CN102993184A - Esomeprazole and preparation method of magnesium trihydrate of esomeprazole - Google Patents
Esomeprazole and preparation method of magnesium trihydrate of esomeprazole Download PDFInfo
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Abstract
The invention provides esomeprazole and a preparation method of magnesium trihydrate of the esomeprazole. The preparation method includes the following steps of subjecting racemization omeprazole and inorganic base to acid-base neutralization reaction in an alcoholic solution to obtain racemization omeprazole sodium salt; dissolving omeprazole sodium salt, organic metal coordination agents, chelating agents and organic base in an organic solvent for complex reaction to obtain esomeprazole complex; subjecting S-mandelic acid and the esomeprazole complex to condensation reaction to obtain an esomeprazole mandelate compound; dissolving the esomeprazole mandelate compound in an acetone solution, and performing filtering to obtain S-omeprazole-S-mandelate compound; and suspending the S-omeprazole-S-mandelate compound in a first solvent to obtain a suspension solution, and adjusting potential of hydrogen (pH) of the suspension solution to be 8-10 to obtain the esomeprazole, wherein the first solvent includes 30-32v/v% of an alkaline aqueous solution and 68-70v/v% of an organic solvent. By means of the preparation method, the technical problem that the yield and the purity of the esomeprazole in prior art are low is solved.
Description
Technical field
The present invention relates to the synthetic field of medicine, especially, relate to a kind of preparation method of esomeprazole, another aspect of the present invention also provides a kind of preparation method of esomeprazole magnesium salts trihydrate.
Background technology
Omeprazole (Omeprazole) is the development of Sweden Astra company, and first is used for clinical proton pump inhibitor in the world, is used for the treatment of the medicine of stomach ulcer, duodenal ulcer and reflux esophagitis.
The chemical structure of omeprazole is comprised of three parts, and the benzimidazole ring links to each other by the methyl sulfoxide base with pyridine ring.Owing to having chirality, the sulphur atom on the sulfoxide radicals has optical activity.Esomeprazole is the S type isomer of omeprazole, and its R configurational isomer mainly contains CYP
2C
19Metabolism, metabolism are that the speed of inactive substance is fast; And S type isomer has CYP more
3A
4Metabolism is to CYP
2C
19Dependency is little, and metabolic rate is very slow, so active medicine concentration height is and lasting in the blood plasma, the medicine interaction is little, and bioavailability and plasma concentration are high than omeprazole and R-configurational isomer, more than the Increased Plasma Half-life 2h.Therefore, the drug effect of S-configuration esomeprazole is higher and lasting than omeprazole and R-configurational isomer, and toxic side effect is low.The esomeprazole magnesium salts went on the market in Sweden in 2000, and commodity are called Nexium.
The chemical name of esomeprazole is:
(S)-and 5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline, shown in the structural formula following (I):
Method for splitting for omeprazole mainly contains following several:
A kind of is to prepare esomeprazole with the chiral column resolution of omeprazole, prepares magnesium salts and magnesium salts with sodium methylate and magnesium methylate again, has reported simultaneously two kinds of different crystal forms (P and Q crystal formation) of Esomeprazole sodium and the amorphous form of esomeprazole magnesium salts.Utilize chiral column that racemic modification is split and be suitable for analysis level, and to higher with the suitability for industrialized production scale cost, be unfavorable for suitability for industrialized production.
A kind of be omeprazole take racemization as starting raw material, use inclusion or crystallization Split Method that the raceme omeprazole is split.Preferably with the S-dinaphthol as resolution reagent, utilize that S-dinaphthol and esomprazole form SS inclusion compound (formula II) and SR inclusion compound solubleness different carry out that recrystallization realizes diastereomer separate the method for the esomprazole that then under alkaline condition, dissociates.The structural formula of SS inclusion compound enters shown in the formula II:
Yet the method has several problems, and wherein: 1) in order to obtain the esomeprazole of high-optical-purity, must use with respect to excessive (the S)-dinaphthol of omeprazole, this reagent is expensive, and cost is higher.2) used benzene kind solvent in the split process, toxicity is larger, and need to do dissolvent residual for the finished product and measure, and dissolvent residual is many.3) optical purity of formula (II) inclusion compound is lower, and enantiomeric excess value about about 90%, need to be further purified final esomeprazole greatly, and yield is low.
Summary of the invention
The object of the invention is to provide the preparation method of a kind of esomeprazole and magnesium salts trihydrate thereof, and low with the yield that solves esomeprazole in the prior art, the enantiomeric excess value of split process is lower, and purity is low, is not suitable for and industrial technical problem.
For achieving the above object, according to an aspect of the present invention, provide a kind of preparation method of esomeprazole, may further comprise the steps:
(1) racemic omeprazole, mineral alkali are carried out the acid-base neutralisation reaction in alcoholic solution and obtain the racemic omeprazole sodium salt;
(2) omeprazole sodium salt, organo-metallic coordination agent, sequestrant, organic bases are dissolved in carry out complex reaction in the organic solvent and obtain the esomeprazole complex compound;
(3) S-MA and esomeprazole complex compound carry out condensation reaction and obtain esomeprazole mandelate mixture;
(4) esomeprazole mandelate mixture is dissolved in the acetone soln filtering and obtains esomprazole-S-MA salt composite;
(5) esomprazole-S-MA salt composite is suspended in the first solvent obtains suspension, suspension is regulated pH 8 ~ 10 obtain esomeprazole, the first solvent comprises alkaline aqueous solution and the 68 ~ 70v/v% organic solvent of 30 ~ 32v/v%.
