Synthesis method of tergorazan intermediate
By employing a synthetic route that first amidation and then esterification, and using thionyl chloride and catalytic hydrogenation steps, the problems of low yield and complex purification in the synthesis of tegorazan intermediates were solved, enabling efficient and low-cost industrial production.
Patent Information
- Application Number
- CN202511668224.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-14
- Publication Date
- 2026-01-13
AI Technical Summary
Existing synthesis processes for tegorazan intermediates suffer from low reaction yields, high costs, complex purification processes, and difficulties in industrialization, especially in the amidation and esterification steps where byproducts and impurities are easily generated.
A synthetic route of amidation followed by esterification was adopted, using thionyl chloride as a carboxyl activator. By employing catalytic hydrogenation and alkaline hydrolysis steps, side reactions in strong acidic and electrophilic environments were avoided, simplifying post-processing.
A high-yield, low-cost synthesis of tegorazan intermediates was achieved, simplifying the purification process and making it suitable for industrial production.
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Figure CN121318858A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical organic synthesis, and more specifically to a method for synthesizing a tegorazan intermediate. Background Technology
[0002] Tegoprazan, also known as tegorazine, is a novel potassium-competitive acid blocker (P-CAB). Due to its rapid onset of action and long-lasting acid suppression, it is widely used in the treatment of gastroesophageal reflux disease and erosive esophagitis. The quality of the synthesis process of its key intermediate, 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazolium-6-carboxamide, directly affects the cost, quality, and industrialization feasibility of the final active pharmaceutical ingredient.
[0003] Currently, there are numerous literature and patent reports on the synthesis of this intermediate, but existing technical routes generally have many shortcomings. For example, Pfizer's Chinese patent CN101341149 uses a coupling reaction that requires expensive metal catalysts (such as tetra(triphenylphosphine)palladium) and involves microwave reaction, column chromatography purification, and other operations. Not only is the reaction yield low (the yield of some steps is less than 40%), but the cost is also high, making it difficult to meet the economic and safety requirements of industrial production.
[0004] Furthermore, in the activation of the carboxyl group, many routes tend to use reagents such as pentyl chloride and acetic anhydride. While these reagents can achieve one-pot protection of the phenolic hydroxyl group by reacting with carboxylic acids to form amides, the reaction generates an equivalent amount of organic acid byproducts (such as pentyl acid and acetic acid), which need to be removed through complex washing and extraction steps. This not only increases the emission of waste gas, wastewater, and solid waste, but also increases the purification cost and operational complexity.
[0005] Therefore, developing a synthetic route with mild reaction conditions, robustness, low cost, and easy purification is of paramount importance for the industrial production of this key intermediate of tegorazan. Summary of the Invention
[0006] To address the shortcomings of existing technologies and solve the aforementioned problems, a method for synthesizing tegorazan intermediates is proposed, and the following technical solution is provided: A method for synthesizing a tagorazan intermediate, characterized in that the structural formula of the tagorazan intermediate is shown in Figure I. I The preparation method includes: using 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid as the starting material, and successively undergoing amidation, esterification with acetyl, catalytic hydrogenation debenzylation, sulfonation, and deacetylation protection to obtain the tegorazan intermediate 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide.
[0007] Furthermore, the synthetic route for the tegorazan intermediate is as follows: S1, starting with 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid, reacts with thionyl chloride and then undergoes amidation with amine compounds to obtain 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide; S2,4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide was esterified with an acetylation reagent to give 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide; Catalytic hydrogenation of S3,4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide yields 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide; S4,4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide reacts with p-toluenesulfonyl chloride to give 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide; S5,4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide is hydrolyzed in alkaline solution to give 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide.
[0008] Furthermore, the hydrolysis temperature in step S5 is 40~70℃.
[0009] Furthermore, the amine compound in S1 is dimethylamine, and the mass ratio of 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid, thionyl chloride and 40% dimethylamine aqueous solution is 1:0.5~0.6:1.4~2.0.
[0010] Furthermore, after the esterification reaction is completed in step S2, water is added and stirred to quench the reaction, followed by layering and concentration.
