CN102757421A - Purification method of esomeprazole - Google Patents
Purification method of esomeprazole Download PDFInfo
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- CN102757421A CN102757421A CN2011101187971A CN201110118797A CN102757421A CN 102757421 A CN102757421 A CN 102757421A CN 2011101187971 A CN2011101187971 A CN 2011101187971A CN 201110118797 A CN201110118797 A CN 201110118797A CN 102757421 A CN102757421 A CN 102757421A
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- esomeprazole
- salt
- sylvite
- mixed solvent
- methyl alcohol
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Abstract
The invention relates to a purification method of esomeprazole. According to the purification method, esomeprazole or salt thereof to be purified is transformed into potassium esomeprazole and then separated by crystallization, and if necessary, the crystallization product is transformed into esomeprazole or salt thereof. Compared with the conventional recrystallization method, the purification method can purify esomeprazole with high efficiency to obtain high-purity esomeprazole or salt thereof. The purification method is particularly suitable for purification of drug compounds with extremely strict requirements on the purity.
Description
Technical field
The present invention relates to the organic synthesis field, in particular to the purification process of esomeprazole.
Background technology
Esomeprazole (Esomeprazole); I.e. (S)-omeprazole; Chemistry is by name: (S)-5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline, gastric acid inhibitory secretion effectively; Be usually used in treatment and the disorderly diseases associated of gastric acid secretion, like stomach ulcer, duodenal ulcer etc.This compound has following structural formula:
Esomeprazole is prepared through peroxo-fractionation or asymmetric oxidation by thioether usually in the prior art, because oxidising process is difficult to control, therefore can't avoid the generation of various by products, for example after sulfide oxidation becomes sulfoxide, further is oxidized to sulfone.
Summary of the invention
The object of the present invention is to provide a kind of purification process of esomeprazole, this method is different from conventional recrystallization method, and this method can be carried out purifying to esomeprazole efficiently, and then obtains highly purified esomeprazole or its salt.This method is particularly suitable for the purifying to the high medical compounds of purity requirement.
Esomeprazole purification process provided by the invention may further comprise the steps:
(I) esomeprazole or its salt are added to contain in the methanol solvate, wherein esomeprazole or its salt are not the sylvite of esomeprazole;
(II) add the reaction of potassium source;
(III) crystallization of esomeprazole sylvite is separated out;
(IV) optionally, with esomeprazole sylvite recrystallization in the methanol mixed solvent;
(V) optionally, esomeprazole sylvite is converted into other salt of esomeprazole or esomeprazole.
In above-mentioned preparing method's step (I):
The salt of esomeprazole refers to metal-salt or organic alkali salt of esomeprazole.Metal-salt comprises an alkali metal salt (like sodium salt or lithium salts etc.), alkaline earth salt (like magnesium salts or calcium salt etc.) or transition metal salt (like zinc salt etc.); Organic alkali salt comprises ammonium salt, quaternary ammonium salt or cyclohexylamine salt etc.Particular certain cancers, magnesium salts or ammonium salt, more preferably sodium salt.
Contain the solvent that methanol solvate nail alcohol content is higher than 40% (volume ratio); Can be the pure methanol solvate or the mixed solvent of methyl alcohol and other solvent; Mixed solvent like one or more solvents in methyl alcohol and ETHYLE ACETATE, toluene, acetone or the methylene dichloride; Be preferably the solvent that methanol content is higher than 50% (volume ratio), more preferably methyl alcohol.Esomeprazole or its salt are 1g: 2-10ml with containing the methanol solvate mass volume ratio, are preferably 1g: 4-7ml.
In above-mentioned preparing method's step (II):
The potassium source refers in reaction, to discharge potassium ion and forms the compound of sylvite with esomeprazole, is preferably Pottasium Hydroxide or alkoxyl group potassium, more preferably potassium methylate or potassium ethylate, most preferably potassium methylate.The consumption in potassium source (to contain the mole number of reactive behavior potassium) is 0.5～3 times of esomeprazole molar weight, preferred 1～1.5 times, and more preferably 1.2 times.Temperature of reaction is preferably 50 ℃ between the reflux temperature between room temperature to reflux temperature.
In above-mentioned preparing method's step (III):
The esomeprazole crystallization can be that direct deposition is separated out after adding the potassium source, also can crystallization separated out through conventional meanses such as cooling or concentrated solvents.
In above-mentioned preparing method's step (IV):
Can select whether needs are further purified according to the purity and the foreign matter content of esomeprazole sylvite; Described methanol mixed solvent; Be meant that the methyl alcohol volume percent is more than or equal to 20% methanol mixed solvent; The particular methanol volume percent is more than or equal to 50% methanol mixed solvent, and more preferably the methyl alcohol volume percent is more than or equal to 80% methanol mixed solvent, and most preferably the methyl alcohol volume percent is more than or equal to 90% methanol mixed solvent.
