CN102329282A - Nizatidine compound and preparation method thereof - Google Patents
Nizatidine compound and preparation method thereof Download PDFInfo
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- CN102329282A CN102329282A CN 201110197859 CN201110197859A CN102329282A CN 102329282 A CN102329282 A CN 102329282A CN 201110197859 CN201110197859 CN 201110197859 CN 201110197859 A CN201110197859 A CN 201110197859A CN 102329282 A CN102329282 A CN 102329282A
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Abstract
The invention relates to a nizatidine compound and a preparation method thereof. A simple and convenient silica gel column chromatography method is selected, and an appropriate stationary phase and an appropriate mobile phase are used. Specifically, nizatidine can be effectively prepared by using silica gel as the stationary phase and a mixed solvent of acetonitrile and ammonium acetate in a certain proportion as the mobile phase, and keeping the column temperature higher than room temperature. By the product, the quality of a preparation product is improved, and the toxic or side effect is reduced.
Description
Technical field
The present invention relates to a kind of compound and method for making thereof, be specifically related to a kind of method for making of nizatidine compound, belong to technical field of pharmaceuticals.
Background technology
Nizatidine (nizatidine), chemical name is: N-[2-[[[2-(dimethylin) methyl]-4-thiazolyl] methyl] sulphur] ethyl]-N '-methyl-2-nitro]-1, the 1-ethylene diamine, molecular formula is: C
12H
21N
5O
2S
2, molecular weight: 331.46, structural formula is:
, go on the market in exploitation in 1986 by the Eli-lilly of u s company in 1987.
Nizatidine is a histamine H2 receptor antagonist; The competitive ground of nizatidine combines with histamine H2-receptor; Reversibility ground suppresses the performance of function of receptors, particularly acts on the H2 acceptor on the parietal cell of secreting hydrochloric acid in gastric juice, and blocking-up hydrochloric acid in gastric juice forms; And basic hydrochloric acid in gastric juice is reduced, also can suppress the gastric acid secretion due to food and the chemical stimulation.Clinically, nizatidine is used to treat heartburn symptom and the benign gastric ulcer that the esophagitis of keeping treatment, endoscopic diagnosis, GORD, GORD after active duodenal ulcer, the duodenal ulcer occur.
The structure of nizatidine can be divided into main ring 2-dimethylamino methyl-4-5-chloromethyl thiazole and side chain N-(2-mercapto ethyl)-N-methyl-2-nitro 1; 1-ethylene diamine two portions; It synthesizes can synthesize main ring earlier; Branch's spreading side chain perhaps synthesizes main chain and side chain, condensation prepared nizatidine under alkaline condition then respectively again.
The low shortcoming of compound ubiquity purity that the nizatidine of method for preparing makes has caused preparation stability to decline to a great extent, and has influenced its clinical application.
Summary of the invention
The method for making that the purpose of this invention is to provide a kind of nizatidine compound has improved its purity, has improved the formulation products quality, has reduced toxic side effect.
In order to realize the foregoing invention purpose, technical scheme of the present invention is following:
The invention provides a kind of method for making of nizatidine compound; It is characterized in that comprising that the nizatidine bullion obtains the step of the pure article of nizatidine through column chromatography for separation; And described column chromatography for separation is as stationary phase with silica gel; Acetonitrile and ammonium acetate (30%) volume ratio is 1: mixed solvent (3-5) is as moving phase, and is higher than under the room temperature condition at column temperature and carries out.
Above-mentioned described method for making, wherein said moving phase are that acetonitrile and ammonium acetate (30%) volume ratio are 1: mixed solvent (3.5-4.3).
Above-mentioned described method for making, the column temperature of wherein said column chromatography keeps 30～40 ℃.
Above-mentioned described method for making, wherein said stationary phase are the column chromatography silica gel specials, and particle diameter is 20-250 μ m, and the aperture is 10-100A
0Preferable particle size is 60-140 μ m, and the aperture is 30-50A
0Kiselgel A.
Above-mentioned described method for making, the pressure of wherein said column chromatography is 0.1-5.0pa, is preferably 0.5-1.5pa.
Above-mentioned described method for making, the flow velocity of wherein said column chromatography are 0.5-1.5ml/min.
