A method for preparing ilaprazole
By using specific oxidants and catalysts under mild conditions, the method for preparing ipramazole has solved the problems of complex operation, low yield and high cost in the existing technology, and has achieved efficient and environmentally friendly preparation of ipramazole, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NANJING WEICHUANGYUAN PHARM TECH CO LTD
- Filing Date
- 2023-06-19
- Publication Date
- 2026-06-09
AI Technical Summary
Existing methods for preparing ipramazole are complex, have low yields, high costs, and require stringent conditions, making them unsuitable for large-scale production. Furthermore, they suffer from the problem of difficult removal of peroxide impurities.
5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole was reacted with 3-methyl-4-methoxy-2-chloromethylpyridine hydrochloride in sodium hydroxide solution. Then, mild oxidants such as tert-butyl perbenzoate, cumene hydroperoxide, or methyl ethyl ketone peroxide were used, and vanadium pentoxide was used as a catalyst. The reaction temperature was controlled at 25-55℃ to avoid the formation of peroxides.
This method enables the preparation of esomeprazole with simple operation, low cost, high product quality, and suitability for large-scale production, while avoiding peroxide impurities and improving yield and product stability.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing a compound, specifically a method for preparing ipramazole. Background Technology
[0002] Ilaprazole, chemically named 5-(1H-pyrrolo-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridinyl]-methyl]-sulfinyl-1H-benzimidazole, is a new generation proton pump inhibitor. This drug was developed by Ilyang Pharmaceutical Co., Ltd. of South Korea and was first launched by Livzon Pharmaceutical Group.
[0003] Esomeprazole is a second-generation proton pump inhibitor. After oral absorption, it is metabolized into the active product sulfenamide, which reacts with H... + / K + —The sulfhydryl groups of ATPase form irreversible covalent disulfide bonds, blocking enzyme transport and thus inhibiting gastric acid secretion. Compared with other proton pump inhibitors, ilaprazole has the strongest anti-acid activity, less individual variability in treatment, and strong ability to control acid at night, making it a promising candidate to become a core product among proton pump inhibitors.
[0004] Chinese patent CN94191913.7 describes a synthetic route for preparing ilaprazole using 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole and 3-methyl-4-methoxy-2-chloromethylpyridine hydrochloride as starting materials. The synthetic route is as follows:
[0005]
[0006] The preparation of the intermediate thioether in this method is complex, has a low yield, and uses diethyl ether, which is highly toxic. In the preparation of ilaprazole, m-chloroperoxybenzoic acid is used as the oxidant and chloroform as the solvent, resulting in high costs, poor process stability, and a tendency to generate peroxide impurities (such as peroxide sulfonylates, which are difficult to remove). Furthermore, the production conditions are harsh, ranging from -30 to -40°C, which is not conducive to large-scale production.
[0007] Chinese patent CN103073536B improved upon this approach, but it still uses acetone, which is highly toxic, and the reaction requires reflux, making the operation cumbersome. It uses sodium hypochlorite as the oxidant, but this requires a high concentration of sodium hypochlorite, easily generates chlorinated impurities, and the solvent is removed by concentration and evaporation after the reaction, making the operation complex.
[0008] Chinese patent CN100478339C prepares ipramazole intermediate thioether from 5-nitro-1H-benzimidazole and 3-methyl-4-methoxy-2-chloromethylpyridine hydrochloride:
[0009]
[0010] This route is cumbersome to operate, the reduction process is prone to producing a lot of by-products, and the yield is low.
[0011] Chinese patent CN1803794A describes a method for preparing ipramazole, which accelerates the reaction by using surfactants or phase transfer catalysts. However, the surfactants or phase transfer catalysts are difficult to remove in the subsequent process, affecting product quality and resulting in low yield.
[0012] Therefore, there is a need to develop a simple, high-quality, high-yield method for preparing ipramazole that is suitable for large-scale production. Summary of the Invention
[0013] The purpose of this invention is to provide a method for preparing ipramazole suitable for industrial production.
