CN108314675B - Preparation method of high-optical-purity anti-gastric ulcer drug R-lansoprazole - Google Patents
Preparation method of high-optical-purity anti-gastric ulcer drug R-lansoprazole Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J29/00—Catalysts comprising molecular sieves
- B01J29/03—Catalysts comprising molecular sieves not having base-exchange properties
- B01J29/0308—Mesoporous materials not having base exchange properties, e.g. Si-MCM-41
- B01J29/0341—Mesoporous materials not having base exchange properties, e.g. Si-MCM-41 containing arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2229/00—Aspects of molecular sieve catalysts not covered by B01J29/00
- B01J2229/10—After treatment, characterised by the effect to be obtained
- B01J2229/18—After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself
- B01J2229/186—After treatment, characterised by the effect to be obtained to introduce other elements into or onto the molecular sieve itself not in framework positions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention belongs to the technical field of chiral synthetic chemical drugs, and particularly relates to a preparation method of high-optical-purity gastric ulcer resistant drug R-lansoprazole, which takes a molecular sieve as a carrier, in-situ prepares tungsten trioxide loaded on the surface of the molecular sieve to obtain a tungsten loaded molecular sieve, L-hydroxyproline and tetraisopropyl titanate form a complex compound to be deposited on the surface of the tungsten loaded molecular sieve and/or in the pore diameter of the tungsten loaded molecular sieve to form a tungsten-titanium bimetallic center catalyst, and the catalyst can catalyze thioether 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl]-methylthio-1HAnd (3) carrying out oxidation reaction on benzimidazole to obtain the R-lansoprazole with high optical purity, wherein the chemical purity and the optical purity of the prepared product both meet the requirements of pharmaceutical-grade bulk drugs.
Description
Technical Field
The invention belongs to the technical field of chiral synthetic chemical drugs, and particularly relates to a preparation method of high-optical-purity gastric ulcer resistant drug R-lansoprazole.
Background
Lansoprazole is the second proton pump inhibitor to be marketed after omeprazole, has increased thermodynamic and oxidative stability due to the introduction of fluorine, and has greatly improved biological activity. Lansoprazole was developed by Wutian, Japan for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis, and for the eradication of helicobacter pylori.
Lansoprazole has one chiral center sulfur atom and thus has two optical isomers. And the lansoprazole sold in the market is racemate, so that adverse reactions such as headache, diarrhea, nausea and the like are clinically shown, and the liver cell tumor and the stomach tumor can be formed by taking the lansoprazole racemate for a long time. Research shows that the drug effect of R-configuration lansoprazole is obviously superior to that of lansoprazole racemate, and the toxic and side effects of optically active lansoprazole are lower than that of the lansoprazole racemate. Therefore, the optically pure lansoprazole has important significance.
The Resolution and asymmetric oxidation methods are mainly used for preparing R-lansoprazole, the 1997-year-old organic chemistry institute (Tetrahedron: Asymmetry,1997,8(15):2505 2508, Resolution of alkyl pyridine derivatives by complex synthesis with a chiral host compound and free from catalytic acid) reports that the Resolution of lansoprazole intermediate analogue alkyl pyridyl sulfoxide is only about 60% too low, which results in high Resolution cost, Jiangsusancon medicine Limited reports a method for preparing R-lansoprazole by asymmetric catalytic oxidation (chemical time journal, 2010,24(7):17-24, R- (+) -lansoprazole synthesis research), the literature reports that tetraisopropyl titanate and L-diethyl tartrate complexes are used as chiral catalysts, cumene hydroperoxide is not subjected to symmetric oxidation in an alkaline environment, R-lansoprazole is obtained by a reaction, GMP (GMP) is a part of the synthesis research of R- (+) -lansoprazole, the synthesis of isopropyl titanate and L-diethyl tartrate complex is not subjected to the symmetric oxidation reaction, GMP (GMP) is not subjected to the selective oxidation reaction, the byproduct of the isopropyl titanate and the byproduct is generated by the subsequent oxidation reaction, the subsequent oxidation reaction is not favorable for purifying the subsequent Lansoprazole by-produced, the byproduct of the catalytic oxidation reaction, and the byproduct of the subsequent oxidation of the byproduct of the selective recovery of the isopropyl titanate is generated.
