A process for the preparation of 2-acetylamino-4-[(2-hydroxyethyl)sulfonyl]benzoic acid
By using methyl 4-fluoro-2-nitrobenzoate as a starting material and employing aromatic nucleophilic substitution reactions to prepare 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid, the problems of complex synthetic routes and environmental unfriendliness in existing technologies are solved, and efficient and safe dye intermediate preparation is achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI UNIV
- Filing Date
- 2026-03-10
- Publication Date
- 2026-06-05
AI Technical Summary
Existing technologies lack an efficient and specific method for synthesizing 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid. Existing synthetic routes suffer from problems such as cumbersome multiple steps, use of highly toxic or corrosive reagents, and environmental unfriendliness.
Using methyl 4-fluoro-2-nitrobenzoate as the starting material, 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid was prepared through aromatic nucleophilic substitution reaction, nitro reduction reaction, ester hydrolysis reaction, amino acylation reaction and thioether oxidation reaction, avoiding the use of highly toxic and corrosive reagents, which meets the requirements of green chemistry.
This invention provides a simple, low-cost, high-yield, safe and reliable large-scale preparation method with high product purity, which conforms to the development direction of green chemical industry and is suitable for the synthesis of high-performance dye intermediates.
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Figure CN122145357A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid. Background Technology
[0002] 2-Acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid is a novel dye intermediate that simultaneously possesses benzoic acid, acetamido, and (2-hydroxyethyl)sulfonyl groups. This gives it a potential advantage in the synthesis of high-performance water-soluble dyes, particularly high-performance azo dyes, acid dyes, or reactive dyes. These dyes have wide applications in the coloring of textiles, leather, inks, and functional materials. Their performance often depends on the structural characteristics of the intermediate, such as color intensity, water solubility, fiber affinity, and reactivity.
[0003] Currently, in the field of dye chemistry, benzoic acid derivatives with sulfonic acid groups or sulfonylamino groups are key building blocks for constructing water-soluble dyes, especially acid dyes and reactive dyes. For example, Suzhou Shiming Technology Co., Ltd. disclosed a method for preparing modified phthalocyanine pigments by sulfonating and modifying them to introduce sulfonyl groups and benzoic acid ester structures in its patent CN117683373A published in 2023. The modified phthalocyanine pigments produced liquid colorants with small particle size, low viscosity, and good storage stability, and the colored polyester fibers subsequently prepared from them have uniform color and good breaking strength, elongation at break, washing fastness, and rubbing fastness.
[0004] However, no methods for preparing this specific compound have been reported in publicly available patents and literature. In the prior art, the synthesis of benzene intermediates containing similar functional groups (carboxyl, sulfonyl, and acetamido) mainly follows two technical routes, each with significant limitations:
[0005] 1. Thioether oxidation method
[0006] This is one of the common strategies for synthesizing sulfonyl benzoic acid compounds. For example, patent CN117886723A discloses a method for synthesizing 2-chloro-4-methanesulfonyl benzoic acid by starting with 3-chloro-4-methylaniline, introducing a methylthio group through diazotization, followed by oxidation with hydrogen peroxide to obtain a methanesulfonyl group. The synthetic route is shown below:
[0007]
[0008] Similarly, patent CN112979506A also uses a route of first constructing a benzyl sulfide intermediate and then oxidizing it to synthesize chlorosulfonyl compounds. The synthetic route is shown below:
[0009]
[0010] The common drawbacks of existing synthetic methods for similar compounds are: the routes involve multiple protecting, deprotecting, or group conversion steps, resulting in numerous byproducts and cumbersome post-processing, which deviates from the environmentally friendly concept of green synthesis. Furthermore, the processes lack versatility and flexibility. When synthesizing derivatives with similar structures but different substituents, the entire lengthy synthetic sequence often needs to be redesigned and optimized, lacking modular efficiency. They also utilize expensive or sensitive reagents, resulting in poor atom economy and industrial feasibility.
