Process for the preparation of an intermediate of arolool hydrochloride
By using esterification, bromination, ethoxyvinylation and hydrolysis of thiophene-2-carboxylic acid, the industrialization problem of synthesizing aprrolol hydrochloride intermediates in existing technologies has been solved, achieving high-purity and high-yield preparation, suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-08
- Publication Date
- 2026-04-07
AI Technical Summary
Existing synthetic routes for aprololol hydrochloride intermediates have problems such as high equipment requirements, large amounts of hazardous waste, and insufficient safety, making it difficult to achieve industrial-scale production.
5-Acetylthiophene-2-carboxylic acid was prepared by a four-step reaction involving esterification, selective bromination, Pd-catalyzed ethoxyvinylation, and acid-promoted hydrolysis of thiophene-2-carboxylic acid, using diethyl sulfate, an NBS/p-toluenesulfonic acid system, and a tetrakis(triphenylphosphine)palladium catalyst, avoiding the use of toxic or highly corrosive reagents, under mild conditions.
The preparation of high-purity, high-yield apronolol hydrochloride intermediates has been achieved, which is suitable for industrial production, avoids the use of toxic reagents, reduces by-products, and improves the safety and efficiency of production.
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Figure CN121471196B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediates, specifically to a method for preparing a pololfol hydrochloride intermediate. Background Technology
[0002] Arprolol hydrochloride was developed by Sumitomo Pharmaceutical Co., Ltd. of Japan and first launched in Japan in 1985. Arprolol hydrochloride is considered a fourth-generation beta-blocker and is a first-line beta-blocker. Clinically, it is mainly used to treat mild to moderate essential hypertension and angina pectoris.
[0003] 5-Acetylthiophene-2-carboxylic acid is an intermediate used in the preparation of aprolol hydrochloride. Its molecular formula is C7H6O3S, molecular weight is 170.19, and CAS number is 4066-41-5. It is a white to yellow solid powder with the structure shown in formula (I).
[0004] Formula (I).
[0005] Currently, the following synthetic routes for 5-acetylthiophene-2-carboxylic acid have been reported:
[0006] (1) Route 1:
[0007]
[0008] This route uses rare earth metals as catalysts and oxygen as oxidants, which requires high-quality equipment and carries significant risks, making it difficult to achieve industrial-scale production.
[0009] (2) Route 2:
[0010]
[0011] This route has a low yield in the Friedel-Crafts acylation step, and uses sodium hypochlorite solution in the haloform reaction. However, commercially available sodium hypochlorite solutions have a content of less than 10%, resulting in a large amount of hazardous waste and making it difficult to carry out large-scale production.
[0012] (3) Route 3:
[0013]
[0014] The second step of this route uses sodium hydride, which is prone to absorbing water and spontaneously combusting, making it unsafe and not feasible for large-scale production.
[0015] Therefore, it is of great significance to develop a process route that is easy to industrialize and has a high yield. Summary of the Invention
[0016] To address the shortcomings of existing technologies, the purpose of this invention is to provide a method for preparing an intermediate of apronolol hydrochloride.
[0017] To achieve the above objectives, the present invention provides the following technical solution:
[0018] A method for preparing an intermediate of apronolol hydrochloride includes the following steps:
[0019] S1: Thiophene-2-carboxylic acid reacts with an esterifying agent in the presence of carbonate to yield ethyl thiophene-2-carboxylate;
[0020] S2: Ethyl thiophene-2-ethyl reacts with a brominating reagent to give ethyl 5-bromothiophene-2-carboxylate;
[0021] S3: 5-Bromothiophene-2-carboxylate ethyl ester reacts with tributyl(1-ethoxyethylene)tin in the presence of a catalyst to yield 5-ethoxyvinyl-2-carboxylate ethyl ester;
[0022] S4: Ethyl 5-ethoxyvinyl-2-carboxylate is hydrolyzed under acidic conditions to give 5-acetylthiophene-2-carboxylic acid.