[0011] Furthermore, the acetylation reagent in S2 is acetic anhydride or acetyl chloride, and the mass ratio of 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide to the acetylation reagent is 1:0.45~0.55.
[0012] Furthermore, the specific steps for the catalytic hydrogenation of 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide in step S3 are as follows: 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, organic solvent, and metal catalyst are mixed, stirred, and heated. The air in the reaction apparatus is replaced with nitrogen, and then the nitrogen is replaced with hydrogen before the reaction begins. The mass ratio of 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, organic solvent, and metal catalyst is 1:4~6:0.05~0.1.
[0013] Furthermore, in S4, 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide is reacted with p-toluenesulfonyl chloride in dichloromethane, followed by the dropwise addition of an organic base. After the reaction is complete, water is added to quench the reaction. Furthermore, in S5, 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide was dissolved in ethanol and hydrolyzed in sodium carbonate solution. After the reaction was completed, the pH was adjusted to 5-6 using hydrochloric acid aqueous solution.
[0014] Furthermore, the concentration of the sodium carbonate solution is 10%, and the mass ratio of 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, ethanol, and sodium carbonate solution is 1:3.2~4:2.5~3.
[0015] Due to the adoption of the above technical solutions, the beneficial technical effects of the present invention are as follows: 1. This application adopts an amidation followed by esterification reaction, first converting the highly active carboxyl group into a stable amide. The amide bond is very stable in the subsequent esterification and hydrogenation reactions and will not cause side reactions. If the phenolic hydroxyl group is acetylated first, the strong acid and electrophilic environment may cause side reactions such as hydrolysis or intramolecular migration of the acetyl group during the subsequent activation of the carboxyl group, increasing impurities. 2. This invention uses thionyl chloride as a carboxyl activating agent. The gaseous byproducts (SO2 and HCl) generated by the reaction can drive the reaction to completion and are easy to remove. These gases can escape from the reaction system during the reaction process, driving the reaction equilibrium to shift to the right. After the reaction is completed, the system mainly contains a dichloromethane solution of the product, with almost no residual solid or liquid byproducts. This makes the post-processing extremely simple. It can be directly used for the next step after simple water washing and drying. Attached Figure Description
[0016] Figure 1 This is a schematic diagram of the reaction principle for preparing tegorazan intermediates. Detailed Implementation
[0017] To enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Based on the embodiments in this application, other similar embodiments obtained by those skilled in the art without creative effort should all fall within the scope of protection of this application.
[0018] A method for synthesizing a tagorazan intermediate, characterized in that the structural formula of the tagorazan intermediate is shown in Figure I. I The preparation method includes: using 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid as the starting material, and successively undergoing amidation, esterification with acetyl, catalytic hydrogenation debenzylation, sulfonation, and deacetylation protection to obtain the tegorazan intermediate 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide.
[0019] This application employs an amidation followed by esterification reaction. First, the highly reactive carboxyl group is converted into a stable amide. The amide bond is very stable in subsequent esterification (acetic anhydride, mild conditions) and hydrogenation reactions, and no side reactions occur. If the phenolic hydroxyl group is acetylated first, the strong acid and electrophilic environment may lead to side reactions such as hydrolysis or intramolecular migration of the acetyl group during subsequent activation of the carboxyl group, increasing impurities.
[0020] like Figure 1 As shown, the synthetic route for the tegorazan intermediate is as follows: S1, starting with 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid, reacts with thionyl chloride and then undergoes amidation with amine compounds to obtain 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide; S2,4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide was esterified with an acetylation reagent to give 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide; Catalytic hydrogenation of S3,4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide yields 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide; S4,4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide reacts with p-toluenesulfonyl chloride to give 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide; S5,4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide is hydrolyzed in alkaline solution to give 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide.
[0021] In S2 of this invention, thionyl chloride is used as a carboxyl activating agent. The gaseous byproducts (SO2 and HCl) generated by the reaction can drive the reaction to completion and are easy to remove. These gases can escape from the reaction system during the reaction process, driving the reaction equilibrium to shift to the right. After the reaction is completed, the system mainly contains a dichloromethane solution of the product, with almost no residual solid or liquid byproducts. This makes the post-processing extremely simple. It can be directly used for the next step after simple water washing and drying.
