CN102010389B - Method for preparing ranitidine hydrochloride - Google Patents
Method for preparing ranitidine hydrochloride Download PDFInfo
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- CN102010389B CN102010389B CN2009101448283A CN200910144828A CN102010389B CN 102010389 B CN102010389 B CN 102010389B CN 2009101448283 A CN2009101448283 A CN 2009101448283A CN 200910144828 A CN200910144828 A CN 200910144828A CN 102010389 B CN102010389 B CN 102010389B
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Abstract
The invention relates to a method for preparing ranitidine hydrochloride, comprising the following steps of: mixing ethanol with 2-[[[5-(dimethylamino)methyl-2-furyl]methyl]thio]ethylamine; adding N-methyl-1-methylthio-2-nitro-vinylamine in reaction liquid; cooling reaction liquid, and fully precipitating crystallize; filtering reaction liquid, and washing, pumping and drying crystals to obtain almost white ranitidine; agitating and mixing ethanol and ranitidine; adding ethanol hydrochloride solution until pH value is 6-6.5, and agitating; immediately adding activated carbon to decolor after the pH value becomes stable; filtering reaction liquid, and cooling filtrate to 4-8 DEG C; and continuously filtering, and washing, pumping and drying crystals to obtain white solid ranitidine hydrochloride. The method for preparing ranitidine hydrochloride has the advantages of simple steps, high yield and low processing cost, and is suitable for large scale production.
Description
Technical field
The present invention relates to prepare the method for ranitidine hydrochloride, belong to medical technical field.
Background technology
Ranitidine hydrochloride; English name: Ranitidine Leinitiding Piam, its pharmacology has the effect of competitive retardance histamine and H2 receptors bind, gastric acid inhibitory effect; Count 5 times～12 times of Cimitidine Type A/AB with mole, so be strong H2 receptor-blocking agent of imitating.Be mainly used in treatment duodenal ulcer, stomach ulcer, reflux esophagitis, Zhuo-Ai (Zollinger-Ellison) syndrome and other high gastric acid secretion diseases.
At present, prior art is for the preparation ranitidine hydrochloride, and its complex steps, yield is lower and tooling cost is higher, and is not suitable for production in enormous quantities.
Summary of the invention
To the problems referred to above, the present invention provides that a kind of step is simple, yield is higher and tooling cost is lower, is fit to produce in enormous quantities the preparation method of ranitidine hydrochloride.
For realizing above goal of the invention, the present invention provides a kind of method for preparing ranitidine hydrochloride, and process step is following:
(1) ethanol and 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine are mixed;
(2) in reaction solution, add N-methyl isophthalic acid-methylthio group-2-nitroethylene amine, slowly heat up 40～45 ℃ and kept 8～10 hours again;
(3) reaction solution is cooled to 4～8 ℃ and kept 32～38 hours, crystallization is fully separated out;
(4) with reacting liquid filtering, and with crystal wash, drain, drying, the Ranitidine HCL of off-white color;
Wherein, the mol ratio of said 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine and N-methyl isophthalic acid-methylthio group-2-nitroethylene amine is 1: 1;
(5) ethanol and Ranitidine HCL are mixed, and temperature is controlled at 28～32 ℃;
(6) add ethanol solution hydrochloride to pH6～6.5, and stir;
(7) treat the pH value stabilization after, add activated carbon immediately and decolour;
(8), and filtrating is cooled to 4～8 ℃ kept 6 hours with reacting liquid filtering;
(9) continue to filter, and with crystal wash, drain, drying, must the white solid ranitidine hydrochloride.
Preferentially, step (4) and the said washing of step (9) are with twice of cold washing with alcohol with crystallization.
Preferentially, the said drying of step (4) is vacuum-drying, and temperature is controlled at 30 ℃, and the time is 4 hours.
Preferentially, the said drying of step (9) is vacuum-drying, and temperature is controlled at 50 ℃, and 4 hours time, vacuum tightness is 0.08Mpa.
The preparation method of ranitidine hydrochloride according to the invention has following advantage: step is simple, yield is higher and tooling cost is lower, is fit to produce in enormous quantities.
