CN102863426A - Improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction - Google Patents
Improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction Download PDFInfo
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Abstract
The invention relates to an improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction. The method mainly comprises the steps as follows: 1) carrying out complexation reaction to 5-difluoro methoxy-2-{[(3, 4-dimethoxy-2-pyridyl) methyl] sulphur} -1H-benzimidazole, a first organic solvent, water, a chiral complexometric reagent and chiral metal complex at high temperature; 2) carrying out oxidization reaction through an acid-binding agent and oxidant at low temperature; 3) separating crude product by extracting with 5-29% ammonia water, extracting with a second organic solvent, and concentrating under reduced pressure to obtain the crude product of (-)-pantoprazole. The method provided by the invention has the following beneficial effects: the products produced before and after (-)-pantoprazole is salified are only needed to be recrystallized once, and the optical purity can reach over 99.5%, and the yield can reach over 70%; and the preparation method is simple, saves the cost, is high in yield, and mild in reaction condition; and the method is an ideal line for industrially producing (-)-pantoprazole.
Description
Technical field
The invention belongs to pharmacy field, particularly improved Sharpless asymmetric epoxidation reaction prepares the method for Levpantoprazole Sodium.
Background technology
Levpantoprazole Sodium (Levpantoprazole sodium) is a kind of H (I); the K-ATP enzyme inhibitors; chemical structure is: S-(-)-5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulfinyl }-1H-benzoglyoxaline sodium salt.
The Sharpless asymmetric epoxidation reaction is lewis acid mediated with the titanic acid esters, (often is tertbutyl peroxide) take the hydrogen peroxide derivative as oxygenant, the epoxidation reaction of olefines that carries out as three-dimensional inducing ligand take ethyl tartrate.(wikipedia: http://zh.wikipedia.org/wiki/ summer Price asymmetric epoxidation reaction).
Adopt Sharpless asymmetric oxidation method to make Levpantoprazole Sodium by efficient catalytic, patent literature is as follows:
Patent CN02109182 discloses and has used sharpless reagent to carry out the preparation method that chiral oxidization prepares multiple chiral pantorazole salt, embodiment 13 discloses uses sharpless reagent to prepare the method for pantoprazole, with 5-difluoro-methoxy-[[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur]-the 1H-benzoglyoxaline is dissolved in the chloroform, add entry, (-)-diethyl tartrate and titanium isopropylate (IV), refluxed 60 minutes, add triethylamine under the room temperature, cumene peroxide, stirred 5 hours, concentrating under reduced pressure reclaims chloroform, adds the second eyeball in residuum, cooling, suction filtration, drying gets S (-) pantoprazole.The method about the description of product optical purity, does not have the record about the method for making of sodium salt yet.
Patent CN201110340811 also discloses and has used sharpless reagent to carry out the preparation method that chiral oxidization prepares Levpantoprazole Sodium, be from the different of CN02109182, after reaction finishes, filter cake washs with methyl tertiary butyl ether, white powder dissolution of solid after the washing in NaOH solution, is added carbon decoloring.Filtrate is regulated pH 9.0～10.0 with Glacial acetic acid (or hydrochloric acid), adds acetone, continues to regulate 7.5,50 ℃ of stirring and crystallizing of pH 1 hour, gets the S-pantoprazole crude product.
This patent also comprises re-crystallization step, becomes the sodium salt step.
Above-mentioned technology mainly has the following disadvantages, and the one, through repeatedly making with extra care the product that could obtain high-optical-purity, complicated operation; The 2nd, the related substance of the finished product is more; The 3rd, yield is lower, cost is high.
Summary of the invention
The invention provides a kind of and can realize that through primary purification the Levpantoprazole Sodium optical purity is more than 99%, adopt the Sharpless asymmetric epoxidation reaction to prepare the method for Levpantoprazole Sodium, the its related substances of the Levpantoprazole Sodium that the method obtains is low, and yield is higher and then cost is lower.The below describes technical scheme of the present invention in detail:
A kind of improved Sharpless asymmetric epoxidation reaction provided by the invention prepares the method for Levpantoprazole Sodium, comprise and use Sharpless reagent and 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline reaction preparation S-pantoprazole step, and salify step, wherein prepare the S-pantoprazole step and comprise:
1) 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-the 1H-benzoglyoxaline
(5-Difluoromethoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] thio) at high temperature carry out complex reaction with the first organic solvent, water, chirality complexometric reagent and chiral metal complex compound;
2) acid binding agent, the oxygenant oxidizing reaction of carrying out at low temperatures;
3) crude product separating step, this step comprises: the extraction of 1-39% ammoniacal liquor, the second organic solvent extraction, concentrating under reduced pressure obtain the S-pantoprazole crude product.
