CN109134291A - A kind of preparation method of Doxycycline Hyclate and Doxycycline Hyclate prepared by this method - Google Patents
A kind of preparation method of Doxycycline Hyclate and Doxycycline Hyclate prepared by this method Download PDFInfo
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- CN109134291A CN109134291A CN201710466136.5A CN201710466136A CN109134291A CN 109134291 A CN109134291 A CN 109134291A CN 201710466136 A CN201710466136 A CN 201710466136A CN 109134291 A CN109134291 A CN 109134291A
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- doxycycline
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- doxycycline hyclate
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- 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
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- 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
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Abstract
The present invention provide a kind of Doxycycline Hyclate preparation method and Doxycycline Hyclate prepared by this method, it is reacted by chlorination antifebrin with terramycin and raw material is provided, improve the yield of Doxycycline Hyclate, reduce the generation of by-product, antifebrin, ethyl alcohol and the methanol etc. in preparation process can recycle simultaneously, it reduces environmental pollution and the wasting of resources, reduces production cost, and product yield is stablized in this method preparation process.The Doxycycline Hyclate purity is high prepared additionally by preparation method of the invention, color are good.
Description
Technical field
The present invention relates to a kind of preparation methods of Doxycycline Hyclate and the how western ring of the hydrochloric acid as made from this preparation method
Element.
Background technique
Doxycycline Hyclate is a kind of semi-synthetic tetracycline antibiotics of wide spectrum, be mainly used for sensitive gram positive bacteria and
The infection of the upper respiratory tract caused by gram negative bacilli, tonsillitis, infection of biliary tract, lymphnoditis, honeycomb group inflammation etc., are also used for controlling
Typhus, Qiang's parasitosis, Eaton agent pneumonia etc. are treated, still for treating cholera, it can also be used to prevent pernicious malaria and hook end spiral shell
Revolve body-sensing dye.The aqueous solubility is strong, good absorbing, and distribution is wide, and clinical application is more and effect is good.Veterinary drug clinic is mainly used for livestock and poultry
Respiratory disease, Escherichia coli, the treatment of salmonella etc..
Stablize under Doxycycline Hyclate drying condition, but chance light is easy to change, it is all unstable under acid and alkaline condition, easily
It hydrolyzes, to influence its effect.And its aqueous acidic is stronger, and it is also larger to the stimulation of stomach, thus to a certain extent
Limit the application of Doxycycline Hyclate.
At present, the preparation of Doxycycline Hyclate is that starting is former with 11- α-chloro- 6- methine terramycin tosilate
Material, hydrogenated reduction generate α -6- deoxidation soil enzyme element sulfosalicylate at salt, then generate α -6- doxycycline through alkalization
Alkali finally turns salt and generates Doxycycline Hyclate.It is unstable that there is yields, and what the solvent in preparation process can not recycle asks
Topic.
And Doxycycline Hyclate is recorded as a kind of common anti-infectives in many National Pharmacopeia, but this
A little pharmacopeia limit it, the standard in relation to substance project are especially improved, to the single impurity and total impurities of product
Propose increasingly tighter requirement.So promoting high yield technique while developing the product of high quality, equally have important
Meaning.
Summary of the invention
To solve the above problems, the present invention provide a kind of Doxycycline Hyclate preparation method and salt prepared by this method
Sour Doxycycline, improves the yield of Doxycycline Hyclate, while reducing production cost.
The technical solution of the present invention is as follows: a kind of preparation method of Doxycycline Hyclate, comprising the following steps:
(1) antifebrin is subjected to chlorination, then terramycin reacts to obtain 11- α-chloro- 6,12- hemiketal soil with chloro antifebrin
Mycin；
(2) 11- α-chloro- 6,12- hemiketal terramycin is dehydrated, obtains 11- α-chloro- 6,12- hemiketal terramycin to toluene sulphur
Hydrochlorate；
(3) 11- α-chloro- 6,12- hemiketal terramycin tosilate in the presence of a catalyst, by hydrogen hydrogenation and sulphur
Base salicylism reaction obtains 6- doxycycline sulfosalicylate；
(4) 6- doxycycline sulfosalicylate obtains Doxycycline Hyclate through alkalization and salt-forming reaction.
