Method for preparing metacycline hydrochloride with low impurity content by taking 11a-chloro-6-methylenetetracycline solution as raw material and directly neutralizing

Abstract

The invention discloses a method for preparing metacycline hydrochloride with low impurity content by directly neutralizing a 11a-chloro-6-methylenetetracycline solution serving as a raw material, and belongs to the technical field of chemical engineering. The method comprises the following steps: adding a neutralizer into a 11a-chlorine-6-methine oxytetracycline solution for neutralization treatment, and filtering to obtain a 11a-chlorine-6-methine oxytetracycline neutralization solution; the method comprises the following steps: adding a 11a-chlorine-6-methyleneoxytetracycline neutralization solution and a regenerated palladium-carbon catalyst into an alcoholic solution, carrying out temperature-controlled hydrodechlorination reaction, filtering, adding sulfosalicylic acid into filtrate, and crystallizing to form salt, so as to obtain the methyleneoxytetracycline, and reacting methyleneoxytetracycline with hydrochloric acid, crystallizing, filtering, and drying to obtain the metacycline hydrochloride. According to the method, a 11a-chloro-6-methyleneoxytetracycline salifying process is not carried out, and the purity and quality of a metacycline hydrochloride product are improved while the production cost is reduced by simplifying a synthetic route, optimizing a process and reducing emission of three wastes (waste gas, waste water and industrial residues).

Description

Technical Field

[0001] This invention belongs to the field of chemical technology, specifically relating to a method for preparing methacycline hydrochloride with low impurity content by direct neutralization using 11a-chloro-6-methylene oxytetracycline solution as a raw material. Background Technology

[0002] Methacycline hydrochloride, also known as methoxycycline, is a tetracycline antibiotic with broad-spectrum antibacterial activity and a mechanism of action similar to tetracyclines. It is used for rickettsial diseases, mycoplasma infections, chlamydia infections, relapsing fever, brucellosis, cholera, tularemia, plague, and chancroid. It is also effective against infections caused by actinomycin, anthrax, Listeria monocytogenes, Clostridium, Nocardia, and Vibrio. Due to the widespread use of tetracyclines over the years, common clinical pathogens have developed serious resistance to methoxycycline, including Gram-positive bacteria such as Staphylococcus and most Enterobacteriaceae. Cross-resistance exists between methoxycycline and different tetracycline varieties.

[0003] The current preparation process for methacycline hydrochloride involves using oxytetracycline as a raw material, which is chlorinated and dehydrated to form 11a-chloro-6-methyleneoxytetracycline p-toluenesulfonate. This is then dechlorinated via hydrogenation using a palladium-on-carbon catalyst, followed by the addition of sulfosalicylic acid to form a salt, ultimately yielding methacycline hydrochloride. This process is currently the most common in the market. However, the salt formation process of 11a-chloro-6-methyleneoxytetracycline solution has certain problems: the use of p-toluenesulfonic acid in the salt formation process not only increases the cost of the raw material but also requires separation and washing after salt formation to remove excess p-toluenesulfonic acid and related impurities, leading to a complex production process and low production efficiency. Furthermore, the salt formation and post-processing generate large amounts of wastewater and waste residue, causing environmental pollution and increasing the company's costs. On the other hand, during the hydrogenation-reduction dechlorination process, the palladium-on-carbon catalyst experiences a decline in activity after use, requiring replacement and incurring high costs. Furthermore, under high pressure and high temperature hydrogenation, the reaction selectivity is poor, easily leading to the formation of byproducts (such as doxycycline), affecting the quality of methacycline and ultimately further impacting the quality of methacycline hydrochloride. Therefore, there is a need to develop a preparation process for methacycline hydrochloride using 11α-chloro-6-methyleneoxycycline solution as a raw material. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing methacycline hydrochloride with low impurity content by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as raw material. This process does not go through the salt formation step of 11a-chloro-6-methyleneoxytetracycline, but directly neutralizes, filters through a filter membrane, and uses a regenerated palladium-on-carbon catalyst for hydrogenation dechlorination. This solves the problems of non-recoverable catalyst, many by-products, and low product purity in traditional processes.

[0005] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0006] A method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material includes the following steps:

[0007] 1) After the waste palladium catalyst on carbon from the production of doxycycline is refluxed with sodium acetate, an organic ligand is added, hydrogen is introduced for replacement, and the mixture is stirred while maintaining the hydrogenation state to obtain a regenerated palladium catalyst on carbon.

