CN103265528B

CN103265528B - Esomeprazole magnesium preparation method

Info

Publication number: CN103265528B
Application number: CN201310172173.7A
Authority: CN
Inventors: 姚亮元; 袁秀菊; 钟爱军; 曾要富; 王雪姣
Original assignee: HUNAN QIANJIN XIANGJIANG PHARMACEUTICAL CO Ltd
Current assignee: HUNAN QIANJIN XIANGJIANG PHARMACEUTICAL CO Ltd
Priority date: 2013-05-10
Filing date: 2013-05-10
Publication date: 2015-05-06
Anticipated expiration: 2033-05-10
Also published as: CN103265528A

Abstract

The invention discloses an esomeprazole preparation method and an esomeprazole magnesium preparation method. The esomeprazole preparation method is characterized in that a catalytic oxidation of omeprazole sulfide is carried out under the action of an added oxidant in the presence of bidentate chiral aminoalcohol and titanium alkoxide at room temperature to obtain a chiral proton pump inhibitor esomeprazole in a single enantiomer or enriched enantiomer form. The above preparation methods have the advantages of no need of the addition of an alkaline reagent, easy obtaining and reuse of the bidentate chiral aminoalcohol participating in the above reaction, increase of the utilization rate of the chiral aminoalcohol, substitution of expensive D-(-)-diethyl tartrate, and production cost reduction; and the chemical purity and the reaction overall yield of the prepared esomeprazole magnesium reach 99.7% and 66% respectively.

Description

Preparation method of esomeprazole magnesium

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a novel preparation method of esomeprazole magnesium.

Background

Esomeprazole magnesium (Esomeprazole magnesium), chemically bis-S-5-methoxy-2 { [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl]The sulfenamide-based } -1H-benzimidazole magnesium hydrate is a dihydrate compound, and the molecular formula is as follows: (C)₁₇H₁₈N₃O₃S)₂Mg·2H₂O, molecular weight: 749.12 its structural formula is shown in the following general formula 1, and is obtained by asymmetric oxidation of omeprazole thioether (shown in the following general formula 2) to form salt.

The S-enantiomer of omeprazole, commonly known as esomeprazole, has improved pharmacokinetic properties and improved therapeutic effects such as a lower degree of inter-individual variation (WO 94/27988). Esomeprazole magnesium is a well-known gastric proton pump inhibitor and has been commercially available from asikon since 2001 under the trade name NEXIUM, and is effective in preventing and treating gastric acid-related disorders and inflammatory gastrointestinal diseases (e.g., gastric ulcer, duodenal ulcer, reflux esophagitis and gastritis). In addition, it can be used for the treatment of other gastrointestinal disorders, where cytoprotective effects and inhibition of gastric secretion are also desirable.

The prior art mainly comprises the following methods for synthesizing S-omeprazole:

CN102702172A discloses a method for synthesizing nano esomeprazole sodium by using pyridine methanol as a starting material and adopting the process technologies of ultrasonic microwave coordinated chemical reaction, reduced pressure reaction, jet flow drying and the like.

CN102633776A discloses a chiral ligand formed by omeprazole thioether, D- (-) -diethyl tartrate and titanium tetraisopropoxide, N-diisopropylethylamine is added, and under the oxidation of oxidant tert-amyl hydroperoxide, esomeprazole is obtained. The method uses D- (-) -diethyl tartrate which is expensive.

CN102603261A discloses a target product of reflux reaction of (S) - ((4-methoxy-3, 5-dimethylpyridin-2-yl) methyl) sulfinyl) ethyl thiocarbamate and 4-methoxy-o-diphenylamine, which is obtained by using a raw material (((4-methoxy-3, 5-dimethylpyridin-2-yl) methyl) sulfinyl) ethyl thiocarbamate through a self-prepared oxidant.

CN102329302A invents isopropanol as a solvent, an alkaline reagent is added, and the chiral camphor sulfomatte compound oxidant is used for oxidizing omeprazole thioether to prepare esomeprazole. The chiral camphor sulfomatte triazine compound is difficult to obtain, and the reaction temperature requirement is strict.

CN102321071A discloses that inorganic alkali (potassium carbonate, sodium hydroxide, potassium hydroxide) is used for replacing organic alkali in the traditional method, but other metal ions (sodium or potassium) are introduced in the reaction, so that corresponding esomeprazole salt can be generated, and the content of magnesium salt obtained later is influenced to a certain extent.

CN102807560A adopts (S, S) -6,6 '-dihydroxy-2, 2' -biphenyl diethyl dicarboxylate as a chiral ligand inducer, adopts a molybdenum-containing compound as a catalyst, and adopts isopropyl hydroperoxide as an oxidant to catalyze and oxidize omeprazole thioether to obtain esomeprazole. The chiral ligand inducer used in the method has large dosage, is not easy to obtain, and uses toluene with high toxicity and boiling point.

CN101914090A discloses that under the condition of refluxing (S) -binaphthol and titanium tetraisopropoxide in tetrahydrofuran solvent, tert-butyl hydrogen peroxide decane solution is added, and omeprazole thioether is oxidized without adding any organic base to obtain esomeprazole. Among them, (S) -binaphthol is expensive.

CN102408412A discloses a method for preparing a compound by using (1R, 2S) -1-amino-2-indanol to replace the traditional D- (-) -diethyl tartrate, acetonitrile as a solvent, 4-methyl-2-pentanone for product aftertreatment, which has low yield and high acetonitrile toxicity, and 4-methyl-2-pentanone increases the production cost and is not suitable for industrial production.

CN1810803A discloses a (R, R) or (S, S) -1, 2-diaryl-1, 2-diol compound (especially (R, R) or (S, S) -1, 2-bis (2-bromo-phenyl) -1, 2-diol) and a metal titanium reagent in the presence of an oxidant tert-butyl hydroperoxide to selectively catalyze and oxidize omeprazole thioether, but the chemical purity does not reach the requirements of pharmacopoeia, the chiral bidentate ligand has high cost, and a solvent toluene with high toxicity is adopted in the reaction.

WO9427988 and WO04/002982 refer to a method for resolving racemic omeprazole by using a chiral resolving agent, but the traditional resolving method is difficult to effectively resolve omeprazole free alkali, and the method wastes excessive raw materials.

WO9617076 and WO9617077 mention the use of biological enzymes to oxidize omeprazole thioether or reduce omeprazole sulphone to obtain a single enantiomer of omeprazole, but this method is expensive in the early stage of industrial production.