[0022] Furthermore, the hydrolysis temperature in step S5 is 40~70℃. This application efficiently drives the hydrolysis of acetoxy groups under mild conditions while effectively avoiding side reactions such as sulfonyl group removal and amide bond breaking that may occur under high temperature and strong alkali conditions, thus ensuring a high product yield.
[0023] Example 1 Preparation of S1,4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide: 110 g of 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid was added to 400 mL of dichloromethane under stirring in an ice-water bath with 60 g of thionyl chloride added dropwise. After the addition was complete, the water bath temperature was raised to 40 °C, maintained under slight reflux, and stirred for 4 hours until the solid was completely dissolved. The temperature was then lowered to about 15 °C. In another reaction flask, 150 g of 40% dimethylamine aqueous solution was added, and the temperature was lowered to 0 °C in an ice-water bath. The prepared acyl chloride solution was then added dropwise to the dimethylamine aqueous solution using a constant pressure dropping funnel, and the temperature was maintained at 0 °C. After the addition was complete, the temperature was maintained and stirred for another 2 hours. The reaction was detected by TLC. 200 mL of water was added and stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The organic phase was washed with 200 mL of water and separated into layers. The organic phase was dried with anhydrous sodium sulfate for 30 minutes and filtered. The mother liquor was used directly for the next reaction.
[0024] Preparation of S2,4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide: The organic phase obtained in the previous step was transferred into a dry 1000 ml four-necked reaction flask and stirred at room temperature. 55 g of acetic anhydride was added, and the temperature of the reaction solution was slowly increased to about 30 °C. The mixture was kept at this temperature and stirred for 6 hours. The reaction was detected by TLC and found to be complete. 300 ml of water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand and separate into layers. The organic phase was washed with 200 ml of 5% sodium bicarbonate solution, allowed to stand and separate into layers, washed with 200 ml of water, allowed to stand and separate into layers, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 124 g of oily 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, with a yield of 90%. 1H-NMR (400MHz, DMSO-d6): 7.5~7.2(m, 5H), 7.0(s, 1H), 6.7(s, 1H), 5.5(s, 2H), 3.0(s, 3H), 2.9(s, 3H), 2.4(s, 3H), 2.0(s, 3H).
[0025] Preparation of S3,4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide: 124 g of 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide was dissolved in 620 mL of methanol and transferred to a 2 L hydrogenation reactor. 10 g of 10% palladium on carbon was added, and the mixture was purged with nitrogen three times. The temperature was raised to 55 °C, hydrogen was introduced, and the pressure was increased to 0.6 MPa. The mixture was kept at this temperature and stirred for 6 hours to carry out the hydrogenation reaction. When the pressure dropped to 0.3 MPa, it was repressurized to 0.6 MPa. The reaction was stopped when no pressure drop occurred, nitrogen was purged, the catalyst was filtered, and the mother liquor was evaporated under reduced pressure to obtain 87.60 g of oily 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide, with a yield of 95%.
[0026] 1H-NMR (CDCl3, 400MHz): 7.0 (s, 1H), 6.7 (s, 1H), 3.0 (s, 3H), 2.9 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
[0027] Preparation of S4,4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide compounds: 87 g of compound 7, an oily substance, was dissolved in 350 g of dichloromethane by stirring at room temperature. 78 g of p-toluenesulfonyl chloride was added, and the temperature was controlled below 30°C in an ice-water bath. 42 g of triethylamine was added dropwise, and the mixture was stirred at room temperature for 4 hours after the addition was complete. 170 g of water was added and stirred for 30 minutes. The mixture was allowed to stand, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 125 g of a yellow oily substance—4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, with a yield of 90%.