[0014] The technical solution of this invention is:
[0015] A method for preparing ilaprazole, the reaction equation of which is as follows:
[0016]
[0017] The method includes the following steps:
[0018] Step 1): 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole (compound I) was dissolved in an aqueous sodium hydroxide solution and a monohydric alcohol, and then 3-methyl-4-methoxy-2-chloromethylpyridine hydrochloride (compound II) was added dropwise to give compound III.
[0019] Step 2): Compound III is dissolved in an organic solvent, an oxidant and a catalyst are added to react, sodium hydroxide is added, and after the reaction is completed, compound IV is obtained, which is the iprazoline mentioned above; the oxidant is one or more of tert-butyl perbenzoate, cumene hydroperoxide, and methyl ethyl ketone peroxide.
[0020] Furthermore, in step 2), the reaction temperature is 25–55°C and the reaction time is 2–10 h; no peroxides are generated in this step.
[0021] Furthermore, the molar ratio of oxidant to compound III is (1.3–2.5):1.
[0022] Furthermore, the catalyst is one or more of vanadium pentoxide, manganese dioxide, sodium vanadate, ammonium metavanadate, sodium metavanadate, and potassium metavanadate, and the weight ratio of catalyst to compound III is 0.01 to 0.1:1.
[0023] Furthermore, in step 1), the purity of compound III obtained in step 1) is above 99%.
[0024] Furthermore, in step 1), the molar ratio of compound I: compound II: sodium hydroxide is (1.0-1.5):1.0:(2.0-2.5).
[0025] Furthermore, in step 1), the reaction temperature is 15–35°C and the reaction time is 3–8 h; the monohydric alcohol is one or more of methanol and ethanol.
[0026] Furthermore, in step 2), the organic solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, and acetone.
[0027] Furthermore, in step 2), the free form is one or more of formic acid, acetic acid, propionic acid, benzoic acid, oxalic acid, and succinic acid.
[0028] The preparation method of elastosteroids of the present invention is simple to operate, produces high-quality products, and has a high yield compared with existing processes, making it suitable for large-scale production.
[0029] Specifically, the present invention has the following advantages:
[0030] (1) The process cost is greatly reduced. The solvents and reagents used in the entire reaction are all from conventional sources, resulting in low production costs; the reaction conditions are mild, greatly reducing energy costs.
[0031] (2) The reaction conditions are mild, the operation is simple, and it is easy to control. In the preparation of compound III, no purification is required, thereby improving the yield and simplifying the process; at the same time, in the preparation of compound IV, the reaction temperature provided in the literature in the background art is -30℃ to -40℃, while the reaction temperature of the present invention is 25-55℃, which avoids ultra-low temperature reaction and the reaction conditions are relatively mild.
[0032] (3) The product quality is good.
[0033] Peroxides pose a significant technical challenge in the preparation of compound IV, but the preparation process of this invention does not generate peroxides.
[0034] (4) It is environmentally friendly and avoids the use of highly toxic reagents or solvents, such as chloroform.
[0035] (5) The obtained sample has good stability. Under accelerated testing conditions, the ipramazole sample prepared in this invention exhibits good stability. Attached Figure Description
[0036] Figure 1 Compound III in Example 6 1 H-NMR spectrum;
[0037] Figure 2 MS chromatogram of compound III in Example 6;
[0038] Figure 3 Compound IV in Example 6 1 H-NMR spectrum;
[0039] Figure 4 MS chromatogram of compound IV in Example 6. Detailed Implementation
[0040] The technical solution of the present invention will be further described below with reference to specific embodiments and accompanying drawings.
[0041] Example 1:
[0042] The synthetic route is shown below:
[0043]
[0044] 1.29 g of sodium hydroxide was dissolved in 15 ml of water and 30 ml of ethanol. The mixture was kept at 15 °C, and 3.50 g of compound I was added and stirred until dissolved. A solution of compound II (3.40 g of compound II dissolved in 10 ml of water) was added dropwise, and the reaction was carried out at 15 °C for 8 h. 15 ml of water was added to induce crystallization. The crystals were filtered and dried under vacuum at 60 °C to obtain 5.36 g of compound III, with a yield of 93.5% and an HPLC purity of 99.36%.