CN101012141A discloses a method for obtaining esomeprazole by catalytic oxidation of omeprazole thioether in the presence of chiral amino alcohol and alkoxy zirconium or alkoxy titanium compound, wherein chiral amino alcohol is S-2-aminopropanol, S-2-amino-1-butanol, S-3-amino-1-butanol, S-phenylglycinol, S-phenylalaninol, S-leucinol, S-glycinol, S-methioninol, S-tryptophanol, S-asparaginol, S-skeleton, S-prolinol, S-valinol, S-isoleucinol, S-serinol, S-hydroxyprolinol, S-threoninol, S-argininol, and the yield of the method is low.

CN101070315A discloses a method for synthesizing omeprazole racemate by using 1-hydroxy-1, 2-phenyliodoyl-3 (1H) -ketone-1-oxide as an oxidizing agent and a quaternary ammonium salt compound as a catalyst, which does not solve the problem of obtaining single enantiomer esomeprazole.

WO2008/018091 discloses a conventional esomeprazole synthesis method, but the requirement on temperature is strict, and the solvent used is still toluene with high toxicity.

In WO2009114981, under the existence of a complex catalyst formed by (+) -or (-) -tartaric acid diamide ligand and titanium, an oxidant is used for directly and asymmetrically oxidizing omeprazole thioether into esomeprazole. But still does not solve the problem of the toxic solvent toluene.

In WO2010043601, esomeprazole salt is obtained in a solvent acetonitrile in the presence of a metal complex with a more complex structure and hydrogen peroxide, but the chemical purity is not high.

The derivative of S-mandelic acid adopted in WO2011120475 and the 1,1, 2-triphenyl-1, 2-diol adopted in WO2007074099 replace D- (-) -diethyl tartrate, so that the product has high chemical purity but low yield, and the post-treatment requires column chromatography to purify the crude product, so that the operation is complex, and the production cost is increased.

WO2011012957 also discloses a synthesis method of the traditional esomeprazole, but the experimental conditions are harsh, and nitrogen protection reaction is required.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects, and research and design a simple method for preparing esomeprazole and esomeprazole magnesium with high chemical purity and high yield, so that the method is simple and easy to implement, reduces the production cost, and is suitable for industrial production.

The above object of the present invention is achieved by the following scheme:

according to one aspect of the present invention, there is provided a method for producing esomeprazole, which is characterized by: oxidizing 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole (namely, omeprazole thioether) by using an oxidizing agent in the presence of bidentate chiral amino alcohol and alkoxy titanium in an organic solvent to obtain the esomeprazole.

Wherein,

preferably, the organic solvent is any one of an ester solvent (e.g., ethyl acetate), an ether solvent (e.g., diethyl ether, tetrahydrofuran), a halogenated hydrocarbon solvent (e.g., dichloromethane, chloroform), an aromatic hydrocarbon solvent (e.g., toluene), a ketone solvent (e.g., acetone), and a nitrile solvent (e.g., acetonitrile), and most preferably dichloromethane. The raw materials and other reagents have high normal-temperature solubility in dichloromethane, and do not need to be heated for dissolution.

Preferably, the bidentate chiral amino alcohol may be a phenyl-containing bidentate chiral amino alcohol, more preferably a bidentate chiral amino alcohol containing two or three phenyl groups. Typically having a total of from 8 to 30 carbon atoms, more preferably from 14 to 26 carbon atoms, and at least one hydroxyl group and at least one amino group, such as one hydroxyl group and one amino group. More preferably, the bidentate chiral amino alcohol is of the structure:

wherein R is₁The alkyl group may be any of hydrogen, phenyl, benzyl, C1-4 alkyl, 1H-indol-3-alkyl, and C1-4 alkyl.

Particularly preferably, the bidentate chiral amino alcohol may be (2R) -2-amino-1, 1, 2-triphenyl-ethanol, (2R) -2-amino-1, 1, 3-triphenyl-1-propanol, (2R) -2-amino-4-methyl-1, 1-diphenyl-1-pentanol, (2R) -2-amino-3- (1H-indol-3-yl) -1, 1-diphenyl-1-propanol, (2R) -2-amino-1, 1-diphenyl-ethanol, or (2R) -2-amino-1, 1-diphenyl-1, 4-pentanediol.

Preferably, the bidentate chiral amino alcohol is the product of a grignard reaction of the D amino acid with a halobenzene (e.g., bromobenzene) in an organic solvent (e.g., diethyl ether).

Bidentate chiral amino alcohol is introduced into a benzene ring through formatting, and the purpose is to improve the stereoselectivity of the chiral amino alcohol by utilizing the steric hindrance of the benzene ring. The selected bidentate chiral amino alcohol can also be recycled. And the chiral amino alcohol has amino group and is alkaline, so that alkali substances are not required to be added additionally, impurities are reduced, and the formation of byproducts is reduced.

Preferably, the molar ratio of the bidentate chiral amino alcohol to the omeprazole thioether is 0.02: 1.0-1.2: 1.0, further preferably 0.05: 1.0-1.0: 1.0, or 0.1: 1.0-0.8: 1.0; more preferably 0.3: 1.0-0.7: 1.0, e.g. 0.5: 1.0.

preferably, the titanium alkoxide is a tetrakis (C1-C10) titanium alkoxide, more preferably a tetrakis (C1-C6) titanium alkoxide, and still more preferably any one or a combination of two or more of tetramethoxytitanium, tetraethoxytitanium, tetrapropoxytitanium, tetrabutoxytitanium, tetraisopropoxytitanium, tetraisobutoxytitanium, and tetra-t-butoxytitanium. The molar ratio of the used alkoxy titanium to the used omeprazole thioether is 0.1: 1.0-1.5: 1.0, more preferably 0.15: 1.0-1.2: 1.0, preferably 0.2: 1.0-0.8: 1.0, preferably 0.3: 1.0-0.7: 1.0; more preferably 0.4: 1.0-0.6: 1.0 e.g. 0.5: 1.0.

preferably, the oxidant required for oxidation is an inorganic peroxide type oxidant or an organic peroxide type oxidant, more preferably hydrogen peroxide (for example, in the form of hydrogen peroxide), potassium persulfate or sodium persulfate, or a C1-C20 organic peroxide type oxidant, and further preferably any one or a combination of two or more of hydrogen peroxide, C1-9 alkyl peroxide (preferably, C2-8 alkyl peroxide, more preferably, C3-6 alkyl peroxide, such as tert-butyl hydroperoxide), and C1-6 alkyl phenyl peroxide (preferably, C3-5 alkyl phenyl peroxide, such as cumene hydroperoxide). Cumene hydroperoxide is particularly preferred. The molar ratio of oxidizing agent to omeprazole thioether is preferably 0.6: 1.0-3.5: 1.0, more preferably 0.7: 1.0-3.0: 1.0, more preferably 0.75: 1.0-2.5: 1.0, more preferably 0.8: 1.0-2.0: 1.0, more preferably 0.9: 1.0-1.6: 1.0, or 1.0: 1.0-1.4: 1.0, or 1.1: 1.0-1.2: 1.0.

preferably, the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole (i.e., omeprazole thioether) is obtained by reacting 2-mercapto-5-methoxybenzimidazole with 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride in a solvent under the condition of dropwise adding an alkali solution.

