CN109134291B - Preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by same - Google Patents
Preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by same Download PDFInfo
- Publication number
- CN109134291B CN109134291B CN201710466136.5A CN201710466136A CN109134291B CN 109134291 B CN109134291 B CN 109134291B CN 201710466136 A CN201710466136 A CN 201710466136A CN 109134291 B CN109134291 B CN 109134291B
- Authority
- CN
- China
- Prior art keywords
- alpha
- oxytetracycline
- doxycycline hydrochloride
- hemiketal
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
Abstract
The invention provides a preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by the method, raw materials are provided by reacting chlorinated antipyretic ice with oxytetracycline, the yield of doxycycline hydrochloride is improved, the generation of byproducts is reduced, meanwhile, antipyretic ice, ethanol, methanol and the like in the preparation process can be recycled, the environmental pollution and the resource waste are reduced, the production cost is reduced, and the product yield in the preparation process is stable. In addition, the doxycycline hydrochloride prepared by the preparation method has high purity and good color.
Description
Technical Field
The invention relates to a preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by the preparation method.
Background
Doxycycline hydrochloride is a broad-spectrum semisynthetic tetracycline antibiotic, is mainly used for upper respiratory tract infection, tonsillitis, biliary tract infection, lymphadenitis, cellulitis and the like caused by sensitive gram-positive bacteria and gram-negative bacteria, is also used for treating typhus, notopterygium, mycoplasma pneumonia and the like, can be used for treating cholera, and can also be used for preventing malignant malaria and leptospira infection. The medicinal liquid has strong solubility, good absorption, wide distribution, and good clinical application and effect. The veterinary drug is mainly used for treating respiratory diseases of livestock and poultry, escherichia coli, salmonella and the like in clinic.
Doxycycline hydrochloride is stable under dry conditions, but is easy to discolor when exposed to light, is unstable under acidic and alkaline conditions, and is easy to hydrolyze, so that the effect of doxycycline hydrochloride is influenced. And the doxycycline hydrochloride has strong water-soluble acidity and large stimulation to the stomach, thereby limiting the application of doxycycline hydrochloride to a certain extent.
At present, doxycycline hydrochloride is prepared by using 11-alpha-chloro-6-methenyl oxytetracycline p-toluenesulfonate as a starting material, performing hydrogenation reduction and salification to generate alpha-6-deoxyoxytetracycline sulfosalicylate, performing alkalization to generate alpha-6-deoxyoxytetracycline base, and finally performing salt conversion to generate doxycycline hydrochloride. The method has the problems of unstable yield and incapability of recycling the solvent in the preparation process.
Doxycycline hydrochloride is a common anti-infective drug and is accepted in many national formulary, but the formulary limits the doxycycline hydrochloride, particularly improves the standards of related substance items, and also puts more and more strict requirements on single impurities and total impurities of products. Therefore, the method has important significance for improving the yield while developing high-quality products.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by the method, which can improve the yield of doxycycline hydrochloride and reduce the production cost.
The technical scheme of the invention is as follows: a preparation method of doxycycline hydrochloride comprises the following steps:
(1) chloridizing the antipyretic ice, and then reacting the oxytetracycline with the chloro antipyretic ice to obtain 11-alpha-chloro-6, 12-hemiketal oxytetracycline;
(2) dehydrating the 11-alpha-chlorine-6, 12-hemiketal oxytetracycline to obtain 11-alpha-chlorine-6, 12-hemiketal oxytetracycline p-toluenesulfonate;
(3) the 11-alpha-chlorine-6, 12-hemiketal oxytetracycline p-toluenesulfonate is hydrogenated by hydrogen and reacts with sulfosalicylic acid in the presence of a catalyst to obtain 6-deoxyoxytetracycline sulfosalicylate;
(4) the 6-doxycycline sulfosalicylate is subjected to alkalization and salt-forming reaction to obtain doxycycline hydrochloride.
In the step (1), sodium hypochlorite is used for chlorinating the antipyretic ice.
In the step (1), the temperature for chlorinating the oxytetracycline is-10 ℃, the solvent is methanol-ammonia, ammonia gas is directly and fully mixed with methanol, and the recovered antipyretic ice can be reused in the previous step after the reaction.
