A preparation method of tegorazan intermediate
A three-step method for preparing tegoprazan intermediates using commercially available compounds and controlled reactions addresses the inefficiencies of existing methods, resulting in high yield and environmentally friendly commercial production.
Patent Information
- Application Number
- CN202211728902.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-12-30
- Publication Date
- 2024-12-10
- Estimated Expiration
- 2042-12-30
AI Technical Summary
Existing methods for preparing tegoprazan intermediates are lengthy, have low overall reaction yield, require costly and toxic reagents, and are not environmentally friendly, making them unsuitable for commercialization.
A three-step synthetic route using commercially available compounds and avoiding highly toxic reagents and expensive catalysts, involving reactions in dichloromethane, hydrogenation with palladium carbon, and controlled temperature benzyl halide addition, with purification by crystallization.
The method achieves high yield, easy purification, and cost-effective production of tegoprazan intermediates suitable for commercial use.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing a tergolan intermediate. Background Art
[0002] Tegoprazan, also known as tegoprazan, tegoprazan, and CJ-12420, was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) in July 2018 for the treatment of gastroesophageal reflux disease and erosive esophagitis. Tegoprazan is a competitive potassium ion acid blocker (P-cab) and hydrogen ion / potassium ion exchange ATPase (H+ / K+ATPase) inhibitor. It has a fast onset of action and can control the pH value of gastric juice for a long time. It is a new drug for the treatment of gastroesophageal reflux disease and erosive esophagitis.
[0003] Patent US2007142448A1 discloses a method for preparing a teglazan intermediate 1, which uses 2-amino-3-nitrophenol as a raw material and is prepared through seven steps including benzyl protection, bromination, acetylation, palladium-catalyzed cyanation, cyclization, cyano hydrolysis, and amidation. The synthetic route is:
[0004]
[0005] This method has a long process, low overall reaction yield, and is difficult to purify. Multi-step products require column chromatography purification, which is not suitable for commercialization. In addition, the fourth step requires the use of highly toxic cyanide and expensive palladium catalysts, which is not environmentally friendly and very costly.
[0006] Patent WO2005111000A1 discloses a method for preparing a teglazan intermediate, which also uses 2-amino-3-nitrophenol as a raw material and is prepared through five steps of benzyl protection, bromination, reduction, cyclization, and high-pressure catalytic coupling. The synthetic route is:
[0007]
[0008] Although it shortens the steps, the reaction conditions of the last step are harsh, requiring high temperature and high pressure, and the use of expensive palladium catalysts, resulting in high costs and not suitable for commercialization.
[0009] Therefore, it is necessary to provide a method for preparing tergolan intermediates which is simple to operate and does not use highly toxic reagents and expensive catalysts. Summary of the invention
[0010] In view of this, the object of the present invention is to provide a method for preparing a tergolan intermediate, which simplifies the preparation steps and improves the yield of the product.
[0011] The preparation method of the tergolan intermediate of the present invention has the following specific synthetic route:
[0012]
[0013] Preferably, the method for preparing the tegorazan intermediate comprises the following steps:
[0014] The first step: adding compound 4 (1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid) to dichloromethane, then adding N,N-dimethylformamide (DMF), dropping thionyl chloride, heating to 30°C to 40°C and reacting for 1.5h to 2h; after the reaction is completed, cooling to 0-15°C, then dropping into a dimethylamine aqueous solution, reacting for 1h to 1.2h, adding water to the reaction system for liquid separation to obtain a dichloromethane layer and a water layer, drying the dichloromethane layer with anhydrous sodium sulfate, filtering, and concentrating to obtain an off-white solid compound 3 (4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide);
[0015] Step 2: Compound 3 is added to glacial acetic acid, and then palladium carbon is added, hydrogen is introduced, and hydrogenation is carried out at a temperature of 50 to 60° C. for 5 h to 8 h, and the filtrate is filtered. The filtrate is adjusted to pH=7 with sodium hydroxide, and a solid is precipitated and filtered to obtain a solid crude product. The solid crude product is purified by slurrying with ethanol and water to obtain an off-white solid compound 2 (4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide);
[0016] Step 3: Add compound 2 to a mixed solution of organic solvent 1, ethanol and water, then add an inorganic base, mix well and cool to -20 to 0°C, drop benzyl halide, control the temperature at -5°C to 5°C and react for 15h to 20h, add water and dichloromethane, extract and separate, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product; the crude product is dissolved in organic solvent 2, dropped into water for crystallization, filtered, and a white solid compound 1 tergorazan intermediate is obtained. Cooling to -20 to 0°C, low temperature is conducive to controlling side reactions and reducing the generation of impurities.
