CN102887885A - Preparation method of esomeprazole sodium - Google Patents
Preparation method of esomeprazole sodium Download PDFInfo
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- CN102887885A CN102887885A CN2012103643140A CN201210364314A CN102887885A CN 102887885 A CN102887885 A CN 102887885A CN 2012103643140 A CN2012103643140 A CN 2012103643140A CN 201210364314 A CN201210364314 A CN 201210364314A CN 102887885 A CN102887885 A CN 102887885A
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Abstract
The invention provides a preparation method of esomeprazole sodium. The preparation method comprises steps as follows: 1, heating omeprazole and (S)-(-)-(1, 1'-dinaphthalene)-2, 2'-diphenol to reach 65-75 DEG C and dissolving into a solvent A, lowering temperature and reacting by heat preservation in the presence of weak base, and cooling and crystallizing, so as to obtain inclusion complex; and 2, heating the inclusion complex and sodium hydroxide and dissolving into an organic solvent B, and heating and reacting by heat preservation, then adding an organic solvent C, cooling to reach 0-15 DEG C to crystallize, and finally filtering, so as to obtain the esomeprazole sodium; or heating the inclusion complex and sodium hydroxide and dissolving into a mixture of the organic solvent B and the organic solvent C, and heating and reacting by heat preservation, then cooling to crystallize, and finally filtering to obtain the esomeprazole sodium. The preparation method of the esomeprazole sodium provided by the invention is simple and convenient in technology, high in purity of products, high in quality, high in yield, less in environmental pollution and suitable for industrial production.
Description
Technical field
The invention belongs to the 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) is the development of Sweden Astra company, 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-((S)-((4-methoxyl group-3 by name; 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 the 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 with the inclusion resolution method and has split the method that obtains enantiomorph esomprazole and salt thereof.
WO2007/013743A1 discloses the preparation method of esomeprazole and salt thereof: under the high temperature, dissolving (S)-(-)-[1 in the mixed solvent that the molten organic solvent of water and water form, 1 '-dinaphthalene]-2,2 '-diphenol and paratartarics omeprazole, reaction in the presence of weak base, cooling mixed liquid is with crystallization esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol; Inclusion Complexes is suspended in the water, uses sodium-hydroxide treatment, extracting and separating (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-two phenol moieties.Esomeprazole sodium, can be by utilizing acetic acid acidifying filtrate, with organic solvent extraction and to the organic layer hydro-oxidation sodium that obtains with the crystallization of inducing desired product or boil off the aqueous solution and in enriched material, add organic solvent to induce the crystallization of desired product, make Esomeprazole sodium.
This method prepares Esomeprazole sodium and is limited in the water and carries out, separate (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol, must use extraction step, and need just to 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 the 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 again extraction after the acidifying, carry out again 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: the 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, (S)-(-) in the removal Inclusion Complexes-[1,1 '-dinaphthalene]-2 obtains esomeprazole behind 2 '-two phenol moieties.
The method uses 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 resulting inclusion complex is black and esomprazole is low, also need be further purified operation.
WO2006/094904A1 has described the preparation method of a kind of esomeprazole and magnesium salts thereof: with paratartarics omeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol and tertiary amine at high temperature are dissolved in the 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, make the esomeprazole magnesium salts with the magnesium chloride brine reaction behind 2 '-two phenol moieties.
The Inclusion Complexes color that makes with the method is intense violet color, and pigment is not easy to remove; The resolving agent mol ratio that reaction is used is 1.5 times of raw material, and production cost is too high; The solvent that the method is used is toluene, and is harmful; Existence extracts in a large number, revolves the steaming operating unit and is not suitable for use in large-scale industrialization production in preparation magnesium salts process;
CN101391993A has described the preparation method of a kind of esomeprazole and magnesium salts thereof: with paratartarics omeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol at high temperature is dissolved in the toluene, cooling adds esomeprazole and (S)-(-)-[1 after the dissolving, 1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes crystal seed continues the cooling crystallization and obtains 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, makes the esomeprazole magnesium salts with the sal epsom reaction behind 2 '-two phenol moieties.
