Process for the preparation of a fexofenadine isomer
The fexofenadine isomer was successfully prepared via a six-step synthetic route, solving the problem of the lack of synthetic methods in the existing technology and realizing industrial production with high purity and strong operability.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- TLC NANJING PHARMA RANDD CO LTD
- Filing Date
- 2023-08-01
- Publication Date
- 2026-05-15
AI Technical Summary
There is a lack of effective chemical synthesis methods in the current technology to prepare the fexofenadine isomer compound VIII.
The six-step synthetic route includes reacting compound I with sodium bicarbonate and m-chloroperoxybenzoic acid to generate intermediate II, followed by reaction with NaH and iodomethane to generate intermediate III, then reaction with an acidic aqueous solution to generate intermediate IV, then reaction with an organic base and methanesulfonyl chloride to generate intermediate V, and finally reaction with an inorganic base and compound VI to generate fexofenadine isomer VIII.
The high-purity preparation of the fexofenadine isomer, with a purity of over 98.5%, was achieved. The process is highly operable and suitable for industrial production.
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Figure CN117209417B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing a fexofenadine isomer. Background Technology
[0002] Fexofenadine, chemically named 2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropionic acid, has a molecular weight of 501.67 and the following structural formula. Its hydrochloride salt is commonly used as a respiratory and anti-allergy medication, and is used to treat seasonal allergic rhinitis, chronic acute urticaria, etc.
[0003]
[0004] Fexofenadine isomer (compound VIII) is an isomer produced during the production and synthesis of fexofenadine, with a molecular weight of 523.65 and a molecular formula of C0. 32 H 38 NNaO4, chemically named sodium2-(2-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoate, has the following structural formula:
[0005]
[0006] Compared to the active pharmaceutical ingredient, the dimethylacetic acid group of the fexofenadine isomer is located in the ortho position. Currently, only a small amount of this isomer can be obtained during the production of the active pharmaceutical ingredient, and there is no method available for chemical synthesis. Summary of the Invention
[0007] Purpose of the invention: The purpose of this invention is to provide a method for preparing the fexofenadine isomer.
[0008] Technical solution: The method for preparing the fenofenadine isomer of the present invention includes the following steps:
[0009] (1) Compound I was suspended in dichloromethane, sodium bicarbonate and m-chloroperoxybenzoic acid were added, and the reaction was stirred to obtain intermediate product II:
[0010]
[0011] (2) Take intermediate product II obtained in step (1), dissolve it in tetrahydrofuran, add sodium hydride (NaH) tetrahydrofuran suspension under ice bath, stir and then add iodomethane to react and generate intermediate product III:
[0012]
[0013] (3) Dissolve intermediate product III obtained in step (2) in tetrahydrofuran, add acidic aqueous solution, and react to obtain intermediate product IV:
[0014]
[0015] (4) Dissolve intermediate IV obtained in step (3) in dichloromethane, add an organic base and methanesulfonyl chloride, and react to obtain intermediate V:
[0016]
[0017] (5) Dissolve intermediate product V obtained in step (4) in acetonitrile, add inorganic base and compound VI, and react to obtain intermediate VII:
[0018]
[0019] (6) Dissolve the intermediate product VII obtained in step (5) in methanol, add an aqueous sodium hydroxide solution, and react to obtain compound VIII, the fexofenadine isomer:
[0020]
[0021] Preferably, in step (1), the molar ratio of compound I to sodium bicarbonate and m-chloroperoxybenzoic acid is 1:3 to 10:1 to 3, more preferably 1:5.5:1.6; the reaction is carried out at around 0°C for 1 to 20 hours, more preferably 1 to 5 hours.
[0022] Preferably, in step (1), after the stirring reaction is completed, the mixture is poured into water under an ice bath, dichloromethane is removed by rotary evaporation, the mixture is extracted with ethyl acetate, the organic layers are combined and dried with anhydrous sodium sulfate, filtered, and then evaporated to obtain intermediate product II.
[0023] Preferably, in step (2), the molar ratio of intermediate product II to NaH and iodomethane is 1:2 to 10:2 to 10, more preferably 1:2.6:2.5; the reaction is carried out at a temperature of 20 to 30°C for a reaction time of 1 to 32 hours, more preferably 8 to 16 hours.