[0045] 1.14 g of sodium hydroxide was dissolved in 40 ml of ethanol. 5.00 g of compound III and 0.05 g of vanadium pentoxide were added, followed by dropwise addition of 5.43 g of 80% cumene hydroperoxide (ω%). After the addition was complete, the reaction was carried out at 25 °C for 10 h. The temperature was lowered to 10–20 °C to allow crystallization for 1 h. The mixture was then filtered, and the filter cake was dried under vacuum at 50 °C. The resulting dry product was added to 15 ml of ethanol, and a 10% propionic acid / ethanol solution (ω%) was added to adjust the pH to 7–8. Crystallization was carried out at 20–30 °C for 2 h. The mixture was then filtered, and the filter cake was dried under vacuum at 50 °C to obtain 3.35 g of compound IV, with a yield of 64.1% and a purity of 99.90%.
[0046] Example 2:
[0047] The synthesis route is the same as in Example 1, and will not be repeated here.
[0048] 1.64 g of sodium hydroxide was dissolved in 15 ml of water and 30 ml of ethanol. The mixture was kept at 35 °C, and 5.30 g of compound I was added and stirred until dissolved. A solution of compound II (3.40 g of compound II dissolved in 10 ml of water) was added dropwise, and the reaction was continued at 35 °C for 3 hours. 15 ml of water was added to induce crystallization. The crystals were filtered, dried under vacuum at 60 °C, and yielded 5.47 g of compound III, with a yield of 95.5% and an HPLC purity of 99.59%.
[0049] 1.14 g of sodium hydroxide was dissolved in 40 ml of acetonitrile. 5.00 g of compound III and 0.5 g of potassium metavanadate were added, followed by dropwise addition of 6.95 g of tert-butyl perbenzoate. After the addition was complete, the reaction was maintained at 55 °C for 2 h. The temperature was lowered to 10–20 °C to crystallize for 1 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C. The resulting dry product was added to 15 ml of ethanol, and a 10% formic acid / ethanol solution (ω%) was added to adjust the pH to 7–8. Crystallization was carried out at 20–30 °C for 2 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C to obtain 3.40 g of compound IV, with a yield of 65.1% and a purity of 99.91%.
[0050] Example 3:
[0051] The synthesis route is the same as in Example 1, and will not be repeated here.
[0052] 1.44 g of sodium hydroxide was dissolved in 15 ml of water and 30 ml of ethanol. The mixture was kept at 25 °C, and 4.22 g of compound I was added and stirred until dissolved. A solution of compound II (3.40 g of compound II dissolved in 10 ml of water) was added dropwise, and the reaction was continued at 25 °C for 5 h. 15 ml of water was added to induce crystallization. The crystals were filtered, dried under vacuum at 60 °C, and yielded 5.47 g of compound III, with a yield of 95.5% and an HPLC purity of 99.63%.
[0053] 1.14 g of sodium hydroxide was dissolved in 40 ml of methanol. 5.00 g of compound III and 0.25 g of manganese dioxide were added, followed by dropwise addition of 7.74 g of 50% methyl ethyl ketone peroxide (ω%). After the addition was complete, the reaction was maintained at 40 °C for 6 h. The temperature was lowered to 10–20 °C to allow crystallization for 1 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C. The resulting dry product was added to 15 ml of ethanol, and a 10% acetic acid / ethanol solution (ω%) was added to adjust the pH to 7–8. Crystallization was carried out at 20–30 °C for 2 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C to obtain 3.39 g of compound IV, with a yield of 64.8% and a purity of 99.88%.
[0054] Example 4:
[0055] The synthesis route is the same as in Example 1, and will not be repeated here.
[0056] 1.44 g of sodium hydroxide was dissolved in 15 ml of water and 30 ml of ethanol. The mixture was kept at 25 °C, and 4.22 g of compound I was added and stirred until dissolved. A solution of compound II (3.40 g of compound II dissolved in 10 ml of water) was added dropwise, and the reaction was carried out at 25 °C for 4 h. 15 ml of water was added to induce crystallization. The crystals were filtered and dried under vacuum at 60 °C to obtain 5.44 g of compound III, with a yield of 94.9% and an HPLC purity of 99.54%.
