CN1315818C - Synthesis method of ranitidine alkali and its hydrochloride - Google Patents
Synthesis method of ranitidine alkali and its hydrochloride Download PDFInfo
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- CN1315818C CN1315818C CNB200510012673XA CN200510012673A CN1315818C CN 1315818 C CN1315818 C CN 1315818C CN B200510012673X A CNB200510012673X A CN B200510012673XA CN 200510012673 A CN200510012673 A CN 200510012673A CN 1315818 C CN1315818 C CN 1315818C
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Abstract
The present invention provides a synthetic method of ranitidine alkali and ranitidine hydrochloride, which has the advantages of simple process, reduced organic solvents for use, low cost and easy commercial production. The present invention is characterized in that 2-[[[5-(dimethylamino)methyl-2-furyl]methyl]thio]ethylamine and 1-methylthio-1-methylamino-2-nitroethylene directly react in a water phase to crystallize and separate ranitidine alkali. The synthetic method comprises the steps that the 2-[[[5-(dimethylamino)methyl-2-furyl]methyl]thio]ethylamine and the 1-methylthio-1-methylamino-2-nitroethylene which have the molar ratio of 1.04 to 1 are added to water, and the mixture is heated to the temperature of 48 to 52 DEG C; the heated mixture reacts for 4.5 hours with the vacuum degree of 0.02 to 0.05MPa, and the temperature drops after reaction; the pH value of the reagent is regulated to 11.0 to 11.4 by 10% of sodium hydroxide solution, and the reagent is filtered; the temperature of the filter liquor drops to 0 to 2 DEG C, and is crystallized for 12 hours; the crystallized product is swung and filtered in a centrifugate mode; filter cakes are rinsed by purification water, and a wet product of the ranitidine alkali is obtained; the ranitidine alkali is dissolved in etanol to react with hydrochloric acid, and the ranitidine hydrochloride is prepared and obtained; the product conforms to the standard of the European pharmacopoeia.
Description
Technical field
The present invention relates to the synthetic method of a kind of ranitidine alkali and hydrochloride thereof, belong to medicine chemical material synthetic method technical field.
Background technology
Ranitidine hydrochloride is a kind of H2-receptor antagonist, the gastric acid secretion that it causes physiological and pentagastrin etc. has obvious restraining effect, than the strong 4-6 of Cimitidine Type A/AB times and longer duration, the domestic and international clinical more satisfactory medicine of current treatment peptide ulceration of thinking.U.S. Pat 5696275 discloses a kind of synthesis technique of ranitidine alkali, be with 2-[[[5-(dimethylamino) methyl-2-furyl] methyl] sulfo-] after ethamine and 1-methylthio group-1-methylamino-2-nitroethylene react in water, 45～50 ℃ of following stirring heating, reacted 3～4 hours, use hcl acidifying then, use chloroform extraction, with the salt of wormwood alkalization, behind adding low-carbon (LC) alcohols (Virahol etc.) azeotropic water removing, add people's normal hexane again, decrease temperature crystalline obtains ranitidine alkali.In the prior art disclosed method, use multiple organic solvent,, not only increased expense aborning, and the solvent that uses is residual in ranitidine alkali, can when the preparation ranitidine hydrochloride, exert an influence as chloroform, Virahol and normal hexane etc.
Summary of the invention
Technical problem to be solved by this invention provide a kind of technology simple, reduce organic solvent uses, cost is low, be easy to suitability for industrialized production the ranitidine alkali and the synthetic method of ranitidine hydrochloride.
Technical scheme of the present invention is achieved in that a kind of synthetic method of ranitidine alkali, it is characterized in that: it is by 2-[[[5-(dimethylamino) methyl-2-furyl] methyl] sulfo-] ethamine and 1-methylthio group-1-methylamino-2-nitroethylene directly separate out ranitidine alkali in aqueous phase reaction and crystallization.
