CN114163419A - Preparation method of lansoprazole - Google Patents
Preparation method of lansoprazole Download PDFInfo
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- CN114163419A CN114163419A CN202111598794.2A CN202111598794A CN114163419A CN 114163419 A CN114163419 A CN 114163419A CN 202111598794 A CN202111598794 A CN 202111598794A CN 114163419 A CN114163419 A CN 114163419A
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- Prior art keywords
- lansoprazole
- methyl
- trifluoroethoxy
- ethanol
- pyridine
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- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229960003174 lansoprazole Drugs 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims abstract description 25
- 239000012043 crude product Substances 0.000 claims abstract description 20
- HEZSBUNWERXKSX-UHFFFAOYSA-N 1-methylsulfanylbenzimidazole Chemical compound C1=CC=C2N(SC)C=NC2=C1 HEZSBUNWERXKSX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- AYPSHJCKSDNETA-UHFFFAOYSA-N 2-chloro-1h-benzimidazole Chemical compound C1=CC=C2NC(Cl)=NC2=C1 AYPSHJCKSDNETA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007670 refining Methods 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 5
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 5
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000011609 ammonium molybdate Substances 0.000 claims description 4
- 229940010552 ammonium molybdate Drugs 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 claims description 2
- 235000018660 ammonium molybdate Nutrition 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- SWXQKHHHCFXQJF-UHFFFAOYSA-N azane;hydrogen peroxide Chemical compound [NH4+].[O-]O SWXQKHHHCFXQJF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000001035 drying Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000000967 suction filtration Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 8
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 6
- 238000007605 air drying Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 4
- 229910015667 MoO4 Inorganic materials 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 238000004042 decolorization Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 1
- CMZBQUWICURDCD-UHFFFAOYSA-N 2-(chloromethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-1-ium;chloride Chemical compound Cl.CC1=C(OCC(F)(F)F)C=CN=C1CCl CMZBQUWICURDCD-UHFFFAOYSA-N 0.000 description 1
- XYBHGJNPHFDGGU-UHFFFAOYSA-L [Na+].[Na+].OC.[O-]C([O-])=O Chemical compound [Na+].[Na+].OC.[O-]C([O-])=O XYBHGJNPHFDGGU-UHFFFAOYSA-L 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- -1 compound sulfoxide Chemical class 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N tetraisopropyl titanate Substances CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of lansoprazole, belonging to the technical field of medicines and comprising the following steps: reacting 2-chlorobenzimidazole with 3-methyl-4- (2,2, 2-trifluoroethoxy) to obtain 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole; then, under the alkaline condition and in the presence of an oxidant and a phase transfer catalyst, oxidizing to generate a lansoprazole crude product; and decoloring and refining to obtain the lansoprazole. The lansoprazole with high yield and high purity is prepared by a simple and safe preparation method, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of lansoprazole.
Background
Lansoprazole (Lansoprazole), a new generation of proton pump inhibitor following omeprazole, is chemically named 2- [ [ [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridinyl ] methyl ] sulfinyl ] -1H-benzimidazole with CAS number: 103577-45-3, molecular formula: C16H14F3N3O2S, molecular weight: 369.36, the structural formula is as follows:
chinese patent CN102617555A discloses a preparation method of lansoprazole, which uses 2-chloromethyl-3-methyl-4-trifluoroethoxy pyridine hydrochloride and 2-mercapto-benzimidazole as starting materials, and the starting materials react in sodium carbonate methanol solution to obtain an intermediate 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylthio-1H-benzimidazole, and the combination of cumyl hydroperoxide-tetraisopropyl titanate is adopted to oxidize to obtain the lansoprazole. The preparation method is a common lansoprazole synthesis process, but the preparation method still has certain defects, and the preparation method needs complex post-treatment processes such as extraction, washing, recrystallization and the like in each step and is not easy for industrial production; and in the second step, the oxidation reaction is violent and difficult to control, peroxide impurities which are difficult to remove are generated, and meanwhile, the oxide impurities are difficult to remove, so that the lansoprazole content can be increased only by extracting, recrystallizing and other purification operations for many times.