Further, the water content of racemize omeprazole sodium salt is 1.5 ~ 2% in the step 1); Alcoholic solution is Virahol and/or methyl alcohol; Mineral alkali is sodium hydroxide.
Further, organic solvent is acetone step 2); Organo-metallic coordination agent is tetrabutyl titanate, and sequestrant is the D-diethyl tartrate; Organic bases is triethylamine or diisopropyl ethyl amine.
Further, the step 5) neutral and alkali aqueous solution is the deionized water solution that contains 5w/v% sodium hydroxide; Organic solvent is methylene dichloride or chloroform, and the pH value of suspension is 8.5 ~ 8.8.
Further, the first solution also comprises the antioxidant of 1 ~ 2w/v% and the metal ion chelation agent of 1 ~ 2w/v% in the step 5).
Further, antioxidant is sodium bisulfite; Metal ion chelation agent is EDTA.
Further, also comprise the preparation method of esomeprazole magnesium salts trihydrate, may further comprise the steps:
(1) adopt esomeprazole drying in siccative to obtain the esomeprazole solid in 2 hours;
(2) esomeprazole solid, mineral alkali are carried out the acid-base neutralisation reaction in alcoholic solution and obtain the esomeprazole an alkali metal salt;
(3) the esomeprazole an alkali metal salt is washed in organic solvent obtain the higher esomeprazole sodium-salt hydrate of purity;
(4) the esomeprazole sodium-salt aqueous solution is mixed according to the 1:3 ratio with inorganic magnesium salt, filter, getting filter residue is that 30 ~ 40 ℃ of lower dryings obtained esomeprazole magnesium trihydrate in 3 hours at drying temperature.。
Further, siccative is sodium sulfate; Organic solvent is acetone or ethyl acetate, and inorganic magnesium salt is selected sal epsom or magnesium chloride, and alcoholic solution is Virahol or methyl alcohol; Mineral alkali is sodium hydroxide.
Further, the water content of esomeprazole magnesium is 6% ~ 8%, and drying temperature is 35 ℃.
The present invention has following beneficial effect:
The preparation method of esomeprazole provided by the invention and magnesium salts trihydrate, utilize Split Method, with organo-metallic coordination agent, sequestrant and racemic omeprazole form title complex, in the presence of amygdalic acid, form non-corresponding isomer mixture, utilize two kinds of diastereomers to go out esomprazole and amygdalic acid mixture in the differential liberation of organic solvent dissolution degree, and then the esomprazole that under alkaline condition, further dissociates, it is stronger to have operability, cost is lower, reaction times is short, the advantage that product is made with extra care easily, the purity of esomeprazole only can reach in 90% the situation in the prior art, chemical purity and the optical purity of the esomeprazole that obtains according to method of the present invention all can reach more than 99%, and enantiomeric excess value reaches 99.9% simultaneously.
Except purpose described above, feature and advantage, the present invention also has other purpose, feature and advantage.Below with reference to accompanying drawings, the present invention is further detailed explanation.
Description of drawings
The accompanying drawing that consists of the application's a part is used to provide a further understanding of the present invention, and illustrative examples of the present invention and explanation thereof are used for explaining the present invention, do not consist of improper restriction of the present invention.In the accompanying drawings:
Fig. 1 is the high-efficient liquid phase chromatogram of the esomeprazole sodium hydrate of the preferred embodiment of the present invention;
Fig. 2 is the high-efficient liquid phase chromatogram of the esomeprazole magnesium trihydrate of the preferred embodiment of the present invention.
Embodiment
Below in conjunction with accompanying drawing embodiments of the invention are elaborated, but the multitude of different ways that the present invention can be defined by the claims and cover is implemented.
One aspect of the present invention provides a kind of preparation method of esomeprazole, may further comprise the steps:
(1) racemic omeprazole, mineral alkali are carried out the acid-base neutralisation reaction in alcoholic solution and obtain omeprazole sodium salt;
(2) omeprazole sodium salt, organo-metallic coordination agent, sequestrant, organic bases are dissolved in organic solvent, carry out complex reaction and obtain the esomeprazole complex compound;
(3) with S-MA the esomeprazole complex compound is carried out condensation reaction and obtain esomeprazole mandelate mixture;
(4) esomeprazole mandelate mixture is dissolved in the acetone soln filtering and obtains esomprazole-S-MA salt composite;
(5) esomprazole-S-MA salt composite is suspended in the first solvent obtains suspension, regulate suspension PH and be 8 ~ 10 and obtain esomeprazole, the first solvent comprises alkaline aqueous solution and the 68 ~ 70v/v% organic solvent of 30 ~ 32v/v%.
The present invention utilizes Split Method, organo-metallic coordination agent, sequestrant and racemic omeprazole are formed title complex, in the presence of amygdalic acid, form non-enantiomer mixture, utilize two kinds of diastereomers to go out esomprazole and amygdalic acid mixture in the differential liberation of organic solvent dissolution degree, and then the esomprazole that under alkaline condition, further dissociates, it is stronger to have operability, and cost is lower, reaction times is short, the advantage that product is made with extra care easily.