The problem of catalyst recovery and separation of co-products of oxidant coproduction can be solved by using catalytic methods to oxidize thioethers to sulfoxides with hydrogen peroxide, but special conditions are often required, such as those reported in the literature (Org. L ett.2005,7:5015-3Loaded on MCM-48, catalyzed by H in methanol solution2O2The yield of sulfoxide is over 90%, but 50% of high-concentration hydrogen peroxide is needed (the high-concentration hydrogen peroxide is easy to explode in the oxidation process), and the chiral problem is not involved.
Therefore, the development of the high-purity chiral sulfoxide prepared by oxidizing the solid catalyst with low-concentration hydrogen peroxide has important significance in obtaining the high-optical-purity R-lansoprazole.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a novel catalytic method for preparing R-lansoprazole with high optical purity. The invention takes a substrate thioether 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole as a raw material, takes hydrogen peroxide as an oxygen source, adopts a solid catalyst to carry out oxidation reaction on the substrate to obtain the R-lansoprazole with high optical purity, and has the following reaction formula:
according to one aspect of the invention, the invention provides a preparation method of R-lansoprazole with high optical purity for an anti-gastric ulcer drug, which comprises the following steps:
1) adding a substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole into an organic solvent, then adding a catalyst at one time, and stirring for 10-20 min;
2) dropwise adding hydrogen peroxide with the mass concentration of 3-30% by weight into the reaction system, and after dropwise adding, keeping the temperature and stirring;
3) HP L C detects that a substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole reacts completely, a reducing agent is added to quench the reaction, and a catalyst is filtered to obtain R-lansoprazole reaction liquid;
4) crystallizing the R-lansoprazole reaction solution to obtain the R-lansoprazole with high optical purity.
The catalyst is a tungsten-titanium bimetallic center catalyst, and the tungsten-titanium bimetallic center catalyst is prepared by the following method:
a) a molecular sieve loading procedure: placing 3.96g of tungsten hexachloride in toluene under the nitrogen atmosphere, then adding 50g of mesoporous silica MSU-H, stirring for 6-8H at room temperature to obtain a gray precipitate, filtering, drying at 60-90 ℃ under a reduced pressure state to constant weight, then carrying out heat treatment for 1-2H at 340-360 ℃ under the hydrogen atmosphere, and finally carrying out heat treatment at 200-250 ℃ under the oxygen atmosphere for 2-3H and cooling to room temperature to obtain a catalyst precursor of silica-supported tungsten;
b) 2.84g of tetraisopropyl titanate is dissolved in isopropanol, 20-50g of silicon dioxide supported tungsten catalyst precursor is added and uniformly stirred, the temperature is raised to 35-45 ℃, L-hydroxyproline isopropanol solution is dripped, stirring is carried out for 12-16 hours at 50-60 ℃ after dripping is finished, then the temperature is lowered to room temperature, filtration and acetone washing are carried out, and decompression drying is carried out at 50-60 ℃ to constant weight, thus obtaining the tungsten-titanium bimetallic center catalyst.
The invention takes a molecular sieve as a carrier, tungsten trioxide is loaded on the surface of the molecular sieve to prepare the tungsten-loaded molecular sieve in situ, L-hydroxyproline and tetraisopropyl titanate form a complex which is deposited on the surface of the tungsten-loaded molecular sieve and/or in the pore diameter of the tungsten-loaded molecular sieve to form a tungsten-titanium bimetallic center catalyst, and the applicant surprisingly finds that the catalyst can catalyze thioether 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole to carry out oxidation reaction to obtain the R-lansoprazole with high optical purity, and the chemical selectivity and the optical selectivity both have unexpected reaction effects.
The preparation method of the anti-gastric ulcer drug R-lansoprazole with high optical purity, which is disclosed by the invention, has the further technical scheme that: the adding amount of the catalyst precursor of the silicon dioxide loaded tungsten in the tungsten-titanium codeposition procedure in the step b) is 30-36 g; the ratio of tungsten to titanium has an effect on the chemical selectivity, and an excessive tungsten content leads to the occurrence of sulfones, which are partial oxidation products.
