Method for preparing Linaclotide

A technology for linaclotide and crude peptides, which is applied in the production of peptides and bulk chemicals, can solve problems such as cumbersome steps, and achieve the effects of cheap and easy-to-obtain raw materials, mild reaction conditions, high reaction selectivity and conversion rate

Pending Publication Date: 2017-06-13
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Prepared by step-by-step oxidation method, if pure products are used for each st...

Method used

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  • Method for preparing Linaclotide
  • Method for preparing Linaclotide
  • Method for preparing Linaclotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Preparation of linaclotide resin

[0049] H-Cys(tBu)-Cys(Trt)-Glu(OtBu)-Tyr(tBu)-Cys(Trt)-Cys(tBu)-Asn(Trt)-Pro-Ala-Cys(Trt)-Thr(tBu) Preparation of -Gly-Cys(Trt)-Tyr(tBu)—Resin

[0050] Weigh 10 g of Wang resin with a substitution degree of 1.14 mmol / g in a solid-phase reactor, swell the Wang resin with DCM for 20 minutes, and drain it.

[0051] Add Fmoc-Tyr(tBu)-OH (15.7g, 13.68mmol), HOBt (5.55g, 4.1mmol), DIC (6.35mL, 4.1mmol), DMAP (0.5g, 4.1mmol) into the solid phase reactor to dissolve In DMF (70ml), react at room temperature for 15 minutes.

[0052] The resin was washed and dried to obtain Fmoc-Tyr(tBu)-Wang resin, and the measured resin substitution degree was 0.426 mmol / g. Add 70 mL of blocking reagent (acetic anhydride (mmol): DIPEA (mmol) = 1:1) to the resin, react for 10 h, block the remaining amino groups, and use DCM (once), MeOH (once) and DMF (once )washing.

[0053] Add 20% PIP / DMF solution to react for 20min to remove the Fmoc protecting group, w...

Embodiment 2

[0068] Preparation of linaclotide resin

[0069] H-Cys(Trt)-Cys(Trt)-Glu(OtBu)-Tyr(tBu)-Cys(tBu)-Cys(Trt)-Asn(Trt)-Pro-Ala-Cys(Trt)-Thr(tBu) Preparation of -Gly-Cys(tBu)-Tyr(tBu)—Resin

[0070] Weigh 10 g of Wang resin with a substitution degree of 1.14 mmol / g in a solid-phase reactor, swell the Wang resin with DCM for 20 minutes, and drain it.

[0071] Add Fmoc-Tyr(tBu)-OH (15.7g, 13.68mmol), HOBt (5.55g, 4.1mmol), DIC (6.35mL, 4.1mmol), DMAP (0.5g, 4.1mmol) into the solid phase reactor to dissolve In DMF (70ml), react at room temperature for 15 minutes.

[0072] The resin was washed and dried to obtain Fmoc-Tyr(tBu)-Wang resin, and the measured resin substitution degree was 0.426 mmol / g. Add 70 mL of blocking reagent (acetic anhydride (mmol): DIPEA (mmol) = 1:1) to the resin, react for 10 h, block the remaining amino groups, and use DCM (once), MeOH (once) and DMF (once )washing.

[0073] Add 20% PIP / DMF solution to react for 20min to remove the Fmoc protecting group, w...

Embodiment 3

[0088] Preparation of linaclotide resin

[0089] H-Cys(Trt)-Cys(tBu)-Glu(OtBu)-Tyr(tBu)-Cys(Trt)-Cys(Trt)-Asn(Trt)-Pro-Ala-Cys(tBu)-Thr(tBu) Preparation of -Gly-Cys(Trt)-Tyr(tBu)—Resin

[0090] Weigh 10 g of Wang resin with a substitution degree of 1.14 mmol / g in a solid-phase reactor, swell the Wang resin with DCM for 20 minutes, and drain it.

[0091]Add Fmoc-Tyr(tBu)-OH (15.7g, 13.68mmol), HOBt (5.55g, 4.1mmol), DIC (6.35mL, 4.1mmol), DMAP (0.5g, 4.1mmol) into the solid phase reactor to dissolve In DMF (70ml), react at room temperature for 15 minutes.

[0092] The resin was washed and dried to obtain Fmoc-Tyr(tBu)-Wang resin, and the measured resin substitution degree was 0.426 mmol / g. Add 70 mL of blocking reagent (acetic anhydride (mmol): DIPEA (mmol) = 1:1) to the resin, react for 10 h, block the remaining amino groups, and use DCM (once), MeOH (once) and DMF (once )washing.

[0093] Add 20% PIP / DMF solution to react for 20min to remove the Fmoc protecting group, wa...

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Abstract

The invention discloses a method for preparing Linaclotide. The method includes the step: performing oxidation reaction for Linaclotide intermediates containing two pairs of disulfide bonds to obtain the Linaclotide. The Linaclotide intermediates containing the two pairs of disulfide bonds are disulfide bonds with second Cys (cysteine) and tenth Cys and disulfide bonds with fifth Cys (cysteine) and thirteenth Cys. According to the method, a reaction route is short, raw materials are low in cost and easy to obtain, reaction conditions are mild, energy consumption is reduced, and production cost is reduced. Compared with a route published by a predecessor, the route is high in reaction selectivity and conversion rate, waste of the raw materials is decreased, and the route has high economy. According to the method, optimal reaction time is 30min, the purity of prepared products can reach 85%, and discharge of waste gas, waste water and solid waste is decreased, and the method is green and safe.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a method for preparing linaclotide. Background technique [0002] Linaclotide is an oral selective guanylate cyclase C receptor agonist, mainly acts on the intestinal tract, can induce the secretion of intestinal juice, and is used for the treatment of constipation-based irritable bowel syndrome and chronic constipation. Its product name is Linzess, which was developed by Ironwood Pharma in the United States and was approved by the FDA in August 2012. Linaclotide is a capsule formulation of a guanylate cyclase C (GC-C) agonist that is taken orally once daily. Binding of linaclotide in undetectable plasma concentrations to intestinal GC-C leads to increased intracellular and extracellular cyclic guanosine monophosphate (cGMP) concentrations. The increase of intracellular cGMP can stimulate the secretion of intestinal juice, accelerate the migration ...

Claims

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Application Information

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IPC IPC(8): C07K7/08
CPCC07K7/08Y02P20/55
Inventor 苏贤斌李裴竹卞亚楠杨洋
Owner NANJING UNIV OF TECH
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