[0028] 1H-NMR (400MHz, DMSO-d6): 8.0 (d, 2H), 7.5 (d, 2H), 7.3 (s, 1H), 6.7 (s, 1H), 3.0 (d, 6H), 2.8 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
[0029] Preparation of S5,4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazol-6-carboxamide: 125 g of 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide was dissolved in 400 g of ethanol by stirring. 325 g of 10% sodium carbonate solution was added and the mixture was stirred at 50-60°C for 3 h. After the reaction was complete, 1M hydrochloric acid solution was added dropwise to adjust the pH to 5. The mixture was concentrated under reduced pressure, and the ethanol in the reaction solution was distilled off. 200 ml of ethyl acetate was added for extraction twice. The organic phase was concentrated under reduced pressure to approximately 200 g of mother liquor. The mixture was heated to 60°C, and 300 ml of ethanol was added dropwise with stirring. The mixture was kept at this temperature and stirred for 0.5 h. The temperature was lowered to below 10°C, and the mixture was kept at this temperature and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 50°C to obtain 107.9 g of white solid 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, with a yield of 96%. 1H-NMR (400MHz, DMSO-d6): 10.4 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.3 (s, 1H), 6.7 (s, 1H), 3.0 (s, 3H), 2.9 (s, 3H), 2.8 (s, 3H), 2.4 (s, 3H).
[0030] Example 2 Preparation of S1,4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide: 110 g of 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid was added to 400 mL of dichloromethane under stirring in an ice-water bath with 66 g of thionyl chloride added dropwise. After the addition was complete, the water bath temperature was raised to 40 °C and maintained under slight reflux with stirring for 4 hours until the solid was completely dissolved. The temperature was then lowered to about 15 °C. In another reaction flask, 200 g of 40% dimethylamine aqueous solution was added and the temperature was lowered to 0 °C in an ice-water bath. The prepared acyl chloride solution was then added dropwise to the dimethylamine aqueous solution using a constant pressure dropping funnel and kept at 0 °C. After the addition was complete, the temperature was maintained with stirring for another 2 hours. The reaction was confirmed by TLC. 200 mL of water was added and stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The organic phase was washed with 200 mL of water and separated into layers. The organic phase was dried with anhydrous sodium sulfate for 30 minutes and filtered. The mother liquor was used directly for the next reaction.
[0031] Preparation of S2,4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide: The organic phase obtained in the previous step was transferred into a dry 1000 ml four-necked reaction flask and stirred at room temperature. 55 g of acetic anhydride was added, and the temperature of the reaction solution was slowly raised to about 30 °C. The mixture was kept at this temperature and stirred for 6 hours. The reaction was detected by TLC and found to be complete. 300 ml of water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand and separate into layers. The organic phase was washed with 200 ml of 5% sodium bicarbonate solution, allowed to stand and separate into layers, washed with 200 ml of water, allowed to stand and separate into layers, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 126 g of oily 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, with a yield of 91.5%. 1H-NMR (400MHz, DMSO-d6): 7.5~7.2(m, 5H), 7.0(s, 1H), 6.7(s, 1H), 5.5(s, 2H), 3.0(s, 3H), 2.9(s, 3H), 2.4(s, 3H), 2.0(s, 3H).
[0032] Preparation of S3,4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide: 126 g of 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide was dissolved in 620 mL of methanol and transferred to a 2 L hydrogenation reactor. 6.0 g of 10% palladium on carbon was added, and the reactor was purged with nitrogen three times. The temperature was raised to 50-60 °C, hydrogen was introduced, and the pressure was increased to 0.6 MPa. The reactor was kept at this temperature and stirred for 6 hours to carry out the hydrogenation reaction. When the pressure dropped to 0.3 MPa, it was repressurized to 0.6 MPa. The reaction was stopped when no pressure drop occurred, nitrogen was purged, the catalyst was filtered, and the mother liquor was evaporated under reduced pressure to obtain 88.50 g of oily 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide, with a yield of 94.46%.
[0033] 1H-NMR (CDCl3, 400MHz): 7.0 (s, 1H), 6.7 (s, 1H), 3.0 (s, 3H), 2.9 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H) Preparation of S4,4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide: 87 g of compound 7, an oily substance, was dissolved in 350 g of dichloromethane by stirring at room temperature. 74 g of p-toluenesulfonyl chloride was added, and the mixture was kept at a temperature below 30°C in an ice-water bath. 40 g of triethylamine was added dropwise, and the mixture was stirred at room temperature for 4 hours after the addition was complete. 170 g of water was added and stirred for 30 minutes. The mixture was allowed to stand, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 126 g of a yellow oily substance—4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, with a yield of 91%.