According to the preparation method of the anti-gastric ulcer drug R-lansoprazole with high optical purity, the further technical scheme is that in the step b) tungsten-titanium codeposition procedure, the molar ratio of L-hydroxyproline to tetraisopropyl titanate is 2-4:1 according to molar ratio calculation, L-hydroxyproline is added to play a role in chiral amplification and form a complex with tetraisopropyl titanate, and finally the complex is deposited on the surface of a tungsten-loaded molecular sieve and/or in the pore diameter of the tungsten-titanium loaded molecular sieve to form a tungsten-titanium bimetallic center catalyst, so that thioether is catalyzed and oxidized to generate R-lansoprazole;
the preparation method of the anti-gastric ulcer drug R-lansoprazole with high optical purity, which is disclosed by the invention, has the further technical scheme that: in the step 1), the adding amount of the catalyst is 1-20% of the weight of the substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole, and the preferable weight is 5-10%;
the preparation method of the anti-gastric ulcer drug R-lansoprazole with high optical purity, which is disclosed by the invention, has the further technical scheme that: in the step 2), the molar ratio of the hydrogen peroxide to the substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole is 1-4: 1;
the preparation method of the anti-gastric ulcer drug R-lansoprazole with high optical purity, which is disclosed by the invention, has the further technical scheme that: the solvent in the step 1) is one or more than two mixed solutions of acetone, butanone, tetrahydrofuran or triethylamine, preferably a mixed solution of tetrahydrofuran and triethylamine, and the volume ratio of tetrahydrofuran: triethylamine 20: 1; the catalytic reaction has stronger solvent effect, and ester, chlorohydrocarbon or alcohol solvents are adopted, so the reaction conversion rate is low;
the preparation method of the anti-gastric ulcer drug R-lansoprazole with high optical purity, which is disclosed by the invention, has the further technical scheme that: step 4), the crystallization is to point to the R-lansoprazole reaction liquid, purified water is dripped into the R-lansoprazole reaction liquid for anti-solvent crystallization, the R-lansoprazole reaction liquid is heated to 50-55 ℃, then the purified water is dripped until the system becomes turbid, the dripping is stopped, the volume of the dripped purified water is recorded to be 1V, and crystal growth and aging are carried out for 1-2h by heat preservation and stirring; and then continuously dropwise adding purified water with the volume of 3V, cooling to room temperature at the cooling rate of 5 ℃/h after dropwise adding, stirring for 30-60 min, filtering, washing with acetone, and vacuum drying at 40-50 ℃ to obtain the R-lansoprazole with high optical purity.
Compared with the prior art, the invention has the following advantages:
1) the invention provides a method for preparing R-lansoprazole by using a solid catalyst, wherein the solid catalyst is conveniently separated from a system, and co-production byproducts are not generated;
2) compared with peroxybenzoic acid and cumyl hydroperoxide in the prior art, the invention adopts the clean oxidant hydrogen peroxide, has lower cost, is easy to separate from the system, and better meets the requirement of QbD idea;
3) according to the invention, high-quality raw material medicines are obtained through experimental optimization, and the ee value and the chemical purity of the prepared R-lansoprazole reach more than 99.89%;
4) the catalytic system has good chemical selectivity, and the contents of thioether and sulfone in the reaction liquid in the oxidation reaction are both below 1.0 percent.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention.
The thioether 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole serving as a raw material substrate used by the invention is prepared according to the teaching in the prior art of ((R) -lansoprazole synthesis, China journal of medical industry, 2013,44 (12): 1205-1207) and is obtained by column chromatography purification (eluent: n-heptane/ethyl acetate with volume ratio: 4/1), and the purity of HP L C is 99.82%;
the mesoporous silica MSU-H used in the invention is from Sigma Aldrich (Shanghai) trade company Limited, and the product number is 643637.
The detection method of the content and purity of the R-lansoprazole comprises HP L C method I, a chromatographic column Microsphere C18 column (4.6mm × 100mm,3 mu m), a mobile phase A acetonitrile-phosphate buffer solution (pH7.6) -water (10: 80), a B acetonitrile-phosphate buffer solution (pH7.6) -water (80: 1: 19), gradient elution (0min, A: B ═ 100: 0; 10min, A: B ═ 0: 20; 30min, A: B ═ 0: 100; 31min, A: B ═ 100: 0; 45min, A: B ═ 0: 20; flow rate 1.0 ml/min; detection wavelength 302 nm;
the method for detecting the enantiomeric excess percentage (ee%) comprises an HP L C method (II), a chromatographic column xylonite Chiral column Chiral AGP column (4.6mm × 150mm,5 mu m), a mobile phase acetonitrile-phosphate buffer solution (15: 85), a flow rate of 0.6ml/min and a detection wavelength of 302 nm.