Wherein select racemic omeprazole, mineral alkali to be dissolved in the step 1) and carry out the sodium salt that the acid-base neutralisation reaction obtains omeprazole in the alcoholic solution, because mineral alkali has certain solubleness in alcohol, in neutralization reaction, sodium ion in the mineral alkali has replaced the hydrogen ion in the omeprazole, form omeprazole sodium salt, sodium salt has larger activity, easily forms complex compound.
In the step (2), racemic omeprazole sodium salt is processed with organo-metallic coordination agent, sequestrant and organic bases in organic solvent; With S-MA resulting esomeprazole complex compound is processed in the step (3), obtained esomeprazole mandelate mixture.Because the mixture that esomprazole and R-omeprazole and amygdalic acid form is diastereomer, therefore have different physical propertiess, the two dissolubility difference in acetone is larger.S-configuration omeprazole-mandelate mixture solubleness is lower, can major part separate out, then can not separating out of R configuration, thus effective omeprazole with S-configuration and R configuration-mandelate mixture is separated the purity of raising S-configuration omeprazole-mandelate mixture.
In the step (5) esomprazole separated-S-MA salt composite is suspended in alkaline aqueous solution and the organic solvent, alkaline aqueous solution is to break away from amygdalic acid under alkaline condition, regulate simultaneously the pH value of the aqueous solution 8 ~ 10, so that esomprazole is free.
Further, the water content of racemize omeprazole sodium salt is 1.5 ~ 2% in the step 1); Alcoholic solution is Virahol and/or methyl alcohol, and the solubleness of omeprazole is higher; Mineral alkali is sodium hydroxide, and neutralization reaction efficient is higher, and impurity is few.Water content in the starting raw material racemic omeprazole sodium salt is larger to the effectiveness affects that splits, and can improve the fractionation efficient of racemic omeprazole sodium salt between 1.5% ~ 2% by controlling water content, improves the yield of esomeprazole complex compound.Preferably moisture content is 1.8%, and it is higher to split efficient.
Further, organic solvent is acetone step 2); Organo-metallic coordination agent is tetrabutyl titanate, and sequestrant is the D-diethyl tartrate; Organic bases is triethylamine or diisopropyl ethyl amine, and it is higher to split efficient.
Further, the step 5) neutral and alkali aqueous solution is the deionized water solution that contains 5w/v% sodium hydroxide; Organic solvent is methylene dichloride or chloroform, and the pH value of suspension is 8.5 ~ 8.8, and the yield of esomeprazole is higher.
Further, the first solution also comprises the antioxidant of 1 ~ 2w/v% and the metal ion chelation agent of 1 ~ 2w/v% in the step 5).In process that esomeprazole mandelate mixture is dissociated, select the different aqueous solution that amygdalic acid is neutralized, esomeprazole dissociates, unstable and sulfoxide radicals easily is oxidized to sulfone because esomeprazole is to acid, therefore need in the aqueous solution, need to add antioxidant, preferably use sodium bisulfite.Working concentration is at 1 ~ 2wt%, preferred 1.5wt%.For fear of the katalysis of metal ion to hydrolysis and oxidizing reaction, need to add metal chelator metal ion is carried out chelating, to eliminate its impact simultaneously.The preferred EDTA-2Na of metal ion chelation agent, concentration between 1 ~ 2wt%, preferred 1.5%.Select deionized water preparation antioxidant solution and metal ion chelation agent solution.
Another aspect of the present invention also provides a kind of preparation method of esomeprazole magnesium salts trihydrate, may further comprise the steps:
(1) adopts aforesaid esomeprazole to carry out drying and obtained the esomeprazole solid in 2 hours;
(2) esomeprazole solid, mineral alkali are carried out neutralization reaction in alcoholic solution and obtain the esomeprazole an alkali metal salt;
(3) the esomeprazole metal-salt is washed in organic solvent obtain the higher esomeprazole sodium salt of purity;
(4) above-mentioned esomeprazole sodium-salt aqueous solution is mixed according to the 1:3 ratio with inorganic magnesium salt, filtering separation is that 30 ~ 40 ℃ of lower dryings obtained esomeprazole magnesium trihydrate in 3 hours at drying temperature.
The present invention selects siccative to carry out drying esomeprazole oily matter, removes residual solvent, has improved the purity of esomeprazole.Then esomeprazole is processed with basic metal, be that the resistates in the esomeprazole is removed, thereby obtain the esomeprazole an alkali metal salt.Resulting metal-salt can wash to remove soluble impurity in organic solvent, improved the enantiomeric excess value of esomeprazole sodium salt, has guaranteed the purity of esomeprazole magnesium salts.
Further, siccative is sodium sulfate in the step (1), and drying effect is good; Inorganic magnesium salt is selected sal epsom or magnesium chloride, and the yield of esomeprazole magnesium salts is higher.Organic solvent is acetone or ethyl acetate, owing to select acetone or ethyl acetate when free esomeprazole prepares sodium salt the sodium salt of gained is washed the purifying that can realize Esomeprazole sodium, improve the optical purity of Esomeprazole sodium, further improve the optical purity of esomeprazole magnesium salts.
