A kind of preparation method of Esomeprazole sodiumTechnical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of preparation method's of Esomeprazole sodium preparation method.
Background technology
Omeprazole (Omeprazole, trade(brand)name Losec) be the development of Astra company of Sweden, first is applied to clinical proton pump inhibitor (PPI) in the world, specially treats the specifics of the ulcer of stomach ulcer, duodenal ulcer and reflux esophagitis.
Esomeprazole; chemistry 5-methoxyl group-2-by name ((S)-((4-methoxyl group-3; 5-dimethyl-2-pyridyl) methyl) sulfinyl-1 H-benzimidazole; it is the S-optically active isomer of omeprazole; be global first isomer proton pump inhibitor, suppress parietal cell proton pump by specificity and reduce gastric acid secretion.Esomeprazole sodium is the sodium salt of esomeprazole, and its structural formula is:
At present existing patent documentation discloses the method that splits acquisition enantiomorph esomprazole and salt thereof by inclusion resolution method.
WO2007/013743A1 discloses the preparation method of esomeprazole and salt thereof: under high temperature, in the mixed solvent of the molten organic solvent of water and water composition, dissolve (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol and paratartarics omeprazole, reaction under weak base exists, cooling mixed liquid is with crystallization esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol; Inclusion Complexes is suspended in water, by sodium-hydroxide treatment, extracting and separating (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-bis-phenol moieties.Esomeprazole sodium, can be by utilizing acetic acid acidifying filtrate, with organic solvent extraction and to the organic layer hydro-oxidation sodium obtaining with the crystallization of induction desired product or boil off the aqueous solution and to adding the crystallization of organic solvent with induction desired product in enriched material, make Esomeprazole sodium.
This method is prepared Esomeprazole sodium and is limited in water and carries out, separate (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol, must use extraction step, and need just can make (S)-(-)-[1,1 '-dinaphthalene]-2 through aqueous phase extracted repeatedly, this separation of 2 '-diphenylol, causes quantity of solvent excessive; Obtaining Esomeprazole sodium needs the evaporate to dryness aqueous solution to add organic solvent crystallization, and steam and remove the Heating temperature that the aqueous solution need to be higher, esomeprazole sodium water solution case of thermal instability, this process can produce a large amount of impurity; Or extraction again after acidifying, then carry out salt-forming reaction, aftertreatment is loaded down with trivial details, is unsuitable for suitability for industrialized production.Residual more (S)-(-)-[1,1 '-dinaphthalene]-2 in the method product, 2 '-diphenol, and optical purity of products is not high, and yield is low.
CN 1087739C has described a kind of preparation method of esomeprazole: inclusion resolution agent is (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol, di-phenanthrol and tartaric derivative, racemic modification omeprazole and resolving agent form Inclusion Complexes, remove (S)-(-)-[1,1 '-dinaphthalene]-2 in Inclusion Complexes, after 2 '-bis-phenol moieties, obtain esomeprazole.
The method is used benzene to make solvent, and benzene is a kind of high toxicity solvent, is not suitable for suitability for industrialized production; The optical purity that the inclusion complex obtaining is black and esomprazole is low, also needs to be further purified operation.
WO2006/094904A1 has described the preparation method of a kind of esomeprazole and magnesium salts thereof: by paratartarics omeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol and tertiary amine are at high temperature dissolved in toluene, crystallisation by cooling obtains esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol, Inclusion Complexes is again through regulating pH, extraction, concentrated (S)-(-)-[1 of removing, 1 '-dinaphthalene]-2, after 2 '-bis-phenol moieties, react with magnesium chloride brine and make esomeprazole magnesium salts.
The Inclusion Complexes color making by the method is intense violet color, and pigment is not easy to remove; The resolving agent mol ratio that reaction is used is raw material 1.5 times, and production cost is too high; The solvent that the method is used is toluene, harmful; Steam operating unit and be not suitable for use in large-scale industrialization and produce preparing in magnesium salts process to exist to extract in a large number, revolve;
CN101391993A has described the preparation method of a kind of esomeprazole and magnesium salts thereof: by paratartarics omeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol is at high temperature dissolved in toluene, after dissolving, cooling adds esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes crystal seed, continue cooling crystallization and obtain esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes.Inclusion Complexes destroys, extracts, concentrates and remove (S)-(-)-[1,1 '-dinaphthalene]-2 through potassium hydroxide again, after 2 '-bis-phenol moieties, reacts make esomeprazole magnesium salts with magnesium sulfate.