In the step (1), carrying out chlorination to antifebrin is sodium hypochlorite.
In the step (1), the temperature for carrying out chlorination to terramycin is subzero 10 DEG C, and solvent is methanol-ammonia, by ammonia
It is directly sufficiently mixed with methanol, which can be reused for previous step for the antifebrin of recycling later.
In the step (2), 11- α-chloro- 6,12- hemiketal terramycin and p-methyl benzenesulfonic acid carry out dehydration generation pair
11- α-chloro- 6,12- hemiketal terramycin tosilate, reaction temperature are 0-5 DEG C, and acid is HF, and solvent is ethyl alcohol.
In the step (3), the catalyst of pressure hydration reaction is palladium carbon, and temperature is 45-50 DEG C.
In the step (4), 6- doxycycline sulfosalicylate is reacted with alkali, is alkalized to obtain α -6- deoxidation
Soil is mould, and alkali used is ammonium hydroxide.
In the step (4), the mould further salt-forming steps of α -6- deoxidation soil are as follows: α -6- doxycycline and ethyl alcohol is molten
Liquid reaction, to arrive Doxycycline Hyclate.
A kind of Doxycycline Hyclate prepared such as the above method.
Advantageous effects of the invention, it is how western that the preparation method of Doxycycline Hyclate provided by the invention improves hydrochloric acid
The yield of ring element, reduces the generation of by-product, while antifebrin, ethyl alcohol and the methanol etc. in preparation process can recycle benefit
With reducing environmental pollution and the wasting of resources, reduce production cost, and product yield is stablized in this method preparation process.Separately
The Doxycycline Hyclate purity is high of preparation method preparation through the invention, color are good outside.
Specific embodiment
Embodiment 1:
A kind of preparation method of Doxycycline Hyclate, comprising the following steps:
(1) chloro antifebrin processed
In the glass-lined reactor of 3 L, it is put into 0.82 L drinking water, puts into 150 g sodium bicarbonate, adjusts PH8-9, opens stirring
30 minutes or so, then 231 g of antifebrin is put into, interlayer opens frozen cooling to 10-15 DEG C.Time of metering is slowly added along tank skin
Sodium chlorate, control temperature must not exceed 15 DEG C, stir 60 minutes after adding, after terminal reaches, blowing rejection filter.It is washed with drinking
Wash filter cake to pH be 7.Filter cake is sufficiently dried 1 hour, chloro antifebrin is obtained, it is spare to be put into freezer.
(2) terramycin chloride -11- α processed-chloro- 6,12- hemiketal terramycin
0.45 L methanol is added in 1L glass-lined reactor, stirs 50 g Oxytetracycline Bases of lower investment, delays after suspension retrogradation
Slow methanol-ammonia that metering is added, stirring are cooled to -10 DEG C, primary that chloro antifebrin obtained in 25 g steps (1) is added, and allow
Temperature is gone up naturally.Continue to be stirred to react 25 minutes, feed liquid puts into a centrifuge carry out rejection filter, and methanol washing reaction is used after drying
Tank and filter cake, filter cake continue drying 25~40 minutes, obtain chloro thing 11- α-chloro- 6,12- hemiketal terramycin, and filtrate recycles first
Pure and mild antifebrin.After chloro thing 11- α-chloro- 6,12- hemiketal terramycin goes out centrifuge, is crushed through granulator and carry out air-flow baking
It is dry, the step yield 99.2%.
(3) it is dehydrated and 11- α-chloro- 6,12- hemiketal terramycin tosilate is made
At salt cellar, then chloro thing 11- α-chloro- 6,12- hemiketal terramycin after the airflow drying that step (2) is obtained is added
200 g of p-methyl benzenesulfonic acid investment is weighed into salt cellar, 0-5 DEG C of reaction temperature is controlled, 0.1 L of ethyl alcohol is added, starts stirring, is made pair
Toluenesulfonic acid all dissolves, and stops stirring.Hydrofluoric acid is added, the liquid being neutralized into salt cellar after neutralization, filters out fluorination
Object washs the feed liquid being adhered on fluoride with ethyl alcohol by several times, and then drying is started into salt and stirred, filtrate is pressed into, to be crystallized
Stopping stirring after precipitation, interlayer is passed through cold liquid, stand 8 hours or more.Rejection filter crystallization, with 0.1 L ethyl alcohol point, 3~4 washings filter
Cake, rejection filter 1 hour, filtrate recycling ethanol obtained dehydrate 11- α-chloro- 6,12- hemiketal terramycin tosilate, received
Rate is 79%.
