Preparation method of doxycycline monohydrate

Abstract

The invention discloses a preparation method of a doxycycline monohydrate. Water is used as a solvent, doxycycline hydrochloride is used as a starting raw material, and the doxycycline monohydrate is prepared through ammonia hydrolysis of salt. The doxycycline monohydrate with high purity and stable crystal water is prepared by the method, and the method is simple in process, high in yield, green, environment-friendly, convenient in post-treatment and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of chemistry or medicinal chemistry, and specifically relates to a method for preparing doxycycline monohydrate. Background Art

[0002] Doxycycline monohydrate is a broad-spectrum antibacterial agent with bactericidal effect at high concentrations. Many Rickettsia, Mycoplasma, Chlamydia, atypical mycobacteria, and spirochetes are also sensitive to this product. This product is more effective against Gram-positive bacteria than Gram-negative bacteria, but Enterococcus is resistant to it. Others such as Actinomycetes, Bacillus anthracis, Listeria monocytogenes, Clostridium, Nocardia, Vibrio, Brucella, Campylobacter, and Yersinia are sensitive to this product. The chemical structure is as follows:

[0003]

[0004] Doxycycline hydrochloride is a tetracycline drug with broad-spectrum antibacterial activity. It can treat chlamydia and mycoplasma infections. It is mainly used to treat respiratory tract, urinary tract and biliary tract infections caused by sensitive bacteria. It is also used to treat typhus, tetanus, mycoplasma pneumonia, etc. This drug is also widely used in veterinary medicine to treat infections caused by various pathogens, and the market demand is very large. The chemical structure is as follows:

[0005]

[0006] It contains 4.3-6.0% ethanol and 1.5-3.0% water.

[0007] Patent CN106946728A discloses a method for preparing doxycycline monohydrate, but the method has a complicated process (in the purification process after obtaining the crude doxycycline monohydrate, sulfosalicylic acid is used to precipitate the salt, and sulfosalicylic acid is toxic, difficult to degrade, and difficult to recycle. If it is directly discharged or improperly handled, it will pollute the environment and cause harm to the human body) and a low yield (for 100g of crude α-6-deoxyoxytetracycline 5-sulfosalicylic acid salt, the final doxycycline monohydrate product is only 43g at most).

[0008] Patent CN113264846B discloses a method for preparing doxycycline monohydrate, using purified water and ethanol as a solvent system, firstly adding ammonia water to adjust the pH value to ≤7.5, stirring until the doxycycline hydrochloride is completely dissolved, and then adjusting the pH value to 5.50-6.50 with acid. The operation is cumbersome, and the crystallization speed is slow and the crystallization state is poor.

[0009] Therefore, the preparation process of doxycycline monohydrate needs to be further optimized, and the mixed solvent system of ethanol and water needs to be replaced with a single solvent system of water. Doxycycline hydrochloride is used to prepare doxycycline monohydrate, which needs to be freed by alkali, because there are phenolic hydroxyl functional groups in doxycycline compounds, and the phenolic hydroxyl functional groups are easily oxidized to quinones in alkaline environments. Therefore, it is necessary to examine the anaerobic conditions: A. The system needs to be protected by nitrogen; B. The equivalent of the base (the purpose is to maintain a slightly acidic or neutral environment while maintaining sufficient freedom). In addition, the finished product is a monohydrate, and the stability of the crystal water needs to be examined. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing doxycycline monohydrate with high purity, stable crystal water, simple process, high yield, green and environmental protection, convenient post-treatment, and suitable for industrial production. The specific technical scheme is as follows:

[0011] A method for preparing doxycycline monohydrate is prepared via the following chemical reaction equation:

[0012]

[0013] The specific preparation steps of the above reaction equation are as follows:

[0014] Using water as solvent and doxycycline hydrochloride as starting material, the mixture is heated and dissolved under nitrogen protection, filtered, the filtrate is desalted by ammonia water, kept warm, filtered, washed and dried to obtain doxycycline monohydrate.

[0015] The amount of solvent water used is 5-10 times the weight of doxycycline hydrochloride; and the heating and dissolving temperature is 20-35°C.

[0016] The molar ratio of ammonia water to doxycycline hydrochloride is 1.05-1.2:1, and the temperature of adding ammonia water is controlled at 20-35°C.

[0017] The insulation time is 4-10 hours, and the insulation temperature is 20-35℃.

[0018] The washing solvent is water, and the amount used is 0.5-3 times the weight of doxycycline hydrochloride.

[0019] The drying vacuum degree is -0.06 to -0.1 MPa, the drying temperature is 30 to 60°C, and the drying time is 36 to 60 hours.

