CN102633776A - Method for preparing esomeprazole and sodium salt thereof - Google Patents
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Abstract
The invention relates to a method for preparing esomeprazole and sodium salt thereof, which includes the steps: using thioether, D-(-)-tartaric acid diethyl ester and titanium tetraisopropoxide to form chiral ligand, obtaining esomeprazole under oxidation of oxidant tert-amylhydroperoxide, and adding sodium hydroxide for salifying and recrystallization to obtain esomeprazole meeting the officinal level, wherein the ee value is larger than 99.9%, and purity (area normalization method) is higher than 99.8%.
Description
Technical field:
The present invention relates to the preparation method of a kind of esomeprazole and sodium salt thereof, belong to medical technical field.
Background technology:
Omeprazole is by a kind of novel proton pump inhibitor class anti-ulcerative drug of Sweden Astra Pharma Inc. in listing in 1988; Omeprazole is R type and 1: 1 mixture of two kinds of optical isomers of S type; And its S isomer, S-(-)-5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline; Promptly be esomeprazole, its chemical structural formula is following:
The characteristics that it had are that the first pass effect after oral is few, and bioavailability and blood concentration are high than omeprazole or R type isomer, and therefore, drug effect is high and lasting than omeprazole.In view of the meliority of esomeprazole, add that U.S. FDA issued the chiral drug governing principle in 1992, research and development esomeprazole individual isomer chiral drug has become the striving direction of current each big drugmaker and research institution.
Use chiral ligand to prepare esomeprazole; The method that this type use chiral catalyst asymmetric oxidation omeprazole thioether obtains esomeprazole has the raw material availability height for traditional Split Method, simple to operate; Therefore the advantage that reactions step is few has higher application prospect.
At present patents such as CN95194956.X, WO9602535A1, WO2005054288A1, WO2005080374A1, WO2006040635A1, CN200610172184.5, WO2008018091A1, WO2010150276A2 are in the presence of chirality tartaric acid derivatives and titan-alkoxide, vanadium, zirconium compounds; Use tertbutyl peroxide or cumyl hydroperoxide that the prochirality thioether is carried out oxidation, obtain the sulfoxide compound of enantiomorph enriched form.
The present invention is a kind of new oxidizing condition of invention; Use new oxygenant tertiary amyl hydrogen peroxide that the chiral ligand of chirality tartaric acid derivatives and alkoxy titanium compound and the formation of prochirality thioether is carried out oxidation; Obtain the esomeprazole sodium compound; Because the large-scale production of domestic tertiary amyl hydrogen peroxide, the present invention provides a kind of new reaction conditions for suitability for industrialized production prepares esomeprazole sodium.The tertiary amyl hydrogen peroxide is compared with traditional tertbutyl peroxide or cumyl hydroperoxide, and tertiary amyl hydrogen peroxide character is more stable, and reaction impurities is few, and toxicity is lower, is beneficial to suitability for industrialized production and application.
Summary of the invention:
One of the object of the invention provides the preparation method of a kind of esomeprazole and sodium salt thereof, it is characterized in that: with forming chiral ligand down at 40-55 ℃ in starting raw material 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline, D-(-)-diethyl tartrate, purified water, the titanium tetraisopropylate adding organic solvent; The cooling back adds N, the N-diisopropyl ethyl amine, and drip the mixing solutions that contains tertiary amyl hydrogen peroxide and organic solvent; Insulated and stirred; What obtain contains the esomeprazole reaction solution through sodium hydroxide extraction, and it is 7-8 that Glacial acetic acid min. 99.5 is regulated the pH value, uses dichloromethane extraction; Dry; Evaporate to dryness, the sodium hydroxide salify also carries out recrystallization to sodium salt, promptly gets.
The esomeprazole sodium of the method for the invention preparation, HPLC detection esomeprazole sodium purity (area normalization method) is 99.80%, always mixes≤0.2%, and maximum is single mixes≤0.05%, and chirality HPLC detection ee value>=99.9% meets medicinal relevant criterion requirement.
Method feature of the present invention is: the ratio of D-(-)-diethyl tartrate and starting raw material is 2～0.4: 1; The ratio of titanium tetraisopropylate and starting raw material is 1～0.2: 1; N, the ratio of N-diisopropyl ethyl amine and starting raw material is 2～0.2: 1; The ratio of tertiary amyl hydrogen peroxide and starting raw material is 3～0.9: 1.