Chinese patent CN101730675A discloses an industrial mass production method for preparing lansoprazole by a one-pot method, wherein condensation and oxidation reactions are continuously completed in the same reactor, and complex post-treatment steps such as extraction, washing, drying, recrystallization and the like are not needed, so that the method optimizes the synthesis process of lansoprazole to a certain extent. However, the method is a one-pot process, and byproducts generated in the reaction process cannot be removed in time and are easily carried into a final product, so that the purity of the lansoprazole as the final product is reduced, and the removal is difficult.
The existing preparation method of lansoprazole usually generates sulfone impurities which are difficult to remove, and once the sulfone impurities are prepared, the yield of target compound sulfoxide is reduced, because the physicochemical properties of the two are very similar, and the separation and purification are difficult. In order to remove sulfone type impurities, it is necessary to conduct a treatment by a chromatographic preparation method and the like, and the operation is complicated, which is disadvantageous for scale-up production.
Therefore, in order to reduce the production cost of lansoprazole, improve the yield and facilitate the safe use in the preparation, the refining process of the starting materials, the reaction solvent and the crude product in the process is optimized.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defects of high production cost and low yield of lansoprazole in the prior art, so that a preparation method of lansoprazole is provided, and lansoprazole with high yield and high purity is prepared by a simple and safe preparation method.
In order to solve the above problems, the present invention provides a process for preparing lansoprazole, comprising the steps of:
step A: placing 2-chlorobenzimidazole and 3-methyl-4- (2,2, 2-trifluoroethoxy) in a first solvent, and reacting under an alkaline condition to obtain 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole;
and B: 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole is put into a second solvent and oxidized under the alkaline condition and in the presence of an oxidant and a phase transfer catalyst to generate a lansoprazole crude product;
and C: placing the lansoprazole crude product in an alcohol solvent, and decolorizing and refining to obtain lansoprazole;
the reaction process is as follows:
preferably, the base in step a is selected from at least one of sodium hydroxide or potassium hydroxide, and the first solvent is ethanol.
Preferably, the base in step B is selected from at least one of sodium carbonate or sodium bicarbonate, and the second solvent is ethyl acetate.
Preferably, the oxidizing agent and the phase transfer catalyst in step B are a hydrogen peroxide-ammonium molybdate composition.
Preferably, the alcoholic solvent in step C is one of ethanol or isopropanol.
Preferably, the decolorizing agent in the refining process in step C is activated carbon.
Preferably, the method of step a is: dissolving 3-methyl-4- (2,2, 2-trifluoroethoxy) in ethanol, adding sodium hydroxide, dropwise adding an ethanol solution of 2-chlorobenzimidazole at 30-40 ℃, reacting for 3-6H at the temperature, dropwise adding dilute hydrochloric acid after the reaction is finished to adjust the pH to 6-7, stirring at 10-20 ℃ for crystallization for 3-6H, and filtering to obtain 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylthio-1H-benzimidazole.
Preferably, the method of step B is: placing 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole in ethyl acetate, adding ammonium molybdate, dropwise adding a mixed solution of hydrogen peroxide and ethyl acetate at 25-35 ℃, continuing to react for 2-6H at the temperature after the addition is finished, adding a sodium carbonate aqueous solution into the reaction solution, removing the aqueous phase after liquid separation, concentrating the organic phase, adding ethanol or isopropanol, separating out a large amount of solids, stirring and crystallizing for 3-6H at 10-20 ℃, and filtering to obtain a lansoprazole crude product.
Preferably, the method of step C is: mixing the lansoprazole crude product with ethanol or isopropanol, heating and dissolving, adding activated carbon for decoloring for 1-2 h, filtering while hot, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 6-10 h, and filtering to obtain lansoprazole.
Preferably, the temperature of the filtrate is reduced in a gradient manner, and the temperature of the gradient temperature is reduced to 0-5 ℃ at the speed of 6-10 ℃/h.
Preferably, the mass ratio of the lansoprazole crude product to the activated carbon in the step C is 1: 0.03 to 0.05.
Preferably, the molar ratio of 3-methyl-4- (2,2, 2-trifluoroethoxy) to 2-chlorobenzimidazole in the step A is 1:1 to 1:1.5, and the molar ratio of 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylthio-1H-benzimidazole to hydrogen peroxide in the step B is 1:0.5 to 1:1.
