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Method for synthesizing goserelin with fragment method

A synthetic method, the technology of goserelin, which is applied in the field of synthesis of goserelin by the fragment method, can solve the problems affecting the separation of the final product

Active Publication Date: 2018-08-10
CHINESE PEPTIDE CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, iron powder or zinc powder needs to reflux in a mixed solvent of water and ethanol for 3 hours to reduce the nitro group. High temperature can cause racemization of some amino acids in the peptide chain and affect the separation of the final product.

Method used

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  • Method for synthesizing goserelin with fragment method
  • Method for synthesizing goserelin with fragment method
  • Method for synthesizing goserelin with fragment method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Synthesis of H-Arg(pbf)-Pro-Azagly-Resin.

[0038] 741 g of MBHA Resin with a degree of substitution of 0.54 mmol / g was added to the solid phase reactor, DCM was added to swell the resin for 2 hours, DCM was removed, and DMF washed once. Add 5% TEA / DMF (v:v) mixed solution of 2.5 times the volume of the resin layer to neutralize the resin for 5 minutes, remove the reaction solution, wash twice with DMF, twice with methanol, twice with DMF, and the ninhydrin method Tested positive.

[0039] Dissolve 648g Rink Amide Linker and 432g HBTU in DMF under ice bath conditions, add to the resin and react for 5 minutes, then add 264mL NMM, and react at room temperature for 2.5 hours. The end point of the reaction is determined by the ninhydrin method. After the reaction, DMF was washed twice, methanol was washed once, and DMF was washed twice.

[0040] 2.5 times the volume of the resin layer was added with DBLK to remove the Fmoc protection. After 30 minutes of reacti...

Embodiment 2

[0045] Example 2: H-Arg-Pro-Azagly-NH 2 preparation.

[0046] Prepare 10L of cleavage reagent, including 9.5L of TFA, 0.25L of water, and 0.25L of triisopropylsilane, and put it in a -20°C refrigerator to pre-cool for more than 30 minutes. Weigh 1000 g of the peptide resin obtained by the method described in Example 1, slowly add the resin to 10 L of cleavage reagent under stirring conditions, and react at room temperature for 3 hours. Filter the resin, collect the filtrate, slowly add the filtrate to 100L of cold ether for precipitation, centrifuge, wash three times with cold ether, and dry under reduced pressure to obtain crude peptide H-Arg-Pro-Azagly-NH 2 178g.

Embodiment 3

[0047] Example 3: H-Arg-Pro-Azagly-NH 2 preparation.

[0048] 12.6 g of Fmoc-Pro-OH was dissolved in 100 mL of DMF solvent, and 8.6 g of EDC·HCl, 6.0 g of HOBt, and 12.46 mL of NMM were added under ice-water bath conditions. After the weight is completely dissolved, slowly add 5.0 g of H-Azagly-NH 2 HCl, the reaction mixture continued to react at 25°C. The progress of the reaction was monitored by TLC on a thin-layer chromatography plate, and after the reaction was completed, it was neutralized with 600 mL of a 5% aqueous phosphoric acid solution. The aqueous phase was extracted with 400 mL of DCM, and the DCM organic phase was washed with 200 mL of water and 200 mL of saturated brine, and dried over anhydrous sodium sulfate after the washing was completed. Filtration, rotary evaporation under reduced pressure to remove DCM to obtain a solid, the obtained solid was vacuum-dried and weighed 20.0 g Fmoc-Pro-Azagly-NH 2 Crude product, purity 66%.

[0049] To 20.0g Fmoc-Pro-A...

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Abstract

The invention discloses a method for synthesizing goserelin with a fragment method. According to the technical scheme, the method includes the following steps that firstly, a first fragment H-Arg-Pro-Azagly-NH2 and a second fragment Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-OH are synthesized respectively, then, the first fragment and the second fragment are coupled under the coupling agent condition toobtain crude goserelin, and purification and lyophilization are carried out to obtain pure goserelin. The method has the advantages of simple reaction operation, convenient post-treatment, no catalytic reduction, high yield, low cost and the like, has considerable practical application prospects, and is applicable to industrial production.

Description

technical field [0001] The invention relates to a method for preparing a polypeptide, in particular to a method for synthesizing goserelin by a fragment method. Background technique [0002] Goserelin is a synthetic analog of luteinizing hormone-releasing hormone with a decapeptide structure, English name: Goserelin, chemical name: Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu -Arg-Pro-Azagly-NH 2 , molecular formula: C 59 H 84 N 18 O 14 , molecular weight: 1269.4, goserelin exists in the form of acetate in the listed drugs. [0003] Long-term use of goserelin can inhibit the secretion of luteinizing hormone from the pituitary gland, thereby causing a decrease in serum testosterone in men and estradiol in women, thereby shrinking hormone-sensitive tumors. It can be used for hormone therapy in prostate cancer and premenopausal and perimenopausal breast cancer. It can also be used in the treatment of endometriosis, such as pain relief and reduction of endometrial damage. [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/04C07K1/06C07K1/02
CPCC07K7/23Y02P20/55
Inventor 李湘刘宝生邱芊倪张钦
Owner CHINESE PEPTIDE CO
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