CN105418588A - Method for preparing high-purity esomeprazole magnesium trihydrate - Google Patents
Method for preparing high-purity esomeprazole magnesium trihydrate Download PDFInfo
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- CN105418588A CN105418588A CN201610028366.9A CN201610028366A CN105418588A CN 105418588 A CN105418588 A CN 105418588A CN 201610028366 A CN201610028366 A CN 201610028366A CN 105418588 A CN105418588 A CN 105418588A
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- esomeprazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
The invention discloses a method for preparing a high-purity esomeprazole magnesium trihydrate. The method comprises the following steps: (1), mixing omeprazole sulfide, (R)-1,1 minute-binaphthyl-2,2 minute-diamine and inorganic metal salt in acetone, thereby obtaining a mixture M; (2), at a condition of 15-45 DEG C, dipping 30% H2O2 into the mixture M of the step (1) to perform an oxidization reaction, and after the oxidization reaction is completed, adding potassium hydroxide and methanol solution, thereby obtaining esomeprazole potassium; (3), mixing the esomeprazole potassium obtained in step (2) with anhydrous magnesium chloride in methyl alcohol, stirring to react, and centrifuging and separating, thereby obtaining the esomeprazole magnesium trihydrate, wherein in step (1), the inorganic metal salt is cobalt (II), iron (II) or magnesium (II) metal salt. The method for preparing the high-purity esomeprazole magnesium trihydrate has high yield, good selectivity and high reaction efficiency, and is suitable for industrial mass production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of method preparing esomeprazole magnesium trihydrate.
Background technology
Esomeprazole magnesium (esomeprazolemagnesium); that AstraZeneca company of Sweden is in the S isomer magnesium salts preparation of the omeprazole of listing in 1988; S-(-)-5-methoxyl group-2-[(4-methoxyl group-3; 5-lutidine-2-base) methylsulfinyl] benzoglyoxaline-1-base magnesium, deposit in the formulation with the form of esomeprazole magnesium trihydrate.As novel proton pump inhibitor, esomeprazole magnesium can suppress H/K-ATP enzymic activity, is used for the treatment of the digestive system such as stomach ulcer, duodenal ulcer and the reflux esophagitis that gastroxia causes.
At present, esomeprazole salt obtains mainly through esomeprazole salify, and therefore, the preparation method of esomeprazole not only affects yield and the purity of esomeprazole, and affects yield and the purity of esomeprazole salt.The method being usually used in preparing esomeprazole has: racemic modification omeprazole Split Method, omeprazole thioether asymmetry catalysis oxidation style and biochemical oxidation method.Racemic modification omeprazole Split Method can cause waste, improves production cost and causes environmental pollution, and chiral separation is complicated harsh, is unfavorable for that heavy industrialization is applied; And biochemical oxidation method due to complicated operation and the cycle long, so its application is also restricted.Omeprazole thioether asymmetry catalysis oxidation style, use chiral ligand to prepare esomeprazole, it is relative to Split Method, has higher raw material availability, and simple to operate, selectivity is high, has higher application prospect.
CN103044402B discloses a kind of Esomeprazole sodium synthesis production method, is divided into following step: 5-methoxyl group-2-(4-methoxyl group-3,5-lutidine-2-base) methyl thio-1H benzoglyoxaline, the i.e. preparation of pro-chiral sulphide; The preparation of Esomeprazole sodium crude product; Esomeprazole sodium crude product refining.The pro-chiral sulphide of preparation stirs with dry toluene and adds D-(-) diethyl tartrate and water by the method, then adds titanium isopropylate, stirs; Constant temperature adds and isopropylamine, stirs, and drips mass concentration 80% hydrogen phosphide cumene, reacts complete, obtains crude product, crude product refining process, finally obtain fine work Esomeprazole sodium through steps such as extraction, salify, concentrated, washing, vacuum-dryings.CN103788069B discloses a kind of preparation method of esomeprazole magnesium trihydrate, comprise the following steps: 1) get omeprazole thioether, then add chiral ligand, catalyzer and organic solvent, heated and stirred is reacted, to form omeprazole thioether chirality mixture; 2) adding inorganic oxidizer and carry out oxidizing reaction, is esomeprazole by omeprazole sulfide oxidation; 3) adding inorganic base aqueous solution to extract, make step 2) esomeprazole that obtains forms esomeprazole inorganic salt and is dissolved in inorganic base aqueous solution layer; 4) to step 3) the inorganic base aqueous solution layer that obtains adds inorganic magnesium salt, stirring reaction, then carries out centrifugal, dry, obtained described esomeprazole magnesium trihydrate.Although aforesaid method has all successfully obtained esomeprazole, but, also there is yield not high (the highest by about 70%) in aforesaid method, selectivity is bad, reaction times is long, and particularly the easy over oxidation of oxidation step becomes sulfone, makes purifying products step complicated, and, above-mentioned reaction all will (lower than 30 degrees Celsius and lower than 10 degrees Celsius) be carried out at a lower temperature, and reaction efficiency is low, delays rhythm of production etc.
