Preparation of valnemulin and hydrochloride of valnemulin

A technology of vonimulin and valine salt, which is applied in the field of preparation of vonimulin and its hydrochloride, can solve the problems such as the target product cannot meet the requirement of purity, it is difficult to realize industrialization, and the danger is increased, Achieve the effect of reducing energy consumption, reducing operating time, and simplifying process operations

Inactive Publication Date: 2013-07-10
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On this basis, in the patent US5284967 reported by Ingolf Macher, the amino group of D-valine is protected by the method of preparing the amino acid Deng salt, and only hydrochloric acid is needed to remove the protecting group, but this method adopts freeze-drying method to The product is separated, this method consumes a lot of energy, the efficiency is low and the target product can not meet the requirements of the purity in the Pharmacopoeia, it is difficult to realize industrialization
In addition, active chloroformate is used in the synthesis process, which increases the danger in the production process

Method used

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  • Preparation of valnemulin and hydrochloride of valnemulin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] The preparation of embodiment 1 warnemulin

[0024] Add 35 g of cbz-D-valine potassium salt and 450 mL of ethyl acetate to a four-necked flask, cool down to -15°C, add 16 mL of N-methylmorpholine, and slowly add 18 mL of pivaloyl chloride dropwise to react 2 h, when cooling down to -20 ℃. Within 10 min, 30 mL of ethyl acetate solution containing 56 g of 14-O-[(2-amino-1, 1-dimethylethyl)thiomethylcarbonyl]muthrin was added dropwise, and stirred for 2 h.

[0025] Pour 500 mL of water into the solution system, adjust the pH to 1~2 with HBr aqueous solution at 20 °C, and stir for 2 h. The aqueous phase was taken, and the pH was adjusted to 9-10 with saturated NaHCO3 solution, and the obtained vonemulin solid had a yield of 75%.

Embodiment 2

[0026] The preparation of embodiment 2 warnemulin hydrochloride

[0027] Dissolve the solid obtained in Example 1 with 200 mL of methyl tert-butyl ether, adjust the pH to 1~2 with hydrochloric acid, add saturated NaCl aqueous solution to precipitate the solid, then dissolve it with ethyl acetate, add cyclohexane dropwise, crystallize, and filter , vacuum-dried at 40 °C, weighed 49.9 g, the total yield of Example 1 and Example 2 was 69%, and the purity was 98.6%.

Embodiment 3

[0028] The preparation of embodiment 3 warnemulin hydrochloride

[0029] Add 35 g of cbz-D-valine potassium salt and 500 mL of dichloromethane into a four-neck flask, cool down to -10°C, add 12 mL of pyridine, slowly add 19 mL of pivaloyl chloride dropwise to react for 1 h, and cool down to -20 °C ℃. Within 10 min, 30 mL of ethyl acetate solution containing 56 g of 14-O-[(2-amino-1, 1-dimethylethyl)thiomethylcarbonyl]muthrin was added dropwise, and stirred for 2 h.

[0030] Pour 1000 mL of water into the solution system, adjust the pH to 1~2 with HBr aqueous solution at 20 °C, and stir for 2 h. Take the water phase, use saturated NaHCO3 solution to adjust the pH to 9~10, dissolve it with 200 mL of methyl tert-butyl ether, adjust the pH to 1~2 with hydrochloric acid, add saturated NaCl aqueous solution to precipitate a solid, then dissolve it with ethyl acetate, add ring Hexane, filtered, dried under vacuum at 40 °C, weighed 53.2 g, yield 71%, purity 98.2%.

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Abstract

The invention relates to a preparation method of valnemulin and hydrochloride of valnemulin. The preparation method comprises the following steps of: reacting amino-protected D-valine and pivaloyl chloride to obtain mixed anhydride; carrying out condensation reaction to the mixed anhydride and 14-O-[(2-amino-1, 1-dimethyl ethyl) thiomethylcarbonyl] mutilin to prepare valnemulin with an amino protecting group; carrying out acid treatment to remove the protecting group; crystallizing to obtain valnemulin; and then reacting with an acid to obtain the hydrochloride. The preparation method is scientific and advanced in technology, and has the advantages of being high in cost, and high in product yield and purity.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to the preparation of warnemulin and its hydrochloride. Background technique [0002] With the widespread use and even abuse of antibiotics, the problem of bacterial resistance is becoming more and more serious. The veterinary Miaolin antibiotics discovered in the 1950s have unique curative effects on many Gram-positive bacteria and Mycoplasma (Mycoplasma) infections, and this type of drug has the characteristics of no cross-resistance with other drugs. , has received widespread attention. Through continuous research on its structural modification, the second-generation pleuromutilin antibiotic Valnemulin Hydrochloride, synthesized by Sandoz in 1984, has a wide antibacterial spectrum and is effective against a variety of bacteria, chains, Cocci and mycoplasma have good antibacterial activity and other characteristics, and were approved by the European Community in 1999 for the pre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/52C07C319/20
CPCY02P20/55
Inventor 赵地顺付江涛梁策郑连义张娟王薇葛京京刘猛帅
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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