Preparation method of high-purity oritavancin key intermediate A82846B

A high-purity, intermediate technology, applied in the preparation methods of peptides, chemical instruments and methods, organic chemistry, etc., can solve the problems of increasing operation steps and production costs, threats to the health of operators, and low adsorption efficiency of cationic resins, etc. Achieve the effect of being beneficial to quality control, overcoming low adsorption efficiency and high product yield

Active Publication Date: 2017-07-07
CHONGQING QIANTAI BIOLOGICAL MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In summary, the existing technologies generally have the following disadvantages: 1) The total yield is low, which affects industrial production efficiency; 2) Multi-step resin separation and other processes are required, which increases operating steps and production costs, and requires more Organic solvents pose a threat to the health of operators and cause pollution to the environment, and are not suitable for industrialized large-scale production; 3) the methods disclosed in the prior art all involve the use of cation exchange resins for adsorption. Experimental studies have found that the adsorption efficiency of cationic resins is very low, and the phenomenon of adsorption failure and leakage adsorption occurs, resulting in a decrease in yield; moreover, the pigment cannot be removed

Method used

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  • Preparation method of high-purity oritavancin key intermediate A82846B
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  • Preparation method of high-purity oritavancin key intermediate A82846B

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Oritavancin key intermediate A82846B was fermented in a 40L tank, and the fermentation unit was 650ug / ml (26g). The pH of the fermentation broth was adjusted to 10.5 with NaOH solution, stirred for 2 hours, and then centrifuged in a tube to obtain 36.8L of centrifuge (HPLC See atlas figure 1 ), the unit is 630ug / ml (23g). Adjust the pH of the centrifugate to 9.3, and then introduce it into HP20 adsorption resin (with a specification of Ф25*75), with a filling volume of 3000ml and a flow rate of 1BV / h. After purifying 9L of resin with water with a pH of 8, desorb it with 8L of 1% acetic acid aqueous solution at a flow rate of 2500ml / h. See figure 2 ), and then the desorbed mixture was concentrated by nanofiltration to a unit of 39102ug / ml (21.9g).

[0044] Introduce the concentrated solution into a well-balanced C18 column (with a specification of Ф25*75), and use acetonitrile: 0.5% NH 4 h 2 PO 4 =2:98 (v / v) for elution, the flow rate is 1500ml / h, and the componen...

Embodiment 2

[0051] The key intermediate of oritavancin A82846B was fermented in a 33L tank, and the fermentation unit was 340ug / ml (11.22g). The fermentation broth was adjusted to pH=10.3 with NaOH solution, stirred for 2 hours, and plate-and-frame pressure filtration was performed to obtain 35L of press-filtered liquid, the unit It is 310ug / ml (10.85g). The press filtrate was adjusted to pH=9.2, and then introduced into LX18 adsorption resin. After purifying 9L of resin with water with a pH of 8, use 8L of 0.5% acetic acid aqueous solution for desorption, and mix the components with higher concentration to form a desorption mixture, and then perform nanofiltration on the desorption mixture, and concentrate it to a unit of 35000ug / ml.

[0052] Introduce the concentrated solution into a well-balanced C18 column, and use the eluent (acetonitrile: 0.5% NH 4 h 2 PO 4 =3:97 (v / v)) to elute, collect components with a purity of more than 90%, and obtain a secondary desorption mixture. The s...

Embodiment 3

[0055] The key intermediate of oritavancin A82846B was fermented in 28.1L tank, and the fermentation unit was 420ug / ml (11.80g). The fermentation liquid was adjusted to pH=10.6 with NaOH solution, stirred for 2 hours and then centrifuged to obtain 25.5L centrifuge liquid, the unit was 432ug / ml (11.10g). Adjust the pH of the centrifuge to 9.5, divide the part into 4 equal volumes (5.5 L each, each containing 2.35 g of the product, and a purity of 25.69%), and introduce them into 4 regenerated and balanced resin columns (HP20, LX18, XAD1600, HZ816), then purify the resin column with 1L of purified water, and elute with 1.5% acetic acid aqueous solution. The components with higher concentration were collected to form a desorption mixture, which was sent for inspection, and the results of various purity tests were shown in Table 2:

[0056] Table 2: Primary purification effect of various resins

[0057] Resin name Resin load Loading amount The amount of product c...

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Abstract

The invention provides a preparation method of high-purity oritavancin key intermediate A82846B. The preparation method comprises the following steps: separating the oritavancin key intermediate A82846B from a fermented solution, first adjusting a pH, purifying by virtue of macroporous resin, then purifying by virtue of inversed phase chromatography, and finally crystallizing to obtain the high-purity A82846B. The method adopted by the invention is simple in operation, less in consumption of organic solvent, and capable of greatly reducing the generation of waste liquid; and moreover, the defects in the prior art that the adsorption efficiency of cation macroporous resin is low and the product yield is reduced due to the leaked adsorption can be overcome, and the preparation method is suitable for the industrialized production.

Description

technical field [0001] The invention belongs to the technical field of industrial microorganisms, and more specifically relates to a method for preparing a high-purity oritavancin key intermediate A82846B. Background technique [0002] Glycopeptide antibiotics are a large class of substances produced by microorganisms, or produced and partially modified by microorganisms. Among the glycopeptides discovered in the 1990s are those known as A82846A (also known as ereomomycin), A82846B (also known as chloroorienticinA), A82846C (also known as orienticinC) and orienticin A . A variety of modifications have been made to naturally occurring glycopeptides, one of which is the reductive alkylation of reactive amines in glycopeptides. Oritavancin is a second-generation glycopeptide antibiotic developed on the basis of the first-generation glycopeptide antibiotic vancomycin, and its mechanism of action is to inhibit the bacterial cell wall by blocking the transglycosidation of peptid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K9/00C07K1/36C07K1/34C07K1/30C07K1/20C07K1/16
CPCC07K9/008
Inventor 杨久林郭明刘省伟张宏福唐恒肖红亮徐星灿袁建栋
Owner CHONGQING QIANTAI BIOLOGICAL MEDICINE
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