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Rifamycin-like vonimulin hybrid antibiotic and preparation method thereof

A technology of rifamycin and warnimulin, which is applied in the field of chemical synthesis of drugs, can solve the problems of insufficient ester bond and short half-life, and achieve good therapeutic effect, enhanced antibacterial effect and stable linking group

Inactive Publication Date: 2016-02-24
WUHAN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But its shortcoming is that the half-life is short, which may be the reason why the attached ester bond is not strong enough

Method used

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  • Rifamycin-like vonimulin hybrid antibiotic and preparation method thereof
  • Rifamycin-like vonimulin hybrid antibiotic and preparation method thereof
  • Rifamycin-like vonimulin hybrid antibiotic and preparation method thereof

Examples

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Effect test

preparation example Construction

[0023] The preparation process of the rifamycin class warnemulin hybrid antibiotic is as follows:

[0024] 1) Dissolve rifamycin s-sodium salt in the solvent DMF and mix evenly, add concentrated sulfuric acid to acidify for 0.5h by mole rifamycin s-sodium salt:concentrated sulfuric acid=1.9~2:1, then add dihydroxy Terbutylamine, dihydroxyterbutylamine and rifamycin S-sodium salt with a molar ratio of 1.5 to 1.9:1, heated to 35 to 50°C, kept warm for 2 hours, cooled, added a precipitant to stand still, filtered and washed with water to obtain Intermediate oxazine rifamycin Ⅱ;

[0025] 2) Mix the intermediate oxazine rifamycin II and anhydrous piperazine in a protic solvent at a molar ratio of 1:1.2-1.5, react at 45-60°C for 2 hours, and obtain the intermediate 3-formazine by column chromatography Acyl rifamycin III;

[0026] 3) Add warnemulin hydrochloride into water to dissolve completely, adjust the pH value to 8-9 with an acid-binding agent, filter, wash with water, and dr...

Embodiment 1

[0034] According to the above steps, the specific process and parameters are determined as follows:

[0035] In step 1), acidify by mole bifamycin s-sodium salt: concentrated sulfuric acid=1.9:1; molar ratio dihydroxyterbumine: rifamycin s-sodium salt=1.5:1 feed; wherein, rifampicin The concentration of mycin s-sodium salt in the solvent DMF was 0.02 g / mL.

[0036] In step 2), the intermediate oxazine rifamycin II: anhydrous piperazine is added according to the molar ratio of 1:1.2. The protic solvent is ethanol.

[0037] Step 3) in, acid binding agent selects saturated NaHCO for use 3 solution.

[0038] In step 4), the intermediate 3-formyl rifamycin III: the intermediate vornimulin IV is added according to the molar ratio of 1:1.1; the intermediate 3-formyl rifamycin III is dissolved in the solvent tetrahydrofuran at a concentration of 0.025g / mL.

[0039]The target product I can be obtained. Dissolve it in 1.2% ethanol aqueous solution to prepare a 0.5 mg / L solution, p...

Embodiment 2

[0041] According to the above steps, the specific process and parameters are determined as follows:

[0042] In step 1), acidify by mole bifamycin s-sodium salt: concentrated sulfuric acid=2:1; molar ratio dihydroxyterbumine: rifamycin s-sodium salt=1.9:1 feed; wherein, rifampicin The concentration of mycin s-sodium salt in the solvent DMF was 0.05 g / mL.

[0043] In step 2), the intermediate oxazine rifamycin II: anhydrous piperazine is added according to the molar ratio of 1:1.2. The protic solvent is ethanol.

[0044] Step 3) in, acid binding agent selects saturated NaHCO for use 3 solution.

[0045] In step 4), the intermediate 3-formyl rifamycin III: the intermediate vornimulin IV is added according to the molar ratio of 1:1.1; the intermediate 3-formyl rifamycin III is dissolved in the solvent tetrahydrofuran at a concentration of 0.0725g / mL.

[0046] The target product I can be obtained. Dissolve it in 1.2% ethanol aqueous solution to prepare a 0.5 mg / L solution, p...

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Abstract

The invention discloses a rifamycin and valnemulin hybrid antibiotic compound and a preparation method thereof. The rifamycin and valnemulin hybrid antibiotic has a structure as shown in the formula (I). The preparation method comprises the following steps: (1) adding concentrated sulfuric acid into a DMF (Dimethyl Formamide) solution of rifamycin s and sodium salt to acidize for 0.5h, and then, dropwise adding dihydroxy-tert-butylamine to react to obtain an intermediate, i.e., oxazine rifamycin II; (2) mixing the intermediate, i.e., the oxazine rifamycin II and piperazine anhydrous in a protonic solvent, and reacting to obtain an intermediate, i.e., 3-formyl rifamycin III; and (3) mixing and dissolving the 3-formyl rifamycin III and valnemulin in a solvent, stirring at the temperature of 15-30 DEG C for 2h under the protection of nitrogen gas, and cooling to obtain the rifamycin and valnemulin hybrid antibiotic. Two drug molecules with different action mechanisms are connected together, the combination way of the rifamycin and valnemulin hybrid antibiotic compound is similar to that of a prodrug with dual functions, the linking group is stable, and the rifamycin and valnemulin hybrid antibiotic compound can take a very good treating effect.

Description

technical field [0001] The invention relates to the field of chemically synthesized drugs, in particular to a rifamycin-like warnemulin hybrid antibiotic compound and a preparation method thereof. Background technique [0002] Rifamycin (rifamycins) is a complex isolated from the metabolites of Streptomycesmediterranoi by Sensi et al. in 1959, and then separated A, B, C, D, E and so on. In 1962, rifamycin B was chemically transformed into rifamycin SV, and was first used clinically. Due to its poor oral absorption, mepirifamycin, namely rifampicin, was screened from multiple derivatives of 3-formylrifamycin SV. This product can be administered orally, and has good curative effect, but it is easy to cause bacterial strains to develop drug resistance, the effective time is short, and the infection activity of Mycobacterium avium complex (MAC) in AIDS complications is relatively low, and the toxicity is relatively high. The course and lesions of tuberculosis vary greatly. Lon...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/08A61P31/04
CPCC07D498/08
Inventor 祝宏孙冬冬胡国元陈默
Owner WUHAN INSTITUTE OF TECHNOLOGY
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