[0011] 2. Sulfonyl chloride solution
[0012] This is a more classic route for synthesizing sulfonamide intermediates. For example, Chongqing University disclosed a method for synthesizing sulfonyl chloride intermediates using acetanilide as a raw material, reacting it with chlorosulfonic acid, and then chlorinating it with phosphorus pentachloride. The synthetic route is shown below:
[0013]
[0014] The core drawback of this method is that it requires the use of highly corrosive and toxic reagents such as chlorosulfonic acid, phosphorus pentachloride, and sulfonyl chloride. The reaction conditions are severe, the operation is highly dangerous, and the post-treatment generates a large amount of halogen- and acid-containing wastewater, which is environmentally unfriendly and goes against the trend of green chemical development.
[0015] In summary, existing technologies lack a method for the efficient and specific synthesis of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid. Both the applicability challenges of the thioether oxidation method and the stringent reaction conditions and environmental issues of the sulfonyl chloride ammonium hydrolysis method restrict the development and application of such high-performance dye intermediates. Therefore, developing a new synthetic route with mild reaction conditions, simple steps, high selectivity, and environmental friendliness is of significant industrial value for filling this technological gap and promoting the creation of novel environmentally friendly dyes. This invention is proposed precisely to address this technological gap. However, it is worth noting that the two methods mentioned above provide technical insights for the synthesis of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid in this invention. Summary of the Invention
[0016] To overcome the shortcomings of the prior art, this invention provides a method for preparing 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid. The method of this invention is simple to operate, low in cost, high in yield, safe and reliable, and suitable for large-scale preparation. This invention uses methyl 4-fluoro-2-nitrobenzoate as the starting material, and obtains the 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid through a series of reactions including aromatic nucleophilic substitution, nitro reduction, ester hydrolysis, amino acylation, and thioether oxidation. This method features mild reaction conditions, high yield, low cost, readily available raw materials, a synthetic process that meets the requirements of green chemistry, an innovative synthetic route, simple post-reaction processing, and easy product purification.
[0017] The 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid prepared by this invention has the following structure:
[0018] .
[0019] The present invention provides a method for preparing 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid, comprising the following steps:
[0020] Step 1: Using methyl 4-fluoro-2-nitrobenzoate as a raw material, in the presence of a base, it reacts with mercaptoethanol via an aromatic nucleophilic substitution reaction to generate methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate;
[0021] Step 2: Using methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene as a raw material, methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate is generated by nitro reduction reaction in the presence of a catalyst and a reducing agent;
[0022] Step 3: Using methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate as a raw material, 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid is generated by ester hydrolysis under alkaline solution conditions;
[0023] Step 4: Using 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid as a raw material, 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid is generated by aminoacylation reaction in the presence of an acylation agent;
[0024] Step 5: Using 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid as a raw material, the target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid is generated by catalytic oxidation reaction in the presence of a catalyst and an oxidant.
[0025] further:
[0026] In step 1, the reaction is carried out in a solvent, which is acetonitrile or tetrahydrofuran; the base is potassium hydroxide, sodium hydroxide or triethylamine; the reaction temperature is 0-10℃; the molar ratio of methyl 4-fluoro-2-nitrobenzoate to the base is 1:(2-3), and the molar ratio of methyl 4-fluoro-2-nitrobenzoate to mercaptoethanol is 1:(2-3).
[0027] In step 2, the reaction is carried out in a solvent, which is DMF, tetrahydrofuran, or ethanol; the catalyst is 4,4'-bipyridine; the reducing agent is tetrahydroxydiboron; the molar ratio of the catalyst 4,4'-bipyridine to methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene is (0.5%-1%):1, and the molar ratio of the reducing agent tetrahydroxydiboron to methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene is (2-3%):1.
[0028] In step 3, the alkaline solution is sodium hydroxide, potassium hydroxide, or sodium carbonate; the reaction temperature is 60-100℃.
[0029] In step 4, the reaction is carried out in a solvent, which is 1,2-dichloroethane or acetonitrile; the acylating agent is acetic anhydride; and the molar ratio of the acylating agent to 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid is (1-2):1.
[0030] In step 5, the reaction is carried out in a solvent, namely acetone or methanol; the catalyst is sodium tungstate, the oxidant is hydrogen peroxide with a concentration of 20 wt%; the molar ratio of the catalyst to 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid is (0.5%-2%):1, and the molar ratio of H2O2 in hydrogen peroxide to 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid is (3-5):1.