[0057] 1.14 g of sodium hydroxide was dissolved in 40 ml of acetone. 5.00 g of compound III and 0.25 g of sodium vanadate were added, followed by dropwise addition of 4.99 g of tert-butyl perbenzoate. After the addition was complete, the reaction was maintained at 40 °C for 6 h. The temperature was lowered to 10–20 °C to allow crystallization for 1 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C. The resulting dry product was added to 15 ml of ethanol, and a 10% benzoic acid / ethanol solution (ω%) was added to adjust the pH to 7–8. Crystallization was carried out at 20–30 °C for 2 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C to obtain 3.36 g of compound IV, with a yield of 64.2% and a purity of 99.89%.
[0058] Example 5:
[0059] The synthesis route is the same as in Example 1, and will not be repeated here.
[0060] 1.44 g of sodium hydroxide was dissolved in 15 ml of water and 30 ml of ethanol. The mixture was kept at 25 °C, and 4.22 g of compound I was added and stirred until dissolved. A solution of compound II (3.40 g of compound II dissolved in 10 ml of water) was added dropwise, and the mixture was reacted at 25 °C for 6 h. 15 ml of water was added to induce crystallization. The crystals were filtered, dried under vacuum at 60 °C, and yielded 5.44 g of compound III, with a yield of 94.9% and an HPLC purity of 99.55%.
[0061] 1.14 g of sodium hydroxide was dissolved in 40 ml of ethanol. 5.00 g of compound III and 0.25 g of ammonium metavanadate were added, followed by dropwise addition of 4.99 g of tert-butyl perbenzoate. After the addition was complete, the reaction was maintained at 40 °C for 6 h. The mixture was then cooled to 10–20 °C to crystallize for 1 h. The crystals were filtered, and the filter cake was dried under vacuum at 50 °C. The resulting dry product was added to 15 ml of ethanol, and a 10% oxalic acid / ethanol solution (ω%) was added to adjust the pH to 7–8. Crystallization was carried out at 20–30 °C for 2 h. The crystals were filtered, and the filter cake was dried under vacuum at 50 °C to obtain 3.38 g of compound IV, with a yield of 64.6% and a purity of 99.86%.
[0062] Example 6:
[0063] The synthesis route is the same as in Example 1, and will not be repeated here.
[0064] 1.44 g of sodium hydroxide was dissolved in 15 ml of water and 30 ml of ethanol. The mixture was kept at 25 °C, and 4.22 g of compound I was added and stirred until dissolved. A solution of compound II (3.40 g of compound II dissolved in 10 ml of water) was added dropwise, and the reaction was continued at 25 °C for 7 h. Crystals were then precipitated by adding 15 ml of water, filtered, and dried under vacuum at 60 °C to obtain 5.49 g of compound III, with a yield of 95.8% and an HPLC purity of 99.67%. 1¹H-NMR, DMSO: 13.00 ppm (s, 1H), 8.27 ppm (s, 1H), 7.55 ppm (d, 2H), 7.32 ppm (m, 3H), 6.98 ppm (d, 2H), 6.25 ppm (t, 2H), 4.72 ppm (s, 2H), 3.86 ppm (d, 3H), 2.22 ppm (s, 3H); Molecular ion peak [M+H] + (m / z is 351.1269)
[0065] 1.14 g of sodium hydroxide was dissolved in 40 ml of ethanol. 5.00 g of compound III and 0.25 g of sodium metavanadate were added, followed by dropwise addition of 4.99 g of tert-butyl perbenzoate. After the addition was complete, the reaction was maintained at 40 °C for 6 h. The temperature was lowered to 10–20 °C to allow crystallization for 1 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C. The resulting dry product was added to 15 ml of ethanol, and a 10% succinic acid / ethanol solution (ω%) was added to adjust the pH to 7–8. Crystallization was carried out at 20–30 °C for 2 h. The product was filtered, and the filter cake was dried under vacuum at 50 °C to obtain 3.44 g of compound IV, with a yield of 65.8% and a purity of 99.93%. 1 ¹H-NMR, DMSO: 13.50 ppm (s, 1H), 8.24 ppm (d, 1H), 7.72 ppm (t, 2H), 7.52 ppm (d, 1H), 7.37 ppm (t, 2H), 6.97 ppm (d, 1H), 6.28 ppm (t, 2H), 4.80 ppm (d, 2H), 3.86 ppm (d, 3H), 2.15 ppm (s, 3H); Molecular ion peak [M+H] + (m / z is 367.1216)
[0066] The stability of compound IV obtained in Example 6 was investigated, and the results are shown in the table below. The accelerated test conditions were 30℃±2℃ and RH (relative humidity) 65±5%.
