CN106946728A - A kind of method for producing Doxycycline monohydrate - Google Patents
A kind of method for producing Doxycycline monohydrate Download PDFInfo
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- CN106946728A CN106946728A CN201710237264.2A CN201710237264A CN106946728A CN 106946728 A CN106946728 A CN 106946728A CN 201710237264 A CN201710237264 A CN 201710237264A CN 106946728 A CN106946728 A CN 106946728A
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- doxycycline
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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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of method for producing Doxycycline monohydrate, including：The sulfosalicylate crude product of 6 doxycyclines of α 5 is by the alkalization generation doxycycline alkali of α 6, the doxycycline alkali of gained α 6 and sulfosalicylic acid are subjected into salt, gained carries out a basification into salt thing again, can obtain the water thing of Doxycycline one of high-purity.The process of Doxycycline monohydrate disclosed by the invention, improves the purity of Doxycycline, up to more than 96%, can obtain the finished product of more high-quality.Because this method is directly improved on the basis of existing production technology, it can directly apply to industrial production, with good practicality.
Description
Technical field
The invention belongs to technical field of compound preparation, and in particular to a kind of method for producing Doxycycline monohydrate.
Background technology
The structural formula of the water thing of Doxycycline one is as follows：
Using Doxycycline as parent, most commonly seen medicine is Doxycycline Hyclate, and the molecular formula of Doxycycline Hyclate is as follows：
Doxycycline Hyclate is a kind of semi-synthetic tetracycline antibiotics of wide spectrum, to gram-positive bacteria, Gram-negative bacteria and
Chlamydia effectively, is clinically used for respiratory tract infection, infection of biliary tract, tonsillitis, the prevention and treatment of Eaton agent pneumonia.Current salt
The preparation of sour Doxycycline is by initiation material of α -6- doxycyclines sulfosalicylates by alkalization generation α -6- deoxidation soil
Mycin alkali, last acid adding generates Doxycycline Hyclate into salt.Doxycycline Hyclate is because good water solubility, good fluidity, it is easier to
Absorbed by oral mode, therefore in clinical practice widely.But, recently as people to the fat-soluble of medicine
With water miscible further investigation, it is found that fat-soluble medicine also there are their specific drug effects, therefore emerge a collection of client now
To the demand of Doxycycline monohydrate, actually during Doxycycline Hyclate is prepared, the intermediate α -6- of generation take off
Oxygen Oxytetracycline Base is exactly the crude product of Doxycycline monohydrate（Purity only has about 75%）, but for how to purify in other words such as
What prepares high-purity（More than 96%）The water thing of Doxycycline one research it is relatively fewer.
The content of the invention
In order to overcome the defect of above-mentioned prior art, high-purity Doxycycline monohydrate is produced the invention provides one kind
Method, purity reaches more than 96%.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：
A kind of method for producing Doxycycline monohydrate, comprises the following steps：
1）α -6- doxycycline 5-sulphosalicylic acid salt crude products are added in 15~20 DEG C of 70~75% ethanol waters,
Stir and ammoniacal liquor is added dropwise to solution dissolved clarification, control temperature is no more than 20 DEG C, and filtrate is heated to 40 ~ 45 DEG C, insulation is cold by filtering
But to 20 ~ 25 DEG C, the damp product of first time alkali compound are filtrated to get；
2）By step 1）The damp product of middle gained are added in 55 ~ 60% ethanol waters, are added hydrochloric acid and are adjusted pH to 3 ~ 3.5, continue to heat up
To 50 ~ 55 DEG C, make material all dissolvings, then add sulfosalicylic acid, stir, be naturally cooling to 20 ~ 25 DEG C, into the analysis of salt thing
Go out, be filtrated to get into the damp product of salt thing；
3）By step 2）Gained is added in 10 ~ 15 DEG C of 70~75% ethanol waters into the damp product of salt thing, after being sufficiently stirred for,
Start to be added dropwise ammoniacal liquor to solution dissolved clarification, control temperature is no more than 18 DEG C, and filtrate is heated to 40 ~ 45 DEG C, insulation is natural by filtering
10 ~ 15 DEG C are cooled to, the damp product of alkali compound are filtrated to get；
4）By step 3）The damp product of alkali compound dried by vacuum drying chamber, obtain the water thing finished product of Doxycycline one.