Above-mentioned described method for making, the applied sample amount of wherein said column chromatography are 100～300mg/ml column volume.
Above-mentioned described method for making, wherein said column chromatography for separation are to carry out appearance on the silicagel column after the nizatidine bullion is dissolved with moving phase, use the moving phase wash-out; Collect the nizatidine position, with the pure water washing, solid drier is dry; Concentrating under reduced pressure steams and removes elutriant, gets the pure article of nizatidine.
Above-mentioned described method for making, wherein said solid drier is selected from one or more in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate and the activated alumina.
Above-mentioned described method for making, the purity of the pure article of wherein said nizatidine is not less than 99.8%.
The present invention selects easy silica gel column chromatography method for use, uses suitable stationary phase and moving phase, can be with purity at 94%-98%, the preferred purity nizatidine bullion at 97%-98.5%; Separate through easy silica gel column chromatography; Acquisition purity is not less than 99.8% the pure article of nizatidine, can prepare highly purified nizatidine effectively, and its yield and purity are all higher; Improve the formulation products quality, reduced toxic side effect.
Embodiment
Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
Embodiment 1
10g nizatidine bullion (purity is 97.7%) is dissolved in 300ml acetonitrile-ammonium acetate (30%) in 1: 3.5, is added to the post top, weighting agent is particle diameter 60-100 μ m, aperture 30-50A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 0.5pa; Pump into acetonitrile-ammonium acetate (30%) 1 again: column chromatography is carried out in (3.5), and flow velocity is 0.5ml/min, and column temperature keeps 40 ℃, pick up counting, and sampling, tracking monitor carries out Fractional Collections, collects liquid; With the pure water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure steams and removes elutriant, gets nizatidine 8.95g, yield 91.5%, purity 99.87%.
Embodiment 2
20g nizatidine bullion (purity is 97.3%) is dissolved in 600ml acetonitrile-ammonium acetate (30%) in 1: 4.3, is added to the post top, weighting agent is particle diameter 100-140 μ m, aperture 30-4A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 1.5pa; Pump into acetonitrile-ammonium acetate (30%) again and carry out column chromatography at 1: 4.3, flow velocity is 1.5ml/min, and column temperature keeps 30 ℃, pick up counting, and sampling, tracking monitor carries out Fractional Collections, collects liquid; With the pure water washing, anhydrous magnesium sulfate drying, concentrating under reduced pressure steams and removes elutriant, gets nizatidine 17.8g, yield 91.3%, purity 99.85%.
Embodiment 3
20g nizatidine bullion (purity is 98.0%) is dissolved in 500ml acetonitrile-ammonium acetate (30%) in 1: 4, is added to the post top, weighting agent is particle diameter 75-150 μ m, aperture 20-30A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 1.5pa; Pump into acetonitrile-ammonium acetate (30%) again and carry out column chromatography at 1: 4, flow velocity is 1.0ml/min, and column temperature keeps 35 ℃, pick up counting, and sampling, tracking monitor carries out Fractional Collections, collects liquid; With the pure water washing, activated alumina is dry, and concentrating under reduced pressure steams and removes elutriant, gets nizatidine 17.3g, yield 88.0%, purity 99.8%.
Comparative example 1
15g nizatidine bullion (purity is 98.1%) is dissolved in 500ml acetonitrile-ammonium acetate (30%) in 1: 5.5, is added to the post top, weighting agent is particle diameter 150-250 μ m, aperture 50-60A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 0.05pa; Pump into acetonitrile-ammonium acetate (30%) again and carry out column chromatography at 1: 5, flow velocity is 2.0ml/min, and column temperature keeps 50 ℃, picks up counting, takes a sample, and tracking monitor carries out Fractional Collections, collects liquid; With the pure water washing, activated alumina is dry, and concentrating under reduced pressure steams and removes elutriant, gets nizatidine 11.3g, yield 75.5%, purity 98.4%.
Comparative example 2
10g nizatidine bullion (purity is 97.8%) is dissolved in 300ml acetonitrile-ammonium acetate (30%) in 1: 1, is added to the post top, weighting agent is particle diameter 20-250 μ m, aperture 30-50A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 5.0pa; Pump into acetonitrile-ammonium acetate (30%) again and carry out column chromatography at 1: 1, flow velocity is 0.3ml/min, and column temperature keeps 25 ℃, picks up counting, takes a sample, and tracking monitor carries out Fractional Collections, collects liquid; With the pure water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure steams and removes elutriant, gets nizatidine 7.9g, yield 79.4%, purity 98.3%.
