Low-cost environment-friendly method for preparing doxycycline hydrochloride

Abstract

The invention discloses a low-cost environment-friendly method for preparing doxycycline hydrochloride, and belongs to the technical field of organic compound synthesis. The method comprises the following steps: filtering a doxycycline hydrochloride hydrogenation reaction solution while the solution is hot, and carrying out reduced pressure distillation on the filtrate to obtain doxycycline mixed salt; carrying out salt conversion reaction on the doxycycline mixed salt, and separating to obtain doxycycline hydrochloride and salt conversion mother liquor; p-toluenesulfonic acid with relatively high purity can be obtained by treating the salt conversion mother liquor, and the p-toluenesulfonic acid can be used for preparing the 11alpha-chloro-6-methylene oxytetracycline p-toluenesulfonate. Hydrogenation reaction liquid is directly subjected to vacuum concentration after being filtered while hot, additional heat supply is not needed in the process, effective control over energy consumption is achieved through optimization of process steps, and production energy consumption is remarkably reduced; in the hydrogenation reaction salification stage, the addition of sulfosalicylic acid is abandoned, and the consumption of the raw material is effectively avoided, so that the purchase cost of the raw material is greatly reduced, and the production economy is improved.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a low-cost and environmentally friendly method for preparing doxycycline hydrochloride. Background Technology

[0002] Doxycycline hydrochloride is a second-generation semi-synthetic tetracycline derivative and is one of the commonly used broad-spectrum antibacterial drugs. It is mainly used to treat upper respiratory tract infections, tonsillitis, biliary tract infections, lymphadenitis, and chronic bronchitis in the elderly caused by susceptible Gram-positive cocci and Gram-negative bacilli. It can also be used to treat anthrax.

[0003] Currently, the preparation process of doxycycline hydrochloride uses 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate as the starting material, and the specific steps are as follows: First, a hydrogenation reduction reaction is carried out, then sulfosalicylic acid is used to form a salt to generate 6-α-deoxyoxytetracycline sulfosalicylic acid; then, doxycycline is generated through an alkalization reaction, and finally doxycycline hydrochloride is obtained through a salt transfer reaction.

[0004] In the above process, after the formation of 6-α-deoxyoxygenase sulfosalicylate from sulfosalicylic acid, the mother liquor contains a mixture of p-toluenesulfonic acid and sulfosalicylic acid. This mixture adversely affects the subsequent recovery of p-toluenesulfonic acid and sulfosalicylic acid, resulting in low purity of the recovered substances. If the mother liquor is not treated, it will form high-salinity wastewater, which has the following main hazards: it will damage the soil structure, increase soil alkalinity, cause soil hardening and plateauing, make it difficult to restore soil physiological activity, cause soil organisms and plants to die due to dehydration, and thus cause the collapse of the soil ecosystem; at the same time, it will accelerate the eutrophication process of rivers and lakes. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the technical problem to be solved by this invention is to provide a low-cost and environmentally friendly method for preparing doxycycline hydrochloride, which is green, environmentally friendly, and suitable for industrial production.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] A low-cost and environmentally friendly method for preparing doxycycline hydrochloride involves hot filtration of the doxycycline hydrochloride hydrogenation reaction solution, followed by vacuum distillation of the filtrate, filtration, and concentration to obtain a mixed doxycycline salt. The mixed doxycycline salt is then subjected to a salt-transfer reaction to separate doxycycline hydrochloride and a salt-transfer mother liquor. The salt-transfer mother liquor is then recycled to obtain p-toluenesulfonic acid, which is used in the preparation of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate.

[0008] Preferably, the preparation process of the doxycycline hydrochloride hydrogenation reaction solution is as follows: 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate, palladium on carbon catalyst and auxiliary agent are mixed and subjected to hydrogenation reaction at a reaction temperature of 60-70°C and a reaction time of 5-6 hours to obtain the doxycycline hydrochloride hydrogenation reaction solution.