In the step (2), the 11-alpha-chloro-6, 12-hemiketal oxytetracycline and p-toluenesulfonic acid are subjected to dehydration reaction to generate p-toluenesulfonate of the 11-alpha-chloro-6, 12-hemiketal oxytetracycline, the reaction temperature is 0-5 ℃, the acid is HF, and the solvent is ethanol.
In the step (3), the catalyst for the pressure hydrogenation reaction is palladium carbon, and the temperature is 45-50 ℃.
In the step (4), 6-deoxyoxytetracycline sulfosalicylate reacts with alkali, and the alpha-6-deoxyoxytetracycline is obtained by alkalization, wherein the alkali is ammonia water.
In the step (4), the step of further salifying the alpha-6-deoxyoxytetracycline is as follows: reacting alpha-6-deoxyoxytetracycline with an ethanol solution to obtain doxycycline hydrochloride.
Doxycycline hydrochloride prepared by the method.
The preparation method of doxycycline hydrochloride provided by the invention has the beneficial technical effects that the yield of doxycycline hydrochloride is improved, the generation of byproducts is reduced, simultaneously, antipyretic ice, ethanol, methanol and the like in the preparation process can be recycled, the environmental pollution and the resource waste are reduced, the production cost is reduced, and the product yield in the preparation process is stable. In addition, the doxycycline hydrochloride prepared by the preparation method has high purity and good color.
Detailed Description
Example 1:
a preparation method of doxycycline hydrochloride comprises the following steps:
(1) chloro-made defervescent ice
0.82L of drinking water is put into a 3L glass-lined reaction tank, 150 g of baking soda is added, the pH is adjusted to 8-9, the stirring is started for about 30 minutes, 231 g of antipyretic ice is added, and the temperature is reduced to 10-15 ℃ by freezing with an interlayer. Slowly adding metered sodium hypochlorite along the wall of the tank, controlling the temperature not to exceed 15 ℃, stirring for 60 minutes after the addition is finished, and discharging and filtering after the end point is reached. The filter cake was washed with drinking water to pH 7. And (3) fully spin-drying the filter cake for 1 hour to obtain the chlorinated antipyretic ice, and putting the chlorinated antipyretic ice into a refrigeration house for later use.
(2) Oxytetracycline chloride-11-alpha-chloro-6, 12-hemiketal oxytetracycline
Adding 0.45L of methanol into a 1L glass-lined reaction tank, adding 50 g of oxytetracycline base while stirring, slowly adding metered methanol-ammonia when the suspension is thickened, stirring and cooling to-10 ℃, adding 25 g of the chloro antipyretic ice prepared in the step (1) at a time, and naturally rising the temperature. And (3) continuously stirring and reacting for 25 minutes, putting the feed liquid into a centrifugal machine for spin-drying, washing the reaction tank and a filter cake by using methanol, continuously spin-drying the filter cake for 25-40 minutes to obtain the chloride 11-alpha-chloro-6, 12-hemiketal oxytetracycline, and recovering the methanol and the antipyretic ice from the filtrate. After the chloride 11-alpha-chloro-6, 12-hemiketal oxytetracycline is taken out of the centrifuge, the chloride is crushed by a granulator and is dried by airflow, and the yield of the step is 99.2 percent.
(3) Dehydrating to obtain 11-alpha-chlorine-6, 12-hemiketal oxytetracycline p-toluenesulfonate
And (3) adding the chloride 11-alpha-chloro-6, 12-hemiketal oxytetracycline obtained after the airflow drying in the step (2) into a salt forming tank, then weighing 200 g of p-toluenesulfonic acid, putting into the salt forming tank, controlling the reaction temperature to be 0-5 ℃, adding 0.1L of ethanol, starting stirring to completely dissolve the p-toluenesulfonic acid, and stopping stirring. Adding hydrofluoric acid, neutralizing the liquid in the salt forming tank, filtering out fluoride after neutralization, washing the feed liquid adhered to the fluoride with ethanol in several times, spin-drying, stirring for forming salt, pressing the filtrate, stopping stirring after crystallization, introducing cold liquid into the interlayer, and standing for more than 8 hours. And (3) performing rotary filtration crystallization, washing the filter cake for 3-4 times by using 0.1L of ethanol, performing rotary filtration for 1 hour, and recovering the ethanol from the filtrate to obtain the dehydrate 11-alpha-chloro-6, 12-hemiketal oxytetracycline p-toluenesulfonate with the yield of 79%.