The method is at preparation esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2, use toluene, dimethylbenzene to make solvent in 2 '-diphenol Inclusion Complexes, because temperature of reaction is high, the Inclusion Complexes color that makes need to a large amount of toluene agent washings, operate human body is poisoned greatly deeply; In preparation magnesium salts process, need repeatedly to extract, revolve to steam and be not suitable for use in large-scale industrialization production.
Summary of the invention
Goal of the invention: the preparation method who the purpose 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 may further comprise the steps:
(1) with omeprazole (II) with (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (III) is heated to 65-75 ℃ and is dissolved in the solvent orange 2 A, is cooled to 45-65 ℃ of insulation reaction in the presence of weak base, be cooled to 30-45 ℃ of crystallization, get Inclusion Complexes (IV);
(2) described Inclusion Complexes (IV) and sodium hydroxide are dissolved in the organic solvent B in 10-30 ℃, be warming up to 30-70 ℃ after insulation reaction, add organic solvent C, be cooled to 0-15 ℃ of crystallization, filter, namely get Esomeprazole sodium (I); Or with described Inclusion Complexes (IV) and sodium hydroxide in 10-30 ℃ of mixture that is dissolved in organic solvent B and organic solvent C, be warming up to 30-70 ℃ after insulation reaction, be cooled to 0-15 ℃ of crystallization, filter, namely get Esomeprazole sodium (I);
Reaction formula is as follows:
The method is by the temperature of control rising temperature for dissolving, insulation reaction and three processes of cooling crystallization, avoided R-omeprazole and Inclusion Complexes together to separate out, thereby obtain the esomeprazole of high-optical-purity and (S)-(-)-[1,1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol, and resulting Inclusion Complexes is off-white color.
A kind of preferred as the preparation method of Esomeprazole sodium of the present invention, 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 of preferred as the preparation method of Esomeprazole sodium of the present invention, solvent orange 2 A is selected from one or more the mixture in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, acetonitrile and the tetrahydrofuran (THF), preferably, organic solvent is selected from one or more the mixture in methyl alcohol, ethanol, 1-propyl alcohol and the 2-propyl alcohol, more preferably, organic solvent is selected from ethanol or 2-propyl alcohol.
Another kind of preferred as the preparation method of Esomeprazole sodium of the present invention, described weak base is diethylamine, triethylamine, ammoniacal liquor or DIPEA, preferably, weak base is triethylamine or ammoniacal liquor.
Another kind of preferred as the preparation method of Esomeprazole sodium of the present invention, described weak base and omeprazole (II) mol ratio is (0.3-1.0): 1.0, preferably, this mol ratio is (0.5-1.0): 1.0; Make reaction more complete.
Another kind of preferred as the preparation method of Esomeprazole sodium of the present invention, the volume mass of solvent orange 2 A and omeprazole (II) is than being (2.0-10.0) mL:1.0g, preferably, this volume mass is than being (3.0-6.0) mL:1.0g.
Another kind of preferred as the preparation method of Esomeprazole sodium of the present invention, in the 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 the methyl iso-butyl ketone (MIBK), preferably, solvent B is selected from one or more the mixture in methyl alcohol, ethanol, acetone and the methyl iso-butyl ketone (MIBK), more preferably, solvent orange 2 A is selected from one or more the mixture in ethanol and the acetone.
Another kind of preferred as the preparation method of Esomeprazole sodium of the present invention, in the 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 the 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 directly to obtain Esomeprazole sodium, and the product yield that obtains is high, purity is high.
Another kind of preferred as the preparation method of Esomeprazole sodium of the present invention, described sodium hydroxide and Inclusion Complexes (IV) mol ratio is (1.0-1.5): 1, preferably, this mol ratio is (1.0-1.2): 1.
Another kind of preferred as the preparation method of Esomeprazole sodium of the present invention, 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 is good, and yield is high, and environmental pollution is little, is fit to suitability for industrialized production.