[0009] Preferably, the mass ratio of the 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate, the palladium on carbon catalyst, and the auxiliary agent is 1:0.05-0.13:0.0028-0.0128.

[0010] The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner includes the following steps:

[0011] 1) Filter the hydrogenation reaction solution of doxycycline hydrochloride while hot, and distill the filtrate under reduced pressure to obtain doxycycline mixed salts;

[0012] 2) The doxycycline mixed salt, ethanol, and hydrochloric acid ethanol obtained in step 1) are mixed and subjected to a salt conversion reaction. After the reaction is completed, the temperature is lowered and filtered to obtain doxycycline hydrochloride wet product and salt conversion mother liquor. The obtained salt conversion mother liquor is recycled to obtain p-toluenesulfonic acid.

[0013] Preferably, in step 1), the temperature of the doxycycline hydrochloride hydrogenation reaction solution is 55–70°C, and the temperature of the filtrate after filtration is 50–60°C.

[0014] Preferably, in step 1), the vacuum degree of the reduced pressure distillation is -0.05 to -0.07 MPa, and the concentration volume is 40 to 50% of the original mother liquor volume.

[0015] Preferably, in step 2), the mass ratio of doxycycline mixed salt, ethanol, and ethanol hydrochloride is 1:0.9-1.2:1.5-3.

[0016] Preferably, in step 2), the reaction temperature of the salt conversion reaction is 45–55°C.

[0017] Preferably, in step 2), the mass fraction of hydrochloric acid in the hydrochloric acid ethanol is 15-20%.

[0018] Preferably, the doxycycline hydrochloride liquid obtained in step 2) is purified as follows:

[0019] 3) Take the doxycycline hydrochloride wet product obtained in step 2) and mix it with 35-40% ethanol. Add ammonia dropwise until the solution is clear. Stop adding ammonia dropwise, filter, keep the filtrate warm for a period of time, then cool down and filter to obtain doxycycline monohydrate wet product.

[0020] 4) Take the doxycycline monohydrate obtained in step 3), ethanol, and ethanol hydrochloride, mix them, and carry out a salt conversion reaction. After the reaction is completed, cool down and filter to obtain the doxycycline hydrochloride.

[0021] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0022] (1) The present invention performs hot filtration of hydrogenation reaction liquid and then direct vacuum concentration. This process does not require additional heating. Through the optimization of process steps, energy consumption is effectively controlled, and production energy consumption is significantly reduced.

[0023] (2) In the salt formation stage of hydrogenation reaction, the present invention eliminates the addition of sulfosalicylic acid, effectively avoiding the consumption of this raw material, thereby significantly reducing the raw material procurement cost and improving the economic efficiency of production.

[0024] (3) Since the mother liquor of the salt conversion contains only p-toluenesulfonic acid, high-purity p-toluenesulfonic acid can be recovered through treatment. The recovered p-toluenesulfonic acid can be directly reused in the production process of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate, forming a raw material recycling system. This not only reduces production costs but also significantly alleviates environmental protection pressure, achieving a synergistic improvement in economic and environmental benefits.

[0025] (4) In the purification step, a lower concentration of ethanol solution can be used to obtain a higher yield than that of traditional alkalization purification. Attached Figure Description

[0026] Figure 1 The process flow diagram for preparing doxycycline hydrochloride according to the present invention is shown below;

[0027] Figure 2 A schematic diagram of the traditional doxycycline hydrochloride preparation process;

[0028] Figure 3 The HPLC chromatogram of doxycycline hydrochloride obtained in step 4) of Example 3 is shown. Detailed Implementation

[0029] 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 should be understood as being for illustrative purposes only and not for limiting the scope of the invention. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0030] The 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate used in the following examples is the product prepared in patent application publication number CN114315627B. The relative content of the main impurities in this 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate is 1.4%, and the relative content of unknown impurities is less than 0.1%. The adjuvants used in the following examples consist of metronidazole, 4-methylpyridine, and 2,4-dihydroxyquinoline in a mass ratio of 1:5:10.

