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Synthesis method for Retapamulin

A technology of retamoline and a synthesis method, applied in the field of pharmaceutical antibiotics, can solve the problems of increasing the difficulty of processing, difficult to control the purity of intermediates of retamoline in each step, unable to guarantee the quality of the final product, etc., and achieves significant economic value. , The effect of low production cost and mild reaction conditions

Inactive Publication Date: 2015-11-11
汕头经济特区鮀滨制药厂
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0032] This route is mainly to replace potassium ethylsulfonate with N,N sodium diethyldithiocarbamate trihydrate in the preparation of the intermediate (TRP-SN). Although the solid product can also be obtained, the subsequent intermediate (TRP-THI) was also directly subjected to the last step of the reaction without purification, which undoubtedly increased the difficulty of post-reaction treatment in the last step, and could not guarantee the quality of the final product
[0033] To sum up, the current existing technology is not easy to control the purity of retapamulin intermediates in each step, so that the quality of the final product cannot be guaranteed, so a new technology needs to be developed to overcome the above shortcomings

Method used

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  • Synthesis method for Retapamulin
  • Synthesis method for Retapamulin
  • Synthesis method for Retapamulin

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0056] Step a: Preparation of pleuromutilin mesylate (PLM-TS)

[0057] Weigh 189.25g (0.5mol) of pleuromutilin, 104.86g (0.55mol) of p-toluenesulfonyl chloride was dissolved in 946mL of dichloromethane, and 55.65g of p-triethylamine (dissolved in 55mL of dichloromethane ), after the dropwise addition, continue to react at 10°C for 2 hours, wash the reaction solution once with 500mL water, once with 250mL saturated saline, spin dry dichloromethane, recrystallize with absolute ethanol to obtain PLM-TS253.03g, Yield 95.0%.

[0058] Step b: Preparation of Tropinol Mesylate (TRP-MS)

[0059] Weigh 200.0g (1.42mol) of tropinol, 158.1g (1.56mol) of triethylamine and dissolve in 1000mL of dichloromethane solution, cool to -10~0°C, add dropwise 178.9g of methanesulfonyl chloride ( Dissolved in 200mL dichloromethane), after the dropwise addition, keep this temperature to continue the reaction for 2 hours, after TLC monitors the reaction is complete, add 300mL of 10% potassium carbonat...

example 2

[0067] Step a: Preparation of pleuromutilin mesylate (PLM-TS)

[0068] Weigh 325.0g (0.86mol) of pleuromutilin, 213.15g (1.12mol) of p-toluenesulfonyl chloride were dissolved in 1625mL of dichloromethane, and 113.13g of p-triethylamine (dissolved in 100mL of dichloromethane ), after the dropwise addition, continue to react at 40°C for 6 hours, wash the reaction solution once with 800mL water, once with 400mL saturated saline, spin dry dichloromethane, recrystallize with absolute ethanol to obtain PLM-TS445.3g, Yield 97.2%.

[0069] Step b: Preparation of Tropinol Mesylate (TRP-MS)

[0070] Weigh 400.0g (2.84mol) of tropinol, and dissolve 477.2g (3.69mol) of diisopropylethylamine in 2000mL of dichloromethane solution, cool down to -10~0°C, add methanesulfonyl chloride dropwise under nitrogen protection 422.9g (dissolved in 400mL dichloromethane), after the dropwise addition, keep the temperature and continue to react for 6 hours, after TLC monitors the reaction is complete, a...

example 3

[0078] Step a: Preparation of pleuromutilin mesylate (PLM-TS)

[0079] Weigh 378.5.0g (1.0mol) of pleuromutilin, 228.78g (1.2mol) of p-toluenesulfonyl chloride were dissolved in 1892mL of dichloromethane, and 121.43g of p-triethylamine (dissolved in 120mL of dichloromethane Middle), after the dropwise addition, continue to react at 30°C for 4 hours, wash the reaction solution with 1000mL water once, wash once with 500mL saturated saline, spin dry dichloromethane, and recrystallize with absolute ethanol to obtain PLM-TS523.6g , yield 98.3%.

[0080] Step b: Preparation of Tropinol Mesylate (TRP-MS)

[0081] Weigh 500.0g (3.54mol) of tropinol, 549.1g (4.25mol) of diisopropylethylamine and dissolve it in 2500mL of dichloromethane solution, cool down to -10~0°C, add methanesulfonyl chloride dropwise under nitrogen protection 486.8g (dissolved in 500mL dichloromethane), after the dropwise addition, keep the temperature and continue to react for 5 hours, after TLC monitors the rea...

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Abstract

The present invention provides a synthesis method for Retapamulin. The method comprises: using pleuromutilin as a starting material of one segment; obtaining PLM-TS by condensation reaction between the starting material and toluenesulfonyl chloride; using tropenol as a raw material of the other segment; obtaining TRP-MS by reaction between the raw material and toluenesulfonyl chloride; after performing substitution reaction between TRP-MS that uses water as a solvent and potassium ethyl xanthate, performing acidification between the substance and sulfuric acid to obtain an intermediate TRP-XAN; TRP-XAN undergoing hydrolysis in an ethanol NaOH solution; performing acidification between the substance and sulfuric acid to obtain an intermediate TRP-THI; the two segments TRP-THI and PLM-TS undergoing condensation reaction under alkaline conditions to obtain the final product, Retapamulin. The synthesis method for Retapamulin provided by the present invention is simple, environmentally friendly, easy in controlling the quality of intermediates of all steps, and suitable for the Retapamulin synthesis process in industrialized production.

Description

technical field [0001] The invention relates to pharmaceutical antibiotics, in particular to a method for synthesizing retapamulin. Background technique [0002] Retapamulin is a pleuromutilin antibiotic developed by GSK Company. In April 2007, Retapamulin ointment of Glaxo Lik Company was approved by the FDA for listing mainly for Staphylococcus aureus and Streptomyces pyogenes. The treatment of pustular dermatitis caused by coccal infection is the first pleuromutilin antibiotic used in humans. It has not yet been marketed in China, and many pharmaceutical companies including imports have applied for registration. Its social welfare and economic value can be seen. [0003] At present, the main synthetic routes of retapamulin are as follows: [0004] Synthetic route 1 (original research compound patent 98812731.8): [0005] The synthetic route of the compound patent with the authorized publication number CN1205211C applied by Smith Klein Beecham Co., Ltd., a subsidiary of...

Claims

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Application Information

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IPC IPC(8): C07D451/02
CPCC07D451/02
Inventor 冯汝洁施涯邻吴毅武贝荣丙陈海龙
Owner 汕头经济特区鮀滨制药厂
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