Method feature of the present invention is: range of reaction temperature is-5 ℃～35 ℃.
Method feature of the present invention is: the reaction solvent classification is the preferred methylene dichloride of halogenated hydrocarbon, the inferior trichloromethane that selects; The ester class is ETHYLE ACETATE or propyl acetate; Aromatic hydrocarbons is chlorobenzene, toluene, YLENE.
Method feature of the present invention is: sodium salt can be replaced by sylvite or other metal-salts.
The tertiary amyl hydrogen peroxide that method of the present invention is used, littler than the toxicity of other oxygenants, and character is relatively stable; Reaction impurities is few; Carry out oxidation according to three kinds of different oxidation agent, after handling according to equal conditions, the product that obtains carries out the comparative experiments of related substance; The impurity in products number that discovery tertiary amyl hydrogen peroxide oxidation obtains is less relatively, and particular case sees the following form:
| The oxygenant title | Total assorted content | The impurity number |
| Cumyl hydroperoxide | 3.4％ | 6 |
| T-butyl hydroperoxide | 7.5％ | 7 |
| The tertiary amyl hydrogen peroxide | 3.5％ | 4 |
Because tertiary amyl hydrogen peroxide solvability relatively stable and degradation production is good and toxicity is low; It is all less relatively to carry out total impurities and single impurity that asymmetric oxidation obtains; Convenient post-treatment is beneficial to industrial applications, and therefore esomeprazole sodium preparation method of the present invention has remarkable advantages; Consult Relational database, do not find to have the report similar with the present invention.
Embodiment
Embodiment one:
In three mouthfuls of reaction flasks of 250mL, add successively 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline (19.76g, 60mmol), methylene dichloride (80mL), D-(-)-diethyl tartrate (12.37g; 60mmol), purified water (0.20g, 11mmol), titanium tetraisopropylate (8.53g, 30mmol); Intensification refluxed it 1 hour, cooled to 20～25 ℃, added N; (3.88g 30mmol), drips in reaction flask and contains tertiary amyl hydrogen peroxide (8.08g the N-diisopropyl ethyl amine; 85%; 66mmol) and the mixing solutions of methylene dichloride (20mL), dropping time control 1.0～1.5h maintains the temperature at 25～30 ℃ and stirred 4 hours.Chirality and achirality HPLC detection reaction liquid contain 2.1% thioether, 0.2% sulfone, the sulfoxide of 96.5% enantiomeric excess 96.0% in the reaction solution.With 5% sodium hydroxide (100mL) extracted organic phase at twice, discard organic phase, with methylene dichloride (20mL) aqueous layer extracted; Discard organic phase, use Glacial acetic acid min. 99.5 water transfer pH value of solution value to be 7-8, with methylene dichloride (200mL) aqueous phase extracted at twice; Saturated sodium-chloride water solution (20mL) washing organic phase, separatory is collected organic phase; The anhydrous sodium sulfate drying organic phase, the evaporated under reduced pressure organic phase.Add the sodium hydroxide salify and sodium salt is carried out recrystallization, obtain the 15.43g target compound, total recovery is 70%.HPLC detection compound purity (area normalization method) is 99.80%, total assorted≤0.2%, maximum single assorted≤0.05%
It is 100% that chirality HPLC detects the ee value
Embodiment two:
In three mouthfuls of reaction flasks of 250mL, add successively 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline (14.82g, 45mmol), ETHYLE ACETATE (80mL), D-(-)-diethyl tartrate (18.56g; 90mmol), purified water (0.81g, 45mmol), titanium tetraisopropylate (10.23g, 36mmol); Be warmed up to 50 ℃, stirred 1 hour, cool to 0～5 ℃; Add N, and the N-diisopropyl ethyl amine (1.74g, 13.5mmol); In reaction flask, drip contain the tertiary amyl hydrogen peroxide (11.02g, 85%, 90mmol) and the mixing solutions of ETHYLE ACETATE (20mL); Dropping time control 1.0～1.5h maintains the temperature at 0～5 ℃ and stirred 6 hours.Chirality and achirality HPLC detection reaction liquid contain 2.8% thioether, 0.5% sulfone, the sulfoxide of 