CN106554348A - A kind of method for preparing Levpantoprazole Sodium - Google Patents
A kind of method for preparing Levpantoprazole Sodium Download PDFInfo
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- CN106554348A CN106554348A CN201610961923.2A CN201610961923A CN106554348A CN 106554348 A CN106554348 A CN 106554348A CN 201610961923 A CN201610961923 A CN 201610961923A CN 106554348 A CN106554348 A CN 106554348A
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- C07—ORGANIC CHEMISTRY
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- 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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Abstract
The invention discloses a kind of method that asymmetric oxidation prepares Levpantoprazole Sodium, under conditions of toluene makees solvent, using brand-new feeding mode, pantoprazole thioether is generated into chiral coordination compound under D () diethyl tartrate., tetraisopropyl titanate, purified water effect, aoxidized by oxidants hydrogen peroxide diisopropylbenzene (DIPB) again, L-pantoprazole is obtained, which can obtain high-purity Levpantoprazole Sodium into salt with sodium hydroxide after primary purification.The preparation method of the present invention, impact of the moisture to reacting can be prevented effectively from, so as to be applied to large batch of industrialized production, and L-pantoprazole into before and after salt merely through a recrystallization, the chromatographic purity and optical purity of product just can reach more than 99.5%, total recovery more than 60%.Additionally, the reaction condition of the preparation method is gentle, environmental pollution is little, yield and product purity are higher, industrialized production is suitable to.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of method for preparing Levpantoprazole Sodium.
Background technology
Levpantoprazole Sodium (Levopantoprazole Sodium), chemical name (-)-(S) -5- difluoro-methoxy -2-
{ [(3,4- dimethoxy-2-pyridinyl)-methyl] sulfinyl } -1H- benzimidazole sodium, by Emcure companies of India in 2006
Year exploitation listing, trade name PanPure.S type optical isomer of the medicine for Pantoprazole Sodium, suppresses as proton pump of new generation
Agent (Proton Pump Inhibitors, PPI), which accurately acts on the core group on H+-K+-ATP enzymes, with than disappearing outward
The effect of the higher gastric acid secretion inhibiting of rotation body Pantoprazole Sodium and R type isomers, damages in the stomach of clinically various patterns for the treatment of
Evil aspect, patient are taken Levpantoprazole Sodium with the dosage of racemic modification 50% and will reach effect equal therewith.Such
Drug half-life is longer, does not induce or suppress the activity of liver cell pigment P450 enzymes, does not affect the metabolism of other medicines, liver, kidney
Functional defect person and gerontal patient need not adjust dosage when using, and safety range is wide.Its structural formula is as follows：
At present, the method for preparing Levpantoprazole Sodium of document report mainly has two classes：One class is to adopt chiral reagent
The method of fractionation is split to racemic modification, and the method material loss is big, and yield is low, and split process is loaded down with trivial details, is not suitable for work
Industry metaplasia is produced；Another kind of is by the way of asymmetric oxidation, i.e., with 5- (difluoro-methoxy) -2- { [(3,4- dimethoxy -2-
Pyridine radicals) methyl] sulfur -1H- benzimidazoles be raw material, at chiral induction thing (such as chiral Ti tartrate, chiral zirconium complex etc.)
In the presence of, carrying out asymmetric oxidation and prepare L-pantoprazole, L-pantoprazole obtains a left side again with sodium hydroxide solution into salt
Rotation Pantoprazole Sodium, the method have certain advantage in terms of operability and yield compared with Split Method, are widely used.
Patent CN102863426A to disclose carry out chiral oxidization using improved sharpless reagents and prepare left-handed dissolves support
The method for drawing azoles, its step is：By 5- (difluoro-methoxy) -2- { [(3,4- dimethoxy-2-pyridinyls) methyl] sulfur } -1H-
Benzimidazole and the first organic solvent, water, D- (-)-diethyl tartrate., tetraisopropyl titanate complexation at high temperature, then at low
Oxidation reaction is carried out under the conditions of temperature, after completion of the reaction with ammonia into salt extraction, glacial acetic acid adjusts pH, and the second organic solvent is extracted,
Concentrating under reduced pressure, plus diisopropyl ether disperses to obtain L-pantoprazole fine work, fine work obtains Levpantoprazole Sodium with sodium hydroxide into salt.
