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Preparation method of high-purity doxycycline hydrochloride

A technology for doxycycline hydrochloride and doxycycline, applied in the separation/purification of carboxylic acid amide, organic chemistry, etc., can solve the problems of reduced yield, increased solvent usage and residue, etc., to achieve production The effect of low cost, short process time and simple process

Inactive Publication Date: 2017-03-29
RINGPU TIANJIN BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantages are: the purity is only 95%, and the use of dilute acid for pretreatment easily destroys doxycycline, resulting in a decrease in yield; the use of water-immiscible solvents for impurity extraction increases the amount of solvent used and residues; When the poor solvent of cyclocycline is added to the aqueous solution, due to the limitation of the solvent ratio, the yield is reduced and the cost of solvent recovery is high
In this method, the purity of doxycycline hydrochloride has reached more than 95%, but the content of impurities is not controlled
There is no guidance on the control of related substances in preparations

Method used

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  • Preparation method of high-purity doxycycline hydrochloride
  • Preparation method of high-purity doxycycline hydrochloride

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Experimental program
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Embodiment 1

[0025] 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-l,4,4a,5,5a,6,11,12a- The preparation method of octahydro-2-tetracenecarboxamide (doxycycline) (attached figure 2 )

[0026] Weigh 100g doxycycline hydrochloride raw material, add in the reactor, then add purified water 500ml, after stirring and dissolving for 90 minutes, the doxycycline hydrochloride aqueous solution is filtered with a filter paper with a pore size of 1 μm, and the solid insoluble impurities are filtered out to obtain doxycycline hydrochloride in water. Add the filtered doxycycline hydrochloride aqueous solution into the reactor, and adjust the temperature to 20°C. 2.5% ammonia water was added dropwise to the reactor at a rate of 3 ml / min to adjust the pH value to 3.0, the reaction crystallized, and a solid was precipitated, which was filtered and dried to obtain 84.5 g of doxycycline free base crystals.

[0027] 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-l,4,4a,...

Embodiment 2

[0030] 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-l,4,4a,5,5a,6,11,12a- The preparation method of octahydro-2-tetracenecarboxamide (doxycycline) (attached figure 2 )

[0031] Weigh 100g doxycycline hydrochloride raw material, add in the reactor, then add purified water 2000ml, after stirring and dissolving for 30 minutes, the doxycycline hydrochloride aqueous solution is filtered with a filter paper with a pore size of 30 μm, and the solid insoluble impurities are filtered out to obtain doxycycline hydrochloride in water. Add the filtered doxycycline hydrochloride aqueous solution into the reactor, and adjust the temperature to 60°C. Sodium bicarbonate was added dropwise to the reactor at a rate of 5 ml / min to adjust the pH value to 2.1, the reaction crystallized, and a solid was precipitated, which was filtered and dried to obtain 82.9 g of doxycycline free base crystals.

[0032] 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-l,4,4...

Embodiment 3

[0035] 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-l,4,4a,5,5a,6,11,12a- The preparation method of octahydro-2-tetracenecarboxamide (doxycycline) (attached figure 2 )

[0036] Weigh 100g doxycycline hydrochloride raw material, add in the reactor, then add purified water 1000ml, after stirring and dissolving for 10 minutes, the doxycycline hydrochloride aqueous solution is filtered with a filter paper with a pore size of 50 μm, and solid insoluble impurities are filtered out to obtain doxycycline hydrochloride in water. Add the filtered doxycycline hydrochloride aqueous solution into the reactor, and adjust the temperature to 50°C. Add sodium hydroxide solution dropwise to the reactor at a rate of 10 ml / min, adjust the pH value to 1.8, react to crystallize, and precipitate a solid, filter, and dry to obtain 83.1 g of doxycycline free base crystals.

[0037] 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-1,11-dioxo-l,4,4a,5,5a,6,11,12a- Octahydro-2...

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Abstract

The invention provides a preparation method of high-purity doxycycline hydrochloride. The preparation method is distinguished from other refining methods of doxycycline hydrochloride. The doxycycline hydrochloride needing to be refined is dissolved in water, the pH value of a solution is adjusted through alkali, and therefore doxycycline crystals are separated out of the solution; then, the doxycycline crystals are added into hydrogen chloride-ethyl alcohol, and the high-purity doxycycline hydrochloride crystals are generated through reacting and crystallizing. The technology is simple, operability is high, process time is short, production cost is low, and the doxycycline hydrochloride crystal product can be stably prepared, wherein the purity is larger than or equal to 99%. The content of isomers in the product is smaller than or equal to 0.1% (the standard is smaller than 2%), the content of other impurities meets requirements, the content of doxycycline is larger than or equal to 99%, and the production requirements for the doxycycline hydrochloride crystal product are completely met.

Description

technical field [0001] The invention belongs to the field of chemical synthesis and purification of veterinary raw materials, in particular to a preparation method of high-purity (≥99%) doxycycline hydrochloride. Background technique [0002] Doxycycline Hydrochloride (Doxycyline Hydrochloride, also known as doxycycline, deoxyoxytetracycline hydrochloride), chemical name: 6-methyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy -1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide hydrochloride hemiethanol hemihydrate (attached figure 1 ), molecular weight 480.90. Soluble in water or methanol, slightly soluble in ethanol or acetone, almost insoluble in chloroform. It is a semi-synthetic broad-spectrum tetracycline antibiotic drug prepared by taking oxytetracycline II as raw material through unit reactions such as chlorination, dehydration, hydrogenation, transformation and salt formation. It is mainly used for upper respiratory tract infection, tonsillitis, bilia...

Claims

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Application Information

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IPC IPC(8): C07C237/26C07C231/24
Inventor 井丁丁李旭东刘爱玲夏雪林郑超魏微付春香
Owner RINGPU TIANJIN BIOLOGICAL PHARMA
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