[0008] 2) Add a neutralizing agent to the 11a-chloro-6-methyleneoxytetracycline solution to control the pH and neutralize it. Filter to obtain the 11a-chloro-6-methyleneoxytetracycline neutralized solution.

[0009] 3) The 11a-chloro-6-methyleneoxytetracycline neutralized solution obtained in step 2) and the regenerated palladium on carbon catalyst obtained in step 1) are added to an ethanol solution and mixed. A temperature-controlled hydrogenation dechlorination reaction is carried out. After filtration, sulfosalicylic acid is added to the filtrate to crystallize into salt. After crystallization, the filtrate is discharged by centrifugation and then washed in batches with anhydrous ethanol to obtain methyloxytetracycline.

[0010] 4) The methacycline obtained in step 3) was reacted with hydrochloric acid and crystallized, filtered, and dried to obtain methacycline hydrochloride.

[0011] Furthermore, in step 1), the mass fraction of the sodium acetate solution is 10% to 30%, and the reflux time is 2 to 3 hours.

[0012] Further, in step 1), the organic ligand is selected from one or a mixture of two of quinoline and pyridine; the mass ratio of the spent palladium catalyst on carbon to the organic ligand is 50-70:1.

[0013] Furthermore, in step 1), the stirring time under hydrogenation is maintained for 2 to 4 hours, the reaction temperature is 40 to 65°C, and the hydrogen pressure is 0.30 to 0.45 MPa.

[0014] Further, in step 2), the neutralizing agent is selected from one or a mixture of sodium carbonate, sodium bicarbonate, and sodium acetate; the mass fraction of the neutralizing agent is 8-10%; and the pH is 5.0-7.0.

[0015] Furthermore, in step 2), the filtration uses a polyvinylidene fluoride or nylon membrane with a pore size of 0.20–0.45 μm.

[0016] Further, in step 3), the mass ratio of 11a-chloro-6-methyleneoxytetracycline neutralization solution: regenerated palladium catalyst on carbon: ethanol solution is 1:0.020-0.035:1.60-1.88, the volume fraction of ethanol solution is 50-60%; the reaction time is 3-5 h, the reaction temperature is 35-45 °C, the crystallization temperature is 5-10 °C, the crystallization time is 3-4 h, and the hydrogen pressure is 0.25-0.30 MPa.

[0017] Further, in step 3), the mass ratio of sulfosalicylic acid to the 11a-chloro-6-methyleneoxytetracycline solution in step 2) is 1:0.3 to 0.35; after crystallization, the product is discharged by centrifugation and then washed in batches with anhydrous ethanol, with the mass-to-volume ratio of 11a-chloro-6-methyleneoxytetracycline neutralization solution to anhydrous ethanol being 1:0.25 to 0.38.

[0018] Further, in step 4), the mass-to-volume ratio of methacycline to aqueous ethanol is 1:1.20-1.50, the mass-to-volume ratio of methacycline to hydrochloric acid is 1:1-1.2, the reaction temperature is 40-45℃, the crystallization temperature is 5-10℃, and the crystallization time is 4-6h.

[0019] Furthermore, in step 4), the volume fraction of the ethanol aqueous solution is 80-95%, and the volume fraction of hydrochloric acid is 32%; the drying temperature of oxytetracycline hydrochloride is 80°C, and the drying time is 3-4 hours.

[0020] Compared with the prior art, the present invention has the following advantages:

[0021] (1) The present invention obtains a regenerated palladium-on-carbon catalyst by refluxing the waste palladium-on-carbon catalyst after doxycycline production with sodium acetate and then adding quinoline or pyridine organic ligands (single or mixed). This not only improves the activity of the catalyst and enhances the selective breaking ability of C-Cl bonds, but also allows it to be reused after production.

[0022] (2) This invention does not go through the salt formation step of 11a-chloro-6-methyleneoxytetracycline solution, but directly neutralizes and filters through a filter membrane to obtain a high-purity 11a-chloro-6-methyleneoxytetracycline solution. At the same time, it also reduces the reaction steps and separation operations, reduces the cost of manpower and time, and improves production efficiency.