[0020] The beneficial effects of the present invention are:

[0021] 1) The method provided by the present invention prepares doxycycline monohydrate with high purity and stable crystal water, has simple process, high yield, is green and environmentally friendly, is convenient for post-processing, and is suitable for industrial production.

[0022] 2) The preparation method provided by the present invention replaces the mixed solvent system of ethanol and water with a single solvent system of water, thereby solving the problems of slow crystallization speed and poor crystallization state when purified water and ethanol are used as solvent systems.

[0023] 3) The content of the prepared doxycycline monohydrate provided by the present invention can reach more than 98.5%, the impurity content is less than 0.5%, and the water content is 3.5-4.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 X-ray diffraction spectrum of doxycycline monohydrate

[0025] Figure 2 This is the thermogravimetric analysis (TGA) diagram of doxycycline monohydrate. DETAILED DESCRIPTION

[0026] The present invention is described in detail below through specific examples. The following examples are used to explain the present invention rather than to limit the present invention.

[0027] Example 1

[0028] Under nitrogen protection, add 12.0L purified water and 2.0Kg doxycycline hydrochloride to a 30L reactor, dissolve the system at 30℃, and pass through a 0.45μm filter. Prepare dilute ammonia water (preparation method: add 0.31Kg ammonia water to 1.0L purified water), pass through a 0.45μm filter, and drop dilute ammonia water. During the dropwise addition, a yellow solid gradually precipitates from the system. After the dropwise addition is completed, stir for 5 hours. Filter, rinse the filter cake with 1.0L purified water, collect the filter cake, dry the filter cake at a vacuum degree of less than -0.06MPa at 55℃ for 36 hours, and after crushing and granulating, inner packaging, and outer packaging, obtain 1.68Kg of doxycycline monohydrate finished product with a yield of 93.3%.

[0029] The results of HPLC related substance detection are as follows:

[0030]

[0031]

[0032] X-ray diffraction data (see attached Figure 1 )as follows:

[0033]

[0034] Thermogravimetric analysis (TGA):

[0035] From the TGA spectrum (see attached Figure 2 ) It can be seen that the sample loses 3.798% of its weight when heated from 30°C to 150°C, and the weight loss is due to the crystalline water or free water in the sample.

[0036] Example 2

[0037] Under nitrogen protection, add 15.0L of purified water and 2.0Kg of doxycycline hydrochloride to a 30L reactor, dissolve the system at 25℃, and pass through a 0.45μm filter. Prepare dilute ammonia water (preparation method: add 0.28Kg of ammonia water to 1.0L of purified water), pass through a 0.45μm filter, and drop dilute ammonia water. During the dropwise addition, a yellow solid gradually precipitates from the system. After the dropwise addition is completed, stir at 25℃ for 7 hours. Filter, rinse the filter cake with 4.0L of purified water, collect the filter cake, dry the filter cake at a vacuum degree of less than -0.1MPa at 40℃ for 50 hours, and after crushing and granulating, inner packaging, and outer packaging, obtain 1.67Kg of doxycycline monohydrate finished product with a yield of 93.0%.

[0038] The results of HPLC related substance detection are as follows:

[0039]

[0040] The present invention is not limited to the above embodiments. Any simple or equivalent changes or modifications made to the above embodiments based on the technical essence of the present invention are within the technical scope of the present invention.

Claims

1. A method for preparing doxycycline monohydrate, characterized in that: Prepared by the following chemical reaction formula: The specific preparation steps of the above reaction equation are as follows: Using water as solvent and doxycycline hydrochloride as starting material, the mixture is heated and dissolved under nitrogen protection, filtered, the filtrate is desalted by ammonia water, kept warm, filtered, washed and dried to obtain doxycycline monohydrate.

2. The method for preparing doxycycline monohydrate according to claim 1, characterized in that: The amount of the solvent water is 5-10 times the weight of doxycycline hydrochloride; and the heating and dissolving temperature is 20-35°C.

3. The method for preparing doxycycline monohydrate according to claim 1, characterized in that: The molar ratio of the amount of ammonia water to the amount of doxycycline hydrochloride is 1.05-1.2:1, and the temperature of the added ammonia water is controlled at 20-35°C.

4. The method for preparing doxycycline monohydrate according to claim 1, characterized in that: The insulation time is 4-10 hours, and the insulation temperature is 20-35°C.

5. The method for preparing doxycycline monohydrate according to claim 1, characterized in that: The washing solvent is water, and the amount used is 0.5-3 times the weight of doxycycline hydrochloride.

6. The method for preparing doxycycline monohydrate according to claim 1, characterized in that: The drying vacuum degree is -0.06 to -0.1 MPa, the drying temperature is 30 to 60° C., and the drying time is 36 to 60 hours.

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