Solid-phase preparation method of pracanatide

A technology for plecanatide and solid-phase preparation, which is applied in the field of solid-phase preparation of plecanatide, can solve the problems of unfavorable industrialized production, complicated operation steps, high waste liquid cost, etc., and achieves easy preparation and purification, and easy avoidance. The effect of reunion and reduction of three wastes

Active Publication Date: 2021-09-28
礼济生物医药科技南京有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Purpose of the invention: In view of the many impurities, low purity, low yield, cumbersome operation steps, many waste liquids and cost in the existing plecanatide preparation process High problem, the current preparation process is not conducive to industrial production, the invention provides a solid-phase preparation method of plecanatide

Method used

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  • Solid-phase preparation method of pracanatide
  • Solid-phase preparation method of pracanatide
  • Solid-phase preparation method of pracanatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Example 1: Synthesis of Acm-protected Fragment One (Fragment One [13,4])

[0164] step one:

[0165] Add Wang resin (90.00g, degree of substitution 0.60mmol / g) and 1100mL DCM to the solid-phase reaction bottle successively, and suction filter after swelling to obtain a filter cake. Fmoc-Thr(tBu)-OH (15.51g), DIC (4.92g), HOBt (5.28g), 1100mL DCM were added sequentially at 24±4°C, and the reaction was stirred for 2h under nitrogen protection. Drain, wash 5 times with 300mL*5DCM, and 2 times with 300mL*3DMF. Add 90 mL of acetic anhydride, 90 mL of pyridine, and 900 mL of DMF, and stir for 8 hours under nitrogen protection. After pumping to dryness, 90 mL of acetic anhydride, 90 mL of pyridine, and 900 mL of DMF were added again, and stirred for 8 hours under nitrogen protection. Drained, washed five times with 300mL*5DCM and three times with 350mL*3MeOH. Vacuum drying at room temperature yielded 108.85 g of Fmoc-Thr(tBu)Wang resin. After testing, the degree of substi...

Embodiment 2

[0170] Embodiment 2: the synthesis of the linker peptide resin of Acm protection

[0171] Step three:

[0172] Add Wang resin (30.00g, degree of substitution 0.60mmol / g) and 300mL DCM successively into the solid-phase reaction bottle, and suction filter after swelling to obtain a filter cake. Fmoc-Leu-OH (3.42g), DIC (1.25g), HOBt (1.27g), 180mL DCM were added sequentially at 24±4°C, and the reaction was stirred for 2h under nitrogen protection. Drain, wash 5 times with 100mL*5DCM. Add 30 mL of acetic anhydride, 30 mL of pyridine, and 30 mL of DMF, and stir for 8 hours under nitrogen protection. Drain. Add 30 mL of acetic anhydride, 30 mL of pyridine, and 30 mL of DMF again, and stir for 8 h under nitrogen protection. Drain. 100mL*5DCM was washed five times, and 60mL*3MeOH was washed three times. The filter cake was alternately washed with MeOH and DCM, sucked dry, and dried under vacuum at room temperature to obtain Fmoc-Leu Wang resin. After testing, the degree of sub...

Embodiment 3

[0174] Example 3: Synthesis of [16-4, disulfide bond S-S (4→12)] peptide resin

[0175] Step four:

[0176] Add 40mL of 20% piperidine / DMF solution to the linker peptide resin reaction bottle, mix and stir for 10 minutes, and drain; then add 40mL of 20% piperidine / DMF solution, mix and stir for 10 minutes, and drain. An appropriate amount of DMF was used to wash the filter cake, and the deprotected linker peptide resin to be used was drained. In a clean activation bottle, add fragment one [13-4, disulfide bond S-S (4→12)] (1.00mmol), DIEA (2.1mmol) and 25mL DCM / NMP (1:1, volume ratio), HATU (1.05 mmol) and HOAt (1.05 mmol) were sequentially added at 5±4° C., and activated under nitrogen for 2 minutes. Under nitrogen protection, transfer the activation solution to the deprotected linker peptide resin reaction vial. React for 2 hours at 24±4°C under nitrogen, and drain; add Fragment 1 [13-4, disulfide bond S-S(4→12)] (1.00mmol), DIEA (2.1mmol) and 25mL DCM to a clean activati...

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Abstract

The invention discloses a novel solid-phase preparation method of pracanatide. The method comprises the following steps of: sequentially synthesizing a disulfide bond-containing fragment I and a linker [16-14] peptide resin according to the peptide sequence of a pracanatide main chain, coupling the disulfide bond-containing fragment I and the linker [16-14] peptide resin, completing a crude product of pracanatide through the following way a or way b, and purifying to finally obtain a pure product of pracanatide, wherein the way a is a way of coupling and then oxidizing and cutting to obtain the crude product of pracanatide, or the way b is a way of selectively removing a sulfydryl protecting group, oxidizing, coupling and cutting to obtain the crude product of pracanatide. The method is simple to operate, and has the advantages of fewer steps and simple process compared with the existing process; and the obtained product is high in purity and yield, easy to purify and relatively low in preparation cost, and is beneficial to industrial production.

Description

technical field [0001] The invention belongs to the technical field of plecanatide synthesis, and in particular relates to a solid-phase preparation method of plecanatide. Background technique [0002] Plecanatide was originally developed by Callisto Pharmaceutical Company of the United States, and then transferred to Synergy Pharmaceutical Company for development. It was approved by the US Food and Drug Administration (FDA) on January 19, 2017, and its trade name is Trulance. Other translations of Plecanatide are Picanatide, and the research codes are SP-304 and GCRA. Plecanatide is a Guanylatecyclase-C (Guanylatecyclase-C, GC-C) agonist, which belongs to the analogue of Uroguanylin, and is indicated for the treatment of chronic idiopathic constipation (CIC) in adults. ), can regulate the acid-base ions in the gastrointestinal tract, induce liquid transport into the gastrointestinal tract, and clinically stimulate the intestinal secretion of intestinal juice and accelerate...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/20C07K1/06C07K1/04
CPCC07K7/08Y02P20/55
Inventor 邹正才
Owner 礼济生物医药科技南京有限公司
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