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Synthetic method for teduglutide

A technology of teduglutide and synthesis method, applied in the field of peptide drug synthesis, can solve the problems of high cost, many impurities, low purity and yield, etc.

Active Publication Date: 2019-03-12
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is to provide an optimized method for the problems existing in the existing synthesis process, such as many impurities, low purity and yield, high cost, cumbersome operation steps, excessive waste liquid, and unfavorable industrial production. A synthetic method for teduglutide, which improves the purity of the crude peptide, greatly reduces the cost of materials and purification, and facilitates industrial scale-up production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1, Experiment 1 of the synthetic method of teduglutide:

[0051] (1) Preparation of Fmoc-Ile-Thr(pro-me-me)-OH Teduglutide Resin

[0052] Weigh 20.00 g of Wang resin (Sub=0.50 mmol / g) and add it to a solid phase reactor, and add 200 mL of DCM to swell the resin for 0.5 h. Drain the solvent, add Fmoc-Asp(Otbu)-OH 12.35g, HOBT4.45g, DIC 5.1mL, 50mL DMF solution, activate in ice bath for 10 minutes, and the activation temperature does not exceed 10 degrees Celsius. After the activation solution is added to the reactor, add 0.366g of DMAP, stirring reaction 5h. (Take a small sample to collect the sample, and measure the Sub=0.418mmol / g of Fmoc-Asp(Otbu)-Wang resin by ultraviolet spectrophotometry.) Drain, add DMF 250mL to wash 3 times, add pyridine / acetic anhydride solution (1:1 )300mL, blocked for 0.5h. Add DMF 250mL to wash 6 times. Add 200mLv / v 20% piperidine / DMF solution for deprotection, and react for 30min. Drain, add DMF 250mL and wash 6 times. The inde...

Embodiment 2

[0057] Example 2, Experiment 2 of the synthetic method of teduglutide:

[0058] (1) Preparation of Fmoc-Gln(Trt)-Thr(pro-me-me)-OH teduglutide peptide resin

[0059] Weigh 20.00 g of Wang resin (Sub=0.50 mmol / g) and add it to a solid phase reactor, and add 200 mL of DCM to swell the resin for 0.5 h. Drain the solvent, add Fmoc-Asp(Otbu)-OH 12.35g, HOBT4.45g, DIC 5.1mL, 50mL DMF solution, activate in ice bath for 10 minutes, and the activation temperature does not exceed 10 degrees Celsius. After the activation solution is added to the reactor, add 0.366g of DMAP, stirring reaction 5h. (Take a small sample and collect the sample, and measure the Sub=0.418mmol / g of Fmoc-Asp(Otbu)-Wang resin by ultraviolet spectrophotometry.) Drain, add DMF 250mL to wash 3 times, add pyridine / acetic anhydride solution (1:1 )300mL, blocked for 0.5h. Add DMF 250mL to wash 6 times. Add 200 mL v / v 20% piperidine / DMF solution for deprotection, and react for 30 min. Drain, add DMF 250mL and wash 6...

Embodiment 3

[0064] Example 3, Experiment 3 of the synthetic method of teduglutide:

[0065] (1) Preparation of Fmoc-Asn(Trt)-Thr(pro-me-me)-OH teduglutide peptide resin

[0066] Weigh 20.00 g of Wang resin (Sub=0.50 mmol / g) and add it into a solid phase reactor, and add 200 mL of DCM to swell the resin for 0.5 h. Drain the solvent, add Fmoc-Asp(Otbu)-OH 12.35g, HOBT4.45g, DIC 5.1mL, 50mL DMF solution, activate in ice bath for 10 minutes, and the activation temperature does not exceed 10 degrees Celsius. After the activation solution is added to the reactor, add 0.366g of DMAP, stirring reaction 5h. (Take a small sample to collect the sample, and measure the Sub=0.418mmol / g of Fmoc-Asp(Otbu)-Wang resin by ultraviolet spectrophotometry.) Drain, add DMF 250mL to wash 3 times, add pyridine / acetic anhydride solution (1:1 )300mL, blocked for 0.5h. Add DMF 250mL to wash 6 times. Add 200mL v / v 20% piperidine / DMF solution for deprotection, react

[0067] 30min. Drain, add DMF 250mL and wash ...

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PUM

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Abstract

The invention discloses a synthetic method for teduglutide and belongs to the field of polypeptide drug synthesis. The method comprises the following steps of by taking amino acids at 2-3 positions ofa teduglutide sequence as pseudo-proline-dipeptide, or amino acids at 5-6 positions of the teduglutide sequence as pseudo-proline-dipeptide, or amino acids at 22-23 positions of the teduglutide sequence as pseudo-proline-dipeptide, or amino acids at 27-28 positions of the teduglutide sequence as pseudo-proline-dipeptide or amino acids at 29-30 positions of the teduglutide sequence as pseudo-proline-dipeptide, sequentially performing solid-phase synthesis on amino acids at other positions of the teduglutide sequence according to a sequence, synthesizing full-protection teduglutide, and performing cracking precipitation to obtain the teduglutide. The method provided by the invention improves the purity of crude peptide, greatly lowers the material cost and the purification cost and is beneficial to industrial amplification production.

Description

technical field [0001] The invention relates to the field of polypeptide drug synthesis, in particular to a synthesis method of teduglutide, a GLP-2 receptor kinetin. Background technique [0002] Teduglutide, English name: teduglutide. The peptide sequence is: [0003] His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-lle-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-lle-Asn-Trp- Leu-lle-Gln-Thr-Lys-lle-Thr-Asp-OH; is a glucagon-like peptide 2 (GLP-2) analog, a naturally occurring hormone that reduces gastric emptying and secretion , and regulate the growth, proliferation and repair of small intestinal lining cells. Teduglutide was designated as an orphan drug in 2001. It is clinically used for the treatment of short bowel syndrome in adults, and has broad application prospects. In the existing synthesis method of teduglutide, the pure solid phase sequential coupling method is mainly used. [0004] For example, the Chinese published patent document CN104072605A discloses a prepar...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/08
CPCC07K14/605
Inventor 赵呈青谷海涛施国强孙美禄
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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