Step 1）In, the mass volume ratio of α -6- doxycyclines 5-sulphosalicylic acid salt crude products and ethanol water is 1：
2 ~ 3, the mass concentration of ammoniacal liquor is 20 ~ 25%.
Step 2）In, the mass volume ratio of first time alkali compound and ethanol water is 1：3 ~ 4, first time alkali compound and sulphur
The salicylic mass ratio of base is 1：1.0 ~ 1.5, the concentration of hydrochloric acid is 10 ~ 15%.
Step 3）In, once the mass volume ratio into salt thing and ethanol water is 1：3 ~ 4, the mass concentration of ammoniacal liquor is 20
~25%。
Step 4）In, drying temperature is 70 ~ 80 DEG C.
Beneficial effect：Compared with prior art, the method for production Doxycycline monohydrate of the invention, α -6- deoxidations soil
Mycin 5-sulphosalicylic acid salt crude product is by alkalization generation α -6- doxycycline alkali, by gained α -6- doxycyclines alkali and sulphur
Base salicylic acid carries out into salt, and gained carries out a basification into salt thing again, can obtain Doxycycline one water of the purity more than 96%
Thing, because this method is directly improved on the basis of existing production technology, can directly apply to industrial production, with good
Practicality.
Embodiment
With reference to specific embodiment, the present invention is described further.
Embodiment 1
A kind of method for producing Doxycycline monohydrate, step is as follows：
1）100g is hydrogenated to salt thing（α -6- doxycycline 5-sulphosalicylic acid salt crude products）It is added to 200mL, the 70% of 15 DEG C
（v/v）Ethanol water in, after stirring 10min, start that ammoniacal liquor is added dropwise, when pH value reaches 5.8, stop that ammoniacal liquor is added dropwise, now
Temperature is 18 DEG C, stirs 10min, and to alkali compound dissolved clarification, filtrate is heated to 45 DEG C, is incubated 30min, is cooled to 25 DEG C by filtering
Discharging, is centrifuged, and obtains the damp product 65g of first time alkali compound.
2）Take step 1）Damp product 60g, be added to 180mL, 60%（v/v）Ethanol water in, add 10% hydrochloric acid
PH is adjusted to 3.5,55 DEG C are warming up to so that material all dissolves, 60g sulfosalicylic acids are then added, 10min, rear drop is stirred
Temperature is secondary to be separated out into salt thing to 25 DEG C, centrifuges, and obtains secondary into the damp product 85g of salt thing.
3）Take step 2）Obtained damp product 80g, is added to 240mL, the 70% of 15 DEG C（v/v）Ethanol in, be sufficiently stirred for
After 30min, start that ammoniacal liquor is added dropwise, during ammoniacal liquor is added dropwise in control, temperature is no more than 18 DEG C, when pH value reaches 6.0, stop drop
Ammonification water, after ammoniacal liquor is added dropwise to complete, temperature is 6 DEG C, stirs 10min, to alkali compound dissolved clarification, and filtrate is heated to 45 DEG C by filtering,
30min is incubated, product precipitation is cooled to, is cooled to 15 DEG C of dischargings, centrifuge, the damp product 50g of second of alkali compound is obtained.
4）By step 3）Damp product by vacuum drying chamber, in 0.08MPa, 70 degree of lower dryings obtain the water of Doxycycline one
Compound finished product 42g, purity is 98.8%.
Embodiment 2
A kind of method for producing Doxycycline monohydrate, step is as follows：
1）100g is hydrogenated into salt thing to be added in 200mL, 19 DEG C of 75% ethanol, after stirring 10min, starts that ammoniacal liquor is added dropwise,
When pH value reaches 5.8, stop that ammoniacal liquor is added dropwise, now temperature is 15 DEG C, stirs 10min, to alkali compound dissolved clarification, filtering, by filtrate
45 DEG C are heated to, 30min is incubated, is cooled to 25 DEG C of dischargings, is centrifuged, the damp product 62g of first time alkali compound is obtained.