[0023] (3) This invention avoids the three wastes generated during the salt formation process of p-toluenesulfonic acid, greatly reduces the discharge of wastewater and waste residue, reduces environmental governance costs, and also reduces environmental pollution.

[0024] (4) This invention reduces the generation of byproducts and improves the purity of methacycline by low-temperature and highly selective hydrogenation and dechlorination, and then obtains high-quality and high-yield methacycline hydrochloride after hydrochloric acid conversion.

[0025] (5) The process of this invention is simple to operate, the reaction conditions are mild, each step is easy to control, and it has good repeatability and stability, making it suitable for large-scale industrial production. Attached Figure Description

[0026] Figure 1 This is a common reaction route diagram for the preparation of methacycline hydrochloride in this application;

[0027] Figure 2 This is the liquid phase detection spectrum of the reaction of the feed liquid in Example 1 of this application after the reaction is completed;

[0028] Figure 3 This is the liquid phase detection spectrum at the end of the reaction in Example 2 of this application;

[0029] Figure 4 This is the liquid phase detection spectrum at the end of the reaction in Example 3 of this application;

[0030] Figure 5 An optimized reaction route for the traditional preparation of methacycline hydrochloride;

[0031] Figure 6 This is a liquid phase detection spectrum of the reaction solution in Comparative Example 1 of this application after the reaction has ended. Detailed Implementation

[0032] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented based on the technical solutions of the present invention, and it should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0033] The spent palladium-on-carbon catalyst used in the following examples is derived from the deactivated catalyst after the hydrogenation reaction during the production of doxycycline. Specifically, in the hydrogenation step of doxycycline synthesis, the fresh palladium-on-carbon catalyst, after use, loses its activity to the point that it cannot meet the efficiency requirements of the doxycycline hydrogenation reaction, resulting in a conversion rate of less than 70%.

[0034] The raw material 11a-chloro-6-methyleneoxytetracycline solution used in the following examples is the preparation product of Example 2 in patent application publication number CN114315627B. The relative content of the main impurities in this solution is 1.4%, and the relative content of unknown impurities is less than 0.1%.

[0035] In the following examples, methacycline hydrochloride was determined by liquid chromatography. The chromatographic conditions were as follows: octadecylsilane-bonded silica gel was used as the stationary phase; acetate buffer (0.25 mol / L ammonium acetate - 0.1 mol / L disodium ethylenediaminetetraacetate - triethylamine (100:10:1, pH adjusted to 8.3 with glacial acetic acid) - acetonitrile (85:15) was used as the mobile phase; the column temperature was 35°C; and the detection wavelength was 280 nm.

[0036] The method provided in this application for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material is as follows: Figure 1 As shown, it includes the following steps:

[0037] 1) After the waste palladium catalyst on carbon from the production of doxycycline is refluxed with sodium acetate, an organic ligand is added, hydrogen is introduced for replacement, and the mixture is stirred while maintaining the hydrogenation state to obtain the palladium catalyst on carbon.

[0038] 2) Add a neutralizing agent to the 11a-chloro-6-methyleneoxytetracycline solution to control the pH and neutralize it. Filter to obtain the 11a-chloro-6-methyleneoxytetracycline neutralized solution.

[0039] 3) The 11a-chloro-6-methyleneoxytetracycline solution obtained in step 2) and the palladium catalyst on carbon obtained in step 1) are added to an ethanol solution and mixed. The mixture is subjected to a temperature-controlled hydrogenation dechlorination reaction. After filtration, sulfosalicylic acid is added to the filtrate to crystallize it into a salt. After crystallization, the filtrate is discharged by centrifugation and then washed in batches with anhydrous ethanol to obtain methyloxytetracycline.

[0040] 4) The methacycline obtained in step 3) was reacted with hydrochloric acid and crystallized, filtered, and dried to obtain methacycline hydrochloride.

[0041] The following embodiments are all carried out according to the above process flow.

[0042] Example 1

[0043] A method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material includes the following steps:

[0044] (1) Pretreatment of waste palladium on carbon catalyst

[0045] Take 200g of spent palladium-on-carbon catalyst from doxycycline production and mix it with 1000mL of 10wt% sodium acetate solution. Heat the mixture to reflux for 2 hours, then cool it to 30℃. Add 4g of quinoline reagent and stir thoroughly for 1 hour. Purge with hydrogen gas to maintain a hydrogen pressure of 0.35MPa. Stir at 65℃ for 2 hours until no more hydrogen is absorbed. Centrifuge the material and wash it with water until neutral to obtain the regenerated palladium-on-carbon catalyst.