[0031] This application provides a low-cost and environmentally friendly method for preparing doxycycline hydrochloride, the process flow diagram of which is shown below. Figure 1 As shown, the hydrogenation reaction solution of doxycycline hydrochloride is filtered while hot, and the filtrate is distilled under reduced pressure to obtain a mixed doxycycline salt. The mixed doxycycline salt is then mixed with ethanol and ethanol hydrochloride to convert the salt into doxycycline hydrochloride. The mother liquor after salt conversion is concentrated, cooled, and crystallized to obtain p-toluenesulfonic acid, which is used in the production of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate. Notably, in the salt formation stage of the hydrogenation reaction, this application eliminates the need for the addition of sulfosalicylic acid, reducing the number of process steps and making the process easier to operate. By reducing process steps, the consumption of the raw material sulfosalicylic acid is effectively avoided, thus significantly reducing raw material procurement costs and improving production economics. Since the mother liquor from the salt conversion process contains only p-toluenesulfonic acid, high-purity p-toluenesulfonic acid can be recovered through treatment. This recovered p-toluenesulfonic acid can be directly reused in the production of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate, forming a raw material recycling system. This reduces production costs and significantly alleviates environmental protection pressure, further embodying the concepts of low cost and environmental protection. Simultaneously, this application implements hot filtration of the hydrogenation reaction liquid followed by direct vacuum concentration. This process requires no additional heating, and the optimization of process steps achieves effective control of energy consumption, further significantly reducing production energy consumption; reducing process costs, and saving energy and reducing emissions.

[0032] Example 1

[0033] A low-cost and environmentally friendly method for preparing doxycycline hydrochloride includes the following steps:

[0034] 1) 1200g of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate wet product was mixed with 2L of 60% ethanol and added to a hydrogenation reactor. After stirring, 96g of palladium on carbon catalyst and 9.6g of auxiliary agent were added. Nitrogen was replaced three times and hydrogen was replaced three times. The reaction temperature was controlled at 60℃. Hydrogen was introduced and the reaction was carried out for 5 hours. After the reaction was completed, the mixture was filtered while hot. 2400mL of the filtrate at 55℃ was placed in a 5L rotary evaporator. The vacuum degree was controlled at -0.06MPa and the filtrate temperature was kept at 55℃. The mixture was concentrated by distillation to 1150mL and cooled to 20℃ to obtain 550g of doxycycline mixed salt.

[0035] 2) Take 200g of the doxycycline mixed salt obtained in step 1) and mix it with 200g of 95% ethanol. Add the mixture to a three-necked flask, place it in a constant temperature water bath, start stirring, add 400g of 15% hydrochloric acid ethanol, continue heating to 45℃, keep at this temperature for 1 hour, then cool to 25℃, filter to obtain 175g of toxycycline hydrochloride wet product and 610g of salt conversion mother liquor. Dry the toxycycline hydrochloride wet product at 80℃ and determine its water solubility. After recycling the obtained salt conversion mother liquor, p-toluenesulfonic acid with a purity of 91.5% was obtained.

[0036] The p-toluenesulfonic acid is directly recycled for the preparation of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate raw material.

[0037] Example 2

[0038] A low-cost and environmentally friendly method for preparing doxycycline hydrochloride includes the following steps:

[0039] 1) 1200 kg of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate wet product was mixed with 2100 L of 60% ethanol and added to a hydrogenation reactor. After stirring, 120 kg of palladium on carbon catalyst and 12 kg of auxiliary agent were added. Nitrogen gas was purged three times and hydrogen gas was purged three times. The reaction temperature was controlled at 70 °C. Hydrogen gas was introduced and the reaction was carried out for 5.5 h. The mixture was filtered while hot. 2500 L of filtrate at 50 °C was passed through a falling film evaporator. The vacuum degree was controlled at -0.07 MPa and the filtrate temperature was kept at 50 °C. The mixture was distilled and concentrated to 1055 L and cooled to 21 °C to obtain 547 kg of doxycycline mixed salt.

