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A new method for preparing retapamulin

A technology of retapamulin and compounds, which is applied in the new field of preparation of retapamulin, can solve the problems of increased impurity research of pharmaceutical manufacturers, affecting the quality of retapamulin products, complex impurity spectrum of fermentation products, etc., and facilitates industrialization Production, clear impurity spectrum, cheap and easy-to-obtain reagents

Active Publication Date: 2019-11-12
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Regarding the preparation method of retapamulin, the starting materials used in the existing methods are all pleuromutilin, which is a bacterial fermentation product and is easily subject to monopoly control. Moreover, because the impurity s

Method used

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  • A new method for preparing retapamulin
  • A new method for preparing retapamulin
  • A new method for preparing retapamulin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1 Preparation of important intermediate (compound shown in formula III)

[0063] The chemical name of the compound shown in formula III is (3aS, 4R, 6S, 8R, 9R, 9aR, 10R)-4,6,9,10-tetramethyloctahydro-8-hydroxyl-1-methoxy-6 - Vinyl-3a,9-propane-3aH-cyclopentacyclooctan-5-one.

[0064] Add 1.21kg of the compound of formula I and 7.5L of anhydrous methanol into a 50L double-layer glass reactor, protect it under nitrogen, dissolve it under stirring, add 1.175kg of trimethyl orthoformate, cool down; start adding concentrated sulfuric acid dropwise at 0-10°C, Keep warm at <15°C, drop it for about 1.0-1.5 hours, a total of 602.7g of concentrated sulfuric acid; heat up to an internal temperature of 45-50°C to react, and the reaction is completed at about 6.0-7.0°C, stop heating, lower the temperature to 10-20°C, and start dripping 50% aqueous sodium hydroxide solution, temperature control <30°C, drop in about 1.0 hour, add a total of 2.164kg of 50% aqueous sodium h...

Embodiment 2

[0065] The preparation of embodiment 2 formula Ⅳ compound

[0066] The chemical name of the compound of formula IV is (3aS, 4R, 6S, 8R, 9R, 9aR, 10R)-4,6,9,10-tetramethyloctahydro-8-hydroxy-1-methoxy-6-ethylene Base-3a,9-propane-3aH-cyclopentacyclooctane-5-one-8-chloroacetate.

[0067] Add 4.8L of methyl tert-butyl ether and 418.2g of the compound of formula III into a 10L double-layer glass reactor, stir to dissolve, and the stirring speed is 200-300 rpm; the high and low temperature cycle machine cools down, and the temperature is controlled at -10 to - Pyridine (445.0g in total) was added dropwise at 15°C, and the dropwise addition was completed in about 15-20 minutes; the temperature was lowered, and the temperature was controlled at -20~-25°C, and the mixed solution of chloroacetyl chloride and 1.5L methyl tert-butyl ether was added dropwise, and the reaction A large amount of yellow-white solids are formed in the kettle, and the dropwise addition is completed in about 2...

Embodiment 3

[0068] The preparation of embodiment 3 formula V compound

[0069] The chemical name of the compound of formula V is [[(3-external)-8-methyl-8-azabicyclo[3.2.1]octane]-3-mercapto]-(3aS, 4R, 6S, 8R, 9R ,9aR,10R)-4,6,9,10-Tetramethyl-1-methoxy-6-vinyl decahydro-1-oxo-3a,9-propane-3aH-cyclopentacyclooctane- 5-keto-8-acetate

[0070] Add 205.5g of the compound of formula IV, 2.05L of methyl tert-butyl ether, 116.2g of exo-tropine-3-mercaptan hydrochloride, 20.5g of TBAB in the 10L reactor, and the stirring speed is controlled at 300-400 rpm, Control the temperature at 10-20°C and add sodium hydroxide aqueous solution (100g sodium hydroxide dissolved in 400mL water) dropwise, the dropwise addition is completed in about 1.0-1.5 hours, then raise the temperature to 20-30°C for 1.0-1.5 hours to complete the reaction, add 2.0 L of drinking water, separated after stirring, the organic layer was washed once with 2.0L 10% ammonium chloride aqueous solution, and then washed once with 2.0...

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Abstract

The invention provides a novel method for preparing an externally applied antibacterial medicine retapamulin. According to the method, tiamulin is used as an initial raw material, and is subjected to five steps of physical chemical reactions and a purifying process to prepare the retapamulin; the initial raw material has controllable quality, and is suitable for new medicine research, development and application; and the method is simple in operation, controllable in condition, low in preparation cost and convenient for industrial production, and is a great innovation for the retapamulin synthesis method.

Description

technical field [0001] The present invention relates to the preparation method of a class of important antibiotic medicine for external use, specifically, relate to the compound name [[(3-external)-8-methyl-8-azabicyclo[3.2.1]octane] -3-Mercapto]-,(3aS,4R,5S,6S,8R,9R,9aR,10R)-4,6,9,10-tetramethyl-5-hydroxy-6-vinyl decahydro-1- Preparation method of oxo-3a,9-propane-3aH-cyclopentacyclooctane-8-acetate. Background technique [0002] Retapamulin, chemical name [[(3-exo)-8-methyl-8-azabicyclo[3.2.1]octane]-3-mercapto]-,(3aS,4R,5S,6S ,8R,9R,9aR,10R)-4,6,9,10-Tetramethyl-5-hydroxy-6-vinyl decahydro-1-oxo-3a,9-propane-3aH-cyclopentacycline Alkane-8-acetate, a semi-synthetic truncated beifenglin antibiotic, can bind to a unique site on the bacterial ribosomal 50S subunit, block the ribosomal P region, and interfere with peptidyltransferase activity, thereby selectively inhibiting the synthesis of bacterial proteins and achieving antibacterial effects. On April 17, 2007, the FDA ...

Claims

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Application Information

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IPC IPC(8): C07D451/04C07C323/52C07C319/20
CPCC07C319/20C07C323/52C07D451/04
Inventor 王帆占肖何志红王绍辉陈小舟杨玉金
Owner CHONGQING HUABANGSHENGKAI PHARM
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