The technical scheme of the invention has the following advantages:
1. according to the preparation method of lansoprazole provided by the invention, a second solvent with high toxicity is not used in the whole reaction process, the toxicity of the solvent is lower, and the reaction condition is mild;
2. according to the preparation method of lansoprazole, the whole post-treatment process does not involve column passing operation, the reverse solvent is adopted for crystallization, the operation is convenient, and the purity of the obtained product is as high as 99.9%;
3. the preparation method of lansoprazole provided by the invention improves the total yield of a lansoprazole final product to 69.0%, and is suitable for industrial mass production.
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
Example 1
A method for synthesizing 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole having the structural formula (III): adding 400mL of ethanol into a 1000mL reaction bottle, then respectively adding 22.4g (100mmol) of 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] methyl mercaptan and 0.6g (15mmol) of sodium hydroxide, stirring at 40 ℃, dropwise adding a mixed solution of 16.7g of 2-chlorobenzimidazole (110mmol) and ethanol (100mL) through a constant-pressure low-liquid funnel, controlling the temperature of 40 ℃ after the addition to react for 6h, monitoring by HPLC, dropwise adding 0.1mol/L of hydrochloric acid into the reaction bottle after the reaction is finished, controlling the temperature to be 20 ℃ in the process, adjusting the pH to be 7, and stirring at 20 ℃ to crystallize for 6 h. And (3) carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake, and leaching the solid by using 44.8g of purified water to obtain a wet product. And (3) drying: and controlling the temperature to be 55 ℃ and drying by blowing for 8h to obtain 30.7g (87mmol) of the product shown in the formula III, wherein the yield is 86.9 percent, and sampling and detecting are carried out.
The synthesis method of the lansoprazole crude product comprises the following steps: to a 1000mL reaction flask was added 300mL of ethyl acetate followed by 0.05g (NH) of each3)2MoO4·4H2O, 0.05g of sodium carbonate and 24.7g (70mmol) of the compound of the formula III, controlling the temperature at 35 ℃ under stirring, dropwise adding a mixed solution of 4.0g (35mmol) of 30% hydrogen peroxide and 100ml of ethyl acetate through a constant-pressure low-liquid funnel, reacting for 2 hours at 35 ℃, and sequentially adding 20% Na into the reaction solution2CO3Washing the solution (200ml) and purified water (150ml × 2), removing the water phase after separating, concentrating the organic phase to 1/2 of the total amount, adding 400ml of ethanol, precipitating a large amount of solid, and stirring and crystallizing for 6h at the temperature of 20 ℃. Carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake; the solids were rinsed with 49.4g of purified water to give a wet product. And (3) drying: controlling the temperature to 55 ℃ and drying by blowing for 10h to obtain22.2g (60mmol) of lansoprazole crude product, 85.6% of yield and sampling detection.
Synthesis method (refining) of lansoprazole: adding 20.3g (55mmol) of lansoprazole crude product into a 500mL reaction bottle, adding 240mL of ethanol, stirring, heating to 50 ℃ for dissolution until the solution is clear, adding 0.8g of activated carbon for decolorization, controlling the temperature to be 50 ℃, stirring for 1h, performing suction filtration while the solution is hot, reducing the speed gradient of 6 ℃/h of the filtrate to 0 ℃, and stirring and crystallizing for 6h at the temperature. Carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake; the solids were rinsed with 40.6g of ethanol to give a wet product. And (3) drying: and controlling the temperature to be 55 ℃ for forced air drying, and drying for 8h to obtain 18.8g (51mmol) of lansoprazole as white crystalline powder, wherein the yield is 92.7%, and the purity is 99.9% by HPLC.
The total yield of lansoprazole preparation was 69.0%.
Example 2
A method for synthesizing 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole having the structural formula (III): adding 400mL of ethanol into a 1000mL reaction bottle, then respectively adding 22.4g (100mmol) of 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] methyl mercaptan and 0.8g (14mmol) of potassium hydroxide, stirring at 30 ℃, dropwise adding a mixed solution of 19.8g of 2-chlorobenzimidazole (130mmol) and ethanol (100mL) through a constant-pressure low-liquid funnel, controlling the temperature of 30 ℃ after the addition for reaction for 3h, monitoring by HPLC, dropwise adding 0.1mol/L of hydrochloric acid into the reaction bottle after the reaction is finished, controlling the process temperature to be 10 ℃, adjusting the pH to be 6, controlling the temperature of 10 ℃ after the addition, stirring and crystallizing for 3 h. And (3) carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake, and leaching the solid by using 67.2g of purified water to obtain a wet product. And (3) drying: and controlling the temperature to be 45 ℃ and carrying out forced air drying for 8h to obtain 31.1g (88mmol) of the product shown in the formula III, wherein the yield is 88.1 percent, and sampling and detecting are carried out.