96.0% enantiomeric excess 95.9% in the reaction solution.Add 20% sodium thiosulfate solution (55mL),, discard organic phase with 5% sodium hydroxide (100mL) extracted organic phase at twice; With ETHYLE ACETATE (20mL) aqueous layer extracted, discard organic phase, use Glacial acetic acid min. 99.5 water transfer pH value of solution value to be 7-8; With ETHYLE ACETATE (200mL) aqueous phase extracted at twice, saturated sodium-chloride water solution (20mL) washing organic phase, separatory; Collect organic phase, anhydrous sodium sulfate drying organic phase, evaporated under reduced pressure organic phase.Add the sodium hydroxide salify and sodium salt is carried out recrystallization, obtain the 11.07g target compound, total recovery is 67%.HPLC detection compound purity (area normalization method) is 99.90%, always mixes≤0.1%, and maximum list mixes≤0.04%, and chirality HPLC detection ee value is 99.95%
Embodiment three:
In three mouthfuls of reaction flasks of 250mL, add successively 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline (14.82g, 45mmol), toluene (80mL), D-(-)-diethyl tartrate (3.71g; 18mmol), purified water (0.49g, 27mmol), titanium tetraisopropylate (5.11g, 18mmol); Be warmed up to 40 ℃, stirred 1 hour, cool to 20～25 ℃; Add N, and the N-diisopropyl ethyl amine (5.81g, 45mmol); In reaction flask, drip contain the tertiary amyl hydrogen peroxide (5.51g, 85%, 45mmol) and the mixing solutions of toluene (20mL); Dropping time control 1.0～1.5h maintains the temperature at 20～25 ℃ and stirred 4 hours.Chirality and achirality HPLC detection reaction liquid contain 4.5% thioether, 0.2% sulfone, the sulfoxide of 94.0% enantiomeric excess 96.4% in the reaction solution.With 5% sodium hydroxide (100mL) extracted organic phase at twice, discard organic phase, with toluene (20mL) aqueous layer extracted; Discard organic phase, use Glacial acetic acid min. 99.5 water transfer pH value of solution value to be 7-8, with ETHYLE ACETATE (200mL) aqueous phase extracted at twice; Saturated sodium-chloride water solution (20mL) washing organic phase, separatory is collected organic phase; The anhydrous sodium sulfate drying organic phase, the evaporated under reduced pressure organic phase.Add the sodium hydroxide salify and sodium salt is carried out recrystallization, obtain the 10.74g target compound, total recovery is 65%.HPLC detection compound purity (area normalization method) is 99.93%, always mixes≤0.07%, and maximum list mixes≤0.05%, and chirality HPLC detection ee value is 99.99%.
Embodiment four:
In three mouthfuls of reaction flasks of 250mL, add successively 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline (14.82g, 45mmol), ETHYLE ACETATE (80mL), D-(-)-diethyl tartrate (11.13g; 54mmol), purified water (0.81g, 45mmol), titanium tetraisopropylate (10.23g, 36mmol); Be warmed up to 45 ℃, stirred 1 hour, cool to 20～25 ℃; Add N, and the N-diisopropyl ethyl amine (2.33g, 18mmol); In reaction flask, drip contain the tertiary amyl hydrogen peroxide (4.96g, 85%, 40.5mmol) and the mixing solutions of ETHYLE ACETATE (20mL); Dropping time control 1.0～1.5h maintains the temperature at 20～25 ℃ and stirred 4 hours.Chirality and achirality HPLC detection reaction liquid contain 13.5% thioether, 0.2% sulfone, the sulfoxide of 84.0% enantiomeric excess 97.3% in the reaction solution.With 5% sodium hydroxide (100mL) extracted organic phase at twice, discard organic phase, with ETHYLE ACETATE (20mL) aqueous layer extracted; Discard organic phase, use Glacial acetic acid min. 99.5 water transfer pH value of solution value to be 7-8, with ETHYLE ACETATE (200mL) aqueous phase extracted at twice; Saturated sodium-chloride water solution (20mL) washing organic phase, separatory is collected organic phase; The anhydrous sodium sulfate drying organic phase, the evaporated under reduced pressure organic phase.Add the sodium hydroxide salify and sodium salt is carried out recrystallization, obtain the 9.59g target compound, total recovery is 58%.HPLC detection compound purity (area normalization method) is 99.88%, always mixes≤0.12%, and maximum list mixes≤0.03%, and chirality HPLC detection ee value is 100%.