Inclusion resolution method resolution of omeprazole is adopted in this invention, and by rising temperature for dissolving, insulation reaction and three control processs of cooling crystallization, obtain the esomeprazole of high-optical-purity and (S)-(-)-[1,1 '-dinaphthalene]-2, the Inclusion Complexes of 2 '-diphenol, and resulting Inclusion Complexes is off-white color, and the product appearance quality is good.Because 65-75 ℃ can guarantee that reactant fully is dissolved in the solvent orange 2 A, 45-65 ℃ can guarantee that reactant fully reacts, particularly 30-45 ℃ can either guarantee 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 guarantee 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, uses extraction step in the time of can avoiding separating on the one hand, has reduced solvent load; Avoid on the other hand the before operation of the evaporate to dryness aqueous solution of crystallization, 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; Simultaneously, avoided the loaded down with trivial details post-processing step of acidifying, extraction, salify.
The method is with the Inclusion Complexes sodium-hydroxide treatment, with Esomeprazole sodium and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol separates, and the combination of employing 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, has avoided extraction, concentrated grade is unfavorable for suitability for industrialized production and the operation that reduces quality product, directly the form with the esomeprazole sodium salt obtains product in the organic solvent, has further guaranteed 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 preferably solvability, effectively reduces the residual quantity of resolution reagent, and its content is lower than 0.1% in the product.
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 entry and induce (S)-(-)-[1,1 '-dinaphthalene]-2, and 2 '-diphenol crystallization filters and namely can be recycled, and has reduced cost, has reduced environmental pollution.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used for explanation the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1 preparation esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes (IV).
In the reactor of 20L, adding paratartarics omeprazole 3.0kg(8.685mol), (S)-(-)-[1,1 '-dinaphthalene]-2, triethylamine 0.879kg(8.685mol) and dehydrated alcohol 12L 2 '-diphenol 1.492kg(5.211mol),, be heated to 75 ℃ of insulation dissolvings, dissolve rear 60 ℃ of insulated and stirred 2h; Be cooled to 30 ℃ of crystallizatioies, with the solid filtering that suspends, filter cake obtains off-white color solid 2.442kg with the 6L washing with alcohol and after 50 ℃ of vacuum-drying.Yield: 89%, HPLC purity (normalization method): 98.69%, optical purity (e.e%): 99.43%.
Embodiment 2 preparation esomeprazoles and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes (IV).
In the reactor of 50L, adding paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2, triethylamine 1.465kg(14.475mol) and 2-propyl alcohol 25L 2 '-diphenol 2.488kg(8.685mol),, be heated to 70 ℃ of insulation dissolvings, dissolve rear 55 ℃ of insulated and stirred 3h; Be cooled to 35 ℃ of crystallizatioies, with the solid filtering that suspends, filter cake is with 2-propyl alcohol 10L washing and obtain off-white color solid 4.001kg after 50 ℃ of vacuum-drying.Yield: 87.5%, HPLC purity (normalization method): 98.34%, optical purity (e.e.%): 99.55%.
Embodiment 3
In the reactor of 50L, adding 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 ℃ of insulation dissolvings, dissolve rear 50 ℃ of insulated and stirred 2h; Be cooled to 40 ℃ of crystallizatioies, with the solid filtering that suspends, filter cake is with methyl alcohol 10L washing and obtain off-white color solid 4.0kg after 50 ℃ of vacuum-drying.Yield: 87.9%, HPLC purity (normalization method): 98.36%, optical purity (e.e%): 99.32%.
Embodiment 4
In the reactor of 50L, adding paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 4.144kg(14.475mol), the ammoniacal liquor and the 1-propyl alcohol 30L that contain NH314.475mol, be heated to 70 ℃ of insulation dissolvings, dissolve rear 65 ℃ of insulated and stirred 2h; Be cooled to 45 ℃ of crystallizatioies, with the solid filtering that suspends, filter cake is with 1-propyl alcohol 15L washing and obtain off-white color solid 3.9kg after 50 ℃ of vacuum-drying.Yield: 85.7%, HPLC purity (normalization method): 98.19%, optical purity (e.e%): 99.17%.
Embodiment 5
In the reactor of 50L, adding 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 ℃ of insulation dissolvings, dissolve rear 45 ℃ of insulated and stirred 2h; Be cooled to 30 ℃ of crystallizatioies, with the solid filtering that suspends, filter cake is with acetonitrile 20L washing and obtain off-white color solid 3.95kg after 50 ℃ of vacuum-drying.Yield: 86.8%, HPLC purity (normalization method): 98.45%, optical purity (e.e%): 99.39%.