[0017] Preferably, the weight ratio of the compound 4, dichloromethane, N,N-dimethylformamide and thionyl chloride described in the first step is 1:8-12:0.01-0.05:0.6-0.8.
[0018] Preferably, the concentration of the dimethylamine aqueous solution in the first step is 35-40%; the weight ratio of the dimethylamine aqueous solution to compound 4 is 2-5:1.
[0019] Preferably, the weight ratio of the compound 3, glacial acetic acid and palladium carbon in the second step is 1:3-5:0.05-0.2.
[0020] Preferably, the amount of hydrogen introduced in the second step is 0.3-0.5 MPa.
[0021] Preferably, during the pulping and purification process in the second step, the volume ratio of ethanol, water and solid crude product is 2-3:4-6:1.
[0022] Preferably, in the third step, the organic solvent 1 is any one of DMSO, NMP, DMF, DMAc, ethanol, isopropanol, dioxane, and acetonitrile; the organic solvent 2 is any one of acetonitrile, methanol, ethanol, and isopropanol; and the volume ratio of the organic solvent 2 to the crude product is 3 to 5:1.
[0023] Preferably, in the mixed solution of the third step, the volume ratio of the organic solvent 1, ethanol and water is 4-5:4-5:1-3; the volume ratio of the compound 2 to the mixed solution is 1:8-12.
[0024] Preferably, the inorganic base in the third step is any one of sodium hydroxide, potassium hydroxide, potassium carbonate, potassium phosphate, and sodium carbonate; and the molar ratio of the inorganic base to compound 2 is 1 to 1.5:1.
[0025] Preferably, the benzyl halide in the third step is any one of benzyl bromide or benzyl chloride, and the molar ratio of the benzyl halide to compound 2 is 0.8-1.2:1.
[0026] Compared with the prior art, the present invention has the following beneficial effects:
[0027] The present invention provides a method for preparing a tergolan intermediate, using a commercial compound 4 as a raw material, and preparing a compound 1 through a three-step reaction, with a high reaction yield, and the intermediate and the product are easy to crystallize and purify, and the quality is controllable. The operation is simple, no highly toxic reagents and expensive catalysts are used, it is environmentally friendly, low in cost, and suitable for commercial production. DETAILED DESCRIPTION
[0028] The present invention will be further described below in conjunction with the embodiments.
[0029] Example 1
[0030] A method for preparing a tegorazan intermediate, comprising the following steps:
[0031] Step 1: Compound 4 was added to dichloromethane, DMF was added, thionyl chloride was added dropwise, and the temperature was raised to 35°C for reaction for 2 hours; after the reaction was completed, the temperature was lowered to 0-15°C, and the mixture was added dropwise to a dimethylamine aqueous solution (mass concentration of 40%), and the reaction was continued for 1 hour, and water was added to the reaction system for separation. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain an off-white solid compound 3 with a yield of 92%;
[0032] The weight ratio of the compound 4, dichloromethane, N,N-dimethylformamide and thionyl chloride is 1:10:0.02:0.7; the weight ratio of the dimethylamine aqueous solution to the compound 4 is 3:1;
[0033] Step 2: Compound 3 was added to glacial acetic acid, and then palladium carbon was added, hydrogen was introduced, and hydrogenation was carried out at 50-60°C for 7 hours, and then filtered. The pH was adjusted to 7 with sodium hydroxide to precipitate a solid, and then filtered to obtain a solid crude product. The solid crude product was purified by slurrying with ethanol and water to obtain an off-white solid compound 2 with a yield of 95%;
[0034] The weight ratio of the compound 3, glacial acetic acid and palladium carbon is 1:3:0.1; the pressure of the hydrogen introduced is 0.3-0.5 MPa; during the purification process, the volume ratio of ethanol, water and solid crude product is 2:4:1;
[0035] Step 3: Compound 2 was added to the mixed solution (the mixed solution was prepared by mixing DMF, ethanol and water in a volume ratio of 4:4:2) at a volume ratio of 1:10, potassium carbonate was added at a molar ratio of the inorganic base to compound 2 of 1.2:1, the temperature was lowered to -10 to 0°C, benzyl bromide was added dropwise at a molar ratio of benzyl bromide to compound 2 of 1.0:1, the temperature was controlled at 0°C for 16 hours, 8 times the volume of water and 8 times the volume of dichloromethane of compound 2 were added, the liquid was extracted and separated, the dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, the crude product was dissolved in methanol (the volume ratio of methanol to the crude product was 3:1), dropped into water for crystallization, filtered, and white solid compound 1 was obtained with a yield of 77%.