The mass volume ratio of the solvent of esomeprazole potassium and recrystallization is 1g: 3-8ml; Be heated to 50 ℃ to the reflux temperature dissolving, be preferably 70 ℃ to reflux temperature; Tc be 0 ℃ to room temperature, crystallization 1-10h.
In above-mentioned preparing method's step (V):
Other salt of esomeprazole refers to the esomeprazole salt except that sylvite, can be sodium salt, lithium salts, magnesium salts, calcium salt, zinc salt, ammonium salt, quaternary ammonium salt or the cyclohexylamine salt of esomeprazole, particular certain cancers, magnesium salts or ammonium salt, most preferably sodium salt or magnesium salts.Salify can carry out through method of the prior art.
The present invention also provides a kind of purification process of preferred esomeprazole, may further comprise the steps:
(I) the esomeprazole sodium salt is added in the methyl alcohol;
(II) add the potassium methylate reaction;
(III) crystallization of esomeprazole sylvite is separated out;
(IV) with esomeprazole sylvite recrystallization in the methanol mixed solvent;
(V) esomeprazole sylvite is converted into the sodium salt or the magnesium salts of esomeprazole.
The reaction conditions of above step is described identical with preamble.
The present invention can be able to specify through the following example.The purpose of specific embodiment is to further specify content of the present invention, but and does not mean that and limit the invention.
Embodiment
Embodiment 1: the purifying of esomeprazole sodium salt
30g (81.7mmol) esomeprazole sodium salt (sulfone content 3.04%) is added in the reaction flask, add 150ml methyl alcohol, be heated to 50 ℃ and add 6.9g (98.0mmol) potassium methylate; Separate out white solid immediately; Reflux 1h is chilled to room temperature and stirs 1h, suction filtration, washing and dry; Output: 30g (containing 12.1% methyl alcohol), methyl alcohol (sulfone content 0.98%) is removed in vacuum-drying.
Embodiment 2: the purifying of esomeprazole sodium salt
30g (81.7mmol) esomeprazole sodium salt (sulfone content 3.04%) is added in the reaction flask; Add 150ml methyl alcohol; Be heated to 50 ℃ and add 5.5g (98.0mmol) Pottasium Hydroxide, reflux 1h is chilled to stirring at room 1h suction filtration, washing and dry; Output: 28g (containing 11.8% methyl alcohol), methyl alcohol (sulfone content 1.12%) is removed in vacuum-drying.
Embodiment 3: the purifying of esomeprazole triethylamine salt
36.5g (82mmol) esomeprazole triethylamine salt (sulfone content 2.93%) is added in the reaction flask; Add 150ml methyl alcohol; Be heated to 50 ℃ of adding 6.9g (98.0mmol) potassium methylates and separate out white solid immediately, reflux 1h is chilled to stirring at room 1h suction filtration, washing and dry; Output: 27g (containing 12.0% methyl alcohol), methyl alcohol (sulfone content 1.04%) is removed in vacuum-drying.
Embodiment 4: the purifying of esomeprazole sodium salt
30g (81.7mmol) esomeprazole sodium salt (sulfone content 3.04%) is added in the reaction flask; Add 150ml methyl alcohol, 150ml toluene is heated to 50 ℃ of adding 6.9g (98.0mmol) potassium methylates and separates out white solid immediately; Reflux 1h; Be chilled to stirring at room 1h suction filtration, washing and dry, output: 31g (containing 11.9% methyl alcohol), methyl alcohol (sulfone content 1.43%) is removed in vacuum-drying.
Embodiment 5: the purifying of esomeprazole sodium salt
30g (81.7mmol) esomeprazole sodium salt (sulfone content 3.04%) is added in the reaction flask; Add 150ml methyl alcohol; Be heated to 50 ℃ of adding 5.7g (81.7mmol) potassium methylates and separate out white solid immediately, reflux 1h is chilled to stirring at room 1h suction filtration, washing and dry; Output: 27g (containing 12.1% methyl alcohol), methyl alcohol (sulfone content 0.98%) is removed in vacuum-drying.
Embodiment 6: the purifying of esomeprazole sylvite
20g esomeprazole sylvite (sulfone content 3.23%) is added in the reaction flask, add 100ml 80% methanol aqueous solution, reflux 1h is chilled to stirring at room 1h suction filtration, the dry 16.1g solid (sulfone content 1.0%) that gets of washing.