The method is being prepared esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2, in 2 '-diphenol Inclusion Complexes, use toluene, dimethylbenzene to make solvent, because temperature of reaction is high, the Inclusion Complexes color making need to, with a large amount of toluene agent washings, operate human body is poisoned greatly deeply; Prepare in magnesium salts process need repeatedly to extract, revolve steam be not suitable for use in large-scale industrialization produce.
Summary of the invention
Goal of the invention: the preparation method who the object of this invention is to provide the esomeprazole that a kind of yield is high, purity is high.
Technical scheme: the preparation method of the esomeprazole of a kind of at least 99.9%e.e optical purity provided by the invention, comprises the following steps:
(1) by omeprazole (II) and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (III) is heated to 65-75 DEG C and is dissolved in solvent orange 2 A, is cooled to 45-65 DEG C of insulation reaction under weak base exists, be cooled to 30-45 DEG C of crystallization, obtain Inclusion Complexes (IV);
(2) described Inclusion Complexes (IV) and sodium hydroxide are dissolved in organic solvent B in 10-30 DEG C, be warming up to 30-70 DEG C after insulation reaction, add organic solvent C, be cooled to 0-15 DEG C of crystallization, filter, obtain Esomeprazole sodium (I); Or by described Inclusion Complexes (IV) and sodium hydroxide in 10-30 DEG C of mixture that is dissolved in organic solvent B and organic solvent C, be warming up to 30-70 DEG C after insulation reaction, be cooled to 0-15 DEG C of crystallization, filter, obtain Esomeprazole sodium (I);
Reaction formula is as follows:
The method is by controlling the temperature of rising temperature for dissolving, insulation reaction and three processes of cooling crystallization, avoid R-omeprazole and Inclusion Complexes together to separate out, thereby obtain esomeprazole and (S)-(-)-[1 of high-optical-purity, 1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol, and the Inclusion Complexes obtaining is off-white color.
One as the preparation method of Esomeprazole sodium of the present invention is preferred, described (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (III) is (0.5-1.0) with omeprazole (II) mol ratio: 1.0, preferably, this mol ratio is (0.6-0.8): 1.0.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, solvent orange 2 A is selected from one or more the mixture in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, acetonitrile and tetrahydrofuran (THF), preferably, organic solvent is selected from one or more the mixture in methyl alcohol, ethanol, 1-propyl alcohol and 2-propyl alcohol, more preferably, organic solvent is selected from ethanol or 2-propyl alcohol.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, and described weak base is diethylamine, triethylamine, ammoniacal liquor or DIPEA, and preferably, weak base is triethylamine or ammoniacal liquor.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, and described weak base and omeprazole (II) mol ratio is (0.3-1.0): 1.0, and preferably, this mol ratio is (0.5-1.0): 1.0; Make reaction more complete.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, and the volume mass of solvent orange 2 A and omeprazole (II) is than being (2.0-10.0) mL:1.0g, and preferably, this volume mass is than being (3.0-6.0) mL:1.0g.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, in step (2), described solvent B is selected from one or more the mixture in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, acetone and methyl iso-butyl ketone (MIBK), preferably, solvent B is selected from one or more the mixture in methyl alcohol, ethanol, acetone and methyl iso-butyl ketone (MIBK), more preferably, solvent orange 2 A is selected from one or more the mixture in ethanol and acetone.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, in step (2), described solvent C is selected from one or more mixture of ethyl acetate, acetonitrile, methylene dichloride, trichloromethane and methyl tertiary butyl ether, preferably, solvent C is selected from one or more the mixture in ethyl acetate, methylene dichloride and methyl tertiary butyl ether.
Adopt the combination of solvent B and solvent C, Esomeprazole sodium is directly separated out, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol stays in solution, filters and directly obtains Esomeprazole sodium, and the product yield that obtains is high, purity is high.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, and described sodium hydroxide and Inclusion Complexes (IV) mol ratio is (1.0-1.5): 1, and preferably, this mol ratio is (1.0-1.2): 1.
Another kind as the preparation method of Esomeprazole sodium of the present invention is preferred, and the volume ratio of described solvent B and solvent C is 1.0:(0.1-2.0), preferably, this volume ratio is 1.0:(0.2-0.8).
Beneficial effect: preparation method's technological operation of Esomeprazole sodium provided by the invention is easy, and product purity is high, quality good, and yield is high, and environmental pollution is little, is applicable to suitability for industrialized production.