Wherein the solvent described herein and the organic solvent described above may be the same or different. The solvent is preferably any one or a combination of two or more of organic alcohol solvents (e.g., C1-C6 organic alcohols such as methanol, ethanol, isopropanol), nitrile solvents such as acetonitrile, ester solvents such as ethyl acetate, etc., preferably methanol, and the raw material has high solubility in methanol and a low boiling point.

The alkali solution is any inorganic alkali solution, the inorganic alkali can be any one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate, and preferably sodium hydroxide aqueous solution.

The reaction molar ratio of the 2-mercapto-5-methoxybenzimidazole, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and the inorganic base is preferably (0.7 to 2.0): (0.7 to 3.5): 1.4 to 7), preferably (0.8 to 1.8): 0.9 to 3.0): 1.6 to 5, preferably (1.0 to 1.6): 1.0 to 2.5): 1.8 to 4, preferably (1.0 to 1.6): 1.1 to 2.2): 2.0 to 3.5, preferably 1.0: 0.9: 1.0-1.0: 1.5: 3.0, more preferably in a ratio of 1.0: 1.05: 2.15. the reaction temperature is 40 to 100 ℃, preferably 45 to 95 ℃, or 50 to 90 ℃, more preferably 55 to 85 ℃, or 60 to 80 ℃, or 65 to 75 ℃, for example 70 ℃. The reaction time is 3-10 h, preferably 4-8 h, further preferably 5-7 h, for example 6 h.

According to another aspect of the present invention, there is provided a process for preparing esomeprazole magnesium, which comprises adding esomeprazole obtained by the above process to an alcohol solution formed by a magnesium alkoxide in an organic alcohol solvent (e.g., C1-C6 alcohol solvent) to perform a reaction. The magnesium alkoxide may be a C1-C6 magnesium alkoxide, preferably a C1-C4 magnesium alkoxide. Preferably magnesium methoxide, magnesium ethoxide, magnesium propoxide, magnesium butoxide, magnesium amyl alcohol, etc., preferably magnesium methoxide. The molar ratio of the used amount of the magnesium alkoxide to the used amount of the omeprazole thioether is preferably 0.3: 1.0-2.5: 1.0, preferably 0.4: 1.0-2.0: 1.0, preferably 0.5: 1.0-1.5: 1.0, more preferably 0.7: 1.0-1.4: 1.0, or 0.8: 1.0-1.2: 1.0. the organic alcohol is methanol, ethanol, propanol, ethylene glycol, etc., preferably methanol. Firstly, the esomeprazole magnesium has high solubility in methanol, secondly, methanol is generated after the magnesium methoxide and the esomeprazole are salified, and a matched solvent is selected. Reacting at normal temperature for 0.5-8h, preferably 1-4 h, preferably 2 h. The reaction can be carried out for 0.5-8h, 1-4 h, preferably 2h at normal temperature and at elevated temperature.

In a preferred embodiment, the process for the preparation of esomeprazole magnesium comprises the steps of:

(1) 2-mercapto-5-methoxybenzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride are added to a solvent, an alkaline solution is added dropwise to carry out a reaction (for example, a reaction is carried out under heating and refluxing with stirring), and omeprazole sulfide (5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole) is obtained through post-treatment (for example, crystallization, suction filtration, washing, etc.). Preferably, the solvent described herein is an organic alcohol solvent (e.g., C1-C6 organic alcohol such as methanol, ethanol, isopropanol), a nitrile solvent such as acetonitrile, an ester solvent such as ethyl acetate.

(2) Dissolving the omeprazole sulfide obtained in the step (1) in an organic solvent (such as dichloromethane) to obtain a reaction system. The organic solvent may be the same as or different from the solvent in step (1). Preferably, the organic solvent is any one of an ester solvent (e.g., ethyl acetate), an ether solvent (e.g., diethyl ether, tetrahydrofuran), a halogenated hydrocarbon solvent (e.g., dichloromethane, chloroform), an aromatic hydrocarbon solvent (e.g., toluene), a ketone solvent (e.g., acetone), and a nitrile solvent (e.g., acetonitrile).

(3) Adding phenyl-containing bidentate chiral amino alcohol (as described above) and titanium alkoxide (as described above) into the reaction system of the step (2) to perform a reaction (for example, a reaction is performed at 10-50 ℃, preferably at 15-40 ℃, more preferably at room temperature), for example, a reaction is performed for 70-250 minutes, preferably for 90-180 minutes, preferably for 100-120 minutes;

(4) dropwise adding an oxidant (as described above) into the reaction system in the step (3), and continuing the reaction (for example, reacting at normal temperature, for example, reacting at 10-50 ℃, preferably at 15-40 ℃, more preferably at room temperature), for example, reacting for 4-35 h, 5-24 h, preferably 8-20 h, or 10-18 h, further preferably 12-16 h;

(5) after the reaction in the step (4) is finished, dropwise adding a reducing agent (for example, an aqueous solution of sulfite such as sodium sulfite or potassium sulfite) to quench the reaction; preferably, the molar ratio of the sulfite to the omeprazole thioether used is 0.6: 1.0-1.8: 1.0, preferably 0.8: 1.0-1.6: 1.0;

(6) separating the solution obtained in the step (5), wherein an organic phase is extracted by ammonia water, and an obtained ammonia water phase is extracted by an organic solvent to obtain an extract organic phase;

(7) removing the solvent from the organic phase of the extract obtained in the step (6), adding an alcohol solution (as described above) formed by magnesium alkoxide in organic alcohol into the obtained residue, and reacting (e.g., reacting at room temperature), for example, for 0.5 to 7 hours, preferably for 1 to 4 hours, preferably for 2 to 3 hours;

(8) after the reaction in the step (7) is finished, filtering the reaction solution, and removing the alcohol solvent from the filtrate (for example, rotary evaporation removal) to obtain a crude esomeprazole magnesium product;

(9) recrystallizing the esomeprazole magnesium crude product obtained in the step (8) by using an organic solvent, and purifying to obtain the esomeprazole magnesium.