Example 1
The catalyst was prepared as follows:
a) a molecular sieve loading procedure: 3.96g of tungsten hexachloride were placed in toluene under nitrogen atmosphere, thenThen 50g of mesoporous silica MSU-H (the specific surface area is about 750 m) is added2Per g, pore volume 0.91cm3The aperture is 7.1nm), stirring for 6-8h at room temperature to obtain gray precipitate, filtering, drying at 60-90 ℃ under reduced pressure to constant weight, then carrying out heat treatment for 1-2h at 360 ℃ under 340-250 ℃ under the atmosphere of hydrogen, and finally carrying out heat treatment for 2-3h at 250 ℃ under 200-250 ℃ under the atmosphere of oxygen to reduce the temperature to room temperature to obtain the catalyst precursor of the silicon dioxide loaded tungsten;
b) dissolving 2.84g of tetraisopropyl titanate in isopropanol, adding 36g of a catalyst precursor of silicon dioxide supported tungsten, uniformly stirring, heating to 35-45 ℃, dropwise adding L-hydroxyproline isopropanol solution (the molar amount of L-hydroxyproline is 2 times of that of tetraisopropyl titanate), stirring for 12-16 hours at 50-60 ℃ after dropwise adding is finished, cooling to room temperature, filtering, washing with acetone, and drying under reduced pressure at 50-60 ℃ to constant weight to obtain the tungsten-titanium bimetallic center catalyst.
One, different W/Ti ratios and the influence of L-hydroxyproline on the catalytic performance of the catalyst
The tungsten-supported silica catalyst precursor and L-hydroxyproline in step b) of example 1 are changed by a one-factor variable method to prepare tungsten-titanium bimetallic catalysts with different components for catalytic oxidation of 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridin-2-yl ] -methylthio-1H-benzimidazole, wherein 1.0g of substrate and 0.1g of catalyst are added into 10ml of tetrahydrofuran, 25% wt of hydrogen peroxide 2eq is dropwise added at room temperature, reaction liquid is taken every 0.5H after the dropwise addition is finished and subjected to HP L C detection, and the conversion rate, the R-lansoprazole ee value and the sulfone content are calculated when the substrate is not changed any more, and the results are shown in Table 1:
TABLE 1 influence of different W/Ti ratios and its L-hydroxyproline on the catalytic performance of catalysts
Note that the sulfone content is the percentage of the area occupied by the reaction solution by the HP L C method (one) according to the area normalization method.
The test results show that the activity of the catalyst is greatly enhanced with the increase of the dosage of the catalyst precursor of the tungsten loaded by the silica, the substrate conversion rate is increased to more than 99% from 58%, but the chemical selectivity is partially reduced, namely excessive oxide sulfone is generated, and the byproduct sulfone can be removed in the subsequent purification process, so that the dosage of the catalyst precursor of the tungsten loaded by the silica is selected to be most excellent from 30 to 36g, the L-hydroxyproline/Ti molar ratio needs to be controlled to be more than 2:1 to realize good optical purity, and the molar ratio is optimal from 2 to 4.
Example 2
The catalyst prepared in example 1 is used as an oxidation reaction catalyst, and a reaction solvent, the catalyst dosage and the oxidant dosage are optimized, wherein the test process is as follows:
1) adding a substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] -methylthio-1H-benzimidazole (3.5g, 10mmol) into 20ml of an organic solvent, adding a catalyst at a time, and stirring for 10-20 min;
2) dropwise adding hydrogen peroxide with the mass concentration of 25 wt% into the reaction system, reacting at room temperature (20-25 ℃), after dropwise adding, taking the reaction solution every 0.5h after dropwise adding, detecting HP L C, calculating the conversion rate, the R-lansoprazole ee value and the content of sulfone when the substrate is not changed any more, and the result is shown in table 2:
TABLE 2 Effect of different influencing factors on the Oxidation reaction
The test results show that the invention has stronger solvent effect, and the reaction conversion rate is low by adopting ester, chlorohydrocarbon or alcohol solvent; wherein the conversion rate of tetrahydrofuran is higher, the selectivity of triethylamine is best, and the generation of sulfone can not be detected; the invention obtains an optimal solvent system by proportioning THF/TEA (tetrahydrofuran/ethylene-propylene) at a volume ratio of 20: 1; the dosage of the catalyst is optimally 5 to 10 percent of the weight of the substrate; the dosage of the hydrogen peroxide is optimal when the substrate is 1.5-2.0eq, and a large amount of by-product sulfone is generated after the dosage of the hydrogen peroxide exceeds 3.0eq, which indicates that the oxidation of the sulfoxide mainly occurs in the later period.