This invention adopts inclusion resolution method resolution of omeprazole, and by rising temperature for dissolving, insulation reaction and three control processs of cooling crystallization, obtain esomeprazole and (S)-(-)-[1 of high-optical-purity, 1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol, and the Inclusion Complexes obtaining is off-white color, and product appearance quality is good.Can ensure that reactant is fully dissolved in solvent orange 2 A due to 65-75 DEG C, 45-65 DEG C can ensure that reactant fully reacts, particularly 30-45 DEG C can either ensure esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol is separated out, can avoid again R-omeprazole, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol and Inclusion Complexes are together separated out, therefore adopt this control process, can avoid R-omeprazole and Inclusion Complexes together to separate out, thereby ensure the higher optical purity of product.
The method is B with an organic solvent, has avoided using aqueous solvent in preparation feedback system and purification system, can avoid separating on the one hand time, uses extraction step, has reduced solvent load; Avoid on the other hand the crystallization operation of the evaporate to dryness aqueous solution before, both reduced energy loss, and avoided the phenomenon of Esomeprazole sodium at aqueous solution case of thermal instability generation impurity, improved the quality of product; Meanwhile, avoided the loaded down with trivial details post-processing step of acidifying, extraction, salify.
The method is by Inclusion Complexes sodium-hydroxide treatment, by Esomeprazole sodium and (S)-(-)-[1, 1 '-dinaphthalene]-2, 2 '-diphenol separates, and adopt the combination of solvent B and solvent C, Esomeprazole sodium is directly separated out, (S)-(-)-[1, 1 '-dinaphthalene]-2, 2 '-diphenol stays in solution, filter and directly obtain Esomeprazole sodium, avoid extraction, concentrated grade is unfavorable for suitability for industrialized production and reduces the operation of quality product, from organic solvent, directly obtain product with the form of esomeprazole sodium salt, further ensure the optical purity that product is higher, solvent B and solvent C are to resolution reagent (S)-(-)-[1,1 '-dinaphthalene]-2, and 2 '-diphenol all has good solvability, effectively reduces the residual quantity of resolution reagent, and in product, its content is lower than 0.1%.
The Esomeprazole sodium optical purity that the present invention prepares is greater than 99.9%e.e; Filtrate can recycle through simple process, as adds water induction (S)-(-)-[1,1 '-dinaphthalene]-2, and 2 '-diphenol crystallization, filters and can be recycled, and has reduced cost, has reduced environmental pollution.
Embodiment
According to following embodiment, the present invention may be better understood.But, those skilled in the art will readily understand, the described concrete material proportion of embodiment, processing condition and result thereof be only for the present invention is described, and should also can not limit the present invention described in detail in claims.
Embodiment 1 prepares esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes (IV).
In the reactor of 20L, add paratartarics omeprazole 3.0kg(8.685mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 1.492kg(5.211mol), triethylamine 0.879kg(8.685mol) and dehydrated alcohol 12L, be heated to 75 DEG C of insulations and dissolve, dissolve rear 60 DEG C of insulated and stirred 2h; Be cooled to 30 DEG C of crystallizatioies, by the solid filtering suspending, filter cake obtains off-white color solid 2.442kg by 6L washing with alcohol and after 50 DEG C of vacuum-drying.Yield: 89%, HPLC purity (normalization method): 98.69%, optical purity (e.e%): 99.43%.
Embodiment 2 prepares esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes (IV).
In the reactor of 50L, add paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 2.488kg(8.685mol), triethylamine 1.465kg(14.475mol) and 2-propyl alcohol 25L, be heated to 70 DEG C of insulations and dissolve, dissolve rear 55 DEG C of insulated and stirred 3h; Be cooled to 35 DEG C of crystallizatioies, by the solid filtering suspending, filter cake is with 2-propyl alcohol 10L washing and after 50 DEG C of vacuum-drying, obtain off-white color solid 4.001kg.Yield: 87.5%, HPLC purity (normalization method): 98.34%, optical purity (e.e.%): 99.55%.
Embodiment 3
In the reactor of 50L, add paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 2.07kg(7.2375mol), diethylamine 4.3425mol and methyl alcohol 15L, be heated to 65 DEG C of insulations and dissolve, dissolve rear 50 DEG C of insulated and stirred 2h; Be cooled to 40 DEG C of crystallizatioies, by the solid filtering suspending, filter cake is with methyl alcohol 10L washing and after 50 DEG C of vacuum-drying, obtain off-white color solid 4.0kg.Yield: 87.9%, HPLC purity (normalization method): 98.36%, optical purity (e.e%): 99.32%.