[0046] (2) Preparation of 11a-chloro-6-methyloxytetracycline neutralization solution

[0047] 600g of 11a-chloro-6-methyleneoxytetracycline solution was placed in a reaction vessel, and 10wt% sodium carbonate aqueous solution was slowly added. The mixture was stirred at room temperature for 30 minutes, and the pH of the reaction system was adjusted to 7.0 to complete the neutralization process. The neutralized solution was then filtered through a polyvinylidene fluoride membrane with a pore size of 0.22µm. The filtered neutralized solution was then transferred to a hydrogenation reactor for further processing.

[0048] (3) Preparation of methoxytetracycline

[0049] The 11a-chloro-6-methyleneoxytetracycline neutralization solution prepared in step (2) was added to 1000 mL of 50% (v / v) ethanol aqueous solution along with 21.0 g of regenerated palladium catalyst on carbon (mass ratio 1:0.035). The mixture was then transferred to a hydrogenation reactor, and hydrogen gas was introduced to maintain a hydrogen pressure of 0.30 MPa. The hydrogenation and dechlorination reaction was carried out at 45 °C, and the reaction progress was monitored by liquid phase for a total of 5 h. After the reaction was completed, the palladium catalyst on carbon was recovered by filtration (it can be reused or regenerated). 200 g of solid sulfosalicylic acid was added to the filtrate, and the mixture was crystallized into salt at 10 °C for 3 h. The crystallized product was transferred to a centrifuge and centrifuged at 1000 r / min for 10 min. It was then washed three times with 150 mL of anhydrous ethanol (50 mL each time). After washing, the product was centrifuged for another 20 min, and finally 533.6 g of methyloxytetracycline was obtained, with a yield of 95.8%.

[0050] (4) Preparation of methacycline hydrochloride

[0051] Dissolve 300g of methacycline in 360mL of 80% (v / v) ethanol aqueous solution, add 300mL of 32% (v / v) hydrochloric acid, stir at 45℃ for 1h; cool to 8℃ for 4h to crystallize, filter, and vacuum dry at 80℃ for 3h to obtain 195.6g of methacycline-1 hydrochloride with a purity of 99.15% and a yield of 65.2%.

[0052] The prepared methacycline hydrochloride-1 was analyzed by liquid chromatography, and the chromatogram is shown below. Figure 2 As shown in Table 1, the content of impurities contained therein is as follows.

[0053] Table 1 Impurity Content Data

[0054]

[0055]

[0056] Example 2

[0057] A method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material includes the following steps:

[0058] (1) Pretreatment of waste palladium on carbon catalyst

[0059] Take 200 kg of spent palladium-on-carbon catalyst from doxycycline production and mix it with 1200 L of 23 wt% sodium acetate solution. Heat the mixture to reflux for 3 h, then cool it to 30 °C. Add 3 kg of pyridine reagent and stir thoroughly for 1 h. Then purge with hydrogen gas to maintain a hydrogen pressure of 0.40 MPa. Stir at 50 °C for 3 h until no more hydrogen is absorbed. Centrifuge the mixture and wash it with water until neutral to obtain the regenerated palladium-on-carbon catalyst.

[0060] (2) Preparation of 11a-chloro-6-methyloxytetracycline neutralization solution

[0061] 800 kg of 11a-chloro-6-methyleneoxytetracycline solution was placed in a reaction vessel, and 8 wt% sodium bicarbonate aqueous solution was slowly added. The mixture was stirred at room temperature for 30 min, and the pH of the reaction system was adjusted to 6.8 to complete the neutralization process. The neutralized solution was then filtered through a polyvinylidene fluoride membrane with a pore size of 0.22 μm. The filtered neutralized solution was then transferred to a hydrogenation reactor for further processing.