The synthesis method of the lansoprazole crude product comprises the following steps: to a 1000mL reaction flask was added 300mL of ethyl acetate followed by 0.06g (NH) of each3)2MoO4·4H2O, 0.05g of sodium carbonate and 28.3g (80mol) of formula III, controlling the temperature to be 25-35 ℃ under stirring, dropwise adding a mixed solution of 4.5g (40mmol) of 30% hydrogen peroxide and 100ml of ethyl acetate (100ml) through a constant-pressure low-liquid funnel, reacting for 2 hours at 25 ℃, and sequentially adding 20% Na into the reaction solution2CO3Solution (200ml) and purified waterWashing (150ml multiplied by 2), removing the water phase after separating, concentrating the organic phase to 1/2 of the total amount, adding 400ml of isopropanol, precipitating a large amount of solid, controlling the temperature to be 10 ℃, stirring and crystallizing for 3 hours. Carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake; the solids were rinsed with 56.6g of purified water to give a wet product. And (3) drying: and controlling the temperature to be 45-55 ℃ and carrying out forced air drying for 10h to obtain 30.9g (67mmol) of lansoprazole crude product, wherein the yield is 83.7%, and sampling and detecting.
Synthesis method (refining) of lansoprazole: adding 22.9g (62mmol) of lansoprazole crude product into a 500mL reaction bottle, adding 350mL of isopropanol, stirring, heating to 40 ℃ for dissolution until the solution is clear, adding 0.8g of activated carbon for decolorization, stirring at 40 ℃ for 2h, performing suction filtration while the solution is hot, reducing the speed gradient of 10 ℃/h of the filtrate to 5 ℃, and stirring at the temperature for crystallization for 10 h. Carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake; the solids were rinsed with 45.8g of isopropanol to give a wet product. And (3) drying: temperature is controlled to 45 ℃ for forced air drying, and drying is carried out for 8h, so as to obtain 20.7g (56mmol) of lansoprazole as white crystalline powder, yield is 90.5%, and purity is 99.9% by HPLC.
The overall yield of lansoprazole preparation was 66.7%.
Example 3
A method for synthesizing 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole having the structural formula (III): adding 400mL of ethanol into a 1000mL reaction bottle, then respectively adding 22.4g (100mmol) of 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridine-2-yl ] methyl mercaptan and 0.8g (20mmol) of sodium hydroxide, stirring at 35 ℃, dropwise adding a mixed solution of 22.8g of 2-chlorobenzimidazole (150mmol) and ethanol (100mL) through a constant-pressure low-liquid funnel, reacting for 5h at 35 ℃, monitoring by HPLC, dropwise adding 0.1mol/L hydrochloric acid into the reaction bottle after the reaction is finished, controlling the temperature to be 15 ℃, adjusting the pH to be 6, and stirring and crystallizing for 5h at 15 ℃. And (3) carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake, and leaching the solid by using 67.2g of purified water to obtain a wet product. And (3) drying: and controlling the temperature to be 50 ℃ and carrying out forced air drying for 8h to obtain 30.4g (86mmol) of the product shown in the formula III, wherein the yield is 86.1 percent, and sampling and detecting are carried out.
The synthesis method of the lansoprazole crude product comprises the following steps: to a 1000mL reaction flask was added 300mL of ethyl acetate followed by 0.06g (NH) of each3)2MoO4·4H2O, 0.05g of sodium carbonate and 28.3g (80mol) of the compound of the formula III, controlling the temperature at 30 ℃ under stirring, dropwise adding a mixed solution of 4.5g (80mmol) of 30% hydrogen peroxide and 100ml of ethyl acetate through a constant-pressure low-liquid funnel, reacting for 2 hours at 30 ℃, and sequentially adding 20% Na into the reaction solution2CO3Washing the solution (250ml) and purified water (150ml × 2), removing the water phase after separating, concentrating the organic phase to 1/2 of the total amount, adding 400ml of isopropanol, precipitating a large amount of solid, and stirring and crystallizing for 5h at the temperature of 15 ℃. Carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake; the solids were rinsed with 56.6g of purified water to give a wet product. And (3) drying: and controlling the temperature to be 50 ℃, blowing and drying for 10 hours to obtain 31.2g (68mmol) of lansoprazole crude product, obtaining yield of 84.6%, and sampling and detecting.
