CN115028546A - Method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate - Google Patents
Method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate Download PDFInfo
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Abstract
The invention discloses a method for preparing doxycycline sulfosalicylate by hydrogenation of metacycline p-toluenesulfonate, belonging to the technical field of metacycline, which comprises the following steps: preparing methyl tert-butyl rhodium chloride, preparing diphenyl butyl rhodium chloride, and preparing doxycycline sulfosalicylate; the preparation method of methyl tert-butyl rhodium chloride comprises the following steps: preparing a rhodium chloride solution, preparing an acetone solution of methyl tert-butyl ether, and mixing rhodium chloride with the methyl tert-butyl ether; the preparation method of the diphenyl butyl rhodium chloride comprises the following steps: preparing a rhodium chloride solution, preparing an acetone solution of diphenyl butyl ether, and mixing the rhodium chloride and the diphenyl butyl ether; the invention can greatly reduce the hydrogenation cost and improve the hydrogenation yield and selectivity.
Description
Technical Field
The invention relates to the technical field of methacycline, and in particular relates to a method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate.
Background
Doxycycline is also called doxycycline, has the density of 1.66g/cm3 and the boiling point of 695.1 ℃ at 760mmHg, is semisynthetic tetracycline, and has broad-spectrum antibacterial activity. The antibacterial mechanism of doxycycline is the same as that of tetracycline, the antibacterial effect is stronger than that of tetracycline, and the doxycycline has high efficiency and long-acting property. Has stronger antibacterial activity to gram positive or negative bacteria; has strong antagonistic effect on rickettsia, chlamydia, mycoplasma, atypical mycobacterium and amebiasis. It can also be used for treating cholera, and preventing malignant malaria and leptospira infection. The traditional Chinese medicine composition is mainly used for upper respiratory tract infection, tonsillitis, biliary tract infection, lymphadenitis, cellulitis, senile chronic bronchitis and the like caused by sensitive gram-positive cocci and gram-negative bacilli, and is also used for typhus, tsutsugamushi disease, mycoplasma pneumonia and the like. It can also be used for treating cholera, and preventing malignant malaria and treponema pallidum infection, and doxycycline sulfosalicylate is intermediate of doxycycline.
The existing method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate mainly comprises the steps of attaching palladium to carrier carbon to be used as a hydrogenation catalyst, and carrying out heterogeneous catalytic hydrogenation by taking ethanol as a solvent. Heterogeneous catalytic hydrogenation means that the catalyst has more active centers and broad MWD (molecular weight distribution) and CCD (chemical composition distribution) tendencies, so that the catalyst preparation is more unstable, less active and less selective, with a yield generally at 60%. In addition, the price of palladium is high, although part of reports can be used repeatedly, in order to obtain high reaction activity, the using amount of the catalyst is often large, impurities are easy to block catalyst pore channels in the later period of use, metacycline paratoluenesulfonate is unstable to alkali, feed liquid in the hydrogenation process is strong in acidity, a large amount of metal can be corroded into the solution, the metacycline paratoluenesulfonate is tightly combined with a catalyst structure and is difficult to elute, and the factors can cause the service life of the catalyst to be short.