(4) 6- doxycycline sulfosalicylate processed
0.7 L of drinking water measured, 0.7 L of ethyl alcohol are added in hydrogenation reactor, controls 45-50 DEG C of reaction temperature, starting
Stirring puts into 11- α-chloro- 6,12- hemiketal terramycin tosilate made from load weighted 1 ∕, 6 batches of palladium carbons, step (3)
450 g stir into paste, close stirring, then tighten hydrogenation tank cover, open the vacuum valve of hydrogenation tank.It is stirring
380 g of sulfosalicylic acid for being added and weighing up in 55~60 DEG C is mixed down, continues to stir 10 min, static 10~12 hours, temperature existed
At 30 DEG C or less, can rejection filter, obtained filter cake is 6- doxycycline sulfosalicylate, the step yield 60.5%.
(5) it is mould that α -6- deoxidation soil is made in quaternization
Ethyl alcohol is pumped into conversion tank, appropriate purified water is added, makes ethanol content 60~70%, starts stirring, put into step (4)
Obtained 6- doxycycline sulfosalicylate, opens freezing and is down to 5 DEG C, by material stirring at uniform paste.It is added
Ammonium hydroxide adjusts pH value 5.9~6.3, makes material dissolution, and temperature is controlled at 10~12 DEG C, continues stirring 5 minutes, pH stable is not
Become, stops stirring, it can blowing filtering.Filtering finishes, and crystallizing tank starts stirring, is warming up to 35~40 DEG C, and insulated and stirred 20~
30 minutes, crystallization, rejection filter.
Mother liquor is sufficiently dried, ethanol washing is then used, is continued rejection filter 30~50 minutes, obtained filter cake is α -6- de-
Oxygen soil is mould, yield 86%.
(6) Doxycycline Hyclate is made in salt-forming reaction
α -6- deoxidation soil obtained in step (5) is mould, it is added in salt-forming reactor, 0.5 L ethyl alcohol is then added, starts and stirs
It mixes, puts into free alkali, logical steam is warming up to 35 DEG C, and steam off stirs 5 minutes, and temperature about rises to 45 DEG C.Metering is added
CP hydrochloric acid, temperature rise to 55 DEG C~60 DEG C, keep the temperature 20~30 minutes, and cooling, being down to room temperature can rejection filter.Mother liquor is abundant
Then drying is used ethanol washing filter cake 3 to 4 times, continue rejection filter 30~50 minutes, filter cake goes out centrifuge and drying room is sent to dry, and obtains
It is crystalline material, purity 99.5%, yield 89% to Doxycycline Hyclate.
Embodiment 2:
A kind of preparation method of Doxycycline Hyclate, comprising the following steps:
(1) chloro antifebrin processed
In the glass-lined reactor of 3 L, it is put into 0.81 L drinking water, puts into 151 g sodium bicarbonate, adjusts PH8-9, opens stirring
30 minutes or so, then 231 g of antifebrin is put into, interlayer opens frozen cooling to 10-15 DEG C.Time of metering is slowly added along tank skin
Sodium chlorate, control temperature must not exceed 15 DEG C, stir 60 minutes after adding, after terminal reaches, blowing rejection filter.It is washed with drinking
Wash filter cake to pH be 7.Filter cake is sufficiently dried 1 hour, chloro antifebrin is obtained, it is spare to be put into freezer.
(2) terramycin chloride -11- α processed-chloro- 6,12- hemiketal terramycin
0.46 L methanol is added in 1L glass-lined reactor, 50.2 g Oxytetracycline Bases of lower investment are stirred, after suspension retrogradation
It is slowly added to methanol-ammonia of metering, stirring is cooled to -10 DEG C, primary chloro obtained in 25.5 g steps (1) is added to bring down a fever
Ice allows temperature to go up naturally.Continue to be stirred to react 25 minutes, feed liquid puts into a centrifuge carry out rejection filter, is washed after drying with methanol
Tank and filter cake are washed, continues to expect for drying 25~40 minutes, obtains chloro thing 11- α-chloro- 6,12- hemiketal terramycin, filtrate recycles first
Pure and mild antifebrin.After chloro thing 11- α-chloro- 6,12- hemiketal terramycin goes out centrifuge, is crushed through granulator and carry out air-flow baking
It is dry, the step yield 98.7%.