[0062] (3) Preparation of methoxytetracycline

[0063] The 11a-chloro-6-methyleneoxytetracycline neutralized solution prepared in step (2) was added to 1500L of 55% (v / v) ethanol aqueous solution along with 24kg of regenerated palladium catalyst on carbon (mass ratio 1:0.030). The mixture was then transferred to a hydrogenation reactor, and hydrogen gas was introduced to maintain a hydrogen pressure of 0.25MPa. The hydrogenation and dechlorination reaction was carried out at 40℃, and the reaction progress was monitored by liquid phase for a total of 4 hours. After the reaction was completed, the regenerated palladium catalyst on carbon was recovered by filtration (it can be reused or regenerated again). 264kg of sulfosalicylic acid solid was added to the filtrate, and crystallization was carried out at 10℃ for 4 hours. The crystallized product was transferred to a centrifuge and centrifuged at 500r / min for 20min. Then, it was washed three times with 300L of anhydrous ethanol (100L each time). After washing, the product was centrifuged for another 30min, and finally 713.2kg of methyloxytetracycline was obtained, with a yield of 96.0%.

[0064] (4) Preparation of methacycline hydrochloride

[0065] 600 kg of methacycline was dissolved in 900 L of 90% (v / v) ethanol aqueous solution, and 620 L of 32% (v / v) hydrochloric acid was added. The mixture was stirred at 43 °C for 1 h. After cooling to 10 °C, the mixture was crystallized for 4 h. The product was then centrifuged and dried in a drying ball at 80 °C for 4 h to obtain 413.4 kg of methacycline-2 hydrochloride with a purity of 99.33% and a yield of 68.9%.

[0066] The prepared methacycline-2 hydrochloride was analyzed by liquid chromatography, and the chromatogram is shown below. Figure 3 As shown in Table 2, the content of impurities is as follows.

[0067] Table 2 Impurity Content Data

[0068]

[0069] Example 3

[0070] A method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material includes the following steps:

[0071] (1) Pretreatment of waste palladium on carbon catalyst

[0072] Take 300 kg of spent palladium-on-carbon catalyst from doxycycline production and mix it with 1800 L of 30 wt% sodium acetate solution. Heat the mixture to reflux for 4 h, then cool it to 30 °C. Add 3 kg of quinoline and 2.25 kg of pyridine reagent and stir thoroughly for 1 h. Then, purge with hydrogen gas to maintain a hydrogen pressure of 0.45 MPa and stir at 40 °C for 4 h until no more hydrogen is absorbed. Centrifuge the mixture and wash it with water until neutral to obtain the regenerated palladium-on-carbon catalyst.

[0073] (2) Preparation of 11a-chloro-6-methyloxytetracycline neutralization solution

[0074] 800 kg of 11a-chloro-6-methyleneoxytetracycline was placed in a reaction vessel, and 10 wt% sodium carbonate aqueous solution was slowly added. The mixture was stirred at room temperature for 30 min, and the pH of the reaction system was adjusted to 5.0 to complete the neutralization process. The neutralized solution was then filtered through a nylon membrane with a pore size of 0.45 μm. The filtered neutralized solution was then transferred to a hydrogenation reactor for further processing.

[0075] (3) Preparation of methoxytetracycline

[0076] The 11a-chloro-6-methyleneoxytetracycline neutralized solution prepared in step (2) was added to 1200L of 60% (v / v) ethanol aqueous solution (mass ratio 1:0.020) and then transferred to a hydrogenation reactor. Hydrogen gas was introduced and maintained at a hydrogen pressure of 0.26 MPa. The hydrogenation and dechlorination reaction was carried out at 35℃, and the reaction progress was monitored by liquid phase for a total of 3 hours. After the reaction was completed, the regenerated palladium catalyst was recovered by filtration. 280kg of sulfosalicylic acid solid was added to the filtrate, and crystallization was carried out at 5℃ for 4 hours. The crystallized product was transferred to a centrifuge and centrifuged at 500r / min for 20min. Then it was washed three times with 300L of anhydrous ethanol (100L each time). After washing, it was centrifuged for another 30min, and finally 715.5kg of methyloxytetracycline was obtained, with a mass yield of 96.30%.

[0077] (4) Preparation of methacycline hydrochloride

[0078] 700 kg of methacycline was dissolved in 1050 L of 95% (v / v) ethanol aqueous solution, and 830 L of 32 wt% hydrochloric acid was added. The mixture was stirred at 40 °C for 1 h, cooled to 6 °C for 6 h to crystallize, centrifuged, and dried in a drying ball at 80 °C for 4 h to obtain 490 kg of methacycline-3 hydrochloride with a purity of 99.42% and a yield of 70.00%.

