CN105418589A - Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases - Google Patents
Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
The invention discloses a preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases. The preparation method comprises the following steps: (1) in the presence of an alkaline compound, carrying out a reflowing reaction on 2-chloromethyl-3,5-dimethyl-4-methoxylpyridine hydrochloride and 2-sulfydryl-5-methoxylbenzimidazole in THF (Tetrahydrofuran) to obtain omeprazole thioether; (2) mixing the omeprazole thioether with a compound represented by formula A and an inorganic metal salt in acetone to obtain a mixture B; (3) adding an oxidant into the mixture B to carry out an oxidization reaction at a temperature of 10 to 50 DEG C; after the reaction is finished, adding a potassium hydroxide methanol solution to obtain esomeprazole potassium; (4) mixing the esomeprazole potassium and anhydrous magnesium chloride in methanol, and stirring and reacting; then centrifuging and separating to obtain the esomeprazole magnesium trihydrate, wherein the inorganic metal salt is cobalt (II), iron (II) or manganese (II) metal salt. The preparation method has high yield, good selectivity and high reaction efficiency and is suitable for industrial large-scale production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of preparation method of 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 the defect of the preparation method overcoming existing esomeprazole, provide that a kind of yield is high, selectivity good and reaction efficiency height is applicable to the preparation method of the esomeprazole magnesium trihydrate of commercial scale production.
To achieve these goals, the invention provides a kind of preparation method of esomeprazole magnesium trihydrate, comprise the following steps:
1) under basic cpd exists, by 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol carry out back flow reaction and obtain omeprazole thioether in THF, wherein, basic cpd is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate and salt of wormwood;
2) by step 1) the omeprazole thioether that obtains mixes in acetone with the compound shown in formula A, inorganic metal salt, obtains mixture B;
3) be, under the condition of 10-50 DEG C, oxygenant is added step 2 in temperature) mixture B in carry out oxidizing reaction, add potassium hydroxide methanol solution after reaction terminates, obtain esomeprazole potassium;
4) by step 3) 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 2) in, described inorganic metal salt is cobalt (II), iron (II) or manganese (II) metal-salt.
In order to improve productive rate and the reaction efficiency of omeprazole thioether, under preferable case, in step 1) in, the consumption mol ratio of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol, basic cpd is 1:0.8-1.2:0.05-0.15.
The present inventor finds that the product purity of omeprazole thioether directly affects yield and the selectivity of subsequent reactions, therefore, in step 1) in, the present invention also comprises the process of refining gained omeprazole thioether, refining process is: first omeprazole thioether is dissolved in acetonitrile at 60-65 DEG C, then sherwood oil is instilled, 10-15 DEG C is cooled to the speed of 0.05-0.15 DEG C/s, leave standstill 1 hour, centrifugal, to filter refining omeprazole thioether, the volume ratio of described acetonitrile and sherwood oil is 1:2-2.5.Adopt solvent of the present invention to combine and cooling rate makes omeprazole thioether can quick spontaneous generation nucleus, separate out from mixing solutions, obtain purity high thus be beneficial to the carrying out of subsequent reactions.
Preferably, in step 2) in, the condition of described mixing comprises: temperature 30-60 DEG C, stirs 0.5-1 hour; The consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.6-1.2:0.1-0.4.
In order to promote the complex compound that the compound shown in described omeprazole thioether and formula A, inorganic metal salt formation are stable further, thus complete omeprazole thioether optionally oxidising process, further preferably, in step 2) in, the condition of described mixing comprises: temperature 50-55 DEG C, stirs 0.5-1 hour; The consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.6-0.7:0.2-0.4.Oxidising process in the present invention, by process monitoring, can complete reaction in 1-1.5 hour, wants fast more than 2 times compared to prior art.
Under preferable case, in step 2) 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 MnCl
2or MnSO
4.Above-mentioned metal can be stablized with the compound formation shown in omeprazole thioether and formula A and have 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, such as described oxygenant is tertbutyl peroxide or tertiary amyl hydrogen peroxide, 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, 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, oxygenant self-decomposition phenomenon is aggravated, selectivity also starts to decline, therefore, under preferable case, in step 3) in, the temperature of described oxidizing reaction is 40-45 DEG C, and the mol ratio of oxygenant and omeprazole thioether is 1.3-1.4.
In the present invention, step 3) 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, adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.3-1.5 with the mol ratio of omeprazole thioether.
In step 4) in, by step 3) 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 preparation method of esomeprazole magnesium trihydrate provided by the invention can also comprise further with other standards as required and 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.