The technique is when complex reaction is carried out by D- (-)-diethyl tartrate., tetraisopropyl titanate, water while adding, then heating life
Into chiral complex.Tetraisopropyl titanate and water directly contact are easily caused tetraisopropyl titanate hydrolysis, cause chirality by the method
Complex content is reduced, so as to further cause big content of starting materials to have neither part nor lot in reaction, when batch amplifies, with the increasing of water input amount
Plus, the destructive effect of tetraisopropyl titanate is further obvious, therefore, the technique is not suitable for large batch of industrialized production.Additionally,
A large amount of ammonia extractive reaction liquid used in last handling process, zest are larger, are unfavorable for labor protection.
Patent CN103992306A discloses to prepare using the route similar to patent CN102863426A left-handed dissolves Tuo La
Azoles, but product is not required to through post processing and refined, directly plus the aqueous isopropanol of Feldalat NM carries out into salt, what is obtained left-handed dissolves support
Azoles sodium crude product is drawn to be refined with acetone again.The technological operation is convenient, but there is certain risk, L-pantoprazole peroxide
Metaplasia into impurity sulfone it is similar to the polarity of product, once be just very difficult to remove into salt.The patent only has optical purity data, and
Chemical purity is not reported.
Patent CN103804355A is disclosed using different feeding modes, under heating condition by 5- (difluoro-methoxy)-
2- { [(3,4- dimethoxy-2-pyridinyl) methyl] sulfur } -1H- benzimidazoles are dissolved in toluene, then add chiral tartaric acid
Temperature control is carried out oxidation reaction after being formed by diethylester, water, tetraisopropyl titanate, chiral complex at 25～35 DEG C, oxidation
Rear filtering reacting liquid is finished, filter cake is washed with methyl tertiary butyl ether(MTBE) beating, obtains L-pantoprazole crude product, and yield is below
68%.The technique post processing is simple, need to only filter and L-pantoprazole crude product is obtained with washing, but there is also some not
Foot：One is that its yield is low, the large-tonnage product remained in have ignored filtrate；Two is that oxidizing reaction temperature is higher, is easily caused a large amount of
Peroxidating impurity sulfone and nitrogen oxides are produced；Three is that tetraisopropyl titanate is equally added together with water by the technique, high-volume work
Industry metaplasia there may be certain risk when producing.
The content of the invention
The invention provides a kind of reaction condition is gentle, environmental pollution is little, yield and product purity are higher, be more suitable for
The method of industrial mass production Levpantoprazole Sodium.
It is an object of the invention to provide a kind of improved sharpless asymmetric oxidations prepare the side of L-pantoprazole
Method, the L-pantoprazole crude product of preparation Jing it is refined once after with sodium hydroxide into salt, obtain Levpantoprazole Sodium.
In embodiments of the invention, the invention provides a kind of preparation method of Levpantoprazole Sodium, including such as
Lower step：
(1) by pantoprazole thioether (i.e. 5- (difluoro-methoxy) -2- { [(3,4- dimethoxy-2-pyridinyls) methyl]
Sulfur } -1H- benzimidazoles), toluene, D- (-)-diethyl tartrate. mix with tetraisopropyl titanate, be warming up to 60～80 DEG C, stir
Mix reaction 20min～1h；
(2) Deca purified water in the solution obtained to step (1), completion of dropping, at 60～80 DEG C insulated and stirred 0.5～
2h；
(3) DIPEA, stirring is added to be cooled to -10～0 DEG C, Deca di-isopropylbenzene hydroperoxide, Deca
Finish rear insulated and stirred and react 10～16h, stopped reaction；
(4) extracted 1～3 time with 5～20 weight % sodium hydroxide solutions, glacial acetic acid adjusts pH, ethyl acetate extraction 1～3
Secondary, ethyl acetate layer Jing concentrating under reduced pressure, low temperature crystallize obtain L-pantoprazole crude product；
(5) L-pantoprazole crude product is dissolved in the first organic solvent under the conditions of 40～55 DEG C, is cooled to 0～30
DEG C, Deca purified water, insulated and stirred 2～7h of crystallize, sucking filtration, the mixed solvent that filter cake is first constituted with the first organic solvent and water are washed
Wash, then with the second organic solvent washing 2 times, obtain final product L-pantoprazole fine work；
(6) L-pantoprazole fine work is dissolved in into the first organic solvent, Deca sodium hydroxide solution is stirred at room temperature 10min
～1h, is cooled to -5～10 DEG C, the second organic solvent of Deca, and completion of dropping is incubated 1～4h of crystallize at -5～10 DEG C, sucking filtration,