The preferred crude product separating step of the present invention is:
A. with the 2nd) reaction product that obtains of step adds ammoniacal liquor extraction 1-5 time of 5-25%, each ammonia volume is by itself and 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-weight ratio of 1H-benzoglyoxaline is 1-10:1, combining water layer;
B. in water layer, add the second organic solvent, cooling, add acid for adjusting pH to 6.0-8.0, extract 1-5 time, each the second consumption of organic solvent is 0.5-2:1 by the volume ratio of itself and ammoniacal liquor, merge organic layer, anhydrous sodium sulfate drying filters, and has been evaporated to obvious solid and has separated out,-10-5 ℃ leaves standstill, and separates out a large amount of solids;
Sharpless reagent of the present invention refers to be water, chirality complexometric reagent and chiral metal complex compound.
Acid in the b step is a kind of in phosphoric acid, hydrochloric acid, the acetic acid, preferred acetic acid.
The method for preparing Levpantoprazole Sodium of the present invention also comprises recrystallization (making with extra care) step, be with the S-pantoprazole dissolving crude product in the first crystallization solvent, the dissolving that refluxes is cooled to 0 ℃ of stirring and crystallizing, filters, and gets the S-pantoprazole highly finished product.
The step that the present invention makes sodium salt with S-pantoprazole is: the S-pantoprazole highly finished product are dissolved in the 3rd organic solvent, add sodium salt, stirring at room 2 hours, be evaporated to driedly, add the second crystallization stirring solvent and disperseed 1 hour, filter, vacuum-drying gets Levpantoprazole Sodium.
Sodium salt of the present invention is a kind of in sodium hydroxide, sodium methylate, yellow soda ash, sodium bicarbonate, the sodium hydride;
Among the present invention, the mol ratio of preferred sodium salt and S-pantoprazole is 0.8-1.2;
Among the present invention, preferred vacuum-drying refers to 30-50 ℃ of lower vacuum-drying.
Chirality complexometric reagent of the present invention is: one or more of D-(-)-diethyl tartrate, D-(-)-dimethyl tartrate or D-(-)-dipropyl tartrate, and most preferred is D-(-)-diethyl tartrate;
Chiral metal complex compound of the present invention is: one or more in Chiral Titanium system, chirality iron system, chirality manganese system, the chirality vanadium system, and most preferred is isopropyl titanate;
Oxygenant of the present invention is: one or more in di-isopropylbenzene hydroperoxide, hydrogen phosphide cumene, the acid of hydrogen peroxide cumene, the Peracetic Acid, and most preferred is hydrogen phosphide cumene;
Acid binding agent of the present invention is: N, and a kind of in N-diisopropyl ethyl amine, the triethylamine, most preferred is N, the N-diisopropyl ethyl amine.
In order better to realize purpose of the present invention, above-mentioned preferred raw material and intermediate 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is preferably:
D-(-)-diethyl tartrate and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 0.7-1.1:1, most preferably is 1:1; With the mol ratio of isopropyl titanate be 2.5-4:1; The mol ratio of water and D-(-)-diethyl tartrate is 0.1-1.0:1; Hydrogen phosphide cumene and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 0.7-1.1:1, preferred 0.9:1; N, N-diisopropyl ethyl amine and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 0.6-1.0:1, preferred 0.75:1.