[0067] Time (month) content(%) purity(%) Total impurities (%) Hygroscopicity (%) 0 99.88 99.93 0.07 0.12 1 99.90 99.92 0.08 0.14 2 99.90 99.92 0.08 0.13 3 99.88 99.93 0.07 0.12 6 99.89 99.92 0.08 0.12
[0068] Comparative Example 1:
[0069] The synthesis route is the same as in Example 1, and will not be repeated here.
[0070] 1.44 g of sodium hydroxide was dissolved in 15 ml of water and 30 ml of ethanol. The mixture was kept at 25 °C, and 4.22 g of compound I was added and stirred until dissolved. A solution of compound II (3.40 g of compound II dissolved in 10 ml of water) was added dropwise, and the reaction was continued at 25 °C for 5 h. 15 ml of water was added to induce crystallization. The crystals were filtered, dried under vacuum at 60 °C, and yielded 5.43 g of compound III, with a yield of 94.8% and an HPLC purity of 99.59%.
[0071] 1.14 g of sodium hydroxide was dissolved in 40 ml of methanol, and 5.00 g of compound III was added. 7.74 g of 50% methyl ethyl ketone peroxide (ω%) was added dropwise. After the addition was complete, the reaction was maintained at 40 °C for 6 h. The temperature was lowered to 10–20 °C to crystallize for 1 h. The crystals were filtered, and the filter cake was dried under vacuum at 50 °C. The resulting dry product was added to 15 ml of ethanol, and a 10% acetic acid / ethanol solution was added to adjust the pH to 7–8. Crystallization was carried out at 20–30 °C for 2 h. The crystals were filtered, and the filter cake was dried under vacuum at 50 °C to obtain 1.45 g of compound IV, with a yield of 27.7% and a purity of 91.56%.
[0072] Comparative Example 2:
[0073] The operation was carried out in accordance with Embodiments 1 and 2 of Chinese Patent CN94191913.7.
[0074] 2 g of 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole was dissolved in 0.74 g of sodium hydroxide and 100 mL of methanol at room temperature. 1.9 g of 4-methoxy-3-methyl-2-chloromethylpyridine hydrochloride was added to the solution, and the mixture was reacted at 50–60 °C for 3 h. The inorganic precipitate was removed by filtration, the solvent was removed under reduced pressure, and the residue was crystallized from diethyl ether. A pale yellow solid, compound III, was obtained in 81.7% yield and 98.1% purity.
[0075] 6.7 g of compound III was dissolved in 150 mL of chloroform and cooled to -40 °C. m-chloroperoxybenzoic acid, dissolved in chloroform, was slowly added dropwise to the above solution. The mixture was stirred at -40 °C for 20 minutes. The reaction mixture was diluted with chloroform, washed with an aqueous sodium bicarbonate solution, and then washed with saturated brine. The chloroform solution was dried over sodium sulfate. The initial product, obtained after removing the solvent under reduced pressure, was dissolved in ethyl acetate and crystallized from diethyl ether to give compound IV, with a yield of 50.3% and a purity of 95.83%.
[0076] Comparative Example 3:
[0077] The procedure was performed in accordance with Experiment C of Example 1 and Example 7 of Chinese Patent CN103073536B.