The second organic solvent washing of filter cake, is dried, obtains Levpantoprazole Sodium.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly the heating-up temperature in (1) is 65～70 DEG C；30～45min of stirring reaction.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly D- (-)-diethyl tartrate. in (1)：The mol ratio of pantoprazole thioether is 0.5～0.8:1, preferably 0.6:1；Metatitanic acid four is different
Propyl ester：The mol ratio of pantoprazole thioether is 0.25～0.4:1, preferably 0.3:1；Toluene：The mol ratio of pantoprazole thioether is
15.0～25.0:1, preferably 18.0～22.0:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly in (2), the rate of addition of purified water is 10～40 drops/minute, and preferably 20～25 drops/minute, dropping temperature are 60～80 DEG C,
It is preferred that 65～70 DEG C；1～the 1.5h of time of insulated and stirred.Purified water：The mol ratio of pantoprazole thioether is 0.125～0.2:1,
It is preferred that 0.15：1.Preferably, D- (-)-diethyl tartrate.：Tetraisopropyl titanate：The mol ratio of purified water is 2:1:0.5.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly N in (3), N- diisopropylethylamine：The mol ratio of pantoprazole thioether is 0.2～0.5:1, preferably 0.3:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly di-isopropylbenzene hydroperoxide in (3)：The mol ratio of pantoprazole thioether is 2.5～3:1, preferably 2.7:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly in (3), the temperature of the temperature and oxidation reaction of Deca di-isopropylbenzene hydroperoxide is -10～0 DEG C, preferably -5～0 DEG C.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly the response time in (3) is 12～15h.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly 7.5～10 weight % sodium hydroxide solutions are adopted in (4).The weight ratio of sodium hydroxide solution and pantoprazole thioether is 8～
12:1, preferably 9～10:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly in (4) glacial acetic acid adjust pH to 7.0～9.0, preferably 8.0～9.0.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly in (4), ethyl acetate consumption used by extraction is 8～10:1, preferably 8.5～9:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly the first organic solvent described in (5) be acetone, the one kind in isopropanol, preferred acetone；For dissolving L-pantoprazole
First organic solvent of crude product is 1.8～2.3 with the weight ratio of pantoprazole thioether:1, preferably 2.1:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly, in (5) in the mixed solvent of the first organic solvent and water composition, the first organic solvent is 1 with the volume ratio of water:2；Mixing is molten
Agent is 0.8～2.2 with pantoprazole thioether weight ratio:1, preferably 1:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly in (5), the temperature of L-pantoprazole dissolving crude product is 40～50 DEG C.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly in (5) Deca purified water：The weight ratio of pantoprazole thioether is 4～6：1, preferably 5～5.5：1.Deca purified water and analysis
Brilliant temperature is 0～30 DEG C, preferably 20～25 DEG C.The crystallize time is 4-6h.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly the second organic solvent used in (5) be methyl tertiary butyl ether(MTBE), ethyl acetate, the one kind in dichloromethane, preferred methyl- tert
Butyl ether；Second organic solvent is 1.4～1.8 with the weight ratio of pantoprazole thioether:1, preferably 1.6:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly the first organic solvent described in (6) be acetone, the one kind in isopropanol, preferred acetone；First organic solvent：It is left-handed to dissolve support
The weight ratio for drawing azoles fine work is 1.8～2.5:1, preferably 2:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly the second organic solvent solvent described in (6) be methyl tertiary butyl ether(MTBE), ethyl acetate, the one kind in dichloromethane, preferred first
Base tertbutyl ether；Second organic solvent：The weight ratio of L-pantoprazole fine work is 8～10:1, preferably 8.8:1；Sodium hydroxide
The concentration of solution be 25～35 weight %, preferably 30 weight %；The weight ratio of sodium hydroxide solution and L-pantoprazole fine work
For 0.3～0.45:1, preferably 0.36:1.
In embodiments of the invention, the preparation method of a kind of Levpantoprazole Sodium that the present invention is provided, wherein, step
Suddenly the recrystallization temperature in (6) is -5～10 DEG C, preferably 0～5 DEG C；The crystallize time is 2～2.5h.
The Levpantoprazole Sodium preparation method of the present invention employs brand-new feeding mode, i.e., reach reaction temperature in system
Again water droplet is added in reactant liquor after degree, so as to directly generate chiral coordination compound, reduce the machine that water is contacted with tetraisopropyl titanate
Meeting, to guarantee that raw material reaction is more complete, so as to lift yield, is particularly suited for mass industrialized production.
