CN105085481B - A kind of recrystallization method of RABEPRAZOLE SODIUM - Google Patents
A kind of recrystallization method of RABEPRAZOLE SODIUM Download PDFInfo
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- CN105085481B CN105085481B CN201410211916.1A CN201410211916A CN105085481B CN 105085481 B CN105085481 B CN 105085481B CN 201410211916 A CN201410211916 A CN 201410211916A CN 105085481 B CN105085481 B CN 105085481B
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- organic solvent
- rabeprazole sodium
- ketone
- rabeprazole
- ring ether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention belongs to medicinal chemistry art, specifically related to a kind of recrystallization method of RABEPRAZOLE SODIUM, recrystallized using the mixed solvent of organic solvent of ketone and ring ether organic solvent, the preferred acetone of organic solvent of ketone, MEK, cyclohexanone, the preferred tetrahydrofuran of ring ether organic solvent, Isosorbide-5-Nitrae dioxane.RABEPRAZOLE SODIUM purity height, the impurity content prepared according to the inventive method is few, meets bulk drug standard.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of recrystallization method of RABEPRAZOLE SODIUM.
Background technology
RABEPRAZOLE SODIUM (SodiumReheprazole) is second generation proton pump inhibitor, and it is by specifically suppressing H
The effects of +/K+-ATP enzyme systems and gastric acid secretion inhibiting.It is after benzimidazole proton newest after Omeprazole, Lansoprazole
Pump inhibitor.Clinically it is applied to treatment peptic ulcer such as gastric ulcer, duodenal ulcer etc., reflux esophagitis and stomach to secrete
Plain knurl.RABEPRAZOLE SODIUM is researched and developed by Japanese Wei Cai companies, and in 1997 in Japan's listing, formulation is enteric coatel tablets.At present in full generation
The country's listing of 21, boundary, Chinese Ye Youduo companies production sodium rabeprazole enteric-coated tablet, two kinds of formulations of capsulae enterosolubilis.Injection thunder
Shellfish draws azoles sodium to be that Cadila pharmaceutical Co. Ltds of India ratify listing first in May, 2004 in India, and specification is 20mg.Thunder shellfish
Azoles sodium is drawn to turn into the leading products of proton pump inhibitor.
RABEPRAZOLE SODIUM it is chemical entitled：2- [[[4- (3- methoxypropoxies) -3- methyl -2- pyridine radicals] methyl] Asia sulphurs
Acyl group] -1H-benzimidazole sodium salt, molecular formula：C18H20N3NaO3S, structural formula is as follows：
The common adverse reactions of RABEPRAZOLE SODIUM are headache, other rare adverse reaction myasthenias, constipation, dizziness, evil
The heart, stomachache and urine are abnormal, may be caused by impurity therein.Initiation material, intermediate in RABEPRAZOLE SODIUM building-up process, end
Product analogues and catabolite etc. are likely to become its impurity, so as to influence the quality of product.Therefore, essence is carried out to bulk drug
It is very necessary to make, improve its purity.
RABEPRAZOLE SODIUM synthetic method report it is more, such as patent document CN102952119A, CN102219777A,
CN102993179, but be but rarely reported on the method for its recrystallization.
The content of the invention
It is high to obtain purity the technical problem to be solved in the present invention is to provide a kind of recrystallization method of RABEPRAZOLE SODIUM
Bulk drug RABEPRAZOLE SODIUM.
A kind of recrystallization method of RABEPRAZOLE SODIUM, using organic solvent of ketone and the mixed solvent of ring ether organic solvent
Recrystallized.
One kind in acetone, MEK, cyclohexanone, espeleton, methylisobutylketone of the organic solvent of ketone or
It is several, preferably acetone, MEK, cyclohexanone.
The ring ether organic solvent is selected from one or both of tetrahydrofuran or 1,4- dioxane.
The RABEPRAZOLE SODIUM recrystallization method that the present invention is provided, specifically includes following steps：In a heated condition, by thunder shellfish
Draw azoles sodium dissolving crude product in organic solvent of ketone and the in the mixed solvent of ring ether organic solvent, thunder shellfish is made using the method for cooling
Draw azoles sodium to separate out crystallization, be filtrated to get RABEPRAZOLE SODIUM crystallization.The preferred Temperature fall of cooling method；Organic solvent of ketone and cyclic ethers
The volume ratio of class organic solvent is 3:1~8:1, preferably 4:1~6:1, more preferably 5:1.