[0040] 2) Take 500 kg of the doxycycline mixed salt obtained in step 1) and mix it with 570 kg of 95% ethanol. Add the mixture to a reaction vessel, start stirring, turn on steam, add 800 kg of 20% hydrochloric acid-ethanol mixture, continue heating to 50°C, maintain the temperature for 1 hour, cool to 24°C, and filter to obtain 438.6 kg of wet doxycycline hydrochloride and 1400 kg of salt conversion mother liquor. After drying the wet doxycycline hydrochloride at 80°C, determine its water solubility. After recycling the obtained salt conversion mother liquor, p-toluenesulfonic acid with a purity of 90.5% is obtained.

[0041] The p-toluenesulfonic acid is directly recycled for the preparation of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate raw material.

[0042] Example 3

[0043] A low-cost and environmentally friendly method for preparing doxycycline hydrochloride includes the following steps:

[0044] 1) 1200g of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate wet product was mixed with 2L of 60% ethanol and added to a hydrogenation reactor. After stirring, 150g of palladium on carbon catalyst and 14.5g of auxiliary agent were added. Nitrogen was replaced three times and hydrogen was replaced three times. The reaction temperature was controlled at 70℃. Hydrogen was introduced and the reaction was carried out for 6 hours. After the reaction was completed, the mixture was filtered while hot. 2400mL of the filtrate at 60℃ was placed in a 5L rotary evaporator. The vacuum degree was controlled at -0.05MPa and the filtrate temperature was kept at 60℃. The mixture was concentrated by distillation to 1080mL and cooled to 22℃ to obtain 555g of doxycycline mixed salt.

[0045] 2) Take 200g of the doxycycline mixed salt obtained in step 1) and mix it with 200g of 95% ethanol. Add the mixture to a three-necked flask, place it in a constant temperature water bath, turn on the stirrer, add 375g of 16% hydrochloric acid ethanol, continue heating to 55℃, keep it at this temperature for 1 hour, and then cool it down to 25℃. Filter to obtain 173.1g of doxycycline hydrochloride wet product and 600g of salt conversion mother liquor. After recycling the obtained salt conversion mother liquor, p-toluenesulfonic acid with a purity of 91% is obtained.

[0046] The p-toluenesulfonic acid is directly recycled for the preparation of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate raw material.

[0047] 3) Take 150g of the doxycycline hydrochloride liquid obtained in step 2) and mix it with 260g of 38% ethanol. Add the mixture to a three-necked flask, place it in a low-temperature bath, and start stirring. When the temperature drops to 8℃, add 11% ammonia water dropwise until the solution is clear. Stop adding ammonia water dropwise, filter, and put the filtrate into a beaker. Place the beaker in a constant temperature water bath and heat it to 40℃. Keep it at that temperature for 1 hour, then cool it down to 25℃ and filter to obtain 135g of doxycycline monohydrate liquid.

[0048] 4) Take 135g of the doxycycline monohydrate (prepared in step 3) and mix it with 270g of 95% ethanol. Add the mixture to a three-necked flask, place it in a constant temperature water bath, start stirring, add 110g of 30% hydrochloric acid-ethanol, heat to 55℃, keep warm for 1 hour, cool to 25℃, and filter to obtain 136g of doxycycline hydrochloride (prepared in 80℃). After drying the doxycycline hydrochloride (prepared in 80℃), determine its water solubility.