, there is no racemization in the Levpantoprazole Sodium preparation method of the present invention, the optical purity of product is high, reaches
More than 99.8%.
The Levpantoprazole Sodium preparation method of the present invention improves labor protection using sodium hydroxide solution into salt, and
Reduce environmental pollution.
The present invention only needs a recrystallization prepare highly purified L-pantoprazole fine work, reduces recrystallization damage
Lose, improve yield.
The single impurity of the Levpantoprazole Sodium that the present invention is prepared is less than 0.3% less than 0.1%, total impurities, purity
Reach more than 99.7%.
Preparation method reaction condition of the present invention is gentle, environmental pollution is little, yield and product purity are higher, be particularly suited for
Mass industrialized production.
Specific embodiment
Below using embodiment further illustrating embodiment of the present invention, for those of ordinary skill in the art
Speech, under the teachings of the present invention, is correspondingly improved according to prior art and is replaced, and still falls within the model that the present invention is claimed
Enclose.
Embodiment 1
Toluene 1.04kg, pantoprazole thioether 200g, D- (-)-diethyl tartrate. 68g, metatitanic acid are added in reaction bulb
Four isopropyl ester 46g, finish and are warming up to 65～70 DEG C of stirring reactions 30min, are slowly added dropwise purified water 1.5g, and drop finishes, stirring reaction
1h.Reactant liquor is cooled to into 20～25 DEG C, DIPEA 20.8g is added, 30min is stirred.Solution is cooled to into -5
～0 DEG C, Deca di-isopropylbenzene hydroperoxide 288g, insulated and stirred 13h, stopped reaction.In reactant liquor respectively with 1000g, 400g,
The 7.5 weight % sodium hydroxide solutions of 400g are extracted 3 times, merge all water layers.Water layer glacial acetic acid regulation pH value to 8.5～
9.0, it is extracted with ethyl acetate 3 times, each consumption 720g, combined ethyl acetate layer, 40～45 DEG C have been evaporated to solid and have analysed
Go out, 0～5 DEG C of crystallize 2h, filter, obtain L-pantoprazole crude product.Acetone 430g is added in crude product, is warming up at 40～45 DEG C
Stirring and dissolving, solution are cooled to 20～25 DEG C, Deca purified water 1000g, insulated and stirred 4h crystallize.Sucking filtration, filter cake 200g third
Ketone-water (1:2, v/v) mixed solvent washing, sucking filtration, filter cake are washed with methyl tertiary butyl ether(MTBE) 2 times again, each 158g, solid 40
～45 DEG C of drying under reduced pressure, obtain L-pantoprazole fine work 149g, and yield is 71.6%.
L-pantoprazole fine work 149g, acetone 298g are added in reaction bulb, is stirred at room temperature, Deca sodium hydroxide solution
(be dissolved in purified water 37g by sodium hydroxide 15.6g and being made), the molten clear rear continuation stirring 20min of system, is cooled to 0～5 DEG C, drips
Methylate tertbutyl ether 1300g, 0～5 DEG C of stirring and crystallizing 2.5h after completion of dropping.Sucking filtration, filter cake methyl tertiary butyl ether(MTBE) 55g are washed
Wash, 35～40 DEG C of drying under reduced pressure obtain Levpantoprazole Sodium 138.2g, and yield is 88.0%, chromatographic purity 99.9%.
Embodiment 2
Toluene 5.2kg, pantoprazole thioether 1.0kg, D- (-)-diethyl tartrate. are added in 20L reactors
0.34kg, tetraisopropyl titanate 0.23kg, finish and are warming up to 65～70 DEG C of stirring reactions 40min, be slowly added dropwise purified water 7.4g,
Drop finishes, insulated and stirred reaction 1h.Reactant liquor is cooled to into 20～25 DEG C, DIPEA 0.1kg, stirring is added
45min.Solution is cooled to into -5～0 DEG C, Deca di-isopropylbenzene hydroperoxide 1.44kg, insulated and stirred 14h, stopped reaction.Instead
Extracted 3 times with the 7.5 weight % sodium hydroxide solutions of 5kg, 2kg, 2kg in answering liquid respectively, merge all water layers.Water layer ice vinegar
Acid for adjusting pH value is extracted with ethyl acetate 3 times to 8.5～9.0, each consumption 3.6kg, combined ethyl acetate layer, 40～45 DEG C
It has been evaporated to solid to separate out, 0～5 DEG C of crystallize 3h, has filtered, obtain L-pantoprazole crude product.Acetone is added in crude product
2.1kg, is warming up to stirring and dissolving at 40～45 DEG C, and solution is cooled to 20～25 DEG C, Deca purified water 5kg, the analysis of insulated and stirred 4h
It is brilliant.Sucking filtration, filter cake 1kg acetone-waters (1:2, v/v) mixed solvent washing, sucking filtration, filter cake are washed with methyl tertiary butyl ether(MTBE) again
2 times, each 0.8kg, 40～45 DEG C of drying under reduced pressure of solid obtain L-pantoprazole fine work 0.72kg, and yield is 69.2%.
