CN108017601A - A kind of method of refined ranitidine alkali - Google Patents
A kind of method of refined ranitidine alkali Download PDFInfo
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- CN108017601A CN108017601A CN201711451926.2A CN201711451926A CN108017601A CN 108017601 A CN108017601 A CN 108017601A CN 201711451926 A CN201711451926 A CN 201711451926A CN 108017601 A CN108017601 A CN 108017601A
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- Prior art keywords
- ranitidine
- refined
- alkali
- ranitidine alkali
- hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Abstract
The present invention relates to the purification technique field of fine chemicals, more specifically, is related to a kind of method of refined ranitidine alkali.By the present invention in that the mixed solvent formed with intensive polar solvent and weak polar solvent, making ranitidine alkali, there are larger difference with solubility of the impurity therein in this solvent, so as to enable ranitidine alkali and impurity be efficiently separated in Crystallization Process, obtained highly finished product purity is high, and character is stablized.The ranitidine alkali refined through the method for the present invention, is analyzed with liquid chromatograph, and ranitidine alkali purity is more than 99.9%, and total impurities is not more than 0.15%, and single impurity is not more than 0.05%.The ranitidine hydrochloride product that the ranitidine alkali purified is obtained into salt again is prepared with method provided by the invention, its purity reaches and grinds the quality level of medicine better than original, so as to further improve the security of the medicine in use.
Description
Technical field
The present invention relates to the purification technique field of fine chemicals, more specifically, is related to a kind of refined thunder Buddhist nun and replaces
The method of fourth alkali.
Background technology
Ranitidine is the medicine of most widely used treatment canker at present.By Britain Ge Lan elements（glaxo）Company opens
Hair.1976 by Britain's Price（price）Deng synthesis, Bradshaw in 1979（bradshaw）Illustrate its pharmacology, 1980
Bass tower（berstad）Report is effective for duodenal ulcer, lists within 1981, in more or less a hundred countries use of the world.China
Produced in 1985 by Shanghai No.6 Pharmaceutical Factory.
This kind bulk pharmaceutical chemicals are at home and abroad used up to more than 20 years, and preparation has the peroral dosage form such as capsule and tablet, its matter
Amount standard has been recorded into pharmacopeia such as USP, BP, EP, JP, CP, and Clinical practice more than 20 years, and security and validity are fully tested
Card, very clearly.But the quality of the kind grinds medicine with original at home more still gap, and product purity is low, Crystallization Process thunder Buddhist nun
It cannot be efficiently separated for fourth alkali and impurity.
The content of the invention
In the presence of overcoming the shortcomings of the prior art, a kind of technique of present invention offer is simple, and highly finished product purity is high
The method of refined ranitidine alkali.
In order to solve the above-mentioned technical problem, the technical solution adopted in the present invention is：
A kind of method of refined ranitidine alkali：
Ranitidine alkali crude product, be placed in intermixture and dissolve by S1, and stirring is warming up to solution turned clear, obtains mixed solution；
S2, mixed solution slow cooling continue to be cooled to 0 DEG C, insulation crystallization to crystal is separated out；
S3, filter to obtain wet product, and naturally dry must refine ranitidine alkali.
The intermixture composition is intensive polar solvent, and weak polar solvent, its weight ratio is 1:2.5-3.
The weight ratio of the ranitidine alkali crude product and intermixture is 1：（2.4-3.2）.
The intensive polar solvent includes isobutanol, absolute ethyl alcohol and methanol；The weak polar solvent includes, petroleum ether, first
Base isobutyl ketone, methyl tertiary butyl ether(MTBE) and methylisobutylketone.
30min is kept the temperature after solution turned clear.
When the insulation crystallization time is 3 small.
Ranitidine alkali can directly feed intake and be used to prepare ranitidine hydrochloride, and its preparation method is：
S1, to refined ranitidine alkali add absolute ethyl alcohol and purified water, stirring and dissolving；
S2,15 DEG C start be added dropwise acidic alcohol, process temperature control at 15 DEG C -25 DEG C, after titration control PH in 6.0-6.5；
S3, be cooled to 10 DEG C, adds 200g ranitidine hydrochloride crystal seeds；
S4, decrease temperature crystalline are to 0 DEG C, when insulation crystallization 4-5 is small；
Ranitidine hydrochloride is obtained after S5, centrifugal drying.
The charged material weight ratio is：Ranitidine alkali：Absolute ethyl alcohol：Purified water=10：30：0.9.