[0023] The reaction route is as follows:
[0024]
[0025] In step S1, the esterification reagent is diethyl sulfate, and the carbonate is one of anhydrous sodium carbonate, anhydrous potassium carbonate, and anhydrous cesium carbonate.
[0026] In step S1, the molar ratio of the thiophene-2-carboxylic acid, carbonate, and esterification reagent is 1:(1-1.5):(1-1.5).
[0027] In step S2, the brominating reagent is one of NBS or bromine.
[0028] In step S2, the molar ratio of thiophene-2-ethyl acetate to the brominated reagent is 1:(1.1-1.5).
[0029] In step S3, the catalyst is tetra(triphenylphosphine)palladium.
[0030] In step S3, the molar ratio of ethyl 5-bromothiophene-2-carboxylate to tributyl(1-ethoxyethylene)tin is 1:(1.2-1.5).
[0031] In step S4, the acid solution used in the acidic condition is a hydrochloric acid solution.
[0032] In step S1, the reaction solvent is DMF, the reaction temperature is 60-70℃, and the reaction time is 5-8h; in step S2, the reaction solvent is acetonitrile, the reaction temperature is 50-60℃, and the reaction time is 2-4h.
[0033] In step S3, the reaction solvent is DMF, the reaction temperature is 60-80℃, and the reaction time is 5-8h; in step S4, the reaction solvent is 1,4-dioxane, the reaction temperature is 60-80℃, and the reaction time is 9-12h.
[0034] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include:
[0035] This invention prepares 5-acetylthiophene-2-carboxylic acid via a four-step reaction involving esterification, selective bromination, Pd-catalyzed ethoxyvinylation, and acid-promoted hydrolysis of thiophene-2-carboxylic acid. The overall process is simple and exhibits high regioselectivity. The esterification step utilizes a diethyl sulfate and carbonate system, efficiently generating the ester under mild conditions without the use of highly corrosive reagents. The bromination step employs an NBS / p-toluenesulfonic acid system to achieve strict 5-position selectivity, avoiding overbromination or 3-position competing reactions. Stille coupling constructs the ethoxyvinyl structure under mild conditions, with good compatibility, few side reactions, and high yield. Finally, acid hydrolysis directly and selectively converts the ethoxyvinyl group to an acetyl group without the need for an oxidant, yielding a high-purity crystalline product. Compared with existing technologies, this route avoids the use of toxic or highly corrosive reagents, produces fewer overall byproducts, has a high total yield, and high product purity (>99.0%), making it suitable for industrial scale-up and green production. Attached Figure Description
[0036] Figure 1 The liquid chromatogram of 5-acetylthiophene-2-carboxylic acid prepared in Example 2;
[0037] Figure 2 The 1H NMR spectrum of 5-acetylthiophene-2-carboxylic acid prepared in Example 2. Detailed Implementation
[0038] The following description, in conjunction with specific embodiments, provides further details, but the present invention is not limited to these embodiments.
[0039] Example 1
[0040] S1: DMF (600 ml) and thiophene-2-carboxylic acid (100 g, 0.78 mol) were stirred and mixed. Then anhydrous cesium carbonate (254.1 g, 0.78 mol) and diethyl sulfate (120.3 g, 0.78 mol) were added in sequence, stirred, and reacted at 60 °C for 8 h. After cooling to room temperature, 1000 ml of deionized water and 1500 ml of ethyl acetate were added, stirred, allowed to stand, and separated. The organic phase was washed twice with saturated sodium chloride solution (500 ml each time), separated, and the organic phase was dried with 100 g of anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to dryness to obtain 134.4 g of thiophene-2-carboxylic acid ethyl ester oil.
[0041] S2: The ethyl thiophene-2-acetate (134.4 g, theoretical yield 121.8 g, 0.78 mol) obtained in step S1 was added to 800 ml of acetonitrile. P-Toluenesulfonic acid monohydrate (150.0 g, 0.78 mol) was added with stirring. The mixture was heated to 50 °C, and an acetonitrile solution of NBS (153 g, 0.86 mol) dissolved in 500 ml of acetonitrile was added dropwise. The addition was completed in 30 min, and the reaction was maintained at this temperature for 4 h. The mixture was concentrated to dryness under reduced pressure, and 1000 ml of ethyl acetate was added. The mixture was washed twice with 10 wt% potassium carbonate solution (500 ml each time). The organic phase was dried with 100 g of anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 167.2 g of ethyl 5-bromothiophene-2-carboxylate oil, with a yield of 91.6%.
