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Preparation method of high-purity tigecycline

A tigecycline, high-purity technology, applied in the field of preparation of high-purity tigecycline, can solve the problems of large amount of solvent used, unstable intermediates, epimerization, etc., and achieve reasonable hydrogenation pressure, Effects of shorter purification process time and reduced solvent consumption

Inactive Publication Date: 2013-04-17
HUNAN SAILONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Tigecycline in the prior art has at least the following problems: 1. The hydrogen pressure in the reduction process is unreasonable, and the optimal pressure range is not disclosed; 2. The amount of solvent used in the refining process of the final product tigecycline is too large, which leads to the treatment of three wastes Difficult; 3. The purity of the product is not high, the purification process is unreasonable, and the incidence of adverse reactions caused by certain impurities is relatively high; 4. When the raw materials are made into freeze-dried powder injections, there are no problems of easy oxidation and epimerization Fundamental solution; 5. The intermediate of tigecycline is very unstable, and the process time is too long

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0043] Under nitrogen protection, at 0°C, dissolve 10.0 g of minocycline hydrochloride in 28 ml (51.52 g) of concentrated sulfuric acid; stir to exhaust the HCl in the system; slowly add 1.9 g of fuming nitric acid dropwise, and stir for 5 hours; after the reaction , the reaction solution was slowly added to isopropanol / n-heptane (mass ratio 7:1) mixed solution 250g, stirred at room temperature for 1 hour; filter, filter cake with isopropanol / n-heptane (mass ratio 7:1) The mixture was washed (16 g x 3 times) and drained; the filter cake was dried under reduced pressure at 40°C for 5 hours to obtain 12.66 g of yellow powder with a yield of 89.5%.

Embodiment 2

[0045] Under nitrogen protection, at 0°C, dissolve 4.85kg of minocycline hydrochloride in 15L of concentrated sulfuric acid; stir to exhaust the HCl in the system; slowly add 1.07kg of fuming nitric acid dropwise, and stir at 0°C for 4.5-5.5 hours; after the reaction , slowly add the reaction solution to isopropanol / n-heptane (volume ratio 7:1) mixed solution 160L, stir at room temperature for 1-1.5 hours; filter, filter cake with isopropanol / n-heptane (volume ratio 7:1 1) The mixture was washed (10 L x 3 times), and drained; the filter cake was dried under reduced pressure at 40°C for 5 hours to obtain 6.24 kg of yellow powder, with a yield of 90.9%.

Embodiment 3

[0047] Basically the same as Example 2, the difference is that the dispersant and crystallizer are isopropanol / n-heptane / cyclohexane (volume ratio 7:1:4), and finally 6.49kg of yellow powder is obtained, with a yield of 94.5% .

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Abstract

The invention relates to a preparation method of high-purity tigecycline, which comprises the steps of taking minocycline hydrochloride as an initial raw material, and conducting nitration, hydrogenation, acid conversion, amidation and purification. According to the preparation method, the hydrogenation pressure is reasonable; time used for a purification technology is shorter; the use amount of a solvent is reduced by more than 30%; when the prepared high-purity tigecycline with the purity of over 99.5% is used for a complicated skin and skin texture infected patient, compared with the existing tigecycline, the incidences of nausea and vomit are decreased to 15.1% and 10.2% respectively; and when tigecycline is used for treating a complicated intra-abdominal infected patient, the incidences of the nausea and the vomit are decreased to 15.4% and 11.3% respectively.

Description

technical field [0001] The invention belongs to the field of glycylcycline drugs, in particular to a method for preparing high-purity tigecycline. Background technique [0002] Tigecycline (tigecycline), chemical name: (4S, 4aS, 5Ar, 12aS)-4,7-bis(dimethyl)-9-[(tert-butylamino)acetamido]-3,10, 12,12a-tetrahydroxy-1,11-dioxo-1,4,4a, 5,5a, 6,11,12a-octahydrotetracene-2-carboxamide, also known as 9-tert-butylglycerol Aminoaminocycline or Dingglyminocycline was approved by the FDA in June 2005 by Wyeth (WYETH). It is the first glycylcycline antibiotic approved for marketing. Its molecular structure is as follows: [0003] [0004] Tigecycline: C 29 h 39 N 5 o 8 [0005] MW: 585.65g / mol [0006] The Chinese patents on tigecycline for which Wyeth claims priority include: [0007] In CN92112130 in 1992, the patent was prepared from minocycline as a starting material through nitration, reduction, acid conversion, amidation and other steps. The reaction process is as follo...

Claims

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Application Information

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IPC IPC(8): C07C237/26C07C231/14
Inventor 李剑峰庞振坤
Owner HUNAN SAILONG PHARMA
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