[0034] 1H-NMR (400MHz, DMSO-d6): 8.0 (d, 2H), 7.5 (d, 2H), 7.3 (s, 1H), 6.7 (s, 1H), 3.0 (d, 6H), 2.8 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H) Preparation of S5,4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazol-6-carboxamide: 125 g of 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide (Formula 8) was dissolved in 400 g of ethanol by stirring. 325 g of 10% sodium carbonate solution was added and stirred at 55°C for 3 h. After the reaction was complete, 1M hydrochloric acid solution was added dropwise to adjust the pH to 6. The mixture was concentrated under reduced pressure, and the ethanol in the reaction solution was distilled off. 200 ml of ethyl acetate was added for extraction twice. The organic phase was concentrated under reduced pressure to approximately 200 g of mother liquor. The mixture was heated to 70°C, and 300 ml of ethanol was added dropwise with stirring. The mixture was kept at this temperature and stirred for 0.5 h. The temperature was lowered to below 10°C, and the mixture was kept at this temperature and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 50°C to obtain 105.6 g of white solid 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, with a yield of 94%. 1H-NMR (400MHz, DMSO-d6): 10.4 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.3 (s, 1H), 6.7 (s, 1H), 3.0 (s, 3H), 2.9 (s, 3H), 2.8 (s, 3H), 2.4 (s, 3H).
[0035] Example 3 Preparation of S1,4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide: 110 g of 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid was added to 400 mL of dichloromethane under stirring in an ice-water bath with 55 g of thionyl chloride added dropwise. After the addition was complete, the water bath temperature was raised to 40 °C and maintained under slight reflux with stirring for 4 hours until the solid was completely dissolved. The temperature was then lowered to about 15 °C. In another reaction flask, 200 g of 40% dimethylamine aqueous solution was added and the temperature was lowered to 0 °C in an ice-water bath. The prepared acyl chloride solution was then added dropwise to the dimethylamine aqueous solution using a constant pressure dropping funnel and kept at 0 °C. After the addition was complete, the temperature was maintained with stirring for another 2 hours. The reaction was detected by TLC. 200 mL of water was added and stirred for 20 minutes. The mixture was allowed to stand and separate into layers. The organic phase was washed with 200 mL of water and separated into layers. The organic phase was dried with anhydrous sodium sulfate for 30 minutes and filtered. The mother liquor was used directly for the next reaction.
[0036] Preparation of S2,4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide: The organic phase obtained in the previous step was transferred into a dry 1000 ml four-necked reaction flask and stirred at room temperature. 45 g of acetic anhydride was added, and the temperature of the reaction solution was slowly increased to about 30 °C. The mixture was kept at this temperature and stirred for 6 hours. The reaction was detected by TLC and the reaction was complete. 300 ml of water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand and separate into layers. The organic phase was washed with 200 ml of 5% sodium bicarbonate solution, allowed to stand and separate into layers, washed with 200 ml of water, allowed to stand and separate into layers, and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 124 g of oily 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, with a yield of 90%. 1H-NMR (400MHz, DMSO-d6): 7.5~7.2(m, 5H), 7.0(s, 1H), 6.7(s, 1H), 5.5(s, 2H), 3.0(s, 3H), 2.9(s, 3H), 2.4(s, 3H), 2.0(s, 3H).
[0037] Preparation of S3,4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide: 124 g of 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide was dissolved in 620 mL of methanol and transferred to a 2 L hydrogenation reactor. 13 g of 10% palladium on carbon was added, and the mixture was purged with nitrogen three times. The temperature was raised to 50 °C, hydrogen was introduced, and the pressure was increased to 0.6 MPa. The mixture was kept at this temperature and stirred for 6 hours to carry out the hydrogenation reaction. When the pressure dropped to 0.3 MPa, it was repressurized to 0.6 MPa. The reaction was stopped when no pressure drop occurred, nitrogen was purged, the catalyst was filtered, and the mother liquor was evaporated under reduced pressure to obtain 87.60 g of oily 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide, with a yield of 95%.