2）Take step 1）Damp product 60g, be added in 180mL, 60% ethanol, add 10% salt acid for adjusting pH to 3.5,
Be warming up to 55 DEG C so that material all dissolves, then add 68g sulfosalicylic acids, stir 10min, after be cooled to 25 DEG C, it is secondary
Separate out, centrifuge into salt thing, obtain secondary into the damp product 83g of salt thing.
3）Take step 2）Obtained damp product 80g, is added in 240mL, 19 DEG C of 75% ethanol, is sufficiently stirred for 30min
Afterwards, start that ammoniacal liquor is added dropwise, during ammoniacal liquor is added dropwise in control, temperature is no more than 15 DEG C, when pH value reaches 6.0, stop that ammonia is added dropwise
Water, after ammoniacal liquor is added dropwise to complete, temperature is 6 DEG C, stirs 10min, and to alkali compound dissolved clarification, filtrate is heated to 45 DEG C, insulation by filtering
30min, is cooled to product precipitation, is cooled to 15 DEG C of dischargings, centrifuge, and obtains the damp product 50g of second of alkali compound.
4）By step 3）Damp product by vacuum drying chamber, in 0.08MPa, 70 degree of lower dryings obtain the water of Doxycycline one
Compound finished product 43g.Purity is 99.2%.
Embodiment 3
A kind of method for producing Doxycycline monohydrate, step is as follows：
1）100g is hydrogenated into salt thing to be added in 200mL, 12 DEG C of 70% ethanol, after stirring 10min, starts that ammoniacal liquor is added dropwise,
When pH value reaches 5.8, stop that ammoniacal liquor is added dropwise, now temperature is 10 DEG C, stirs 10min, to alkali compound dissolved clarification, filtering, by filtrate
45 DEG C are heated to, 30min is incubated, is cooled to 25 DEG C of dischargings, is centrifuged, the damp product 56g of first time alkali compound is obtained.
2）Take step 1）Damp product 50g, be added in 180mL, 60% ethanol, add 10% salt acid for adjusting pH to 3.5,
Be warming up to 55 DEG C so that material all dissolves, then add 70g sulfosalicylic acids, stir 10min, after be cooled to 25 DEG C, it is secondary
Separate out, centrifuge into salt thing, obtain secondary into the damp product 65g of salt thing.
3）Take step 2）Obtained damp product 60g, is added in 240mL, 12 DEG C of 70% ethanol, is sufficiently stirred for 30min
Afterwards, start that ammoniacal liquor is added dropwise, during ammoniacal liquor is added dropwise in control, temperature is no more than 10 DEG C, when pH value reaches 6.0, stop that ammonia is added dropwise
Water, after ammoniacal liquor is added dropwise to complete, temperature is 6 DEG C, stirs 10min, and to alkali compound dissolved clarification, filtrate is heated to 45 DEG C, insulation by filtering
30min, is cooled to product precipitation, is cooled to 15 DEG C of dischargings, centrifuge, and obtains the damp product 35.8g of second of alkali compound.
4）By step 3）Damp product by vacuum drying chamber, in 0.08MPa, 70 degree of lower dryings obtain the water of Doxycycline one
Compound finished product 39g, purity is 98.5%.
Claims (5)
1. a kind of method for producing Doxycycline monohydrate, it is characterised in that comprise the following steps：
1）α -6- doxycycline 5-sulphosalicylic acid salt crude products are added in 15~20 DEG C of 70~75% ethanol waters,
Stir and ammoniacal liquor is added dropwise to solution dissolved clarification, control temperature is no more than 20 DEG C, and filtrate is heated to 40 ~ 45 DEG C, insulation is cold by filtering
But to 20 ~ 25 DEG C, the damp product of first time alkali compound are filtrated to get；
2）By step 1）The damp product of middle gained are added in 55 ~ 60% ethanol waters, are added hydrochloric acid and are adjusted pH to 3 ~ 3.5, continue to heat up
To 50 ~ 55 DEG C, make material all dissolvings, then add sulfosalicylic acid, stir, be naturally cooling to 20 ~ 25 DEG C, into the analysis of salt thing
Go out, be filtrated to get into the damp product of salt thing；
3）By step 2）Gained is added in 10 ~ 15 DEG C of 70~75% ethanol waters into the damp product of salt thing, after being sufficiently stirred for,
Start to be added dropwise ammoniacal liquor to solution dissolved clarification, control temperature is no more than 18 DEG C, and filtrate is heated to 40 ~ 45 DEG C, insulation is natural by filtering
10 ~ 15 DEG C are cooled to, the damp product of alkali compound are filtrated to get；
4）By step 3）The damp product of alkali compound dried by vacuum drying chamber, obtain the water thing finished product of Doxycycline one.