Further, the water content of esomeprazole magnesium is 6% ~ 8%, and drying temperature is 35 ℃, and the yield of esomeprazole magnesium trihydrate is higher.
Embodiment
The instrument that adopts in following examples and material are commercially available.
Embodiment 1
The preparation of esomeprazole:
(1) weighing methyl alcohol 5L, Virahol 8L put in the 20L reactor, drop into reactor taking by weighing 348.0g sodium hydroxide, and with the temperature regulation to 20 in the reactor ℃, mechanical stirring 0.5h obtains solution one.Solution one usefulness diatomite suction filtration is obtained filtrate, get filtrate 10L to reactor, add again the racemic omeprazole of 2kg, be spin-dried for to get white solid 45 ℃ of lower decompressions behind the mechanical stirring 2h.In the reactor that the gained white solid is housed, add 4L ethyl acetate stirring 1h, suction filtration, getting filter cake washs with the 1.6L ethyl acetate, filter cake obtains the 2.2kg water content behind 40 ℃ of forced air drying 8h be 1.5% Omeprazole Sodium white solid, the Omeprazole Sodium of 2.2kg is clayed into power, join 2.5L hexanaphthene and 193ml deionized water, suction filtration behind the continuation stirring 2h in the mixing solutions of formation, 0.5h obtains the omeprazole sodium hydrate in the air seasoning of placement stink cupboard.
The chemical formula of Omeprazole Sodium is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium.
(2) under mechanical stirring, the adding of omeprazole sodium hydrate is filled in the 100L reactor of 26L acetone, solution is the slight haze shape after reacting 3 ~ 4 minutes under 38 ℃.Add successively in order the D-diethyl tartrate of 1L, the tetrabutyl titanate of 0.9L under 38 ℃, the triethylamine that adds at last 2.5L stirs again.Then the L-amygdalic acid that adds rapidly 0.9kg, have a little faint yellow precipitation to produce, continue stirring and a large amount of white precipitates occurred in 2 hours, suction filtration obtains filter cake while hot, with filter cake 3.5L washing with acetone, obtain 1.5kg omeprazole mandelate mixture white solid at 40 ℃ of forced air drying 8h.
The chemical formula of omeprazole mandelate mixture is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline mandelate mixture.
(3) 1.5kg omeprazole mandelate mixture is added in the 20L reactor, the solution I that adding 4L prepares (solution I is for preparing 5w/v% sodium hydroxide+1.5w/v% sodium bisulfite 1.5w/v%EDTA-2Na aqueous solution with deionized water) and 8.5L methylene dichloride obtain mixed solution, mixed solution is filtered, isolate water layer and organic layer.Organic layer is extracted liquid 1 time with the extraction of 3L solution I, and extraction liquid is monitored extraction results with TLC, and DCM/MeOH=20/1 guarantees that organic layer does not contain the product spot.Water layer solution is added in the extraction liquid, regulate PH to water layer appearance precipitation (PH=8) with 20% hydrochloric acid (preparing with deionized water); Use saturated ammonium chloride solution (preparing with deionized water) instead and continue to regulate water layer to precipitation no longer occurring.With water layer dichloromethane extraction 3 times; use for the first time 10L; use for the second time 7.5L; use for the third time 5L; the organic layer that merges three extractions after 10L saturated nacl aqueous solution (preparing with deionized water) washing 1 time, carries out the esomeprazole oily matter that concentrating under reduced pressure gets 544g; chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline.
The preparation of esomeprazole sodium salt:
(taking by weighing 94gNaOH puts in the 2L three-necked bottle to add the sodium methylate/aqueous isopropanol of 1.5 equivalents (calculating according to sodium hydroxide) under the room temperature in the esomeprazole oily matter of 544g; add methyl alcohol 1.8L; Virahol 2.2L; stirring at room is to getting sodium methylate/aqueous isopropanol without sodium hydrate particle); 20 ℃ of temperature controls; mechanical stirring 2h; reaction solution is concentrated into dried; in residue, add 0.55L ethyl acetate and 1.1L sherwood oil; suction filtration behind 20 ℃ of mechanical stirring 2h of temperature control; filter cake washs at twice with 0.55L ethyl acetate and 1.1L sherwood oil; 40 ℃ of dry white solid product Esomeprazole sodiums that get; its chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium.The esomeprazole sodium salt is carried out magnetic resonance detection, and detected result is: 1H-NMR (500MHz, DMSO-d6, δ ppm): 2.23 (s, 3H), (2.24 s, 3H), 3.71 (s, 3H), (3.75 s, 3H), 4.40 (d, 1H), (4.78 d, 1H), 6.58 (dd, 1H), (7.00 d, 1H), 7.35 (d, 1H), 8.25 (s, 1H).