[0031] The synthetic route of this invention is shown below:
[0032]
[0033] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0034] This invention provides a method for preparing 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid. Starting with methyl 4-fluoro-2-nitrobenzoate, the method involves sequential aromatic nucleophilic substitution, nitro reduction, ester hydrolysis, amino acylation, and thioether oxidation to obtain the 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid. The route is shorter, the conditions are milder, the operation is simpler, the process is stable, purification is convenient, and it is easy to scale up for production. More importantly, it effectively avoids the use of highly toxic, corrosive, and hazardous reagents such as chlorosulfonic acid and phosphorus pentachloride in existing technologies. The reaction conditions are milder and more controllable, reducing production safety risks and minimizing the generation of halogen-containing and strongly acidic wastewater, aligning with the development direction of green chemistry. Furthermore, this synthetic route yields a product with higher purity and fewer impurities, ensuring its stability as a dye intermediate in downstream synthesis and contributing to the preparation of dye products with brighter colors and better color fastness. Attached Figure Description
[0035] Figure 1 NMR of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate in step (1) of Example 1 1 H NMR spectrum.
[0036] Figure 2 The LCMS spectrum of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate in step (1) of Example 1 is shown.
[0037] Figure 3 NMR of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate in step (2) of Example 1 1 H NMR spectrum.
[0038] Figure 4 The LCMS spectrum of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate in step (2) of Example 1 is shown.
[0039] Figure 5 The HPLC spectrum of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid in step (3) of Example 1 is shown.
[0040] Figure 6 The LCMS spectrum of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid in step (3) of Example 1 is shown.
[0041] Figure 7 NMR of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid in step (4) of Example 1 1 H NMR spectrum.
[0042] Figure 8The LCMS spectrum of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid in step (4) of Example 1 is shown.
[0043] Figure 9 NMR of the target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid in step (5) of Example 1 1 H NMR spectrum.
[0044] Figure 10 The HPLC spectrum of the target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid in step (5) of Example 1 is shown.
[0045] Figure 11 The image shows the LCMS spectrum of the target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid in step (5) of Example 1. Detailed Implementation
[0046] The technical solution of the present invention is further illustrated below through specific embodiments. These embodiments are only for illustrative purposes and are not intended to limit the scope of the invention.
[0047] Example 1:
[0048] The preparation method of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid in this embodiment includes the following steps:
[0049] 1. Synthesis of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate
[0050] In an ice-water bath, 500 mL of acetonitrile (5°C) was added to a 1000 mL three-necked flask. Then, sodium hydroxide (40.2 g, 1 mol), mercaptoethanol (78.1 g, 1 mol), and the starting material methyl 4-fluoro-2-nitrobenzene (100 g, 0.5 mol) were added sequentially. The mixture was stirred and kept at the ice-water bath temperature for 5–6 h, with HPLC monitoring during the reaction. Once the reaction was complete (residual starting material ≤ 5%), the reaction was removed from the treatment. The mixture was kept at the ice-water bath temperature, and a prepared 4 mol / L HCl solution was slowly added dropwise to adjust the pH to 4–6. The solution was then extracted with 250 mL of methyl ether to separate the organic phase. The aqueous phase was then back-extracted twice with methyl ether. The organic phases were then combined, washed with 300 mL of saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under vacuum. The solid was then dried at a constant temperature of 40-45℃ in a forced-air drying oven to obtain 124 g of the reddish-brown solid intermediate product methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate, with a yield of 96%.
[0051] 1H NMR (400 MHz, Chloroform-d) δ 7.81-7.61 (m, 2H), 7.52 (dd, J =8.2, 1.9 Hz, 1H), 3.88 (s, 5H), 3.22 (t, J = 6.1 Hz, 2H). ESI-MS, m / z (%):258.0[M+H] + .
[0052] 2. Synthesis of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate
[0053] At room temperature, 300 mL of DMF (3 V) was added to a 1000 mL three-necked reaction flask, followed by the addition of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate (100 g, 0.39 mol), 4,4'-bipyridine (0.3 g, 2 mmol), and tetrahydroxydiboron (104.6 g, 1.17 mol). The mixture was stirred and reacted at room temperature for 0.5–1 h. The reaction was monitored using TLC during this period. Once no absorption was observed under UV light at the starting material spot, the reaction was considered complete. 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture, and after stirring for 5 min, the mixture was allowed to stand and separate into layers. The organic phase was then separated, and the aqueous phase was back-extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation under vacuum. The resulting solid was placed in a forced-air drying oven and dried at a constant temperature of 40-45℃ to obtain 87.1 g of the light yellow solid intermediate product methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate, with a yield of 98.6%.