The present invention is the result that contriver accumulates at long campaigns organic synthesis asymmetry catalysis, for useful technique effect of the present invention, the present inventor thinks that key is that contriver have found and can forms the chipal compounds (compound shown in formula A of stable comple with omeprazole thioether, R configuration), and combine the central metallic ions combination forming three-dimensional arrangement, make in oxidising process, avoid oxygen to the attack of sulphur atom in conjunction with side, complete three-dimensional selection thus, make the present invention have the incomparable selectivity of prior art; This combinative stability simultaneously, thus improve the efficiency of reaction.
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
A preparation method for esomeprazole magnesium trihydrate, comprises the following steps:
1) under sodium hydroxide exists, by 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-sulfydryl-5-methoxybenzimidazol 432g carries out back flow reaction and obtains omeprazole thioether in 3 hours in 4LTHF, then refine, refining process is: first omeprazole thioether is dissolved in 1.5L acetonitrile at 60 DEG C, then 3L sherwood oil is instilled, 10 DEG C are cooled to the speed of 0.1 DEG C/s, leave standstill 1 hour, centrifugal, the omeprazole thioether 650g filtering refining, yield is 85.9%, purity is 99.81%, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol, the consumption mol ratio of sodium hydroxide is 1:0.8:0.1,
2) by step 1) the omeprazole thioether 630g that obtains mixes in 5L acetone with the compound shown in formula A, inorganic metal salt, and mixing condition is: temperature 50 C, stirs 0.5 hour, obtains mixture B; Wherein, the consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.65:0.2, and described inorganic metal salt is MnSO
4.
3) be, under the condition of 45 DEG C, oxygenant is added step 2 in temperature) mixture B in carry out oxidizing reaction, add potassium hydroxide methanol solution after reaction terminates, obtain esomeprazole potassium; Described oxygenant is tertbutyl peroxide, and the mol ratio of oxygenant and omeprazole thioether is 1.4; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.4 with the mol ratio of omeprazole thioether.
4) by step 3) 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 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
A preparation method for esomeprazole magnesium trihydrate, comprises the following steps:
1) under potassium hydroxide exists, by 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-sulfydryl-5-methoxybenzimidazol 649g carries out back flow reaction and obtains omeprazole thioether in 4 hours in 4LTHF, then refine, refining process is: first omeprazole thioether is dissolved in 1.5L acetonitrile at 65 DEG C, then 3.5L sherwood oil is instilled, 15 DEG C are cooled to the speed of 0.1 DEG C/s, leave standstill 1 hour, centrifugal, the omeprazole thioether 845g filtering refining, yield is 89.1%, purity is 99.79%, wherein, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol, the consumption mol ratio of potassium hydroxide is 1:1.2:0.1,
2) by step 1) the omeprazole thioether 630g that obtains mixes in 5L acetone with the compound shown in formula A, inorganic metal salt, and mixing condition is: temperature 53 DEG C, stirs 1 hour, obtains mixture B; Wherein, the consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.7:0.3, and described inorganic metal salt is MnCl
2.
3) be, under the condition of 40 DEG C, oxygenant is added step 2 in temperature) mixture B in carry out oxidizing reaction, add potassium hydroxide methanol solution after reaction terminates, obtain esomeprazole potassium; Described oxygenant is tertiary amyl hydrogen peroxide, and the mol ratio of oxygenant and omeprazole thioether is 1.3; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.5 with the mol ratio of omeprazole thioether.
4) by step 3) 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 3
A preparation method for esomeprazole magnesium trihydrate, comprises the following steps:
1) under sodium carbonate exists, by 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-sulfydryl-5-methoxybenzimidazol 540g carries out back flow reaction and obtains omeprazole thioether in 4 hours in 4LTHF, then refine, refining process is: first omeprazole thioether is dissolved in 1.5L acetonitrile at 65 DEG C, then 3.7L sherwood oil is instilled, 12 DEG C are cooled to the speed of 0.15 DEG C/s, leave standstill 1 hour, centrifugal, the omeprazole thioether 790g filtering refining, yield is 83.5%, purity is 99.58%, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol, the consumption mol ratio of sodium carbonate is 1:1:0.15,
2) by step 1) the omeprazole thioether 630g that obtains mixes in 5L acetone with the compound shown in formula A, inorganic metal salt, and mixing condition is: temperature 55 DEG C, stirs 1 hour, obtains mixture B; Wherein, the consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.6:0.4, and described inorganic metal salt is CoCl
2.
3) be, under the condition of 45 DEG C, oxygenant is added step 2 in temperature) mixture B in carry out oxidizing reaction, add potassium hydroxide methanol solution after reaction terminates, obtain esomeprazole potassium; Described oxygenant is tertbutyl peroxide, and the mol ratio of oxygenant and omeprazole thioether is 1.3; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.3 with the mol ratio of omeprazole thioether.
