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Synthesis method of Tirzeptide

A synthesis method and fmoc-asp technology, applied in the synthesis field of Tirzepatide, can solve problems such as unfavorable industrial production, complicated operation steps, high cost, etc., and achieve the advantages of improving crude peptide purity, high promotion value, reducing material cost and purification cost. Effect

Pending Publication Date: 2022-07-12
HANGZHOU SINOPEP ALLSINO PHARMA TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, there are many impurities in the Tirzepatide synthesis process of the prior art, the purity and yield are low, the cost is expensive, the operation steps are cumbersome, and the waste liquid is excessive, which is unfavorable for industrialized production. The present invention solves such problems

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  • Synthesis method of Tirzeptide
  • Synthesis method of Tirzeptide
  • Synthesis method of Tirzeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Preparation of Fmoc-Thr(tBu)-Ser(Psi(Me,Me)pro)-OH Tirzepatide peptide resin:

[0046] Step 1, the 7th-8th amino acid of tirzepatide sequence is used as pseudo-pro dipeptide Fmoc-Thr(tBu)-Ser(Psi(Me,Me)pro)-OH;

[0047] In step 2, 30.00 g (Sub=0.33 mmol / g) of Rink Amide-MBHA resin was weighed into the solid-phase reactor, and 200 mL of DCM was added to swell the resin for 0.5 h. The solvent was drained, 200 mL v / v (volume ratio) 20% piperidine / DMF solution was added, that is, a DMF solution containing 20% ​​piperidine by volume, and the deprotection reaction was performed for 10+20 min. Suction dry, add DMF 250mL to wash 6 times. The indene test was positive. Weigh 11.387 g of Fmoc-Ser(tBu)-OH, 4.82 g of HOBT, 5.5 mL of DIC, and 200 mL of DMF solution, activate in ice bath for 10 minutes, and the activation temperature does not exceed 10 degrees Celsius. The activated solution was added to the reactor and reacted for 1 hour. After the indene test result wa...

Embodiment 2

[0059] Example 2: Preparation of Fmoc-Tyr(tBu)-Ser(Psi(Me,Me)pro)-OH Tirzepatide Peptide Resin:

[0060] Step 1: use the 10th-11th amino acids of the tirzepatide sequence as the pseudo-pro dipeptide Fmoc-Tyr(tBu)-Ser(Psi(Me,Me)pro)-OH;

[0061]In step 2, 30.00 g (Sub=0.33 mmol / g) of Rink Amide-MBHA resin was weighed into the solid-phase reactor, and 200 mL of DCM was added to swell the resin for 0.5 h. The solvent was drained, 200 mL v / v (volume ratio) 20% piperidine / DMF solution was added for deprotection, and the reaction was performed for 10+20 min. Suction dry, add DMF 250mL to wash 6 times. The indene test was positive. Weigh 11.387 g of Fmoc-Ser(tBu)-OH, 4.82 g of HOBT, 5.5 mL of DIC, and 200 mL of DMF solution, activate in ice bath for 10 minutes, and the activation temperature does not exceed 10 degrees Celsius. The activated solution was added to the reactor and reacted for 1 hour. After the indene test result was negative, it was drained. Add DMF to wash 3 times,...

Embodiment 3

[0070] Example 3: Preparation of Fmoc-Ser(tBu)-Ser(Psi(Me,Me)pro)-OH Tirzepatide Peptide Resin:

[0071] Step 1, take the 32-33rd amino acid of tirzepatide sequence as pseudo-pro dipeptide Fmoc-Ser(tBu)-Ser(Psi(Me,Me)pro)-OH;

[0072] In step 2, 30.00 g (Sub=0.33 mmol / g) of Rink Amide-MBHA resin was weighed into the solid-phase reactor, and 200 mL of DCM was added to swell the resin for 0.5 h. The solvent was drained, 200 mL v / v (volume ratio) 20% piperidine / DMF solution was added for deprotection, and the reaction was performed for 10+20 min. Suction dry, add DMF 250mL to wash 6 times. The indene test was positive. Weigh 11.387 g of Fmoc-Ser(tBu)-OH, 4.82 g of HOBT, 5.5 mL of DIC, and 200 mL of DMF solution, activate in ice bath for 10 minutes, and the activation temperature does not exceed 10 degrees Celsius. The activated solution was added to the reactor and reacted for 1 hour. After the indene test result was negative, it was drained. Add DMF to wash 3 times, each 200...

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Abstract

The invention discloses a synthesis method of Tirzeptide, which comprises the following steps: step 1, taking the 7th to 8th amino acids, the 10th to 11th amino acids and the 32th to 33rd amino acids of a Tirzeptide sequence as pseudo-proline dipeptides; the 29th to 30th amino acids are used as dipeptides; step 2, carrying out solid-phase synthesis on amino acids at other sites of the tizatide sequence in a reaction solvent by using a condensing agent in sequence, and synthesizing full-protection tizatide by using an Fmoc removal reagent; step 3, carrying out cracking precipitation by adopting a cracking reagent, so as to obtain Tirzepine; according to the method, the purity of the crude peptide is improved, the material cost and the purification cost are greatly reduced, and industrial large-scale production is facilitated.

Description

technical field [0001] The invention relates to the field of polypeptide drug synthesis, in particular to a method for synthesizing Tirzepatide. Background technique [0002] English name: Tirzepatide. [0003] The peptide sequence is: [0004] Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Ile-Ala-Gln-Lys(AEEA-AEEA-γGlu-Eicosanedioicacid)-Ala -Phe-Val-Gln-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 [0005] Tirzepatide, is a once-weekly glucose-dependent insulinotropic polypeptide (GIP, also known as: gastric inhibitory polypeptide) receptor and glucagon-like peptide-1 (GLP-1) receptor dual agonist. Both GIP and GLP-1 are hormones secreted by the gut that promote insulin secretion. Tirzepatide integrates two insulinotropic actions into a single molecule and represents a new class of drugs for the treatment of type 2 diabetes. In adults with type 2 diabetes, 3 doses of tirzepatide (subcutaneous, weekly) were associated with lower b...

Claims

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Application Information

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IPC IPC(8): C07K14/00C07K1/02C07K1/04C07K1/107C07K1/30C07K1/36
CPCC07K14/001C07K1/026C07K1/04C07K1/30C07K1/1075C07K1/36Y02P20/55
Inventor 李敏周奕赵呈青
Owner HANGZHOU SINOPEP ALLSINO PHARMA TECH DEV CO LTD
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