[0054] 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 1.9Hz, 3H), 6.43 (dd, J = 8.5, 1.9 Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 3.76 (s,3H), 3.60 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H). ESI-MS, m / z (%):228.0[M+H] + .
[0055] 3. Synthesis of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid
[0056] At room temperature, 1.5 L (1.5 mol) of prepared 1 mol / L NaOH solution was added to a 2000 mL three-necked reaction flask, followed by the addition of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate (100 g, 0.44 mol). The mixture was then transferred to an oil bath and heated at a constant temperature of 60 °C with stirring for 2 h. The reaction was monitored using HPLC during the reaction. Once the reaction was complete, the reaction solution was removed from the heat. The reaction solution was then transferred to an ice-water bath to cool to room temperature. Subsequently, a prepared 4 mol / L HCl solution was slowly added dropwise to adjust the pH of the system to 3–5. The solution was then extracted with 500 mL of ethyl acetate to separate the organic phase, and the aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was evaporated in a vacuum rotary evaporator. The resulting solid was then dried in a vacuum drying oven at 40-45℃ to obtain 93 g of the light brown solid intermediate product 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid, with a yield of 99% and an HPLC purity of 96.5%.
[0057] 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 7.8 Hz, 1H), 6.99-6.93 (m,2H), 6.01 (d, J = 7.0 Hz, 1H), 5.95 (d, J = 7.0 Hz, 1H), 4.49 (t, J = 6.7 Hz,1H), 3.71 (q, J = 6.6 Hz, 2H), 3.09 (t, J = 6.6 Hz, 2H). ESI-MS, m / z (%):212.0[MH] - .
[0058] HPLC: Column: Inert Sustain C18 (250 mm × 4.6 mm × 5 μm); Detector: 254 nm; Flow rate: 1.0 mL / min; Temperature: 30 °C; Injection volume: 5 μL; Solvent: Methanol; Concentration: 0.2 mg / mL; Run time: 20 min; Mobile phase A: Acetonitrile; Mobile phase B: Aqueous phosphoric acid solution; Elution gradient: Mobile phase A / Mobile phase B = 10 / 90:t R =5.6min, purity: 96.5%.
[0059] 4. Synthesis of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid
[0060] At room temperature, 500 mL of 1,2-dichloroethane (5 V) and 100 g (0.47 mol) of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid were added sequentially to a 1000 mL three-necked reaction flask. Stirring was started, and then acetic anhydride (48 g, 0.47 mol) was added. The mixture was transferred to an oil bath and heated to 60 °C for 2–3 h. During the reaction, solid precipitation was observed. The reaction solution was monitored using HPLC. Once the reactants in the solution were completely consumed, the reaction was considered complete. The system was removed from the oil bath and cooled to room temperature. Filtration was then performed, and the filter cake was washed with a small amount of 1,2-dichloroethane. Finally, the obtained filter cake solid was dried in a forced-air drying oven at 40–45 °C to obtain 103 g of the yellowish-brown solid intermediate product 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid, with a yield of 86%.
[0061] 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.47 (d, J = 1.9 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.5, 2.0 Hz, 1H), 5.03 (s, 1H), 3.63(t, J = 6.6 Hz, 2H), 3.10 (t, J = 6.7 Hz, 2H), 2.14 (s, 3H). ESI-MS, m / z (%):254.1[MH] - .
[0062] 5. Synthesis of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid
[0063] At room temperature, in a 1000 mL three-necked reaction flask, 100 g (0.39 mol) of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid, 300 mL (3 V) of acetone, and 0.12 g (0.39 mmol) of sodium tungstate were added sequentially. Then, 370 mL (2 mol) of 20 wt% hydrogen peroxide solution was added. The mixture was heated to 50 °C and stirred continuously for 4-5 h. The reaction was monitored by TLC during the process. Once the reactants had completely reacted, the reaction was removed. The system was transferred to a vacuum distillation tank to remove the solvent. The resulting concentrate was then slowly poured into 300 mL of saturated Na₂S₂O₃ solution. 300 mL of ethyl acetate was added to the mixture for extraction. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic phase was separated, and the aqueous phase was back-extracted once with 300 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under vacuum. Finally, the solid obtained by rotary evaporation was dried in a forced-air drying oven at 40-45℃ to obtain 105.3 g of the white target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid, with a yield of 93.6% and an HPLC purity of 95.88%.