Huhanfeng et al (Huhanfeng. research on the synthesis of doxycycline hydrochloride [ J ]. Jiangsu chemical industry, 2003, 31 (4): 36-37) adopt homogeneous catalyst rhodium to fix on silica gel, the catalyst is used for hydrogenation of doxycycline, the activity is high, the selectivity is good, the catalyst is easy to separate, but the cost is too high.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate, which can greatly reduce the hydrogenation cost and improve the hydrogenation yield and selectivity.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for preparing doxycycline sulfosalicylate by hydrogenating metacycline p-toluenesulfonate comprises the following steps: preparing methyl tert-butyl rhodium chloride, preparing diphenyl butyl rhodium chloride, and preparing doxycycline sulfosalicylate;
the preparation method of the methyl tert-butyl rhodium chloride comprises the following steps: preparing a rhodium chloride solution, preparing an acetone solution of methyl tert-butyl ether, and mixing the rhodium chloride solution and the acetone solution of the methyl tert-butyl ether;
adding a hydrochloric acid solution with the concentration of 12mol/L into a reaction container, raising the temperature of the reaction container to 65-80 ℃, then adding rhodium chloride, stirring at the stirring speed of 340-400r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding acetone with the mass fraction of 95%, and diluting to obtain a rhodium chloride solution;
in the rhodium chloride solution for preparing methyl tert-butyl rhodium chloride, the molar ratio of hydrochloric acid in the hydrochloric acid solution with the concentration of 12mol/L to rhodium chloride is 0.2004: 0.019;
in the rhodium chloride solution prepared in the preparation of the methyl tert-butyl rhodium chloride, the volume ratio of a hydrochloric acid solution with the concentration of 12mol/L to a rhodium chloride solution is 16.7: 50;
dissolving methyl tert-butyl ether in acetone, stirring at a stirring speed of 400r/min, and heating to 50 ℃ to dissolve the methyl tert-butyl ether to obtain an acetone solution of the methyl tert-butyl ether;
in the acetone solution for preparing the methyl tert-butyl ether in the preparation of the methyl tert-butyl rhodium chloride, the mass volume ratio of the methyl tert-butyl ether to the acetone is 3.35g:100 mL;
mixing a rhodium chloride solution with an acetone solution of methyl tert-butyl ether in the preparation of methyl tert-butyl rhodium chloride, stirring the acetone solution of the methyl tert-butyl ether at the rotation speed of 720-760r/min, then dropwise adding the rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55-65 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20-30min, then cooling, filtering, washing three times with an acetone aqueous solution with the mass fraction of 50%, pumping, vacuum drying, controlling the vacuum drying temperature at 50 ℃, the vacuum degree at 0.05MPa, and the drying time at 6.7-7.5h to finally obtain the methyl tert-butyl rhodium chloride;
the preparation method of the diphenyl butyl rhodium chloride comprises the following steps: preparing a rhodium chloride solution, preparing an acetone solution of diphenyl butyl ether, and mixing the rhodium chloride solution with the acetone solution of diphenyl butyl ether;
the preparation method comprises the steps of adding a hydrochloric acid solution with the concentration of 12mol/L into a reaction container, heating the temperature of the reaction container to 70 ℃, then adding rhodium chloride, stirring at the stirring speed of 340-;
in the rhodium chloride solution prepared in the preparation of the diphenyl butyl rhodium chloride, the molar ratio of hydrochloric acid in a hydrochloric acid solution with the concentration of 12mol/L to rhodium chloride is 0.2004: 0.019;
in the rhodium chloride solution prepared in the preparation of the diphenyl butyl rhodium chloride, the volume ratio of the hydrochloric acid solution with the concentration of 12mol/L to the rhodium chloride solution is 16.7: 50;
in the acetone solution for preparing the diphenyl butyl ether in the preparation of the diphenyl butyl rhodium chloride, the diphenyl butyl ether is dissolved in acetone and heated to 50 ℃ for dissolution, so that the acetone solution of the diphenyl butyl ether is obtained;
in the acetone solution for preparing the diphenyl butyl ether in the preparation of the diphenyl butyl rhodium chloride, the mass volume ratio of the diphenyl butyl ether to the acetone is 3.35g:100 mL;
mixing a rhodium chloride solution with an acetone solution of diphenyl butyl ether in the preparation of the diphenyl butyl rhodium chloride, stirring the acetone solution of diphenyl butyl ether at the rotating speed of 700 plus 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20-22min, then cooling, filtering, washing for three times by using an acetone aqueous solution with the mass fraction of 50%, carrying out suction drying and vacuum drying, controlling the temperature of vacuum drying to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, thus obtaining the diphenyl butyl rhodium chloride.