L-pantoprazole fine work 0.72kg, acetone 1.44kg are added in reactor, is stirred at room temperature, Deca sodium hydroxide is molten
Liquid (is dissolved in purified water 0.18kg by sodium hydroxide 0.075kg and being made), system it is molten it is clear after continue stirring 30min, be cooled to 0～
5 DEG C, Deca methyl tertiary butyl ether(MTBE) 6.3kg, 0～5 DEG C of stirring and crystallizing 3h after completion of dropping.Sucking filtration, filter cake methyl tertiary butyl ether(MTBE)
0.27kg is washed, and 35～40 DEG C of drying under reduced pressure obtain Levpantoprazole Sodium 0.66kg, and yield is 86.8%, chromatographic purity
99.7%, optical purity 99.9%.
Embodiment 3
Toluene 15.6kg, pantoprazole thioether 3.0kg, D- (-)-diethyl tartrate. are added in 50L reactors
1.02kg, tetraisopropyl titanate 0.69kg, finish and are warming up to 65～70 DEG C of stirring reactions 40min, be slowly added dropwise purified water
22.2g, drop finish, stirring reaction 1h.Reactant liquor is cooled to into 15～20 DEG C, DIPEA 0.31kg, stirring is added
45min.Solution is cooled to into -5～0 DEG C, Deca di-isopropylbenzene hydroperoxide 4.32kg, insulated and stirred 14h, stopped reaction.Instead
Extracted 3 times with the 7.5 weight % sodium hydroxide solutions of 15kg, 6kg, 6kg in answering liquid respectively, merge all water layers.Water layer ice
Vinegar acid for adjusting pH value is extracted with ethyl acetate 3 times to 8.0～8.5, each consumption 10.8kg, combined ethyl acetate layer, and 40～45
DEG C being evaporated to solid separates out, 0～5 DEG C of crystallize 4h, filters, obtains L-pantoprazole crude product.Acetone is added in crude product
6.3kg, is warming up to stirring and dissolving at 45～50 DEG C, and solution is cooled to 20～25 DEG C, Deca purified water 15kg, the analysis of insulated and stirred 4h
It is brilliant.Sucking filtration, filter cake 3kg acetone-waters (1:2, v/v) mixed solvent washing, sucking filtration, filter cake are washed with methyl tertiary butyl ether(MTBE) again
2 times, each 2.4kg, 40～45 DEG C of drying under reduced pressure of solid obtain L-pantoprazole fine work 2.28kg, and yield is 72.8%.
L-pantoprazole fine work 2.28kg, acetone 4.56kg are added in reactor, is stirred at room temperature, Deca sodium hydroxide is molten
Liquid (is dissolved in purified water 0.57kg by sodium hydroxide 0.25kg and being made), the molten clear rear continuation stirring 30min of system, is cooled to 0～5
DEG C, Deca methyl tertiary butyl ether(MTBE) 20kg, 0～5 DEG C of stirring and crystallizing 3h after completion of dropping.Sucking filtration, filter cake methyl tertiary butyl ether(MTBE)
0.84kg is washed, and 35～40 DEG C of drying under reduced pressure obtain Levpantoprazole Sodium 2.21kg, and yield is 92.1%, chromatographic purity
99.7%, optical purity 99.9%.