[0064] 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.64 (dd, J = 8.3, 1.9 Hz, 1H), 3.70 (t, J = 6.2Hz, 2H), 3.48 (t, J = 6.2 Hz, 2H), 2.17 (s, 3H). ESI-MS, m / z (%): 286.0[MH] - .
[0065] HPLC: Column: Inert Sustain C18 (250 mm × 4.6 mm × 5 μm); Detector: 254 nm; Flow rate: 1.0 mL / min; Temperature: 30 °C; Injection volume: 5 μL; Solvent: Methanol; Concentration: 0.2 mg / mL; Run time: 20 min; Mobile phase A: Acetonitrile; Mobile phase B: Aqueous phosphoric acid solution; Elution gradient: Mobile phase A / Mobile phase B = 10 / 90:t R =3.888 min, purity: 95.88%.
[0066] Example 2:
[0067] The preparation method of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid in this embodiment includes the following steps:
[0068] 1. Synthesis of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate
[0069] In an ice-water bath, 500 mL of tetrahydrofuran (5V) was added to a 1000 mL three-necked flask, followed by potassium hydroxide (84.6 g, 1.5 mol), mercaptoethanol (117.2 g, 1.5 mol), and the starting material methyl 4-fluoro-2-nitrobenzene (100 g, 0.5 mol). The mixture was stirred and kept at the ice-water bath temperature for 5–6 h, with HPLC monitoring during the reaction. Once the reaction was complete (the remaining percentage of the starting material ≤ 5%), the reaction was removed from the treatment. The mixture was kept at the ice-water bath temperature, and a prepared 4 mol / L HCl solution was slowly added dropwise to adjust the pH to 4–6. The solution was then extracted with 250 mL of methyl ether to separate the organic phase, and the aqueous phase was back-extracted twice with methyl ether. The organic phases were then combined, washed with 300 mL of prepared saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under vacuum. The solid was then dried at a constant temperature of 40-45℃ in a forced-air drying oven to obtain 117.9 g of the reddish-brown solid intermediate methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate, with a yield of 91.3%.
[0070] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0071] 2. Synthesis of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate
[0072] At room temperature, 300 mL of ethanol (3 V) was added to a 1000 mL three-necked reaction flask, followed by the addition of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene (100 g, 0.39 mol), 4,4'-bipyridine (0.6 g, 4 mmol), and tetrahydroxydiboron (104.6 g, 1.17 mol). The mixture was stirred and reacted at room temperature for 0.5–1 h. The reaction was monitored using TLC during this period. Once no absorption was observed under UV light at the starting material spot, the reaction was considered complete. 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture, and after stirring for 5 min, the mixture was allowed to stand and separate into layers. The organic phase was then separated, and the aqueous phase was back-extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation under vacuum. The resulting solid was placed in a forced-air drying oven and dried at a constant temperature of 40-45℃ to obtain 81.8 g of the light yellow solid intermediate product methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate, with a yield of 92.6%.
[0073] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0074] 3. Synthesis of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid
[0075] At room temperature, 1.5 L (1.5 mol KOH) of a prepared 1 mol / L KOH solution was added to a 2000 mL three-necked reaction flask, followed by the addition of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate (100 g, 0.44 mol). The mixture was then transferred to an oil bath and heated at a constant temperature of 60 °C with stirring for 2 h. The reaction was monitored using HPLC during the reaction. Once the reaction was complete, the reaction mixture was removed from the heat. The reaction solution was then transferred to an ice-water bath to cool to room temperature. Subsequently, a prepared 4 mol / L HCl solution was slowly added dropwise to adjust the pH of the system to 3–5. The solution was then extracted with 500 mL of ethyl acetate to separate the organic phase, and the aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was evaporated in a vacuum rotary evaporator. The resulting solid was placed in a vacuum drying oven and dried at a constant temperature of 40-45℃ to obtain 92 g of the light brown solid intermediate product 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid, with a yield of 98% and an HPLC purity of 95.3%.