(3) it is dehydrated and 11- α-chloro- 6,12- hemiketal terramycin tosilate is made
Chloro thing 11- α after airflow drying in step (2)-chloro- 6,12- hemiketal terramycin is added into salt cellar, is then weighed
205 g of p-methyl benzenesulfonic acid investment controls 0-5 DEG C of reaction temperature at salt cellar, and 0.11 L of ethyl alcohol is added, starts stirring, makes to toluene
Sulfonic acid all dissolves, and stops stirring.Hydrofluoric acid is added, the concentrate neutralization in neutralizing tank is finished, fluoride is filtered out, uses ethyl alcohol
The feed liquid being adhered on fluoride is washed by several times, is dried, is then started into salt and stir, filtrate is pressed into, stop after precipitation to be crystallized
Only stirring, interlayer is passed through cold liquid, stand 8 hours or more.Rejection filter crystallization, with 0.1 L ethyl alcohol point, 3~4 washing filter cakes, rejection filter 1
Hour, filtrate recycling ethanol obtains dehydrate 11- α-chloro- 6,12- hemiketal terramycin tosilate, yield 80%.
(4) 6- doxycycline sulfosalicylate processed
0.71 L of drinking water measured, 0.69 L of ethyl alcohol are added in hydrogenation reactor, controls 45-50 DEG C of reaction temperature, opens
Dynamic stirring puts into 11- α-chloro- 6,12- hemiketal terramycin p-methyl benzenesulfonic acid made from load weighted 1 ∕, 6 batches of palladium carbons, step (3)
450 g of salt stirs into paste, closes stirring, then tightens hydrogenation tank cover, opens the vacuum valve of hydrogenation tank.At
380 g of sulfosalicylic acid weighed up is added under stiring in 55~60 DEG C in filtrate in salt cellar, continues to stir 10 min, static
10~12 hours, temperature at 30 DEG C or less, can rejection filter, obtained filter cake is 6- doxycycline sulfosalicylate,
The step yield 59%.
(5) it is mould that α -6- deoxidation soil is made in quaternization
Ethyl alcohol is pumped into conversion tank, appropriate purified water is added, makes ethanol content 60~70%, starts stirring, put into step (4)
Obtained 6- doxycycline sulfosalicylate, opens freezing and is down to 5 DEG C, by material stirring at uniform paste.It is added
Ammonium hydroxide adjusts pH value 5.9~6.3, dissolves material, and temperature is controlled at 10~12 DEG C, continues stirring 5 minutes, and pH stable is constant,
Stop stirring, it can blowing filtering.Filtering finishes, and crystallizing tank starts stirring, is warming up to 35~40 DEG C, insulated and stirred 20~30
Minute, crystallization, rejection filter.
Mother liquor is sufficiently dried, ethanol washing is then used, is continued rejection filter 30~50 minutes, obtained filter cake is α -6- de-
Oxygen soil is mould, yield 85%.
(6) Doxycycline Hyclate is made in salt-forming reaction
α -6- deoxidation soil obtained in step (5) is mould, it is added in salt-forming reactor, 0.51 L ethyl alcohol is then added, starts and stirs
It mixes, puts into free alkali, logical steam is warming up to 35 DEG C, and steam off stirs 5 minutes, and temperature about rises to 45 DEG C.Metering is added
CP hydrochloric acid, temperature rise to 55 DEG C~60 DEG C, keep the temperature 20~30 minutes, and cooling, being down to room temperature can rejection filter.Mother liquor is abundant
Then drying is used ethanol washing filter cake 3 to 4 times, continue rejection filter 30~50 minutes, filter cake goes out centrifuge and drying room is sent to dry, and obtains
It is crystalline material, purity 99.6%, yield 89% to Doxycycline Hyclate.
