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Synthesizing method of buserelin

A synthesis method and a condensing agent technology, which are applied in the field of pure liquid-phase fragment synthesis of buserelin, can solve problems such as being unsuitable for industrial production, and achieve the effects of shortening the synthesis cycle, mild reaction conditions, and low cost

Inactive Publication Date: 2010-06-16
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • 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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  • Synthesizing method of buserelin
  • Synthesizing method of buserelin
  • Synthesizing method of buserelin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1: Synthetic pentapeptide fragment Pyr-His-Trp-Ser-Tyr-OH

[0064] 1. Synthesis of Fmoc-Ser(Tbu)-Tyr-OMe:

[0065] 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).

[0066] HPLC purity: more than 92, the yield is 90.5MS=561 (M+).

[0067] 2. Synthesis of Fmoc-Trp(Boc)-Ser(Tbu)-Tyr-OMe:

[0068] Weigh Fmoc-Ser(Tbu)-Tyr-OMe ...

Embodiment 2

[0083] Example 2 Synthesis of Tetrapeptide Fragment D-Ser(Tbu)-Leu-Arg-Pro-NHEt

[0084] 1. Synthesis of Fmoc-Pro-NHEt

[0085] Weigh Fmoc-Pro-OH (20mmol) and place it in a 100ml round bottom flask, dissolve it with 55ml DMF, then add HOSU (22mmol), add 20ml DMF solution of DCC (22mmol) under ice-water bath, and react at room temperature For 4 hours, filter off the precipitate, concentrate the solution to 40 ml, add 20 ml of concentrated ethylamine aqueous solution, and react overnight at room temperature. Washing, washing with brine, drying over anhydrous sodium sulfate, and spin-drying the solvent to obtain a light yellow solid (Fmoc-Pro-NHEt).

[0086] HPLC purity: greater than 92, yield 81% MS = 365 (M+).

[0087] 2. Synthesis of Boc-Arg(NO2)-Pro-NHEt

[0088] Weigh Fmoc-Pro-NHEt (20mmol) and place it in a 100ml round-bottomed flask, add 30ml of piperidine / DMF 25% solution, react at room temperature for 30 minutes, detect that the reaction is complete, add a large amoun...

Embodiment 3

[0102] The synthesis of embodiment 3Pyr-His-Trp-Ser-Tyr-Ser(Tbu)-Leu-Arg-Pro-NHEt

[0103] 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, 20 ml of DMF solution of NH2-Ser(Tbu)-Leu-Arg-Pro-NHEt (20mmol) was added, reacted in ice-salt bath for 60 minutes, stirred at room temperature for 12 hours, and detected that the reaction was 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-NHEt).

[0104] HPLC purity: greater than 85, yield 72% MS=1240 (M+1). The HPLC spectrum of the crude product of Buserelin is as follows Image 6 shown.

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Abstract

The invention belongs to the field of medicament synthesis, in particular to a new method for synthesizing buserelin by using a pure liquid-phase segment method. In the synthesizing method of the buserelin, the buserelin Pyr-His-Trp-Ser-Tyr-D-Ser(Tbu)-Leu-Arg-Pro-NHEt is formed by condensing a pentapeptide segment Pyr-His-Trp-Ser-Tyr-OH and a tetrapeptide segment D-Ser(Tbu)-Leu-Arg-Pro-NHEt in the existence of a condensing agent. In the invention, the buserelin is formed by directly condensing the pentapeptide segment Pyr-His-Trp-Ser-Tyr-OH and the tetrapeptide segment D-Ser(Tbu)-Leu-Arg-Pro-NHEt in the existence of the condensing agent by adopting a 5+4 segment synthesizing method. The method not only shortens the synthesis period and avoids the severe reaction condition of a traditional method, but also 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 buserelin by a pure liquid phase fragment method. Background technique [0002] Buserelin, its compound chemical formula is: Pyr-His-Trp-Ser-Tyr-D-Ser(TBU)-Leu-Arg-Pro-NHET, the structural formula is as follows: [0003] [0004] The synthetic method of buserelin mainly includes two kinds of 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 of various existing materials, the liquid-phase synthesis of buserelin is the main method used by major companies and scientific research i...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/02
CPCY02P20/55
Inventor 徐峰路杨杨东晖穆斌朱夏明
Owner ADLAI NORTYE BIOPHARMA CO LTD
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