The synthetic method of described ranitidine alkali, comprise with mol ratio being 2-[[[5-(dimethylamino) methyl-2-furyl of 1.04: 1] methyl] sulfo-] ethamine and 1-methylthio group-1-methylamino-2-nitroethylene add in people's water, be warming up to 48-52 ℃, in vacuum tightness 0.02～0.05Mpa reaction 4.5 hours, react the cooling that finishes, transfer pH=11.0-11.4 with 10% sodium hydroxide solution, suction filtration, filtrate is cooled to 0～2 ℃, crystallization 12 hours, centrifugally get rid of filter, with purified water rinsing filter cake, the wet product of ranitidine alkali.
The synthetic method of described ranitidine alkali, comprise 367.5kg 2-[[[5-(dimethylamino) methyl-2-furyl] methyl] sulfo-] ethamine and 655kg purified water add in the retort, stir and add 1-methylthio group-1-methylamino-2-nitroethylene 245kg down, slowly be warming up to 48-52 ℃, control vacuum tightness 0.02～0.05Mpd, insulation reaction 4.5 hours, reaction finishes; With cool brine feed liquid is cooled to 25 ℃～35 ℃, transfers pH=11.00-11.40 with 10% sodium hydroxide solution, suction filtration is cooled to 0～2 ℃ of crystallization to crystallizer, gets rid of filter, and with 50-70kg purified water rinsing filter cake, gets the wet product of ranitidine alkali in freezing 12 hours.
A kind of synthetic method of ranitidine hydrochloride is characterized in that ranitidine alkali is dissolved in the ethanol and hydrochloric acid reaction, prepares ranitidine hydrochloride.
The synthetic method of described ranitidine hydrochloride comprises after the water removal in the wet product of above-mentioned ranitidine alkali, is dissolved in the ethanol and hydrochloric acid reaction, prepares ranitidine hydrochloride.
Described ranitidine hydrochloride synthetic method comprises:
A, with ranitidine alkali in vacuum tightness 0.09～0.098Mpa, temperature concentrates the back and adds the ethanol stirring and dissolving below 65 ℃, filter;
B, with the filtrate of steps A with hydrochloric acid-ethanol liquid adjust pH to 6.2～6.8, be cooled to below 0 ℃, add people's crystal seed stirred crystallization, kept 6 hours, get rid of filter, usefulness frozen ethanol rinsing filter cake, dry Ranitidine hydrochloride.
Above-mentioned any ranitidine hydrochloride synthetic method comprises that ethanolic soln with ranitidine alkali with hydrochloric acid-ethanol liquid adjust pH to 6.2～6.8, is cooled to below 0 ℃, add people's crystal seed stirred crystallization, kept 6 hours, get rid of filter, with frozen ethanol rinsing filter cake, dry Ranitidine hydrochloride.
Described ranitidine hydrochloride synthetic method, comprise that also the ethanolic soln cooling with ranitidine alkali reaches 3-8 ℃, open and stir, slowly, evenly add people's hydrochloric acid-ethanol liquid adjust pH to 6.2～6.8 then in jar, cooling adds people's crystal seed, to 0 ℃ of following stirred crystallization, kept 6 hours, get rid of filter, with frozen ethanol rinsing filter cake 2 times, dry the wet product of Ranitidine hydrochloride.
Above-mentioned ranitidine hydrochloride synthetic method comprises the Ranitidine hydrochloride wet-milling is sieved that controlled temperature is 75～90 ℃, and vacuum tightness＞0.094Mpa was dried 6 hours, gets the ranitidine hydrochloride finished product.
The synthetic method technical progress effect of ranitidine alkali of the present invention and hydrochloride thereof is that technology is simple, does not use organic solvent in the process of preparation ranitidine alkali, and cost is low, is easy to suitability for industrialized production, and product meets the European Pharmacopoeia standard.
Embodiment
1, with 367.5kg 2-[[[5-(dimethylamino) methyl-2-furyl] methyl] sulfo-] ethamine and 655kg purified water add in people's retort, add people 1-methylthio group-1-methylamino-2-nitroethylene 245kg under stirring, the mol ratio of two reactants is 1.04: 1, slowly be warming up to 48-52 ℃, control vacuum tightness 0.02～0.05Mpa, insulation reaction 4.5 hours, reaction finishes.