The doxycycline sulfosalicylate is prepared by adding an ethanol solution of metacycline p-toluenesulfonate into a reaction vessel, mixing a catalyst and purified water, controlling the stirring speed to be 980-1140r/min, heating to 35 ℃, replacing for 3 times by using nitrogen, charging hydrogen to be 0.7MPa, stopping the reaction after reacting for 100min, controlling the pressure of the reaction vessel to be 0.25MPa, filtering, controlling the temperature of the filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the adding time of the 5-sulfosalicylic acid to be 30min, controlling the speed in the adding process to be 440-450r/min, preserving heat at 10 ℃ for 6-6.5h, filtering, and drying the filter cake at 30 ℃ for 7h to obtain the doxycycline sulfosalicylate;
in the preparation of doxycycline sulfosalicylate, the mass ratio of the methacycline p-toluenesulfonate to ethanol in the ethanol solution of the methacycline p-toluenesulfonate is 1: 5-10;
in the preparation of doxycycline sulfosalicylate, a mixed catalyst is a mixed catalyst of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride, wherein the volume ratio of the methyl tert-butyl rhodium chloride to the diphenyl butyl rhodium chloride is 1: 1;
in the preparation of doxycycline sulfosalicylate, the mass ratio of an ethanol solution of metacycline p-toluenesulfonate, a mixed catalyst and purified water is 10:0.5: 0.3;
in the preparation of doxycycline sulfosalicylate, the molar ratio of 5-sulfosalicylic acid to methacycline p-toluenesulfonate in an ethanol solution of the methacycline p-toluenesulfonate is 3: 1.
Compared with the prior art, the invention has the beneficial effects that:
(1) compared with the prior art, the method for preparing doxycycline sulfosalicylate by hydrogenation of metacycline p-toluenesulfonate has the defects of low activity, poor selectivity, high cost and the like, the method adopts methyl tert-butyl ether, diphenyl butyl ether and rhodium chloride as raw materials to prepare the mixed catalyst of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride, and performs hydrogenation reaction on the metacycline p-toluenesulfonate by using the mixed catalyst, the catalyst prepared by the process is a homogeneous catalyst, the using amount is small, the price is low compared with palladium rhodium, the activity is high, the selectivity to beta-doxycycline is far less than that to alpha-doxycycline, and the selectivity is high; no toxic agent is required to be added additionally, so that the damage of materials to the environment and workers can be greatly reduced; compared with the method that rhodium is fixed on silica gel to perform doxycycline hydrogenation by adopting a homogeneous catalyst, the mixed catalyst of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride performs hydrogenation reaction on metacresol sulfonate of metacycline, so that the cost is lower, and the method is more favorable for industrialization;
(2) the method for preparing doxycycline sulfosalicylate by hydrogenating metadoxycycline p-toluenesulfonate can improve the purity and yield of the prepared doxycycline sulfosalicylate, wherein the purity of the prepared doxycycline sulfosalicylate is 75.89-95.11%, and the yield of the prepared doxycycline sulfosalicylate is 84.06-90.02%.
Drawings
FIG. 1 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 1;
FIG. 2 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 2;
figure 3 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 4;
FIG. 4 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 4;
FIG. 5 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 5;
FIG. 6 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 6;
FIG. 7 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 7;
FIG. 8 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 8;
FIG. 9 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 9;
figure 10 is a gas phase spectrum of doxycycline sulfosalicylate prepared in example 10.
Detailed Description
In order to more clearly understand the technical features, objects, and effects of the present invention, specific embodiments of the present invention will now be described.
Example 1
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 400r/min, and heating to 50 ℃ for dissolving to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring an acetone solution of methyl tert-butyl ether at the rotating speed of 750r/min, then dropwise adding a rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 30min, then cooling, filtering, washing with an acetone aqueous solution with the mass fraction of 50% for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7h, and finally obtaining 5.3g of methyl tert-butyl rhodium chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 350r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% acetone aqueous solution for three times, carrying out pumping drying and vacuum drying, controlling the vacuum drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa and the drying time to be 7.5h, and finally obtaining 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing methacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:5 to obtain an ethanol solution of the methacycline p-toluenesulfonate;
(2) adding 10g of methacycline p-toluenesulfonate ethanol solution into a liner of a high-pressure reaction kettle, adding 0.3g of purified water into 0.5g of a catalyst mixed by methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1000r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of the filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the mol ratio of the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving the temperature for 6h at 10 ℃, then filtering, placing the filter cake at the constant temperature of 30 ℃ for drying for 7h to obtain 1.68g of doxycycline sulfosalicylate, and carrying out gas chromatography analysis on the prepared doxycycline sulfosalicylate, wherein the analysis result is shown in figure 1, the purity of the prepared doxycycline sulfosalicylate is 94.92%, and the yield is 86.66%.