[0078] At room temperature, 85.9 g of 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole, 31.9 g of sodium hydroxide, and 2120 ml of acetone were added sequentially. The mixture was stirred over ice water, and then 84.0 g of 4-methoxy-3-methyl-2-chloromethylpyridine hydrochloride and 3.3 g of potassium iodide were slowly added. The mixture was refluxed for 1 h. Part of the solvent was removed by vacuum distillation, and purified water was added to give a white solid. After drying, ilaprazole sulfide was obtained with a yield of 91.7% and a purity of 98.97%.
[0079] 100g of ilaprazole sulfide was added to a flask, followed by 2000ml of acetonitrile. The temperature was raised to 40-60℃, and 400g of a 10% sodium hypochlorite aqueous solution was slowly added dropwise. After most of the raw materials were completely converted, the reaction was quenched by adding sodium thiosulfate solution. The mixture was allowed to stand and separate into layers. The organic phase was concentrated under reduced pressure, extracted with dichloromethane, and washed successively with sodium carbonate aqueous solution and purified water. The organic phase was decolorized and dried with anhydrous magnesium sulfate and activated carbon. A portion was removed by vacuum distillation, and then ethyl acetate was added to crystallize the mixture. The crystals were filtered, and the filter cake was washed with ethyl acetate and dried to obtain ilaprazole with a yield of 57.6% and a purity of 98.78%.
[0080] Comparative Example 4:
[0081] The operation was carried out in accordance with Embodiments 5, 11 and 26 of Chinese Patent CN100478339C.
[0082] 102g of sodium hydroxide was dissolved in methanol, and 184g of 5-nitro-1-hydrobenzimidazole was added and stirred until dissolved. Then, 1000ml of a methanol solution containing 294g of 4-methoxy-3-methyl-2-chloromethylpyridine hydrochloride was slowly added. The mixture was stirred at room temperature for 48h, filtered, and the filter cake was washed with water until the washing liquid was neutral. The cake was then washed with 300ml of methanol and dried to obtain 5-nitro-2-[(4-methoxy-3-methyl-2-pyridyl)-methylmercapto]-1-hydro-benzimidazole, with a yield of 88.2%.
[0083] 140 g of stannous chloride hydrate was dissolved in a mixed solvent of 140 ml concentrated hydrochloric acid and 140 ml methanol. The solution was cooled to 0 °C, and 46.8 g of 5-nitro-2-[(4-methoxy-3-methyl-2-pyridinyl)-methylmercapto]-1-hydro-benzimidazole was slowly added. The reaction mixture was kept at this temperature for 3 h. The reaction solution was then slowly added to 3000 ml of ice water containing 239 g of sodium hydroxide. The mixture was extracted with 1000 ml of ethyl acetate three times. The organic phases were combined, washed with 800 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 5-amino-2-[(4-methoxy-3-methyl-2-pyridinyl)-methylmercapto]-1-hydro-benzimidazole, with a yield of 87.3%.
[0084] 0.655 g of 5-amino-2-[(4-methoxy-3-methyl-2-pyridyl)-methylmercapto]-1-hydro-benzimidazole was dissolved in a mixture of 2.2 ml glacial acetic acid, 2.2 ml water, and 6.6 ml tetrahydrofuran at room temperature. 0.7 ml of 2,5-dimethoxy-tetrahydrofuran was added to the solution with stirring, and the mixture was heated to 80-90 °C and reacted for 1.5 h. The solvent was evaporated to dryness, and 10 ml water and 30 ml dichloromethane were added. The mixture was allowed to stand for separation, and the layers were extracted with 2 × 30 ml dichloromethane. The organic phases were combined, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography to obtain ilaprazole sulfide with a yield of 52.2% and a purity of 96.88%.
[0085] Comparative Example 5:
[0086] The operation is performed according to Example 26 of Chinese Patent CN1803794A.