The preparation of esomeprazole magnesium trihydrate:
Dissolve 110gMgSO with the 750ml purified water under the room temperature
4.7H
2O drops into the 2L there-necked flask, drips the aqueous solution that 750ml contains the 150g Esomeprazole sodium under the Quick mechanical whipped state.Dropwise rear continuation stirring at room 0.5h, be warming up to 40 ℃, reaction 3h obtains esomeprazole magnesium trihydrate.Aforesaid esomeprazole magnesium suction filtration is obtained filter cake; the washing filter cake; filter cake dry 3 days of 35 ℃ of loft drier water content is 8% esomeprazole magnesium trihydrate; its chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium magnesium trihydrate.Esomeprazole magnesium trihydrate is carried out magnetic resonance detection, and detected result is: [R]
25D-138 ° of (c) 0.5in methanol), 1H NMR (500MHz, CDCl
3): δ 7.53 (1H, br s), 6.94 (1H, br s), 7.90 (1H), 4.75 (2H, m), 8.18 (1H, s), 3.69 (3H, s), 2.22 (1H, s), 3.83 (1H, s), 2.22 (1H, s).
Embodiment 2
The preparation of esomeprazole:
(1) weighing methyl alcohol 5L, Virahol 8L put in the 20L reactor, drop into reactor taking by weighing 348.0g sodium hydroxide, and with the temperature regulation to 25 of reactor ℃, mechanical stirring 0.5h obtains solution one.Solution one usefulness diatomite suction filtration is obtained filtrate, get filtrate 10L to reactor, add again the racemic omeprazole of 2kg, be spin-dried for to get white solid 45 ℃ of lower decompressions behind the mechanical stirring 2h.In the reactor that the gained white solid is housed, add 4L ethyl acetate stirring 1h, suction filtration, getting filter cake washs with the 1.6L ethyl acetate, filter cake obtains the Omeprazole Sodium white solid of 2.2kg behind 40 ℃ of forced air drying 8h, the 2.2kg Omeprazole Sodium is clayed into power, join 2.5L hexanaphthene and 193ml deionized water, continue to stir suction filtration behind the 2h in the mixing solutions of formation, to obtain water content be 1.7% omeprazole sodium hydrate placing stink cupboard air seasoning 0.5h.
The chemical formula of Omeprazole Sodium is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium.
(2) under mechanical stirring, the adding of omeprazole sodium hydrate is filled in the 100L reactor of 26L acetone, solution is the slight haze shape after reacting 3 minutes under 40 ℃.Add successively in order the D-diethyl tartrate of 1L, the tetrabutyl titanate of 0.9L under 40 ℃, the triethylamine that adds at last 2.5L stirs again.Then the L-amygdalic acid that adds rapidly 0.9kg, have a little faint yellow precipitation to produce, continue stirring and a large amount of white precipitates occurred in 2 hours, suction filtration obtains filter cake while hot, with filter cake 3.5L washing with acetone, obtain 1.5kg omeprazole mandelate mixture white solid at 40 ℃ of forced air drying 8h.
The chemical formula of omeprazole mandelate mixture is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline mandelate mixture.
(3) 1.5kg omeprazole mandelate mixture is added in the 20L reactor, the solution I that adding 4L prepares (solution I is for preparing 5% sodium hydroxide+1.5% sodium bisulfite+1.5%EDTA-2Na aqueous solution with deionized water) and 8.5L chloroform obtain mixed solution, mixed solution is filtered, isolate water layer and organic layer.Organic layer is extracted liquid 1 time with the extraction of 3L solution I, and extraction liquid is monitored extraction results with TLC, and DCM/MeOH=20/1 guarantees that organic layer does not contain the product spot.Water layer solution is added in the extraction liquid, regulate PH to precipitation (PH=8.5 ~ 8.8) just just having occurred with 20% hydrochloric acid (preparing with deionized water), and precipitation no longer disappears, use saturated ammonium chloride instead and continue to regulate water layer to precipitation no longer occurring.With water layer dichloromethane extraction 3 times; use for the first time 10L; use for the second time 7.5L; use for the third time 5L; the organic layer that merges three extractions behind the adding 200g anhydrous sodium sulfate drying 2h, carries out the esomeprazole oily matter that concentrating under reduced pressure gets 544g; chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline.
The preparation of Esomeprazole sodium:
(taking by weighing 94g NaOH puts in the 2L three-necked bottle to add the sodium methylate/aqueous isopropanol of 1.5 equivalents (calculating according to sodium hydroxide) under the room temperature in the esomeprazole oily matter of 544g; add methyl alcohol 1.8L; Virahol 2.2L; stirring at room is to getting sodium methylate/aqueous isopropanol without sodium hydrate particle); 23 ℃ of temperature controls; mechanical stirring 2h; reaction solution is concentrated into dried; in residue, add 0.55L acetone and 1.1L sherwood oil; suction filtration behind 23 ℃ of mechanical stirring 2h of temperature control; filter cake washs at twice with 0.55L ethyl acetate and 1.1L sherwood oil; 40 ℃ of dry white solid product Esomeprazole sodiums that get; its chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium.
The preparation of esomeprazole magnesium trihydrate:
Dissolve 110gMgSO with the 750ml purified water under the room temperature
4.7H
2O drops into the 2L there-necked flask, drips the aqueous solution that 750ml contains the 150g Esomeprazole sodium under the Quick mechanical whipped state.Dropwise rear continuation stirring at room 0.5h, heat up 40 ℃, reaction 3h obtains esomeprazole magnesium trihydrate.Aforesaid esomeprazole magnesium suction filtration is obtained filter cake; the washing filter cake; filter cake dry 3 days of 30 ℃ of loft drier water content is 7% esomeprazole magnesium trihydrate; its chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium magnesium trihydrate.