[0079] The prepared methacycline-3 hydrochloride was analyzed by liquid chromatography, and the chromatogram is shown below. Figure 4 As shown in Table 3, the content of impurities is as follows.

[0080] Table 3 Impurity Content Data

[0081]

[0082] Comparative Example 1 (Traditional Process)

[0083] The traditional method for processing methacycline hydrochloride is as follows: Figure 5 As shown, the specific steps are as follows:

[0084] (1) Pretreatment of waste palladium on carbon catalyst

[0085] Take 200g of spent palladium-on-carbon catalyst from doxycycline production and mix it with 1000mL of 10wt% sodium acetate solution. Heat the mixture to reflux for 2 hours, then cool it to 30℃. Add 4g of quinoline reagent and stir thoroughly for 1 hour. Purge with hydrogen gas to maintain a hydrogen pressure of 0.30MPa. Stir at 50℃ for 2 hours until no more hydrogen is absorbed. Centrifuge the material and wash it with water until neutral to obtain the regenerated palladium-on-carbon catalyst.

[0086] (2) Preparation of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate

[0087] 600g of 11a-chloro-6-methyleneoxytetracycline solution was placed in a reaction vessel, and 150g of p-toluenesulfonate was added. The mixture was stirred at room temperature for 0.5h, allowed to stand for 4h, and then centrifuged. During centrifugation, the product was washed with 400mL of 95% (v / v) ethanol solution to obtain 354kg of 11a-chloro-6-methyleneoxytetracycline p-toluenesulfonate.

[0088] (3) Preparation of methoxytetracycline

[0089] The 11a-chloro-6-methyleneoxytetracycline p-toluenesulfonate prepared in step (2) and 25.6 g of regenerated palladium catalyst on carbon were added to 1000 mL of 50% (v / v) ethanol aqueous solution and transferred to a hydrogenation reactor. Hydrogen gas was introduced and maintained at a hydrogen pressure of 0.30 MPa. The hydrogenation and dechlorination reaction was carried out at 35 °C. The reaction progress was monitored by liquid phase and the reaction was carried out for a total of 5 h. After the reaction was completed, the regenerated palladium catalyst on carbon was recovered by filtration. 150 g of sulfosalicylic acid solid was added to the filtrate and crystallized into salt at 10 °C for 4 h. The crystallized product was transferred to a centrifuge and centrifuged at 1000 r / min for 10 min. Then it was washed three times with 150 mL of anhydrous ethanol (50 mL each time). After washing, it was centrifuged for another 20 min. Finally, 334.8 g of methyloxytetracycline was obtained, with a mass yield of 94.57%.

[0090] (4) Preparation of methacycline hydrochloride

[0091] 300g of methacycline was dissolved in 360mL of 80% ethanol aqueous solution, and 300mL of 32% hydrochloric acid was added. The mixture was stirred at 45℃ for 1h, cooled to 8℃ for 4h to crystallize, filtered, and dried under vacuum at 80℃ for 3h to obtain 196.3g of methacycline-4 hydrochloride with a purity of 98.91% and a yield of 65.50%.

[0092] The prepared methacycline-4 hydrochloride was analyzed by liquid chromatography, and the chromatogram is shown below. Figure 6 As shown in Table 4, the content of impurities is as follows.

[0093] Table 4 Impurity Content Data

[0094]

[0095] Comparative Example 2

[0096] The method for preparing methacycline hydrochloride in this comparative example is the same as in Example 1, except that in step 3), 11a-chloro-6-methyleneoxytetracycline solution is directly reacted with the catalyst (without neutralization). After the reaction, the yield of methacycline is 94.60%; the final product, methacycline-5 hydrochloride, has a purity of 98.66% and a yield of 66.33%. The content of impurities is shown in Table 5 below.

[0097] Table 5 Impurity Content Data

[0098]

[0099] Comparative Example 3

[0100] The preparation method of methacycline hydrochloride in this comparative example is the same as in Example 1, except that: in step 3), the hydrogenation dechlorination reaction temperature is adjusted to 50°C, while other operations remain the same, and the reaction time is shortened to 2 hours. The yield of methacycline is 95.80%. The final product, methacycline-6 ​​hydrochloride, has a purity of 98.50% and a mass yield of 63.70%. The content of impurities is shown in Table 6 below.