[0038] 1H-NMR (CDCl3, 400MHz): 7.0 (s, 1H), 6.7 (s, 1H), 3.0 (s, 3H), 2.9 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
[0039] Preparation of S4,4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide compounds: 87 g of 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide was dissolved in 350 g of dichloromethane by stirring at room temperature. 78 g of p-toluenesulfonyl chloride was added, and the mixture was kept at a temperature below 30°C in an ice-water bath. 42 g of triethylamine was added dropwise, and the mixture was stirred at room temperature for 4 hours after the addition was complete. 170 g of water was added and stirred for 30 minutes. The mixture was allowed to stand, and the layers separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 125 g of a yellow oily substance—4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, with a yield of 90%.
[0040] 1H-NMR (400MHz, DMSO-d6): 8.0 (d, 2H), 7.5 (d, 2H), 7.3 (s, 1H), 6.7 (s, 1H), 3.0 (d, 6H), 2.8 (s, 3H), 2.4 (s, 3H), 2.0 (s, 3H).
[0041] Preparation of S5,4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazol-6-carboxamide: 125 g of 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide was dissolved in 400 g of ethanol by stirring. 325 g of 10% sodium carbonate solution was added and stirred at 50°C for 3 h. After the reaction was complete, 1M hydrochloric acid solution was added dropwise to adjust the pH to 6. The mixture was concentrated under reduced pressure, and the ethanol in the reaction solution was distilled off. 200 ml of ethyl acetate was added for extraction twice. The organic phase was concentrated under reduced pressure to approximately 200 g of mother liquor. The mixture was heated to 70°C, and 300 ml of ethanol was added dropwise with stirring. The mixture was kept at this temperature and stirred for 0.5 h. The temperature was lowered to below 10°C, and the mixture was kept at this temperature and stirred for 1 h. The mixture was filtered and dried under reduced pressure at 50°C to obtain 107.9 g of white solid 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, with a yield of 96%. 1H-NMR (400MHz, DMSO-d6): 10.4 (s, 1H), 8.0 (d, 2H), 7.5 (d, 2H), 7.3 (s, 1H), 6.7 (s, 1H), 3.0 (s, 3H), 2.9 (s, 3H), 2.8 (s, 3H), 2.4 (s, 3H).
[0042] Comparative Example 1 The only difference between this comparative example and Example 1 is that step S2 was performed before step S1; all other conditions were the same. The final yield was 101.2 g of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazolium-6-carboxamide, with a yield of 81%.
[0043] Comparative Example 2 The only difference between this comparative example and Example 1 is that thionyl chloride was not added in step S1, while all other conditions were the same. The final product 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazol-6-carboxamide was not obtained.
[0044] Comparative Example 3 The only difference between this comparative example and Example 1 is that the hydrolysis temperature in step S5 was 10°C; all other conditions were the same. The reaction was not complete after 3 hours and was allowed to continue. Monitoring showed that the reaction was complete after 24 hours, ultimately yielding 95g of 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzo[D]imidazolium-6-carboxamide, with a yield of 76%.
[0045] In Examples 1-3 of this application, the amounts of thionyl chloride and dimethylamine were changed in step S1, the amount of acetic anhydride was changed in step S2, the amount of metal catalyst was changed in step S3, the amounts of p-toluenesulfonyl chloride and triethylamine were changed in step S4, and the hydrolysis temperature and pH were changed in step S5. However, the final yield remained stable in the extremely high range of 94%-96%. This strongly demonstrates that the technical solution provided by this invention is not only highly efficient, but also has excellent repeatability and process robustness, which are characteristics highly valued in industrial production.