Embodiment five:
In three mouthfuls of reaction flasks of 250mL, add successively 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline (14.82g, 45mmol), methylene dichloride (80mL), D-(-)-diethyl tartrate (5.57g; 27mmol), purified water (0.49g, 27mmol), titanium tetraisopropylate (5.11g, 18mmol); Refluxing and stirring 1 hour cools to 20～25 ℃, adds N; (2.91g 22.5mmol), drips in reaction flask and contains tertiary amyl hydrogen peroxide (5.51g the N-diisopropyl ethyl amine; 85%; 45mmol) and the mixing solutions of methylene dichloride (20mL), dropping time control 1.0～1.5h maintains the temperature at 20～25 ℃ and stirred 4 hours.Chirality and achirality HPLC detection reaction liquid contain 3.2% thioether, 0.2% sulfone, the sulfoxide of 95.2% enantiomeric excess 96.2% in the reaction solution.With 5% sodium hydroxide (100mL) extracted organic phase at twice, discard organic phase, with methylene dichloride (20mL) aqueous layer extracted; Discard organic phase, use Glacial acetic acid min. 99.5 water transfer pH value of solution value to be 7-8, with methylene dichloride (200mL) aqueous phase extracted at twice; Saturated sodium-chloride water solution (20mL) washing organic phase, separatory is collected organic phase; The anhydrous sodium sulfate drying organic phase, the evaporated under reduced pressure organic phase.Add the sodium hydroxide salify and sodium salt is carried out recrystallization, obtain the 11.74g target compound, total recovery is 71%.HPLC detection compound purity (area normalization method) is 99.87%, always mixes≤0.13%, and maximum list mixes≤0.05%, and chirality HPLC detection ee value is 99.97%.
Embodiment six:
In three mouthfuls of reaction flasks of 250mL, add successively 5-methoxyl group-2-[[(4-methoxyl group-3,5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline (19.76g, 60mmol), toluene (80mL), D-(-)-diethyl tartrate (18.56g, 90mmol), purified water (0.54g; 30mmol), (12.79g 45mmol), stirred 1 hour down at 55 ℃ titanium tetraisopropylate; Cool to 20～25 ℃, add N, N-diisopropyl ethyl amine (4.65g; 36mmol), dropping contains tertiary amyl hydrogen peroxide (8.08g, 85% in reaction flask; 66mmol) and the mixing solutions of toluene (20mL), dropping time control 1.0～1.5h maintains the temperature at 25～30 ℃ and stirred 4 hours.Chirality and achirality HPLC detection reaction liquid contain 1.7% thioether, 0.3% sulfone, the sulfoxide of 96.5% enantiomeric excess 96.8% in the reaction solution.With 5% sodium hydroxide (100mL) extracted organic phase at twice, discard organic phase, with toluene (20mL) aqueous layer extracted; Discard organic phase, use Glacial acetic acid min. 99.5 water transfer pH value of solution value to be 7-8, with ETHYLE ACETATE (200mL) aqueous phase extracted at twice; Saturated sodium-chloride water solution (20mL) washing organic phase, separatory is collected organic phase; The anhydrous sodium sulfate drying organic phase, the evaporated under reduced pressure organic phase.Add the sodium hydroxide salify and sodium salt is carried out recrystallization, obtain the 16.09g target compound, total recovery is 73%.HPLC detection compound purity (area normalization method) is 99.90%, always mixes≤0.10%, and maximum list mixes≤0.05%, and chirality HPLC detection ee value is 99.98%.