Further, the temperature of complex reaction of the present invention is 40-59 ℃;
Further, the temperature of oxidizing reaction of the present invention is 0-15 ℃;
The method for preparing Levpantoprazole Sodium of the present invention, wherein,
The first organic solvent is one or more mixed solvents in methylene dichloride, toluene, the ethyl acetate, preferred toluene, and the 6-12 that its adding volume is raw materials quality is doubly;
The second organic solvent is one or more mixed solvents in hexone, ethyl acetate, methylene dichloride, acetone, the toluene;
The 3rd organic solvent is a kind of in acetone, methyl alcohol, ethanol, the methylene dichloride, particular methanol;
The first crystallization solvent is one or more mixed solvents in acetone, methyl alcohol, acetonitrile, the isopropyl ether, preferred isopropyl ether; Described isopropyl ether and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 1-15:1;
The second crystallization solvent is one or more mixed solvents in sherwood oil, normal hexane, isopropyl ether, the ether, preferred isopropyl ether, described isopropyl ether and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 1-15:1
Based on foregoing, the better method for preparing Levpantoprazole Sodium of the present invention comprises the steps:
1) 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline and methylene dichloride, water, D-(-)-diethyl tartrate and isopropyl titanate, be warming up to 45-55 ℃, stirring reaction 1 hour;
2) be cooled to 10-20 ℃, add N, the N-diisopropyl ethyl amine stirs, and drips 70% hydrogen phosphide cumene oxygenant, and after dropwising, 0-15 ℃ was reacted 2 hours;
3) with the 2nd) reaction product that obtains of step adds 12% ammoniacal liquor extraction 4 times, combining water layer;
4) add methylene dichloride in water layer, cooling adds acid for adjusting pH to 6.0-8.0, extracts 4 times, merges organic layer, and anhydrous sodium sulfate drying filters, and has been evaporated to obvious solid and has separated out, and-10-5 ℃ leaves standstill, and separates out a large amount of solids, gets the S-pantoprazole crude product;
5) with 4) step S-pantoprazole dissolving crude product is in the 100ml isopropyl ether, and the dissolving that refluxes is cooled to 0 ℃ of stirring and crystallizing, filters, and gets the S-pantoprazole highly finished product;
6) with 5) step S-pantoprazole highly finished product are dissolved in methyl alcohol, be that the mol ratio of 0.8-1.2 adds sodium hydroxide by sodium hydroxide and S-pantoprazole, stirring at room 2 hours, be evaporated to dried, with isopropyl ether dispersed with stirring 1 hour, filter, 30-50 ℃ of lower vacuum-drying gets Levpantoprazole Sodium.
Preparation method of the present invention adds the chirality complexometric reagent by changing, as changes L-(+)-diethyl tartrate into, can obtain dextral-pantoprazole sodium equally.
Beneficial effect of the present invention is, among the present invention, product is all only through a recrystallization before and after the S-pantoprazole salify, optical purity can reach more than 99.5%, yield can reach more than 70%, this preparation method is simple, save cost, productive rate is high, and reaction conditions is gentle, is the route of a desirable suitability for industrialized production Levpantoprazole Sodium.
Embodiment:
Further explain the present invention below by embodiment, but embodiment not limitation of the present invention, meet the inventive method but all belong to the scope of protection of present invention to what the present invention improved to some extent.
Embodiment 1: S-pantoprazole synthetic
39.4g(is equivalent to 0.1mol) 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline (molecular weight: 367.37) be dissolved in the 200ml toluene in 50 ℃, add successively entry 0.144ml, D-(-)-diethyl tartrate (density: 1.205g/mL, molecular weight: 206.19) 13.68ml (0.08mol) and isopropyl titanate (molecular weight 284.26, relative density 0.96) 8.0ml (0.027mol), stirring reaction 1 hour.Be cooled to 20 ℃, add N, N '-diisopropylethylamine (molecular weight: 129.24 density: 0.782) 10ml (0.06mol), stirred 15 minutes, slowly drip 70% hydrogen phosphide cumene (density 1.05g/mL, molecular weight 152.19) 14.1ml(0.1mol), 0 ℃ was reacted 2 hours.Add 12% ammoniacal liquor 160ml(molecular weight: 35.05, the about 0.9g/mL of density), fully stirred 15 minutes, minute water-yielding stratum, organic layer are again with four times (100ml * 4) of 12% ammoniacal liquor extraction, combining water layer, in water layer, add ethyl acetate 200ml, the ice-water bath cooling, ice acetic acid is regulated pH to 7.0-7.5 under the vigorous stirring, standing demix, collected organic layer, water layer are used ethyl acetate extraction four times (100ml * 4) again, merge organic layer, being evaporated to obvious solid separates out, 0 ℃ of hold over night has a large amount of solids to separate out, and adds 100ml isopropyl ether dispersed with stirring, filter, get the off-white color solid, 40 ℃ of drying under reduced pressure get the white crystalline powder S-pantoprazole, yield 68%, optical purity 97-99%.
