodiment of the invention, the four segments are synthesized in solid phase synthesis and the coupling reaction is performed in solution phase. Preferably, the segments are produced by coupling a protected designated amino acid to a growing

Problems solved by technology

The synthetic route is very lengthy and inefficiently since several coupling and deprotected steps have to be repeated.

Method used

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  • Process for the Preparation of Pramlintide
  • Process for the Preparation of Pramlintide
  • Process for the Preparation of Pramlintide

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Protected Fragment S1 (1-8)

[0008]

[0009]Synthesis of the protected peptide was carried out by a stepwise Fmoc SPPS (solid phase peptide synthesis) procedure starting with loading a Fmoc-Ala-OH to 2-Cl-Trt-Cl resin (CTC resin). The CTC resin (4 g) after washing was stirred with a solution of Fmoc-Ala-OH (1.49 g) in DMF in the presence of diisopropylethylamine (DIEA, 2.3 g) for 1.5 h. The resin was further capped by treatment with mixed solvent of 5:4:1 volume ratio of DCM / MeOH / DIEA for 0.5 h. After washing of the resin the Fmoc protecting group was removed by treatment with 20% piperidine in DMF twice for 10 min and 30 min, respectively. After washing of residual reagents the second amino acid (Fmoc-Cys (Acm)-OH) was introduced to start the first coupling step. The Fmoc protected amino acid was activated in situ using 1:1:2 molar ratio of HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) / HOBt (N-Hydroxybenzotriazole) / DIEA in DMF and subsequently ...

example 2

Preparation of Protected Fragment S2 (9-19)

Fmoc-Thr(tBu)-Gln(Trt)-Arg(Pbf)-Leu-Ala-Asn(Trt)-Phe-Leu-Val-His(Trt)-Ser(tBu)-OH

[0012]Synthesis of the protected peptide was carried out by a stepwise Fmoc SPPS (solid phase peptide synthesis) procedure starting with loading a Fmoc-Ser(tBu)-OH to 2-Cl-Trt-Cl resin (CTC resin). The CTC resin (10 g) after washing was stirred with a solution of Fmoc-Ser(tBu)-OH (4.6 g) in DMF in the presence of diisopropylethylamine (2.3 g) for 1.5 h. After washing of the resin the Fmoc protecting group was removed by treatment with 20% piperidine in DMF twice for 10 min and 30 min, respectively. After washing of residual reagents the second amino acid (Fmoc-His(Trt)-OH) was introduced to start the first coupling step. The Fmoc protected amino acid was activated in situ using 1:1:2 molar ratio of HBTU / HOBt / DIEA in DMF and subsequently coupled to the growing peptide on resin for 3 h. Completion of the coupling was indicated by a Kaiser test. After washing of t...

example 3

Preparation of Protected Fragment S3 (20-29)

Fmoc-Ser(tBu)-Asn(Trt)-Asn(Trt)-Phe-Gly-Pro-Ile-Leu-Pro-Pro-OH

[0014]Synthesis of the protected peptide was carried out by a stepwise Fmoc SPPS (solid phase peptide synthesis) procedure starting with loading a Fmoc-Pro-OH to 2-Cl-Trt-Cl resin (CTC resin). The CTC resin (3 g) after washing was stirred with a solution of Fmoc-Pro-OH (1.2 g) in DMF in the presence of diisopropylethylamine (2.3 g) for 1.5 h. After washing of the resin the Fmoc protecting group was removed by treatment with 20% piperidine in DMF twice for 10 min and 30 min, respectively. After washing of residual reagents the second amino acid (Fmoc-Pro-OH) was introduced to start the first coupling step. The Fmoc protected amino acid was activated in situ using 1:1:2 molar ratio of HBTU / HOBt / DIEA in DMF and subsequently coupled to the growing peptide on resin for 3 h. Completion of the coupling was indicated by a Kaiser test. After washing of the resin, the Fmoc protecting grou...

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Abstract

The present invention provides for an efficient process for making Pramlinitide, as well as novel intermediates for the making of the same.

Description

RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Patent Application Ser. No. 61 / 190,928 which was filed on Sep. 3, 2008. The entire content of which is herein incorporated by reference.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to the efficient commercial synthesis for the making of pramilintide, a synthetic analog of human amylin which is a peptide hormone. Pramilintide is indicated to treat type 1 and type 2 diabetics who use insulin. The process for making pramilintide substantially comprises the syntheses of various fragments of the polypeptide and the coupling of the fragments to produce pramilintide.[0004]2. Description of the Related Arts[0005]The preparation and use of pramlintide is disclosed in U.S. Pat. No. 5,686,411, which is herein incorporated in its entirety by reference. Pramlintide is known to be prepared by solid phase synthesis that successively adds the desired amino acid to a grow...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/00
CPCC07K14/815C07K7/06A61P7/02A61P9/10A61P3/10A61K38/16A61K38/22C07K1/00
InventorHSIAO, TSUNG YUDING, JIN GUC
OwnerSCINOPHARM TAIWAN LTD