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Improved preparation method of telavancin or salt thereof

A technology of acid addition salts and compounds, applied in the field of drug synthesis, can solve problems such as short retention time and difficult removal

Active Publication Date: 2019-01-15
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The bis-Mannich by-product has similar properties to the main component telavancin, and the retention time in the high performance liquid chromatogram is relatively close, so it is difficult to remove in the purification process

Method used

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  • Improved preparation method of telavancin or salt thereof
  • Improved preparation method of telavancin or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The preparation of embodiment 1 compound I

[0050]

[0051] Add 40L of N,N-dimethylformamide and 4kg of vancomycin hydrochloride into a 100L reaction tank, stir for 10 minutes, control the temperature of the feed liquid at 0-10°C, and add 1.6L of N,N-diisopropyl Ethylamine, after dropping, stirred for 10 minutes, controlled the temperature of the feed liquid at 0-10°C, and slowly added 1.6 kg of decyl (2-oxoethyl) carbamic acid 9H-fluorene-9-methyl ester (compound of formula II) After the addition is complete, the temperature of the feed liquid is controlled at 5±5° C. and the reaction is stirred for 24 hours. Samples are tracked and detected by HPLC until the end of the reaction.

[0052] Add 16L of anhydrous methanol, control the temperature at 0-10°C, slowly add 1.1L of trifluoroacetic acid dropwise to the feed liquid, after dropping, keep the feed liquid temperature at 5±5°C and stir for 1 hour, add 0.4kg of borane-tert For the butylamine complex, keep the temp...

Embodiment 2

[0054] The preparation of embodiment 2 compound III

[0055]

[0056] Add 22L of N,N-dimethylformamide and 6.16kg of the compound of formula I into a 50L reaction tank, stir for 10 minutes, cool down to 10-20°C, slowly add 1.13L of diethylamine dropwise to the feed solution, and dropwise, Raise the temperature, control the temperature of the feed solution to 23-33°C, stir and react for 2 hours, take samples, and track and detect by HPLC until the end of the reaction. Filter and collect the filtrate.

[0057] Add 327L of isopropyl ether to a 500L reactor, control the temperature at 10-20°C, slowly add the collected filtrate dropwise to the isopropyl ether while stirring, and keep the temperature of the material liquid at 10-20°C to stir and crystallize for 2 hours Above, after the crystallization is completed, shake off the filter, and the filter cake is beaten twice with 65L isopropyl ether on average, and dried under reduced pressure at 25±5°C for more than 12 hours to ob...

Embodiment 3

[0058] The preparation of embodiment 3 compound IV

[0059]

[0060] Preparation of aminomethylphosphonic acid solution: at room temperature, add 13L of purified water into a 20L glass reaction tank, add 1.5kg of aminomethylphosphonic acid under stirring, stir for 10 minutes, slowly add N,N-diisopropylethyl Amine 2.17L, stirred until the material solution is clear, cooled to 0-5°C, set aside.

[0061] In a 200L reaction tank, add 35.2L of acetonitrile, 30.4L of purified water, and 5.02kg of the compound of formula III, stir for 10 minutes, cool down, control the temperature of the feed liquid at -15~-5°C, and slowly add 4.48L of N , 4.48L of N-diisopropylethylamine, after dropping, stir until the material solution is clear. Control the feed liquid temperature at -15 to -5°C, add the above aminomethylphosphonic acid solution dropwise to the solution of the compound of formula III, control the feed liquid temperature at -15 to -5°C and stir for 10 minutes. Control the tempe...

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Abstract

Belonging to the drug synthesis field, the invention in particular relates to an improved preparation method of telavancin or a salt thereof. The preparation method adjusts the feeding sequence of Mannich reaction, controls the reaction temperature, greatly shortens the reaction time, and significantly reduces the content of bis-Mannich by-product. In addition, an intermediate compound III obtained by post-treatment with a low boiling point solvent is easy in industrial operation and has purity up to 95% or more.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an improved preparation method of telavancin or its hydrochloride. Background technique [0002] Telavancin hydrochloride (Telavancin) is a semi-synthetic lipoglycopeptide antibiotic jointly developed by Theravance and Clinigen. The trade name is Vibativ. It was first approved by the U.S. Food and Drug Administration (FDA) on September 11, 2009. It was then approved for marketing by the European Medicines Agency (EMA) on September 2, 2011. Telavancin hydrochloride inhibits the synthesis of bacterial cell walls by interfering with the polymerization and cross-linking of peptidoglycan, and has the barrier function of binding to bacterial cell membranes and destroying membranes. It is suitable for complex skin and skin diseases caused by sensitive Gram-positive bacteria. Skin structural infection (cSSSI) and hospital-acquired and ventilator-associated bacterial pneumonia (HABP / VABP) c...

Claims

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Application Information

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IPC IPC(8): C07K9/00C07K1/02C07K1/30
CPCC07K9/008
Inventor 周舟张喜全张爱明
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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