Example 3
And (3) process amplification test:
10L double layer glass reactor was charged with 1.0kg of substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridin-2-yl]-methylthio-1H-benzimidazole, 100g of catalyst (prepared by the method of example 1), 6L mixed solvent (V)THF/TEA＝20:1) After stirring uniformly, controlling the temperature to 15-20 ℃;
dropwise adding 25% wt of hydrogen peroxide solution (2eq, calculated by a substrate) under the condition of heat preservation, and detecting the reaction solution by using HP L C after 2 hours (the conversion rate is 99.84%, the sulfone content is 0.62%, and the ee% value is 99.8%);
filtering with microporous filter membrane with pore diameter of 0.45 μm to remove catalyst; adding sodium hydrosulfite into the filtrate until the starch potassium iodide test paper does not show oxidability to obtain a neutral solution;
heating the neutral solution in a 30L glass kettle to 50-55 deg.C, adding purified water until the system becomes turbid, stopping adding, recording the amount of the added purified water at 1V volume, stirring under heat preservation for 1-2h, adding purified water at 3V volume, cooling to room temperature at a cooling rate of 5 deg.C/h, stirring for 30-60 min, filtering, washing with acetone, and vacuum drying at 40-50 deg.C to obtain high optical purity white solid R-lansoprazole 960g (yield 87.8%, purity 99.85%, ee% 99.9%, sulfone content 0.02%), MS (M/z):369[ M ] ([ M/z) ]+]，1H-NMR(500MHz,DMSO-d6):2.23(s,3H),4.71～4.83(d,J＝3.6Hz,2H),4.88(q,J＝1.2Hz,2H),7.06(d,J＝1.2Hz,2H),7.25(m,2H),7.62(m,2H),8.24(d,J＝1.2Hz,1H),13.49(s,1H)。
The test method can be used for carrying out kilogram-level test amplification and provides a certain basis for industrial production.
Example 4
In order to verify the durability of the catalyst of the present invention, the catalyst filtered in the scale-up test (example 3) was dried in vacuum at 40 ℃ after being subjected to ultrasonic washing with tetrahydrofuran, and the catalytic oxidation reaction (substrate amount of 1.0 g) was continued using the conditions of example 3, and the test result showed that the substrate conversion rate was only 87.3%, demonstrating that the catalyst was partially poisoned.
Combining the conversion rates of different solvents in example 2, the inventor guesses that the catalyst is poisoned due to the use of triethylamine, and the inventor verifies that the catalyst obtained by separation after the reaction is carried out by using pure tetrahydrofuran as the solvent, and the application result shows that the substrate conversion rate is 98, 9%, which proves that the catalyst after the use can be applied mechanically in the reaction carried out by using tetrahydrofuran as the solvent, and the catalyst after the use of the THF/TEA system has partial catalyst poisoning phenomenon.
Although the embodiments of the present invention have been described in detail, it should be understood that various changes, substitutions, and alterations can be made hereto without departing from the spirit and scope of the invention.
Claims (10)
1. A preparation method of high-optical-purity anti-gastric ulcer drug R-lansoprazole comprises the following steps:
1) the substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl]-methylthio-1HAdding benzimidazole into an organic solvent, then adding a catalyst at one time, and stirring for 10-20 min;
2) dropwise adding hydrogen peroxide with the mass concentration of 3-30% by weight into the reaction system, and after dropwise adding, keeping the temperature and stirring;
3) HP L C detects substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridin-2-yl]-methylthio-1HAfter the benzimidazole reaction is completed, adding a reducing agent to quench the reaction, and filtering out the catalyst to obtain R-lansoprazole reaction liquid;
4) crystallizing the R-lansoprazole reaction solution to obtain high-optical-purity R-lansoprazole;
the catalyst is a tungsten-titanium bimetallic center catalyst, and the tungsten-titanium bimetallic center catalyst is prepared by the following method:
a) a molecular sieve loading procedure: placing 3.96g of tungsten hexachloride in toluene under the nitrogen atmosphere, then adding 50g of mesoporous silica MSU-H, stirring for 6-8H at room temperature to obtain a gray precipitate, filtering, drying at 60-90 ℃ under a reduced pressure state to constant weight, then carrying out heat treatment for 1-2H at 340-360 ℃ under the hydrogen atmosphere, and finally carrying out heat treatment at 200-250 ℃ under the oxygen atmosphere for 2-3H and cooling to room temperature to obtain a catalyst precursor of silica-supported tungsten;
b) 2.84g of tetraisopropyl titanate is dissolved in isopropanol, 20-50g of silicon dioxide supported tungsten catalyst precursor is added and uniformly stirred, the temperature is raised to 35-45 ℃, L-hydroxyproline isopropanol solution is dripped, stirring is carried out for 12-16 hours at 50-60 ℃ after dripping is finished, then the temperature is lowered to room temperature, filtration and acetone washing are carried out, and decompression drying is carried out at 50-60 ℃ to constant weight, thus obtaining the tungsten-titanium bimetallic center catalyst.