Compare through the foregoing description and the used parameter of comparative example and result, can find out, in the process for purification scope of nizatidine compound provided by the invention, the purifying article yield that makes is high, and purity is good; And the product that the outer parameter of the scope of the invention obtains, purity is low, and yield is also low.Proved absolutely the practical application effect of the inventive method.
Claims (10)
1. the nizatidine compound of a formula (I) structure,
It is characterized in that comprising that the nizatidine bullion obtains the step of the pure article of nizatidine through column chromatography for separation; Described column chromatography for separation is as stationary phase with silica gel; Acetonitrile and ammonium acetate (30%) volume ratio is 1: mixed solvent (3-5) is as moving phase, and is higher than under the room temperature condition at column temperature and carries out.
2. method for making according to claim 1 is characterized in that described moving phase is that acetonitrile and ammonium acetate (30%) volume ratio are 1: mixed solvent (3.5-4.3).
3. method for making according to claim 1 is characterized in that the column temperature of described column chromatography keeps 30～40 ℃.
4. method for making according to claim 1 is characterized in that described stationary phase is the column chromatography silica gel special, and particle diameter is 20-250 μ m, and the aperture is 10-100A
0Preferable particle size is 60-140 μ m, and the aperture is 30-50A
0Kiselgel A.
5. method for making according to claim 1 is characterized in that the pressure of described column chromatography is 0.1-5.0pa, is preferably 0.5-1.5pa.
6. method for making according to claim 1, the flow velocity that it is characterized in that described column chromatography is 0.5-1.5ml/min.
7. method for making according to claim 1, the applied sample amount that it is characterized in that described column chromatography is 100～300mg/ml column volume.
8. method for making according to claim 1 is characterized in that described column chromatography for separation is to carry out appearance on the silicagel column after the nizatidine bullion is dissolved with moving phase, uses the moving phase wash-out; Collect the nizatidine position; With the pure water washing, solid drier is dry, concentrating under reduced pressure; Steam and remove elutriant, get the pure article of nizatidine.
9. method for making according to claim 8, wherein said solid drier is selected from one or more in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous calciumsulphate and the activated alumina.
10. the purity of the nizatidine compound that makes according to each described method for making of claim 1-9 is not less than 99.8%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110197859 CN102329282A (en) | 2011-07-15 | 2011-07-15 | Nizatidine compound and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110197859 CN102329282A (en) | 2011-07-15 | 2011-07-15 | Nizatidine compound and preparation method thereof |
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| CN102329282A true CN102329282A (en) | 2012-01-25 |
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| CN 201110197859 Pending CN102329282A (en) | 2011-07-15 | 2011-07-15 | Nizatidine compound and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4382090A (en) * | 1980-10-02 | 1983-05-03 | Eli Lilly And Company | N-Thiazolylmethylthioalkyl-N'alkylamidines and related compounds |
| CN86108424A (en) * | 1985-12-18 | 1987-08-05 | 伊莱利利公司 | The synthetic method of nizatidine |
| US5700945A (en) * | 1994-07-11 | 1997-12-23 | Torcan Chemical Ltd. | Process for preparing nizatidine |
| CN1397553A (en) * | 2002-08-19 | 2003-02-19 | 卞路声 | Process for preparing Nizatidine |
-
2011
- 2011-07-15 CN CN 201110197859 patent/CN102329282A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4382090A (en) * | 1980-10-02 | 1983-05-03 | Eli Lilly And Company | N-Thiazolylmethylthioalkyl-N'alkylamidines and related compounds |
| CN86108424A (en) * | 1985-12-18 | 1987-08-05 | 伊莱利利公司 | The synthetic method of nizatidine |
| US5700945A (en) * | 1994-07-11 | 1997-12-23 | Torcan Chemical Ltd. | Process for preparing nizatidine |
| CN1397553A (en) * | 2002-08-19 | 2003-02-19 | 卞路声 | Process for preparing Nizatidine |
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Application publication date: 20120125 |