[0042] S3: Add 164.6 g, 0.7 mol of ethyl 5-bromothiophene-2-carboxylate obtained in step S2 to 500 ml of DMF, add tributyl(1-ethoxyethylene)tin (303.4 g, 0.84 mol) and tetra(triphenylphosphine)palladium (161.8 g, 0.14 mol), react the mixture at 60 °C for 8 h, cool to room temperature, add 1500 ml of saturated ammonium chloride solution and stir for 1 h, add 200 g of diatomaceous earth, filter, add 1500 ml of deionized water and 2000 ml of ethyl acetate to the filtrate, separate the liquid and wash the organic phase twice with saturated sodium chloride solution (750 ml each time), separate the organic phase, concentrate under reduced pressure to dryness, and obtain 127.4 g of ethyl 5-ethoxyethylene-2-carboxylate oil, with a yield of 80.4%.
[0043] S4: Add 113.1 g, 0.5 mol of 5-ethoxyvinyl-2-carboxylate obtained in step S3 to 200 ml of 1,4-dioxane, stir, add 2800 ml of 2M hydrochloric acid, and react the reaction solution at 60 °C for 12 h; cool to 0 °C, crystallize for 2 h, filter, add 3000 ml of methanol to recrystallize the solid, and dry under vacuum at 50 °C for 12 h to obtain 75.6 g of 5-acetylthiophene-2-carboxylic acid, with a yield of 88.8% and a purity of 99.3%.
[0044] The overall yield for the four steps was 65.4%.
[0045] Example 2
[0046] S1: DMF (600 ml) and thiophene-2-carboxylic acid (100 g, 0.78 mol) were stirred and mixed. Then anhydrous sodium carbonate (99.6 g, 0.94 mol) and diethyl sulfate (144.9 g, 0.94 mol) were added sequentially, stirred, and reacted at 65 °C for 7 h. 1000 ml of deionized water and 1500 ml of ethyl acetate were added, stirred, allowed to stand, and separated. The organic phase was washed twice with saturated sodium chloride solution (500 ml each time), separated, and the organic phase was dried with 100 g of anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to dryness to obtain 135.6 g of ethyl thiophene-2-carboxylic acid oil.
[0047] The mass spectrometry data are as follows: ESI-MS: m / z = 157.0 [M+H] + .
[0048] S2: The ethyl thiophene-2-acetate (135.9 g, theoretical yield 121.8 g, 0.78 mol) obtained in step S1 was added to 800 ml of acetonitrile, and p-toluenesulfonic acid monohydrate (165.0 g, 0.86 mol) was added with stirring. The temperature was raised to 55 °C, and an acetonitrile solution of NBS (178.0 g, 1.0 mol of NBS dissolved in 500 ml of acetonitrile) was added dropwise. The addition was completed in 30 min, and the reaction was kept at this temperature for 3 h. The solution was concentrated to dryness under reduced pressure, and 1000 ml of ethyl acetate was added. The solution was washed twice with 10 wt% potassium carbonate solution (500 ml each time). The organic phase was dried with 100 g of anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 170.5 g of ethyl 5-bromothiophene-2-carboxylate oil, with a yield of 93.0%.
[0049] The mass spectrometry data are as follows: ESI-MS: m / z=234.1 [M+H] + .
[0050] The proton NMR data are as follows: 1 H NMR (CDCl3, 400 MHz): δ 7.55-7.53 (d, J = 4Hz, 1H), 7.07-7.05 (d, J = 4 Hz, 1H), 4.36-4.30 (m, 2H), 1.38-1.34 (m, 3H).
