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Preparation method of teriparatide

A technology of teriparatide and peptide resin, which is applied in the field of preparation of teriparatide, can solve the problems of unsuitability for large-scale production, low synthesis purity, and high cost, so as to reduce the difficulty of HPLC purification, optimize the synthesis process, and use safely Effect

Pending Publication Date: 2019-06-18
哈尔滨吉象隆生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing synthetic methods, the preparation of teriparatide found that the existing technical problems are: low synthetic purity, high cost, especially the large content of impurity D-His 32-teriparatide, not suitable for large-scale production The problem

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Preparation of Fmoc-Phe-resin:

[0035] Take 0.1mol DIEA and 20g N, N-diisopropylcarbodiimide / 4-dimethylaminopyridine dual-system coupling reagent, join in the reaction vessel containing 0.6mol 2-CTC resin, then add 0.3molFmoc- Phe-OH carries out coupling reaction to obtain Fmoc-Phe-resin;

[0036] (2) Preparation of teriparatide-resin complex:

[0037]Add the mixture of triethylamine and DMF to the Fmoc-Phe-resin at a ratio of 1:2, stir to allow it to react for 30 minutes, then remove the liquid, wash the product 6 times with DMF, and wash it with N,N-DMF after the reaction After washing, the Phe-resin was obtained, and then 50 ml of the prepared 1:1:1 TBTU / HOBT / DIEA mixture was added, and the amino acids were extended and coupled one by one according to the order of teriparatide from the C-terminus to the N-terminus. The corresponding peptide resin was obtained after the second extension coupling, and after 120 minutes of coupling reaction, the teriparatide-resi...

Embodiment 2

[0046] (1) Preparation of Fmoc-Phe-resin:

[0047] Take 0.15molTEA and 25gN, N-diisopropylcarbodiimide / 4-dimethylaminopyridine dual-system coupling reagent, add to the reaction vessel filled with 0.75mol of 2-CTC resin, then add 0.5molFmoc- Phe-OH carries out coupling reaction to obtain Fmoc-Phe-resin;

[0048] (2) Preparation of teriparatide-resin complex:

[0049] Add the mixture of triethylamine and DMF to the Fmoc-Phe-resin at a ratio of 1:3.5, stir to allow it to react for 40 minutes, then remove the liquid, wash the product 6 times with DMF, and wash it with N,N-DMF after the reaction After washing, the Phe-resin was obtained, and then 60ml of 1:1:1 TBTU / Cl-HOBT / DIEA mixture was added, and the amino acids were extended and coupled one by one according to the order of teriparatide from C-terminal to N-terminal , the corresponding peptide resin was obtained after each extension coupling, and after 120 minutes of coupling reaction, the teriparatide-resin was obtained;

...

Embodiment 3

[0058] (1) Preparation of Fmoc-Phe-resin:

[0059] Take 0.2molDBU and 15gN, N-diisopropylcarbodiimide / 4-dimethylaminopyridine dual system coupling reagent, join in the reaction container that fills the 2-CTC resin of 0.55mol, then add 0.3molFmoc- Phe-OH carries out coupling reaction to obtain Fmoc-Phe-resin;

[0060] (2) Preparation of teriparatide-resin complex:

[0061] Add the mixture of triethylamine and DMF to the Fmoc-Phe-resin at a ratio of 1:4.5, stir to allow it to react for 30 minutes, then remove the liquid, wash the product 6 times with DMF, and wash it with N,N-DMF after the reaction After washing, the Phe-resin was obtained, and then 50 ml of the prepared 1:1:1 TBTU / HOBT / DIEA mixture was added, and the amino acids were extended and coupled one by one according to the order of teriparatide from the C-terminus to the N-terminus. The corresponding peptide resin was obtained after the second extension coupling, and after 120 minutes of coupling reaction, the teripa...

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Abstract

The invention discloses a preparation method of teriparatide. The preparation method comprises steps as follows: 2-CTC resin is taken as a resin carrier and is coupled with Fmoc-Phe-OH under the action of an activator and a coupling reagent, and Fmoc-Phe-resin is obtained, an Fmoc deprotection reagent is added to the Fmoc-Phe-resin, after a reaction ends, washing is performed with N,N-DMF, Phe-resin is obtained, one-by-one extension coupling is performed on amino acid under the action of a condensation reagent and an activating reagent, and teriparatide-resin is obtained; a lysate containing PhSMe / PhOH / EDT system is added to the teriparatide-resin, and a crude product of teriparatide is obtained; the crude product of teriparatide is separated, purified and freeze-dried by use of a C18 column, and high-purity teriparatide is obtained. The preparation method of teriparatide is low in cost and adopts a simple process. The total yield of teriparatide is increased, and no harm is caused toany environment. The preparation method is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of polypeptide drugs and relates to a preparation method of teriparatide. Background technique [0002] Teriparatide, British name: Teriparatide, is a synthetic peptide hormone developed by Eli Lilly and Company. The U.S. Food and Drug Administration approved Teriparatide for the treatment of men on November 26, 2002. Osteoporosis with a high risk of fracture in menopausal and postmenopausal women, and osteoporosis with a high risk of fracture in men, primary and / or due to hyposexuality. The current conventional osteoporosis drugs generally only act on osteoclasts to slow down or block bone loss, while teriparatide, a derivative of parathyroid hormone, can increase the number of osteoblasts, enhance their activity and prevent bone loss. The role of osteocyte apoptosis. Because it can increase the activity and number of osteoblasts, which can promote bone growth, it is used for the second-line treatment of severe ost...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/635C07K1/36C07K1/34C07K1/20C07K1/06C07K1/04
CPCY02P20/55
Inventor 冷国庆张琪苏宏健王丽莉田辉杨文龙余荣熹景文岩王艳张凤莲侯继元谢俊杨桦于通浩冷青
Owner 哈尔滨吉象隆生物技术有限公司
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