Preferably, the conditions of each step are as described above. The amounts or relative amounts of the respective raw materials in the above-mentioned methods are as described above.

preferably, the molar ratio of the alkoxy titanium to the omeprazole thioether is 0.1: 1.0-1.5: 1.0, more preferably 0.15: 1.0-1.2: 1.0, preferably 0.2: 1.0-0.8: 1.0, preferably 0.3: 1.0-0.7: 1.0; more preferably 0.4: 1.0-0.6: 1.0 e.g. 0.5: 1.0.

preferably, the molar ratio of oxidizing agent to omeprazole thioether is preferably 0.6: 1.0-3.5: 1.0, more preferably 0.7: 1.0-3.0: 1.0, more preferably 0.75: 1.0-2.5: 1.0, more preferably 0.8: 1.0-2.0: 1.0, more preferably 0.9: 1.0-1.6: 1.0, or 1.0: 1.0-1.4: 1.0, or 1.1: 1.0-1.2: 1.0.

preferably, the reaction molar ratio of the 2-mercapto-5-methoxybenzimidazole, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and the inorganic base is preferably (0.7 to 2.0): 0.7 to 3.5): 1.4 to 7), preferably (0.8 to 1.8): 0.9 to 3.0): 1.6 to 5, preferably (1.0 to 1.6): 1.0 to 2.5): 1.8 to 4, preferably (1.0 to 1.6): 1.1 to 2.2): 2.0 to 3.5, preferably 1.0: 0.9: 1.0-1.0: 1.5: 3.0, more preferably in a ratio of 1.0: 1.05: 2.15.

preferably, the molar ratio of the magnesium alkoxide to the omeprazole thioether is preferably 0.3: 1.0-2.5: 1.0, preferably 0.4: 1.0-2.0: 1.0, preferably 0.5: 1.0-1.5: 1.0, more preferably 0.7: 1.0-1.4: 1.0, or 0.8: 1.0-1.2: 1.0.

further preferred embodiments are the following:

in the step (1), the solvent adopted by the reaction is any one or more than two of methanol, ethanol, ethyl acetate, isopropanol, acetonitrile and the like, preferably methanol, and the raw material has high solubility in methanol and low boiling point; the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, etc., preferably sodium hydroxide, and has easily available raw materials and suitable price. The reaction molar ratio of 2-mercapto-5-methoxybenzimidazole, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride to sodium hydroxide is 1.0: 0.9: 1.0-1.0: 1.5: 3.0, preferably in a ratio of 1.0: 1.05: 2.15 of; the temperature is 40-100 ℃, and preferably 85 ℃; the reaction time is 3-10 h, preferably 5 h.

The solvent used in step (2) is one or more selected from ethyl acetate, dichloromethane, toluene, acetone, chloroform, tetrahydrofuran, acetonitrile, etc., preferably dichloromethane, because the solubility of the raw materials and other reagents in dichloromethane at normal temperature is high and the dissolution by heating is not required.

The bidentate chiral amino alcohol adopted in the step (3) is a product obtained by Grignard reaction of D-type amino acid and bromobenzene under the condition of diethyl ether, and the structure of the product is as follows:

wherein R is₁The alkyl group may be any of hydrogen, phenyl, benzyl, C1-4 alkyl, 1H-indole-3-methyl, and C1-4 alkyl alcohol. The bidentate chiral amino alcohol may be one or more of (2R) -2-amino-1, 1, 2-triphenyl-ethanol, (2R) -2-amino-1, 1, 3-triphenyl-1-propanol, (2R) -2-amino-4-methyl-1, 1-diphenyl-1-pentanol, (2R) -2-amino-3- (1H-indol-3-yl) -1, 1-diphenyl-1-propanol, (2R) -2-amino-1, 1-diphenyl-ethanol, (2R) -2-amino-1, 1-diphenyl-1, 4-pentanediol and the like. The molar ratio of bidentate chiral amino alcohol to omeprazole thioether was 0.02: 1.0-0.8: 1.0, preferably 0.5: 1.0. the bidentate chiral amino alcohol is introduced into a benzene ring through formattingThe aim is to improve the stereoselectivity of chiral amino alcohols by using the steric hindrance of the benzene ring. The selected bidentate chiral amino alcohol can also be recycled. And the chiral amino alcohol has amino group and is alkaline, so that an alkali substance is not required to be added additionally. The adopted alkoxy titanium is one or more than two of tetramethoxy titanium, tetraethoxy titanium, tetrapropoxy titanium, tetrabutoxy titanium, tetraisopropoxy titanium, tetraisobutoxy titanium and tetra-tert-butoxy titanium. The molar ratio of titanium alkoxide to omeprazole thioether was 0.2: 1.0-0.8: 1.0, preferably 0.5: 1.0.

the oxidant used in the step (4) is hydrogen peroxide, C1-4 alkyl peroxide or C1-4 alkyl phenyl peroxide, and cumene hydroperoxide is preferred. The molar ratio of the oxidizing agent to the omeprazole thioether is 1.0: 1.0-1.5: 1.0, preferably 1.0: 1.0. and reacting at normal temperature for 5-24 h, preferably 12 h.

The sulfite used in the step (5) is sodium sulfite; preferably, the molar ratio of the sulfite to the omeprazole thioether used is 0.6: 1.0-1.8: 1.0, preferably 0.8: 1.0-1.6: 1.0; preferably 1.0: 1.0-1.5: 1.0, preferably 1.1: 1.0-1.4: 1.0, or 1.2: 1.0-1.3: 1.0.

the organic solvent used in step (6) is one or more of ethyl acetate, toluene, diethyl ether, etc., preferably ethyl acetate. Firstly, the extraction effect is good, and the use of an expensive extractant is avoided; secondly, the boiling point is low and the recovery is easy. The magnesium alkoxide used in step (7) may be magnesium methoxide or magnesium ethoxide, preferably magnesium methoxide. The molar ratio of the used magnesium alkoxide to the used omeprazole thioether is preferably 0.5: 1.0-1.5: 1.0, more preferably 0.7: 1.0-1.4: 1.0, or 0.8: 1.0-1.2: 1.0. the solvent alcohol is methanol, ethanol and the like, preferably methanol, the solubility of esomeprazole magnesium in methanol is high, the methanol is generated after the magnesium methoxide and esomeprazole are salified, and a matched solvent is selected. Reacting for 1-4 h at normal temperature, preferably for 2 h.