2. the method for production Doxycycline monohydrate according to claim 1, it is characterised in that step 1）In, α -6-
The mass volume ratio of doxycycline 5-sulphosalicylic acid salt crude product and ethanol water is 1：2 ~ 3, the mass concentration of ammoniacal liquor is
20~25%。
3. the method for production Doxycycline monohydrate according to claim 1, it is characterised in that step 2）In, first
The mass volume ratio of secondary alkali compound and ethanol water is 1：3 ~ 4, the mass ratio of first time alkali compound and sulfosalicylic acid is 1：
1.0 ~ 1.5, the concentration of hydrochloric acid is 10 ~ 15%.
4. the method for production Doxycycline monohydrate according to claim 1, it is characterised in that step 3）In, once
Mass volume ratio into salt thing and ethanol water is 1：3 ~ 4, the mass concentration of ammoniacal liquor is 20 ~ 25%.
5. the method for production Doxycycline monohydrate according to claim 1, it is characterised in that step 4）In, dry
Temperature is 70 ~ 80 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710237264.2A CN106946728B (en) | 2017-04-12 | 2017-04-12 | A method of producing Doxycycline monohydrate |
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| CN201710237264.2A CN106946728B (en) | 2017-04-12 | 2017-04-12 | A method of producing Doxycycline monohydrate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113264846A (en) * | 2021-04-25 | 2021-08-17 | 镇江高海生物药业有限公司 | Preparation method of doxycycline monohydrate |
Citations (5)
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|---|---|---|---|---|
| EP0086046A1 (en) * | 1982-01-19 | 1983-08-17 | Plurichemie Anstalt | A process for the preparation of alpha-6-DEOXYTETRACYCLINES |
| US5049683A (en) * | 1989-01-04 | 1991-09-17 | Houba, Inc. | Process for the production of alpha-6-deoxytetracyclines |
| CN101209978A (en) * | 2006-12-25 | 2008-07-02 | 林广德 | Method for synthesizing dexocycline hydrochloridele from 6-methyl terramycin salt of organic acid |
| CN101786971A (en) * | 2010-03-01 | 2010-07-28 | 扬州联博药业有限公司 | Preparation process of doxycycline hydrochloride |
| CN105924367A (en) * | 2016-04-18 | 2016-09-07 | 镇江高海生物药业有限公司 | Substance related to doxycycline monohydrate as well as analysis and detection method thereof |
-
2017
- 2017-04-12 CN CN201710237264.2A patent/CN106946728B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0086046A1 (en) * | 1982-01-19 | 1983-08-17 | Plurichemie Anstalt | A process for the preparation of alpha-6-DEOXYTETRACYCLINES |
| US5049683A (en) * | 1989-01-04 | 1991-09-17 | Houba, Inc. | Process for the production of alpha-6-deoxytetracyclines |
| CN101209978A (en) * | 2006-12-25 | 2008-07-02 | 林广德 | Method for synthesizing dexocycline hydrochloridele from 6-methyl terramycin salt of organic acid |
| CN101786971A (en) * | 2010-03-01 | 2010-07-28 | 扬州联博药业有限公司 | Preparation process of doxycycline hydrochloride |
| CN105924367A (en) * | 2016-04-18 | 2016-09-07 | 镇江高海生物药业有限公司 | Substance related to doxycycline monohydrate as well as analysis and detection method thereof |
Non-Patent Citations (6)
| Title |
|---|
| ALEXANDRE O.LEGENDRE 等: "Solid state chemistry of the antibiotic doxycycline: structure of the neutral monohydrate and insights into its poor water solubility", 《CRYSTENGCOMM》 * |
| BOGARDUS,JOSEPH B. 等: "Solubility of doxycycline in aqueous solution", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113264846A (en) * | 2021-04-25 | 2021-08-17 | 镇江高海生物药业有限公司 | Preparation method of doxycycline monohydrate |
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