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Buserelin preparation method

A technology of resin and conditions, applied in the field of preparation of buserelin, can solve the problems of difficult realization of strategies, complex protection strategies, expensive Rink and Sieber resins, etc.

Inactive Publication Date: 2014-07-23
CHENGDE MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The structure of buserelin contains ethylamine modification, as well as D-serine protected by histidine, arginine, tryptophan, serine and tert-butyl. It is difficult to find a suitable protection and deprotection strategy, and the synthesis is difficult
The liquid phase synthesis process adopted by CN101735308A involves complex protection strategies, resulting in complicated operations, which is not conducive to the adoption of industrial production
Fmoc-His(Mmt)-OH and Fmoc-Tyr(2-Cl-Trt)-OH used in US6897289 are expensive and not easy to obtain
The Rink and Sieber resins used in CN102190709A are expensive, and how the protection of Tyr (tBu), Ser (tBu), D-Ser (tBu), and His (Trt) are selectively removed is not specified, and it is also very strategically Difficult to achieve
CN103554229A uses expensive sodium amide and ethyl iodide to prepare ethylamino-CTC resin, the process is complicated, and the synthesis cost is greatly increased

Method used

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Experimental program
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Effect test

Embodiment 1

[0060] Embodiment 1: preparation buserelin

[0061] The implementation steps of this embodiment are as follows:

[0062] A. Using solid-phase synthesis, Fmoc-Pro with a degree of substitution of 0.4mmol / g was obtained from Fmoc-Pro-OH and a CTC resin with a degree of substitution of 0.6mmol / g in the presence of N,N-diisopropylethylamine -CTC resin; wherein the molar ratio of CTC resin to N,N-diisopropylethylamine is 1:3;

[0063] B. Treat the Fmoc-Pro-CTC resin obtained in step A with a solution of 10% piperidine in N,N-dimethylformamide by volume to remove Fmoc in the protected amino acid. After removing Fmoc, in the same manner as step A, according to the peptide sequence Pyr-His(Trt)-Trp-Ser-Tyr(Bzl)-D-Ser(tBu)-Leu-Arg(NO 2 )-Pro-OH, using coupling agent DIC / HOBt and organic base N,N-diisopropylethylamine to gradually couple and protect amino acids to obtain buserelin-CTC resin;

[0064] C. In a solution of 0.5% trifluoroacetic acid in dichloromethane by volume, the buse...

Embodiment 2

[0070] Embodiment 2: preparation buserelin

[0071] The implementation steps of this embodiment are as follows:

[0072] A. Using solid-phase synthesis, Fmoc-Pro with a degree of substitution of 0.5 mmol / g was obtained from Fmoc-Pro-OH and a CTC resin with a degree of substitution of 0.7 mmol / g in the presence of N,N-diisopropylethylamine. -CTC resin; wherein the molar ratio of CTC resin to N,N-diisopropylethylamine is 1:4;

[0073] B. Treat the Fmoc-Pro-CTC resin obtained in step A with a solution of 15% piperidine in N,N-dimethylformamide by volume to remove Fmoc in the protected amino acid. After removing Fmoc, in the same manner as step A, according to the peptide sequence Pyr-His(Trt)-Trp-Ser-Tyr(Bzl)-D-Ser(tBu)-Leu-Arg(NO 2 )-Pro-OH, using coupling agent PyBOP / HOBt and organic base N,N-diisopropylethylamine to gradually couple and protect amino acids to obtain buserelin-CTC resin;

[0074] C. In a solution of 1.0% trifluoroacetic acid in dichloromethane by volume, the...

Embodiment 3

[0080] Embodiment 3: preparation buserelin

[0081] The implementation steps of this embodiment are as follows:

[0082] A. Using solid-phase synthesis, Fmoc-Pro-OH with a substitution degree of 0.8mmol / g was obtained from Fmoc-Pro-OH and a CTC resin with a substitution degree of 0.8mmol / g in the presence of N,N-diisopropylethylamine. Fmoc-Pro with a substitution degree of 0.6mmol / g -CTC resin; wherein the molar ratio of CTC resin to N,N-diisopropylethylamine is 1:5;

[0083] B. Treat the Fmoc-Pro-CTC resin obtained in step A with a solution of 20% piperidine in N,N-dimethylformamide by volume to remove Fmoc in the protected amino acid. After removing Fmoc, in the same manner as step A, according to the peptide sequence Pyr-His(Trt)-Trp-Ser-Tyr(Bzl)-D-Ser(tBu)-Leu-Arg(NO 2 )-Pro-OH, using coupling agent TBTU / HOBt and organic base N,N-diisopropylethylamine to gradually couple and protect amino acids to obtain buserelin-CTC resin;

[0084] C. In a solution of 1.5% trifluoroac...

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Abstract

The invention relates to a buserelin preparation method which comprises the following steps of: preparation of Fmoc-Pro-CTC resin through solid-phase synthesis, coupling protection of amino acid through a coupling agent, cracking of buserelin-CTC resin, ethylamination, hydrogenation, de-protection, purification and the like. Compared with the pure liquid-phase synthesis process in the prior art, the synthesis method provided by the invention is simple to operate, intermediate compounds do not need to be purified, the after treatment is easy, and the total yield is up to 31%. According to the invention, in normal-pressure catalytic hydrogenation reaction de-protection, ammonium formate is used instead of hydrogen, the reaction is performed under normal temperature conditions, and the operation is convenient and safe; and furthermore, trifluoroacetic acid is used as a peptide cutting reagent to avoid the use of virulent hydrofluoric acid, and the used raw material palladium carbon can be recycled, all of which are beneficial to reducing environmental pollution. The process provided by the invention has the advantages of low cost, operation convenience, mild reaction conditions, low environmental pollution and the like, and is easy to implement industrialized production.

Description

【Technical field】 [0001] The invention relates to the technical field of polypeptide synthesis. More specifically, the present invention relates to a preparation method of buserelin. 【Background technique】 [0002] The chemical name of Buserelin is L-pyroglutamyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-D-(O-tert-butyl) -seryl-L-leucyl-L-arginyl-L-prolylethylamide, which has the formula C 60 h 86 N 16 o 13 , molecular weight 1239.4. The chemical structural formula of buserelin is as follows: [0003] [0004] Pyr-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NHEt [0005] Buserelin is a synthetic analogue of luteinizing hormone-releasing hormone (LH-RH), which consists of 9 amino acids. The difference between its molecular structure and LH-RH is that the latter's 6-position and 10 The -position Gly residue was replaced by D-Ser(tBu)-OH and ethylamine. LH-RH is a decapeptide hormone secreted by the hypothalamus, which can promote the pituitary gland to synthesize and ...

Claims

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Application Information

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IPC IPC(8): C07K14/60C07K1/06C07K1/04
CPCC07K7/23
Inventor 王良友代涛李松涛尹志峰赵红玲高杨
Owner CHENGDE MEDICAL UNIV
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