WO2017114382A1 - Procédé de synthèse d'un peptide modifié en position c-terminale - Google Patents

Procédé de synthèse d'un peptide modifié en position c-terminale Download PDF

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Publication number
WO2017114382A1
WO2017114382A1 PCT/CN2016/112317 CN2016112317W WO2017114382A1 WO 2017114382 A1 WO2017114382 A1 WO 2017114382A1 CN 2016112317 W CN2016112317 W CN 2016112317W WO 2017114382 A1 WO2017114382 A1 WO 2017114382A1
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fmoc
resin
mmol
solid phase
modified peptide
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PCT/CN2016/112317
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English (en)
Chinese (zh)
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伍柯瑾
戴政清
宓鹏程
陶安进
袁建成
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深圳翰宇药业股份有限公司
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Publication of WO2017114382A1 publication Critical patent/WO2017114382A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/062—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha- or omega-carboxy functions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • modified polypeptide drug can significantly reduce immunogenicity, reduce toxic side effects, increase water solubility, prolong the time of action in vivo, change its biodistribution status, etc., and significantly improve the efficacy of the drug.
  • the C-terminal chemical modification of peptides is becoming a research hotspot, and the introduction of some small molecule drugs at the C-end has become a new research direction.
  • the modification of the amino group is generally carried out by amide bond reaction directly with the carboxyl group at the C-terminus of the peptide chain in the liquid phase; for the carboxyl group modification at the C-terminus, it is generally required
  • the introduction of a diamino Linker between the C-terminal carboxyl group of the peptide chain and the modified carboxyl group will undoubtedly increase the chemical synthesis difficulty of such a peptide because it generally performs two amide bond reactions in the liquid phase.
  • the post-treatment difficulty of the synthesis is greatly increased, and the yield of the target peptide is greatly reduced.
  • the main synthetic technique is to first perform the coupling of peptide sequences on 2-Chlorotrityl Chloride Resin using Fmoc solid phase peptide synthesis strategy, in which the N-terminal amino group is protected by Boc and then cleaved. Fully protective peptide, then introduce a diamino Linker (usually ethylenediamine, butanediamine, hexamethylenediamine, octanediamine%) in the liquid phase at the C-terminus of the peptide chain, after post-treatment, again A modified carboxyl group is introduced into the liquid phase.
  • GHWDFRQWWQPSGGGS-hexanediamine-Biotin as an example to illustrate the existing synthetic technical scheme, as shown in Figure 1.
  • the present invention aims to introduce a novel diamino Linker direct coupling resin method.
  • we directly couple the diamino Linker to The solid phase resin is then coupled to the peptide sequence in turn, and then cleaved after coupling to obtain a fully protected peptide.
  • the above fully protected peptide is directly reacted with a carboxyl group-containing modifying group, and the target product is directly obtained in one step.
  • the synthesis of the target product can be accomplished directly on the solid phase, as shown in Figure 2.
  • the method of the present invention accomplishes the coupling of the diamine compound to the solid support and the loading of the first amino acid residue on the solid support by controlling the reaction conditions.
  • the by-product is avoided by a two-step blocking method. Occurs, solving the technical barrier that is difficult to uniformly couple a bifunctional compound to a solid phase carrier in the prior art. This undoubtedly has the advantages of simple operation, energy saving and environmental protection, and improved yield.
  • One aspect of the present invention provides a method for synthesizing a C-terminal modified peptide, which comprises the steps of:
  • the diamino compound is selected from a linear symmetric diamino compound or a branched symmetric diamino compound or a symmetrical spatial diamino compound, preferably ethylenediamine, propylenediamine, butanediamine, pentane Diamine, hexamethylenediamine, heptanediamine, octanediamine,
