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Leuprorelin synthesis method

A technology of leuprolide and synthesis method, which is applied in the preparation method of peptide, chemical instrument and method, organic chemistry and other directions, and can solve problems such as reducing yield and the like

Inactive Publication Date: 2016-02-17
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method cannot completely avoid the side reaction of diketopiperazine. When the production is scaled up, the side reaction of diketopiperazine will cause the peptide chain to fall off, which will significantly reduce the yield.

Method used

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  • Leuprorelin synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1, a synthetic method of leuprolide: the method adopts liquid-phase synthesis of a dipeptide intermediate and then uses it in solid-phase synthesis to obtain a fully protected nonapeptide resin, and the fully protected nonapeptide is cut off from the resin in the liquid phase In the phase, ethylamine is connected to obtain fully protected leuprolide, and the crude product of leuprolide is obtained through cracking;

[0037] The specific steps are as follows:

[0038] (1) Fmoc-Leu-OSU fat is obtained by condensing Fmoc-Leu-OH and HOSU under the action of a condensing agent;

[0039] (2) Reaction of Fmoc-Leu-OSU lipid with H-Arg(pbf)-OH under the action of alkali to obtain Fmoc-Leu-Arg(pbf)-OH;

[0040] (3) Fmoc-Pro-OH reacts with CTCResin under the action of alkali to obtain Fmoc-Pro-CTCResin;

[0041] (4) Remove Fmoc, and under the action of a condensing agent, sequentially couple the following amino acids: Fmoc-Leu-Arg(pbf)-OH, Fmoc-D-Leu-OH, Fmoc-Tyr(tBu)-OH...

Embodiment 2

[0044]Example 2, in a synthesis method of leuprolide described in Example 1: the condensing agent described in step (1) is selected from any one of DCC, DIC, and EDC·HCl.

Embodiment 3

[0045] Example 3, in a synthetic method of leuprolide described in Example 1 or 2: the base described in step (2) is selected from any one of DIEA, NMM, Py, DMAP, NaOH, NaHCO3, Na2CO3 kind.

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Abstract

The invention discloses a leuprorelin synthesis method. According to the method, a dipeptide midbody is obtained through liquid-phase synthesis and then used for solid-phase synthesis to generate full-protection nonapeptide peptide resin, full-protection nonapeptide is cut off from the resin and then inoculated with ethylamine in the liquid phase to generate full-protection leuprorelin, and a leuprorelin crude product is obtained through splitting decomposition. The method specifically comprises the steps of obtaining Fmoc-Leu-OSU fat through condensation under the action of a condensing agent; reacting with H-Arg(pbf)-OH under the action of alkali to generate Fmoc-Leu-Arg(pbf)-OH; obtaining Fmoc-Pro-CTC Resin through reaction under the action of the alkali; removing Fmoc, and conducting amino acid coupling in sequence under the action of a condensing agent to generate full-protection nonapeptide peptide resin; cutting the full-protection nonapeptide peptide resin with a cutting reagent to generate full-protection nonapeptide; generating leuprorelin full-protection peptide by means of full-protection nonapeptide and ethylamine hydrochloride under the action of a condensing agent, and obtaining the leuprorelin crude product through splitting decomposition. By the adoption of the method, the yield and purity of leuprorelin are improved remarkably, ammonolysis is not needed, and reaction is easy and controllable. The method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug preparation methods, in particular to a solid-liquid synthesis method of leuprolide. Background technique [0002] The foreign name of leuprorelin or common name is Leuprorelin, which has the following structure: [0003] L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-L - prolylethylamide [0004] [0005] Leuprolide is a highly active derivative of luteinizing-releasing hormone (LHRH), which produces transient stimulation of the pituitary-gonadal system (acute effect) immediately after the first dose, and then inhibits pituitary production and release of gonadotropins hormone. It also further suppresses the response of the ovaries and testes to gonadotropins, thereby reducing the production of estradiol and testosterone (chronic effects). Therefore, it can effectively inhibit the function of the pituitary-gonadal system. Leuprolide is widel...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/06C07K1/04C07K1/02
CPCY02P20/55
Inventor 王蔡典刘标谷海涛徐峰孙美禄李家瑾
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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