Embodiment 4
Toluene 41.6kg, pantoprazole thioether 8.0kg, D- (-)-diethyl tartrate. are added in 100L reactors
2.72kg, tetraisopropyl titanate 1.84kg, finish and are warming up to 65～70 DEG C of stirring reactions 45min, be slowly added dropwise purified water
59.2g, drop finish, stirring reaction 1.5h.Reactant liquor is cooled to into 20～25 DEG C, DIPEA 0.83kg is added, is stirred
Mix 45min.Solution is cooled to into -5～0 DEG C, Deca di-isopropylbenzene hydroperoxide 11.52kg, insulated and stirred 14.5h stop anti-
Should.Extracted 3 times with the 7.5 weight % sodium hydroxide solutions of 40kg, 16kg, 16kg in reactant liquor respectively, merge all water layers.Water
Layer glacial acetic acid adjusts pH value to 8.0～8.5, is extracted with ethyl acetate 3 times, each consumption 28.8kg, combined ethyl acetate layer,
40～45 DEG C have been evaporated to solid and have separated out, 0～5 DEG C of crystallize 4h, filter, obtain L-pantoprazole crude product.Add in crude product
Enter acetone 16.8kg, be warming up to stirring and dissolving at 40～45 DEG C, solution is cooled to 20～25 DEG C, Deca purified water 40kg, be incubated
Stirring 5h crystallizes.Sucking filtration, filter cake 8kg acetone-waters (1:2, v/v) mixed solvent washing, sucking filtration, filter cake use methyl- tert fourth again
Base ether is washed 2 times, and each 6.4kg, 40～45 DEG C of drying under reduced pressure of solid obtain L-pantoprazole fine work 5.96kg, and yield is
71.4%.
L-pantoprazole fine work 5.96kg, acetone 11.92kg are added in reactor, is stirred at room temperature, Deca sodium hydroxide
Solution (is dissolved in purified water 1.49kg by sodium hydroxide 0.648kg and being made), the molten clear rear continuation stirring 30min of system, is cooled to 0
～5 DEG C, Deca methyl tertiary butyl ether(MTBE) 52.4kg, after completion of dropping at 0～5 DEG C stirring and crystallizing 4h.Sucking filtration, filter cake methyl- tert
Butyl ether 2.2kg is washed, and 35～40 DEG C of drying under reduced pressure obtain Levpantoprazole Sodium 5.15kg, and yield is 81.7%, chromatographic purity
99.8%, optical purity 99.8%.
Embodiment 5
Toluene 52kg, pantoprazole thioether 10kg, D- (-)-diethyl tartrate. 3.4kg are added in 200L reactors,
Tetraisopropyl titanate 2.3kg, finishes and is warming up to 65～70 DEG C of stirring reactions 45min, is slowly added dropwise purified water 74g, and drop finishes, stirring
Reaction 1.5h.Reactant liquor is cooled to into 20～25 DEG C, DIPEA 1.04kg is added, 45min is stirred.Solution is dropped
Extremely -5～0 DEG C of temperature, Deca di-isopropylbenzene hydroperoxide 14.4kg, insulated and stirred 14.5h, stopped reaction.Reactant liquor is used respectively
The 7.5 weight % sodium hydroxide solutions of 50kg, 20kg, 20kg are extracted 3 times, merge all water layers.Water layer adjusts pH with glacial acetic acid
It is worth to 8.0～8.5, is extracted with ethyl acetate 3 times, each consumption 36kg, combined ethyl acetate layer, 40～45 DEG C are evaporated to
There is solid to separate out, 0～5 DEG C of crystallize 3h is filtered, obtained L-pantoprazole crude product.Acetone 21kg is added in crude product, 40 are warming up to
Stirring and dissolving at～45 DEG C, solution are cooled to 20～25 DEG C, Deca purified water 50kg, insulated and stirred 4h crystallize.Sucking filtration, filter cake are used
10kg acetone-waters (1:2, v/v) mixed solvent washing, sucking filtration, filter cake are washed with methyl tertiary butyl ether(MTBE) 2 times again, each 8kg,
40～45 DEG C of drying under reduced pressure of solid, obtain L-pantoprazole fine work 7.51kg, and yield is 72.2%.
L-pantoprazole fine work 7.51kg, acetone 15kg are added in reactor, is stirred at room temperature, Deca sodium hydroxide solution
(be dissolved in purified water 1.88kg by sodium hydroxide 0.784kg and being made), the molten clear rear continuation stirring 30min of system, is cooled to 0～5
DEG C, Deca methyl tertiary butyl ether(MTBE) 66.1kg, 0～5 DEG C of stirring and crystallizing 3h after completion of dropping.Sucking filtration, filter cake methyl tertiary butyl ether(MTBE)
2.78kg is washed, and 35～40 DEG C of drying under reduced pressure obtain Levpantoprazole Sodium 6.73kg, and yield is 84.8%, and total recovery is
61.2%, chromatographic purity 99.9%, optical purity 99.9%.