Embodiment 4
In the reactor of 50L, add paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 4.144kg(14.475mol), containing ammoniacal liquor and the 1-propyl alcohol 30L of NH314.475mol, be heated to 70 DEG C of insulations and dissolve, dissolve rear 65 DEG C of insulated and stirred 2h; Be cooled to 45 DEG C of crystallizatioies, by the solid filtering suspending, filter cake is with 1-propyl alcohol 15L washing and after 50 DEG C of vacuum-drying, obtain off-white color solid 3.9kg.Yield: 85.7%, HPLC purity (normalization method): 98.19%, optical purity (e.e%): 99.17%.
Embodiment 5
In the reactor of 50L, add paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 2.491kg(8.7mol), N, N-diisopropylethylamine 14.5mol and acetonitrile 10L, be heated to 65 DEG C of insulations and dissolve, dissolve rear 45 DEG C of insulated and stirred 2h; Be cooled to 30 DEG C of crystallizatioies, by the solid filtering suspending, filter cake is with acetonitrile 20L washing and after 50 DEG C of vacuum-drying, obtain off-white color solid 3.95kg.Yield: 86.8%, HPLC purity (normalization method): 98.45%, optical purity (e.e%): 99.39%.
Embodiment 6
In the reactor of 50L, add paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 3.321kg(11.6mol), ammoniacal liquor and the N of tetrahydrofuran (THF) 30L and 11.6mol arbitrary proportion, N-diisopropylethylamine mixture, be heated to 75 DEG C of insulations and dissolve, dissolve rear 65 DEG C of insulated and stirred 2h; Be cooled to 45 DEG C of crystallizatioies, by the solid filtering suspending, filter cake is with tetrahydrofuran (THF) 20L washing and after 50 DEG C of vacuum-drying, obtain off-white color solid 3.85kg.Yield: 84.6%, HPLC purity (normalization method): 98.34%, optical purity (e.e%): 99.28%.
Embodiment 7
In the reactor of 50L, add paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 2.48kg(8.65mol), mixture, the diethylamine of 14.475mol arbitrary proportion, triethylamine, ammoniacal liquor, the NN-diisopropylethylamine mixture of methyl alcohol, ethanol, 1 propyl alcohol, 2-propyl alcohol, acetonitrile and the tetrahydrofuran (THF) of 50L arbitrary proportion, be heated to 75 DEG C of insulations and dissolve, dissolve rear 60 DEG C of insulated and stirred 2h; Be cooled to 30 DEG C of crystallizatioies, by the solid filtering suspending, filter cake washs and obtains after 50 DEG C of vacuum-drying off-white color solid 3.9kg with the mixture of methyl alcohol, ethanol, 1 propyl alcohol, 2-propyl alcohol, acetonitrile and the tetrahydrofuran (THF) of 10L arbitrary proportion.Yield: 85.7%, HPLC purity (normalization method): 98.58%, optical purity (e.e%): 99.40%.
Embodiment 8 prepares Esomeprazole sodium (I).
In the reactor of 20L, at 20 DEG C, add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 2.442kg(3.866mol) in 12.2L acetone, then add sodium hydroxide 0.233kg(5.799mol).After stirring and dissolving, add ethyl acetate 4.9L, be heated to 55 DEG C and stir 1h, be cooled to 5 DEG C, by the solid filtering suspending, filter cake obtains white solid 1.250kg with 4.9L washing with acetone and after 40 DEG C of vacuum-drying, yield: 88%, HPLC purity (normalization method): 99.98%, optical purity (e.e%): 99.96%, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol content (external standard method): 0.02%.
1H-NMR(500MHz,DMSO-d6)δ(ppm):8.22(s,1H),7.31(d,1H),6.98(s,1H),6.53(d,1H),4.55(d,1H),4.38(d,1H),3.70(s,3H),3.67(s,3H),2.19(s,3H),2.14(s,3H)。
13C-NMR(125MHz,DMSO-d6)δ(ppm):163.32,161.58,153.40,151.70,148.96,147,11,141.72,126.34,124.82,117.27,108.64,99.50,60.51,59.62,55.13,12.85,11.20。
MS(ESI+):368.1[M+H]+。
Embodiment 9: prepare Esomeprazole sodium (I)
In the reactor of 50L, 25 DEG C add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in 16L methyl iso-butyl ketone (MIBK), then add sodium hydroxide 0.380kg(9.50mol).After stirring and dissolving, add ethyl acetate 8L, be heated to 60 DEG C and stir 1h, be cooled to 10 DEG C, by the solid filtering suspending, filter cake is with the washing of 16L ethyl acetate and after 40 DEG C of vacuum-drying, obtain white solid 2.141kg, yield: 92%, HPLC purity (normalization method): 99.97%, optical purity (e.e.%): 99.98%, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol content (external standard method): 0.02%.