[0051] S3: Add 166.9 g (0.71 mol) of ethyl 5-bromothiophene-2-carboxylate obtained in step S2 to 500 ml of DMF, add tributyl(1-ethoxyethylene)tin (384.5 g, 1.07 mol) and tetra(triphenylphosphine)palladium (161.8 g, 0.14 mol), react the mixture at 70 °C for 6.5 h, cool to room temperature, add 1500 ml of saturated ammonium chloride solution and stir for 1 h, add 200 g of diatomaceous earth, filter, add 1500 ml of deionized water and 2000 ml of ethyl acetate to the filtrate, separate the liquid and wash the organic phase twice with saturated sodium chloride solution (750 ml each time), separate the organic phase, concentrate under reduced pressure to dryness, and obtain 130.8 g of ethyl 5-ethoxyethylene-2-carboxylate oil, with a yield of 82.6%.
[0052] The proton NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 5.8 Hz, 1H), 7.21 (s, 1H), 4.35 (q, J = 6.4 Hz, 2H), 4.28 (d, J = 2.2 Hz, 1H), 4.11 (d, J = 2.6 Hz, 1H), 4.07 (q, J = 6.9 Hz, 2H), 1.34 (s, 3H), 1.24 (t, J = 6.7Hz, 3H).
[0053] S4: Ethyl 5-ethoxyvinyl-2-carboxylate (113.1 g, 0.5 mol) obtained in step S3 was added to 200 ml of 1,4-dioxane, stirred, and 2800 ml of 2M hydrochloric acid was added. The reaction solution was reacted at 70 °C for 10 h; cooled to 0 °C, crystallized for 2 h, filtered, and the solid was recrystallized in 3000 ml of methanol. It was then dried under vacuum at 50 °C for 12 h to obtain 76.1 g of 5-acetylthiophene-2-carboxylic acid, with a yield of 89.4% and a purity of 99.2% (see [link to product description]). Figure 1 ).
[0054] The proton NMR data are as follows: 1 H NMR (400 MHz, d6-DMSO) δ 13.66 (s, 1H), 7.94 (d, J = 4.0 Hz, 1H), 7.77 (d, J = 3.9 Hz, 1H), 2.59 (s, 3H).
[0055] The overall yield for the four steps was 68.7%.
[0056] Example 3
[0057] S1: Mix DMF (600 ml) and thiophene-2-carboxylic acid (100 g, 0.78 mol) thoroughly, then add anhydrous potassium carbonate (161.7 g, 1.17 mol) and diethyl sulfate (180.4 g, 1.17 mol) sequentially, stir, and react at 60-70℃ for 5-8 h; add 1000 ml deionized water and 1500 ml ethyl acetate, stir, let stand, and separate the liquid. Wash the organic phase twice with saturated sodium chloride solution (500 ml each time), separate the liquid, add 100 g of anhydrous sodium sulfate to dry the organic phase, filter and concentrate under reduced pressure to dryness to obtain 135.9 g of thiophene-2-carboxylic acid ethyl ester oil.
[0058] S2: The ethyl thiophene-2-acetate (134.4 g, theoretical 121.8 g, 0.78 mol) obtained in step S1 was added to 800 ml of acetonitrile. P-Toluenesulfonic acid monohydrate (180.0 g, 0.94 mol) was added with stirring. The temperature was raised to 60 °C, and an acetonitrile solution of NBS (208.2 g, 1.17 mol) dissolved in 500 ml of acetonitrile was added dropwise. The addition was completed in 30 min, and the reaction was maintained at this temperature for 2 h. The solution was concentrated to dryness under reduced pressure, and 1000 ml of ethyl acetate was added. The solution was washed twice with 10 wt% potassium carbonate solution (500 ml each time). The organic phase was dried with 100 g of anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 169.2 g of ethyl 5-bromothiophene-2-carboxylate oil, with a yield of 92.3%.