Embodiment 6
In the reactor of 50L, adding 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 ℃ of insulation dissolvings, dissolve rear 65 ℃ of insulated and stirred 2h; Be cooled to 45 ℃ of crystallizatioies, with the solid filtering that suspends, filter cake is with tetrahydrofuran (THF) 20L washing and obtain off-white color solid 3.85kg after 50 ℃ of vacuum-drying.Yield: 84.6%, HPLC purity (normalization method): 98.34%, optical purity (e.e%): 99.28%.
Embodiment 7
In the reactor of 50L, adding paratartarics omeprazole 5.0kg(14.475mol), (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol 2.48kg(8.65mol), the diethylamine of the mixture of the methyl alcohol of 50L arbitrary proportion, ethanol, 1 propyl alcohol, 2-propyl alcohol, acetonitrile and tetrahydrofuran (THF), 14.475mol arbitrary proportion, triethylamine, ammoniacal liquor, NN-diisopropylethylamine mixture, be heated to 75 ℃ of insulation dissolvings, dissolve rear 60 ℃ of insulated and stirred 2h; Be cooled to 30 ℃ of crystallizatioies, with the solid filtering that suspends, filter cake washs and obtains 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 after 50 ℃ of vacuum-drying.Yield: 85.7%, HPLC purity (normalization method): 98.58%, optical purity (e.e%): 99.40%.
Embodiment 8 preparation Esomeprazole sodiums (I).
In the reactor of 20L, 20 ℃ lower adds esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 2.442kg(3.866mol) in 12.2L acetone, add again sodium hydroxide 0.233kg(5.799mol).Add ethyl acetate 4.9L after the stirring and dissolving, be heated to 55 ℃ and stir 1h, be cooled to 5 ℃, with the solid filtering that suspends, filter cake obtains white solid 1.250kg with the 4.9L washing with acetone and after 40 ℃ 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-d
6)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-d
6)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: preparation Esomeprazole sodium (I)
In the reactor of 50L, 25 ℃ add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in the 16L methyl iso-butyl ketone (MIBK), add again sodium hydroxide 0.380kg(9.50mol).Add ethyl acetate 8L after the stirring and dissolving, be heated to 60 ℃ and stir 1h, be cooled to 10 ℃, with the solid filtering that suspends, filter cake is with the washing of 16L ethyl acetate and obtain white solid 2.141kg after 40 ℃ of vacuum-drying, 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 preparation Esomeprazole sodiums (I).
In the reactor of 50L, 10 ℃ add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in 20L methyl alcohol, add again sodium hydroxide 0.254kg(6.35mol).Add acetonitrile 8L after the stirring and dissolving, be heated to 40 ℃ and stir 1h, be cooled to 0 ℃, with the solid filtering that suspends, filter cake obtains white solid 2.095kg with the 6.4L methanol wash and after 40 ℃ 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 preparation Esomeprazole sodiums (I).
In the reactor of 50L, 30 ℃ add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in 20L ethanol, add again sodium hydroxide 0.3048kg(7.62mol).Add methylene dichloride 8L after the stirring and dissolving, be heated to 30 ℃ and stir 1h, be cooled to 15 ℃, with the solid filtering that suspends, filter cake obtains white solid 2.115kg with the 1.6L washing with alcohol and after 40 ℃ 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 preparation Esomeprazole sodiums (I).
In the reactor of 50L, 15 ℃ add esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 4.000kg(6.35mol) in the 20L1-propyl alcohol, add again sodium hydroxide 0.381kg(9.525mol).Add trichloromethane 8L after the stirring and dissolving, be heated to 70 ℃ and stir 1h, be cooled to 10 ℃, with the solid filtering that suspends, filter cake is with the washing of 0.8L1-propyl alcohol and obtain white solid 2.085kg after 40 ℃ of vacuum-drying, 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 present embodiment is substantially the same manner as Example 9, and difference only is: the 2-propyl alcohol is as solvent B, and methyl tertiary butyl ether is as solvent C.