4) by step 3) 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 686.6g, yield: 89.5%, detect through HPLC, purity is 99.92%, and isomer-free becomes the impurity of sulfone with over oxidation.
Embodiment 4
A preparation method for esomeprazole magnesium trihydrate, comprises the following steps:
1) under sodium hydroxide exists, by 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-sulfydryl-5-methoxybenzimidazol carry out back flow reaction and obtain omeprazole thioether in 4 hours in 4LTHF, then refine, refining process is: first omeprazole thioether is dissolved in 1.5L acetonitrile at 60 DEG C, then 3L sherwood oil is instilled, 10 DEG C are cooled to the speed of 0.1 DEG C/s, leave standstill 1 hour, centrifugal, the omeprazole thioether 613g filtering refining, yield is 80.2%, purity is 99.70%, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol, the consumption mol ratio of sodium hydroxide is 1:0.8:0.05,
2) by step 1) the omeprazole thioether 630g that obtains mixes in 5L acetone with the compound shown in formula A, inorganic metal salt, and mixing condition is: temperature 30 DEG C, stirs 1 hour, obtains mixture B; Wherein, the consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.8:0.2, and described inorganic metal salt is FeCl
2.
3) be, under the condition of 50 DEG C, oxygenant is added step 2 in temperature) mixture B in carry out oxidizing reaction, add potassium hydroxide methanol solution after reaction terminates, obtain esomeprazole potassium; Described oxygenant is tertiary amyl hydrogen peroxide, and the mol ratio of oxygenant and omeprazole thioether is 1.4; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.5 with the mol ratio of omeprazole thioether.
4) by step 3) 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 5
A preparation method for esomeprazole magnesium trihydrate, comprises the following steps:
1) under salt of wormwood exists, by 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride 625g and 2-sulfydryl-5-methoxybenzimidazol carry out back flow reaction and must then refine by omeprazole thioether for 4 hours in 4LTHF, refining process is: first omeprazole thioether is dissolved in 1.5L acetonitrile at 60 DEG C, then 3L sherwood oil is instilled, 10 DEG C are cooled to the speed of 0.15 DEG C/s, leave standstill 1 hour, centrifugal, the omeprazole thioether 768.5g filtering refining, yield is 81.3%, purity is 99.85%, wherein, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol, the consumption mol ratio of salt of wormwood is 1:1:0.15,
2) by step 1) the omeprazole thioether 630g that obtains mixes in 5L acetone with the compound shown in formula A, inorganic metal salt, and mixing condition is: temperature 60 C, stirs 1 hour, obtains mixture B; Wherein, the consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:1:0.1, and described inorganic metal salt is CoSO
4.
3) be, under the condition of 10 DEG C, oxygenant is added step 2 in temperature) mixture B in carry out oxidizing reaction, add potassium hydroxide methanol solution after reaction terminates, obtain esomeprazole potassium; Described oxygenant is tertbutyl peroxide, and the mol ratio of oxygenant and omeprazole thioether is 1.3; Adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.4 with the mol ratio of omeprazole thioether.
4) by step 3) 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 686.6g, yield: 89.5%, detect through HPLC, purity is 99.92%, and isomer-free becomes the impurity of sulfone with over oxidation.
Embodiment 6
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 2) in be 20 DEG C by omeprazole thioether with the compound shown in formula A, the inorganic metal salt temperature mixed in acetone.White solid 563.7g, yield: 73.4%, detect through HPLC, purity is 99.81%, and content of isomer is 0.05% impurity becoming sulfone with without over oxidation.
Embodiment 7
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 2) in be 70 DEG C by omeprazole thioether with the compound shown in formula A, the inorganic metal salt temperature mixed in acetone.White solid 587.6g, yield: 76.6%, detect through HPLC, purity is 99.77%, and content of isomer is 0.02% impurity becoming sulfone with without over oxidation.
Embodiment 8
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) described in the compound shown in omeprazole thioether and formula A, inorganic metal salt consumption mol ratio be 1:0.4:0.05.White solid 556.2g, yield: 72.5%, detect through HPLC, purity is 98.72%, and content of isomer is 0.11% impurity becoming sulfone with without over oxidation.
Embodiment 9
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) described in the compound shown in omeprazole thioether and formula A, inorganic metal salt consumption mol ratio be 1:3:1.White solid 614.5g, yield: 80.1%, detect through HPLC, purity is 97.87%, and content of isomer is 0.01% impurity becoming sulfone with without over oxidation.