Comparative example
With reference to the technique of patent CN102863426A, present inventor has performed the enlarged experiment research of 10kg, reacts to 15h
When sampling HPLC detections, still have 34.4% pantoprazole thioether to have neither part nor lot in reaction in reactant liquor, and prolongation response time raw material
Also without significant change.Abnormal reaction causes L-pantoprazole crude product purity only 76.9%, and (mainly pantoprazole thioether is residual
Stay), need to can be only achieved for exquisite 2 times purity requirement, raw material reaction is incomplete and the increase of refined number of times, finally only obtains 2.06kg
Finished product, total recovery 16.8%, chromatographic purity 99.9%, optical purity 99.9%.Although product purity is close with embodiment 5,
Yield difference is larger.
Wherein, above example and detection method involved in comparative example:
1st, detection method of the Levpantoprazole Sodium about material
Chromatographic condition and system suitability：It is filler (Agilent with octadecylsilane chemically bonded silica
μm chromatographic column of Eclipse XDB-C18,150mm × 4.6mm, 5)；Mobile phase A (takes disodium hydrogen phosphate for phosphate buffer
1.12g and sodium dihydrogen phosphate 0.18g, is dissolved in water and is diluted to 1000ml, adjusts pH value to 7.6), and Mobile phase B is acetonitrile, stream
Dynamic phase A：Mobile phase B=70:30；Flow velocity is 1.0ml/min；Detection wavelength is 292nm.Precision measures system suitability solution 20
μ l, inject chromatograph of liquid, record chromatogram.
2nd, the detection method of Levpantoprazole Sodium optical isomer
Chromatographic condition and system suitability：It is filler (Diamonsil- with octadecylsilane chemically bonded silica
C18,150mm × 4.6mm, 5 μm of chromatographic columns)；Mobile phase A (adds water molten for sodium dihydrogen phosphate-Sulfobutyl ether β _ cyclodextrin aqueous solution
Solving and being diluted to 1000ml, pH value is adjusted to 2.5), Mobile phase B is acetonitrile, mobile phase A：Mobile phase B=80:20；Flow velocity is
0.8ml/min；Detection wavelength is 292nm.Precision measures 10 μ l of system suitability solution, injects chromatograph of liquid, records chromatograph
Figure.
Claims (10)
1. a kind of preparation method of Levpantoprazole Sodium, comprises the following steps：
(1) pantoprazole thioether, toluene, D- (-)-diethyl tartrate. are mixed with tetraisopropyl titanate, is heated to 60～80
DEG C, stirring reaction 20min～1h；
(2) Deca purified water in the solution obtained to step (1), after completion of dropping, at 60～80 DEG C insulated and stirred 0.5～
2h；
(3) DIPEA, stirring is added to be cooled to -10～0 DEG C, Deca di-isopropylbenzene hydroperoxide, completion of dropping
Insulated and stirred reacts 10～16h, stopped reaction afterwards；
(4) extracted 1～3 time with 5～20 weight % sodium hydroxide solutions, glacial acetic acid adjusts pH, ethyl acetate is extracted 1～3 time；Second
Ethyl acetate layer Jing concentrating under reduced pressure, low temperature crystallize obtain L-pantoprazole crude product；
(5) L-pantoprazole crude product is dissolved in the first organic solvent under the conditions of 40～55 DEG C, is cooled to 0～30 DEG C,
Deca purified water, insulated and stirred 2～7h of crystallize, sucking filtration, the mixed solvent that filter cake is first constituted with the first organic solvent and water are washed,
Again with the second organic solvent washing 2 times, L-pantoprazole fine work is obtained final product；
(6) L-pantoprazole fine work is dissolved in into the first organic solvent, Deca sodium hydroxide solution is stirred at room temperature 10min～1h,
- 5～10 DEG C are cooled to, the second organic solvent of Deca, completion of dropping are incubated 1～4h of crystallize at -5～10 DEG C, sucking filtration, filter cake are used
Second organic solvent washing, is dried, obtains Levpantoprazole Sodium.
2. preparation method according to claim 1, wherein, the heating-up temperature in step (1) is 65～70 DEG C；Stirring reaction
Time is 30～45min；D- (-)-diethyl tartrate.：The mol ratio of pantoprazole thioether is 0.5～0.8:1, preferably 0.6:
1；Tetraisopropyl titanate：The mol ratio of pantoprazole thioether is 0.25～0.4:1, preferably 0.3:1.