Embodiment 10 prepares Esomeprazole sodium (I).
In the reactor of 50L, 10 DEG C add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in 20L methyl alcohol, then add sodium hydroxide 0.254kg(6.35mol).After stirring and dissolving, add acetonitrile 8L, be heated to 40 DEG C and stir 1h, be cooled to 0 DEG C, by the solid filtering suspending, filter cake obtains white solid 2.095kg by 6.4L methanol wash and after 40 DEG C of vacuum-drying, yield: 90.1%, HPLC purity (normalization method): 99.98%, optical purity (e.e.%): 99.98%, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol content (external standard method): 0.02%.
Embodiment 11 prepares Esomeprazole sodium (I).
In the reactor of 50L, 30 DEG C add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in 20L ethanol, then add sodium hydroxide 0.3048kg(7.62mol).After stirring and dissolving, add methylene dichloride 8L, be heated to 30 DEG C and stir 1h, be cooled to 15 DEG C, by the solid filtering suspending, filter cake obtains white solid 2.115kg by 1.6L washing with alcohol and after 40 DEG C of vacuum-drying, yield: 91.2%, HPLC purity (normalization method): 99.96%, optical purity (e.e.%): 99.97%, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol content (external standard method): 0.02%.
Embodiment 12 prepares Esomeprazole sodium (I).
In the reactor of 50L, 15 DEG C add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in 20L1-propyl alcohol, then add sodium hydroxide 0.381kg(9.525mol).After stirring and dissolving, add trichloromethane 8L, be heated to 70 DEG C and stir 1h, be cooled to 10 DEG C, by the solid filtering suspending, filter cake is with the washing of 0.8L1-propyl alcohol and after 40 DEG C of vacuum-drying, obtain white solid 2.085kg, yield: 89.7%, HPLC purity (normalization method): 99.97%, optical purity (e.e%): 99.98%, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol content (external standard method): 0.02%.
Embodiment 13
The preparation method of the present embodiment is substantially the same manner as Example 9, and difference is only: 2-propyl alcohol is as solvent B, and methyl tertiary butyl ether is as solvent C.
Embodiment 14
The preparation method of the present embodiment is substantially the same manner as Example 9, difference is only: the mixture of methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, acetone and the methyl iso-butyl ketone (MIBK) of arbitrary proportion is as solvent B, and the mixture of the ethyl acetate of arbitrary proportion, acetonitrile, methylene dichloride, trichloromethane and methyl tertiary butyl ether is as solvent C.
Comparative example 1: prepare esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes (III).
In the there-necked flask of 5L, by 49.6g(173mmol) (S)-(-)-[1, 1 '-dinaphthalene]-2, 2 '-diphenol is dissolved in the mixing solutions of 800mL ethanol and 200mL water, be heated to 60 ~ 65 DEG C and stir and add triethylamine 29.2g(289mmol) and paratartarics omeprazole 100.0g(289mmol), 50 ~ 55 DEG C of stirring 0.5h of temperature in keeping, reaction solution is slowly cooled to room temperature insulation reaction 12h, by the solid filtering suspending, filter cake is with 200mL85% ethanolic soln and the washing of 200mL normal hexane and after 50 DEG C of vacuum-drying, obtain white solid 27.5g, yield: 30%, HPLC purity (normalization method): 97.91%, optical purity (e.e%): 94.33%.
Comparative example 2: prepare Esomeprazole sodium (I).
In the reaction flask of 2L, under room temperature by esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 50g(79.1mmol) and 230mL isopropyl acetate, add and contain sodium hydroxide 3.8g(94.9mmol) the aqueous solution in, under room temperature, stir 30min.Organic layer is separated and further uses 120mL isopropyl acetate aqueous layer extracted, and 50 DEG C of decompressions, by water layer evaporate to dryness, join 15mL methyl iso-butyl ketone (MIBK) and 62mL acetonitrile in residue, by its stirring.By sedimentation and filtration, after 40 DEG C of vacuum-drying, obtain white solid 24.7g, yield: 85%, HPLC purity (normalization method): 97.51%, optical purity (e.e.%): 97.63%, (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol content (external standard method): 0.78%.