[0076] HPLC: Column: Inert Sustain C18 (250 mm × 4.6 mm × 5 μm); Detector: 254 nm; Flow rate: 1.0 mL / min; Temperature: 30 °C; Injection volume: 5 μL; Solvent: Methanol; Concentration: 0.2 mg / mL; Run time: 20 min; Mobile phase A: Acetonitrile; Mobile phase B: Aqueous phosphoric acid solution; Elution gradient: Mobile phase A / Mobile phase B = 10 / 90:t R =5.5min, purity: 95.3%.
[0077] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0078] 4. Synthesis of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid
[0079] At room temperature, 500 mL of 1,2-dichloroethane (5 V) and 100 g (0.47 mol) of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid were added sequentially to a 1000 mL three-necked reaction flask. Stirring was started, and then acetic anhydride (96 g, 0.94 mol) was added. The mixture was transferred to an oil bath and heated to 60 °C for 2–3 h. During the reaction, solid precipitation was observed. The reaction solution was monitored using HPLC. Once the reactants in the solution were completely consumed, the reaction was considered complete. The system was removed from the oil bath and cooled to room temperature. Filtration was then performed, and the filter cake was washed with a small amount of 1,2-dichloroethane. Finally, the obtained filter cake solid was dried in a forced-air drying oven at 40–45 °C to obtain 94.6 g of the yellowish-brown solid intermediate product 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid, with a yield of 79%.
[0080] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0081] 5. Synthesis of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid
[0082] At room temperature, in a 1000 mL three-necked reaction flask, 100 g (0.39 mol) of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid, 300 mL (3 V) of methanol, and 0.24 g (0.78 mmol) of sodium tungstate were added sequentially. Then, 225 mL (1.2 mol) of 20 wt% hydrogen peroxide solution was added. The mixture was heated to 50 °C and stirred continuously for 4-5 h. The reaction was monitored by TLC during the process. Once the reactants had completely reacted, the reaction was removed. The system was transferred to a vacuum distillation tank to remove the solvent. The resulting concentrate was then slowly poured into 300 mL of saturated Na₂S₂O₃ solution. 300 mL of ethyl acetate was added to the mixture for extraction. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic phase was separated, and the aqueous phase was back-extracted once with 300 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under vacuum. Finally, the solid obtained by rotary evaporation was dried in a forced-air drying oven at 40-45℃ to obtain 99.4 g of the white target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid, with a yield of 88.3% and an HPLC purity of 89.6%.
[0083] HPLC: Column: Inert Sustain C18 (250 mm × 4.6 mm × 5 μm); Detector: 254 nm; Flow rate: 1.0 mL / min; Temperature: 30 °C; Injection volume: 5 μL; Solvent: Methanol; Concentration: 0.2 mg / mL; Run time: 20 min; Mobile phase A: Acetonitrile; Mobile phase B: Aqueous phosphoric acid solution; Elution gradient: Mobile phase A / Mobile phase B = 10 / 90:t R =3.92min, purity: 89.6%.
[0084] The NMR and mass spectrometry characterization results of the target product are the same as those in Example 1.
[0085] Example 3:
[0086] The preparation method of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid in this embodiment includes the following steps:
[0087] 1. Synthesis of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate
[0088] In an ice-water bath, 500 mL of acetonitrile (5°C) was added to a 1000 mL three-necked flask. Then, triethylamine (101.2 g, 1 mol), mercaptoethanol (78.5 g, 1 mol), and the starting material methyl 4-fluoro-2-nitrobenzene (100 g, 0.5 mol) were added sequentially. The mixture was stirred and kept at the ice-water bath temperature for 5–6 h, with HPLC monitoring during the reaction. Once the reaction was complete (residual starting material ≤ 5%), the reaction was removed from the treatment. The mixture was kept at the ice-water bath temperature, and a prepared 4 mol / L HCl solution was slowly added dropwise to adjust the pH to 4–6. The solution was then extracted with 250 mL of methyl ether to separate the organic phase. The aqueous phase was then back-extracted twice with methyl ether. The organic phases were then combined, washed with 300 mL of prepared saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under vacuum. The solid was then dried at a constant temperature of 40-45℃ in a forced-air drying oven to obtain 111.6 g of the reddish-brown solid intermediate methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate, with a yield of 86.4%.