When the acidic alcohol is added dropwise to the 90% of acidic alcohol, PH controls are surveyed in 6.0-6.5, stirring 5mim, then survey PH,
Confirm to control in 6.0-6.5, otherwise, add remaining acidic alcohol until PH is in 6.0-6.5.
The drying uses double cone dryer.
Compared with prior art, the advantageous effect of present invention is that：
The method of the refined ranitidine alkali of the present invention, using intensive polar solvent and the intermixture of weak polar solvent, can make thunder Buddhist nun
For fourth alkali and solubility of the impurity therein in this solvent there are larger difference, so as to make ranitidine in Crystallization Process
Alkali and impurity can be efficiently separated, and the purity of ranitidine alkali greatly improves, and character is stablized, so as to reach refined mesh
's.The ranitidine hydrochloride product that the ranitidine alkali purified is obtained into salt again, its purity are prepared with method provided by the invention
Reach and grind the quality level of medicine better than original, so as to further improve the security of the medicine in use.
Embodiment
The technical solution in the embodiment of the present invention will be clearly and completely described below, it is clear that described implementation
Example is only part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this area is common
Technical staff's all other embodiments obtained without making creative work, belong to the model that the present invention protects
Enclose.
Embodiment 1
By ranitidine alkali crude product 100g（Purity 99.6%）, isopropanol 60g, petroleum ether 180g, add in reaction bulb, are warming up to
Become limpid after 42 DEG C of heating for dissolving, keep the temperature 30 minutes, to 20 DEG C, solution starts to separate out crystal slow cooling, continues to be cooled to 0
DEG C, when insulation crystallization 3 is small, filter to obtain wet product, the ranitidine alkali that naturally dry must refine.Liquid chromatograph is analyzed, after refining
Ranitidine alkali maximum single miscellaneous 0.020%, purity 99.95%.
Embodiment 2
By ranitidine alkali crude product 100g（Purity 99.6%）, isopropanol 80g, methyl isobutyl alcohol 200g, add in reaction bulb, rise
Temperature becomes limpid after being dissolved by heating to 42 DEG C, keeps the temperature 30 minutes, and to 20 DEG C, solution starts to separate out crystal slow cooling, continues to cool down
To 0 DEG C, when insulation crystallization 3 is small, wet product, the ranitidine alkali that naturally dry must refine are filtered to obtain.Liquid chromatograph is analyzed, and is refined
Ranitidine alkali afterwards maximum single miscellaneous 0.013%, purity 99.95%.
Embodiment 3
By ranitidine alkali crude product 100g（Purity 99.6%）, absolute ethyl alcohol 60g, methyl tertiary butyl ether(MTBE) 180g, add reaction bulb
In, become limpid after being warming up to 40 DEG C of heating for dissolving, keep the temperature 30 minutes, to 20 DEG C, solution starts to separate out crystal slow cooling, continues
0 DEG C is cooled to, when insulation crystallization 3 is small, filters to obtain wet product, the ranitidine alkali that naturally dry must refine.Liquid chromatograph is analyzed,
Ranitidine alkali maximum single miscellaneous 0.010% after refined, purity 99.95%.
Embodiment 4
By ranitidine alkali crude product 100g（Purity 99.6%）, methanol 70g, methylisobutylketone 196g, add in reaction bulb, heating
Become limpid after being dissolved by heating to 45 DEG C, keep the temperature 30 minutes, to 20 DEG C, solution starts to separate out crystal slow cooling, continues to be cooled to 0
DEG C, when insulation crystallization 3 is small, filter to obtain wet product, the ranitidine alkali that naturally dry must refine.Liquid chromatograph is analyzed, after refining
Ranitidine alkali maximum single miscellaneous 0.004%, purity 99.96%.
Embodiment 5
By ranitidine alkali crude product 100g（Purity 99.6%）, absolute ethyl alcohol 64g, methyl tertiary butyl ether(MTBE) 192g, add reaction bulb
In, become limpid after being warming up to 38 DEG C of heating for dissolving, keep the temperature 30 minutes, to 20 DEG C, solution starts to separate out crystal slow cooling, continues
0 DEG C is cooled to, when insulation crystallization 3 is small, filters to obtain wet product, the ranitidine alkali that naturally dry must refine.Liquid chromatograph is analyzed,
Ranitidine alkali maximum single miscellaneous 0.02% after refined, purity 99.94%.