Embodiment 10
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 1) the omeprazole thioether that obtains is without treating process, and obtaining omeprazole thioether purity is 90.3%.Then use 698g (significant quantity 630g) for subsequent reactions, obtain esomeprazole magnesium trihydrate white solid 624.4g, yield: 81.4%, detects through HPLC, purity is 98.22%, and content of isomer is 0.01% impurity becoming sulfone with without over oxidation.
Comparative example 1
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 2) in do not add the compound shown in formula A.White solid 315.3g, yield: 41.1%, detect through HPLC, purity is 85.47%, and content of isomer is 8.43% become the content of sulfone impurity to be 5.58% with over oxidation.
Comparative example 2
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 2) ZnCl of middle equal in quality
2replace CoCl
2.White solid 404.3g, yield: 65.4%, detect through HPLC, purity is 93.80%, and content of isomer is 4.35% become the content of sulfone impurity to be 1.71% with over oxidation.
Comparative example 3
As the preparation method of the esomeprazole magnesium trihydrate in embodiment 1, difference is, in step 2) described in temperature be 65 DEG C.White solid 394.3g, yield: 51.4%, detect through HPLC, purity is 92.90%, and content of isomer is 1.93% become the content of sulfone impurity to be 4.22% with over oxidation.
Comparative example 4
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 462.4g, yield is 60.3%.The content 99.71% of esomeprazole magnesium trihydrate, omeprazole thioether content is 0.06%, and superoxide " sulfone " foreign matter content is 0.10%, and isomer impurities content is 0.12%.
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 (9)
1. treat an esomeprazole magnesium trihydrate preparation method for digestive system, it is characterized in that, comprise the following steps:
1) under basic cpd exists, by 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol carry out back flow reaction and obtain omeprazole thioether in THF, wherein, basic cpd is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate and salt of wormwood;
2) by step 1) the omeprazole thioether that obtains mixes in acetone with the compound shown in formula A, inorganic metal salt, obtains mixture B;
3) be, under the condition of 10-50 DEG C, oxygenant is added step 2 in temperature) mixture B in carry out oxidizing reaction, add potassium hydroxide methanol solution after reaction terminates, obtain esomeprazole potassium;
4) by step 3) 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 2) in, described inorganic metal salt is cobalt (II), iron (II) or manganese (II) metal-salt.
2. method according to claim 1, it is characterized in that, in step 1) in, the consumption mol ratio of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride and 2-sulfydryl-5-methoxybenzimidazol, basic cpd is 1:0.8-1.2:0.05-0.15.
3. method according to claim 1, it is characterized in that, in step 1) in, also comprise the process of refining gained omeprazole thioether, refining process is: first omeprazole thioether is dissolved in acetonitrile at 60-65 DEG C, then instills sherwood oil, 10-15 DEG C is cooled to the speed of 0.05-0.15 DEG C/s, leave standstill 1 hour, centrifugal, filter refining omeprazole thioether, the volume ratio of described acetonitrile and sherwood oil is 1:2-2.5.
4. preparation method according to claim 1, is characterized in that, in step 2) in, the condition of described mixing comprises: temperature 30-60 DEG C, stirs 0.5-1 hour; The consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.6-1.2:0.1-0.4;
Preferably, in step 2) in, the condition of described mixing comprises: temperature 50-55 DEG C, stirs 0.5-1 hour; The consumption mol ratio of described omeprazole thioether and the compound shown in formula A, inorganic metal salt is 1:0.6-0.7:0.2-0.4.
5. the preparation method according to claim 1-4, is characterized in that, in step 2) in, described inorganic metal salt is CoCl
2, FeCl
2, MnCl
2, CoSO
4, FeSO
4or MnSO
4.
6. preparation method according to claim 5, is characterized in that, in step 2) in, described inorganic metal salt is MnCl
2or MnSO
4.
7. preparation method according to claim 1, it is characterized in that, in step 3) in, described oxygenant is tertbutyl peroxide or tertiary amyl hydrogen peroxide, the temperature of described oxidizing reaction is 40-45 DEG C, and the mol ratio of oxygenant and omeprazole thioether is 1.3-1.4.
8. preparation method according to claim 1, is characterized in that, in step 3) in, adding the amount of potassium hydroxide methanol solution, in potassium hydroxide, is 1.3-1.5 with the mol ratio of omeprazole thioether.
9. preparation method according to claim 1, is characterized in that, in step 4) in, the mol ratio of omeprazole thioether and Magnesium Chloride Anhydrous is 1:0.6-0.8.
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| CN113387929A (en) * | 2021-06-30 | 2021-09-14 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
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