(4) Preparation of 6-deoxyoxytetracycline sulfosalicylate
Adding 0.7L of metered drinking water and 0.7L of ethanol into a hydrogenation reactor, controlling the reaction temperature to be 45-50 ℃, starting stirring, adding 450 g of weighed 1/6 batches of palladium carbon and 11-alpha-chloro-6, 12-hemiketal oxytetracycline p-toluenesulfonate prepared in the step (3), stirring into paste, closing the stirring, then fastening a tank cover of the hydrogenation reaction tank, and opening a vacuum valve of the hydrogenation reaction tank. Adding 380 g of weighed sulfosalicylic acid at 55-60 ℃ while stirring, continuing stirring for 10 min, standing for 10-12 h, and performing filter spinning when the temperature is below 30 ℃ to obtain a filter cake, namely 6-deoxyoxytetracycline sulfosalicylate, wherein the yield of the step is 60.5%.
(5) The alpha-6-deoxyoxytetracycline is prepared by alkalization reaction
Pumping ethanol into a conversion tank, adding a proper amount of purified water to enable the ethanol content to be 60-70%, starting stirring, adding the 6-deoxyoxytetracycline sulfosalicylate prepared in the step (4), starting freezing, reducing the temperature to 5 ℃, and stirring the materials into uniform paste. Adding ammonia water, adjusting the pH value to 5.9-6.3 to dissolve the materials, controlling the temperature to be 10-12 ℃, continuing stirring for 5 minutes until the pH value is stable, stopping stirring, and discharging and filtering. And after filtering, starting stirring in a crystallizing tank, heating to 35-40 ℃, keeping the temperature and stirring for 20-30 minutes, crystallizing, and performing filter throwing.
And (3) fully drying the mother liquor, washing with ethanol, and continuously performing spin filtration for 30-50 minutes to obtain a filter cake, namely the alpha-6-deoxyoxytetracycline, with the yield of 86%.
(6) Salifying reaction to obtain doxycycline hydrochloride
Adding the alpha-6-deoxyoxytetracycline obtained in the step (5) into a salt forming reactor, then adding 0.5L of ethanol, starting stirring, adding free alkali, introducing steam, heating to 35 ℃, closing the steam, stirring for 5 minutes, and heating to about 45 ℃. Adding measured CP hydrochloric acid, raising the temperature to 55-60 ℃, preserving the heat for 20-30 minutes, cooling, and reducing the temperature to room temperature to carry out filtration. And (3) sufficiently spin-drying the mother liquor, washing the filter cake for 3 to 4 times by using ethanol, continuously carrying out spin-filtration for 30 to 50 minutes, and taking the filter cake out of a centrifugal machine and drying the filter cake in a drying chamber to obtain doxycycline hydrochloride which is a crystalline substance with the purity of 99.5 percent and the yield of 89 percent.
Example 2:
a preparation method of doxycycline hydrochloride comprises the following steps:
(1) chloro-made defervescent ice
0.81L of drinking water is put into a 3L glass-lined reaction tank, 151 g of baking soda is added, the pH is adjusted to 8-9, the stirring is started for about 30 minutes, 231 g of antipyretic ice is added, and the temperature is reduced to 10-15 ℃ by freezing with an interlayer. Slowly adding metered sodium hypochlorite along the wall of the tank, controlling the temperature not to exceed 15 ℃, stirring for 60 minutes after the addition is finished, and discharging and filtering after the end point is reached. The filter cake was washed with drinking water to pH 7. And (3) fully spin-drying the filter cake for 1 hour to obtain the chlorinated antipyretic ice, and putting the chlorinated antipyretic ice into a refrigeration house for later use.
(2) Oxytetracycline chloride-11-alpha-chloro-6, 12-hemiketal oxytetracycline
Adding 0.46L of methanol into a 1L glass-lined reaction tank, adding 50.2 g of oxytetracycline base under stirring, slowly adding metered methanol-ammonia when the suspension becomes thick, stirring and cooling to-10 ℃, adding 25.5 g of the chloro antipyretic ice prepared in the step (1) at a time, and naturally rising the temperature. And (3) continuously stirring and reacting for 25 minutes, putting the feed liquid into a centrifugal machine for spin-drying, washing a tank and a filter cake with methanol for 25-40 minutes after spin-drying, obtaining the chloro-compound 11-alpha-chloro-6, 12-hemiketal oxytetracycline, and recovering methanol and de-icing from the filtrate. The chloride 11-alpha-chloro-6, 12-hemiketal oxytetracycline is taken out of the centrifuge, crushed by a granulator and dried by airflow, and the yield of the step is 98.7 percent.