Embodiment 2: S-pantoprazole synthetic
With 39.4g 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-the 1H-benzoglyoxaline is dissolved in the 200ml methylene dichloride in 40 ℃, add successively entry 0.144ml, D-(-)-diethyl tartrate 13.68ml and isopropyl titanate 8.0ml, stirring reaction 1 hour.Be cooled to 20 ℃, and the adding triethylamine (molecular weight: 101.19, relative density: 0.726) 6.96ml(0.05mol), stirred 15 minutes, slowly drip 70% hydrogen phosphide cumene 14.1ml, 0 ℃ was reacted 2 hours.Add 12% ammoniacal liquor 160ml, fully stirred 15 minutes, divide water-yielding stratum, with four times (100ml * 4) of 24% ammoniacal liquor extraction, combining water layer adds hexone 200ml to organic layer in water layer again, the ice-water bath cooling, ice acetic acid is regulated pH to 7.0-7.5, standing demix, collected organic layer under the vigorous stirring, water layer is again with four times (100ml * 4) of hexone extraction, merge organic layer, be evaporated to obvious solid and separated out, 0 ℃ of hold over night, there are a large amount of solids to separate out, add 100ml isopropyl ether dispersed with stirring, filter, get the off-white color solid, 40 ℃ of drying under reduced pressure, get the white crystalline powder S-pantoprazole, yield 71.7%, optical purity 97-99%.
Embodiment 3: S-pantoprazole synthetic
With 39.4g 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-the 1H-benzoglyoxaline is dissolved in the 200ml ethyl acetate in 65 ℃, add successively entry 0.145ml, D-(-)-diethyl tartrate 13.90ml and isopropyl titanate 8.0ml, stirring reaction 1 hour.Be cooled to 20 ℃, add triethylamine 6.95ml, stirred 15 minutes, slowly drip 70% hydrogen phosphide cumene 14.1ml, 0 ℃ was reacted 2 hours.Add 12% ammoniacal liquor 160ml, fully stirred 15 minutes, divide water-yielding stratum, with four times (100ml * 4) of 12% ammoniacal liquor extraction, combining water layer adds hexone 200ml to organic layer in water layer again, the ice-water bath cooling, ice acetic acid is regulated pH to 7.0-7.5, standing demix, collected organic layer under the vigorous stirring, water layer is again with four times (100ml * 4) of hexone extraction, merge organic layer, be evaporated to obvious solid and separated out, 0 ℃ of hold over night, there are a large amount of solids to separate out, add 100ml isopropyl ether dispersed with stirring, filter, get the off-white color solid, 40 ℃ of drying under reduced pressure, get the white crystalline powder S-pantoprazole, yield 72.0%, optical purity 97-99%.
Embodiment 4: S-pantoprazole refining
In 60ml acetone, the dissolving that refluxes is cooled to 0 ℃ of stirring and crystallizing, filters, and gets the S-pantoprazole highly finished product with 20g S-pantoprazole dissolving crude product, yield 70%, and the optical purity measurement result is: external standard method 99.2%, peak area normalizing are greater than 99.99%.
Embodiment 5: S-pantoprazole refining
In the 60ml acetonitrile, the dissolving that refluxes is cooled to 0 ℃ of stirring and crystallizing, filters, and gets the S-pantoprazole highly finished product with 20g S-pantoprazole dissolving crude product, yield 67%, and the optical purity measurement result is: external standard method 99.5%, peak area normalizing are greater than 99.99%.
Embodiment 6: S-pantoprazole refining
In 30ml methyl alcohol and 30ml acetone, the dissolving that refluxes is cooled to 0 ℃ of stirring and crystallizing with 20g S-pantoprazole dissolving crude product, filter, get the S-pantoprazole highly finished product, yield 74%, the optical purity measurement result is: external standard method 99.7%, peak area normalizing are greater than 99.99%.