With cool brine feed liquid is cooled to about 25 ℃～35 ℃, transfer alkali with 10% sodium hydroxide solution, measure with pH meter, to pH=11.00-11.40, transfer alkali to finish, suction filtration is to crystallizer, be cooled to 0～2 ℃ of crystallization, got rid of filter in freezing 12 hours, every whizzer gets the wet product of ranitidine alkali with 50-70kg purified water rinsing filter cake.Reaction equation is as follows
2, the ranitidine alkali that will wet is thrown people's concentration tank, and temperature under vacuum tightness 0.09～0.098Mpa, is steamed water below 65 ℃ in jar, steams water and finishes, and takes out ethanol people concentration tank, and stirring and dissolving is filtered to the ranitidine hydrochloride crystallizer.
3, make feed temperature be reduced to 3-8 ℃ with chuck salt solution the feed liquid in the crystallizer, open and stir, in jar, slowly, evenly add people's hydrochloric acid-ethanol liquid acid adjustment then, adjust pH to 6.2～6.8, cooling adds crystal seed, to 0 ℃ of following stirred crystallization, kept about 6 hours.Reaction equation is as follows:
4, open the crystallizer baiting valve, make the crystallization feed liquid put into whizzer and get rid of filter, every whizzer dries with 50-60kg frozen ethanol rinsing filter cake twice, gets the wet product of Ranitidine hydrochloride.
5, will show powder and sieve, and be transferred in the double cone dryer, and open bipyramid chuck hot-water valve, the control hot water temperature is 75～90 ℃, and vacuum tightness＞0.094Mpa was dried about 6 hours, got finished product.
Listed examples of the present invention is intended to further illustrate the synthetic method of this ranitidine alkali and hydrochloride thereof, and scope of the present invention is not constituted any restriction, the product that obtains with the embodiment of the invention and via described ranitidine alkali and the ranitidine hydrochloride product of all can obtaining of claims of the present invention.
Claims (8)
1, a kind of synthetic method of ranitidine alkali, it is by 2-[[[5-(dimethylamino) methyl-2-furyl] methyl] sulfo-] ethamine and 1-methylthio group-1-methylamino-2-nitroethylene directly separate out ranitidine alkali in aqueous phase reaction and crystallization, it is characterized in that: 2-[[[5-(dimethylamino) methyl-2-furyl that with mol ratio is 1.04: 1] methyl] sulfo-] ethamine and 1-methylthio group-1-methylamino-2-nitroethylene add in the entry, be warming up to 48-52 ℃, in vacuum tightness 0.02～0.05Mpa reaction 4.5 hours, react the cooling that finishes, transfer pH=11.0-11.4 with 10% sodium hydroxide solution, suction filtration, filtrate is cooled to 0～2 ℃, crystallization 12 hours, centrifugally get rid of filter, with purified water rinsing filter cake, get the wet product of ranitidine alkali.
2, according to the synthetic method of the described ranitidine alkali of claim 1, it is characterized in that: with 367.5kg2-[[[5-(dimethylamino) methyl-2-furyl] methyl] sulfo-] ethamine and 655kg purified water add in the retort, stir and add 1-methylthio group-1-methylamino-2-nitroethylene 245kg down, slowly be warming up to 48-52 ℃, control vacuum tightness 0.02～0.05Mpa, insulation reaction 4.5 hours, reaction finishes; With cool brine feed liquid is cooled to 25 ℃～35 ℃, transfers pH=11.00-11.40 with 10% sodium hydroxide solution, suction filtration is cooled to 0～2 ℃ of crystallization to crystallizer, gets rid of filter, and with 50-70kg purified water rinsing filter cake, gets the wet product of ranitidine alkali in freezing eastern 12 hours.
3, the method for preparing ranitidine hydrochloride according to the synthetic method of the described ranitidine alkali of claim 1 is characterized in that ranitidine alkali is dissolved in the ethanol and hydrochloric acid reaction, prepares ranitidine hydrochloride.