Therefore, the huge application demand of the activity good in view of esomeprazole salt and market, this area needs that a kind of yield is high, selectivity good badly and reaction efficiency height is applicable to the method preparing esomeprazole of commercial scale production.
Summary of the invention
The object of the invention is to overcome the existing defect preparing esomeprazole method, provide that a kind of yield is high, selectivity good and reaction efficiency height is applicable to the method preparing esomeprazole magnesium trihydrate of commercial scale production.
The present inventor surprisingly finds under study for action, mixes, omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt then with H
2o
2s-configuration sulfoxide product is obtained for oxygen source carries out oxidation to omeprazole thioether, this method for oxidation can not produce the phenomenon that over oxidation generates sulfone, and due to (R)-1, 1'-dinaphthalene-2, 2'-diamines, inorganic metal salt is in mixing process, form the metal complex of certain three-dimensional arrangement, this complex compound sulphur atom effect in omeprazole thioether is simultaneously combined, make in oxidising process, avoid oxygen to the attack of sulphur atom in conjunction with side, complete three-dimensional selection thus, the present invention is made to have selectivity excellent especially, in addition, due to stablizing of method oxidizing reaction of the present invention, still good stereoselectivity and yield can be had at heated condition, thus improve the efficiency of reaction.
To achieve these goals, the invention provides a kind of method preparing esomeprazole magnesium trihydrate, comprise the following steps:
1) omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in acetone, obtain mixture M;
2) be under the condition of 15-45 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium;
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction, then centrifugal, be separated and obtain esomeprazole magnesium trihydrate;
Wherein, in step 1) in, described inorganic metal salt is cobalt (II), iron (II) or manganese (II) metal-salt.
Under preferable case, in step 1) in, omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt mixing condition are in acetone comprised: temperature 30-55 DEG C, stir 0.5-2 hour; Further preferably, omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt mixing condition are in acetone comprised: temperature 45-50 DEG C, stir 1 hour.Aforesaid method makes omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt can form highly stable metal complex, thus complete the stereoselective process in omeprazole sulfide oxidation process.
The consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt can be 1:0.4-1.5:0.05-0.6; Further preferably, the consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:0.4-0.8:0.1-0.2.
Under preferable case, in step 1) in, described inorganic metal salt is CoCl
2, FeCl
2, MnCl
2, CoSO
4, FeSO
4or MnSO
4; Further preferably, described inorganic metal salt is CoCl
2or CoSO
4.Above-mentioned metal can with omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines is formed stable and has the complex compound of octahedral structure, simultaneously, above-mentioned metal has certain reductibility as complex compound central atom simultaneously, as the buffer reagent in oxidising process, the unlikely over oxidation of oxidising process can be ensure that.
In prior art, no matter use organic or inorganic oxide compound, all must react at low temperatures, such as, under being less than 20 DEG C of conditions, if temperature increase, selectivity is had a greatly reduced quality, R-type sulfoxide structure increases, increase the difficulty of product separation, over oxidation becomes the ratio of sulfone also to increase simultaneously.And in the present invention, react owing to have employed more stable complex compound, adopt H
2o
2for oxygen source is oxidized, the highest can to more than 40 DEG C the above-mentioned phenomenon of unlikely generation.If continuation raised temperature, although reaction can be accelerated, H
2o
2decomposing phenomenon aggravates, and selectivity also starts to decline, therefore, under preferable case, in step 2) in, described temperature is 38-45 DEG C; With H
2o
2meter, 30%H
2o
2be 1.2-1.7 with the mol ratio of omeprazole thioether.