Embodiment 14
The preparation method of present embodiment is substantially the same manner as Example 9, difference only is: the mixture of the methyl alcohol of arbitrary proportion, ethanol, 1-propyl alcohol, 2-propyl alcohol, acetone and methyl iso-butyl ketone (MIBK) 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 Examples 1: preparation esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes (III).
In the there-necked flask of 5L, with 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 ℃ and stir and add triethylamine 29.2g(289mmol) and paratartarics omeprazole 100.0g(289mmol), 50 ~ 55 ℃ of stirrings of temperature 0.5h in keeping, reaction solution is slowly cooled to room temperature and insulation reaction 12h, with the solid filtering that suspends, filter cake is with 200mL85% ethanolic soln and the washing of 200mL normal hexane and obtain white solid 27.5g after 50 ℃ of vacuum-drying, yield: 30%, HPLC purity (normalization method): 97.91%, optical purity (e.e%): 94.33%.
Comparative Examples 2: preparation Esomeprazole sodium (I).
In the reaction flask of 2L, under the room temperature with esomeprazole and (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol Inclusion Complexes 50g(79.1mmol) and 230mL isopropyl acetate, add and to contain sodium hydroxide 3.8g(94.9mmol) the aqueous solution in, stir 30min under the room temperature.The organic layer separation is also further used 120mL isopropyl acetate aqueous layer extracted, and 50 ℃ of decompressions join 15mL methyl iso-butyl ketone (MIBK) and 62mL acetonitrile in the residue, the water layer evaporate to dryness with its stirring.With sedimentation and filtration, after 40 ℃ 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%.
Claims (9)
1. preparation method of the Esomeprazole sodium of 99.9%e.e optical purity (I) at least is characterized in that: may further comprise the steps:
(1) with omeprazole (II) with (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (III) is heated to 65-75 ℃ and is dissolved in the solvent orange 2 A, is cooled to 45-65 ℃ of insulation reaction in the presence of weak base, be cooled to 30-45 ℃ of crystallization, get Inclusion Complexes (IV);
(2) described Inclusion Complexes (IV) and sodium hydroxide are dissolved in the organic solvent B in 10-30 ℃, be warming up to 30-70 ℃ after insulation reaction, add organic solvent C, be cooled to 0-15 ℃ of crystallization, filter, namely get Esomeprazole sodium (I); Or with described Inclusion Complexes (IV) and sodium hydroxide in 10-30 ℃ of mixture that is dissolved in organic solvent B and organic solvent C, be warming up to 30-70 ℃ after insulation reaction, be cooled to 0-15 ℃ of crystallization, filter, namely get Esomeprazole sodium (I).
2. the preparation method of the Esomeprazole sodium of a kind of at least 99.9%e.e. optical purity according to claim 1, it is characterized in that: in the step (1), described (S)-(-)-[1,1 '-dinaphthalene]-2,2 '-diphenol (III) is (0.5-1.0) with omeprazole (II) mol ratio: 1.0.
3. the preparation method of the Esomeprazole sodium of a kind of at least 99.9%e.e. optical purity according to claim 1, it is characterized in that: in the step (1), solvent orange 2 A is selected from one or more the mixture in methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, acetonitrile and the tetrahydrofuran (THF).
4. the preparation method of a kind of Esomeprazole sodium according to claim 1, it is characterized in that: in the step (1), described weak base is diethylamine, triethylamine, ammoniacal liquor or DIPEA.
5. the preparation method of the Esomeprazole sodium of a kind of at least 99.9%e.e. optical purity according to claim 1, it is characterized in that: in the step (1), described weak base and omeprazole (II) mol ratio is (0.3-1.0): 1.0.
6. the preparation method of the Esomeprazole sodium of a kind of at least 99.9%e.e. optical purity according to claim 1, it is characterized in that: in the 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 the methyl iso-butyl ketone (MIBK).
7. the preparation method of the Esomeprazole sodium of a kind of at least 99.9%e.e. optical purity according to claim 1, it is characterized in that: in the step (2), described solvent C is selected from one or more mixture of ethyl acetate, acetonitrile, methylene dichloride, trichloromethane and methyl tertiary butyl ether.