4, according to the described method for preparing ranitidine hydrochloride of claim 3, it is characterized in that after the water removal in the wet product of ranitidine alkali, be dissolved in the ethanol and hydrochloric acid reaction, prepare ranitidine hydrochloride.
5, according to the described method for preparing ranitidine hydrochloride of claim 4, it is characterized in that:
A, with ranitidine alkali in vacuum tightness 0.09～0.098Mpa, temperature concentrates the back and adds the ethanol stirring and dissolving below 65 ℃, filter;
B, with the filtrate of steps A with hydrochloric acid-ethanol liquid adjust pH to 6.2～6.8, be cooled to below 0 ℃, add the crystal seed stirred crystallization, kept 6 hours, get rid of filter, usefulness frozen ethanol rinsing filter cake, dry Ranitidine hydrochloride.
6, according to claim 4 or the 5 described methods that prepare ranitidine hydrochloride, it is characterized in that: the ethanolic soln of ranitidine alkali is used hydrochloric acid-ethanol liquid adjust pH to 6.2～6.8, be cooled to below 0 ℃, add the crystal seed stirred crystallization, kept 6 hours, get rid of filter, with frozen ethanol rinsing filter cake, dry Ranitidine hydrochloride.
7, according to the described method for preparing ranitidine hydrochloride of claim 6, it is characterized in that: the ethanolic soln cooling of ranitidine alkali is reached 3-8 ℃, open and stir, slowly, evenly add hydrochloric acid-ethanol liquid adjust pH to 6.2～6.8 then in jar, cooling adds crystal seed, to 0 ℃ of following stirred crystallization, kept 6 hours, get rid of filter, with frozen ethanol rinsing filter cake 2 times, dry the wet product of Ranitidine hydrochloride.
8, according to the described method for preparing ranitidine hydrochloride of claim 7, it is characterized in that the Ranitidine hydrochloride wet-milling is sieved, controlled temperature is 75～90 ℃, and vacuum tightness＞0.094Mpa was dried 6 hours, gets the ranitidine hydrochloride finished product.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200510012673XA CN1315818C (en) | 2005-07-11 | 2005-07-11 | Synthesis method of ranitidine alkali and its hydrochloride |
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| CNB200510012673XA CN1315818C (en) | 2005-07-11 | 2005-07-11 | Synthesis method of ranitidine alkali and its hydrochloride |
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| CN1724526A CN1724526A (en) | 2006-01-25 |
| CN1315818C true CN1315818C (en) | 2007-05-16 |
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010388B (en) * | 2009-09-04 | 2012-09-05 | 江苏汉斯通药业有限公司 | Preparation method of ranitidine |
| CN102010389B (en) * | 2009-09-04 | 2012-11-14 | 江苏汉斯通药业有限公司 | Method for preparing ranitidine hydrochloride |
| CN102408398B (en) * | 2011-09-20 | 2012-12-05 | 江苏汉斯通药业有限公司 | Preparation method of ranitidine bismuth citrate |
| CN106432147B (en) * | 2015-05-26 | 2018-04-17 | 烟台市华文欣欣医药科技有限公司 | A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble |
| CN105030694A (en) * | 2015-08-04 | 2015-11-11 | 青岛蓝盛洋医药生物科技有限责任公司 | Ranitidine hydrochloride composition dry suspension for treating gastric ulcer |
| CN108017601B (en) * | 2017-12-28 | 2021-07-13 | 云鹏医药集团有限公司 | Method for refining ranitidine alkali |
| 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5696275A (en) * | 1994-05-13 | 1997-12-09 | Ranbaxy Laboratories Limited | Process for the manufacture of pharmaceutical grade ranitidine base |
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2005
- 2005-07-11 CN CNB200510012673XA patent/CN1315818C/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5696275A (en) * | 1994-05-13 | 1997-12-09 | Ranbaxy Laboratories Limited | Process for the manufacture of pharmaceutical grade ranitidine base |
Non-Patent Citations (1)
| Title |
|---|
| 盐酸雷尼替丁精制方法的改进 黄龙祥 吕春绪，中国医药工业杂志，第5卷 2003 * |
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