2. The method of claim 1, wherein: the adding amount of the catalyst precursor of the silicon dioxide loaded tungsten in the tungsten-titanium codeposition procedure in the step b) is 30-36 g.
3. The method according to claim 1, wherein the molar ratio of L-hydroxyproline to tetraisopropyl titanate in the tungsten-titanium co-deposition step of step b) is 2-4: 1.
4. The production method according to any one of claims 1 to 3, characterized in that: the adding amount of the catalyst in the step 1) is the substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl]-methylthio-1H-1% to 20% by weight of benzimidazole.
5. The production method according to any one of claims 1 to 3, characterized in that: in the step 2), the dosage of hydrogen peroxide and the substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl]-methylthio-1H-benzimidazole in a molar ratio of 1 to 4: 1.
6. The method of claim 5, wherein: in the step 2), the dosage of hydrogen peroxide and the substrate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl]-methylthio-1HThe molar ratio of benzimidazole to benzimidazole is 1.5-2.0: 1.
7. The production method according to any one of claims 1 to 3, characterized in that: the solvent in the step 1) is one or more than two mixed solutions of acetone, butanone, tetrahydrofuran or triethylamine.
8. The method of claim 7, wherein: the solvent in the step 1) is a mixed solution of tetrahydrofuran and triethylamine, and the mixed solution is prepared by calculating the volume ratio of tetrahydrofuran: triethylamine =20: 1.
9. The method of claim 7, wherein: the solvent in the step 1) is tetrahydrofuran.
10. The production method according to any one of claims 1 to 3, characterized in that: step 4), the crystallization is to point to the R-lansoprazole reaction liquid, purified water is dripped into the R-lansoprazole reaction liquid for anti-solvent crystallization, the R-lansoprazole reaction liquid is heated to 50-55 ℃, then the purified water is dripped until the system becomes turbid, the dripping is stopped, the volume of the dripped purified water is recorded to be 1V, and crystal growth and aging are carried out for 1-2h by heat preservation and stirring; and then continuously dropwise adding purified water with the volume of 3V, cooling to room temperature at the cooling rate of 5 ℃/h after dropwise adding, stirring for 30-60 min, filtering, washing with acetone, and vacuum drying at 40-50 ℃ to obtain the R-lansoprazole with high optical purity.
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| WO2011098938A1 (en) * | 2010-02-11 | 2011-08-18 | Orchid Chemicals And Pharmaceuticals Limited | Novel solvate of dexlansoprazole |
| CN107141280A (en) * | 2017-07-10 | 2017-09-08 | 长沙康普大药房有限责任公司 | A kind of preparation method of Dexlansoprazole |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011098938A1 (en) * | 2010-02-11 | 2011-08-18 | Orchid Chemicals And Pharmaceuticals Limited | Novel solvate of dexlansoprazole |
| CN107141280A (en) * | 2017-07-10 | 2017-09-08 | 长沙康普大药房有限责任公司 | A kind of preparation method of Dexlansoprazole |
Non-Patent Citations (1)
| Title |
|---|
| WO3-30% H2O2-cinchona alkaloids: a new heterogeneous catalytic system for the asymmetric oxidation of sulfides and the kinetic resolution of racemic sulfoxides;Vinay V. Thakur et al.;《Tetrahedron: Asymmetry》;20031231;第14卷;第407-410页 * |
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