Embodiment 7: synthetic (pilot scale) of S-pantoprazole
In reactor, add successively 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline 2.1kg, ethyl acetate 20L, be warming up to 60 ℃ of stirring and dissolving, stir lower add successively entry 20ml, D-(-)-diethyl tartrate 1.2kg and isopropyl titanate 0.54kg, stirring reaction 1 hour.Be cooled to 20 ℃, add N, N '-diisopropylethylamine 0.48kg stirred 15 minutes, slowly dripped 70% hydrogen phosphide cumene 1.15kg, and 30 ℃ were reacted 2 hours.Finish reaction.Add 12% ammoniacal liquor 12L, fully stirred 15 minutes, collect water layer, organic layer extracts four times (8L * 4) with 12% ammoniacal liquor, and combining water layer adds ethyl acetate 15L, be cooled to 0 ℃, ice acetic acid is regulated pH to 7.0-7.5, collected organic layer under the vigorous stirring, water layer merges organic layer, anhydrous sodium sulfate drying with ethyl acetate extraction four times (8L * 4), filter, 40 ℃ of filtrates have been evaporated to obvious solid and have separated out, and 0 ℃ of hold over night has a large amount of solids to separate out.With isopropyl ether 8L dispersed with stirring, filter, product must wet.40 ℃ of drying under reduced pressure 6 hours, get the S-pantoprazole elaboration, be dissolved in methyl alcohol, be that the mol ratio of 0.8-1.2 adds sodium hydroxide by sodium hydroxide and S-pantoprazole, stirring at room 2 hours is evaporated to dried, add 8L isopropyl ether dispersed with stirring 1 hour, filter, 30-50 ℃ of lower vacuum-drying gets Levpantoprazole Sodium.The optical purity measurement result is: external standard method 99.8%, peak area normalizing are greater than 99.99%.
Embodiment 8: synthetic (pilot scale) of Levpantoprazole Sodium
In reactor, add successively intermediate two 2.1kg, ethyl acetate 20L, be warming up to 60 ℃ of stirring and dissolving, stir lower add successively entry 30ml, D-(-)-diethyl tartrate 1.2kg and isopropyl titanate 0.54g, stirring reaction 1 hour.Be cooled to 20 ℃, add N, N '-diisopropylethylamine 0.48kg stirred 15 minutes, slowly dripped 70% hydrogen phosphide cumene 1.13kg, and 30 ℃ were reacted 2 hours.Finish reaction.Add 12% ammoniacal liquor 12L, fully stirred 15 minutes, collect water layer, organic layer extracts four times (8L * 4) with 12% ammoniacal liquor, and combining water layer adds ethyl acetate 15L, be cooled to 0 ℃, ice acetic acid is regulated pH to 7.0-7.5, collected organic layer under the vigorous stirring, water layer merges organic layer, anhydrous sodium sulfate drying with ethyl acetate extraction four times (8L * 4), filter, 40 ℃ of filtrates have been evaporated to obvious solid and have separated out, and 0 ℃ of hold over night has a large amount of solids to separate out.With isopropyl ether 8L dispersed with stirring, filter, product must wet.40 ℃ of drying under reduced pressure 4 hours, get the S-pantoprazole elaboration, be dissolved in methyl alcohol, be that the mol ratio of 0.8-1.2 adds sodium hydroxide by sodium hydroxide and S-pantoprazole, stirring at room 2 hours is evaporated to dried, add 8L isopropyl ether dispersed with stirring 1 hour, filter, 30-50 ℃ of lower vacuum-drying gets Levpantoprazole Sodium.The optical purity measurement result is: external standard method 99.6%, peak area normalizing are greater than 99.99%.
Embodiment 9: synthetic (pilot scale) of Levpantoprazole Sodium
In reactor, add successively 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline 2.1kg, ethyl acetate 20L, be warming up to 60 ℃ of stirring and dissolving, stir lower add successively entry 30ml, D-(-)-diethyl tartrate 1.2kg and isopropyl titanate 0.54kg, stirring reaction 1 hour.Be cooled to 20 ℃, add N, N'-diisopropylethylamine 0.48kg stirred 15 minutes, slowly dripped 70% hydrogen phosphide cumene 1.13kg, and 30 ℃ were reacted 2 hours.Finish reaction.Add 12% ammoniacal liquor 12L, fully stirred 15 minutes, collect water layer, organic layer extracts four times (8L * 4) with 12% ammoniacal liquor, and combining water layer adds ethyl acetate 15L, be cooled to 0 ℃, ice acetic acid is regulated pH to 7.0-7.5, collected organic layer under the vigorous stirring, water layer merges organic layer, anhydrous sodium sulfate drying with ethyl acetate extraction four times (8L * 4), filter, 40 ℃ of filtrates have been evaporated to obvious solid and have separated out, and 0 ℃ of hold over night has a large amount of solids to separate out.With isopropyl ether 8L dispersed with stirring, filter, product must wet.40 ℃ of drying under reduced pressure 4 hours, get the S-pantoprazole elaboration, be dissolved in methyl alcohol, be that the mol ratio of 0.8-1.2 adds sodium hydroxide by sodium hydroxide and S-pantoprazole, stirring at room 2 hours is evaporated to dried, add 8L isopropyl ether dispersed with stirring 1 hour, filter, 30-50 ℃ of lower vacuum-drying gets Levpantoprazole Sodium.The optical purity measurement result is: external standard method 99.7%, peak area normalizing are greater than 99.99%.