Embodiment 6
Ranitidine alkali prepared by embodiment 1 ~ 5 can be directly used for preparing ranitidine hydrochloride, and embodiment is：
Absolute ethyl alcohol and purified water are added to ranitidine alkali made from above-described embodiment, is stirred evenly, 15 DEG C start that salt is added dropwise
Sour ethanol, process temperature control is at 15 DEG C -25 DEG C；PH controls are surveyed when being added dropwise to 90% amount of acidic alcohol in 6.0-6.5；Stirring
5min, then pH is surveyed, confirm that pH is controlled in 6.0-6.5, otherwise, add remaining acidic alcohol until PH is in 6.0-6.5；Drip
Finish, be cooled to 10 DEG C of addition 100g ranitidine hydrochloride crystal seeds；Continue to be cooled to less than 0 DEG C insulation crystallization 4-5 it is small when, centrifugation,
At room temperature, under the conditions of -0.09MPa, when the static drying 4 of double cone dryer is small；30-40 DEG C is warming up to again, -0.09MPa rotating speeds
20r/min is rotated, and when drying 4 is small, then is warming up to 40-50 DEG C, when -0.09MPa dryings 2 are small, then is warming up to 50-55 DEG C, -
When 0.09MPa dryings 2 are small, less than 40 DEG C are cooled to, is discharged with nitrogen vacuum breaker, is obtained ranitidine hydrochloride, use liquid chromatogram
Instrument is analyzed, maximum single miscellaneous 0.012% in ranitidine hydrochloride, purity 99.94%.
Reactant weight ratio is：Ranitidine alkali：Absolute ethyl alcohol：Purified water=10：30：0.9.
In the above-described embodiments, the testing conditions of liquid chromatograph analysis are：It is to fill out with octadecylsilane chemically bonded silica
Fill agent,
Chromatographic column：C18 chromatographic columns（4.6*150mm, 5um）
Detection wavelength：230nm
Column temperature：35℃
Sample size：10μl
Flow velocity：1.5ml/min
Blank solvent：Water
Gradient is set：
| t(min) | Mobile phase A % | Mobile phase B % |
| 0 | 100 | 0 |
| 10 | 0 | 100 |
| 25 | 0 | 100 |
| 25.10 | 100 | 0 |
| 33 | 100 | 0 |
Mobile phase is prepared：
The preparation of phosphate buffer：Weigh after potassium dihydrogen phosphate 6.8g dissolves in 950ml water, add 50%NaOH solution to adjust
PH to 7.10 ± 0.05, adds water and is diluted to 1000ml.
Mobile phase A：Phosphate buffer：Acetonitrile=98:2
Mobile phase B：Phosphate buffer：Acetonitrile=78:22
Only presently preferred embodiments of the present invention is explained in detail above, but the present invention is not limited to above-described embodiment, at this
In the knowledge that field those of ordinary skill possesses, various changes can also be made on the premise of present inventive concept is not departed from
Change, various change should all be included in the protection scope of the present invention.
Claims (10)
- A kind of 1. method of refined ranitidine alkali, it is characterised in that：Ranitidine alkali crude product, be placed in intermixture and dissolve by S1, and stirring is warming up to solution turned clear, obtains mixed solution；S2, mixed solution slow cooling continue to be cooled to 0 DEG C, insulation crystallization to crystal is separated out；S3, filter to obtain wet product, and naturally dry must refine ranitidine alkali.
- A kind of 2. method of refined ranitidine alkali according to claim 1, it is characterised in that：The ranitidine alkali is thick The weight ratio of product and intermixture is 1：（2.4-3.2）.
- A kind of 3. method of refined ranitidine alkali according to claim 1, it is characterised in that：The intermixture forms Intensive polar solvent, weak polar solvent, its weight ratio are 1：（2.5-3）.
- A kind of 4. method of refined ranitidine alkali according to claim 1 and 2, it is characterised in that：It is described highly polar molten Agent includes isobutanol, absolute ethyl alcohol and methanol；The weak polar solvent includes, petroleum ether, methylisobutylketone, methyl tertiary butyl ether(MTBE) And methylisobutylketone.
- A kind of 5. method of refined ranitidine alkali according to claim 1, it is characterised in that：Kept the temperature after solution turned clear 30min。
- A kind of 6. method of refined ranitidine alkali according to claim 1, it is characterised in that：The insulation crystallization time For 3 it is small when.