[0059] S3: Add 166.9 g (0.71 mol) of ethyl 5-bromothiophene-2-carboxylate obtained in step S2 to 500 ml of DMF, add 422.5 g (1.17 mol) of tributyl(1-ethoxyethylene)tin and 208.0 g (0.18 mol) of tetra(triphenylphosphine)palladium, react the mixture at 80 °C for 5 h, cool to room temperature, add 1500 ml of saturated ammonium chloride solution and stir for 1 h, add 200 g of diatomaceous earth, filter, add 1500 ml of deionized water and 2000 ml of ethyl acetate to the filtrate, separate the liquid and wash the organic phase twice with saturated sodium chloride solution (750 ml each time), separate the organic phase, concentrate under reduced pressure to dryness, and obtain 129.5 g of ethyl 5-ethoxyethylene-2-carboxylate oil, with a yield of 81.8%.
[0060] S4: Add 113.1 g, 0.5 mol of 5-ethoxyvinyl-2-carboxylate obtained in step S3 to 200 ml of 1,4-dioxane, stir, add 2800 ml of 2M hydrochloric acid, and react the reaction solution at 80 °C for 9 h; cool to 0 °C, crystallize for 2 h, filter, add 3000 ml of methanol to the solid for recrystallization, and dry under vacuum at 50 °C for 12 h to obtain 74.8 g of 5-acetylthiophene-2-carboxylic acid, with a yield of 87.9% and a purity of 99.5%.
[0061] The overall yield for the four steps was 66.4%.
[0062] Examples 4 and Comparative Examples 1-7 are experiments on the preparation of 5-acetylthiophene-2-carboxylic acid under different process parameters than those in Example 2. The different process parameters and yields are shown in Table 1.
[0063] Table 1
[0064]
[0065] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.
Claims
1. A method for preparing an intermediate of apronolol hydrochloride, characterized in that, Includes the following steps: S1: Thiophene-2-carboxylic acid reacts with an esterifying agent in the presence of carbonate to yield ethyl thiophene-2-carboxylate; S2: Ethyl thiophene-2-ethyl acetate reacts with a brominating agent in the presence of p-toluenesulfonic acid monohydrate to give ethyl 5-bromothiophene-2-carboxylate; S3: 5-Bromothiophene-2-carboxylate ethyl ester reacts with tributyl(1-ethoxyethylene)tin in the presence of a catalyst to yield 5-ethoxyvinyl-2-carboxylate ethyl ester; S4: Ethyl 5-ethoxyvinyl-2-carboxylate is hydrolyzed under acidic conditions to give 5-acetylthiophene-2-carboxylic acid; In step S1, the esterification reagent is diethyl sulfate; In step S2, the brominating agent is NBS; In step S3, the catalyst is tetra(triphenylphosphine)palladium; In step S1, the reaction solvent is DMF, the reaction temperature is 60-70℃, and the reaction time is 5-8h; in step S2, the reaction solvent is acetonitrile, the reaction temperature is 50-60℃, and the reaction time is 2-4h. In step S3, the reaction solvent is DMF, the reaction temperature is 60-80℃, and the reaction time is 5-8h. In step S4, the reaction solvent is 1,4-dioxane, the reaction temperature is 60-80℃, and the reaction time is 9-12h.
2. The method for preparing an intermediate of apronolol hydrochloride according to claim 1, characterized in that, In step S1, the carbonate is one of anhydrous sodium carbonate, anhydrous potassium carbonate, and anhydrous cesium carbonate.
3. The method for preparing an intermediate of apronolol hydrochloride according to claim 1, characterized in that, In step S1, the molar ratio of thiophene-2-carboxylic acid, carbonate and esterification reagent is 1:(1-1.5):(1-1.5).
4. The method for preparing an intermediate of apronolol hydrochloride according to claim 1, characterized in that, In step S2, the molar ratio of thiophene-2-ethyl acetate to the brominated reagent is 1:(1.1-1.5).
5. The method for preparing an intermediate of apronolol hydrochloride according to claim 1, characterized in that, In step S3, the molar ratio of ethyl 5-bromothiophene-2-carboxylate to tributyl(1-ethoxyethylene)tin is 1:(1.2-1.5).
6. The method for preparing an intermediate of apronolol hydrochloride according to claim 1, characterized in that, In step S4, the acid solution used in the acidic condition is a hydrochloric acid solution.
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