Cyclization preparation method of compounds related with polymyxin B

A polymyxin and compound technology, which is applied in the field of cyclization preparation of polymyxin B related compounds, can solve the problems of unsuitability for large-scale production, low yield, poor stability of polymyxin B, and the like, and achieves good medicine. The effect of using prospects, reducing costs, and improving yields

Pending Publication Date: 2020-07-14
TLC NANJING PHARMA RANDD CO LTD
View PDF3 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the poor stability of polymyxin B, the existing synthetic method of polymyxin B is prepared by fermentation, and the obtained is a mixture, and there are few reports in the literature that can obtain a single polymyxa Prime B
Patents CN201110385129 and CN201310506594 all report that polymyxin B is prepared by fermentation, but all obtained are mixtures, and the yield is low, which is not suitable for large-scale production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Cyclization preparation method of compounds related with polymyxin B
  • Cyclization preparation method of compounds related with polymyxin B
  • Cyclization preparation method of compounds related with polymyxin B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The cyclization preparation method of polymyxin B1, the synthesis process is as follows figure 1 As shown, it specifically includes the following steps:

[0035] step one:

[0036] CH 3 CH 2 (CH 3 )CH(CH 2 ) 4 Synthesis of CO-Dab(Boc)-Thr(tBu)-Dab(Boc)-Dab-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr(tBu)-OH:

[0037] 1) Add 10 g of CTC-Resin with a degree of substitution of 0.4 to 0.6 mmol / g into the polypeptide reactor, add 2 g of Fmoc-Thr(tBu)-OH and 10 ml of DIEA to react for 2 hours, remove the reaction liquid, and wash twice with DMF; After removing the Fmoc protection, wash twice with DMF, once with DCM, and twice with DMF;

[0038] 2) Then Fmoc--Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab- OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, CH 3 CH 2 (CH 3 )CH(CH 2 ) 4 COOH, the reaction time is 2 hours, the deprotection time is 0.5 hours, and the end point of the reaction is determined b...

Embodiment 2

[0057] The cyclization preparation method of polymyxin B1 comprises the following steps:

[0058] step one:

[0059] CH3CH2(CH3)CH(CH2)4CO-Dab(Boc)-Thr(tBu)-Dab(Boc)-Dab-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr( Synthesis of tBu)-OH:

[0060] 1) Add 10 g of CTC-Resin with a degree of substitution of 0.4 to 0.6 mmol / g into the polypeptide reactor, add 2 g of Fmoc-Thr(tBu)-OH and 10 ml of DIEA to react for 2 hours, remove the reaction solution, and wash twice with DMF; After removing the Fmoc protection, wash twice with DMF, once with DCM, and twice with DMF;

[0061] 2) Then Fmoc--Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab- OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, CH3CH2(CH3)CH(CH2)4COOH, reaction time Both are 2 hours, the deprotection time is 0.5 hours, and the reaction end point is determined by the ninhydrin method; after the reaction, wash twice with DMF, once with DCM, and twice with DMF;

...

Embodiment 3

[0080] The cyclization preparation method of polymyxin B1 comprises the following steps:

[0081] step one:

[0082] CH3CH2(CH3)CH(CH2)4CO-Dab(Boc)-Thr(tBu)-Dab(Boc)-Dab-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr( Synthesis of tBu)-OH:

[0083] 1) Add 10 g of CTC-Resin with a degree of substitution of 0.4 to 0.6 mmol / g into the polypeptide reactor, add 2 g of Fmoc-Thr(tBu)-OH and 10 ml of DIEA to react for 2 hours, remove the reaction solution, and wash twice with DMF; After removing Fmoc protection, wash twice with DMF, once with DCM, and twice with DMF

[0084] 2) Then Fmoc--Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab- OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, CH3CH2(CH3)CH(CH2)4COOH, reaction time Both are 2 hours, the deprotection time is 0.5 hours, and the reaction end point is determined by the ninhydrin method; after the reaction, wash twice with DMF, once with DCM, and twice with DMF;

[0085]...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses a cyclization preparation method of compounds related with polymyxin B. A reaction operation of the cyclization preparation method is easy, aftertreatment is convenient, the yield is high, and the cyclization preparation method has a very high reference value in synthesis of single compounds B1, B1-I, B2 and B3 of the polymyxin B. By preparing each single compound of the polymyxin B, an important basis is provided for scientific evaluation, pharmacological researches, pharmacokinetics and the like of the polymyxin B, and deeper researches on a metabolic process of the polymyxin B in a human body and the pharmacokinetics are facilitated, so that the cyclization preparation method has better pharmaceutical prospects.

Description

technical field [0001] The invention relates to a synthesis method of polypeptide antibiotics, in particular to a preparation method of cyclization of polymyxin B related compounds. [0002] technical background [0003] Polymyxin is a group of polypeptide antibiotics produced by bacillus polymyxa. The English name is Polymyxin. B1(C 56 h 98 N 16 o 13 ) and B2(C 55 h 96 N 16 o 13 ) in the majority, and the content of polymyxin B1 is the most, generally reaching more than 50%. [0004] Polymyxin B has inhibitory or bactericidal effects on Gram-negative bacilli, such as Escherichia coli, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, acidophilus, pertussis and Shigella. Clinically, it is mainly used for infections caused by sensitive bacteria and urinary system infections caused by Pseudomonas aeruginosa, as well as eye, trachea, meningitis, sepsis, burn infections, and skin and mucous membrane infections. [0005] Due to the poor stability of polymy...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07K7/62C07K1/08C07K1/06C07K1/04C07K1/02C07K1/16
CPCC07K7/62
Inventor 童巍王洪飞
Owner TLC NANJING PHARMA RANDD CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap