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Synthesis method of goserelin

A synthetic method and liquid-phase synthesis technology, applied in the field of goserelin synthesis, can solve the problems of high cost, low yield, and expensive price, and achieve the effect of simple and controllable reaction, improved yield and purity

Active Publication Date: 2017-04-26
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The catalyst palladium carbon is more expensive, and has a strong adsorption on polypeptides, resulting in low yield and high cost, which is not conducive to industrialized large-scale production

Method used

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  • Synthesis method of goserelin
  • Synthesis method of goserelin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1, a synthetic method of goserelin: the method adopts solid phase synthesis of 1-5 pentapeptide fragments and then inserts D-Ser(tBu) to form 1-6 hexapeptide fragments; solid phase or liquid phase 7-9 tripeptide fragments are synthesized; 7-9 tripeptides are inserted into semicarbazide in the liquid phase; in the liquid phase, the 1-6 hexapeptide fragments and 7-9 tripeptide fragments are coupled to goserelin to obtain Crude goserelin.

Embodiment 2

[0034] Embodiment 2, a kind of synthetic method of goserelin, concrete steps are as follows:

[0035] (1) Under the action of a condensing agent, Fmoc-Tyr(tBu)-Resin is obtained by condensing Fmoc-Tyr(tBu)-OH and resin;

[0036] (2) Remove Fmoc, and under the action of a condensing agent, sequentially couple the following amino acids: Fmoc-Ser(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-His(Trt)-OH, H-Pyr- OH, to obtain Pyr-His(Trt)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-Resin pentapeptide resin P-1;

[0037] (3) Use a cleavage reagent to cleave the pentapeptide resin to obtain the Pyr-His-Trp-Ser-Tyr pentapeptide fragment P-2;

[0038] (4) Under the action of a condensing agent, P-2 is condensed with H-D-Ser(tBu)-OMe HCl, and then alkaline hydrolyzed to obtain Pyr-His-Trp-Ser-Tyr-D-Ser(tBu), namely P-3 ;

[0039] (5) Under the action of alkali, Fmoc-Pro-OH and CTC Resin are condensed to obtain Fmoc-Pro-CTC Resin;

[0040] (6) Remove Fmoc, under the action of condensing agent, sequentially couple...

experiment example 1

[0052] Experimental example 1, preparation of Fmoc-Pro-CTC Resin

[0053] Take 50.00g of CTC Resin (1.2mmol / g) and place it in a polypeptide reactor, add 400mL of DCM and blow and stir with nitrogen for 30 minutes to fully swell the resin and drain the DCM. Weigh 60.75g of Fmoc-Pro-OH, add DMF 340mL and stir to dissolve, add DIEA 94.5mL, ice bath for 15 minutes, add to the polypeptide reactor, nitrogen blowing and stirring for 2 hours, drain the reaction solution, wash with DMF 3 times, each 400mL each time, 1 minute. Add blocking reagent (anhydrous methanol / DIEA / DCM=1 / 2 / 17 (volume ratio)) to block twice, 400 mL each time, for 10 minutes. Wash with DCM 4 times, 400 mL each time, for 10 minutes. Remove the resin and dry it. Obtained Fmoc-Pro-CTCResin 82.35g. The degree of substitution was 0.73 mmol / g.

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Abstract

The invention relates to a synthesis method of goserelin. The synthesis method comprises the following steps: respectively synthesizing 1st to 5th pentapeptide fragments by adopting solid phases, and then inducing D-Ser(tBu), thus forming 1st to 6th hexapeptide fragments; synthesizing 7th to 9th tripeptide fragments by using a solid phase or a liquid phase; inducing semicarbazide in the 7th to 9th tripeptide fragments in a liquid phase; coupling the 1st to 6th hexapeptide fragments and the 7th to 9th tripeptide fragments into the goserelin in the liquid phase, thus obtaining a goserelin crude product. According to the synthesis method disclosed by the invention, the yield and the purity of the goserelin are remarkably increased, catalytic reduction is not needed, the synthesis method just involves the technologies of condensation and deprotection of amino acid, the reaction is simple and controllable, and the synthesis 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 synthesis method of goserelin. Background technique [0002] The foreign name or common name of Goserelin is Goserelin, which has the following structure: [0003] Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-NHCONH 2 [0004] [0005] Goserelin is a GnRH structural analogue with a nonapeptide structure. By competing for most of the pituitary LHRH receptors, it feedback inhibits the secretion of LH and FSH, thereby inhibiting the production of ovarian estrogen and achieving drug-induced ovariectomy. therapeutic effect. For male patients, the concentration of serum testosterone drops to the level of castration about 21 days after the first injection of the drug, and this concentration is maintained in the subsequent treatment, which can make the prostate tumors of most patients regress and the symptoms improve. [0006] The existing synthet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/14C07K1/10C07K1/06C07K1/04
CPCC07K7/23
Inventor 王蔡典谷海涛陈烨赵呈青高鲁刘标
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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