Embodiment
In order to make those skilled in the art person understand the present invention program better, and make above-mentioned purpose of the present invention, feature and advantage can be more obviously understandable, below in conjunction with embodiment the present invention done further detailed explanation.
Embodiment 1
1, the preparation of Ranitidine HCL
Get ethanol 200kg, 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine 17.0kg in a retort, to wherein adding N-methyl isophthalic acid-methylthio group-2-nitroethylene amine 12.3kg.Finish, slowly heat up 40 ℃ and make it solubilizing reaction, and kept 8～10 hours.
Reaction finishes, and reaction solution is cooled to 4 ℃ kept 36 hours, and crystallization is fully separated out; Filter then, crystallization is drained with cold washing with alcohol twice (20ml/ time); Crystal vacuum-drying (30 ℃ of temperature, 4 hours time), the Ranitidine HCL crystallization 21.09kg of off-white color.
2, the preparation of ranitidine hydrochloride and refining
Get ethanol 50L, Ranitidine HCL 20.0kg, stir make it dissolving after, 30 ± 2 ℃ of controlled temperature, the dripping hydrochloric acid ethanolic soln to pH be 6 (needing ethanol solution hydrochloride 8L approximately); Continue to stir 10 minutes, treat the pH value stabilization after, add activated carbon 1.0kg immediately, stir decolouring 15 minutes; Filter, filtrating cooling (4～8 ℃) 6 hours is taken out and is filtered; Crystal is used cold washing with alcohol, drains drying under reduced pressure (temperature: 50 ℃; 4 hours time, vacuum tightness: 0.08Mpa), get white solid ranitidine hydrochloride 20.02kg.
Embodiment 2
1, the preparation of Ranitidine HCL
Get ethanol 200kg, 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine 17.0kg in a retort, to wherein adding N-methyl isophthalic acid-methylthio group-2-nitroethylene amine 12.3kg.Finish, slowly heat up 42 ℃ and make it solubilizing reaction, and kept 8～10 hours.
Reaction finishes, and reaction solution is cooled to 6 ℃ kept 36 hours, and crystallization is fully separated out; Filter then, crystallization is drained with cold washing with alcohol twice (20ml/ time); Crystal vacuum-drying (30 ℃ of temperature, 4 hours time), the Ranitidine HCL crystallization 21.04kg of off-white color.
2, the preparation of ranitidine hydrochloride and refining
Get ethanol 50L, Ranitidine HCL 20.0kg, stir make it dissolving after, 30 ± 2 ℃ of controlled temperature, the dripping hydrochloric acid ethanolic soln to pH be 6.2 (needing ethanol solution hydrochloride 8L approximately); Continue to stir 10 minutes, treat the pH value stabilization after, add activated carbon 1.0kg immediately, stir decolouring 15 minutes; Filter, filtrating cooling (4～8 ℃) 6 hours is taken out and is filtered; Crystal is used cold washing with alcohol, drains drying under reduced pressure (temperature: 50 ℃; 4 hours time, vacuum tightness: 0.08Mpa), get white solid ranitidine hydrochloride 20.06kg.
Embodiment 3
Get ethanol 200kg, 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine 17.0kg in a retort, to wherein adding N-methyl isophthalic acid-methylthio group-2-nitroethylene amine 12.3kg.Finish, slowly heat up 45 ℃ and make it solubilizing reaction, and kept 8～10 hours.
Reaction finishes, and reaction solution is cooled to 8 ℃ kept 36 hours, and crystallization is fully separated out; Filter then, crystallization is drained with cold washing with alcohol twice (20ml/ time); Crystal vacuum-drying (30 ℃ of temperature, 4 hours time), the Ranitidine HCL crystallization 21.09kg of off-white color.
2, the preparation of ranitidine hydrochloride and refining
Get ethanol 50L, Ranitidine HCL 20.0kg, stir make it dissolving after, 30 ± 2 ℃ of controlled temperature, the dripping hydrochloric acid ethanolic soln to pH be 6.5 (needing ethanol solution hydrochloride 8L approximately); Continue to stir 10 minutes, treat the pH value stabilization after, add activated carbon 1.0kg immediately, stir decolouring 15 minutes; Filter, filtrating cooling (4～8 ℃) 6 hours is taken out and is filtered; Crystal is used cold washing with alcohol, drains drying under reduced pressure (temperature: 50 ℃; 4 hours time, vacuum tightness: 0.08Mpa), get white solid ranitidine hydrochloride 20.00kg.
