Veterinary drug doxycycline composition and preparation process thereof

Abstract

The invention belongs to the technical field of doxycycline, and particularly relates to a veterinary drug doxycycline composition and a preparation process thereof, the veterinary drug doxycycline composition comprises 24%-26% of methanol, 3.5%-6.5% of oxytetracycline base, 0.03%-0.1% of methanol ammonia, 1.7%-3.2% of NBS, 24%-26% of 11 alpha-bromine-6, 12-hemiketal oxytetracycline, 7%-8% of HZSM-5, 24%-26% of toluenesulfonic acid and 3%-4% of palladium on carbon, the veterinary drug doxycycline composition further comprises catalysts, the catalysts comprise 2.7%-3.2% of titanium tetraisopropylate and 3.07%-4% of S-diphenol, and the reaction temperature is controlled to be 30-50 DEG C; the preparation method comprises the following steps: sequentially putting 100g of methanol, 10g of oxytetracycline base and 0.1 g of methanol ammonia into a reaction bottle, stirring for 30 minutes in an environment of 20-30 DEG C by using an ultrasonic stirrer, starting to cool to-10 to-15 DEG C, adding 5g of dried and crushed NBS, and carrying out dechlorination and asymmetric hydrogenation by using a self-made palladium-carbon catalyst, so that the yield and the chemical and stereoselectivity of the reaction are remarkably improved, the total yield reaches 53%, and the yield is up to 90%. The method has the advantages of high yield, good product quality and the like, and the doxycycline primary liquid is heated by heating equipment and lasts for a fixed time, so that the drug property of the doxycycline primary liquid is enhanced at a specific temperature, and the adverse reaction of drugs to animals is reduced.

Description

Technical Field

[0001] This invention belongs to the field of doxycycline technology, specifically relating to a veterinary drug doxycycline composition and its preparation process. Background Technology

[0002] Currently, doxycycline, also known as doxycycline hydrochloride or deoxyoxytetracycline hydrochloride, is mainly used as an antibiotic to treat infections caused by violet-positive cocci and violet-negative bacilli. It can also be used for rickettsial infections such as typhus and scrub typhus, and is effective against amoebic dysentery and atypical pneumonia. The current production process for doxycycline uses oxytetracycline as a raw material, which is purified through chlorination, dehydration, hydrogenation, and conversion.

[0003] In the production process of doxycycline, the hydrogenation reaction is the most crucial step, significantly impacting product quality and yield. During dechlorination and hydrogenation, the metal catalyst greatly influences the isomer selectivity, directly affecting the quality, yield, and cost of the final product. Current technologies often use 11α-chloro-methyloxytetracycline p-toluenesulfonate as a raw material, with Pd / C2 or silica-bonded Rh(PPh)Cl as a catalyst, simultaneously performing dechlorination and hydrogenation. This results in poor stereoselectivity and low yield. Summary of the Invention

[0004] To address the problems mentioned in the background section, this invention provides a veterinary drug doxycycline composition and its preparation process, which features improved stereoselectivity and yield.

[0005] To achieve the above objectives, the present invention provides the following technical solution: a veterinary drug doxycycline composition, comprising 24%-26% methanol, 3.5%-6.5% oxytetracycline base, 0.03%-0.1% methanol ammonia, 1.7%-3.2% NBS, 24%-26% 11α-bromo-6,12-hemiacetal oxytetracycline, 7%-8% HZSM-5, 24%-26% toluenesulfonic acid, and 3%-4% palladium on carbon.

[0006] Preferably, the catalyst is further comprising 2.7%-3.2% tetraisopropyltitanium oxychloride and 3.07%-4% S-biphenol.