Beneficial effects of the present invention：Bulk drug RABEPRAZOLE SODIUM purity height, the impurity obtained according to technical solution of the present invention
Content is very low.
Embodiment
The present invention is further illustrated below by specific embodiment, but the present invention is not limited to these embodiments, it should
Understand, embodiments of the invention are to be used to illustrate rather than limitation of the present invention.According to the essence of the present invention
The scope of protection of present invention is belonged to for the simple modifications that the present invention is carried out.
The RABEPRAZOLE SODIUM crude product of the present invention is purchased from Changzhou Kangli Pharmaceutical Co., Ltd.
The impurity content of the embodiment of the present invention is detected using following methods：
Take this product appropriate, plus 0.001mol/L sodium hydroxide solutions be made it is molten containing about 0.5mg RABEPRAZOLE SODIUMs in every 1mL
Liquid is used as need testing solution；Precision measures reference substance in right amount, plus 0.001mol/L sodium hydroxide solutions are made in every 1mL and contain 5 μ g
Solution is used as contrast solution.It is filler with octadecylsilane chemically bonded silica；Disodium hydrogen phosphate (is taken with phosphate buffer
1.119g and sodium dihydrogen phosphate 0.179g, the 1000mL that adds water dissolve, and mix)-acetonitrile (60:40) it is mobile phase；Detection wavelength is
286nm.Number of theoretical plate is calculated by Rabeprazole peak should be not less than 2000.The μ l of contrast solution 20 are taken to inject liquid chromatograph, regulation
Monitoring sensitivity, the peak height for making principal component chromatographic peak is about the 20% of full scale.Need testing solution and each 20 μ of contrast solution are taken again
L, is injected separately into liquid chromatograph, 2 times of record chromatogram to main peak retention time.If any miscellaneous in the chromatogram of need testing solution
Mass peak, measures the sum of each impurity peak area, cannot be greater than 1.0 times of contrast solution main peak area.
Reference example 1
RABEPRAZOLE SODIUM crude product 10g is added in 500mL eggplant-shape bottles, acetone is added under heating condition until crude product is all molten
Solution.Stop heating, stand crystallization, overnight.Filtering, obtains 8.1g RABEPRAZOLE SODIUMs, HPLC analyses, impurity content 0.8%.
Reference example 2
RABEPRAZOLE SODIUM crude product 10g will be added in 500mL eggplant-shape bottles, and add cyclohexanone under heating condition until crude product is complete
Dissolve in portion.Stop heating, stand crystallization, overnight.Filtering, obtains 8.3g RABEPRAZOLE SODIUMs, HPLC analyses, impurity content 1.2%.It is real
Apply example 1
RABEPRAZOLE SODIUM crude product 10g is added in 500mL eggplant-shape bottles, acetone-tetrahydrofuran (3 is added under heating condition:1)
Mixed solvent is until crude product all dissolves.Stop heating, stand crystallization, overnight.Filtering, obtains 8.5g RABEPRAZOLE SODIUMs, HPLC points
Analysis, impurity content is 0.4%.
Embodiment 2
RABEPRAZOLE SODIUM crude product 10g will be added in 500mL eggplant-shape bottles, acetone-Isosorbide-5-Nitrae-dioxy six is added under heating condition
Ring (3:1) mixed solvent is until crude product all dissolves.Stop heating, stand crystallization, overnight.Filtering, obtains 8.3g RABEPRAZOLE SODIUMs,
HPLC is analyzed, and impurity content is 0.28%.
Embodiment 3
RABEPRAZOLE SODIUM crude product 10g is added in 500mL eggplant-shape bottles, acetone-tetrahydrofuran (5 is added under heating condition:1)
Mixed solvent is until crude product all dissolves.Stop heating, stand crystallization, overnight.Filtering, obtains 8.1g RABEPRAZOLE SODIUMs, HPLC points
Analysis, impurity content is 0.21%.