In the present invention, step 2) in the oxidation methanol solution that terminates to add potassium hydroxide react, this reaction can be carried out according to the ordinary method of prior art, preferably, add the amount of potassium hydroxide methanol solution, in potassium hydroxide, be 1.3-1.5 with the mol ratio of omeprazole thioether.
In step 3) in, by step 2) the esomeprazole potassium that obtains and inorganic magnesium salt react in methyl alcohol, stirring can obtain esomeprazole magnesium trihydrate, such as, esomeprazole potassium and Magnesium Chloride Anhydrous react in methyl alcohol, stir 1-2 hour, can complete reaction, described reaction can be carried out under normal temperature again.Then centrifugation can obtain the esomeprazole magnesium trihydrate of high purity highly selective.Preferably, the mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.6-0.8.
The method preparing esomeprazole magnesium trihydrate according to the embodiment of the present invention, can comprise the following steps:
1) omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in acetone, mixing condition comprises: temperature 30-55 DEG C, stirs 0.5-2 hour, obtains mixture M; Wherein, described omeprazole thioether and (R)-1, the consumption mol ratio of 1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:0.4-1.5:0.05-0.6, and described inorganic metal salt is cobalt (II), iron (II) or manganese (II) metal-salt.
2) be under the condition of 15-45 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium; With H
2o
2meter, 30%H
2o
2be 1.2-1.7 with the mol ratio of omeprazole thioether; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.3-1.5 with the mol ratio of omeprazole thioether.
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction, then centrifugal, be separated and obtain esomeprazole magnesium trihydrate; The mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.6-0.8.
The method preparing esomeprazole magnesium trihydrate provided by the invention can also comprise with other standards as required further carries out the step such as purifying and crystallization, and these steps can with reference to the method for this area routine.
In the present invention, can adopt the method for this area routine to reaction carry out monitoring follow the tracks of, such as TLC, LCMS, GCMS etc., react complete fingers TLC monitor inexcessive also raw material disappeared or in LCMS, GCMS not excess raw material remain be less than 2%.
Compared with prior art, the present invention is owing to adopting diverse chirality stereoselective reaction system, method of the present invention is had, and yield is high, selectivity good and reaction efficiency height is applicable to the advantage such as commercial scale production, and the method is simple, is particularly suitable for industrialization promotion.
Other features and advantages of the present invention are described in detail in embodiment part subsequently.。
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to the present invention instead of the further restriction to protection scope of the present invention are described.
Embodiment 1
Prepare a method for esomeprazole magnesium trihydrate, comprise the following steps:
1) omeprazole thioether 630g (2mol) and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in 5L acetone, mixing condition is: temperature 48 DEG C, stirs 1 hour, obtains mixture M; Wherein, the consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:0.65:0.1, and described inorganic metal salt is CoCl
2.
2) be under the condition of 45 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium; With H
2o
2meter, 30%H
2o
2be 1.6 with the mol ratio of omeprazole thioether; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.5 with the mol ratio of omeprazole thioether.
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction 1 hour, the mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.7, then centrifugal, separation obtains esomeprazole magnesium trihydrate, vacuum-drying, obtains white solid 686.6g, yield: 89.5%, detect through HPLC, purity is 99.92%, and isomer-free becomes the impurity of sulfone with over oxidation.
Embodiment 2
Prepare a method for esomeprazole magnesium trihydrate, comprise the following steps:
1) omeprazole thioether 630g (2mol) and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in 5L acetone, mixing condition is: temperature 50 C, stirs 1.5 hours, obtains mixture M; Wherein, the consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:0.8:0.15, and described inorganic metal salt is CoSO
4.
2) be under the condition of 38 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium; With H
2o
2meter, 30%H
2o
2be 1.7 with the mol ratio of omeprazole thioether; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.3 with the mol ratio of omeprazole thioether.