[0007] Preferably, a process for preparing a veterinary drug doxycycline composition includes the following steps: Step 1: Place 100g of methanol, 10g of oxytetracycline base and 0.1g of methanol ammonia into a reaction flask in sequence. Stir with an ultrasonic stirrer at 20~30℃ for 30min, then start cooling to -10~-15℃. Add 5g of dried and pulverized NBS and stir for 15min. Monitor the reaction of the raw materials by TLC until the reaction is complete. A large amount of solid precipitates in the reaction flask. Filter the solid using a centrifuge to obtain a filter cake. Step 2: The filter cake was washed with cold methanol to obtain 11α-bromo-6,12-hemiacetal oxytetracycline with a yield of 95%. It was dried at low temperature to a content of about 90%. The mother liquor was fractionated and the methanol obtained was reused. Step 3: Add 500 mL of anhydrous benzene to a reaction vessel equipped with a dehydration device. Purge the reaction vessel with nitrogen gas. Slowly add 100 g of 11α-bromo-6,12-hemiacetal oxytetracycline while stirring, and then add 20 g of HZSM-5. Stir at room temperature for 2 hours, then slowly heat to reflux and drain the water generated in the reaction in time. Step 4: Dilute the residual liquid with ethanol, add ammonia in ethanol solution (7%) at a uniform rate to neutralize the reaction solution to pH 1-2, cool to 0℃, filter, monitor the reaction of the raw materials by TLC until the reaction is complete, cool naturally to 50℃, filter the reaction solution while hot, filter out the solid hydroxyl dehydrating agent, remove the reaction solvent benzene from the filtrate by evaporation, wash with 50mL of cold ethanol, add 50g of p-toluenesulfonic acid to the filtrate, and add a small amount of seed crystals to precipitate crystals, cool to 0℃ and filter, wash with cold ethanol to obtain 105g of 11α-bromo-6-methyleneoxytetracycline p-toluenesulfonic acid, yield 100%. After neutralizing the mother liquor with alkali to neutral, the benzene and ethanol obtained by distillation can be reused. Step 5: First, add 400mL of DMF and 200mL of water to the reaction flask, then add 100g of 11α-bromo-6-methyleneoxytetracycline p-toluenesulfonic acid and 12g of palladium on carbon (5wt%). Finally, add 4g of the chiral catalyst tetraisopropyloxytitanium and 5g of S-biphenol. Stir for 10 minutes, then add p-toluenesulfonate and stir until homogeneous. Aspirate into the hydrogenation tank, close the valve, and use a vacuum pump to evacuate to 40mmHg. Maintain this for 15 minutes, then introduce hydrogen gas at 30~35℃ while stirring. Continue introducing hydrogen gas for 2 hours until hydrogen absorption slows down. Take a sample for TLC. When the amount of methyleneoxytetracycline is trace, continue introducing hydrogen gas for 2 hours and then stop the reaction. Step 6: Slowly release hydrogen until the internal pressure is zero, then introduce nitrogen to remove the remaining hydrogen. Heat to 50°C, introduce nitrogen again, and filter through a filter press. Wash thoroughly with a DMF solution containing 10wt%~50wt% in several passes, then wash the palladium on carbon with an appropriate amount of distilled water. Combine the filtrate and washings and draw them into the reaction vessel to make the DMF content in the solution 40wt%~42wt%. Cool to 5°C, centrifuge and filter. Wash the filter cake once with a small amount of cold ethanol, and dry to obtain deoxyoxytetracycline hydrochloride with a yield of 53%. Feed it into a tablet press according to different needs to obtain fixed tablets and package them.

[0008] Preferably, in step five, the internal pressure is maintained at 1.5~2 kg / cm2 when hydrogen is introduced.

[0009] Preferably, in step six, the 10wt%~50wt% DMF solution is heated to 50°C.

[0010] Preferably, in step six, the specific steps for adding the drug powder into the capsule and tablet press according to different needs to obtain capsules and fixed tablets and then packaging them are as follows: put the veterinary drug doxycycline powder into the tablet press and start the equipment to press the powder into tablets of uniform size, and then package the processed tablets.

[0011] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention utilizes a self-made palladium-carbon catalyst for dechlorination and asymmetric hydrogenation, significantly improving the yield and chemical and stereoselectivity of the reaction, with a total yield of 53%. It has the advantages of high yield and good product quality. Furthermore, by heating the initial doxycycline solution using a heating device for a fixed duration, the drug efficacy of the initial doxycycline solution is enhanced at a specified temperature, and adverse drug reactions in animals are reduced. Detailed Implementation

[0012] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0013] Example 1 The present invention provides the following technical solution: a veterinary drug doxycycline composition, comprising 24%-26% methanol, 3.5%-6.5% oxytetracycline base, 0.03%-0.1% methanol ammonia, 1.7%-3.2% NBS, 24%-26% 11α-bromo-6,12-hemiacetal oxytetracycline, 7%-8% HZSM-5, 24%-26% toluenesulfonic acid and 3%-4% palladium on carbon.

[0014] Specifically, it also includes a catalyst, which consists of 2.7%-3.2% tetraisopropyltitanium oxychloride and 3.07%-4% S-biphenol.