After the reaction in the step (8) is finished, membrane filtration is adopted, and the alcohol solvent is dried in a spinning mode, so that a light yellow solid esomeprazole magnesium crude product is obtained;

in step (9), the crude product may be dissolved first, and the solvent for dissolving the crude product may be any one or more of methanol, ethanol, acetone, acetonitrile, etc., preferably methanol. The ratio of crude product to dissolution solvent is 1: 1-1: 10 (mass/g: volume/ml), preferably 1: 3-1: 8, or 1: 4-1: 6.

the recrystallization solvent can be any one or more of ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide and acetone, preferably ethyl acetate, the product has low solubility in ethyl acetate, and other impurities can be removed. The volume ratio of the dissolving solvent to the crystallization solvent is 1: 5-1: 20, preferably 1: 8-1: 15, or 1: 10-1: 12. the crystallization temperature is 20-35 ℃, preferably 22-32 ℃ or 25-28 ℃. The crystallization time is 1-2 h, preferably 2 h. And (4) carrying out suction filtration after recrystallization, and carrying out vacuum drying on the solid at 50 ℃. The recrystallization purification according to the proportion can be repeated, for example, 1,2 or 3 times, and the purity of the obtained purified esomeprazole magnesium can reach 95-99.9 wt%, preferably 97-99.9 wt%, even 99.95%.

The synthetic route of the preparation method of esomeprazole magnesium is as follows:

as a preferred embodiment of the present invention, the method for synthesizing esomeprazole magnesium comprises:

dissolving 2-mercapto-5-methoxybenzimidazole in methanol, dripping aqueous solution of sodium hydroxide to obtain clear solution, stopping dripping sodium hydroxide, adding 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride in batches, further dripping residual sodium hydroxide, heating to 85 deg.C, and stirring for refluxing for 5 hr. After the reaction is finished, recovering methanol under reduced pressure, adjusting the acidity of the residual aqueous solution to pH =8 by using acetic acid, extracting the aqueous solution for three times by using dichloromethane, recovering the dichloromethane under reduced pressure, adding a proper amount of ethyl acetate, refluxing, cooling, and stirring at room temperature for crystallization. And (4) carrying out suction filtration and washing with ethyl acetate to obtain an omeprazole thioether white solid.

Taking a reaction bottle, adding omeprazole thioether, dissolving with dichloromethane, adding bidentate chiral amino alcohol and alkoxy titanium, continuously reacting for 2h at the temperature, dropwise adding an oxidant, finishing dropwise adding, carrying out thin-layer chromatography tracking reaction, stirring at normal temperature for reacting for 12h, and dropwise adding an aqueous solution of sodium sulfite for quenching reaction. Separating, extracting dichloromethane with ammonia water for three times, extracting the aqueous solution with ethyl acetate for three times, combining ethyl acetate phases, and recovering ethyl acetate under reduced pressure to obtain a yellowish-brown oily substance, namely esomeprazole. Adding magnesium methoxide, using methanol as a solvent, and stirring and reacting for 2 hours at normal temperature. And filtering the reaction solution by using a membrane, and removing methanol from the filtrate by decompression to obtain a light yellow solid (esomeprazole magnesium crude product).

Dissolving the omeprazole magnesium crude product in a proper amount of methanol, dropwise adding a certain amount of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. And (4) carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain white or off-white esomeprazole magnesium solid powder.

The preparation method has the following advantages:

1. the preparation method adopts bidentate chiral amino alcohol to replace D- (-) -diethyl tartrate of the traditional method, and the used bidentate chiral amino alcohol is a product obtained by Grignard reaction of D-type amino acid and bromobenzene under the condition of diethyl ether, and is simple and easy to obtain. And secondly, the selected bidentate chiral amino alcohol can be recycled, and the chiral amino alcohol has amino groups and is alkaline, so that an alkali substance is not required to be additionally added, and the production cost is greatly reduced.

2. The chemical purity of the product prepared by the method reaches 99.7 percent, the total yield of the three-step reaction reaches 66 percent, and the method is suitable for industrial production.

In the step (1), 2-mercapto-5-methoxybenzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride are added into an alcohol solvent, an alkali solution is dropwise added, reflux is carried out, and the omeprazole thioether is obtained through post-treatment, wherein the purity is up to 99.8%, and the yield is up to 96%.

3. In the method for preparing esomeprazole magnesium, the obtained organic phase esomeprazole does not need to be dried, magnesium methoxide is directly added for reaction to obtain high-selectivity esomeprazole magnesium, the ee value reaches 99.7%, and the total reaction yield reaches 66%.

4. The preparation method disclosed by the invention adopts normal-temperature reaction, and does not need reaction at low temperature or under the protection of nitrogen, so that the requirements on instruments and equipment are reduced; moreover, the reaction condition is mild, the reaction is easy to control, and the pollution is small.

5. The reaction condition is mild, the reaction is easy to control, and the pollution is small; the bidentate chiral amino alcohol adopted by the invention can also be recycled (the dichloromethane phase is directly decompressed and recycled after being extracted by ammonia water, and the residue is bidentate chiral amino alcohol), so that the production cost is reduced; the bidentate chiral amino alcohol synthesized by using lower cost has high selectivity, and the ee value of the final product even reaches 99.9 percent.

Drawings

Figure 1 is an IR spectrum of omeprazole sulfide, an intermediate of example 1.

Figure 2 is an HPLC diagram of the final product esomeprazole magnesium of example 1.

Figure 3 is an IR spectrum of the final product esomeprazole magnesium of example 1.

FIG. 4 is a drawing of the final product esomeprazole magnesium of example 1¹H-NMR spectrum.

Detailed Description

For a further understanding of the invention, reference will now be made to the following examples which are provided in connection with the accompanying drawings. Unless otherwise specified, various starting materials of the present invention are commercially available; or prepared according to conventional methods in the art. The raw materials used in the method are all industrial grade, and the used equipment is common experimental equipment. Unless defined or stated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any method and primer similar or equivalent to those described herein can be used in the method of the present invention. It is to be understood that such description is merely illustrative of the features and advantages of the present invention, and is not intended to limit the scope of the claims.