[0049] Comparative Example 1

[0050] This comparative example provides a traditional method for preparing doxycycline hydrochloride, with the process flow diagram shown below. Figure 2 As shown, it includes the following steps:

[0051] 1) Mix 1200g of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate with 2L of... After mixing with 60% ethanol, the mixture was added to a hydrogenation reactor. 96g of palladium on carbon catalyst and 9.6g of auxiliary agent were added with stirring. Nitrogen was purged three times, followed by hydrogen purging three times. The reaction temperature was controlled at 60℃, and hydrogen was introduced. The reaction was carried out for 6 hours, and the mixture was filtered while hot. 380g of sulfosalicylic acid was added to 2400mL of the filtrate, and the mixture was stirred to form a salt. After standing, the solution was filtered to obtain 920g of the sulfosalicylic acid wet product. The mother liquor was then subjected to recovery of p-toluenesulfonic acid and sulfosalicylic acid. This process involved neutralization, filtration, distillation and concentration, and cooling crystallization to obtain a mixed salt of p-toluenesulfonic acid and sulfosalicylic acid. This mixed salt was then converted to acid to obtain a further mixture of p-toluenesulfonic acid and sulfosalicylic acid. Only 72% purity p-toluenesulfonic acid could be recovered, which is unsuitable for the production of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate as it would affect the subsequent hydrogenation reaction.

[0052] 2) Take 300g of the sulfonate product obtained in step 1) and mix it with 500g of 60% ethanol. Add the mixture to a three-necked flask, place it in a low-temperature bath, and start stirring. When the temperature drops to 10℃, add 10% ammonia water dropwise until the solution is clear. Stop adding ammonia water dropwise, filter, and put the filtrate into a beaker. Place the beaker in a constant temperature water bath and heat it to 45℃. Keep it at that temperature for 1 hour, then cool it down to 25℃ and filter to obtain 153g of doxycycline monohydrate product.

[0053] 3) Take 150g of the doxycycline monohydrate (prepared in step 2) and mix it with 300g of 95% ethanol. Add the mixture to a three-necked flask, place it in a constant temperature water bath, start stirring, add 120g of 30% hydrochloric acid-ethanol mixture, heat to 55℃, keep warm for 1 hour, cool to 25℃, and filter to obtain 155g of doxycycline hydrochloride (prepared in 80℃). After drying, determine its water solubility.

[0054] Comparative Example 2

[0055] 1200g of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate wet product was mixed with 2L of 60% ethanol and added to a hydrogenation reactor. After stirring, 96g of palladium catalyst on carbon and 9.6g of auxiliary agent were added. Nitrogen gas was purged three times and hydrogen gas was purged three times. The reaction temperature was controlled at 60℃ and hydrogen gas was introduced. The reaction was carried out for 6 hours. The mixture was not filtered while hot and was cooled to 25℃. The reaction intermediate had precipitated and mixed with the palladium catalyst on carbon, making it impossible to carry out subsequent operations.

[0056] Comparative Example 3

[0057] 1200g of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate was mixed with 2L of 60% ethanol and added to a hydrogenation reactor. After stirring, 96g of palladium on carbon catalyst and 9.6g of auxiliary agent were added. Nitrogen was purged three times and hydrogen was purged three times. The reaction temperature was controlled at 60℃. Hydrogen was introduced and the reaction was carried out for 5 hours. After the reaction was completed, the mixture was filtered while hot to obtain 2400mL of filtrate. The filtrate was cooled to 20℃ to obtain 230g of doxycycline mixed salt.

[0058] 2) Mix 230g of the doxycycline mixed salt obtained in step 1) with 250g of 95% ethanol, add the mixture to a three-necked flask, place it in a constant temperature water bath, start stirring, add 500g of 15% hydrochloric acid-ethanol mixture, continue heating to 45℃, keep at this temperature for 1 hour, then cool to 25℃, filter to obtain 175g of toxycycline hydrochloride wet product and 785g of the salt conversion mother liquor. Dry the toxycycline hydrochloride wet product at 80℃, and determine its water solubility. After recycling the obtained salt conversion mother liquor, p-toluenesulfonic acid with a purity of 91.1% was obtained.

