New process for preparing teriparatide

A technology of teriparatide and peptide resin, which is applied in the field of solid-phase synthesis technology to realize the synthesis process of teriparatide, which can solve the problems of many impurities, excessive waste liquid, cumbersome operation steps, etc.

Pending Publication Date: 2020-04-24
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a Teripar Peptide Synthesis Method

Method used

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  • New process for preparing teriparatide
  • New process for preparing teriparatide
  • New process for preparing teriparatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: Synthesis of Fragment [1-12] Peptide Resin

[0079] Add Fmoc-Phe-Wang resin (10.00g substitution degree 0.35mmol / g) into the solid-phase reaction bottle, swell with 200mL DCM and drain it. The filter cake was mixed with 300ml of 20% piperidine / DMF solution, stirred for 5 minutes and then drained; then 300mL of 20% piperidine / DMF solution was added, mixed and stirred for 15 minutes, and drained. Wash the filter cake with an appropriate amount of DMF, drain it, and store it in a solid-phase reaction bottle for use. In another dry reaction flask, add Fmoc-Asn(Trt)-OH (6.45g), HOBT (1.46g), 30mL DMF in sequence, stir, add DIC (1.36g) within 30min under ice bath, and stir to obtain an activated solution. The newly obtained solution was added to the above-mentioned solid-phase reaction flask, and stirred for 2 h under the protection of nitrogen until the coupling reaction was detected by ninhydrin to complete. Drained, the filter cake was washed with an appropria...

Embodiment 2

[0081] Embodiment two: the synthesis of fragment one

[0082] Add 2-CTC Resin (25.00g, degree of substitution 1.12mmol / g) and 400mL DCM in sequence to the solid-phase reaction bottle, and suction filter after swelling to obtain a filter cake. Fmoc-Glu(OtBu)-OH (8.51g) and 100mL DCM were added sequentially, stirred under nitrogen protection, and DIEA (about 9.53g) was added dropwise. After dropping, stir the reaction for 2h. MeOH (25 mL) was added and stirring was continued for 30 min. After draining, the filter cake was washed alternately with MeOH and DCM, drained, and vacuum-dried at room temperature to obtain the linker resin. After testing, the degree of substitution is 0.73mmol / g;

[0083] Add the above-mentioned resin and 200mL DCM sequentially into the solid-phase reaction bottle, drain it after swelling. Add 100mL of 20% piperidine / DMF solution, mix and stir for 5 minutes, and drain; then add 100mL of 20% piperidine / DMF solution, mix and stir for 15 minutes, and dr...

Embodiment 3

[0086] Embodiment three: the synthesis of fragment two

[0087] Add 2-CTC Resin (25.00g, degree of substitution 1.12mmol / g) and 400mL DCM sequentially into the solid-phase reaction flask, swell and drain to obtain a filter cake. Add 100 mL of DCM, Fmoc-Gly-OH (5.95 g) in sequence, stir under nitrogen protection, and add DIEA (9.53 g) dropwise. After dropping, the reaction was stirred for 2 h, MeOH (25 mL) was added, and the reaction was stirred for 30 min with nitrogen bubbling. Drained, and the filter cake was alternately washed with DCM and MeOH. Drained and vacuum-dried at room temperature to obtain joint resin. After testing, the degree of substitution was 0.74mmol / g.

[0088] Swell the above material with 200mL DCM and drain it. The filter cake was mixed with 100 mL of 20% piperidine / DMF solution, stirred for 5 minutes, and drained; then 100 mL of 20% piperidine / DMF solution was added, mixed and stirred for 15 minutes, and drained. An appropriate amount of DMF was us...

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Abstract

The invention provides a teriparatide synthesis method. According to the method, according to the main chain peptide sequence of teriparatide, the teriparatide is divided into a fragment [1-12] peptide resin, a fragment I and a fragment II, the three short peptides can be respectively synthesized, the fragment [1-12] peptide resin, the fragment I and the fragment II are linked one by one, a terminal Fmoc protecting group is removed to obtain a teriparatide resin, and finally cracking, purifying and salifying are performed to finally obtain the target product, wherein the structures of the fragments and the fragment resin are defined in the specification. The method is simple to operate, the obtained product is high in purity and low in cost, and industrial production is facilitated.

Description

technical field [0001] The present invention relates to the synthesis technology of polypeptide, especially the synthesis technology of teriparatide realized by solid phase synthesis technology. Background technique [0002] Teriparatide Forteo (Teriparatide) was developed by Eli Lilly and is used for primary osteoporosis, hypogonadal osteoporosis, and postmenopausal osteoporosis. It is the first bone-promoting new drug approved by the U.S. Food and Drug Administration (FDA). This derivative of parathyroid hormone can promote bone growth by increasing the activity and number of osteoblasts, while the current conventional osteoporosis drugs Generally, it only acts on osteoclasts to slow down or block bone loss. The original teriparatide was first approved for marketing in the United States in December 2002, and was approved for marketing in China in March 2011. In a clinical study involving 1,637 postmenopausal osteoporosis patients, 96 percent of the patients who received ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/635C07K1/06C07K1/04
CPCC07K14/635Y02P20/55
Inventor 邹正才杨凯张孝清宋志春包金远
Owner NANJING HUAWE MEDICINE TECH DEV
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