- 7. ranitidine alkali according to claim 1, it is characterised in that can directly feed intake and be used to prepare ranitidine hydrochloride Method, it is specific as follows：S1, to refined ranitidine alkali add absolute ethyl alcohol and purified water, stirring and dissolving；S2,15 DEG C start be added dropwise acidic alcohol, process temperature control at 15 DEG C -25 DEG C, after titration control PH in 6.0-6.5；S3, be cooled to 10 DEG C, adds 200g ranitidine hydrochloride crystal seeds；S4, decrease temperature crystalline are to 0 DEG C, when insulation crystallization 4-5 is small；Ranitidine hydrochloride is obtained after S5, centrifugal drying.
- 8. the method that refined ranitidine alkali according to claim 7 is used to prepare ranitidine hydrochloride, it is characterised in that The charged material weight ratio is：Ranitidine alkali：Absolute ethyl alcohol：Purified water=10：30：0.9.
- 9. the method that refined ranitidine alkali according to claim 7 is used to prepare ranitidine hydrochloride, it is characterised in that： The acidic alcohol is added dropwise to PH in 6.0-6.5, stirring 5mim, then surveys PH, confirms to control in 6.0-6.5, otherwise, adds residue Acidic alcohol until PH in 6.0-6.5.
- 10. the method that refined ranitidine alkali according to claim 7 is used to prepare ranitidine hydrochloride, its feature exist In：The drying uses double cone dryer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711451926.2A CN108017601B (en) | 2017-12-28 | 2017-12-28 | Method for refining ranitidine alkali |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711451926.2A CN108017601B (en) | 2017-12-28 | 2017-12-28 | Method for refining ranitidine alkali |
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| Publication Number | Publication Date |
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| CN108017601A true CN108017601A (en) | 2018-05-11 |
| CN108017601B CN108017601B (en) | 2021-07-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201711451926.2A Active CN108017601B (en) | 2017-12-28 | 2017-12-28 | Method for refining ranitidine alkali |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110579542A (en) * | 2019-09-04 | 2019-12-17 | 北京悦康科创医药科技股份有限公司 | method for measuring ranitidine hydrochloride related substances by high performance liquid chromatography |
| CN112028862A (en) * | 2020-08-18 | 2020-12-04 | 北京云鹏鹏程医药科技有限公司 | Preparation method of ranitidine hydrochloride with low NDMA content |
| CN114591274A (en) * | 2022-03-09 | 2022-06-07 | 河北海力香料股份有限公司 | Preparation method of ranitidine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0697411A1 (en) * | 1994-06-24 | 1996-02-21 | Ranbaxy Laboratories Limited | Process for the manufacture of pharmaceutical grade ranitidine base |
| CN1724526A (en) * | 2005-07-11 | 2006-01-25 | 石药集团中诺药业（石家庄）有限公司 | Synthesis method of ranitidine alkali and its hydrochloride |
-
2017
- 2017-12-28 CN CN201711451926.2A patent/CN108017601B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0697411A1 (en) * | 1994-06-24 | 1996-02-21 | Ranbaxy Laboratories Limited | Process for the manufacture of pharmaceutical grade ranitidine base |
| CN1724526A (en) * | 2005-07-11 | 2006-01-25 | 石药集团中诺药业（石家庄）有限公司 | Synthesis method of ranitidine alkali and its hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 黄龙祥，吕春绪: "盐酸雷尼替丁精制方法的改进", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110579542A (en) * | 2019-09-04 | 2019-12-17 | 北京悦康科创医药科技股份有限公司 | method for measuring ranitidine hydrochloride related substances by high performance liquid chromatography |
| CN112028862A (en) * | 2020-08-18 | 2020-12-04 | 北京云鹏鹏程医药科技有限公司 | Preparation method of ranitidine hydrochloride with low NDMA content |
| CN114591274A (en) * | 2022-03-09 | 2022-06-07 | 河北海力香料股份有限公司 | Preparation method of ranitidine hydrochloride |
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| CN108017601B (en) | 2021-07-13 |
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Address after: 041000 No.81 Jiefang East Road, Linfen City, Shanxi Province Applicant after: Yunpeng Pharmaceutical Group Co.,Ltd. Address before: 041000 No.81 Jiefang East Road, Linfen City, Shanxi Province Applicant before: SHANXI YUNPENG PHARMACEUTICAL Co.,Ltd. |
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