[0089] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0090] 2. Synthesis of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate
[0091] At room temperature, 300 mL of DMF (3 V) was added to a 1000 mL three-necked reaction flask, followed by the addition of methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene (100 g, 0.39 mol), 4,4'-bipyridine (0.3 g, 2 mmol), and tetrahydroxydiboron (70 g, 0.78 mol). The mixture was stirred and reacted at room temperature for 0.5–1 h. The reaction was monitored using TLC during this period. Once no absorption was observed under UV light at the starting material spot, the reaction was considered complete. 200 mL of water and 200 mL of ethyl acetate were added to the reaction mixture, and after stirring for 5 min, the mixture was allowed to stand and separate into layers. The organic phase was then separated, and the aqueous phase was back-extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and then the solvent was removed by rotary evaporation under vacuum. The resulting solid was placed in a forced-air drying oven and dried at a constant temperature of 40-45℃ to obtain 84.6 g of the light yellow solid intermediate product methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate, with a yield of 95.8%.
[0092] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0093] 3. Synthesis of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid
[0094] At room temperature, 1.5 L (1.5 mol) of a prepared 1 mol / L Na₂CO₃ solution was added to a 2000 mL three-necked reaction flask, followed by the addition of methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate (100 g, 0.44 mol). The mixture was then transferred to an oil bath and heated at 80 °C with stirring for 3–4 h. The reaction was monitored using HPLC during this period. Once the reaction was complete, the reaction mixture was removed from the heat. The reaction solution was then transferred to an ice-water bath to cool to room temperature. Subsequently, a prepared 4 mol / L HCl solution was slowly added dropwise to adjust the pH of the system to 3–5. The solution was then extracted with 500 mL of ethyl acetate to separate the organic phase, and the aqueous phase was back-extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was evaporated in a vacuum rotary evaporator. The resulting solid was then dried in a vacuum drying oven at 40-45℃ to obtain 84 g of the light brown solid intermediate product 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid, with a yield of 89.5% and an HPLC purity of 93.7%.
[0095] HPLC: Column: Inert Sustain C18 (250 mm × 4.6 mm × 5 μm); Detector: 254 nm; Flow rate: 1.0 mL / min; Temperature: 30 °C; Injection volume: 5 μL; Solvent: Methanol; Concentration: 0.2 mg / mL; Run time: 20 min; Mobile phase A: Acetonitrile; Mobile phase B: Aqueous phosphoric acid solution; Elution gradient: Mobile phase A / Mobile phase B = 10 / 90:t R =5.5min, purity: 93.7%.
[0096] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0097] 4. Synthesis of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid
[0098] At room temperature, 500 mL of acetonitrile (5°C) and 100 g (0.47 mol) of 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid were added sequentially to a 1000 mL three-necked reaction flask. Stirring was started, and then acetic anhydride (48 g, 0.47 mol) was added. The mixture was transferred to an oil bath and heated to 60°C for 2–3 h. During the reaction, solid precipitation was observed. The reaction solution was monitored using HPLC. Once the reactants in the solution were completely consumed, the reaction was considered complete. The system was removed from the oil bath and cooled to room temperature. Filtration was then performed, and the filter cake was washed with a small amount of acetonitrile. Finally, the obtained filter cake solid was dried in a forced-air drying oven at 40–45°C to obtain 91.5 g of the yellowish-brown solid intermediate product 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid, with a yield of 76.4%.
[0099] The NMR and mass spectrometry characterization results of this intermediate are the same as those in Example 1.