Embodiment 3:
A kind of preparation method of Doxycycline Hyclate, comprising the following steps:
(1) chloro antifebrin processed
In the glass-lined reactor of 3 L, it is put into 0.79 L drinking water, puts into 150 g sodium bicarbonate, opens 30 minutes left sides of stirring
The right side, then 231 g of antifebrin is put into, interlayer opens frozen cooling to 10-15 DEG C.The sodium hypochlorite of metering, control are slowly added along tank skin
Temperature processed must not exceed 15 DEG C, stir 60 minutes after adding, after terminal reaches, blowing rejection filter.With drinking water washing filter cake to pH
It is 7.Filter cake is sufficiently dried 1 hour, chloro antifebrin is obtained, it is spare to be put into freezer.
(2) terramycin chloride -11- α processed-chloro- 6,12- hemiketal terramycin
0.45 L methanol is added in 1L glass-lined reactor, 49.9 g Oxytetracycline Bases of lower investment are stirred, after suspension retrogradation
It is slowly added to methanol-ammonia of metering, stirring is cooled to -10 DEG C, primary chloro obtained in 25.5 g steps (1) is added to bring down a fever
Ice allows temperature to go up naturally.Continue to be stirred to react 25 minutes, feed liquid puts into a centrifuge carry out rejection filter, is washed after drying with methanol
Tank and filter cake are washed, continues to expect for drying 25~40 minutes, obtains chloro thing 11- α-chloro- 6,12- hemiketal terramycin, filtrate recycles first
Pure and mild antifebrin.After chloro thing 11- α-chloro- 6,12- hemiketal terramycin goes out centrifuge, is crushed through granulator and carry out air-flow baking
It is dry, then put into salt cellar into, the step yield 99%.
(3) it is dehydrated and 11- α-chloro- 6,12- hemiketal terramycin tosilate is made
By the chloro thing 11- α after airflow drying in step (2)-chloro- 6,12- hemiketal terramycin investment at salt cellar, then weigh
195 g of p-methyl benzenesulfonic acid investment controls 0-5 DEG C of reaction temperature at salt cellar, and 0.11 L of ethyl alcohol is added, starts stirring, makes to toluene
Sulfonic acid all dissolves, and stops stirring.Hydrofluoric acid is added, the liquid for being neutralized into salt cellar after neutralization, filters out fluorination
Object washs the feed liquid being adhered on fluoride with ethyl alcohol by several times, and then drying is started into salt and stirred, filtrate is pressed into, to be crystallized
Stopping stirring after precipitation, interlayer is passed through cold liquid, stand 8 hours or more.Rejection filter crystallization, with 0.1 L ethyl alcohol point, 3~4 washings filter
Cake, rejection filter 1 hour, filtrate recycling ethanol obtained dehydrate 11- α-chloro- 6,12- hemiketal terramycin tosilate, received
Rate is 78%.
(4) 6- doxycycline sulfosalicylate processed
0.70 L of drinking water measured, 0.69 L of ethyl alcohol are added in hydrogenation reactor, controls 45-50 DEG C of reaction temperature, opens
Dynamic stirring puts into 11- α-chloro- 6,12- hemiketal terramycin p-methyl benzenesulfonic acid made from load weighted 1 ∕, 6 batches of palladium carbons, step (3)
450 g of salt stirs into paste, closes stirring, then tightens hydrogenation tank cover, opens the vacuum valve of hydrogenation tank.At
380 g of sulfosalicylic acid weighed up is added under stiring in 55~60 DEG C in filtrate in salt cellar, continues to stir 10 min, static
10~12 hours, temperature at 30 DEG C or less, can rejection filter, obtained filter cake is 6- doxycycline sulfosalicylate,
The step yield 60%.
(5) it is mould that α -6- deoxidation soil is made in quaternization
Ethyl alcohol is pumped into conversion tank, appropriate purified water is added, makes ethanol content 60~70%, starts stirring, investment hydrogenation investment
6- doxycycline sulfosalicylate obtained by step (4), opens freezing and is down to 5 DEG C, by material stirring at uniform paste
Object.Ammonium hydroxide is added, adjusts pH value 5.9~6.3, dissolves material, temperature is controlled at 10~12 DEG C, continues stirring 5 minutes, pH value is steady
It is fixed constant, stop stirring, it can blowing filtering.Filtering finishes, and crystallizing tank starts stirring, is warming up to 35~40 DEG C, insulated and stirred
20~30 minutes, crystallization, rejection filter.
