Synthetic intermediate of pleuromutilin antibiotics and synthetic method thereof

A technology for pleuromutilin and a synthesis method, which is applied to the synthetic intermediates of pleuromutilin antibiotics and the field of synthesis thereof, can solve the problems of destruction selectivity, the inability of mtriptyline to be used for the synthesis of antibiotics, etc., and achieves cost controllable Effect

Inactive Publication Date: 2016-03-09
宁夏泰瑞制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the synthesis of tiamulin is mainly obtained by modifying the two active hydroxyl groups on the inner core of mutriptyline, but since mutriptyline itself has two non-selective hydroxyl groups, if pleuromutilin is directly hydrolyzed to obtain mutriptyline , will destroy its selectivity, making mutriptyline unusable for antibiotic synthesis
For example, in the traditional synthesis process of tiamulin, since the 7-OH of pleuromutilin itself has a glycolic acid side chain, it is necessary to use 2-diethylaminoethanethiol, which is controlled by hazardous chemicals, to form sulfur with it. ether reaction

Method used

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  • Synthetic intermediate of pleuromutilin antibiotics and synthetic method thereof
  • Synthetic intermediate of pleuromutilin antibiotics and synthetic method thereof
  • Synthetic intermediate of pleuromutilin antibiotics and synthetic method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Take 1000kg of pleuromutilin crystals, put them into a 10m3 glass-lined reactor, add 4000kg of pyridine, stir to dissolve, cool down to 0°C, put in 300kg of di-tert-butyl dicarbonate and 50kg of tetrahydrofuran, and keep warm for 3 hours. After the reaction was completed, it was concentrated and distilled under reduced pressure until a dry solid was obtained. Add 4000kg of water to the tank, adjust the pH to 10.5 with 20% sodium hydroxide, heat up to 40°C, hydrolyze for 20 hours, add 2000kg of methyl isobutyl ketone according to the ratio of water: methyl isobutyl ketone = 2:1 base ketone, keep warm at 40°C for extraction, and keep the organic phase after the extraction is completed. In the state of heat preservation, slowly add 250kg of acetic anhydride dropwise to the organic phase, and keep the reaction for 3 hours to obtain a methyl isobutyl ketone solution of double-protected mutriptyline, with a content of 37.68% and a yield of 90.44%, which can be directly used f...

Embodiment 2

[0023] Take 200kg of pleuromutilin crystals, put them into a 6m3 glass-lined reactor, add 900kg of piperidine, stir to dissolve, cool down to 5°C, put in 50kg of di-tert-butyl dicarbonate and 12kg of tetrahydrofuran, and keep warm for 4 hours. After the reaction was completed, the mixture was concentrated by raising the temperature and distilled under reduced pressure until a dry solid was obtained. Add 1000kg of water to the tank, adjust the pH to 11.0 with 15% potassium hydroxide, heat up to 42°C, hydrolyze for 22 hours, add 400kg of methyl isobutyl ketone according to the ratio of water:methyl isobutyl ketone=2.5:1 Ketones were kept at 42°C for extraction, and the organic phase was retained after the extraction was completed. In the state of heat preservation, 40 kg of acetic anhydride was slowly added dropwise to the organic phase, and the heat preservation reaction was carried out for 4 hours to obtain a methyl isobutyl ketone solution of double-protected mutriptyline wit...

Embodiment 3

[0025] Take 100g of pleuromutilin crystals, put them into a 1000L three-necked flask, add 500g of diethylamine, stir to dissolve, cool down to 2°C, put in 25g of di-tert-butyl dicarbonate and 7.5g of tetrahydrofuran, and keep warm for 5 hours. After the reaction was completed, the mixture was concentrated by raising the temperature and distilled under reduced pressure until a dry solid was obtained. Add 450g of water to the tank, adjust the pH to 10.7 with 20% ethanol / sodium ethylate, heat up to 44°C, hydrolyze for 21 hours, add 150g of methyl isobutyl ketone according to the ratio of water: methyl isobutyl ketone = 3:1 Butyl ketone, keep warm at 44°C for extraction, keep the organic phase after the extraction is completed. In the state of heat preservation, 30 g of acetic anhydride was slowly added dropwise to the organic phase, and the heat preservation reaction was carried out for 5 hours to obtain a methyl isobutyl ketone solution of double-protected mutriptyline with a co...

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Abstract

The invention relates to a synthetic intermediate of pleuromutilin antibiotics and a synthetic method thereof. The synthetic intermediate and the synthetic method have the beneficial effects that pleuromutilin is used as a synthetic precursor; double protection Mutilin capable of selectively modifying two active hydroxyl respectively is obtained after a molecule-glycolic acid is removed through hydrolysis; such 4,7-OH double protection Mutilin can be used for further synthesizing tiamulin fumarate or other pleuromutilin antibiotics as needed and is a good semi-synthetic antibiotic precursor; double protection Mutilin is synthesized with pleuromutilin; the yield is between 85% and 96% according to changes of selected raw materials and process ratios; the organic amine recovery rate is more than 84%; the cost is controllable.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, in particular to a synthetic intermediate of pleuromutilin antibiotics and a synthetic method thereof. Background technique [0002] Pleuromutilin antibiotics are a group of relatively mature semi-synthetic veterinary antibiotics: among them, tiamulin and warnimulin are effective against a variety of Gram-positive cocci, including most staphylococci and streptococci, as well as a variety of mycoplasma and Certain spirochetes have good antibacterial activity, and tiamulin fumarate is also a widely used pleuromutilin antibiotic. At present, the synthesis of tiamulin is mainly obtained by modifying the two active hydroxyl groups on the inner core of mutriptyline, but since mutriptyline itself has two non-selective hydroxyl groups, if pleuromutilin is directly hydrolyzed to obtain mutriptyline , will destroy its selectivity, so that mutriptyline cannot be used for antibiotic synthesis. For exam...

Claims

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Application Information

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IPC IPC(8): C07C69/28C07C67/08
CPCC07C69/28C07C67/03C07C67/08C07C67/297C07C69/675
Inventor 赵伯龙
Owner 宁夏泰瑞制药股份有限公司
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