[0101] Table 6 Impurity Content Data

[0102]

[0103] Comparative Example 4

[0104] The preparation method of methacycline hydrochloride in this comparative example is the same as that in Example 1, except that the drying temperature in step 4) is adjusted to 90°C. All other operations are the same. The final product, methacycline hydrochloride-7, has a purity of 98.21% and a yield of 64.83%. The content of impurities is shown in Table 7 below.

[0105] Table 7 Impurity Content Data

[0106]

[0107] Comparative Example 5

[0108] Comparison of data on palladium-on-carbon catalysts in the preparation of oxytetracycline

[0109]

Claims

1. A method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11α-chloro-6-methyleneoxytetracycline solution as a raw material, characterized in that: Includes the following steps: 1) After the waste palladium catalyst on carbon from the production of doxycycline is refluxed with sodium acetate, an organic ligand is added, hydrogen is introduced for replacement, and the mixture is stirred while maintaining the hydrogenation state to obtain a regenerated palladium catalyst on carbon. 2) Add a neutralizing agent to the 11a-chloro-6-methyleneoxytetracycline solution to control the pH and neutralize it. Filter to obtain the 11a-chloro-6-methyleneoxytetracycline neutralized solution. 3) The 11a-chloro-6-methyleneoxytetracycline neutralized solution obtained in step 2) and the regenerated palladium on carbon catalyst obtained in step 1) are added to an ethanol solution and mixed. A temperature-controlled hydrogenation dechlorination reaction is carried out. After filtration, sulfosalicylic acid is added to the filtrate to crystallize into salt. After crystallization, the filtrate is discharged by centrifugation and then washed in batches with anhydrous ethanol to obtain methyloxytetracycline. 4) The methacycline obtained in step 3) was reacted with hydrochloric acid and crystallized, filtered, and dried to obtain methacycline hydrochloride.

2. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 1), the sodium acetate solution has a mass fraction of 10% to 30%, and the reflux time is 2 to 3 hours.

3. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 1), the organic ligand is selected from one or a mixture of two of quinoline and pyridine; the mass ratio of the spent palladium catalyst on carbon to the organic ligand is 50-70:

1.

4. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 1), the stirring time under hydrogenation is 2 to 4 hours, the reaction temperature is 40 to 65°C, and the hydrogen pressure is 0.30 to 0.45 MPa.

5. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 2), the neutralizing agent is selected from one or a mixture of sodium carbonate, sodium bicarbonate, and sodium acetate; the mass fraction of the neutralizing agent is 8-10%; and the pH is 5.0-7.

0.

6. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 2), the filtration uses a polyvinylidene fluoride or nylon membrane with a pore size of 0.20–0.45 μm.

7. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 3), the mass ratio of 11a-chloro-6-methyleneoxytetracycline neutralization solution: regenerated palladium catalyst on carbon: ethanol solution is 1:0.020-0.035:1.60-1.88, the volume fraction of ethanol solution is 50-60%; the reaction time is 3-5 h, the reaction temperature is 35-45 °C, the crystallization temperature is 5-10 °C, the crystallization time is 3-4 h, and the hydrogen pressure is 0.25-0.30 MPa.

8. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11a-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 3), the mass ratio of sulfosalicylic acid to the 11a-chloro-6-methyleneoxytetracycline solution in step 2) is 1:0.3-0.

35. After crystallization, the product is discharged by centrifugation and then washed in batches with anhydrous ethanol. The mass-volume ratio of the 11a-chloro-6-methyleneoxytetracycline neutralization solution to anhydrous ethanol is 1:0.25-0.

38.

9. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11α-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 4), the mass-to-volume ratio of methacycline to aqueous ethanol is 1:1.20-1.50, the mass-to-volume ratio of methacycline to hydrochloric acid is 1:1-1.2, the reaction temperature is 40-45℃, the crystallization temperature is 5-10℃, and the crystallization time is 4-6h.

10. The method for preparing low-impurity methacycline hydrochloride by direct neutralization using 11α-chloro-6-methyleneoxytetracycline solution as a raw material according to claim 1, characterized in that: In step 4), the volume fraction of the ethanol aqueous solution is 80-95%, and the volume fraction of hydrochloric acid is 32%; the drying temperature of oxytetracycline hydrochloride is 80℃, and the drying time is 3-4 hours.

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