Synthesis method (refining) of lansoprazole: adding 22.9g (62mmol) of lansoprazole crude product into a 500mL reaction bottle, adding 350mL of isopropanol, stirring, heating to 45 ℃ for dissolution until the solution is clear, adding 1.1g of activated carbon for decolorization, controlling the temperature at 45 ℃, stirring for 1h, performing suction filtration while the solution is hot, reducing the speed gradient of 8 ℃/h of the filtrate to 3 ℃, and stirring and crystallizing for 8h at the temperature. Carrying out suction filtration on the system through a Buchner funnel to obtain a filter cake; the solids were rinsed with 50.8g of isopropanol to give a wet product. And (3) drying: temperature is controlled to 50 ℃ for forced air drying for 8h, 21.6g (58mmol) of lansoprazole is obtained as white crystalline powder, yield is 94.4%, and purity is 99.9% by HPLC.
The total yield of lansoprazole preparation was 68.7%.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. A preparation method of lansoprazole is characterized by comprising the following steps:
step A: placing 2-chlorobenzimidazole and 3-methyl-4- (2,2, 2-trifluoroethoxy) in a first solvent, and reacting under an alkaline condition to obtain 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole;
and B: 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole is put into a second solvent and oxidized under the alkaline condition and in the presence of an oxidant and a phase transfer catalyst to generate a lansoprazole crude product;
and C: placing the lansoprazole crude product in an alcohol solvent, and decolorizing and refining to obtain lansoprazole;
the reaction process is as follows:
2. the process for preparing lansoprazole according to claim 1, wherein the base in step A is selected from at least one of sodium hydroxide or potassium hydroxide, and the first solvent is ethanol.
3. The process for preparing lansoprazole of claim 1, wherein the base in step B is selected from at least one of sodium carbonate or sodium bicarbonate, and the second solvent is ethyl acetate.
4. The process for producing lansoprazole of claim 1, wherein the oxidizing agent and the phase transfer catalyst in step B are a hydrogen peroxide-ammonium molybdate composition.
5. The process for preparing lansoprazole of claim 1, wherein the alcoholic solvent in step C is one of ethanol or isopropanol.
6. The process for producing lansoprazole according to claim 1, wherein the decolorizing agent used in the refining process in step C is activated carbon.
7. The process for preparing lansoprazole according to any one of claims 1 to 6, wherein the process of step A is: dissolving 3-methyl-4- (2,2, 2-trifluoroethoxy) in ethanol, adding sodium hydroxide, dropwise adding an ethanol solution of 2-chlorobenzimidazole at 30-40 ℃, reacting for 3-6H at the temperature, dropwise adding dilute hydrochloric acid after the reaction is finished to adjust the pH to 6-7, stirring at 10-20 ℃ for crystallization for 3-6H, and filtering to obtain 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylthio-1H-benzimidazole.
8. The process for preparing lansoprazole of claim 7, wherein the process of step B is: placing 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole in ethyl acetate, adding ammonium molybdate, dropwise adding a mixed solution of hydrogen peroxide and ethyl acetate at 25-35 ℃, continuing to react for 2-6H at the temperature after the addition is finished, adding a sodium carbonate aqueous solution into the reaction solution, removing the aqueous phase after liquid separation, concentrating the organic phase, adding ethanol or isopropanol, separating out a large amount of solids, stirring and crystallizing for 3-6H at 10-20 ℃, and filtering to obtain a lansoprazole crude product.
9. The process for preparing lansoprazole of claim 8, wherein the process of step C is: mixing the lansoprazole crude product with ethanol or isopropanol, heating and dissolving, adding activated carbon for decoloring for 1-2 h, filtering while hot, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 6-10 h, and filtering to obtain lansoprazole.
10. The process for producing lansoprazole according to any one of claims 1 to 9, wherein the molar ratio of 3-methyl-4- (2,2, 2-trifluoroethoxy) to 2-chlorobenzimidazole in step a is 1:1 to 1:1.5, and the molar ratio of 2- [ 3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridine ] methylsulfanyl-1H-benzimidazole to hydrogen peroxide in step B is 1:0.5 to 1:1.
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