Preparation method for linaclotide

A technology of linaclotide and protecting group, which is applied in the field of preparation of linaclotide, can solve the problems of a large amount of time for separation and purification, consumption of large solvent and raw materials, inconvenience of industrial production, etc., and achieves simple operation and high total yield , the effect of improving the yield of cyclization

Inactive Publication Date: 2015-05-20
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Chinese Patent Publication No. CN102875655A, its oxidation step is further simplified, and its yield is also improved, but its yield is still unsatisfactory, the cyclization process is complicated and the cyclization yield is low, it needs to consume a large amount of solvent and raw materials, and requires a lot of time Separation and purification bring inconvenience to industrial production

Method used

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  • Preparation method for linaclotide
  • Preparation method for linaclotide
  • Preparation method for linaclotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Step 1 WANG resin (1.28mmol / g, 640mg), tert-butyl (tBu) protected Fmoc tyrosine (Fmoc-Tyr(tBU)-OH) (689.33mg, 1.5mmol) and DIPEA (414μL, 5mmol) , HBTU (113.77mg, 3mmol) was placed in a reaction flask, added DMF (20mL) to dissolve, and stirred for 6-12 hours. After the reaction is complete, let it stand still, drain the DMF, wash the resin with DMF to obtain a yellow resin, then use hexahydropiperidine-DMF (1 / 4; 20mL) to remove the protective group, and react for 20-40 minutes. The synthetic method is carried out with reference to the same steps.

[0051] In step 2, the WANG resin reacted with tyrosine was directly mixed with trityl (Trt)-protected Fmoc cysteine ​​(Fmoc-Cys(Trt)-OH) (878.58 mg, 1.5 mmol) and DIPEA (414 μL, 5mmol), HBTU (113.77mg, 3mmol) was placed in a reaction flask, DMF (20mL) was added to dissolve, and stirred for 6-12 hours. After the reaction is complete, let it stand still, drain the DMF, wash the resin with DMF to obtain a yellow resin, then use...

Embodiment 2

[0067] Step 1 WANG resin (1.28mmol / g, 640mg), tert-butyl (tBu) protected Fmoc tyrosine (Fmoc-Tyr(tBU)-OH) (689.33mg, 1.5mmol) and DIPEA (414μL, 5mmol) , HBTU (113.77mg, 3mmol) was placed in a reaction flask, added DMF (20mL) to dissolve, and stirred for 6-12 hours. After the reaction is complete, let it stand still, drain the DMF, wash the resin with DMF to obtain a yellow resin, then use hexahydropiperidine-DMF (1 / 4; 20mL) to remove the protective group, and react for 20-40 minutes. The synthetic method is carried out with reference to the same steps.

[0068] In step 2, the WANG resin reacted with tyrosine was directly mixed with trityl (Trt)-protected Fmoc cysteine ​​(Fmoc-Cys(Trt)-OH) (878.58 mg, 1.5 mmol) and DIPEA (414 μL, 5mmol), HBTU (113.77mg, 3mmol) was placed in a reaction flask, DMF (20mL) was added to dissolve, and stirred for 6-12 hours. After the reaction is complete, let it stand still, drain the DMF, wash the resin with DMF to obtain a yellow resin, then use...

Embodiment 3

[0084] Step 1 WANG resin (1.28mmol / g, 640mg), tert-butyl (tBu) protected Fmoc tyrosine (Fmoc-Tyr(tBU)-OH) (689.33mg, 1.5mmol) and DIPEA (414μL, 5mmol) , HBTU (113.77mg, 3mmol) was placed in a reaction flask, added DMF (20mL) to dissolve, and stirred for 6-12 hours. After the reaction is complete, let it stand still, drain the DMF, wash the resin with DMF to obtain a yellow resin, then use hexahydropiperidine-DMF (1 / 4; 20mL) to remove the protective group, and react for 20-40 minutes. The synthetic method is carried out with reference to the same steps.

[0085] In step 2, the WANG resin reacted with tyrosine was directly mixed with trityl (Trt)-protected Fmoc cysteine ​​(Fmoc-Cys(Trt)-OH) (878.58 mg, 1.5 mmol) and DIPEA (414 μL, 5mmol), HBTU (113.77mg, 3mmol) was placed in a reaction flask, DMF (20mL) was added to dissolve, and stirred for 6-12 hours. After the reaction is complete, let it stand still, drain the DMF, wash the resin with DMF to obtain a yellow resin, then use...

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Abstract

The invention provides a preparation method for linaclotide. The method includes: utilizing a standard Fmoc technology to connect a side chain protected amino acid with Wang resin, adding a condensing agent HBTU and alkali DIPEA, carrying out condensation reaction in a DMF solvent, employing a DMF solution containing 20% hexahydropiperidine to perform de-Fmoc protection, then conducting cutting from the solid phase resin, adding elemental iodine into a sodium phosphate buffer solution to carry out Cysteine oxidation, thus obtaining linaclotide. The preparation method for linaclotide provided by the invention is the technology for highyield synthesis of linaclotide, simplifies the cyclization process and enhances the cyclization yield, and the final product yield reaches 30%-60%. The preparation method has the advantages of simplicity, mild reaction conditions, high yield, and high product purity, is a feasible preparation method for industrialization of linaclotide, and provides good prospects for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of linaclotide. Background technique [0002] Linaclotide is a drug (an agonist of guanylate cyclase-C (GC-C)) for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults. Binding of linaclotide to intestinal GC-C leads to increased intracellular and intracellular cyclic guanosine monophosphate (cGMP) concentrations. The increase of intracellular cGMP can stimulate the secretion of intestinal juice, accelerate the migration of gastrointestinal tract, thereby increasing the frequency of defecation. Elevated extracellular cGMP concentration can reduce the sensitivity of pain sensory nerves and reduce intestinal pain. In addition, linaclotide can also be used to treat and prevent colon cancer, rectal cancer and inflammation in the body. The sequence of linaclotide is the sequence sho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/06C07K1/04
CPCY02P20/55
Inventor 吴君臣刘奔邹荣峰王琦田禾
Owner EAST CHINA UNIV OF SCI & TECH
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