The above embodiment only is that preferred implementation of the present invention is described; be not that scope of the present invention is limited; design under the prerequisite of spirit not breaking away from the present invention; various distortion and improvement that those of ordinary skills make technical scheme of the present invention all should fall in the definite protection domain of claims of the present invention.
Claims (9)
1. an improved Sharpless asymmetric epoxidation reaction prepares the method for Levpantoprazole Sodium, comprise and use Sharpless reagent and 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline reaction preparation S-pantoprazole step, and salify step, described preparation S-pantoprazole step comprises:
1) 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline and the first organic solvent, water, chirality complexometric reagent and chiral metal complex compound at high temperature carry out complex reaction;
2) acid binding agent, the oxygenant oxidizing reaction of carrying out at low temperatures;
3) crude product separating step comprises:
The extraction of 1-39% ammoniacal liquor, the second organic solvent extraction, concentrating under reduced pressure obtain the S-pantoprazole crude product.
2. the method for preparing Levpantoprazole Sodium as claimed in claim 1 is characterized in that, described crude product separating step is:
A. with the 2nd) reaction product that obtains of step adds ammoniacal liquor extraction 1-5 time of 5-25%, each ammonia volume is by itself and 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-weight ratio of 1H-benzoglyoxaline is 1-10:1, combining water layer;
B. in water layer, add the second organic solvent, cooling, add acid for adjusting pH to 6.0-8.0, extract 1-5 time, each the second consumption of organic solvent is 0.5-2:1 by the volume ratio of itself and ammoniacal liquor, merge organic layer, anhydrous sodium sulfate drying filters, and has been evaporated to obvious solid and has separated out,-10-5 ℃ leaves standstill, and separates out a large amount of S-pantoprazole crude products.2, arbitrary method for preparing Levpantoprazole Sodium as claimed in claim 1 or 2 is characterized in that, also comprises re-crystallization step, that is:
In the first crystallization solvent, the dissolving that refluxes is cooled to 0 ℃ of stirring and crystallizing, filters, and gets the S-pantoprazole highly finished product with described S-pantoprazole dissolving crude product.
3. the method for preparing Levpantoprazole Sodium as claimed in claim 2 is characterized in that, described salify step is:
Described S-pantoprazole highly finished product are dissolved in the 3rd organic solvent, add sodium salt, stirring at room 2 hours is evaporated to driedly, adds the second crystallization stirring solvent and disperses 1 hour, filters, and vacuum-drying gets Levpantoprazole Sodium.
4. the preparation method of S-pantoprazole as claimed in claim 3 is characterized in that,
Described sodium salt is a kind of in sodium hydroxide, sodium methylate, yellow soda ash, sodium bicarbonate, the sodium hydride;
The mol ratio of described sodium salt and S-pantoprazole is 0.8-1.2;
Described vacuum-drying refers to 30-50 ℃ of lower vacuum-drying.
5. the method for preparing Levpantoprazole Sodium as claimed in claim 1 is characterized in that,
Described chirality complexometric reagent is: one or more of D-(-)-diethyl tartrate, D-(-)-dimethyl tartrate or D-(-)-dipropyl tartrate;
Described chiral metal complex compound is: one or more in Chiral Titanium system, chirality iron system, chirality manganese system, the chirality vanadium system;
Described oxygenant is: one or more in di-isopropylbenzene hydroperoxide, hydrogen phosphide cumene, the acid of hydrogen peroxide cumene, the Peracetic Acid;
Described acid binding agent is: N, a kind of in N-diisopropyl ethyl amine, the triethylamine.
6. the method for preparing Levpantoprazole Sodium as claimed in claim 5 is characterized in that,
Described chirality complexometric reagent is D-(-)-diethyl tartrate;
Described Chiral Titanium system is isopropyl titanate;
Described oxygenant is hydrogen phosphide cumene;
Described acid binding agent is N, the N-diisopropyl ethyl amine;
Wherein D-(-)-diethyl tartrate and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 0.7-1.1:1; With the mol ratio of isopropyl titanate be 2.5-4:1; The mol ratio of water and D-(-)-diethyl tartrate is 0.1-1.1:1; Hydrogen phosphide cumene and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 0.7-1.1:1; N, N-diisopropyl ethyl amine and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 0.6-1.0:1.