[0036] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A method for preparing a tegorazan intermediate, characterized in that: The specific synthetic route is: ； The preparation method of the tegorazan intermediate comprises the following steps: The first step: adding compound 4 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid to dichloromethane, then adding N,N-dimethylformamide, dropping thionyl chloride, heating to 30°C~40°C and reacting for 1.5h~2h; after the reaction is completed, cooling to 0-15°C, dropping into a dimethylamine aqueous solution, reacting for 1h~1.2h, adding water to the reaction system for liquid separation to obtain a dichloromethane layer and a water layer, drying the dichloromethane layer, filtering, and concentrating to obtain an off-white solid compound 3 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide; Step 2: Compound 3 is added to glacial acetic acid, and then palladium carbon is added, hydrogen is introduced, and hydrogenation is carried out at a temperature of 50-60°C for 5h-8h, and the filtrate is filtered. The filtrate is adjusted to pH=7 with sodium hydroxide, and a solid is precipitated and filtered to obtain a solid crude product. The solid crude product is purified by slurrying with ethanol and water to obtain an off-white solid compound 2 4-hydroxy-N,N,2-trimethylbenzimidazole-6-carboxamide; Step 3: Add compound 2 to a mixed solution of organic solvent 1, ethanol and water, then add an inorganic base, mix well and cool to -20~0°C, add benzyl halide dropwise, control the temperature at -5°C~5°C to react for 15h~20h, add water and dichloromethane, extract and separate the liquids, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product; the crude product is dissolved with organic solvent 2, dripped into water for crystallization, and filtered to obtain a white solid compound 1 tergolan intermediate.
2. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: The weight ratio of compound 4, dichloromethane, N,N-dimethylformamide and thionyl chloride described in the first step is 1:8~12:0.01~0.05:0.6~0.
8.
3. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: The mass concentration of the dimethylamine aqueous solution in the first step is 35-40%; the weight ratio of the dimethylamine aqueous solution to compound 4 is 2-5:
1.
4. The method for preparing the tergolan intermediate according to claim 1, characterized in that: In the second step, the weight ratio of the compound 3, glacial acetic acid and palladium carbon is 1:3~5:0.05~0.2; the pressure of the hydrogen introduced is 0.3~0.5MPa.
5. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: During the pulping and purification process in the second step, the volume ratio of ethanol, water and solid crude product is 2-3:4-6:
1.
6. The method for preparing the tergolan intermediate according to claim 1, characterized in that: In the third step, the organic solvent 1 is any one of DMSO, NMP, DMF, DMAc, ethanol, isopropanol, dioxane, and acetonitrile; the organic solvent 2 is any one of acetonitrile, methanol, ethanol, and isopropanol; and the volume ratio of the organic solvent 2 to the crude product is 3-5:
1.
7. The method for preparing the tergolan intermediate according to claim 1, characterized in that: In the mixed solution of the third step, the volume ratio of the organic solvent 1, ethanol and water is 4-5:4-5:1-3; the volume ratio of the compound 2 to the mixed solution is 1:8-12.
8. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: In the third step, the inorganic base is any one of sodium hydroxide, potassium hydroxide, potassium carbonate, potassium phosphate, and sodium carbonate; and the molar ratio of the inorganic base to compound 2 is 1-1.5:
1.
9. The method for preparing the tegorazan intermediate according to claim 1, characterized in that: In the third step, the benzyl halide is any one of benzyl bromide and benzyl chloride, and the molar ratio of the benzyl halide to compound 2 is 0.8-1.2:1.