Embodiment 3
The preparation of esomeprazole:
(1) weighing methyl alcohol 5L, Virahol 8L put in the 20L reactor, drop into reactor taking by weighing 348.0g sodium hydroxide, and with the temperature regulation to 28 of reactor ℃, mechanical stirring 0.5h obtains solution one.Solution one usefulness diatomite suction filtration is obtained filtrate, get filtrate 10L to reactor, add again the racemic omeprazole of 2kg, be spin-dried for to get white solid 45 ℃ of lower decompressions behind the mechanical stirring 2h.In the reactor that the gained white solid is housed, add 4L ethyl acetate stirring 1h, suction filtration, getting filter cake washs with the 1.6L ethyl acetate, filter cake obtains the Omeprazole Sodium white solid of 2.2kg behind 40 ℃ of forced air drying 8h, the 2.2kg Omeprazole Sodium is clayed into power, join 2.5L hexanaphthene and 193ml deionized water, continue to stir suction filtration behind the 2h in the mixing solutions of formation, to obtain water content be 2% omeprazole sodium hydrate placing stink cupboard air seasoning 0.5h.
The chemical formula of Omeprazole Sodium is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium.
(2) under mechanical stirring, the adding of omeprazole sodium hydrate is filled in the 100L reactor of 26L acetone, solution is the slight haze shape after reacting 4 minutes under 41 ℃.Add successively in order the D-diethyl tartrate of 1L, the tetrabutyl titanate of 0.9L under 41 ℃, the triethylamine that adds at last 2.5L stirs again.Then the L-amygdalic acid that adds rapidly 0.9kg, have a little faint yellow precipitation to produce, continue stirring and a large amount of white precipitates occurred in 2 hours, suction filtration obtains filter cake while hot, with filter cake 3.5L washing with acetone, obtain 1.5kg omeprazole mandelate mixture white solid at 40 ℃ of forced air drying 8h.
The chemical formula of omeprazole mandelate mixture is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline mandelate mixture.
(3) 1.5kg omeprazole mandelate mixture is added in the 20L reactor, the solution I that adding 4L prepares (solution I is for preparing 5% sodium hydroxide+1.5% sodium bisulfite 1.5%EDTA-2Na aqueous solution with deionized water) and 8.5L methylene dichloride obtain mixed solution, mixed solution is filtered, isolate water layer and organic layer.Organic layer is extracted liquid 1 time with the extraction of 3L solution I, and extraction liquid is monitored extraction results with TLC, and DCM/MeOH=20/1 guarantees that organic layer does not contain the product spot.Water layer solution is added in the extraction liquid, and regulating PH with 20% hydrochloric acid (preparing with deionized water) is 10, and just just appearance precipitation, and precipitation no longer disappears, and uses saturated ammonium chloride instead and continues the adjusting water layer to precipitation no longer occurring.With water layer dichloromethane extraction 3 times; use for the first time 10L; use for the second time 7.5L; use for the third time 5L; the organic layer that merges three extractions after 10L saturated nacl aqueous solution (preparing with deionized water) washing 1 time, carries out concentrating under reduced pressure and gets esomeprazole oily matter; chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-the 1H-benzoglyoxaline.
The preparation of esomeprazole sodium salt:
(taking by weighing 94g NaOH puts in the 2L three-necked bottle to add the sodium methylate/aqueous isopropanol of 1.5 equivalents (calculating according to sodium hydroxide) under the room temperature in the esomeprazole oily matter; add methyl alcohol 1.8L; Virahol 2.2L; stirring at room is to getting sodium methylate/aqueous isopropanol without sodium hydrate particle); 25 ℃ of temperature controls; mechanical stirring 2h; reaction solution is concentrated into dried; in residue, add 0.55L ethyl acetate and 1.1L sherwood oil; suction filtration behind 25 ℃ of mechanical stirring 2h of temperature control; filter cake washs at twice with 0.55L ethyl acetate and 1.1L sherwood oil; 40 ℃ of dry white solid product Esomeprazole sodiums that get; its chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium.
The preparation of esomeprazole magnesium trihydrate:
Dissolve 110gMgSO with the 750ml purified water under the room temperature
4.7H
2O drops into the 2L there-necked flask, drips the aqueous solution that 750ml contains the 150g Esomeprazole sodium under the Quick mechanical whipped state.Dropwise rear continuation stirring at room 0.5h, heat up 40 ℃, reaction 3h obtains esomeprazole magnesium.Aforesaid esomeprazole magnesium suction filtration is obtained filter cake; the washing filter cake; filter cake dry 3 days of 40 ℃ of loft drier water content is 6% esomeprazole magnesium trihydrate; its chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium magnesium trihydrate.
Comparative Examples 1
The preparation of esomeprazole:
(1) weighing methyl alcohol 13L and 348.0g sodium hydroxide carry out mechanical stirring 0.5h and obtain solution one.It is 3% omeprazole that the solution of getting 10L adds the 2kg water content again and again, is spin-dried for 45 ℃ of lower decompressions behind the mechanical stirring 2h and obtains white solid.Add the 4L ethyl acetate and stir 1h in white solid, suction filtration obtains the Omeprazole Sodium white solid.