[0059] The p-toluenesulfonic acid is directly recycled for the preparation of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate raw material.

[0060] Comparative Example 4

[0061] 1) 1200g of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate wet product was mixed with 2L of 60% ethanol and added to a hydrogenation reactor. After stirring, 96g of palladium on carbon catalyst and 9.6g of auxiliary agent were added. Nitrogen was replaced three times and hydrogen was replaced three times. The reaction temperature was controlled at 60℃. Hydrogen was introduced and the reaction was carried out for 5h. After the reaction was completed, the mixture was filtered while hot. 2400mL of the filtrate at 55℃ was placed in a 5L rotary evaporator. The vacuum degree was controlled at -0.06MPa and the filtrate temperature was kept at 55℃. The mixture was concentrated by distillation to 550mL and cooled to 21℃ to obtain 610g of doxycycline mixed salt.

[0062] 2) Take 200g of the doxycycline mixed salt obtained in step 1) and mix it with 200g of 95% ethanol. Add the mixture to a three-necked flask, place it in a constant temperature water bath, start stirring, add 400g of 15% hydrochloric acid ethanol, continue heating to 45℃, keep at this temperature for 1 hour, then cool to 25℃, filter to obtain 162g of tidal doxycycline hydrochloride and 605g of the salt conversion mother liquor. After drying the tidal doxycycline hydrochloride at 80℃, its water solubility was determined to be non-dissolving. After recycling the obtained salt conversion mother liquor, p-toluenesulfonic acid with a purity of 90.8% was obtained.

[0063] The p-toluenesulfonic acid is directly recycled for the preparation of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate raw material.

[0064] Comparative Example 5

[0065] This comparative example provides a traditional method for preparing doxycycline hydrochloride, with the process flow diagram shown below. Figure 2 As shown, it includes the following steps:

[0066] 1) Mix 1200g of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate with 2L of... After mixing with 60% ethanol, the mixture was added to a hydrogenation reactor. 96g of palladium on carbon catalyst and 9.6g of auxiliary agent were added with stirring. Nitrogen was purged three times, followed by hydrogen purging three times. The reaction temperature was controlled at 60℃, and hydrogen was introduced. The reaction was carried out for 6 hours, and the mixture was filtered while hot. 380g of sulfosalicylic acid was added to 2400mL of the filtrate, and the mixture was stirred to form a salt. After standing, the solution was filtered to obtain 920g of the sulfosalicylic acid wet product. The mother liquor was then subjected to recovery of p-toluenesulfonic acid and sulfosalicylic acid. This process involved neutralization, filtration, distillation and concentration, and cooling crystallization to obtain a mixed salt of p-toluenesulfonic acid and sulfosalicylic acid. This mixed salt was then converted to acid to obtain a further mixture of p-toluenesulfonic acid and sulfosalicylic acid. Only 75% pure p-toluenesulfonic acid could be recovered, which is unsuitable for the production of 11α-chloro-6-methyleneoxytetracycline p-toluenesulfonate as it would affect the subsequent hydrogenation reaction.

[0067] 2) Take 300g of the sulfonate product obtained in step 1) and mix it with 500g of 38% ethanol. Add the mixture to a three-necked flask, place it in a low-temperature bath, and start stirring. When the temperature drops to 10℃, add 10% ammonia water dropwise until the solution is clear. Stop adding ammonia water dropwise, filter, and put the filtrate into a beaker. Place the beaker in a constant temperature water bath and heat it to 45℃. Keep it at that temperature for 1 hour, then cool it down to 25℃ and filter to obtain 155g of doxycycline monohydrate product.

[0068] 3) Take 155g of the doxycycline monohydrate (prepared in step 2) and mix it with 300g of 95% ethanol. Add the mixture to a three-necked flask, place it in a constant temperature water bath, start stirring, add 120g of 30% hydrochloric acid-ethanol, heat to 55℃, keep warm for 1 hour, cool to 25℃, and filter to obtain 160g of doxycycline hydrochloride (prepared in 80℃). After drying, its water solubility was determined to be non-dissolving.