Example 1

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After the reaction was completed, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the residue, and then heating reflux, cooling, and crystallization was performed with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.76kg of omeprazole thioether white solid with the yield of 96%, the purity of 99.8% and the m.p.121-122 ℃. IR (KBr), v/cm^-1: 3120, 2995, 2958, 2900, 1634, 1593, 1480, 1466, 1264, 1154, 1078, 1026, 805 (see fig. 1).

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500ml of dichloromethane, adding 43.9g of (2R) -2-amino-1, 1, 2-triphenyl-ethanol (0.152mol) and 43.2g of titanium tetraisopropoxide (0.152mol), continuing to react for 2h at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) as an oxidant, stirring for reacting for 12h at normal temperature after dropwise adding, performing thin-layer chromatography tracking reaction, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined, the combined aqueous ammonia phases were extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered from the extract under reduced pressure to give a yellowish brown oil.

To the resulting yellowish brown oil was added 13.2g of magnesium methoxide (0.152mol), and 200ml of methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution was filtered through a membrane, and the filtrate was subjected to rotary removal under reduced pressure (rotary evaporation under reduced pressure) of methanol to obtain 92.7g of a pale yellow solid (crude esomeprazole magnesium), with a total yield of 85.5% in the two-step reaction.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. Carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain 80g of off-white esomeprazole magnesium solid powder, wherein the ee value is 99.7%, the recrystallization yield is 80%, and the total reaction yield is 66%; the ee value was 99.9% (HPLC detection, chiral AGP column, acetonitrile-sodium dihydrogen phosphate solution mobile phase, see FIG. 2). IR (KBr), v/cm^-1: 3185, 2993, 2951, 1613, 1570, 1477, 1410, 1200, 1154, 1003, 834, 806, 632 (see fig. 3).¹H-NMR(400MHz，CDCl₃)，：2.13[s，3H]，2.25[s，3H]，3.69[s，3H],3.82[s，3H]，4.62[d，2H]，6.83[d，1H]，7.09[s，1H]，7.45[d，1H]，8.17[s，1H](see FIG. 4).

Example 2

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After completion of the reaction, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the obtained residue, and then the mixture was refluxed under heating, cooled, and crystallized with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.74kg of omeprazole thioether white solid with the yield of 95 percent, the purity of 99.5 percent and the m.p.121-122 ℃.

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500ml of dichloromethane, adding 87.8g of (2R) -2-amino-1, 1, 2-triphenyl-ethanol (0.304mol) and 43.2g of titanium tetraisopropoxide (0.152mol), continuing to react for 2h at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) as an oxidant, stirring for reacting for 12h at normal temperature after dropwise adding, carrying out thin-layer chromatography tracking reaction, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined and the combined aqueous ammonia phases were extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered under reduced pressure to give a yellowish brown oil. To the yellowish brown oil was added 13.2g of magnesium methoxide (0.152mol), and 200ml of methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution is filtered by a membrane, and methanol is removed from the filtrate by rotary evaporation under reduced pressure to obtain 65.8g of light yellow solid (crude esomeprazole magnesium product), wherein the total yield of the two-step reaction is 60%.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. And (3) carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain 82g of off-white esomeprazole magnesium solid powder, wherein the ee value is 99.6%, the recrystallization yield is 82%, and the total reaction yield is 51.4%.

Example 3

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After the reaction was completed, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the residue, and then heating reflux, cooling, and crystallization was performed with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.78kg of omeprazole thioether white solid with the yield of 97%, the purity of 99.5% and the m.p.121-122 ℃.

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500ml of dichloromethane, adding 22.0g of (2R) -2-amino-1, 1, 2-triphenyl-ethanol (0.076mol) and 43.2g of titanium tetraisopropoxide (0.152mol), continuing to react for 2h at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) serving as an oxidant, carrying out thin-layer chromatography tracking reaction, stirring at normal temperature for reacting for 12h, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined and the combined aqueous ammonia phases were extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered from the extract under reduced pressure to give a yellowish brown oil.

To the resulting yellowish brown oil, 13.2g of magnesium methoxide (0.152mol) was added, and 200ml of a methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution is filtered by a membrane, and methanol is removed from the filtrate by rotary evaporation under reduced pressure to obtain 35.8g of light yellow solid (crude esomeprazole magnesium), wherein the total yield of the two-step reaction is 33%.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. And (3) carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain 85g of off-white esomeprazole magnesium solid powder, wherein the ee value is 99.3%, the recrystallization yield is 85%, and the total reaction yield is 27.2%.

Example 4

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After the reaction was completed, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the residue, and then heating reflux, cooling, and crystallization was performed with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.69kg of omeprazole thioether white solid with the yield of 92 percent, the purity of 99.8 percent and the m.p.121-122 ℃.

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500ml of dichloromethane, adding 46.1g of (2R) -2-amino-1, 1, 3-triphenyl-1-propanol (0.152mol) and 43.2g of titanium tetraisopropoxide (0.152mol), continuing to react for 2 hours at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) serving as an oxidant, carrying out thin-layer chromatography tracking reaction after dropwise adding, stirring at normal temperature for reacting for 12 hours, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined and the combined aqueous ammonia phases were extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered from the extract under reduced pressure to give a yellowish brown oil. To the resulting yellowish brown oil, 13.2g of magnesium methoxide (0.152mol) was added, and 200ml of a methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution is filtered by a membrane, methanol is removed from the filtrate by rotary evaporation under reduced pressure, 89.0g of light yellow solid (crude esomeprazole magnesium) is obtained, and the total yield of the two-step reaction is 82.1%.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. And (3) carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain 83g of off-white esomeprazole magnesium solid powder, wherein the ee value is 97%, the recrystallization yield is 83%, and the total reaction yield is 62.6%.

Example 5

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After completion of the reaction, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the residue, and then the mixture was refluxed, cooled, and crystallized with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.72kg of omeprazole thioether white solid with the yield of 94%, the purity of 99.6% and the m.p.121-122 ℃.