Mother liquor is sufficiently dried, ethanol washing is then used, is continued rejection filter 30~50 minutes, obtained filter cake is α -6- de-
Oxygen soil is mould, yield 85.5%.
(6) Doxycycline Hyclate is made in salt-forming reaction
α -6- deoxidation soil obtained in step (5) is mould, it is added in salt-forming reactor, 0.5 L ethyl alcohol is then added, starts and stirs
It mixes, puts into free alkali, logical steam is warming up to 35 DEG C, and steam off stirs 5 minutes, and temperature about rises to 45 DEG C.Metering is added
CP hydrochloric acid, temperature rise to 55 DEG C~60 DEG C, keep the temperature 20~30 minutes, and cooling, being down to room temperature can rejection filter.Mother liquor is abundant
Then drying is used ethanol washing filter cake 3 to 4 times, continue rejection filter 30~50 minutes, filter cake goes out centrifuge and drying room is sent to dry, and obtains
It is crystalline material, purity 99.4%, yield 88% to Doxycycline Hyclate.
What has been described above is only a preferred embodiment of the present invention, it is noted that for those skilled in the art,
Without depart from that overall concept of the invention, several changes and improvements can also be made, these also should be considered as of the invention
Protection scope.
Claims (8)
1. a kind of preparation method of Doxycycline Hyclate, it is characterised in that: the following steps are included:
(1) antifebrin is subjected to chlorination, then terramycin reacts to obtain 11- α-chloro- 6,12- hemiketal soil with chloro antifebrin
Mycin；
(2) 11- α-chloro- 6,12- hemiketal terramycin is dehydrated, obtains 11- α-chloro- 6,12- hemiketal terramycin to toluene sulphur
Hydrochlorate；
(3) 11- α-chloro- 6,12- hemiketal terramycin tosilate in the presence of a catalyst, by hydrogen hydrogenation and sulphur
Base salicylism reaction obtains 6- doxycycline sulfosalicylate；
(4) 6- doxycycline sulfosalicylate desalination oxygen terramycin sulfosalicylic acid obtains salt through alkalization and salt-forming reaction
Sour Doxycycline.
2. the preparation method of Doxycycline Hyclate according to claim 1, it is characterised in that: in the step (1), to moving back
It is sodium hypochlorite that hot ice, which carries out chlorination,.
3. the preparation method of Doxycycline Hyclate according to claim 1, it is characterised in that: in the step (1), to soil
The temperature that mycin carries out chlorination is subzero 10 DEG C, and solvent is methanol-ammonia.
4. the preparation method of Doxycycline Hyclate according to claim 1, it is characterised in that: in the step (2), 11-
The chloro- 6,12- hemiketal terramycin of α-and p-methyl benzenesulfonic acid carry out dehydration and generate to 11- α-chloro- 6,12- hemiketal terramycin
Tosilate, reaction temperature are 0-5 DEG C, and acid is HF, and solvent is ethyl alcohol.
5. the preparation method of Doxycycline Hyclate according to claim 1, it is characterised in that: in the step (3), pressurization
The catalyst of hydrogenation is palladium carbon, and temperature is 45-50 DEG C.
6. the preparation method of Doxycycline Hyclate according to claim 1, it is characterised in that: in the step (4), by 6-
Doxycycline sulfosalicylate is reacted with alkali, is alkalized to obtain that α -6- deoxidation soil is mould, and alkali used is ammonium hydroxide.
7. the preparation method of Doxycycline Hyclate according to claim 6, it is characterised in that: in the step (4), α -6-
The mould further salt-forming steps of deoxidation soil are as follows: react α -6- doxycycline with ethanol solution, to arrive Doxycycline Hyclate.
8. the how western ring of hydrochloric acid of the preparation method preparation of Doxycycline Hyclate described in -7 any claims according to claim 1
Element.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248397A (en) * | 2021-07-01 | 2021-08-13 | 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 |
| CN115677524A (en) * | 2022-08-12 | 2023-02-03 | 山东国邦药业有限公司 | Method for preparing doxycycline sulfosalicylate by hydrogenating methacycline p-toluenesulfonate |
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