(3) Dehydrating to obtain 11-alpha-chlorine-6, 12-hemiketal oxytetracycline p-toluenesulfonate
And (3) adding the chloride 11-alpha-chloro-6, 12-hemiketal oxytetracycline dried by the airflow in the step (2) into a salt forming tank, then weighing 205 g of p-toluenesulfonic acid, putting into the salt forming tank, controlling the reaction temperature to be 0-5 ℃, adding 0.11L of ethanol, starting stirring to completely dissolve the p-toluenesulfonic acid, and stopping stirring. Adding hydrofluoric acid, neutralizing the concentrated solution in the neutralizing tank, filtering out fluoride, washing the feed liquid adhered to the fluoride with ethanol, spin-drying, stirring for forming salt, pressing the filtrate, stopping stirring after crystallization, introducing cold liquid into the interlayer, and standing for more than 8 hours. And (3) performing rotary filtration crystallization, washing the filter cake for 3-4 times by using 0.1L of ethanol, performing rotary filtration for 1 hour, and recovering the ethanol from the filtrate to obtain the dehydrate 11-alpha-chloro-6, 12-hemiketal oxytetracycline p-toluenesulfonate with the yield of 80%.
(4) Preparation of 6-deoxyoxytetracycline sulfosalicylate
Adding 0.71L of metered drinking water and 0.69L of ethanol into a hydrogenation reactor, controlling the reaction temperature to be 45-50 ℃, starting stirring, adding 450 g of weighed 1/6 batches of palladium carbon and 11-alpha-chloro-6, 12-hemiketal oxytetracycline p-toluenesulfonate prepared in the step (3), stirring into paste, closing the stirring, then fastening a tank cover of the hydrogenation reaction tank, and opening a vacuum valve of the hydrogenation reaction tank. And adding 380 g of weighed sulfosalicylic acid into the filtrate in the salt forming tank under stirring at 55-60 ℃, continuing stirring for 10 min, standing for 10-12 h, and performing filter spinning when the temperature is below 30 ℃ to obtain a filter cake, namely 6-deoxyoxytetracycline sulfosalicylate, wherein the yield of the step is 59%.
(5) The alpha-6-deoxyoxytetracycline is prepared by alkalization reaction
Pumping ethanol into a conversion tank, adding a proper amount of purified water to enable the ethanol content to be 60-70%, starting stirring, adding the 6-deoxyoxytetracycline sulfosalicylate prepared in the step (4), starting freezing, reducing the temperature to 5 ℃, and stirring the materials into uniform paste. Adding ammonia water, adjusting the pH value to 5.9-6.3 to dissolve the materials, controlling the temperature to be 10-12 ℃, continuing stirring for 5 minutes until the pH value is stable, stopping stirring, and discharging and filtering. And after filtering, starting stirring in a crystallizing tank, heating to 35-40 ℃, keeping the temperature and stirring for 20-30 minutes, crystallizing, and performing filter throwing.
And (3) fully drying the mother liquor, washing with ethanol, and continuously performing spin filtration for 30-50 minutes to obtain a filter cake, namely the alpha-6-deoxyoxytetracycline, wherein the yield is 85%.
(6) Salifying reaction to obtain doxycycline hydrochloride
Adding the alpha-6-deoxyoxytetracycline obtained in the step (5) into a salt forming reactor, then adding 0.51L of ethanol, starting stirring, adding free alkali, introducing steam, heating to 35 ℃, closing the steam, stirring for 5 minutes, and heating to about 45 ℃. Adding measured CP hydrochloric acid, raising the temperature to 55-60 ℃, preserving the heat for 20-30 minutes, cooling, and reducing the temperature to room temperature to carry out filtration. And (3) sufficiently spin-drying the mother liquor, washing the filter cake for 3 to 4 times by using ethanol, continuously carrying out spin-filtration for 30 to 50 minutes, and taking the filter cake out of a centrifugal machine and drying the filter cake in a drying chamber to obtain doxycycline hydrochloride which is a crystalline substance with the purity of 99.6 percent and the yield of 89 percent.