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500ml of dichloromethane, adding 40.9g of (2R) -2-amino-4-methyl-1, 1-diphenyl-1-pentanol (0.152mol) and 43.2g of tetraisopropoxy titanium (0.152mol), continuing to react for 2 hours at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) as an oxidant, carrying out thin-layer chromatography tracking reaction, stirring at normal temperature for reacting for 12 hours, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined and the combined aqueous ammonia phases were extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered from the extract under reduced pressure to give a yellowish brown oil. To the yellowish brown oil was added 13.2g of magnesium methoxide (0.152mol), and 200ml of methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution is filtered by a membrane, and methanol is removed from the filtrate by rotary evaporation under reduced pressure to obtain 85.6g of light yellow solid (crude esomeprazole magnesium product), and the total yield of the two-step reaction is 79%.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. And (3) carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain 81g of off-white esomeprazole magnesium solid powder, wherein the ee value is 91%, the recrystallization yield is 81%, and the total reaction yield is 60%.

Example 6

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After the reaction was completed, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the residue, and then heating reflux, cooling, and crystallization was performed with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.76kg of omeprazole thioether white solid with the yield of 96%, the purity of 99.5% and the m.p.121-122 ℃.

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500m dichloromethane, adding 52.0g of (2R) -2-amino-3- (1H-indol-3-yl) -1, 1-diphenyl-1-propanol (0.152mol) and 43.2g of titanium tetraisopropoxide (0.152mol), continuing to react for 2H at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) as an oxidant, carrying out dropwise addition, carrying out thin-layer chromatography tracking reaction, stirring at normal temperature for reacting for 12H, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined and the combined aqueous ammonia phases were extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered from the extract under reduced pressure to give a yellowish brown oil. To the resulting yellowish brown oil, 13.2g of magnesium methoxide (0.152mol) was added, and 200ml of a methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution was filtered through a membrane, and the filtrate was subjected to rotary removal of methanol under reduced pressure to obtain 81.8g of a pale yellow solid (crude esomeprazole magnesium), with a total yield of 75.4% in the two-step reaction.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. And (3) carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain 84.5g of off-white esomeprazole magnesium solid powder, wherein the ee value is 94%, the recrystallization yield is 84.5%, and the total reaction yield is 61.2%.

Example 7

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After the reaction was completed, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the residue, and then heating reflux, cooling, and crystallization was performed with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.69kg of omeprazole thioether white solid with the yield of 93 percent, the purity of 99.8 percent and the m.p.121-122 ℃.

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500ml of dichloromethane, adding 32.4g of (2R) -2-amino-1, 1-diphenyl-ethanol (0.152mol) and 43.2g of titanium tetraisopropoxide (0.152mol), continuing to react for 2h at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) as an oxidant, dropwise adding the oxidant, carrying out thin-layer chromatography tracking reaction, stirring at normal temperature for reacting for 12h, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined and the aqueous phase was extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered from the extract under reduced pressure to give a yellowish brown oil. To the resulting yellowish brown oil was added 13.2g of magnesium methoxide (0.152mol), and 200ml of methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution is filtered by a membrane, and methanol is removed from the filtrate by rotary evaporation under reduced pressure to obtain 85.6g of light yellow solid (crude esomeprazole magnesium product), and the total yield of the two-step reaction is 79.0%.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. And (3) carrying out suction filtration, washing with ethyl acetate, and carrying out vacuum drying on the solid at 50 ℃ to obtain 80.1g of off-white esomeprazole magnesium solid powder, wherein the ee value is 82%, the recrystallization yield is 80.1%, and the total reaction yield is 58.9%.

Example 8

Dissolving 1kg of 2-mercapto-5-methoxybenzimidazole (5.56mol) in 12L of methanol, dropwise adding 478g of sodium hydroxide (12 mol) aqueous solution, dropwise adding to a clear solution, stopping dropwise adding sodium hydroxide, adding 1.08kg of 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride (5.84 mol) in batches, then continuously dropwise adding the rest sodium hydroxide, heating to 85 ℃, and stirring and refluxing for 5 hours. After the reaction was completed, methanol was recovered under reduced pressure, the remaining aqueous solution was adjusted to pH =8 with acetic acid, the aqueous solution was extracted three times with 3L of dichloromethane, dichloromethane was recovered under reduced pressure, 1.1L of ethyl acetate was added to the residue, and then heating reflux, cooling, and crystallization was performed with stirring at room temperature. And (3) carrying out suction filtration and washing with ethyl acetate to obtain 1.71kg of omeprazole thioether white solid with the yield of 93.3%, the purity of 99.6% and the m.p.121-122 ℃.

Taking a reaction bottle, adding 100g of omeprazole thioether (0.304mol) at normal temperature, dissolving with 500ml of dichloromethane, adding 39.1g of (2R) -2-amino-1, 1-diphenyl-1, 4-pentanediol (0.152mol) and 43.2g of tetraisopropoxytitanium (0.152mol), continuing to react for 2 hours at the temperature, dropwise adding 46.9g of cumene hydroperoxide (0.304mol) as an oxidant, carrying out thin-layer chromatography tracking reaction, stirring at normal temperature for reacting for 12 hours, and dropwise adding 100ml of aqueous solution of 38.1g of sodium sulfite (0.304mol) to quench the reaction. The layers were separated and the dichloromethane phase was extracted three times with 1L of aqueous ammonia, the aqueous ammonia phases were combined and the combined aqueous ammonia phases were extracted three times with 1L of ethyl acetate and the ethyl acetate was recovered from the extract under reduced pressure to give a yellowish brown oil. To the resulting yellowish brown oil, 13.2g of magnesium methoxide (0.152mol) was added, and 200ml of a methanol solvent was added, followed by stirring at room temperature for 2 hours. The reaction solution is filtered by a membrane, and methanol is removed from the filtrate by rotary evaporation under reduced pressure to obtain 90.5g of light yellow solid (crude esomeprazole magnesium), wherein the total yield of the two-step reaction is 83.5%.

Dissolving 100g of the crude omeprazole magnesium product in 100ml of methanol, dropwise adding 1000ml of ethyl acetate under stirring at normal temperature, and stirring for 2 hours at normal temperature after dropwise adding. Filtering, washing with ethyl acetate, and vacuum drying the solid at 50 ℃ to obtain 83.2g of off-white esomeprazole magnesium solid powder, wherein the ee value is 98.9%, the recrystallization yield is 83.2%, and the total reaction yield is 64.8%.