  • the solid phase synthetic resin is selected from the group consisting of 2-Chlorotrityl Chloride Resin resin, and preferably, the solid phase synthetic resin has a degree of substitution in the range of 0.1 to 1.2 mmol/g, more preferably 0.2 to 0.8 mmol/g, and most preferably 0.3 to 0.5. Mmmol/g.
  • the coupling system used in the Fmoc solid phase peptide synthesis strategy in step 2) is DIC+A or B+A+C, wherein A is HOBt or HOAt, B is HBTU, HATU, TBTU or PyBOP, and C is DIPEA. Or TMP.
  • step 4 a purification step is further included, and the preferred purification step is purification by HPLC method.
  • the solid phase synthetic resin is weighed and placed in a solid phase reaction column, DMF is added, and nitrogen gas is bubbled and swollen; the diamino compound is weighed, dissolved in DMF, and DIPEA is added to the solid.
  • the reaction column after completion of the reaction, methanol and DIPEA were added, and the mixture was sealed for 10 to 60 minutes, washed with DCM, and the resin was shrunk and the resin was drained to obtain a diamino compound-coupled solid phase synthetic resin.
  • the step of coupling the first amino acid to the amino group at the other terminal of the diamino compound in the step 2) is: adding DMF to the diamino compound-coupled solid phase synthetic resin obtained in the step 1), bubbling nitrogen gas Swelling; after activation of the Fmoc-protected amino acid by the coupling system, the activated Fmoc-protected amino acid is added to the reaction column for reaction, then acetic anhydride and pyridine are added, and the mixture is closed to obtain the Fmoc-protected amino acid diamino compound coupled solid phase synthesis. Resin.
  • amino acid sequence on the amino group of the other terminal in which the amino compound is sequentially coupled is selected from a polypeptide comprising 1-20 amino acids, preferably a polypeptide of 5-15 amino acids.
  • carboxyl group-containing modifying group is selected from the group consisting of Biotin, fluorescein, carnitine, formic acid, acetic acid, palmitic acid, stearic acid, cholic acid, a carboxyl group-containing small molecule drug, and a pharmacological functional group.
  • Figure 1 is a flow chart showing the synthesis of a polypeptide C-terminal modified Biotin
  • Figure 2 is a flow chart showing the synthesis of the C-terminal modified Biotin of the polypeptide of the present invention.
  • the structure of the ibirapeptide is: H-Met(O 2 )-Glu-His-Phe-D-Lys-Phe-NH-(CH 2 ) 8 -NH 2 .
  • the reaction was carried out at room temperature for 2.5 hours, the resin was filtered off, the resin was washed with 50 ml of TFA, and the filtrate was combined, and then added to 00 ml of chilled anhydrous diethyl ether to precipitate a white solid.
  • the yield was 99.8%, and the HPLC purity was 91.4%.
  • Example 7 138 g of the peptide resin obtained in Example 7 was placed in a 2000 ml single-necked flask, and 1500 ml of a 0.1% TFA solution of DCM was placed in a flask, and reacted at room temperature for 2.0 hours. The resin was filtered off, and the solvent was evaporated to give a white-protected. The crude peptide was 68 g.
  • Ebolapeptides were prepared by the methods of Examples 1-5 (invention) and Examples 6-11 (prior art) at the same dosage, with a total yield nearly three times different for 7 peptide conjugates.
  • the total yield of sperm peptide can usually reach about 60%, and by the method of the present invention, the inventors unexpectedly found that the effect far exceeds the expected yield, and is as high as 80% or more.
  • Example 12 100 g of NH 2 -(CH 2 ) 2 -NH-2-Chlorotrityl Chloride Resin obtained in Example 12 was weighed into a solid phase reaction column, DMF was added, and nitrogen gas was bubbled and swollen for 60 minutes; Fmoc-Leu-OH 21.2 was weighed. ⁇ (60mmol), HOBt 9.72g (72mmol), dissolved in DMF, added 16.4ml DIC (72mmol) in 0°C ice water bath, activated for 5 minutes, added to the reaction column, after reaction for 2 hours, add 70ml acetic anhydride and 60ml pyridine.
  • the structure of the target compound is prepared: H-Phe-Phe-Gly-Ala-Ser-Cys-Leu-NH-(CH 2 ) 2 -NH-L-Carnitine (L-Carnitine: L-Carnitine: Compounds are used for weight loss, and peptide sequences are linked to increase metabolic stability.