Example 3:
a preparation method of doxycycline hydrochloride comprises the following steps:
(1) chloro-made defervescent ice
0.79L of drinking water is put into a 3L glass-lined reaction tank, 150 g of baking soda is added, the stirring is started for about 30 minutes, 231 g of antipyretic ice is added, and the interlayer is frozen and cooled to 10-15 ℃. Slowly adding metered sodium hypochlorite along the wall of the tank, controlling the temperature not to exceed 15 ℃, stirring for 60 minutes after the addition is finished, and discharging and filtering after the end point is reached. The filter cake was washed with drinking water to pH 7. And (3) fully spin-drying the filter cake for 1 hour to obtain the chlorinated antipyretic ice, and putting the chlorinated antipyretic ice into a refrigeration house for later use.
(2) Oxytetracycline chloride-11-alpha-chloro-6, 12-hemiketal oxytetracycline
Adding 0.45L of methanol into a 1L glass-lined reaction tank, adding 49.9 g of oxytetracycline while stirring, slowly adding metered methanol-ammonia when the suspension becomes thick, stirring and cooling to-10 ℃, adding 25.5 g of the chloro antipyretic ice prepared in the step (1) at a time, and naturally rising the temperature. And (3) continuously stirring and reacting for 25 minutes, putting the feed liquid into a centrifugal machine for spin-drying, washing a tank and a filter cake with methanol for 25-40 minutes after spin-drying, obtaining the chloro-compound 11-alpha-chloro-6, 12-hemiketal oxytetracycline, and recovering methanol and de-icing from the filtrate. The chloride 11-alpha-chlorine-6, 12-hemiketal terramycin is taken out of the centrifuge, crushed by a granulator, dried by airflow and then put into a salt tank, and the yield of the step is 99 percent.
(3) Dehydrating to obtain 11-alpha-chlorine-6, 12-hemiketal oxytetracycline p-toluenesulfonate
And (3) putting the chloride 11-alpha-chloro-6, 12-hemiketal oxytetracycline dried by the airflow in the step (2) into a salt forming tank, weighing 195 g of p-toluenesulfonic acid, putting into the salt forming tank, controlling the reaction temperature to be 0-5 ℃, adding 0.11L of ethanol, starting stirring to completely dissolve the p-toluenesulfonic acid, and stopping stirring. Adding hydrofluoric acid for neutralizing the liquid in the salt forming tank, filtering out fluoride after neutralization, washing the feed liquid adhered to the fluoride with ethanol in several times, spin-drying, stirring for forming salt, pressing the filtrate, stopping stirring after crystallization, introducing cold liquid into the interlayer, and standing for more than 8 hours. And (3) performing swing filtration crystallization, washing the filter cake for 3-4 times by using 0.1L of ethanol, performing swing filtration for 1 hour, and recovering the ethanol from the filtrate to obtain the dehydrate 11-alpha-chloro-6, 12-hemiketal oxytetracycline p-toluenesulfonate with the yield of 78%.
(4) Preparation of 6-deoxyoxytetracycline sulfosalicylate
Adding 0.70L of metered drinking water and 0.69L of ethanol into a hydrogenation reactor, controlling the reaction temperature to be 45-50 ℃, starting stirring, adding 450 g of weighed 1/6 batches of palladium carbon and 11-alpha-chloro-6, 12-hemiketal oxytetracycline p-toluenesulfonate prepared in the step (3), stirring into paste, closing the stirring, then fastening a tank cover of the hydrogenation reaction tank, and opening a vacuum valve of the hydrogenation reaction tank. And adding 380 g of weighed sulfosalicylic acid into the filtrate in the salt forming tank under stirring at 55-60 ℃, continuing stirring for 10 min, standing for 10-12 h, and performing filter spinning when the temperature is below 30 ℃ to obtain a filter cake, namely 6-deoxyoxytetracycline sulfosalicylate, wherein the yield of the step is 60%.
(5) The alpha-6-deoxyoxytetracycline is prepared by alkalization reaction
Pumping ethanol into a conversion tank, adding a proper amount of purified water to enable the ethanol content to be 60-70%, starting stirring, adding the 6-deoxyoxytetracycline sulfosalicylate prepared in the step (4) for hydrogenation, cooling to 5 ℃, and stirring the materials into uniform paste. Adding ammonia water, adjusting the pH value to 5.9-6.3 to dissolve the materials, controlling the temperature to be 10-12 ℃, continuing stirring for 5 minutes until the pH value is stable, stopping stirring, and discharging and filtering. And after filtering, starting stirring in a crystallizing tank, heating to 35-40 ℃, keeping the temperature and stirring for 20-30 minutes, crystallizing, and performing filter throwing.