Claims

1. A preparation method of esomeprazole is characterized by comprising the following steps: oxidizing 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole by adopting an oxidant in an organic solvent in the presence of phenyl-containing bidentate chiral amino alcohol and alkoxy titanium to obtain esomeprazole; wherein the bidentate chiral amino alcohol has the structure:

wherein R is₁Is any one of hydrogen, phenyl, benzyl, C1-4 alkyl, 1H-indole-3-methylene and C1-4 alkyl alcohol.

2. The method of claim 1, wherein: the bidentate chiral amino alcohol is (2R) -2-amino-1, 1, 2-triphenyl-ethanol, (2R) -2-amino-1, 1, 3-triphenyl-1-propanol, (2R) -2-amino-4-methyl-1, 1-diphenyl-1-pentanol, (2R) -2-amino-3- (1H-indol-3-yl) -1, 1-diphenyl-1-propanol, (2R) -2-amino-1, 1-diphenyl-ethanol, or (2R) -2-amino-1, 1-diphenyl-1, 4-pentanediol.

3. The method of claim 1, wherein: the dosage molar ratio of the bidentate chiral amino alcohol to the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is 0.02: 1.0-1.2: 1.0.

4. the production method according to claim 3, characterized in that: the dosage molar ratio of the bidentate chiral amino alcohol to the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is 0.05: 1.0-1.0: 1.0.

5. the method of claim 1, wherein: the alkoxy titanium is tetra (C1-C10) alkoxy titanium.

6. The method of claim 5, wherein: the alkoxy titanium is any one of tetramethoxy titanium, tetraethoxy titanium, tetrapropoxy titanium, tetrabutoxy titanium, tetraisopropoxy titanium, tetraisobutoxy titanium and tetra-tert-butoxy titanium.

7. The production method according to claim 3, characterized in that: the molar ratio of the used alkoxy titanium to the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is 0.1: 1.0-1.5: 1.0.

8. the method of claim 5, wherein: the molar ratio of the used alkoxy titanium to the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is 0.1: 1.0-1.5: 1.0.

9. the method of claim 7, wherein: the molar ratio of the used alkoxy titanium to the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is 0.15: 1.0-1.2: 1.0.

10. the production method according to claim 1 or 2, characterized in that: the organic solvent is one or more than two of ester solvent, ether solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ketone solvent and nitrile solvent.

11. The method of manufacturing according to claim 10, wherein: the organic solvent is dichloromethane.

12. The production method according to claim 1 or 2, characterized in that: the oxidant required by the oxidation is an inorganic peroxide type oxidant or an organic peroxide type oxidant.

13. The method of manufacturing according to claim 12, wherein: the oxidant required by the oxidation is hydrogen peroxide, potassium persulfate or sodium persulfate or C1-C20 organic radical peroxide type oxidant.

14. The method of manufacturing according to claim 12, wherein: the oxidant required by the oxidation is cumene hydroperoxide.

15. The method of manufacturing according to claim 12, wherein: the molar ratio of the oxidant to the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is 0.6: 1.0-3.5: 1.0.

16. the method of claim 15, wherein: the molar ratio of the oxidant to the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is 0.7: 1.0-3.0: 1.0.

17. the production method according to claim 1 or 2, characterized in that: the 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole is obtained by reacting 2-mercapto-5-methoxybenzimidazole with 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride in a solvent under the condition of dropwise adding an inorganic base solution, wherein: the solvent is any one or more than two of organic alcohol solvents, nitrile solvents or ester solvents; and/or

The inorganic alkali is any one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate.

18. The method of claim 17, wherein: the reaction molar ratio of the 2-mercapto-5-methoxybenzimidazole, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and the inorganic base is (0.7-2.0): (0.7-3.5): 1.4-7.

19. The method of claim 18, wherein: the reaction molar ratio of the 2-mercapto-5-methoxybenzimidazole, 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride and the inorganic base is (0.8-1.8): (0.9-3.0): 1.6-5).

20. The method of claim 17, wherein: the reaction temperature is 40-100 ℃; the reaction time is 3-10 h.

21. The method of claim 20, wherein: the reaction temperature is 60-80 ℃; the reaction time is 4-8 h.

22. A preparation method of esomeprazole magnesium comprises the following steps:

(1) adding 2-mercapto-5-methoxybenzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride into a solvent, dropwise adding an alkali solution for reaction, and performing post-treatment to obtain 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole, namely omeprazole thioether;

(2) dissolving the omeprazole thioether obtained in the step (1) in an organic solvent to obtain a reaction system;

(3) adding phenyl-containing bidentate chiral amino alcohol and alkoxy titanium into the reaction system in the step (2) for reaction; wherein the bidentate chiral amino alcohol has the structure:

wherein R is₁Any one of hydrogen, phenyl, benzyl, C1-4 alkyl, 1H-indole-3-methylene and C1-4 alkyl alcohol;

(4) dropwise adding an oxidant into the reaction system in the step (3), and continuing to react;

(5) after the reaction in the step (4) is finished, dropwise adding a reducing agent to quench the reaction;

(7) removing the solvent in the organic phase of the extract obtained in the step (6), and adding an alcoholic solution formed by magnesium alkoxide in an organic alcohol solvent into the obtained residue to perform reaction;

(8) after the reaction in the step (7) is finished, filtering the reaction solution, and removing the alcohol solvent of the filtrate to obtain a crude esomeprazole magnesium product;

23. The method of claim 22, wherein: the reducing agent used in step (5) of the process is sulfite; the molar ratio of the usage amount of the sulfite to the usage amount of the omeprazole thioether is 0.6: 1.0-1.8: 1.0; and/or

The magnesium alkoxide adopted in the step (6) of the method is C1-C6 magnesium alkoxide; the molar ratio of the magnesium alkoxide to the omeprazole thioether is 0.3: 1.0-2.5: 1.0.

24. the method of claim 23, wherein: the reducing agent used in step (5) of the process is sulfite; the molar ratio of the usage amount of the sulfite to the usage amount of the omeprazole thioether is 0.8: 1.0-1.6: 1.0; and/or

The magnesium alkoxide adopted in the step (6) of the method is C1-C6 magnesium alkoxide; the molar ratio of the magnesium alkoxide to the omeprazole thioether is 0.4: 1.0-2.0: 1.0.

25. the production method according to any one of claims 22 to 24, characterized in that: in the step (9), the recrystallization solvent is one or more of ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide and acetone.

26. The method of claim 25, wherein: in the step (9), the recrystallization solvent is ethyl acetate.