  • Example 14 165 g of the peptide resin obtained in Example 14 was placed in a 2000 ml single-necked flask, and 1800 ml of a 0.1% TFA solution of DCM was placed in a flask, and reacted at room temperature for 2.0 hours. The resin was filtered off, and the solvent was evaporated to give a white-protected. Crude peptide 64g.
  • L-Carnitine 16.1 g (100 mmol) was added to a 500 ml one-necked flask, dissolved in 50 ml of DMF, and 16.3 g (120 mmol) of HOBt, and 15.1 g of DIC (120 mmol) were added.
  • the 64 g of the fully protected crude peptide obtained in Example 15 was dissolved in 200 ml of DCM, and slowly added dropwise to the L-Carnitine solution. After the completion of the dropwise addition, the reaction was continued for 2 hours to complete the reaction.
  • L-Carnitine 16.1 g (100 mmol) was added to a 500 ml one-necked flask, dissolved in 50 ml of DMF, and 16.3 g (120 mmol) of HOBt, and 15.1 g of DIC (120 mmol) were added.
  • the 42 g of the fully protected crude peptide obtained in Example 22 was dissolved in 200 ml of DCM, and slowly added dropwise to the L-Carnitine solution. After the completion of the dropwise addition, the reaction was continued for 2 hours to complete the reaction.
  • Example 24 The crude product obtained in Example 24 was 16.3 g, using a Waters 2454 RP-HPLC system, a wavelength of 220 nm, a column of 100 ⁇ 500 mm reverse phase C18 column, mobile phase: phase A: 0.3% TFA/acetonitrile solution (v/v); Phase: acetonitrile, gradient: B%: 38% to 68%, flow rate: 6 ml/min, the peak fraction of the target was collected, concentrated by rotary evaporation, and lyophilized to obtain the target sperm peptide 9.7 g, HPLC purity 99.26%, total yield 20.9% .
  • Example 26 100 g of NH 2 -(CH 2 ) 6 -NH-2-Chlorotrityl Chloride Resin obtained in Example 26 was weighed into a solid phase reaction column, DMF was added, and nitrogen gas was bubbled and swollen for 60 minutes; Fmoc-Ser (tBu) was weighed.
  • the structure of the target compound was prepared: GHWDFRQWWQPSGGGS-hexanediamine-Biotin.
  • Biotin 24.4 g (100 mmol) was added to a 1000 ml one-neck flask, dissolved in 100 ml of DMF, and 16.3 g (120 mmol) of HOBt, and 15.1 g DIC (120 mmol) were added.
  • the 169 g of the fully protected crude peptide obtained in Example 29 was dissolved in 500 ml of DCM, and slowly added dropwise to the Biotin solution. After the completion of the dropwise addition, the reaction was continued for 2 hours to terminate the reaction.
  • Example 31 The crude product obtained in Example 31 was obtained from 92.6 g, using a Waters 2454 RP-HPLC system with a wavelength of 220 nm, a column of 100 ⁇ 500 mm reverse phase C18 column, mobile phase: phase A: 0.3% TFA/acetonitrile solution (v/v); Phase: acetonitrile, gradient: B%: 38% to 68%, flow rate: 6 ml/min, collection of the peak fraction of interest, concentration by rotary evaporation, lyophilization to obtain 40.5 g of the target spermatin, HPLC purity 98.90%, total yield 36.6% .
  • the mixture was shredded with methanol and dried in vacuo to give 268 g of peptide resin.
  • Biotin 24.4 g (100 mmol) was added to a 1000 ml one-neck flask, dissolved in 100 ml of DMF, and 16.3 g (120 mmol) of HOBt, and 15.1 g DIC (120 mmol) were added.
  • the 158 g of the fully protected crude peptide obtained in Example 36 was dissolved in 500 ml of DCM, and slowly added dropwise to the Biotin solution. After the completion of the dropwise addition, the reaction was continued for 2 hours to complete the reaction.
  • Example 38 The crude product obtained in Example 38 was obtained in 45.9 g, using a Waters 2454 RP-HPLC system, a wavelength of 220 nm, a column of 100 ⁇ 500 mm reverse phase C18 column, mobile phase: phase A: 0.3% TFA/acetonitrile solution (v/v); Phase: acetonitrile, gradient: B%: 38% to 68%, flow rate: 6 ml/min, the peak fraction of the target was collected, concentrated by rotary evaporation, and lyophilized to obtain the target sperm peptide 16.3 g, HPLC purity 99.2%, total yield 14.7% .
  • GHWDFRQWWQPSGGGS-hexanediamine-Biotin was prepared by the method of Examples 26-33 (present invention) and Examples 34-39 (prior art) at the same dosage, with a total yield of more than 2 times, by the method of the present invention, Although only the order of synthesis was changed, the overall yield far exceeded the expected yield.

