Method for preparing teriparatide

A technology of teriparatide and synthesis method, which is applied in the field of preparation of teriparatide, can solve the problems of only 32.2% total yield, large content of teriparatide, complicated work and the like

Active Publication Date: 2017-12-22
YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lilly obtains teriparatide through gene expression, such as patent US6590081. However, the gene expression method has technical barriers, complicated work, and serious three wastes.
Chinese patent CN102731643A discloses that CTC Resin is used as a solid phase carrier and is divided into 5 fragments for coupling. Although this method c

Method used

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  • Method for preparing teriparatide
  • Method for preparing teriparatide
  • Method for preparing teriparatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] (1) Preparation of Fmoc-Phe-CTC Resin resin

[0076] Add 20g (28 mmol) of CTC Resin resin with a substitution degree of 1.4mmol / g into the glass reaction column, add 200mL of DCM to dissolve it for 20min, drain it, and repeat 3 times; at the same time, weigh 10mmol of Fmoc-Phe-OH and 60 mmol of DIEA, these two substances were dissolved in 200 mL of DCM, stirred evenly, poured into a glass reaction column, and stirred for 1 hour. Extract liquid thereafter, wash with DCM, wash 6 times, each consumption 200mL, then wash with DMF, wash 6 times, each consumption 200mL; promptly obtain Fmoc-Phe-CTC Resin resin 45.1g, substitution degree is 0.4mmol / g.

[0077] (2) Synthesis of full peptide resin

[0078] To the Fmoc-Phe-CTC Resin resin that step 1) generates, add the DMF solution of 20% piperidine that the volume concentration that 400mL configures is good, stir and make it react for 30min, extract liquid afterwards, wash product 6 times with DMF, every Use 200mL each time,...

Embodiment 2

[0099] 1) Take 3.3g of Fmoc-Phe-wang-Resin resin with a degree of substitution of 0.3mmol / g and add 20mL of DMF solution of piperidine with a volume concentration of 20% and stir it to react for 30min, then remove the liquid and use DMF Wash the product 6 times, each time 20mL, drain the washing solution DMF, then weigh 1mmol of Fmoc-Asn(trt)-OH, 1mmol of TBTU and 1mmol of HOBT, and use 20mL of DMF for these three substances: DCM = 1:1 mixed solvent dissolved, after the dissolution is complete, add 10mmol of DIEA to form a mixed solution, stir evenly again, add the mixed solution into the glass reaction column, stir for 2 hours, then remove the liquid, and use DMF to prepare the product Wash 6 times, each time with 20 mL, and drain to obtain 5.1 g of Fmoc-Asn(trt)-Phe-wang Resin resin.

[0100] 2) Take half of the above resin, add piperidine / DMF solution with a volume ratio of 1:4 to remove the Fmoc protecting group on the resin, react for 30min, add 1mmol of Fmoc-His(trt)-OH,...

Embodiment 3

[0104] 1) Take 3.3g of Fmoc-Phe-wang-Resin resin with a degree of substitution of 0.3mmol / g and add 20mL of DMF solution of piperidine with a volume concentration of 20% and stir it to react for 30min, then remove the liquid and use DMF Wash the product 6 times, each time 20mL, drain the washing solution DMF, then weigh 1mmol of Fmoc-Asn(trt)-OH, 1mmol of TBTU and 1mmol of HOBT, and use 20mL of DMF for these three substances: DCM = 1:1 mixed solvent dissolved, after the dissolution is complete, add 10mmol of DIEA to form a mixed solution, stir evenly again, add the mixed solution into the glass reaction column, stir for 2 hours, then remove the liquid, and use DMF to prepare the product After washing 6 times, the dosage of each time was 20 mL, and then drained to obtain 5.1 g of Fmoc-Asn(trt)-Phe-wang-Resin resin.

[0105] 2) Take half of the above resin, remove the Fmoc protecting group on the resin with a deprotecting agent with a volume percentage concentration of 1:1:8 pip...

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Abstract

The invention discloses a method for preparing teriparatide. The method comprises synthesis and purification of the teriparatide, and belongs to the field of preparation of medicaments. The method disclosed by the invention comprises the following steps: 1) in the presence of an activator system, coupling a resin solid carrier with Fmoc-Phe-OH to obtain Fmoc-Phe-resin; 2) by solid-phase synthesis, sequentially coupling amino acids having N-terminal Fmoc protection and side chain protection according to a teriparatide backbone peptide sequence to obtain whole peptide resin; 3) when the whole peptide resin is condensed at amino acid No. 32, using COMU as a condensing agent and adopting a DMF solution of piperidine/Cl-HOBT as a deprotection agent during a synthesis process in each step; and 4) cracking the peptide resin to obtain a crude product, and subjecting the crude product to processes such as preliminary purification, purification and desalination to obtain the teriparatide, with a content of racemization impurity D-His32-teriparatide in process impurities being less than 0.1%. The invention provides a process for preparing the teriparatide with high purity, low cost and suitability for large-scale production. The process not only effectively controls technological impurities, but also obviously increases the total yield of the teriparatide.

Description

technical field [0001] The invention belongs to the field of polypeptide drugs, and in particular relates to a preparation method of teriparatide. Background technique [0002] Teriparatide (Cas No: 52232-67-4) is a synthetic polypeptide hormone developed by Eli Lilly and Company, mainly used for the treatment of primary and hypogonadal osteoporosis, postmenopausal osteoporosis. The molecular formula of teriparatide is C 181 h 291 N 55 o 51 S 2 , its corresponding molecular weight is 4117.75, teriparatide is composed of 34 natural amino acids, and its peptide sequence is: H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly- Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH. Lilly obtains teriparatide through gene expression, such as patent US6590081. However, the gene expression method has defects such as technical threshold, complicated work, and serious wastes. Chinese patent CN102731643A discloses that CTC Resin is used as a ...

Claims

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Application Information

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IPC IPC(8): C07K14/635C07K1/10C07K1/08C07K1/06C07K1/04
CPCC07K14/635
Inventor 高剑李元波王艳峰叶鑫发余昊杨柱柱周芯宇何晓
Owner YANGTZE RIVER PHARM GRP SICHUAN HAIRONG PHARM CO LTD
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