Example 2
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 380r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 360r/min, and heating to 50 ℃ for dissolution to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring the acetone solution of methyl tert-butyl ether at the rotating speed of 740r/min, then dropwise adding the rhodium chloride solution into the acetone solution of methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 23min, then cooling, filtering, washing with 50% acetone aqueous solution for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl rhodium chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 380r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 22min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:10 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of ethanol solution of methacycline p-toluenesulfonate into an inner container of a high-pressure reaction kettle, adding 0.3g of purified water into a catalyst mixed by 0.5g of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1100r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the molar ratio of the 5-sulfosalicylic acid to the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 440r/min, and then preserving heat for 6h at 10 ℃, then filtering, drying the filter cake at the constant temperature of 30 ℃ for 7h to obtain 0.95g of doxycycline sulfosalicylate, and analyzing the prepared doxycycline sulfosalicylate by gas chromatography, wherein the analysis result is shown in figure 2, the purity of the prepared doxycycline sulfosalicylate is 95.11%, and the yield is 90.02%.
Example 3
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 400r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 360r/min, and heating to 50 ℃ for dissolving to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring the acetone solution of methyl tert-butyl ether at the rotating speed of 740r/min, then dropwise adding the rhodium chloride solution into the acetone solution of methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass acetone aqueous solution for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl rhodium chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 350r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 700r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:7 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of ethanol solution of methacycline p-toluenesulfonate into an inner container of a high-pressure reaction kettle, adding 0.3g of purified water into a catalyst mixed by 0.5g of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1100r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the molar ratio of the 5-sulfosalicylic acid to the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving heat for 6h at 10 ℃, then filtering is carried out, the filter cake is dried for 7 hours at the constant temperature of 30 ℃ to obtain 1.26g of doxycycline sulfosalicylate, and the analysis result of the prepared doxycycline sulfosalicylate is shown in figure 3 by gas chromatography, wherein the purity of the prepared doxycycline sulfosalicylate is 95.01%, and the yield is 86.75%.
Example 4
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 340r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 350r/min, and heating to 50 ℃ to dissolve to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring an acetone solution of methyl tert-butyl ether at the rotating speed of 720r/min, then dropwise adding a rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with an acetone aqueous solution with the mass fraction of 50% for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 350r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% acetone aqueous solution for three times, carrying out pumping drying and vacuum drying, controlling the vacuum drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa and the drying time to be 7.5h, and finally obtaining 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:8 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of ethanol solution of methacycline p-toluenesulfonate into a liner of a high-pressure reaction kettle, adding 0.3g of purified water into 0.5g of a catalyst mixed by methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1140r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the molar ratio of the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving the temperature for 6h at 10 ℃, then filtering, placing the filter cake at the constant temperature of 30 ℃ for drying for 7h to obtain 1.17g of doxycycline sulfosalicylate, and carrying out gas chromatography analysis on the prepared doxycycline sulfosalicylate, wherein the analysis result is shown in figure 4, the purity of the prepared doxycycline sulfosalicylate is 93.03%, and the yield is 88.73%.
Example 5
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 65 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at a stirring speed of 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 340r/min, and heating to 50 ℃ to dissolve to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring an acetone solution of methyl tert-butyl ether at the rotating speed of 750r/min, then dropwise adding a rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with an acetone aqueous solution with the mass fraction of 50% for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 340r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve the diphenyl butyl ether to obtain acetone solution of the diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, controlling the vacuum degree to be 0.05MPa, and drying for 7.5h to finally obtain 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:10 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of ethanol solution of methacycline p-toluenesulfonate into a liner of a high-pressure reaction kettle, adding 0.3g of purified water into 0.5g of a catalyst mixed by methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 980r/min, heating to 35 ℃, then replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of the filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the molar ratio of the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 440r/min, then preserving the temperature for 6h at 10 ℃, then filtering, placing the filter cake at the constant temperature of 30 ℃ for drying for 7h to obtain 1.15g of doxycycline sulfosalicylate, and carrying out gas chromatography analysis on the prepared doxycycline sulfosalicylate, wherein the analysis result is shown in figure 5, the purity of the prepared doxycycline sulfosalicylate is 77.99%, and the yield is 89.36%.