The solid ranitidine hydrochloride that the method for the invention makes, yield about 90.0%, fusing point: 138～140 ℃.
The above; Be merely embodiment of the present invention; Should be noted that protection scope of the present invention is not limited thereto; Any technician who is familiar with the present technique field is in the technical scope that the present invention discloses, and the variation that can expect easily or replacement all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain that claim was defined.
Claims (4)
1. method for preparing ranitidine hydrochloride is characterized in that process step is following:
(1) ethanol and 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine are mixed;
(2) in reaction solution, add N-methyl isophthalic acid-methylthio group-2-nitroethylene amine, slowly heat up 40～45 ℃ and kept 8～10 hours again;
(3) reaction solution is cooled to 4～8 ℃ and kept 32～38 hours, crystallization is fully separated out;
(4) with reacting liquid filtering, and with crystal wash, drain, drying, the Ranitidine HCL of off-white color; Wherein, the mol ratio of said 2-[[[5-(dimethylamino) methyl-2-furans] methyl] sulfenyl] ethamine and N-methyl isophthalic acid-methylthio group-2-nitroethylene amine is 1: 1;
(5) ethanol and Ranitidine HCL are mixed, and temperature is controlled at 28～32 ℃;
(6) add ethanol solution hydrochloride to pH6～6.5, and stir;
(7) treat the pH value stabilization after, add gac immediately and decolour;
(8), and filtrating is cooled to 4～8 ℃ kept 6 hours with reacting liquid filtering;
(9) continue to filter, and with crystal wash, drain, drying, must the white solid ranitidine hydrochloride.
2. the method for preparing ranitidine hydrochloride according to claim 1 is characterized in that, step (4) and the said washing of step (9) are with twice of cold washing with alcohol with crystallization.
3. the method for preparing ranitidine hydrochloride according to claim 1 is characterized in that, the said drying of step (4) is vacuum-drying, and temperature is controlled at 30 ℃, and the time is 4 hours.
4. the method for preparing ranitidine hydrochloride according to claim 1 is characterized in that, the said drying of step (9) is vacuum-drying, and temperature is controlled at 50 ℃, and 4 hours time, vacuum tightness is 0.08MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101448283A CN102010389B (en) | 2009-09-04 | 2009-09-04 | Method for preparing ranitidine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101448283A CN102010389B (en) | 2009-09-04 | 2009-09-04 | Method for preparing ranitidine hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102010389A CN102010389A (en) | 2011-04-13 |
| CN102010389B true CN102010389B (en) | 2012-11-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2009101448283A Expired - Fee Related CN102010389B (en) | 2009-09-04 | 2009-09-04 | Method for preparing ranitidine hydrochloride |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817523B (en) * | 2015-05-26 | 2016-11-09 | 烟台市华文欣欣医药科技有限公司 | A kind of medicine ranitidine hydrochloride compound treating gastropathy and preparation method thereof |
| 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 |
| CN114591274B (en) * | 2022-03-09 | 2024-05-24 | 石家庄海力药业有限公司 | Preparation method of ranitidine hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0059082A1 (en) * | 1981-02-20 | 1982-09-01 | Glaxo Group Limited | Process for the preparation of a furan derivative |
| GB2169600A (en) * | 1985-01-11 | 1986-07-16 | Richter Gedeon Vegyeszet | Process for preparing a basic thioether and the salt thereof |
| 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 |
-
2009
- 2009-09-04 CN CN2009101448283A patent/CN102010389B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0059082A1 (en) * | 1981-02-20 | 1982-09-01 | Glaxo Group Limited | Process for the preparation of a furan derivative |
| GB2169600A (en) * | 1985-01-11 | 1986-07-16 | Richter Gedeon Vegyeszet | Process for preparing a basic thioether and the salt thereof |
| 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 |
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| CN102010389A (en) | 2011-04-13 |
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