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction 1.5 hours, the mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.6, then centrifugal, separation obtains esomeprazole magnesium trihydrate, vacuum-drying, obtains white solid 692g, yield: 90.2%, detect through HPLC, purity is 99.89%, and isomer-free becomes the impurity of sulfone with over oxidation.
Embodiment 3
Prepare a method for esomeprazole magnesium trihydrate, comprise the following steps:
1) omeprazole thioether 630g (2mol) and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in 5L acetone, mixing condition is: temperature 45 C, stirs 1.5 hours, obtains mixture M; Wherein, the consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:0.4:0.2, and described inorganic metal salt is FeCl
2.
2) be under the condition of 40 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium; With H
2o
2meter, 30%H
2o
2be 1.4 with the mol ratio of omeprazole thioether; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.4 with the mol ratio of omeprazole thioether.
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction 1 hour, the mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.8, then centrifugal, separation obtains esomeprazole magnesium trihydrate, vacuum-drying, obtains white solid 663.6g, yield: 86.5%, detect through HPLC, purity is 99.82%, and isomer-free becomes the impurity of sulfone with over oxidation.
Embodiment 4
Prepare a method for esomeprazole magnesium trihydrate, comprise the following steps:
1) omeprazole thioether 630g (2mol) and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in 5L acetone, mixing condition is: temperature 43 DEG C, stirs 1.5 hours, obtains mixture M; Wherein, the consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:1.2:0.6, and described inorganic metal salt is MnCl
2.
2) be under the condition of 15 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium; With H
2o
2meter, 30%H
2o
2be 1.2 with the mol ratio of omeprazole thioether; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.5 with the mol ratio of omeprazole thioether.
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction 1 hour, the mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.8, then centrifugal, separation obtains esomeprazole magnesium trihydrate, vacuum-drying, obtains white solid 642.1g, yield: 83.7%, detect through HPLC, purity is 99.87%, and isomer-free becomes the impurity of sulfone with over oxidation.
Embodiment 5
Prepare a method for esomeprazole magnesium trihydrate, comprise the following steps:
1) omeprazole thioether 630g (2mol) and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in 5L acetone, mixing condition is: temperature 43 DEG C, stirs 1.5 hours, obtains mixture M; Wherein, the consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:1.5:0.05, and described inorganic metal salt is FeSO
4.
2) be under the condition of 25 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium; With H
2o
2meter, 30%H
2o
2be 1.6 with the mol ratio of omeprazole thioether; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.3 with the mol ratio of omeprazole thioether.
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction 1 hour, the mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.6, then centrifugal, separation obtains esomeprazole magnesium trihydrate, vacuum-drying, obtains white solid 627.5g, yield: 81.8%, detect through HPLC, purity is 99.77%, and content of isomer is 0.01% impurity becoming sulfone with without over oxidation.
Embodiment 6
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) in be 20 DEG C by the temperature of omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt mixing in acetone.White solid 592.2g, yield: 77.2%, detect through HPLC, purity is 99.74%, and content of isomer is 0.04% impurity becoming sulfone with without over oxidation.
Embodiment 7
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) in be 70 DEG C by the temperature of omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt mixing in acetone.White solid 599.1g, yield: 78.1%, detect through HPLC, purity is 99.67%, and content of isomer is 0.05% impurity becoming sulfone with without over oxidation.
Embodiment 8
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) described in omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt consumption mol ratio be 1:0.2:0.1.White solid 589.2g, yield: 76.8%, detect through HPLC, purity is 98.64%, and content of isomer is 0.11% impurity becoming sulfone with without over oxidation.
Embodiment 9
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) described in omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt consumption mol ratio be 1:2:0.7.White solid 608.4g, yield: 79.3%, detect through HPLC, purity is 98.21%, and content of isomer is 0.01% impurity becoming sulfone with without over oxidation.
Comparative example 1
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) in do not add (R)-1,1'-dinaphthalene-2,2'-diamines.White solid 379.7g, yield: 49.5%, detect through HPLC, purity is 82.32%, and content of isomer is 12.71% become the content of sulfone impurity to be 3.58% with over oxidation.