[0046] In Comparative Example 1, the phenolic hydroxyl group was first acetylated (S2). In the subsequent S1 step, when the carboxyl group was activated using thionyl chloride, a strongly acidic and electrophilic reagent, the harsh conditions of the reaction system easily led to side reactions such as hydrolysis or intramolecular migration of the sensitive acetoxy group, resulting in impurities. These impurities not only reduced the yield of the main reaction but also added a purification burden and yield loss to subsequent steps (especially the hydrogenation step, which requires extremely high purity). Comparative Example 2, without thionyl chloride, achieved an amidation yield of over 90% compared to Example 1 with thionyl chloride. The results of Comparative Example 2 highlight the importance of thionyl chloride in obtaining the final product; it is indispensable for achieving high conversion, high yield, and simple post-processing. Comparative Example 3 had a long reaction time, leading to an increase in byproducts and impurities, resulting in a certain degree of yield reduction. The hydrolysis temperature in step S5 not only affects the reaction rate but is also crucial in determining the efficiency of subsequent separation and purification. The 40-70℃ temperature ensures that the reaction solution is in a low-viscosity, homogeneous state, creating the necessary conditions for subsequent high-yield cooling and crystallization. However, even if the reaction is completed at low temperatures, the purity of the product will be severely compromised, leading to a significant decrease in yield. This highlights that the process parameters of this invention are interconnected as a complete system.
[0047] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
1. A method for synthesizing a tegorazan intermediate, characterized in that, The structural formula of the tegolazan intermediate is shown in Figure I. I The preparation method includes: using 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid as the starting material, and successively undergoing amidation, esterification with acetyl, catalytic hydrogenation debenzylation, sulfonation, and deacetylation protection to obtain the tegorazan intermediate 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide.
2. The method for synthesizing the tegorazan intermediate according to claim 1, characterized in that, The synthetic route is as follows: S1, starting with 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid, reacts with thionyl chloride and then undergoes amidation with amine compounds to obtain 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide; S2,4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide was esterified with an acetylation reagent to give 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide; Catalytic hydrogenation of S3,4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide yields 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide; S4,4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide reacts with p-toluenesulfonyl chloride to give 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide; S5,4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide is hydrolyzed in alkaline solution to give 4-hydroxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide.
3. The method for synthesizing the tegorazan intermediate according to claim 2, characterized in that, The hydrolysis temperature in step S5 is 40~70℃.
4. The method for synthesizing the tegorazan intermediate according to claim 2, characterized in that, The amine compound in S1 is dimethylamine, and the mass ratio of 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid, thionyl chloride and 40% dimethylamine aqueous solution is 1:0.5~0.6:1.4~2.
0.
5. The method for synthesizing the tegorazan intermediate according to claim 2, characterized in that, After the esterification reaction is completed in step S2, water is added and stirred to quench the reaction, followed by layering and concentration.
6. The method for synthesizing the tegorazan intermediate according to claim 2, characterized in that, In S2, the acetylation reagent is acetic anhydride or acetyl chloride, and the mass ratio of 4-hydroxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide to the acetylation reagent is 1:0.45~0.
55.
7. The method for synthesizing the tegorazan intermediate according to claim 2, characterized in that, The specific steps for the catalytic hydrogenation of 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide in step S3 are as follows: 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, organic solvent, and metal catalyst are mixed, stirred, and heated. The air in the reaction apparatus is replaced with nitrogen, and then the nitrogen is replaced with hydrogen before the reaction begins. The mass ratio of 4-acetoxy-N,N,2-trimethyl-1-(benzyl)-1H-benzimidazole-6-carboxamide, organic solvent, and metal catalyst is 1:4~6:0.05~0.
1.
8. The method for synthesizing the tegorazan intermediate according to claim 2, characterized in that, In S4, 4-acetoxy-N,N,2-trimethyl-1H-benzimidazole-6-carboxamide is reacted by adding p-toluenesulfonyl chloride to dichloromethane, followed by the addition of an organic base. After the reaction is complete, water is added to quench the reaction.
9. The method for synthesizing the tegorazan intermediate according to claim 2, characterized in that, In S5, 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide is dissolved in ethanol and hydrolyzed in sodium carbonate solution. After the reaction is complete, the pH is adjusted to 5-6 using hydrochloric acid aqueous solution.
10. The method for synthesizing the tegorazan intermediate according to claim 9, characterized in that, The concentration of the sodium carbonate solution is 10%, and the mass ratio of 4-acetoxy-N,N,2-trimethyl-1-p-toluenesulfonyl-1H-benzimidazole-6-carboxamide, ethanol, and sodium carbonate solution is 1:3.2~4:2.5~3.