And (3) sufficiently drying the mother liquor, washing with ethanol, and continuously filtering for 30-50 minutes to obtain a filter cake, namely the alpha-6-deoxyoxytetracycline, with the yield of 85.5%.
(6) Salifying reaction to obtain doxycycline hydrochloride
Adding the alpha-6-deoxyoxytetracycline obtained in the step (5) into a salt forming reactor, then adding 0.5L of ethanol, starting stirring, adding free alkali, introducing steam, heating to 35 ℃, closing the steam, stirring for 5 minutes, and heating to about 45 ℃. Adding measured CP hydrochloric acid, raising the temperature to 55-60 ℃, preserving the heat for 20-30 minutes, cooling, and reducing the temperature to room temperature to carry out filtration. And (3) sufficiently spin-drying the mother liquor, washing the filter cake for 3 to 4 times by using ethanol, continuously carrying out spin-filtration for 30 to 50 minutes, and taking the filter cake out of a centrifugal machine and drying the filter cake in a drying chamber to obtain doxycycline hydrochloride which is a crystalline substance with the purity of 99.4 percent and the yield of 88 percent.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the overall concept of the present invention, and these should also be considered as the protection scope of the present invention.
Claims (5)
1. A preparation method of doxycycline hydrochloride is characterized in that: the method comprises the following steps:
(1) chloridizing the antipyretic ice, and then reacting the oxytetracycline with the chloro antipyretic ice to obtain 11-alpha-chloro-6, 12-hemiketal oxytetracycline;
(2) dehydrating the 11-alpha-chlorine-6, 12-hemiketal oxytetracycline to obtain 11-alpha-chlorine-6, 12-hemiketal oxytetracycline p-toluenesulfonate;
(3) the 11-alpha-chlorine-6, 12-hemiketal oxytetracycline p-toluenesulfonate is hydrogenated by hydrogen and reacts with sulfosalicylic acid in the presence of a catalyst to obtain 6-deoxyoxytetracycline sulfosalicylate;
(4) 6-doxycycline sulfosalicylate desalinization oxytetracycline sulfosalicylic acid is subjected to alkalization and salt-forming reaction to obtain doxycycline hydrochloride;
in the step (2), the 11-alpha-chloro-6, 12-hemiketal oxytetracycline and p-toluenesulfonic acid are subjected to dehydration reaction to generate p-toluenesulfonate of the 11-alpha-chloro-6, 12-hemiketal oxytetracycline, the reaction temperature is 0-5 ℃, the acid is HF, and the solvent is ethanol; in the step (3), the catalyst for the pressure hydrogenation reaction is palladium carbon, and the temperature is 45-50 ℃.
2. A process for the preparation of doxycycline hydrochloride according to claim 1, characterized in that: in the step (1), sodium hypochlorite is used for chlorinating the antipyretic ice.
3. A process for the preparation of doxycycline hydrochloride according to claim 1, characterized in that: in the step (1), the temperature for chlorinating the oxytetracycline is below 10 ℃ and the solvent is methanol-ammonia.
4. A process for the preparation of doxycycline hydrochloride according to claim 1, characterized in that: in the step (4), 6-deoxyoxytetracycline sulfosalicylate reacts with alkali, and the alpha-6-deoxyoxytetracycline is obtained by alkalization, wherein the alkali is ammonia water.