(2) under mechanical stirring, Omeprazole Sodium is added in the 26L acetone, add successively in order the D-diethyl tartrate of 1L, the tetrabutyl titanate of 0.9L, the triethylamine of 2.5L, the L-amygdalic acid of 0.9kg, stirred 2 hours, suction filtration obtains filter cake while hot, and filter cake is obtained omeprazole mandelate mixture white solid at 40 ℃ of forced air drying 8h.
(3) omeprazole mandelate mixture is added the chloroform of 4L and the mixed solution of 5% sodium hydroxide solution, mixed solution is filtered obtain filtrate, filtrate is carried out concentrating under reduced pressure get esomeprazole oily matter.
The preparation of esomeprazole magnesium trihydrate:
The magnesium methylate methanol solution Quick mechanical that adds 8% in the esomeprazole oily matter is stirred 0.5h, 40 ℃ of lower decompressions of solvent are spin-dried for, add deionized water and be warming up to 40 ℃, reaction 3h obtains esomeprazole magnesium trihydrate.Aforesaid esomeprazole magnesium is carried out suction filtration obtain filter cake; the washing filter cake; filter cake dry 3 days of 40 ℃ of loft drier water content is 6% esomeprazole magnesium trihydrate; its chemical formula is (S)-5-methoxyl group-2{[(4-methoxyl group-3,5-dimethyl-2-pyridyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium magnesium trihydrate.
Esomeprazole, esomeprazole magnesium salts, the esomeprazole magnesium trihydrate of embodiment 1 to 3 and Comparative Examples 1 are carried out quality examination, and detected result is listed in the table 1.
Adopt chiral column chromatogram detecting reactant chemical purity and optical purity, chiral purity adopts HPLC to monitor.
The quality examination of table 1 esomeprazole and salt thereof and hydrate is table as a result
As can be known from the results of Table 1, the esomeprazole of embodiment 1 ~ 3, the esomeprazole magnesium salts, its yield of esomeprazole magnesium trihydrate is apparently higher than Comparative Examples 1, the purity of the ee value of esomeprazole sodium salt and esomeprazole magnesium salts is higher simultaneously, proof is higher according to the esomeprazole productive rate that method of the present invention obtains, purity is higher, preparation method's dissolvent residual provided by the invention still less simultaneously, more be applicable to suitability for industrialized production, the esomeprazole that the method for employing Comparative Examples 1 obtains is oily matter, can't make with extra care, the enantiomeric excess value of split process is lower simultaneously, about 90%, and in most cases on free esomeprazole basis, prepare esomeprazole magnesium with the direct salify of MAGNESIUM METAL, so the optical purity of final product reduces obviously.
Fig. 1 is the high-efficient liquid phase chromatogram of the esomeprazole sodium-salt hydrate of embodiment 1, and its chromatographic data is listed in the table 2.
The HPLC of table 2 esomeprazole sodium-salt hydrate is table as a result.
| Numbering | Retention time (t) | Peak area (s) |
| 1 | 2.004 | 10.5 |
| 2 | 2.281 | 13.1 |
| 3 | 2534 | 5.9 |
| 4 | 2.651 | 6.8 |
| 5 | 2934 | 10.3 |
| 6 | 10.871 | 1.2 |
| 7 | 13.915 | 16980 |
Fig. 2 is the high-efficient liquid phase chromatogram of the esomeprazole magnesium trihydrate of embodiment 1, and its chromatographic data is listed in the table 3.
The HPLC of table 3 Esomeprazole sodium magnesium trihydrate is table as a result.
| Numbering | Retention time (t) | Peak area (s) |
| 1 | 1.889 | 12.8 |
| 2 | 2.43 | 14.9 |
| 3 | 2.613 | 9.4 |
| 4 | 2.842 | 12.1 |
| 5 | 6.806 | 3.1 |
| 6 | 7.499 | 7.9 |
| 7 | 11.499 | 6.5 |
| 8 | 14.912 | 4102.4 |
In conjunction with Fig. 1,2, comprehensively than the data results of the high performance liquid chromatography of table 2 and table 3 as can be known, the optical purity value of the esomeprazole sodium salt that makes according to the method for embodiment 1 reaches 99.99%, and the impurity of esomeprazole magnesium trihydrate obviously reduces.
The above is the preferred embodiments of the present invention only, is not limited to the present invention, and for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (9)
1. the preparation method of an esomeprazole is characterized in that, may further comprise the steps:
(1) racemic omeprazole, mineral alkali are carried out the acid-base neutralisation reaction in alcoholic solution and obtain omeprazole sodium salt;
(2) described omeprazole sodium salt, organo-metallic coordination agent, sequestrant, organic bases are dissolved in carry out complex reaction in the organic solvent and obtain the esomeprazole complex compound;
(3) S-MA and described esomeprazole complex compound carry out condensation reaction and obtain esomeprazole mandelate mixture;
(4) described esomeprazole mandelate mixture is dissolved in the acetone soln filtering and obtains esomprazole-S-MA salt composite;
(5) described esomprazole-S-MA salt composite is suspended in the first solvent obtains suspension, described suspension is regulated pH 8 ~ 10 obtain esomeprazole, described the first solvent comprises alkaline aqueous solution and the 68 ~ 70v/v% organic solvent of 30 ~ 32v/v%.