Claims (6)
1. the preparation method of esomeprazole and sodium salt thereof; It is characterized in that: described method is with starting raw material 5-methoxyl group-2-[[(4-methoxyl group-3; 5-dimethyl--2-pyridyl) methyl] sulfenyl]-1H-benzoglyoxaline, D-(-)-diethyl tartrate, purified water, titanium tetraisopropylate add in the organic solvent and form chiral ligand down at 40-55 ℃; The cooling back adds N, the N diisopropyl ethyl amine, and drip the mixing solutions that contains tertiary amyl hydrogen peroxide and organic solvent; Insulated and stirred, what obtain contains the esomeprazole reaction solution.Through sodium hydroxide extraction, it is 7-8 that Glacial acetic acid min. 99.5 is regulated pH value of water solution, uses organic solvent extraction, drying, and evaporate to dryness, the sodium hydroxide salify also carries out recrystallization to sodium salt, promptly gets.
2. method according to claim 1 is characterized in that: HPLC detection esomeprazole sodium purity (area normalization method) is 99.80%, always mixes≤0.2%, and maximum list mixes≤0.05%, chirality HPLC detection ee value>=99.9%.
3. method according to claim 1 is characterized in that: the ratio of D-(-)-diethyl tartrate and starting raw material is 2～0.4: 1; The ratio of titanium tetraisopropylate and starting raw material is 1～0.2: 1; N, the ratio of N-diisopropyl ethyl amine and starting raw material is 2～0.2: 1; The ratio of tertiary amyl hydrogen peroxide and starting raw material is 3～0.9: 1.
4. method according to claim 1 is characterized in that: range of reaction temperature is-5 ℃～35 ℃.
5. method according to claim 1 is characterized in that: the reaction solvent classification is the preferred methylene dichloride of halogenated hydrocarbon, the inferior trichloromethane that selects; The ester class is ETHYLE ACETATE or propyl acetate; Aromatic hydrocarbons is chlorobenzene, toluene, YLENE.
6. method according to claim 1 is characterized in that: sodium salt can be replaced by sylvite or other metal-salts.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275064A (en) * | 2012-11-06 | 2013-09-04 | 寿光富康制药有限公司 | Preparation method of Esomeprazole and preparation method of Esomeprazole sodium |
| CN103739592A (en) * | 2014-01-24 | 2014-04-23 | 山东科源制药有限公司 | Method for producing esomeprazole sodium |
| CN104557867A (en) * | 2015-01-16 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of esomeprazole sodium salt |
| CN104557866A (en) * | 2015-01-16 | 2015-04-29 | 江苏中邦制药有限公司 | Method for preparing esomeprazole sodium salt from esomeprazole solution |
| CN104610226A (en) * | 2014-12-31 | 2015-05-13 | 广东东阳光药业有限公司 | Asymmetric oxidation method for dexlansoprazole |
| CN109467527A (en) * | 2017-09-07 | 2019-03-15 | 江苏奥赛康药业股份有限公司 | Tartaric acid sulfur ester and its preparation method and application |
| CN113845510A (en) * | 2020-06-27 | 2021-12-28 | 鲁南制药集团股份有限公司 | Preparation method of esomeprazole |
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| CN101429192A (en) * | 2008-08-22 | 2009-05-13 | 扬子江药业集团有限公司 | Novel method for producing chiral sulfoxide derivant |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275064A (en) * | 2012-11-06 | 2013-09-04 | 寿光富康制药有限公司 | Preparation method of Esomeprazole and preparation method of Esomeprazole sodium |
| CN103739592A (en) * | 2014-01-24 | 2014-04-23 | 山东科源制药有限公司 | Method for producing esomeprazole sodium |
| CN104610226A (en) * | 2014-12-31 | 2015-05-13 | 广东东阳光药业有限公司 | Asymmetric oxidation method for dexlansoprazole |
| CN104557867A (en) * | 2015-01-16 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of esomeprazole sodium salt |
| CN104557866A (en) * | 2015-01-16 | 2015-04-29 | 江苏中邦制药有限公司 | Method for preparing esomeprazole sodium salt from esomeprazole solution |
| CN109467527A (en) * | 2017-09-07 | 2019-03-15 | 江苏奥赛康药业股份有限公司 | Tartaric acid sulfur ester and its preparation method and application |
| CN109467527B (en) * | 2017-09-07 | 2021-04-06 | 江苏奥赛康药业有限公司 | Tartrate thioester compound and preparation method and application thereof |
| CN113845510A (en) * | 2020-06-27 | 2021-12-28 | 鲁南制药集团股份有限公司 | Preparation method of esomeprazole |
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