Synthesis of intermediate compound of warnemulin hydrochloride and preparation method of warnemulin hydrochloride

A technology of warnemulin hydrochloride and intermediates, which is applied in the field of medicine and can solve the problems of high preparation cost and environmental pollution

Inactive Publication Date: 2018-01-26
盐城市优化医药化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In these reported synthetic methods, dimethylcysteamine hydrochloride is used as an important raw material to synthesize warnemulin hydrochloride, but there are relatively serious environmental problems in the preparation of dimethylcysteamine hydrochloride. Pollution
In addition, the preparation cost of the compound is relatively high

Method used

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  • Synthesis of intermediate compound of warnemulin hydrochloride and preparation method of warnemulin hydrochloride
  • Synthesis of intermediate compound of warnemulin hydrochloride and preparation method of warnemulin hydrochloride
  • Synthesis of intermediate compound of warnemulin hydrochloride and preparation method of warnemulin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] (1) Synthesis of 2-methyl-2-hydroxypropylamine (intermediate 6)

[0031] Dissolve 11.81 g (0.10 mol) of β-hydroxyisovaleric acid in 250 mL of THF, add 30 mL (0.22 mol) of triethylamine, and then add 30.25 g (0.11 mol) of phosphoric acid diazide dropwise at room temperature Phenyl ester, after 15-20 min dropwise addition, the reaction was stirred at room temperature for 4 h. Then add 100 mL of distilled water, stir and reflux for 2 h. After the reaction, THF was evaporated to dryness under reduced pressure. Add 50 mL of ethyl acetate, stir, and adjust the pH to 2-3 with 5 M HCl. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate, 30 mL each time. 50 mL of ethyl acetate was added to the aqueous phase, and 5 M NaOH was added to adjust the pH to about 9. The two phases were separated, and the organic phase was extracted with water twice, 20 mL each time. Then add anhydrous Na2SO4 to dry overnight, and evaporate the solvent to ob...

Embodiment 2

[0043] (1) Synthesis of 2-methyl-2-hydroxypropylamine (intermediate 6)

[0044] Dissolve 5.91 g (50 mmol) of β-hydroxyisovaleric acid in 150 mL of THF, add 15 mL of N-methylmorpholine, and add 13.76 g (50 mmol) of diphosphodiazido dropwise at room temperature After the phenyl ester was added dropwise for 15 min, the reaction was stirred for 4 h. Then add 60 mL of distilled water, stir and reflux for 2 h. After the reaction, THF was evaporated to dryness under reduced pressure. Add 30 mL of ethyl acetate, stir, and adjust the pH to 2-3. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate, 20 mL each time. Add 30 mL of ethyl acetate to the aqueous phase to adjust the pH to about 9. The two phases were separated and extracted twice with 15 mL each. After drying with Na2SO4 and evaporating the solvent to dryness, 3.79 g of the product was obtained (85% yield).

[0045] (2) Synthesis of D-valine Deng's salt (8)

[0046] The difference ...

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Abstract

The invention discloses an intermediate compound used for synthesizing valnemulin hydrochloride. The chemical structure of the intermediate compound used for synthesizing valnemulin hydrochloride is represented by a formula in the invention. A preparation method of the intermediate compound comprises following steps: beta-hydroxyisovaleric acid is subjected to Curtius rearrangement reaction so as to obtain 2-methyl-2-hydroxy propylamine; 2-methyl-2-hydroxy propylamine and D-valine Dane salt are subjected to mixed anhydride method reaction so as to obtain an amide product; the amide product is subjected to hydroxy activation under alkaline conditions with methylsulfonyl chloride, and then is reacted with potassium thioacetate. The preparation method of valnemulin hydrochloride comprises following steps: pleuromutilin is reacted with paratoluensulfonyl chloride so as to obtain pleuromutilin p-tosylate; pleuromutilin p-tosylate is reacted with the intermediate compound, and hydrochloric acid deprotection is carried out so as to obtain valnemulin hydrochloride. In the preparation method of valnemulin hydrochloride, no dimethyl cysteamine hydrochloride is needed, production conditions are mild, no environment pollution is caused, and the preparation method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to an intermediate compound for synthesizing warnemulin hydrochloride and a preparation method for warnemulin hydrochloride. Background technique [0002] Valnemulin Hydrochloride is a second-generation pleuromutilin antibiotic for animals. This antibiotic was first developed by Sandoz in 1984. It has the advantages of relatively broad antibacterial spectrum and low toxicity. The drug has good antibacterial activity against mycoplasma and various Gram-positive bacteria, such as Streptococcus, Staphylococcus aureus, Actinobacillus, etc., and its antibacterial effect in vitro is 10-100 times that of Tiamectin, and its biological Utilization is close to 100%. In 1999, the hydrochloride salt of Vernicarin was approved by the European Community for the prevention or treatment of swine dysentery caused by Brachyspira hyodysenteriae infection and porcine enzootic pneumonia caused by M...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C327/30C07C319/14C07C323/52
CPCC07C213/02C07C227/18C07C231/02C07C303/28C07C319/14C07C327/30C07C323/52C07C215/08C07C229/30C07C237/08C07C309/73
Inventor 许水金杨薇薇
Owner 盐城市优化医药化工科技有限公司
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