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Fragment-process synthesis method of goserelin

A synthesis method and fragment technology, applied in the field of polypeptide drug preparation, can solve the problems of unfavorable industrial production, complicated operation steps, low purity and yield, etc., and achieve the effects of easy synthesis and purification, improved preparation efficiency and high purity

Active Publication Date: 2020-06-05
NANJING LEEWE BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved by the present invention is to provide a Ghoshere forest synthesis method

Method used

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  • Fragment-process synthesis method of goserelin
  • Fragment-process synthesis method of goserelin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Step (1) synthesis of fragment one

[0054] Add 60.00 g of Wang Reasin and 600 mL of DCM to the solid-phase reaction bottle in turn, stir for 15 minutes, and filter with suction after swelling to obtain a filter cake. Add DMF120mL, Fmoc-Tyr(tBu)-OH (3eq, 41.40g), catalyst DMAP (0.6eq, 2.19g), DIC (3.0eq, 11.37g), HOBt (3.0eq, 12.17g) to the above bottle in turn , stirred and reacted under nitrogen for 2 hours, and filtered with suction to obtain a filter cake. The filter cake was washed with an appropriate amount of DMF, and the filter cake was obtained by suction filtration. The Fmoc deprotection group reaction adopts Pip / DMF mixed solution: the filter cake is mixed with 300mL20% Pip / DMF solution (the volume ratio of DMF and Pip is 80:20, the same below), stirred for 5 minutes, and suction filtered to obtain the filter cake; 300mL of 20% Pip / DMF solution, stirred for 15 minutes, and filtered with suction. The filter cake was washed with an appropriate amount of DMF,...

Embodiment 2

[0067] The difference from Example 1 is the synthesis of Fragment One

[0068] 60.00 g of Wang resin and 600 mL of DCM were sequentially added into the solid-phase reaction bottle for the synthesis of Fragment 1, stirred for 15 minutes, and filtered with suction to obtain a filter cake. Add DMF120mL, Fmoc-Tyr(tBu)-OH (3eq, 41.40g), catalyst DMAP (0.6eq, 2.19g), HBTU (3.0eq, 34.14g), HOBt (3.0eq, 12.17g) to the above bottle in turn , DIEA (3.0 equivalents, 11.67g) was stirred and reacted under nitrogen for 2 hours, and the filter cake was obtained by suction filtration. The filter cake was washed with an appropriate amount of DMF, and the filter cake was obtained by suction filtration. The filter cake was mixed with 300 mL of 20% Pip / DMF solution, stirred for 5 minutes, and suction filtered to obtain the filter cake; then 300 mL of 20% Pip / DMF solution was added, stirred for 15 minutes, and suction filtered. The filter cake is washed with an appropriate amount of DMF, and the...

Embodiment 3

[0071] The difference from Example 1 is the synthesis of Fragment One

[0072] Synthesis of Fragment One

[0073] Add 60.00 g of Wang resin and 600 mL of DCM in sequence to the solid-phase reaction flask, stir for 15 minutes, and filter with suction to obtain a filter cake. Add DMF120mL, Fmoc-Tyr(tBu)-OH (3 equivalents, 41.40g), catalyst DMAP (0.6 equivalents, 2.19g), PyBop (3.0eq, 46.87g), HOBt (3.0eq, 12.17g) to the above bottle in sequence ), DIEA (3.0eq, 11.67g) was stirred and reacted under nitrogen for 2 hours, and the filter cake was obtained by suction filtration. The filter cake was washed with an appropriate amount of DMF, and the filter cake was obtained by suction filtration. The filter cake was mixed with 300mL 20% Pip / DMF solution (DMF:Pip; 80:20, volume ratio), stirred for 5 minutes, and suction filtered to obtain the filter cake; then 300mL 20% Pip / DMF solution was added, stirred for 15 minutes, and suction filtered. The filter cake was washed with an approp...

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Abstract

The invention synthesizes goserelin by a synthesis method of combining a solid-phase method and a liquid-phase method. Fragments II and III are easy to synthesize and purify and high in purity; different fragments can be synthesized simultaneously, so that the synthesis time of the goserelin is effectively shortened, and the preparation efficiency is improved; and finally, the two fragments are butt-jointed by the liquid-phase method to obtain a goserelin precursor, low-cost coupling is realized, and industrial enlarged preparation is facilitated.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of polypeptide drugs, and in particular relates to a method for synthesizing goserelin by a fragment method. Background technique [0002] Goserelin is a potent synthetic decapeptide gonadotropin-releasing hormone (GnRH) analogue. It can promote the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), which are 40-200 times stronger than natural hormones. Goserelin was developed by the British company AstraZeneca and launched in France in 1987. It was approved for marketing by FDA in December 1989. [0003] The structural formula of goserelin is: [0004] H-Pyr 9 -His 8 -Trp 7 -Ser 6 -Tyr 5 -D-Ser 4 (tBu)-Leu 3 -Arg 2 -Pro 1 -NHNHCONH 2 10 [0005] Goserelin is an extended-release implant that is a synthetic, luteinizing hormone-releasing hormone analog. Long-term use can inhibit the secretion of luteinizing hormone in the pituitary...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/23C07K1/20C07K1/06C07K1/04C07K1/02
CPCC07K7/23Y02P20/55
Inventor 宋志春杨凯邹正才王晶候蓓张孝清
Owner NANJING LEEWE BIOPHARMACEUTICAL CO LTD
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