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Method for preparing tiamulin

A technology of tiamulin and pleuromutilin, which is applied in the fields of thioether preparation and organic chemistry, can solve the problems of toxicity, strong pungent odor, and restriction of the market scale of tiamulin fumarate, and achieve mild conditions and low cost. Inexpensive, environmentally friendly effect

Active Publication Date: 2018-03-06
山东德信生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method needs to use 2-diethylaminoethanethiol as an important raw material, and this compound has greater toxicity and a strong pungent smell, especially the main raw material for the synthesis of chemical weapon nitrogen mustard, so it is restricted in use and procurement. The strict control of many departments or organizations in the country has seriously restricted the market size of tiamulin fumarate

Method used

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  • Method for preparing tiamulin
  • Method for preparing tiamulin
  • Method for preparing tiamulin

Examples

Experimental program
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Effect test

Embodiment 1

[0023] A preparation method of tiamulin, the steps are as follows:

[0024] (1) Synthesis of 14-O-[(1-hydroxypropan-2-yl)mercaptoyl]mpirin (intermediate of formula 2)

[0025] Add 8.90g (20mmol) of pleuromutilin with a purity of 85%, 4.28g (22mmol) of 98% p-toluenesulfonyl chloride and 80mL of methyl isobutyl ketone into a 250mL three-necked flask, and heat up , stirred to dissolve pleuromutilin and p-toluenesulfonyl chloride, and when the temperature rose to 60°C, 4.0 mL of NaOH aqueous solution with a concentration of 10 mol / L was added dropwise and reacted for 30 min; then 1.72 g (22 mmol) of mercaptoethanol and 20 mL of Methanol, the reaction was continued at 60°C for 3h. After the reaction, it was extracted three times with 25 mL of distilled water, and the organic phase was washed with anhydrous Na 2 SO 4 After drying and evaporating methyl isobutyl ketone to dryness, 7.55 g (yield 89%) of viscous 14-O-[(1-hydroxypropan-2-yl)mercaptoyl]mylline was obtained.

[0026] ...

Embodiment 2

[0030] A preparation method of tiamulin, the steps are as follows:

[0031] (1) Synthesis of 14-O-[(1-hydroxypropan-2-yl)mercaptoyl]mpirin (intermediate of formula 2)

[0032] Add 8.90g (20mmol) of pleuromutilin with a purity of 85%, 4.62g (24mmol) of p-toluenesulfonyl chloride and 80mL of methyl isobutyl ketone into a 250mL three-necked flask, heat and stir to make pleuromutilin Pleuromutilin and p-toluenesulfonyl chloride were dissolved, and when the temperature rose to 60°C, 4.0 mL of NaOH aqueous solution with a concentration of 10 mol / L was added dropwise and reacted for 30 min; then a mixed solution (1.57 g The mercaptoethanol was dissolved in 20 mL of methanol, and 2 mL of NaOH with a concentration of 10 mol / L was added to react for 30 min), and the reaction was continued at 60° C. for 2.5 h. After the reaction, it was extracted three times with 25 mL of distilled water, and the organic phase was washed with anhydrous Na 2 SO 4 After drying and evaporating methyl iso...

Embodiment 3

[0036] A preparation method of tiamulin, the steps are as follows:

[0037] (1) The synthesis of 14-O-[(1-hydroxypropan-2-yl)mercaptoyl]mpirin (intermediate of Formula 2) is the same as in Example 2.

[0038] (2) Synthesis of Tiamulin (Formula 4 Compound)

[0039] The intermediate 14-O-[(1-hydroxypropan-2-yl) mercaptoyl] Mutilin (compound of formula 2) synthesized by 4.24g (10mmol) is added in the methyl tert-butyl ether of 20mL, drops to After 0°C, 20 mL of a methyl tert-butyl ether solution containing 0.90 g (3.33 mmol) of PBr3 was added dropwise, and after the addition was completed, the temperature was raised to room temperature, and the reaction was stirred for 12 h. After the reaction, add 5-7mL of 1mol / L Na 2 CO 3 The pH of the solution was adjusted to about 8, and the two phases were separated. The organic phase was washed twice with 10 mL of distilled water and evaporated to dryness. Add 30 mL of dimethylformamide, 0.73 g (10 mmol) of diethylamine and 1.66 g (12 ...

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Abstract

The invention discloses a method for preparing tiamulin. The method comprises the following synthesis routes: by taking a compound of formula 1, namely pleuromutilin, as a raw material, performing p-tosylation; synthesizing an intermittent, namely tosylate; performing a direct nucleophilic substitution reaction with beta-mercaptoethanol without separation so as to obtain an intermittent of formula2, namely 14-O-[(1-hydroxyl propane-2-yl) sulfur acetyl] tiamulin; activating the intermittent of the formula 2 by using a halogenation reagent or a sulfonylation reagent so as to form an intermittent of formula 3; enabling the intermittent to react with diethylamine directly without separation, thereby synthesizing a compound of formula 4, namely tiamulin. By adopting the method, 2-lignocaine ethanethiol which is supervised is not used, current main adverse factors which restrict the yield of tiamulin are solved, and tiamulin is prepared through synthesis routes which are low in cost, gentlein condition, environmental-friendly and applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical medicines, and in particular relates to a preparation method of tiamulin. Background technique [0002] Tiamulin fumarate (Formula 1) is the first generation of pleuromutilin antibiotics for animals, which was first developed by Sandoz in 1974. The drug is modified by modifying the C22 position of pleuromutilin into a (diethylaminoethyl) sulfhydryl group. After the modification, the water solubility and antibacterial effect are better improved compared with pleuromutilin. In addition to the antibacterial activity of pleuromutilin, it also shows strong activity against Shigella, Klebsiella and Colon bacillus. In addition, the most important biological activity of tiamulin is that it has good antibacterial activity against various Mycoplasma, Brachyspira hyodysenteriae and Brachyspira pilosicoli. MIC of tiamulin against Mycoplasma hyopneumoniae 50 0.039μg / m1, MIC against Mycoplasma gallisepticum...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07C319/14C07C319/20
Inventor 尚若锋刘宇衣云鹏郝宝成杨珍梁剑平
Owner 山东德信生物科技有限公司
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