8. the preparation method of the Esomeprazole sodium of a kind of at least 99.9%e.e. optical purity according to claim 1 is characterized in that: described sodium hydroxide and Inclusion Complexes (IV) mol ratio is (1.0-1.5): 1.0.
9. the preparation method of the Esomeprazole sodium of a kind of at least 99.9%e.e. optical purity according to claim 1, it is characterized in that: the volume ratio of described solvent B and solvent C is 1.0:(0.1-1.2).
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664888A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole trihydrate |
| CN104163814A (en) * | 2014-05-27 | 2014-11-26 | 浙江新东港药业股份有限公司 | Preparation method of highly pure 5-methoxy-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl)-1H-benzimidazole sodium |
| CN104478856A (en) * | 2014-12-25 | 2015-04-01 | 北京华禧联合科技发展有限公司 | Purificationmethod of esomeprazole magnesiumkey intermediate |
| CN105418588A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Method for preparing high-purity esomeprazole magnesium trihydrate |
| CN105924430A (en) * | 2016-06-27 | 2016-09-07 | 杭州富阳伟文环保科技有限公司 | Refinement method of esomeprazole sodium |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008004245A1 (en) * | 2006-07-05 | 2008-01-10 | Lupin Limited | Process for the preparation of optically pure or optically enriched enantiomers of sulphoxide compounds |
| CN101133049A (en) * | 2005-03-03 | 2008-02-27 | 埃斯特维化学股份有限公司 | Process for the preparation of optically active derivatives of 2-(2-pyridylmethylsulfinyl)-benzimidazole via inclusion complex with 1,1'-binaphthalene-2, 2'diol |
| CN101296921A (en) * | 2005-10-26 | 2008-10-29 | 韩美药品株式会社 | S-omeprazole strontium or hydrate thereof, method for preparing same, and pharmaceutical composition comprising same |
| WO2010118575A1 (en) * | 2009-04-16 | 2010-10-21 | Chengdu Organic Chemicals Co., Ltd, Chinese Academy Of Science | Racemic enantiomers resoluting |
-
2012
- 2012-09-26 CN CN201210364314.0A patent/CN102887885B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101133049A (en) * | 2005-03-03 | 2008-02-27 | 埃斯特维化学股份有限公司 | Process for the preparation of optically active derivatives of 2-(2-pyridylmethylsulfinyl)-benzimidazole via inclusion complex with 1,1'-binaphthalene-2, 2'diol |
| CN101296921A (en) * | 2005-10-26 | 2008-10-29 | 韩美药品株式会社 | S-omeprazole strontium or hydrate thereof, method for preparing same, and pharmaceutical composition comprising same |
| WO2008004245A1 (en) * | 2006-07-05 | 2008-01-10 | Lupin Limited | Process for the preparation of optically pure or optically enriched enantiomers of sulphoxide compounds |
| WO2010118575A1 (en) * | 2009-04-16 | 2010-10-21 | Chengdu Organic Chemicals Co., Ltd, Chinese Academy Of Science | Racemic enantiomers resoluting |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103664888A (en) * | 2013-12-18 | 2014-03-26 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole trihydrate |
| CN103664888B (en) * | 2013-12-18 | 2015-07-08 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole trihydrate |
| CN104163814A (en) * | 2014-05-27 | 2014-11-26 | 浙江新东港药业股份有限公司 | Preparation method of highly pure 5-methoxy-2-((S)-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl)-1H-benzimidazole sodium |
| CN104163814B (en) * | 2014-05-27 | 2016-08-24 | 浙江新东港药业股份有限公司 | A kind of high-purity 5-methoxyl group-2-((S)-((4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl) sulfinyl)-1H-benzimidazole sodium preparation method |
| CN104478856A (en) * | 2014-12-25 | 2015-04-01 | 北京华禧联合科技发展有限公司 | Purificationmethod of esomeprazole magnesiumkey intermediate |
| CN105418588A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Method for preparing high-purity esomeprazole magnesium trihydrate |
| CN105924430A (en) * | 2016-06-27 | 2016-09-07 | 杭州富阳伟文环保科技有限公司 | Refinement method of esomeprazole sodium |
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