3. preparation method according to claim 1, wherein, in step (2) at 65～70 DEG C Deca purified water；Insulation is stirred
The time mixed is 1～1.5h；
Purified water：The mol ratio of pantoprazole thioether is 0.125～0.2:1；Preferably, D- (-)-diethyl tartrate.：Metatitanic acid
Four isopropyl esters：The mol ratio of purified water is 2:1:0.5.
4. preparation method according to claim 1, wherein, DIPEA in step (3)：Pantoprazole thioether
Mol ratio be 0.2～0.5:1, preferably 0.3:1；Di-isopropylbenzene hydroperoxide：The mol ratio of pantoprazole thioether is 2.5～3:
1, preferably 2.7:1；
The temperature of Deca di-isopropylbenzene hydroperoxide and the temperature of reaction are -5～0 DEG C；The time of reaction is 12～15h.
5. preparation method according to claim 1, wherein, it is molten using 7.5～10 weight % sodium hydroxide in step (4)
Liquid；
Glacial acetic acid adjusts pH to 8.0～9.0.
6. preparation method according to claim 1, wherein, the first organic solvent described in step (5), step (6) is third
One kind in ketone, isopropanol, it is preferable that for acetone.
7. preparation method according to claim 1, wherein, the second organic solvent described in step (5), step (6) is first
One kind in base tertbutyl ether, ethyl acetate, dichloromethane, preferred methyl tertiary butyl ether(MTBE).
8. preparation method according to claim 1, wherein, in step (5), the temperature of dissolving crude product is 40～50 DEG C；
The temperature of Deca purified water and crystallize is 0～30 DEG C, preferably 20～25 DEG C；
Purified water：The weight ratio of pantoprazole thioether is 4～6：1, preferably 5～5.5：1；
The crystallize time is 4-6h.
9. preparation method according to claim 1, wherein, the first organic solvent in step (6)：L-pantoprazole fine work
Weight ratio be 1.8～2.5:1, preferably 2:1；
Second organic solvent：The weight ratio of L-pantoprazole fine work is 8～10:1, preferably 8.8:1.
10. preparation method according to claim 1, wherein, the recrystallization temperature of step (6) is -5～10 DEG C, preferably 0～5
℃；
The crystallize time is 2～2.5h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114230554A (en) * | 2021-12-24 | 2022-03-25 | 湖南赛隆药业有限公司 | L-pantoprazole sodium impurity and preparation method thereof |
| CN114249709A (en) * | 2021-12-24 | 2022-03-29 | 湖南赛隆药业有限公司 | L-pantoprazole sodium impurity and preparation method thereof |
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| CN102863426A (en) * | 2012-09-21 | 2013-01-09 | 湖南赛隆药业有限公司 | Improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction |
| CN103804355A (en) * | 2012-11-14 | 2014-05-21 | 陕西合成药业有限公司 | Preparation and purification method of pantoprazole optical antimer |
| CN104138357A (en) * | 2014-05-22 | 2014-11-12 | 浙江磐谷药源有限公司 | Specific L-pantoprazole sodium superfine powder lyophilized preparation and preparation method thereof |
| CN104203938A (en) * | 2012-01-21 | 2014-12-10 | 朱比兰特生命科学有限公司 | Process for the preparation of 2-pyridinylmethylsulfinyl benzimidazoles, their analogs and optically active enantiomers |
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| CN104203938A (en) * | 2012-01-21 | 2014-12-10 | 朱比兰特生命科学有限公司 | Process for the preparation of 2-pyridinylmethylsulfinyl benzimidazoles, their analogs and optically active enantiomers |
| CN102863426A (en) * | 2012-09-21 | 2013-01-09 | 湖南赛隆药业有限公司 | Improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction |
| CN103804355A (en) * | 2012-11-14 | 2014-05-21 | 陕西合成药业有限公司 | Preparation and purification method of pantoprazole optical antimer |
| CN104138357A (en) * | 2014-05-22 | 2014-11-12 | 浙江磐谷药源有限公司 | Specific L-pantoprazole sodium superfine powder lyophilized preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114230554A (en) * | 2021-12-24 | 2022-03-25 | 湖南赛隆药业有限公司 | L-pantoprazole sodium impurity and preparation method thereof |
| CN114249709A (en) * | 2021-12-24 | 2022-03-29 | 湖南赛隆药业有限公司 | L-pantoprazole sodium impurity and preparation method thereof |
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