Comparative example 2
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) CuCl of middle equal in quality
2replace CoCl
2.White solid 501.7g, yield: 65.4%, detect through HPLC, purity is 90.11%, and content of isomer is 7.35% become the content of sulfone impurity to be 2.49% with over oxidation.
Comparative example 3
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 2) described in described temperature be 55 DEG C.White solid 526.3g, yield: 68.6%, detect through HPLC, purity is 93.70%, and content of isomer is 0.79% become the content of sulfone impurity to be 5.22% with over oxidation.
Comparative example 4
As the method preparing esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 2) described in described temperature be 5 DEG C.White solid 474.1g, yield: 61.8%, detect through HPLC, purity is 96.60%, and content of isomer is 0.05% impurity becoming sulfone with without over oxidation.
Comparative example 5
Esomeprazole magnesium trihydrate is prepared according to the method for CN103788069B embodiment 1, particularly:
630g omeprazole thioether, 203gD-diethyl tartrate, 213g titanium isopropylate, 2200g acetic acid butyl ester, 4g water are added in 5L three-necked bottle, is warming up to 50 DEG C, stirring reaction 1.5 hours; Be cooled to 10 DEG C, add 20g benzyltriethylammoinium chloride, 2438g chlorine bleach liquor (efficient content is 4%), temperature control reacts 3 hours at 10 DEG C.By high performance liquid chromatography monitoring reaction, when omeprazole thioether content less than 1%, stopped reaction, obtained esomeprazole.Subsequently, to reaction system add 7000g mass concentration be 12.5% aqueous sodium hydroxide solution extract, esomeprazole forms Esomeprazole sodium and be dissolved in buck layer; Discard acetic acid butyl ester layer, collect buck layer, add 2200g acetic acid butyl ester, and be the aqueous hydrochloric acid adjust ph to 7.0 of 10% by mass concentration, Esomeprazole sodium forms esomeprazole and is dissolved in organic layer after acidifying; Collected organic layer, add 7000g mass concentration be 12.5% aqueous sodium hydroxide solution extract, esomeprazole forms Esomeprazole sodium and be dissolved in buck layer.Collect buck layer, pH to 11 is regulated with the aqueous hydrochloric acid that mass concentration is 10%, then low price magnesium chloride brine (240g magnesium chloride dihydrate is dissolved in 1000g water and is prepared from, by low price magnesium chloride brine, to prevent in crystallisate containing impurity), stirring reaction 2 hours, centrifugal, collect solid, vacuum-drying, obtain esomeprazole magnesium trihydrate 459.3g, yield is 59.9%.The content 99.63% of esomeprazole magnesium trihydrate, omeprazole thioether content is 0.07%, and superoxide " sulfone " foreign matter content is 0.10%, and isomer impurities content is 0.19%.
To sum up, the invention provides that a kind of yield is high, selectivity good and reaction efficiency height be applicable to the preparation esomeprazole magnesium trihydrate of commercial scale production method.
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.
It should be noted that in addition, each concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode, in order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.
In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (6)
1. prepare a method for high purity esomeprazole magnesium trihydrate, it is characterized in that, comprise the following steps:
1) omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt are mixed in acetone, obtain mixture M;
2) be under the condition of 15-45 DEG C in temperature, by 30%H
2o
2instillation step 1) mixture M in carry out oxidizing reaction, reaction terminate after add potassium hydroxide methanol solution, obtain esomeprazole potassium;
3) by step 2) the esomeprazole potassium that obtains mixes in methyl alcohol with Magnesium Chloride Anhydrous, stirring reaction, then centrifugal, be separated and obtain esomeprazole magnesium trihydrate;
Wherein, in step 1) in, described inorganic metal salt is cobalt (II), iron (II) or manganese (II) metal-salt.
2. method according to claim 1, is characterized in that, in step 1) in, by omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt mixing condition in acetone comprise: temperature 30-55 DEG C, stir 0.5-2 hour; The consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:0.4-1.5:0.05-0.6; Preferably, omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt mixing condition are in acetone comprised: temperature 45-50 DEG C, stir 1 hour; The consumption mol ratio of described omeprazole thioether and (R)-1,1'-dinaphthalene-2,2'-diamines, inorganic metal salt is 1:0.4-0.8:0.1-0.2.