[0069] Example 4

[0070] The performance of doxycycline hydrochloride prepared in Examples 1-3 and Comparative Examples 1 and 3-5 was tested, and the results are shown in Table 1.

[0071] Table 1 Performance test results of doxycycline hydrochloride

[0072]

[0073]

[0074] As shown in Table 1 above, the doxycycline hydrochloride prepared in this application complies with the relevant provisions of the European Pharmacopoeia 11.0.

[0075] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A low-cost and environmentally friendly method for preparing doxycycline hydrochloride, characterized in that, The hydrogenation reaction solution of doxycycline hydrochloride was filtered while hot, and the filtrate was distilled under reduced pressure to obtain a mixed salt of doxycycline. The mixed salt of doxycycline was subjected to a salt conversion reaction to separate doxycycline hydrochloride and a salt conversion mother liquor. The salt conversion mother liquor was recovered to obtain p-toluenesulfonic acid, which was used in the preparation of 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate.

2. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 1, characterized in that, The preparation process of the doxycycline hydrochloride hydrogenation reaction solution is as follows: The 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate product, palladium on carbon catalyst, and auxiliary agent were mixed and subjected to hydrogenation reaction at a temperature of 60–70 °C for 5–6 h to obtain doxycycline hydrochloride hydrogenation reaction solution.

3. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 2, characterized in that, The mass ratio of the 11α-chloro-6-methylene oxytetracycline p-toluenesulfonate, palladium on carbon catalyst, and auxiliary agent is 1:0.05-0.13:0.0028-0.0128.

4. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 1, characterized in that, Includes the following steps: 1) Filter the hydrogenation reaction solution of doxycycline hydrochloride while hot, and distill the filtrate under reduced pressure to obtain doxycycline mixed salts; 2) The doxycycline mixed salt, ethanol, and hydrochloric acid ethanol obtained in step 1) are mixed and subjected to a salt conversion reaction. After the reaction is completed, the temperature is lowered and filtered to obtain doxycycline hydrochloride wet product and salt conversion mother liquor. The obtained salt conversion mother liquor is recycled to obtain p-toluenesulfonic acid.

5. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 4, characterized in that, In step 1), the temperature of the doxycycline hydrochloride hydrogenation reaction solution is 55-70°C, and the temperature of the filtrate after filtration is 50-60°C.

6. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 4, characterized in that, In step 1), the vacuum degree of vacuum distillation is -0.05 to -0.07 MPa, and the concentration volume is reduced to 40 to 50% of the original mother liquor volume.

7. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 4, characterized in that, In step 2), the mass ratio of doxycycline mixed salt, ethanol, and ethanol hydrochloride is 1:0.9-1.2:1.5-3.

8. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 4, characterized in that, In step 2), the reaction temperature for the salt conversion reaction is 45–55°C.

9. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 4, characterized in that, In step 2), the mass fraction of hydrochloric acid in the hydrochloric acid ethanol is 15-20%.

10. The method for preparing doxycycline hydrochloride at low cost and in an environmentally friendly manner according to claim 4, characterized in that, Step 2) The obtained doxycycline hydrochloride solution was purified as follows: 3) Take the doxycycline hydrochloride wet product obtained in step 2) and mix it with 35-40% ethanol. Add ammonia dropwise until the solution is clear. Stop adding ammonia dropwise, filter, keep the filtrate warm for a period of time, then cool down and filter to obtain doxycycline monohydrate wet product. 4) Take the doxycycline monohydrate obtained in step 3), ethanol, and ethanol hydrochloride, mix them, and carry out a salt conversion reaction. After the reaction is completed, cool down and filter to obtain the doxycycline hydrochloride.

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