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  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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Abstract

L'invention concerne un procédé de synthèse d'un peptide modifié en position C-terminale, consistant à : 1) coupler une extrémité N-terminale d'un composé diamine à une résine pour effectuer une synthèse en phase solide; 2) coupler successivement un acide aminé à l'autre extrémité N-terminale du composé diamine à l'aide d'un procédé de synthèse peptidique en phase solide en stratégie Fmoc pour obtenir une résine polypeptidique entièrement protégée; 3) cliver de la résine un polypeptide entièrement protégé pour obtenir le polypeptide entièrement protégé; 4) éliminer un groupe protecteur sur le polypeptide entièrement protégé pour obtenir le peptide modifié en position C-terminal cible, ou 5) coupler le polypeptide entièrement protégé à un groupe de modification contenant un carboxyle pour obtenir le peptide modifié en position C-terminal cible.
PCT/CN2016/112317 2015-12-31 2016-12-27 Procédé de synthèse d'un peptide modifié en position c-terminale WO2017114382A1 (fr)

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CN109485713A (zh) * 2018-12-10 2019-03-19 倪京满 具有强抗菌活性和低毒性的二聚化修饰抗菌肽类似物及其合成和应用
CN111349147A (zh) * 2018-12-21 2020-06-30 国家纳米科学中心 一种多肽的大规模制备方法和应用
CN112940103A (zh) * 2019-12-10 2021-06-11 深圳翰宇药业股份有限公司 一种特立帕肽杂质f的合成方法
CN112940104A (zh) * 2019-12-10 2021-06-11 深圳翰宇药业股份有限公司 一种特立帕肽杂质f
CN113135979A (zh) * 2020-01-18 2021-07-20 深圳市健翔生物制药有限公司 一种肽的固相合成方法
CN113461775A (zh) * 2021-08-23 2021-10-01 成都诺和晟泰生物科技有限公司 一种多肽化合物的制备方法
CN113755475A (zh) * 2021-10-12 2021-12-07 西南医科大学附属中医医院 一种ace2环肽模拟物及其在抑制新冠假病毒中的用途
CN114685616A (zh) * 2020-12-31 2022-07-01 哈尔滨三联药业股份有限公司 醋酸曲普瑞林的合成方法
CN114716515A (zh) * 2022-03-31 2022-07-08 深圳深创生物药业有限公司 一种多肽类似物及其制备方法和应用
CN114736286A (zh) * 2021-12-27 2022-07-12 杭州诺泰澳赛诺医药技术开发有限公司 一种多肽杂质单硫化物的合成方法

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CN109485713A (zh) * 2018-12-10 2019-03-19 倪京满 具有强抗菌活性和低毒性的二聚化修饰抗菌肽类似物及其合成和应用
CN111349147A (zh) * 2018-12-21 2020-06-30 国家纳米科学中心 一种多肽的大规模制备方法和应用
CN112940103A (zh) * 2019-12-10 2021-06-11 深圳翰宇药业股份有限公司 一种特立帕肽杂质f的合成方法
CN112940104A (zh) * 2019-12-10 2021-06-11 深圳翰宇药业股份有限公司 一种特立帕肽杂质f
CN113135979A (zh) * 2020-01-18 2021-07-20 深圳市健翔生物制药有限公司 一种肽的固相合成方法
CN114685616A (zh) * 2020-12-31 2022-07-01 哈尔滨三联药业股份有限公司 醋酸曲普瑞林的合成方法
CN114685616B (zh) * 2020-12-31 2024-03-29 哈尔滨三联药业股份有限公司 醋酸曲普瑞林的合成方法
CN113461775A (zh) * 2021-08-23 2021-10-01 成都诺和晟泰生物科技有限公司 一种多肽化合物的制备方法
CN113755475A (zh) * 2021-10-12 2021-12-07 西南医科大学附属中医医院 一种ace2环肽模拟物及其在抑制新冠假病毒中的用途
CN113755475B (zh) * 2021-10-12 2024-06-11 西南医科大学附属中医医院 一种ace2环肽模拟物及其在抑制新冠假病毒中的用途
CN114736286A (zh) * 2021-12-27 2022-07-12 杭州诺泰澳赛诺医药技术开发有限公司 一种多肽杂质单硫化物的合成方法
CN114716515A (zh) * 2022-03-31 2022-07-08 深圳深创生物药业有限公司 一种多肽类似物及其制备方法和应用

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