[0100] 5. Synthesis of 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid
[0101] At room temperature, in a 1000 mL three-necked reaction flask, 100 g (0.39 mol) of 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid, 300 mL (3 V) of acetone, and 0.06 g (0.2 mmol) of sodium tungstate were added sequentially. Then, 370 mL (2 mol) of 20 wt% hydrogen peroxide solution was added. The mixture was heated to 50 °C and stirred continuously for 4-5 h. The reaction was monitored by TLC during the process. Once the reactants had completely reacted, the reaction was removed. The system was transferred to a vacuum distillation tank to remove the solvent. The resulting concentrate was then slowly poured into 300 mL of saturated Na₂S₂O₃ solution. 300 mL of ethyl acetate was added to the mixture for extraction. After thorough stirring, the mixture was allowed to stand and separate into layers. The organic phase was separated, and the aqueous phase was back-extracted once with 300 mL of ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under vacuum. Finally, the solid obtained by rotary evaporation was dried in a forced-air drying oven at 40-45℃ to obtain 87.1 g of the white target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid, with a yield of 77.4% and an HPLC purity of 91.5%.
[0102] HPLC: Column: Inert Sustain C18 (250 mm × 4.6 mm × 5 μm); Detector: 254 nm; Flow rate: 1.0 mL / min; Temperature: 30 °C; Injection volume: 5 μL; Solvent: Methanol; Concentration: 0.2 mg / mL; Run time: 20 min; Mobile phase A: Acetonitrile; Mobile phase B: Aqueous phosphoric acid solution; Elution gradient: Mobile phase A / Mobile phase B = 10 / 90:t R =3.85min, purity: 91.5%.
[0103] The NMR and mass spectrometry characterization results of the target product are the same as those in Example 1.
[0104] It should be noted that the above description is only a preferred embodiment of the present invention. It should be pointed out that for those skilled in the art, several improvements can be made without departing from the principle of the present invention, and these improvements are also considered to be within the scope of protection of the present invention.
Claims
1. A method for preparing 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid, characterized in that... Includes the following steps: Step 1: Using methyl 4-fluoro-2-nitrobenzoate as a raw material, in the presence of a base, it reacts with mercaptoethanol via an aromatic nucleophilic substitution reaction to generate methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzoate; Step 2: Using methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene as a raw material, methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate is generated by nitro reduction reaction in the presence of a catalyst and a reducing agent; Step 3: Using methyl 2-amino-4-[(2-hydroxyethyl)thio]benzoate as a raw material, 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid is generated by ester hydrolysis under alkaline solution conditions; Step 4: Using 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid as a raw material, 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid is generated by aminoacylation reaction in the presence of an acylation agent; Step 5: Using 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid as a raw material, the target product 2-acetamido-4-[(2-hydroxyethyl)sulfonyl]benzoic acid is generated by catalytic oxidation reaction in the presence of a catalyst and an oxidant; The synthesis route is shown below: 。 2. The preparation method according to claim 1, characterized in that: In step 1, the alkali is potassium hydroxide, sodium hydroxide, or triethylamine.
3. The preparation method according to claim 2, characterized in that: The molar ratio of methyl 4-fluoro-2-nitrobenzoate to base is 1:(2-3), and the molar ratio of methyl 4-fluoro-2-nitrobenzoate to mercaptoethanol is 1:(2-3).
4. The preparation method according to claim 1, characterized in that: In step 2, the catalyst is 4,4'-bipyridine, and the reducing agent is tetrahydroxydiboron.
5. The preparation method according to claim 4, characterized in that: The molar ratio of catalyst 4,4'-bipyridine to methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene is (0.5%-1%):1, and the molar ratio of reducing agent tetrahydroxydiboron to methyl 4-[(2-hydroxyethyl)thio]-2-nitrobenzene is (2-3):
1.
6. The preparation method according to claim 1, characterized in that: In step 3, the alkaline solution is sodium hydroxide, potassium hydroxide, or sodium carbonate.
7. The preparation method according to claim 1, characterized in that: In step 4, the acylating agent is acetic anhydride.
8. The preparation method according to claim 7, characterized in that: The molar ratio of the acylating agent to 2-amino-4-[(2-hydroxyethyl)thio]benzoic acid is (1-2):
1.
9. The preparation method according to claim 1, characterized in that: In step 5, the catalyst is sodium tungstate and the oxidant is hydrogen peroxide with a concentration of 20 wt%.
10. The preparation method according to claim 9, characterized in that: The molar ratio of catalyst to 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid is (0.5%-2%):1, and the molar ratio of H2O2 in hydrogen peroxide to 2-acetamido-4-[(2-hydroxyethyl)thio]benzoic acid is (3-5):1.