Embodiment 7: the purifying of esomeprazole sylvite
20g esomeprazole sylvite (sulfone content 3.23%) is added in the reaction flask, add 50ml methyl alcohol, 50ml ETHYLE ACETATE, reflux 1h is chilled to stirring at room 1h suction filtration, the dry 16.7g solid (sulfone content 2.06%) that gets of washing.
Embodiment 8: the purifying of esomeprazole sylvite
20g esomeprazole sylvite (sulfone content 3.23%) is added in the reaction flask, add 100ml 90% methanol aqueous solution, reflux is chilled to stirring at room 1h suction filtration, the dry 15.2g solid (sulfone content 0.6%) that gets of washing.
Sulfone content is under following condition, to record through chirality HPLC (HPLC) among the embodiment.
Chromatographic column: Dikma PlatisilTM ODS, 150 * 4.6mm, 5 μ m
Column temperature: 25 ℃
Moving phase: A acetonitrile: B damping fluid (10mM Sodium phosphate, dibasic, pH=7.6) (40: 60)
Wavelength: 208nm.
Claims (10)
1. the purification process of an esomeprazole may further comprise the steps:
(I) esomeprazole or its salt are added to contain in the methanol solvate, wherein esomeprazole or its salt are not the sylvite of esomeprazole;
(II) add the reaction of potassium source;
(III) crystallization of esomeprazole sylvite is separated out;
(IV) optionally, with esomeprazole sylvite recrystallization in the methanol mixed solvent;
(V) optionally, esomeprazole sylvite is converted into other salt of esomeprazole or esomeprazole.
2. the process of claim 1 wherein that the salt of the middle esomeprazole of step (I) is sodium salt, lithium salts, magnesium salts, calcium salt, zinc salt, ammonium salt, quaternary ammonium salt or the cyclohexylamine salt of esomeprazole.
3. the method for claim 2, wherein the salt of esomeprazole is sodium salt, magnesium salts or ammonium salt in the step (I).
4. each method of claim 1-3 wherein contains methanol solvate nail alcohol in the step (I).
5. the process of claim 1 wherein that the middle potassium source of step (II) is potassium methylate or potassium ethylate.
6. the process of claim 1 wherein that other salt of the middle esomeprazole of step (V) is sodium salt, lithium salts, magnesium salts, calcium salt, zinc salt, ammonium salt, quaternary ammonium salt or the cyclohexylamine salt of esomeprazole.
7. the method for claim 6, wherein other salt of esomeprazole is sodium salt, magnesium salts or ammonium salt in the step (V).
8. the esomeprazole purification process of claim 1 may further comprise the steps:
(I) the esomeprazole sodium salt is added in the methyl alcohol;
(II) add the potassium methylate reaction;
(III) crystallization of esomeprazole sylvite is separated out;
(IV) with esomeprazole sylvite recrystallization in the methanol mixed solvent;
(V) esomeprazole sylvite is converted into the sodium salt or the magnesium salts of esomeprazole.
9. claim 1 or 8 each methods, wherein the methanol mixed solvent is the methyl alcohol volume percent more than or equal to 50% methanol mixed solvent in the step (IV).
10. right is wanted 9 method, and wherein the methanol mixed solvent is the methyl alcohol volume percent more than or equal to 80% methanol mixed solvent in the step (IV).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2011101187971A CN102757421A (en) | 2011-04-29 | 2011-04-29 | Purification method of esomeprazole |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101187971A CN102757421A (en) | 2011-04-29 | 2011-04-29 | Purification method of esomeprazole |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087048A (en) * | 2013-02-26 | 2013-05-08 | 四川尚锐生物医药有限公司 | Method for purifying esomeprazole sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1258295A (en) * | 1997-05-30 | 2000-06-28 | 阿斯特拉公司 | Novel form of S-omeprazole |
| US20070259921A1 (en) * | 2006-05-04 | 2007-11-08 | Vijayabhaskar Bolugoddu | Polymorphic forms of esomeprazole sodium |
-
2011
- 2011-04-29 CN CN2011101187971A patent/CN102757421A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1258295A (en) * | 1997-05-30 | 2000-06-28 | 阿斯特拉公司 | Novel form of S-omeprazole |
| US20070259921A1 (en) * | 2006-05-04 | 2007-11-08 | Vijayabhaskar Bolugoddu | Polymorphic forms of esomeprazole sodium |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087048A (en) * | 2013-02-26 | 2013-05-08 | 四川尚锐生物医药有限公司 | Method for purifying esomeprazole sodium |
| CN103087048B (en) * | 2013-02-26 | 2014-04-09 | 四川唯拓生物医药有限公司 | Method for purifying esomeprazole sodium |
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Address after: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Applicant after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Applicant before: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd. |
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Application publication date: 20121031 |