Example 6
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 75 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 350r/min, and heating to 50 ℃ to dissolve to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring an acetone solution of methyl tert-butyl ether at the rotating speed of 750r/min, then dropwise adding a rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with an acetone aqueous solution with the mass fraction of 50% for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 350r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 730r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:10 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of ethanol solution of methacycline p-toluenesulfonate into an inner container of a high-pressure reaction kettle, adding 0.3g of purified water into a catalyst mixed by 0.5g of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1100r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the molar ratio of the 5-sulfosalicylic acid to the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving heat for 6.5 hours at 10 ℃, then filtering, placing the filter cake at the constant temperature of 30 ℃ for drying for 7h to obtain 1.18g of doxycycline sulfosalicylate, and carrying out gas chromatography analysis on the prepared doxycycline sulfosalicylate, wherein the analysis result is shown in figure 6, the purity of the prepared doxycycline sulfosalicylate is 76.05%, and the yield is 89.41%.
Example 7
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 80 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 340r/min, and heating to 50 ℃ for dissolving to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring an acetone solution of methyl tert-butyl ether at the rotating speed of 760r/min, then dropwise adding a rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with an acetone aqueous solution with the mass fraction of 50% for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl rhodium chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 350r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, controlling the vacuum degree to be 0.05MPa, and drying for 7.5h to finally obtain 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:10 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of methacycline p-toluenesulfonate ethanol solution into a liner of a high-pressure reaction kettle, adding 0.3g of purified water into 0.5g of a catalyst mixed by methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1000r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of the filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the mol ratio of the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving the temperature for 6h at 10 ℃, then filtering is carried out, the filter cake is dried for 7 hours at the constant temperature of 30 ℃ to obtain 1.16g of doxycycline sulfosalicylate, and the analysis result of the gas chromatography analysis of the prepared doxycycline sulfosalicylate is shown in figure 7, wherein the purity of the prepared doxycycline sulfosalicylate is 75.90%, and the yield is 87.72%.
Example 8
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 90% by mass of acetone, and diluting to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 350r/min, and heating to 50 ℃ to dissolve to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring an acetone solution of methyl tert-butyl ether at the rotating speed of 760r/min, then dropwise adding a rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with an acetone aqueous solution with the mass fraction of 50% for three times, pumping, carrying out vacuum drying, controlling the temperature of the vacuum drying to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 6.7h, and finally obtaining 5.3g of methyl tert-butyl rhodium chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-neck flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring that the temperature is below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the mixture to 50mL of the total volume so as to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve the diphenyl butyl ether to obtain acetone solution of the diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, controlling the vacuum degree to be 0.05MPa, and drying for 7.5h to finally obtain 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:8 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of ethanol solution of methacycline p-toluenesulfonate into an inner container of a high-pressure reaction kettle, adding 0.3g of purified water into a catalyst mixed by 0.5g of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to 1050r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of the filtrate to 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the molar ratio of the 5-sulfosalicylic acid to the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving heat for 6h at 10 ℃, then, the filtration was carried out, the filter cake was dried at a constant temperature of 30 ℃ for 7 hours to obtain 1.39g of doxycycline sulfosalicylate, and the analysis result of the gas chromatography analysis of the prepared doxycycline sulfosalicylate is shown in fig. 8, and the purity of the prepared doxycycline sulfosalicylate was 78.13%, and the yield was 88.53%.
Example 9
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 98% by mass of acetone, and diluting to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 350r/min, and heating to 50 ℃ to dissolve to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring the acetone solution of methyl tert-butyl ether at the rotating speed of 740r/min, then dropwise adding the rhodium chloride solution into the acetone solution of methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55 ℃ after the dropwise adding is finished, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass acetone aqueous solution for three times, pumping, vacuum-drying, controlling the vacuum-drying temperature to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl rhodium chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 350r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, controlling the vacuum degree to be 0.05MPa, and drying for 7.5h to finally obtain 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:8 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of methacycline p-toluenesulfonate ethanol solution into a liner of a high-pressure reaction kettle, adding 0.3g of purified water into 0.5g of a catalyst mixed by methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1000r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of the filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the mol ratio of the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving the temperature for 6h at 10 ℃, then, the filtration was carried out, the filter cake was dried at a constant temperature of 30 ℃ for 7 hours to obtain 1.43g of doxycycline sulfosalicylate, and the analysis result of the gas chromatography analysis of the prepared doxycycline sulfosalicylate was as shown in fig. 9, and the purity of the prepared doxycycline sulfosalicylate was 75.89%, and the yield was 88.47%.