[0015] Specifically, the preparation process of a veterinary drug doxycycline composition includes the following steps: Step 1: Place 100g of methanol, 10g of oxytetracycline base and 0.1g of methanol ammonia into a reaction flask in sequence. Stir with an ultrasonic stirrer at 20~30℃ for 30min, then start cooling to -10~-15℃. Add 5g of dried and pulverized NBS and stir for 15min. Monitor the reaction of the raw materials by TLC until the reaction is complete. A large amount of solid precipitates in the reaction flask. Filter the solid using a centrifuge to obtain a filter cake. Step 2: The filter cake was washed with cold methanol to obtain 11α-bromo-6,12-hemiacetal oxytetracycline with a yield of 95%. It was dried at low temperature to a content of about 90%. The mother liquor was fractionated and the methanol obtained was reused. Step 3: Add 500 mL of anhydrous benzene to a reaction vessel equipped with a dehydration device. Purge the reaction vessel with nitrogen gas. Slowly add 100 g of 11α-bromo-6,12-hemiacetal oxytetracycline while stirring, and then add 20 g of HZSM-5. Stir at room temperature for 2 hours, then slowly heat to reflux and drain the water generated in the reaction in time. Step 4: Dilute the residual liquid with ethanol, add ammonia in ethanol solution (7%) at a uniform rate to neutralize the reaction solution to pH 1-2, cool to 0℃, filter, monitor the reaction of the raw materials by TLC until the reaction is complete, cool naturally to 50℃, filter the reaction solution while hot, filter out the solid hydroxyl dehydrating agent, remove the reaction solvent benzene from the filtrate by evaporation, wash with 50mL of cold ethanol, add 50g of p-toluenesulfonic acid to the filtrate, and add a small amount of seed crystals to precipitate crystals, cool to 0℃ and filter, wash with cold ethanol to obtain 105g of 11α-bromo-6-methyleneoxytetracycline p-toluenesulfonic acid, yield 100%. After neutralizing the mother liquor with alkali to neutral, the benzene and ethanol obtained by distillation can be reused. Step 5: First, add 400mL of DMF and 200mL of water to the reaction flask, then add 100g of 11α-bromo-6-methyleneoxytetracycline p-toluenesulfonic acid and 12g of palladium on carbon (5wt%). Finally, add 4g of the chiral catalyst tetraisopropyloxytitanium and 5g of S-biphenol. Stir for 10 minutes, then add p-toluenesulfonate and stir until homogeneous. Aspirate into the hydrogenation tank, close the valve, and use a vacuum pump to evacuate to 40mmHg. Maintain this for 15 minutes, then introduce hydrogen gas at 30~35℃ while stirring. Continue introducing hydrogen gas for 2 hours until hydrogen absorption slows down. Take a sample for TLC. When the amount of methyleneoxytetracycline is trace, continue introducing hydrogen gas for 2 hours and then stop the reaction. Step 6: Slowly release hydrogen until the internal pressure is zero, then introduce nitrogen to remove the remaining hydrogen. Heat to 50°C, introduce nitrogen again, and filter through a filter press. Wash thoroughly with a DMF solution containing 10wt%~50wt% in several passes, then wash the palladium on carbon with an appropriate amount of distilled water. Combine the filtrate and washings and draw them into the reaction vessel to make the DMF content in the solution 40wt%~42wt%. Cool to 5°C, centrifuge and filter. Wash the filter cake once with a small amount of cold ethanol, and dry to obtain deoxyoxytetracycline hydrochloride with a yield of 53%. Feed it into a tablet press according to different needs to obtain fixed tablets and package them.

[0016] Specifically, in step five, when hydrogen is introduced, the internal pressure should be maintained at 1.5~2 kg / cm2.

[0017] Specifically, in step six, the 10wt%~50wt% DMF solution is heated to 50°C.

[0018] Specifically, in step six, the specific steps for adding the drug powder into the capsule and tablet press according to different needs to obtain capsules and fixed tablets and then packaging them are as follows: put the veterinary drug doxycycline powder into the tablet press and start the equipment to press the powder into tablets of uniform size, and then package the processed tablets.

[0019] Finally, it should be noted that the above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A veterinary drug doxycycline composition, characterized in that: It includes 24%-26% methanol, 3.5%-6.5% oxytetracycline base, 0.03%-0.1% methanol ammonia, 1.7%-3.2% NBS, 24%-26% 11α-bromo-6,12-hemiacetal oxytetracycline, 7%-8% HZSM-5, 24%-26% toluenesulfonic acid, and 3%-4% palladium on carbon.