Embodiment 4
RABEPRAZOLE SODIUM crude product 10g is added in 500mL eggplant-shape bottles, cyclohexanone-tetrahydrofuran (8 is added under heating condition:
1) mixed solvent is until crude product all dissolves.Stop heating, stand crystallization, overnight.Filtering, obtains 7.8g RABEPRAZOLE SODIUMs, HPLC
Analysis, impurity content is 0.30%.
Embodiment 5
RABEPRAZOLE SODIUM crude product 10g is added in 500mL eggplant-shape bottles, butanone-tetrahydrofuran (5 is added under heating condition:1)
Mixed solvent is until crude product all dissolves.Stop heating, stand crystallization, overnight.Filtering, obtains 8.2g RABEPRAZOLE SODIUMs, HPLC points
Analysis, impurity content is 0.20%.
Claims (5)
1. a kind of RABEPRAZOLE SODIUM recrystallization method, it is characterised in that using organic solvent of ketone and ring ether organic solvent
Mixed solvent is recrystallized, and the ring ether organic solvent is selected from one or both of tetrahydrofuran, 1,4- dioxane.
2. according to the method described in claim 1, it is characterised in that the organic solvent of ketone is selected from acetone, cyclohexanone, first and second
One or more in ketone, butanone.
3. according to the method described in claim 1, it is characterised in that specifically include following steps：RABEPRAZOLE SODIUM crude product is molten
Solution makes RABEPRAZOLE SODIUM separate out knot in organic solvent of ketone and the in the mixed solvent of ring ether organic solvent using the method for cooling
Crystalline substance, is filtrated to get RABEPRAZOLE SODIUM crystallization.
4. according to the method described in claim 1, it is characterised in that organic solvent of ketone and the volume ratio of ring ether organic solvent
For 3:1~8:1.
5. method according to claim 4, it is characterised in that organic solvent of ketone and the volume ratio of ring ether organic solvent
For 5:1.
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| CN201410211916.1A CN105085481B (en) | 2014-05-19 | 2014-05-19 | A kind of recrystallization method of RABEPRAZOLE SODIUM |
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| CN201410211916.1A CN105085481B (en) | 2014-05-19 | 2014-05-19 | A kind of recrystallization method of RABEPRAZOLE SODIUM |
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| CN105085481B true CN105085481B (en) | 2017-09-29 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107501238A (en) * | 2017-07-31 | 2017-12-22 | 上药康丽（常州）药业有限公司 | A kind of process for purification of Rabeprazole |
| CN112834628A (en) * | 2019-11-22 | 2021-05-25 | 扬子江药业集团有限公司 | Method for determining rabeprazole sodium and impurities thereof by high performance liquid chromatography |
| CN113336741B (en) * | 2021-05-07 | 2022-06-24 | 湖南德虹制药有限公司 | Rabeprazole sodium anhydride crystal form and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008155780A2 (en) * | 2007-06-21 | 2008-12-24 | Matrix Laboratories Ltd | Improved process for the preparation of pure rabeprazole |
| WO2009116072A2 (en) * | 2008-02-08 | 2009-09-24 | Ipca Laboratories Limited | Process for preparation of pyridinylmethylsulphinyl benzimidazole compounds and pyridine intermediates |
| CN102584793A (en) * | 2012-01-13 | 2012-07-18 | 山东罗欣药业股份有限公司 | Rabeprazole sodium crystal compound and preparing method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8071781B2 (en) * | 2008-11-11 | 2011-12-06 | Syn-Tech Chem. & Pharm. Co., Ltd. | Process for preparing rabeprazole sodium |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008155780A2 (en) * | 2007-06-21 | 2008-12-24 | Matrix Laboratories Ltd | Improved process for the preparation of pure rabeprazole |
| WO2009116072A2 (en) * | 2008-02-08 | 2009-09-24 | Ipca Laboratories Limited | Process for preparation of pyridinylmethylsulphinyl benzimidazole compounds and pyridine intermediates |
| CN102584793A (en) * | 2012-01-13 | 2012-07-18 | 山东罗欣药业股份有限公司 | Rabeprazole sodium crystal compound and preparing method thereof |
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