Example 10
A method for preparing doxycycline sulfosalicylate by metacycline p-toluenesulfonate hydrogenation specifically comprises the following steps:
1. preparation of methyl tert-butyl rhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, stirring at the stirring speed of 350r/min at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding 95% by mass of acetone, and diluting to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of methyl tert-butyl ether in 100ml of acetone, stirring at a stirring speed of 400r/min, and heating to 50 ℃ for dissolving to obtain an acetone solution of the methyl tert-butyl ether;
(3) stirring an acetone solution of methyl tert-butyl ether at the rotating speed of 750r/min, then pouring a rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, cooling to 55 ℃ after pouring, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing for three times by using an acetone aqueous solution with the mass fraction of 50%, draining, vacuum drying, controlling the temperature of the vacuum drying to be 50 ℃, the vacuum degree to be 0.05MPa, and the drying time to be 7.5h, and finally obtaining 5.3g of methyl tert-butyl chloride.
2. Preparation of diphenylbutylrhodium chloride
(1) Adding 16.7mL of 12mol/L hydrochloric acid solution into a three-necked flask provided with an electric stirrer and a thermometer, heating to 70 ℃, then adding 5g (0.019 mol) of rhodium chloride, completely dissolving the rhodium chloride at 70 ℃ at a stirring speed of 350r/min, ensuring the temperature to be below 75 ℃ in the dissolving process, and then adding 95% by mass of acetone to dilute the rhodium chloride solution to 50mL of the total volume to obtain a rhodium chloride solution;
(2) dissolving 3.35g of diphenyl butyl ether in 100ml of acetone, heating to 50 ℃ to dissolve, and obtaining acetone solution of diphenyl butyl ether;
(3) stirring the acetone solution of diphenyl butyl ether at the rotating speed of 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20min, then cooling, filtering, washing with 50% by mass of acetone aqueous solution for three times, pumping, vacuum-drying at the temperature of 50 ℃, controlling the vacuum degree to be 0.05MPa, and drying for 7.5h to finally obtain 7.98g of diphenyl butyl rhodium chloride.
3. Preparation of doxycycline sulfosalicylate
(1) Uniformly mixing metacycline p-toluenesulfonate and absolute ethanol according to the mass ratio of 1:8 to obtain an ethanol solution of metacycline p-toluenesulfonate;
(2) adding 10g of ethanol solution of methacycline p-toluenesulfonate into an inner container of a high-pressure reaction kettle, adding 0.3g of purified water into a catalyst mixed by 0.5g of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride according to the volume ratio of 1:1, controlling the stirring speed to be 1080r/min, heating to 35 ℃, replacing the high-pressure reaction kettle with nitrogen for 3 times, charging hydrogen to 0.7MPa, stopping the reaction after 100min of reaction, controlling the pressure of the high-pressure reaction kettle to be 0.25MPa, opening the kettle, filtering, controlling the temperature of filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the molar ratio of the 5-sulfosalicylic acid to the methacycline p-toluenesulfonate in the ethanol solution of the 5-sulfosalicylic acid and the methacycline p-toluenesulfonate to be 3:1, controlling the adding time to be 30min, controlling the rotating speed in the adding process to be 450r/min, and then preserving heat for 6h at 10 ℃, then filtering, drying the filter cake at constant temperature of 30 ℃ for 7h to obtain 1.27g of doxycycline sulfosalicylate, and analyzing the prepared doxycycline sulfosalicylate by gas chromatography, wherein the analysis result is shown in figure 10, the purity of the prepared doxycycline sulfosalicylate is 81.19%, and the yield is 84.06%.
All percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A method for preparing doxycycline sulfosalicylate by hydrogenation of metacycline p-toluenesulfonate is characterized by comprising the following steps of: preparing methyl tert-butyl rhodium chloride, preparing diphenyl butyl rhodium chloride, and preparing doxycycline sulfosalicylate;
the preparation method of methyl tert-butyl rhodium chloride comprises the following steps: preparing a rhodium chloride solution, preparing an acetone solution of methyl tert-butyl ether, and mixing the rhodium chloride solution with the acetone solution of the methyl tert-butyl ether;
adding a hydrochloric acid solution with the concentration of 12mol/L into a reaction container, heating the temperature of the reaction container to 65-80 ℃, then adding rhodium chloride, stirring at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding acetone with the mass fraction of 95%, and diluting to obtain a rhodium chloride solution;
in the rhodium chloride solution prepared in the preparation of methyl tert-butyl rhodium chloride, the mol ratio of hydrochloric acid and rhodium chloride in the hydrochloric acid solution with the concentration of 12mol/L is 0.2004: 0.019;
in the rhodium chloride solution prepared in the preparation of methyl tert-butyl rhodium chloride, the volume ratio of a hydrochloric acid solution with the concentration of 12mol/L to a rhodium chloride solution is 16.7: 50;
dissolving methyl tert-butyl ether in acetone, starting stirring, and heating to 50 ℃ for dissolving to obtain an acetone solution of the methyl tert-butyl ether;
in the acetone solution for preparing the methyl tert-butyl ether in the preparation of the methyl tert-butyl rhodium chloride, the mass volume ratio of the methyl tert-butyl ether to the acetone is 3.35g:100 mL;
mixing a rhodium chloride solution with an acetone solution of methyl tert-butyl ether in the preparation of methyl tert-butyl chloride, stirring the acetone solution of the methyl tert-butyl ether at the rotating speed of 720-760r/min, then dropwise adding the rhodium chloride solution into the acetone solution of the methyl tert-butyl ether, controlling the dropwise adding time to be 1h, keeping the temperature at 55-65 ℃ after the dropwise adding is finished, reacting for 20-30min at 55 ℃, cooling, filtering, washing for three times by using an acetone aqueous solution with the mass fraction of 50%, draining, vacuum drying, and controlling the vacuum drying time to be 6.7-7.5h to obtain the methyl tert-butyl rhodium chloride;
the preparation method of the diphenyl butyl rhodium chloride comprises the following steps: preparing a rhodium chloride solution, preparing an acetone solution of diphenyl butyl ether, and mixing the rhodium chloride solution and the acetone solution of diphenyl butyl ether;
adding a hydrochloric acid solution with the concentration of 12mol/L into a reaction container, heating the temperature of the reaction container to 70 ℃, then adding rhodium chloride, stirring at 70 ℃ until the rhodium chloride is completely dissolved, ensuring the temperature to be below 75 ℃ in the dissolving process, then adding acetone with the mass fraction of 95%, and diluting to obtain a rhodium chloride solution;
in the rhodium chloride solution prepared in the preparation of the diphenyl butyl rhodium chloride, the molar ratio of hydrochloric acid in a hydrochloric acid solution with the concentration of 12mol/L to rhodium chloride is 0.2004: 0.019;
in the rhodium chloride solution prepared in the preparation of the diphenyl butyl rhodium chloride, the volume ratio of the hydrochloric acid solution with the concentration of 12mol/L to the rhodium chloride solution is 16.7: 50;
in the acetone solution for preparing the diphenyl butyl ether in the preparation of the diphenyl butyl rhodium chloride, the diphenyl butyl ether is dissolved in acetone and heated to 50 ℃ for dissolution, so that the acetone solution of the diphenyl butyl ether is obtained;
in the acetone solution for preparing the diphenyl butyl ether in the preparation of the diphenyl butyl rhodium chloride, the mass volume ratio of the diphenyl butyl ether to the acetone is 3.35g:100 mL;