2. The veterinary drug doxycycline composition according to claim 1, characterized in that: It also includes a catalyst, which is 2.7%-3.2% tetraisopropyltitanium oxychloride and 3.07%-4% S-biphenol.

3. The preparation process of the veterinary drug doxycycline composition according to any one of claims 1-2, characterized in that: Includes the following steps: Step 1: Place 100g of methanol, 10g of oxytetracycline base and 0.1g of methanol ammonia into a reaction flask in sequence. Stir with an ultrasonic stirrer at 20~30℃ for 30min, then start cooling to -10~-15℃. Add 5g of dried and pulverized NBS and stir for 15min. Monitor the reaction of the raw materials by TLC until the reaction is complete. A large amount of solid precipitates in the reaction flask. Filter the solid using a centrifuge to obtain a filter cake. Step 2: The filter cake was washed with cold methanol to obtain 11α-bromo-6,12-hemiacetal oxytetracycline with a yield of 95%. It was dried at low temperature to a content of about 90%. The mother liquor was fractionated and the methanol obtained was reused. Step 3: Add 500 mL of anhydrous benzene to a reaction vessel equipped with a dehydration device. Purge the reaction vessel with nitrogen gas. Slowly add 100 g of 11α-bromo-6,12-hemiacetal oxytetracycline while stirring, and then add 20 g of HZSM-5. Stir at room temperature for 2 hours, then slowly heat to reflux and drain the water generated in the reaction in time. Step 4: Dilute the residual liquid with ethanol, add ammonia in ethanol solution (7%) at a uniform rate to neutralize the reaction solution to pH 1-2, cool to 0℃, filter, monitor the reaction of the raw materials by TLC until the reaction is complete, cool naturally to 50℃, filter the reaction solution while hot, filter out the solid hydroxyl dehydrating agent, remove the reaction solvent benzene from the filtrate by evaporation, wash with 50mL of cold ethanol, add 50g of p-toluenesulfonic acid to the filtrate, and add a small amount of seed crystals to precipitate crystals, cool to 0℃ and filter, wash with cold ethanol to obtain 105g of 11α-bromo-6-methyleneoxytetracycline p-toluenesulfonic acid, yield 100%. After neutralizing the mother liquor with alkali to neutral, the benzene and ethanol obtained by distillation can be reused. Step 5: First, add 400mL of DMF and 200mL of water to the reaction flask, then add 100g of 11α-bromo-6-methyleneoxytetracycline p-toluenesulfonic acid and 12g of palladium on carbon (5wt%). Finally, add 4g of the chiral catalyst tetraisopropyloxytitanium and 5g of S-biphenol. Stir for 10 minutes, then add p-toluenesulfonate and stir until homogeneous. Aspirate into the hydrogenation tank, close the valve, and use a vacuum pump to evacuate to 40mmHg. Maintain this for 15 minutes, then introduce hydrogen gas at 30~35℃ while stirring. Continue introducing hydrogen gas for 2 hours until hydrogen absorption slows down. Take a sample for TLC. When the amount of methyleneoxytetracycline is trace, continue introducing hydrogen gas for 2 hours and then stop the reaction. Step 6: Slowly release hydrogen until the internal pressure is zero, then introduce nitrogen to remove the remaining hydrogen. Heat to 50°C, introduce nitrogen again, and filter through a filter press. Wash thoroughly with a DMF solution containing 10wt%~50wt% in several passes, then wash the palladium on carbon with an appropriate amount of distilled water. Combine the filtrate and washings and draw them into the reaction vessel to make the DMF content in the solution 40wt%~42wt%. Cool to 5°C, centrifuge and filter. Wash the filter cake once with a small amount of cold ethanol, and dry to obtain deoxyoxytetracycline hydrochloride with a yield of 53%. Feed it into a tablet press according to different needs to obtain fixed tablets and package them.

4. The preparation process of the veterinary drug doxycycline composition according to claim 3, characterized in that: In step five, when hydrogen is introduced, the internal pressure is maintained at 1.5~2 kg / cm2.

5. The preparation process of the veterinary drug doxycycline composition according to claim 3, characterized in that: In step six, a 10wt%~50wt% DMF solution is heated to 50°C.

6. The preparation process of the veterinary drug doxycycline composition according to claim 3, characterized in that: In step six, the specific steps for adding the drug powder into the capsule and tablet press according to different needs to obtain capsules and fixed tablets and then packaging them are as follows: put the veterinary drug doxycycline powder into the tablet press and start the equipment to press the powder into tablets of uniform size, and then package the processed tablets.