[0087] 0.263 g of m-chloroperoxybenzoic acid (86% w / w) was dissolved in 3 ml of dichloromethane and 0.75 ml of ethanol, and cooled to approximately 0 °C for later use. 0.172 g of potassium bicarbonate was dissolved in 1.5 ml of water and cooled to 0 °C for later use. 0.5 g of ilaprazole sulfide was dissolved in 5 ml of dichloromethane, 6% SDS was added, and the above potassium bicarbonate aqueous solution was added. The mixture was cooled to 0-5 °C, and the above m-chloroperoxybenzoic acid solution was added dropwise. After the reaction was complete, the mixture was separated and extracted with 3 × 5 ml of dichloromethane. The organic phases were combined, triethylamine was added, and the mixture was dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and 5 ml of acetone was added. The mixture was stirred at approximately 0 °C in the dark for 1.5 h, filtered, and dried to obtain ilaprazole with a yield of 45.2% and a purity of 81.52%.
[0088] Data for compound IV obtained from Examples 1-6 and Comparative Examples 1, 2, 3 and 5 are shown in Table 2 below:
[0089] Table 2: Data from Example and Comparative Studies
[0090] source purity(%) Total impurities (%) peroxide(%) Yield (%) Hygroscopicity (%) Example 1 99.90 0.10 none 64.1 0.15 Example 2 99.91 0.09 none 65.1 0.14 Example 3 99.88 0.12 none 64.8 0.14 Example 4 99.89 0.11 none 64.2 0.15 Example 5 99.86 0.14 none 64.6 0.13 Example 6 99.93 0.07 none 65.8 0.12 Comparative Example 1 91.56 8.44 none 27.7 0.16 Comparative Example 2 95.83 4.17 1.37 50.3 0.72 Comparative Example 3 98.78 1.22 0.85 57.6 0.88 Comparative Example 5 81.52 18.48 2.56 45.2 1.03
[0091] Data for compound III obtained in Examples 1-6 and Comparative Example 4 are shown in Table 3 below:
[0092] Table 3: Data from Example and Comparative Studies
[0093] source purity(%) Total impurities (%) Yield (%) Example 1 99.36 0.64 93.5 Example 2 99.59 0.33 95.5 Example 3 99.63 0.37 95.5 Example 4 99.54 0.46 94.9 Example 5 99.55 0.45 94.9 Example 6 99.67 0.41 95.8 Comparative Example 4 96.88 3.12 52.2
[0094] The above embodiments are merely illustrative of the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. Any modifications made to the technical solution based on the technical concept proposed in this invention shall fall within the scope of protection of this invention.
Claims
1. A method for preparing ilaprazole, characterized in that, The reaction equation for the method is as follows: ； The method includes the following steps: Step 1): 5-(1H-pyrrolo-1-yl)-2-mercaptobenzimidazole (compound I) was dissolved in an aqueous sodium hydroxide solution and a monohydric alcohol, and then 3-methyl-4-methoxy-2-chloromethylpyridine hydrochloride (compound II) was added dropwise. The reaction temperature was 15~35°C and the reaction time was 3~8 hours to obtain compound III. The molar ratio of compound I:compound II:sodium hydroxide was (1.0~1.5):1.0:(2.0~2.5). The purity of compound III was above 99%. Step 2): Compound III is dissolved in an organic solvent, an oxidant and a catalyst are added to react, sodium hydroxide is added, and after liberation treatment, compound IV is obtained, which is the elastosazole mentioned above; the oxidant is one or more of tert-butyl perbenzoate, cumene hydroperoxide, and methyl ethyl ketone peroxide; the catalyst is one or more of vanadium pentoxide, manganese dioxide, sodium vanadate, ammonium metavanadate, sodium metavanadate, and potassium metavanadate, and the weight ratio of catalyst to compound III is 0.01~0.1:1; the reaction temperature is 25~55℃, and the reaction time is 2~10h; no peroxide is generated in this step; the organic solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, and acetone; the liberation is carried out using one or more of formic acid, acetic acid, propionic acid, benzoic acid, oxalic acid, and succinic acid.
2. The method for preparing ilaprazole according to claim 1, characterized in that: In step 2), the molar ratio of oxidant to compound III is (1.3~2.5):
1.
3. A method for preparing ilaprazole according to any one of claims 1-2, characterized in that: In step 1), the monohydric alcohol is one or more of methanol and ethanol.