3. method according to claim 1 and 2, is characterized in that, in step 1) in, described inorganic metal salt is CoCl
2, FeCl
2, MnCl
2, CoSO
4, FeSO
4or MnSO
4.
4. method according to claim 3, is characterized in that, in step 1) in, described inorganic metal salt is CoCl
2or CoSO
4.
5. method according to claim 1, is characterized in that, in step 2) in, described temperature is 38-45 DEG C; With H
2o
2meter, 30%H
2o
2be 1.2-1.7 with the mol ratio of omeprazole thioether.
6. the method according to claim 3 or 4, is characterized in that, in step 2) in, adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.3-1.5 with the mol ratio of omeprazole thioether.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928193A (en) * | 2017-03-09 | 2017-07-07 | 上海华源医药科技发展有限公司 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
| CN113698389A (en) * | 2021-08-26 | 2021-11-26 | 安徽鼎旺医药有限公司 | Synthetic method of esomeprazole |
| CN116496250A (en) * | 2023-04-18 | 2023-07-28 | 新沂大江化工有限公司 | Esomeprazole sodium synthesis process |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1753893A (en) * | 2003-02-24 | 2006-03-29 | 三菱制药株式会社 | The enantiomer of tenatoprazole and the use thereof in therapy |
| CN101914090A (en) * | 2010-08-13 | 2010-12-15 | 埃斯特维华义制药有限公司 | Method for preparing levo-omeprazole |
| WO2012104863A2 (en) * | 2011-02-01 | 2012-08-09 | Hetero Research Foundation | Process for controlling the content of single enantiomer of omeprazole |
| CN102887885A (en) * | 2012-09-26 | 2013-01-23 | 江苏正大丰海制药有限公司 | Preparation method of esomeprazole sodium |
| CN103275064A (en) * | 2012-11-06 | 2013-09-04 | 寿光富康制药有限公司 | Preparation method of Esomeprazole and preparation method of Esomeprazole sodium |
| CN104447699A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Preparation method of esomeprazole magnesium trihydrate |
| CN104892575A (en) * | 2015-04-13 | 2015-09-09 | 江苏中邦制药有限公司 | Novel synthesis method of chiral imidazole sulfoxide compound |
-
2016
- 2016-01-17 CN CN201610028366.9A patent/CN105418588A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1753893A (en) * | 2003-02-24 | 2006-03-29 | 三菱制药株式会社 | The enantiomer of tenatoprazole and the use thereof in therapy |
| CN101914090A (en) * | 2010-08-13 | 2010-12-15 | 埃斯特维华义制药有限公司 | Method for preparing levo-omeprazole |
| WO2012104863A2 (en) * | 2011-02-01 | 2012-08-09 | Hetero Research Foundation | Process for controlling the content of single enantiomer of omeprazole |
| CN102887885A (en) * | 2012-09-26 | 2013-01-23 | 江苏正大丰海制药有限公司 | Preparation method of esomeprazole sodium |
| CN103275064A (en) * | 2012-11-06 | 2013-09-04 | 寿光富康制药有限公司 | Preparation method of Esomeprazole and preparation method of Esomeprazole sodium |
| CN104447699A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Preparation method of esomeprazole magnesium trihydrate |
| CN104892575A (en) * | 2015-04-13 | 2015-09-09 | 江苏中邦制药有限公司 | Novel synthesis method of chiral imidazole sulfoxide compound |
Non-Patent Citations (1)
| Title |
|---|
| 宋来东: "手性亚砜不对称合成方法研究及其在药物合成中的应用", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928193A (en) * | 2017-03-09 | 2017-07-07 | 上海华源医药科技发展有限公司 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
| CN113698389A (en) * | 2021-08-26 | 2021-11-26 | 安徽鼎旺医药有限公司 | Synthetic method of esomeprazole |
| CN116496250A (en) * | 2023-04-18 | 2023-07-28 | 新沂大江化工有限公司 | Esomeprazole sodium synthesis process |
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