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Method for synthesizing goserelin impurities

A synthesis method and the technology of goserelin are applied in the preparation methods of peptides, chemical instruments and methods, production of bulk chemicals, etc., which can solve the problems of many reaction steps, complicated operations such as washing and rotary evaporation, and improve the yield. Effect

Inactive Publication Date: 2019-08-16
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the pure liquid phase synthesis method can also obtain the target product, there are many reaction steps, and the operations such as washing and rotary evaporation are complicated.

Method used

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  • Method for synthesizing goserelin impurities
  • Method for synthesizing goserelin impurities
  • Method for synthesizing goserelin impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] A kind of synthetic method of goserelin impurity, flow process is as follows figure 1 shown, including the following steps:

[0039] step one:

[0040] Synthesis of Pyr-His(Trt)-Trp(Boc)-Ser(Trt)-Tyr(tBu)-D-Ser(tBu)-Leu-Arg(NO2)-Pro-OH:

[0041] 1) Add 10g of CTC-Resin with a substitution degree of 0.47mmol / g into a solid-phase reactor, add 2g of Fmoc-Pro-OH and 10ml of DIEA to react for 2 hours, remove the reaction solution, and wash twice with DMF; After Fmoc protection, wash twice with DMF, once with DCM, and twice with DMF;

[0042] 2) Add Fmoc-Arg(NO2)-OH, Fmoc-Leu-OH, Fmoc-D-Ser(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(Trt)-OH, Fmoc- Trp(Boc)-OH, Fmoc-His(Trt)-OH, Pyr-OH, the reaction time is 2 hours, the deprotection time is 0.5 hours, the reaction end point is determined by the ninhydrin method; after the reaction, DMF Wash twice, once with DCM, twice with DMF;

[0043] 3) After the washed resin was washed twice with methanol, the resin was removed twice with 20...

Embodiment 2

[0059] On the basis of Example 1, replace Step 4 and Step 5 as follows, and the rest of the operations are the same as Example 1.

[0060] Step 4: a cracking method of goserelin impurities, comprising the following steps:

[0061] Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-NH 2 Synthesis:

[0062] Prepare 50ml of trifluoroacetic acid: water: triisopropylsilane solution, the volume ratio is 80:10:10. 8.1g Pyr-His(Trt)-Trp(Boc)-Ser(Trt)-Tyr(tBu)-D-Ser(tBu)-Leu-Arg-Pro-NH-NH 2 Added to the solution, stirred for 2 hours. Take out the reaction solution, add it to 200ml, stir well, and then rotary evaporate to obtain 3.6g of oily liquid; add 3.6g of oily liquid to 500ml of ether, precipitate and centrifuge, wash with ether three times, and dry under reduced pressure to finally obtain 2.9g of white solid .

[0063] Step 5: Purification of goserelin impurities:

[0064] 2.9g white solid Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-NH 2 Dissolve with 10% acetonitrile and wat...

Embodiment 3

[0068] On the basis of Example 1, replace Step 4 and Step 5 as follows, and the rest of the operations are the same as Example 1.

[0069] Step 4: a cracking method of goserelin impurities, comprising the following steps:

[0070] Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-NH 2 Synthesis:

[0071] Prepare 50ml of trifluoroacetic acid: water: triisopropylsilane solution, the volume ratio is 80:10:10. 7.8g Pyr-His(Trt)-Trp(Boc)-Ser(Trt)-Tyr(tBu)-D-Ser(tBu)-Leu-Arg-Pro-NH-NH 2 Added to the solution, stirred for 2 hours. Take out the reaction solution, add it to 200ml, stir well, and rotary evaporate to obtain 3.4g oily liquid; add 3.4g oily liquid to 500ml ether, precipitate and centrifuge, wash with ether three times, and dry under reduced pressure to finally obtain 2.7g white solid .

[0072] Step 5: Purification of goserelin impurities:

[0073] 2.7g white solid Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-NH 2 Dissolve with 10% acetonitrile and water, filter;

[0...

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Abstract

The invention discloses a method for synthesizing goserelin impurities. According to the technical scheme, the method comprises the following steps: firstly synthesizing a first fragment: Pyr-His-Trp-Ser-Tyr-D-Ser (tBu)-Leu-Arg-Pro-OH, coupling the first fragment and Boc-NH-NH2 under a coupling agent to obtain a goserelin impurity crude product, removing side chain protection under the condition of trifluoroacetic acid, and purifying and freeze-drying to obtain the pure product of the goserelin impurities. The method has the advantages of simplicity in reaction operation, convenience in post-treatment and high yield, and has high reference value for the synthesis of goserelin. In addition, the scientific evaluation, pharmacological research, pharmacokinetics and the like of the goserelin are provided.

Description

technical field [0001] The invention relates to a polypeptide synthesis method, in particular to a method for synthesizing goserelin impurities from fragments. [0002] technical background [0003] Goserelin is a synthetic analogue 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-NH2, molecular formula: C59H84N18O14, molecular weight: 1269.4. The impurity synthesized in this patent is the impurity produced by the side reaction during the synthesis of goserelin, chemical name: Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NH-NH2 , molecular formula: C58H83N17O13, molecular weight: 1226.41. [0004] Long-term use of goserelin can inhibit the secretion of luteinizing hormone in the pituitary gland, thereby causing a decrease in serum testosterone in men and serum estradiol in women, thereby shrinking hormone-sensitive tumors. It can be used for hormone therapy for pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/04C07K1/02C07K1/06
CPCC07K7/06Y02P20/55
Inventor 童巍王洪飞
Owner TLC NANJING PHARMA RANDD CO LTD
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