Leuprorelin synthesis preparation method

A technology of leuprolide and condensation reaction, which is applied to the preparation method of peptides, chemical instruments and methods, animal/human protein, etc., can solve the problems of high production cost, cumbersome process, and low yield, and achieve improved yield , low-cost mass production, and the effect of simplifying the process flow

Active Publication Date: 2017-03-22
合肥国肽生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Currently, the methods for synthesizing leuprolide in the market usually require two or more cutting reactions, the process is cumbersome, the yield is low, and the production cost is high, which is not conducive to the large demand and rapid production of leuprolide

Method used

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  • Leuprorelin synthesis preparation method
  • Leuprorelin synthesis preparation method
  • Leuprorelin synthesis preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 1. Swelling of 2-Cl resin

[0031] Weigh 0.1 g of 2-Cl resin with a degree of substitution of 0.9-1.1 mmol / g into a polypeptide synthesis reactor, add DCM solvent to completely immerse the chlorine resin, and swell for 30 minutes.

[0032] 2. Chlorine resin ethylamination

[0033] Weigh 10 mg of mercaptoethylamine, dissolve it with 1 ml of DCM, add 0.2 ml of DIEA to dissolve it completely, then add it to the swollen chlorine resin, and react overnight at 30°C.

[0034] 3. Head-capping reaction of ethylamine chlorine resin

[0035] Add 0.5ml of methanol and 0.5ml of DIEA solution into the reaction container, so that the resin in the container is in the state of quicksand in the solution, and the reaction container is placed on a shaker and shaken for 20 minutes.

[0036] 4. Synthesis of Fully Protected Leuprolide Peptide-Chloride Resin

[0037] Add 3ml of DMF solution to the reaction vessel, shake and wash for 1min, then drain the liquid in the reaction vessel, then a...

Embodiment 2

[0064] 1. Swelling of 2-Cl resin

[0065] Weigh 0.1 g of 2-Cl resin with a degree of substitution of 0.9-1.1 mmol / g into a polypeptide synthesis reactor, add DCM solvent to completely immerse the chlorine resin, and swell for 30 minutes.

[0066] 2. Chlorine resin ethylamination

[0067] Weigh 10 mg of mercaptoethylamine, dissolve it with 1 ml of DCM, add 0.2 ml of DIEA to dissolve it completely, then add it to the swollen chlorine resin, and react overnight at 30°C.

[0068] 3. Head-capping reaction of ethylamine chlorine resin

[0069] Add 0.5ml of methanol and 0.5ml of DIEA solution into the reaction container, so that the resin in the container is in the state of quicksand in the solution, and the reaction container is placed on a shaker and shaken for 20 minutes.

[0070] 4. Synthesis of Fully Protected Leuprolide Peptide-Chloride Resin

[0071] Add 3ml of DMF solution to the reaction vessel, shake and wash for 1min, then drain the liquid in the reaction vessel, then a...

Embodiment 3

[0085] 1. Swelling of 2-Cl resin

[0086] Weigh 1 g of 2-Cl resin with a degree of substitution of 0.9-1.1 mmol / g in a polypeptide synthesis reactor, add DCM solvent to completely immerse the chlorine resin, and swell for 40 minutes.

[0087] 2. Chlorine resin ethylamination

[0088] Weigh 100mg of mercaptoethylamine, dissolve it with 12ml of DCM, add 4ml of DIEA to dissolve it completely, then add it to the swollen chlorine resin, and react overnight at 30°C.

[0089] 3. Head-capping reaction of ethylamine chlorine resin

[0090] Drain the resin in the reaction container, then add 10ml of methanol and 10ml of DIEA solution to make the resin in the container in the state of quicksand in the solution, and place the reaction container on a shaker for 20 minutes to react.

[0091] 4. Synthesis of Fully Protected Leuprolide Peptide-Chloride Resin

[0092] Add 30ml of DMF solution to the reaction vessel, shake and wash for 1min, then drain the liquid in the reaction vessel, then...

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Abstract

The invention discloses a leuprorelin synthesis preparation method. The method comprises the following steps: using a chloride resin as a starting resin carrier, dissolving mercaptoethylamine with alkaline solvent, mixing with the chloride resin under a homothermal condition, and reacting over night to obtain an ethylamine chloride resin; adding methanol and DIEA (diisopropylethylamine) having equal volume ratios into the ethylamine chloride resin, and performing end-capping reaction; washing the end-capped ethylamine chloride resin with DMF (N,N-dimethylformamide), sequentially putting activated Fmoc protective amino acid into a reaction vessel, and performing continuous peptide chain condensation reaction; treating the reactive chloride resin by means of a microwave technique, and washing the peptide chain-chloride resin obtained after the reaction with a DMF solution; and performing cleavage reaction on the fully-protected leuprorelin-chloride resin by means of a cleavage reagent to obtain a leuprorelin crude peptide, and then purifying through reversed-phase high-performance liquid chromatography. The method disclosed by the invention greatly simplifies the process flow, shortens the production time, lowers the production cost, and improves the reaction condensation efficiency and pure product yield, thereby having considerable market competitiveness and application prospects.

Description

technical field [0001] The invention belongs to the technical field of synthesis and preparation methods of polypeptide drugs, and in particular relates to a synthesis and preparation method of leuprolide. Background technique [0002] Chinese name: Leuprolide [0003] English name: Leuprorelin [0004] Structural formula: Pyr-His-Trp-Ser-Tyr-(D-Leu)-Leu-Arg-Pro-NHEt [0005] Molecular formula: C 59 h 84 N 16 o 12 [0006] Molecular weight: 1209.45 [0007] Leuprorelin is a potent gonadotropin-releasing hormone (GnRH) agonist, a highly active analogue of luteinizing hormone-releasing hormone (LHRH) produced by the hypothalamus, and is a synthetic terminal Blocked water-soluble nonapeptide. Leuprolide can stimulate the pituitary gland to secrete gonadotropins and induce reproductive organs to produce steroids. Long-term large-scale use will desensitize LHRH receptors, inhibit the secretion of gonadotropins and complete or ovarian steroid production. It is used clinic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K14/695C07K1/20C07K1/14C07K1/06C07K1/04
Inventor 郑范娜陈为光
Owner 合肥国肽生物科技有限公司
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