mixing a rhodium chloride solution with an acetone solution of diphenyl butyl ether in the preparation of diphenyl butyl rhodium chloride, stirring the acetone solution of diphenyl butyl ether at the rotating speed of 700 plus 750r/min, dropwise adding the rhodium chloride solution into the acetone solution of diphenyl butyl ether, controlling the dropwise adding time to be 1h, controlling the temperature in the dropwise adding process to be 55 ℃, carrying out heat preservation reaction at 55 ℃ for 20-22min, then cooling, filtering, washing with an acetone aqueous solution with the mass fraction of 50% for three times, pumping, vacuum drying, and controlling the vacuum drying time to be 7.5h to obtain the diphenyl butyl rhodium chloride;
the doxycycline sulfosalicylate is prepared by adding an ethanol solution of metacycline p-toluenesulfonate into a reaction vessel, mixing a catalyst and purified water, controlling the stirring speed to be 980-1140r/min, heating to 35 ℃, replacing for 3 times by using nitrogen, charging hydrogen to be 0.7MPa, stopping the reaction after reacting for 100min, controlling the pressure of the reaction vessel to be 0.25MPa, filtering, controlling the temperature of the filtrate to be 10 ℃, adding 5-sulfosalicylic acid into the filtrate, controlling the adding time of the 5-sulfosalicylic acid to be 30min, controlling the speed in the adding process to be 440-450r/min, preserving heat at 10 ℃ for 6-6.5h, filtering, and drying the filter cake at 30 ℃ for 7h to obtain the doxycycline sulfosalicylate;
in the preparation of doxycycline sulfosalicylate, the mass ratio of the methacycline p-toluenesulfonate to ethanol in the ethanol solution of the methacycline p-toluenesulfonate is 1: 5-10;
in the preparation of doxycycline sulfosalicylate, a mixed catalyst is a mixed catalyst of methyl tert-butyl rhodium chloride and diphenyl butyl rhodium chloride, wherein the volume ratio of the methyl tert-butyl rhodium chloride to the diphenyl butyl rhodium chloride is 1: 1;
in the preparation of doxycycline sulfosalicylate, the mass ratio of the ethanol solution of methacycline p-toluenesulfonate, the mixed catalyst and the purified water is 10:0.5: 0.3;
in the preparation of doxycycline sulfosalicylate, the molar ratio of 5-sulfosalicylic acid to methacycline p-toluenesulfonate in an ethanol solution of the methacycline p-toluenesulfonate is 3: 1.
2. The method for preparing doxycycline sulfosalicylate through metacycline p-toluenesulfonate hydrogenation according to claim 1, wherein in the preparation of methyl tert-butyl rhodium chloride, a rhodium chloride solution and an acetone solution of methyl tert-butyl ether are mixed, and the temperature of vacuum drying is 50 ℃ and the vacuum degree is 0.05 MPa.
3. The method for preparing doxycycline sulfosalicylate by hydrogenating metacycline p-toluenesulfonate according to claim 1, wherein in the preparation of the diphenyl butyl rhodium chloride, a rhodium chloride solution is mixed with an acetone solution of diphenyl butyl ether, and the temperature of vacuum drying is 50 ℃ and the vacuum degree is 0.05 MPa.
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| CN202210964450.7A CN115028546A (en) | 2022-08-12 | 2022-08-12 | Method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate |
| CN202211036720.4A CN115677524A (en) | 2022-08-12 | 2022-08-29 | Method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate |
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| CN202211036720.4A Pending CN115677524A (en) | 2022-08-12 | 2022-08-29 | Method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate |
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| HUP0202798A3 (en) * | 1999-09-14 | 2003-11-28 | Trustees Of Tufts College Medf | Methods of preparing substituted tetracyclines with transition metal-based reactions |
| CN101357341A (en) * | 2007-07-31 | 2009-02-04 | 顾鸣海 | Hydrogenation technique rhodium catalyst for producing antibiotic doxycycline and use thereof |
| CN103467335B (en) * | 2013-09-22 | 2014-10-15 | 河南师范大学 | Method for synthesizing doxycycline hydrochloride intermediate alpha-6-deoxytetracycline based on hydrogenation of carbon-based rhodium catalyst |
| CN109134291B (en) * | 2017-06-19 | 2021-04-16 | 河南后羿制药有限公司 | Preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by same |
| CN108440329A (en) * | 2018-02-27 | 2018-08-24 | 河南师范大学 | A kind of method of green high-efficient synthetic hydrochloric acid Doxycycline |
| CN108440330B (en) * | 2018-06-27 | 2021-03-02 | 常州制药厂有限公司 | Preparation method of doxycycline hydrochloride |
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