5. A process for the preparation of doxycycline hydrochloride according to claim 4, wherein: in the step (4), the step of further salifying the alpha-6-deoxyoxytetracycline is as follows: reacting alpha-6-deoxyoxytetracycline with an ethanol solution to obtain doxycycline hydrochloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710466136.5A CN109134291B (en) | 2017-06-19 | 2017-06-19 | Preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710466136.5A CN109134291B (en) | 2017-06-19 | 2017-06-19 | Preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109134291A CN109134291A (en) | 2019-01-04 |
| CN109134291B true CN109134291B (en) | 2021-04-16 |
Family
ID=64804471
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710466136.5A Active CN109134291B (en) | 2017-06-19 | 2017-06-19 | Preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by same |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109134291B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248397B (en) * | 2021-07-01 | 2021-11-05 | 山东国邦药业有限公司 | Preparation method of doxycycline hydrochloride |
| CN114835603A (en) * | 2022-06-17 | 2022-08-02 | 盐城苏海制药有限公司 | Synthesis method for directly synthesizing doxycycline hydrochloride from hydride |
| CN114957033A (en) * | 2022-06-17 | 2022-08-30 | 盐城苏海制药有限公司 | Continuous production method for recovering annealed ice |
| CN115028546A (en) * | 2022-08-12 | 2022-09-09 | 山东国邦药业有限公司 | Method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989002429A1 (en) * | 1987-09-18 | 1989-03-23 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Improved process for the preparation of tetracycline derivatives |
| US4902447A (en) * | 1988-10-28 | 1990-02-20 | Ranbaxy Laboratories Limited | Process for the production of alpha-6-deoxytetracyclines and hydrogenation catalyst useful therein |
| CN101786971A (en) * | 2010-03-01 | 2010-07-28 | 扬州联博药业有限公司 | Preparation process of doxycycline hydrochloride |
| CN103467336A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Synthesis process of doxycycline hydrochloride intermediate 11alpha-chlorinated methacycline |
| CN103467335A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Method for synthesizing doxycycline hydrochloride intermediate alpha-6-deoxytetracycline based on hydrogenation of carbon-based rhodium catalyst |
-
2017
- 2017-06-19 CN CN201710466136.5A patent/CN109134291B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1989002429A1 (en) * | 1987-09-18 | 1989-03-23 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Improved process for the preparation of tetracycline derivatives |
| US4902447A (en) * | 1988-10-28 | 1990-02-20 | Ranbaxy Laboratories Limited | Process for the production of alpha-6-deoxytetracyclines and hydrogenation catalyst useful therein |
| CN101786971A (en) * | 2010-03-01 | 2010-07-28 | 扬州联博药业有限公司 | Preparation process of doxycycline hydrochloride |
| CN103467336A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Synthesis process of doxycycline hydrochloride intermediate 11alpha-chlorinated methacycline |
| CN103467335A (en) * | 2013-09-22 | 2013-12-25 | 河南师范大学 | Method for synthesizing doxycycline hydrochloride intermediate alpha-6-deoxytetracycline based on hydrogenation of carbon-based rhodium catalyst |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109134291A (en) | 2019-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109134291B (en) | Preparation method of doxycycline hydrochloride and doxycycline hydrochloride prepared by same | |
| SK280544B6 (en) | Process for the preparation of creatine or creatine-monohydrate | |
| CN1321121C (en) | Post processing method for preparing levo-ofloxacin | |
| CN106117038B (en) | A kind of technique that calcium lactate is produced using nisin waste water | |
| CN113173956B (en) | Preparation method of clarithromycin lactobionate | |
| CN102399176B (en) | Preparation method of high-content 2-hydroxy-4-(methylthio) butyl calcium | |
| CN111393319B (en) | Preparation method of oxytetracycline chloride | |
| CN108101812B (en) | Production and purification process of lauroyl arginine ethyl ester hydrochloride | |
| CN104193674B (en) | A kind of synthetic method of flunixin meglumine | |
| CN107400069B (en) | Preparation method of lauroyl arginine ethyl ester hydrochloride | |
| CN108752250B (en) | Synthesis method of high-purity fudosteine | |
| CN104610385B (en) | A kind of process for purification of aminoglucose hydrochloride | |
| CN103539745B (en) | A kind of preparation method of secnidazole | |
| CN113292513B (en) | Preparation method of high-purity promethazine hydrochloride | |
| CN111217760B (en) | Synthetic method of sulfachloropyrazine sodium | |
| CN110407737B (en) | Preparation method of cyproheptadine hydrochloride | |
| CN103896798A (en) | Tetracycline purifying process | |
| US3019232A (en) | Process for producing synthetic tryptophane | |
| CN101823980B (en) | Preparation method of large-grain occrycetin | |
| WO2021212535A1 (en) | Method for refining benzhexol hydrochloride | |
| CN111362997A (en) | Synthesis of androstenedione (2,2,4,6,6,16, 16-D) by deuterium exchange7) Method (2) | |
| CN111393341A (en) | Preparation method of water-soluble florfenicol amino acid salt | |
| CN114478283A (en) | Preparation method of 6-aminocaproic acid | |
| CN115710218B (en) | Crystallization method for improving flunixin meglumine fluidity | |
| CN102372743B (en) | Synthesizing method for aminobenzene arsenic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |