Method for synthesizing goserelin

A synthesis method and a technology for goserelin, which are applied in the field of pure liquid-phase fragment method synthesis of goserelin, can solve problems such as being unsuitable for industrialized production, and achieve the effects of shortening synthesis cycle, mild reaction conditions and high yield

Active Publication Date: 2010-06-30
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis strategy of 2+2+3+2 is adopted, and the specific steps are as follows: 1. Synthesis of the dipeptide fragment Pyr-His-Ome; 2. Synthesis of the dipeptide fragment Z-Trp-Ser-Ome; 3. Synthesis of the tripeptide fragment Z-Tyr(Bzl)-A-Leu-Ome (where A is: Gly, Ser, D-Phe, D-Tyr(Ome), D-Ser(Tbu)); 4. Synthesis of Boc-Arg(NO2)- Pro-C (where C is -Azgly-NH2, -NHEt, -Gly); finally, these fragments are condensed in series by the azide method to form Pyr-His-Trp-Ser-Tyr-A-Leu-Arg- Pro-C, but it also has the common fault of the azide compound synthesis method, which is not suitable for industrial production

Method used

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

Examples

Experimental program
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Effect test

Embodiment 2

[0068] Example 2 Synthesis of Tetrapeptide Fragment D-Ser(Tbu)-Leu-Arg-Pro-AZgly-NH2

[0069] 1. Synthesis of Boc-Pro-AZgly-NH2

[0070] Weigh Boc-Pro-OH (20mmol) into a 100ml round bottom flask, dissolve it with 55ml DMF, then add HOSU (22mmol), add 20ml of DMF solution of DCC (22mmol) under ice-water bath, and react at room temperature After 4 hours, filter off the precipitate, concentrate the solution to 40 ml, add 20 ml of concentrated ethylamine aqueous solution, react overnight at room temperature, and the plate reaction is complete, filter off the precipitate, remove the solution, dissolve with ethyl acetate, and wash with dilute alkali , washed with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a pale yellow solid (Boc-Pro-AZgly-NH2).

[0071] HPLC purity: greater than 92%, yield 81% MS=273 (M+).

[0072] 2. Synthesis of Boc-Arg(NO2)-Pro-AZgly-NH2

[0073] Weigh Boc-Pro-AZgly-NH2 (20mmol) is placed in the round bottom flask of 100 milliliters,...

Embodiment 1

[0074] Embodiment 1: Synthetic pentapeptide fragment Pyr-His-Trp-Ser-Tyr-OH

[0075] 1. Synthesis of Fmoc-Ser(Tbu)-Tyr-OMe:

[0076] Add Fmoc-Ser(Tbu)-OH (20mmol), NH2-Tyr-OMe (20mmol), HOSU (22mmol) in the round bottom flask of 50 milliliters, dissolve with 40 milliliters of anhydrous DMF, add DCC (22mmol) under ice-water bath ), stirred at room temperature for 2 hours, and the detection reaction was complete. The precipitate produced by the reaction was removed by suction filtration, concentrated under reduced pressure to remove DMF, and then dissolved with a large amount of ethyl acetate, and then dissolved with NaHCO 3 Washing, washing with dilute hydrochloric acid, washing with saturated brine, drying over anhydrous sodium sulfate, and spin-drying ethyl acetate gave a pale yellow solid (Fmoc-Ser(Tbu)-Tyr-OMe).

[0077]HPLC purity: greater than 90%, yield 93% MS=561 (M+).

[0078] 2. Synthesis of Fmoc-Trp(Boc)-Ser(Tbu)-Tyr-OMe:

[0079] Weigh Fmoc-Ser(Tbu)-Tyr-OMe (20m...

Embodiment 3

[0100] Example 3 Synthesis of Pyr-His-Typ-Ser-Tyr-Ser(Tbu)-Leu-Arg-Pro-AZgly-NH2

[0101] Add Pyr-His-Trp-Ser-Tyr-OH (20mmol) in a 50ml round bottom flask, dissolve with 40ml of anhydrous DMF, add tert-butyl chloroformate (8ml) under ice-salt bath, react 5-20 Minutes, add NH2-Ser(Tbu)-Leu-Arg-Pro-AZgly-NH2 (20mmol) DMF solution 20 milliliters, react in ice-salt bath for 30 minutes, stir at room temperature for 12 hours, detect that the reaction is complete. The precipitate produced by the reaction was removed by suction filtration, and concentrated under reduced pressure to remove DMF to obtain a light yellow crude product (Pyr-His-Trp-Ser-Tyr-Ser(Tbu)-Leu-Arg-Pro-AZgly-NH2).

[0102] HPLC purity: greater than 85%, yield 70% MS = 1269 (M+). The HPLC spectrum of the crude product of goserelin is as follows Image 6 shown.

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Abstract

The invention belongs to the field of the synthesis of medicines, which particularly relates to a novel method for synthesizing goserelin by a pure liquid-phase fragment method. In the method for synthesizing the goserelin, the goserelin Pyr-His-Trp-Ser-Tyr-D-Ser(Tbu)-Leu-Arg-Pro-AZgly-NH2 is formed by condensing a pentapeptide fragment Pyr-His-Trp-Ser-Tyr-OH and a tetrapeptide fragment D-Ser(Tbu)-Leu-Arg-Pro-AZgly-NH2 under the existence of a condensing agent. The invention adopts a 5+4 fragment synthesis method and can directly condense the pentapeptide fragment Pyr-His-Trp-Ser-Tyr-OH and the tetrapeptide fragment D-Ser(Tbu)-Leu-Arg-Pro-AZgly-NH2 into the goserelin under the existence of the condensing agent. The method shortens the synthesis period, avoids rigorous reaction conditions in the traditional method, has high yield, good product purity, low cost and mild reaction condition and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a new method for synthesizing goserelin by a pure liquid phase fragment method. Background technique [0002] Goserelin is a long-acting gonadotropin-releasing hormone agonist (GnRH-a), which has been widely used in the field of gynecology in recent years. The chemical formula of its compound is: Pyr-His-Trp-Ser-Tyr-D-Ser(TBU)-Leu-Arg-Pro-AZGLY-NH2, and the structural formula is as follows: [0003] [0004] The synthetic methods of goserelin mainly include solid-phase synthesis and liquid-phase synthesis. [0005] Solid-phase synthesis requires the use of a large amount of expensive peptide resin, which brings cost pressure to the large-scale production of enterprises. Not only that, in the final peptide cutting process, the tert-butyl group is easily removed under acidic conditions , will generate other impurity products. [0006] Judging from the research status...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/02
Inventor 徐峰路杨杨东晖闫庆连邓德雄
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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