Preparation method of pexiganan

A liquid phase method and peptide fragment technology, which is applied in the field of preparation of polypeptide antibiotics, can solve the problems of unsuitability for large-scale production, low purity and yield, and long synthesis cycle, and achieve low cost, low cost, and short synthesis cycle. short effect

Active Publication Date: 2015-02-18
上海飞腾医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The inventors used the existing synthetic method to prepare Percyganan, and found that the technical problems in the prior art are: more synthetic steps, long synthetic cycle, low efficiency, low purity and yield, especially in the coupling of two It is difficult to avoid the generation of missing peptide impurities when there are 1 lysine, which is not suitable for large-scale production

Method used

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  • Preparation method of pexiganan

Examples

Experimental program
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Effect test

Embodiment 1

[0064] Example 1: Synthesis of Fmoc-Lys(Boc)-OSu Activated Ester

[0065] Weigh 468.50g Fmoc-Lys(Boc)-OH (1.0mol), add 138.10g HOSu (1.2mol) into 2000ml DMF, add 247.59g DCC (1.2mol) under ice-water bath, react for 1 hour, heat up to room temperature for reaction 3 After 1 hour, the reaction solution was filtered, the mother liquor was spin-dried, dissolved in DCM, filtered, recrystallized from ice ethanol 3 times, filtered, and dried by a solid oil pump to obtain 503.37g of Fmoc-Lys(Boc)-OSu activated ester with a yield of 89%.

Embodiment 2

[0066] Example 2: Synthesis of Fmoc-Lys(Boc)-Lys(Boc)-OH

[0067] Weigh 123.15g H-Lys(Boc)-OH (0.5mol), 282.79g Fmoc-Lys(Boc)-OSu (0.5mol) and 79.50g Na 2 CO 3 (0.75mol) was added to a mixed solution of 500ml water and 500ml THF to dissolve, react overnight at room temperature, adjust the pH to 7 with 10% dilute hydrochloric acid, remove THF by rotary evaporation, and then adjust the pH to 3. A large white precipitate was obtained which was filtered. The obtained white precipitate is recrystallized with glacial ethanol, and the obtained solid oil pump is dried to obtain 296.15g of Fmoc-Lys(Boc)-Lys(Boc)-OH and its HPLC spectrogram is as follows: figure 2 Shown, HPLC purity is 98.95%, yield 85%; Its mass spectrum is as image 3 Shown, [M+Na] + : 719.525, [M+K] + : 735.773, the theoretical exact molecular weight of the dipeptide fragment Fmoc-Lys(Boc)-Lys(Boc)-OH is: 696.37, the mass spectrometry result of the sample is consistent with the theoretical molecular weight, and...

Embodiment 3

[0068] Embodiment three: adopting degree of substitution is the synthesis of the Rink Amide AM resin of 0.10mmol / g to Fmoc-Lys(Boc)-Lys(Boc)-Rink Amide AM resin

[0069] Weigh 100.00 g of Rink amide AM resin (10 mmol) with a substitution degree of 0.10 mmol / g, add it to a solid-phase reaction column, wash it once with DMF, and swell the resin with DCM for 30 minutes, and use a volume ratio of 1:4 The deprotection solution composed of piperidine and DMF was reacted for 5 minutes, washed once with DMF, reacted for 10 minutes with the deprotection solution composed of piperidine and DMF with a volume ratio of 1:4, washed 6 times with DMF, and weighed 20.91g Fmoc -Lys(Boc)-Lys(Boc)-OH (30mmol) and 4.05g HOBt (30mmol) were added to the mixed solution of DCM and DMF with a volume ratio of 1:1, and 3.79g DIC (30mmol) was added under ice-water bath for activation and then added to the above In the reaction column that resin is housed, react for 2 hours, wash 3 times with DMF, DCM wash...

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Abstract

The invention relates to the technical field of polypeptide synthesis, in particular to a preparation method of pexiganan. The preparation method comprises the following specific steps: A) synthesizing a dipeptide fragment FmoC-Lys (BoC)-Lys (BoC)-OH by a liquid phase method; B) by a solid-phase synthesis method, with amino resin as starting resin, sequentially coupling amino acids with FmoC protections at N terminals and side chain protections according to a peptide sequence of a main chain of the pexiganan, wherein the amino acids at 7 and 8 positions, the amino acids 10 and 11 positions and the amino acids at 21 and 22 positions are coupled by the dipeptide fragment FmoC-Lys (BoC)-Lys (BoC)-OH; C) cracking, purifying and freeze-drying peptide resin to obtain the pexiganan. The invention provides a synthesis process of the pexiganan, which is high in synthesis efficiency and low in cost, can avoid deleted peptide impurities caused by incomplete coupling of two lysines and is suitable for mass production.

Description

technical field [0001] The invention relates to a method for preparing polypeptide antibiotics, in particular to a method for preparing pexicanan. Background technique [0002] Pexiganan, English name: pexiganan, is a linear polypeptide containing 22 amino acids, the peptide sequence is: [0003] [0004] Percycanan is a product jointly developed by GlaxoSmithKline and Genaera (formerly Magainin Pharmaceuticals). It is used as a broad-spectrum topical antimicrobial agent in the treatment of infected diabetic foot ulcers. Percycanan was originally isolated from the abdominal skin of Xenopus laevis. It is a polypeptide antibacterial drug of animal origin. It is a member of the polypeptide antibiotic family magainin, and it is also the second new antibiotic family in the past 20 years. It can effectively Against more than 3,000 isolates, including bacteria (gram-negative, gram-positive and anaerobic), amoebas, fungi and parasites. The mechanism of action of peciganan is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/46C07K1/06C07K1/04C07K1/02
CPCC07K14/463
Inventor 沈柯刘霁莉周亮杨东晖路杨
Owner 上海飞腾医药科技有限公司
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