2. preparation method according to claim 1 is characterized in that, the water content of racemic omeprazole sodium salt described in the described step 1) is 1.5 ~ 2%; Described alcoholic solution is Virahol and/or methyl alcohol; Described mineral alkali is sodium hydroxide.
3. preparation method according to claim 1 is characterized in that, described step 2) described in organic solvent be acetone; Described organo-metallic coordination agent is tetrabutyl titanate, and described sequestrant is the D-diethyl tartrate; Described organic bases is triethylamine or diisopropyl ethyl amine.
4. preparation method according to claim 1 is characterized in that, alkaline aqueous solution described in the described step 5) is the deionized water solution that contains 5w/v% sodium hydroxide; Described organic solvent is methylene dichloride or chloroform, and the pH value of described suspension is 8.5 ~ 8.8.
5. preparation method according to claim 1 is characterized in that, the first solution described in the described step 5) also comprises the antioxidant of 1 ~ 2w/v% and the metal ion chelation agent of 1 ~ 2w/v%.
6. preparation method according to claim 5 is characterized in that, described antioxidant is sodium bisulfite; Described metal ion chelation agent is EDTA.
7. preparation method according to claim 1 is characterized in that, also comprises the preparation method of esomeprazole magnesium trihydrate, may further comprise the steps:
(1) adopt described esomeprazole drying in siccative to obtain the esomeprazole solid in 2 hours;
(2) described esomeprazole solid, mineral alkali are carried out the acid-base neutralisation reaction in alcoholic solution and obtain the esomeprazole an alkali metal salt;
(3) described esomeprazole metal-salt is washed in organic solvent obtain the esomeprazole sodium-salt hydrate;
(4) described esomeprazole sodium-salt aqueous solution is mixed according to the 1:3 ratio with inorganic magnesium salt, filter, getting filter residue is that 30 ~ 40 ℃ of lower dryings obtained esomeprazole magnesium trihydrate in 3 hours at drying temperature.
8. preparation method according to claim 7 is characterized in that, described siccative is sodium sulfate, described organic solvent is acetone or ethyl acetate, described inorganic magnesium salt is selected sal epsom or magnesium chloride, and described alcoholic solution is Virahol or methyl alcohol, and described mineral alkali is sodium hydroxide.
9. preparation method according to claim 7 is characterized in that, the water content of described esomeprazole magnesium is 6% ~ 8%, and described drying temperature is 35 ℃.
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| CN103288801A (en) * | 2013-06-04 | 2013-09-11 | 四川百利药业有限责任公司 | Preparation method for high-purity esomeprazole sodium |
| CN103664887A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole |
| CN103664888A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole trihydrate |
| CN104356114A (en) * | 2014-11-17 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN104610227A (en) * | 2015-01-08 | 2015-05-13 | 浙江亚太药业股份有限公司 | High-pressure hydrothermal preparation method for esomeprazole magnesium polymorphic compound |
| CN104803978A (en) * | 2015-03-19 | 2015-07-29 | 山东鲁抗立科药业有限公司 | Preparation method of esomeprazole magnesium |
| CN106928193A (en) * | 2017-03-09 | 2017-07-07 | 上海华源医药科技发展有限公司 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
| CN108409714A (en) * | 2018-03-29 | 2018-08-17 | 成都通德药业有限公司 | The preparation method of esomeprazole, esomeprazole salt and esomeprazole magnesium |
| CN111072633A (en) * | 2019-12-19 | 2020-04-28 | 山东达因海洋生物制药股份有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN112194650A (en) * | 2020-02-26 | 2021-01-08 | 南京国星生物技术研究院有限公司 | Omeprazole refining method |
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| CN103288801B (en) * | 2013-06-04 | 2016-01-20 | 四川百利药业有限责任公司 | A kind of preparation method of high-purity esomeprazole sodium |
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| CN103664887A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole |
| CN103664888A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole trihydrate |
| CN103664888B (en) * | 2013-12-18 | 2015-07-08 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole trihydrate |
| CN104356114A (en) * | 2014-11-17 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN104610227A (en) * | 2015-01-08 | 2015-05-13 | 浙江亚太药业股份有限公司 | High-pressure hydrothermal preparation method for esomeprazole magnesium polymorphic compound |
| CN104803978A (en) * | 2015-03-19 | 2015-07-29 | 山东鲁抗立科药业有限公司 | Preparation method of esomeprazole magnesium |
| CN104803978B (en) * | 2015-03-19 | 2019-06-18 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of esomeprazole magnesium |
| CN106928193A (en) * | 2017-03-09 | 2017-07-07 | 上海华源医药科技发展有限公司 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
| CN108409714A (en) * | 2018-03-29 | 2018-08-17 | 成都通德药业有限公司 | The preparation method of esomeprazole, esomeprazole salt and esomeprazole magnesium |
| CN111072633A (en) * | 2019-12-19 | 2020-04-28 | 山东达因海洋生物制药股份有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN112194650A (en) * | 2020-02-26 | 2021-01-08 | 南京国星生物技术研究院有限公司 | Omeprazole refining method |
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