7. the method for preparing Levpantoprazole Sodium as claimed in claim 1 is characterized in that,
The temperature of described complex reaction is 40-59 ℃;
The temperature of described oxidizing reaction is 0-15 ℃.
8. the method for preparing Levpantoprazole Sodium as claimed in claim 3 is characterized in that,
Described the first organic solvent is one or more mixed solvents in methylene dichloride, toluene, the ethyl acetate;
Described the second organic solvent is one or more mixed solvents in hexone, ethyl acetate, methylene dichloride, acetone, the toluene;
Described the 3rd organic solvent is a kind of in acetone, methyl alcohol, ethanol, the methylene dichloride, particular methanol;
Described the first crystallization solvent is one or more mixed solvents in acetone, methyl alcohol, acetonitrile, the isopropyl ether, preferred isopropyl ether; Described isopropyl ether and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 1-15:1;
Described the second crystallization solvent is one or more mixed solvents in sherwood oil, normal hexane, isopropyl ether, the ether, preferred isopropyl ether, described isopropyl ether and 5-difluoro-methoxy-2-{[(3,4-dimethoxy-2-pyridinyl) methyl] sulphur }-mol ratio of 1H-benzoglyoxaline is 1-15:1.
9. the method for preparing Levpantoprazole Sodium as claimed in claim 1 is characterized in that, comprises the steps:
1) 5-difluoro-methoxy-2-{[(3, the 4-dimethoxy-2-pyridinyl) methyl] sulphur }-1H-benzoglyoxaline and methylene dichloride, water, D-(-)-diethyl tartrate and isopropyl titanate, be warming up to 45-55 ℃, stirring reaction 1 hour;
2) be cooled to 10-20 ℃, add N, the N-diisopropyl ethyl amine stirs, and drips 70% hydrogen phosphide cumene oxygenant, and after dropwising, 0-15 ℃ was reacted 2 hours;
3) with the 2nd) reaction product that obtains of step adds 12% ammoniacal liquor extraction 4 times, combining water layer;
4) add methylene dichloride in water layer, cooling adds acid for adjusting pH to 6.0-8.0, extracts 4 times, merges organic layer, and anhydrous sodium sulfate drying filters, and has been evaporated to obvious solid and has separated out, and-10-5 ℃ leaves standstill, and separates out a large amount of solids, gets the S-pantoprazole crude product;
5) with 4) step S-pantoprazole dissolving crude product is in the 100ml isopropyl ether, and the dissolving that refluxes is cooled to 0 ℃ of stirring and crystallizing, filters, and gets the S-pantoprazole highly finished product;
6) with 5) step S-pantoprazole highly finished product are dissolved in methyl alcohol, be that the mol ratio of 0.8-1.2 adds sodium hydroxide by sodium hydroxide and S-pantoprazole, stirring at room 2 hours, be evaporated to dried, with isopropyl ether dispersed with stirring 1 hour, filter, 30-50 ℃ of lower vacuum-drying gets Levpantoprazole Sodium.
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| CN103242294A (en) * | 2013-03-23 | 2013-08-14 | 广东华南药业集团有限公司 | (S)-pantoprazole sodium dihydrate and preparation method thereof |
| CN103992306A (en) * | 2014-04-23 | 2014-08-20 | 南京优科生物医药研究有限公司 | Preparing and refining method of S-pantoprazole sodium |
| CN105693694A (en) * | 2016-04-22 | 2016-06-22 | 广东华南药业集团有限公司 | Method for refining (S)-pantoprazole |
| CN105968097A (en) * | 2016-05-17 | 2016-09-28 | 杭州华东医药集团新药研究院有限公司 | Industrial production method of S-pantoprazole sodium |
| CN106554348A (en) * | 2016-11-04 | 2017-04-05 | 扬子江药业集团有限公司 | A kind of method for preparing Levpantoprazole Sodium |
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| CN106554348A (en) * | 2016-11-04 | 2017-04-05 | 扬子江药业集团有限公司 | A kind of method for preparing Levpantoprazole Sodium |
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