[0024] Preferably, in step (3), the acidic aqueous solution is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution; the molar ratio of the intermediate product III to the acidic aqueous solution is 1:1 to 30, more preferably 1:5 to 10; the reaction temperature is 0 to 50°C, more preferably 0 to 25°C; and the reaction time is 1 to 24 hours, more preferably 1 to 5 hours.
[0025] Preferably, in step (4), the molar ratio of intermediate product IV to organic base and methanesulfonyl chloride is 1:1 to 5:1 to 5, more preferably 1:1.5 to 3:1.2 to 2; the reaction is carried out at a temperature of 0-50°C, more preferably 25-35°C, and for a reaction time of 1-30 h, more preferably 1-5 h.
[0026] Preferably, in step (4), the organic base is pyridine, triethylamine, or N,N-diisopropylethylamine.
[0027] Preferably, in step (5), the molar ratio of intermediate product V to inorganic base and compound VI is 1:2 to 10:1 to 2, more preferably 1:5:1.5; the reaction is carried out at a temperature of 0-100℃, more preferably 60-95℃, and for a reaction time of 1-32h, more preferably 8-16h.
[0028] Preferably, in step (5), the inorganic base is sodium carbonate, potassium carbonate or cesium carbonate.
[0029] Preferably, the molar ratio of intermediate product VII to sodium hydroxide in step (6) is 1:1 to 20, more preferably 1:2 to 6; the volume ratio of methanol to intermediate product VII is 1:5 to 30, more preferably 1:7 to 20; the reaction temperature is 30-100℃, more preferably 60-85℃, and the reaction time is 1-36h, more preferably 8-20h.
[0030] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the preparation method of the present invention is highly operable, the process design is reasonable, and industrial production can be realized. Moreover, the reagents used in the synthesis method are simple and readily available. The prepared fexofenadine isomer has a purity of over 98.5%. Attached Figure Description
[0031] Figure 1 This is the mass spectrum of compound II;
[0032] Figure 2 The NMR spectrum of compound II;
[0033] Figure 3 This is the mass spectrum of compound III;
[0034] Figure 4 The NMR spectrum of compound III;
[0035] Figure 5 This is the mass spectrum of compound IV;
[0036] Figure 6 The NMR spectrum of compound IV;
[0037] Figure 7The mass spectrum of compound VII;
[0038] Figure 8 The NMR spectrum of compound VII;
[0039] Figure 9 This is the mass spectrum of compound VIII;
[0040] Figure 10 This is the NMR spectrum of compound VIII. Detailed Implementation
[0041] The technical solution of the present invention will be further described below with reference to the accompanying drawings.
[0042] Example 1
[0043] The method for preparing the fenofenadine isomer of the present invention is as follows:
[0044]
[0045] Preparation of Compound II: 20.00 g of Compound I was suspended in 360 mL of dichloromethane. 27.59 g of sodium bicarbonate and 22.67 g of m-chloroperoxybenzoic acid were added under ice bath conditions, and the mixture was stirred for 2 hours under ice bath conditions. After the reaction was complete, the reaction solution was poured into 1 L of water under ice bath conditions. Most of the dichloromethane was evaporated. The mixture was extracted three times with 300 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 30 g of crude product. Column chromatography yielded 18.50 g of Compound II, with a yield of 87.89%. Mass spectra are shown below. Figure 1 See MRI Figure 2 .
[0046]
[0047] Preparation of Compound III: 18.50 g of Compound II was dissolved in 148 mL of tetrahydrofuran to prepare solution A. 5.08 g of NaH was suspended in 76.2 mL of tetrahydrofuran solution under ice bath conditions. Solution A was slowly added dropwise under ice bath conditions, and the mixture was stirred for 10 minutes under ice bath conditions. Then, 18.02 g of iodomethane was slowly added dropwise. The reaction was allowed to proceed at room temperature for 16 hours. After the reaction was completed, the reaction solution was slowly added dropwise to ~300 mL of crushed ice to quench the reaction, removing most of the tetrahydrofuran. The mixture was extracted three times with 160 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 23 g of crude product. Column chromatography yielded 16.70 g of Compound III, with a yield of 83.00%. Mass spectrometry results are shown below. Figure 3 See MRI Figure 4 .
[0048]
[0049] Preparation of compound IV: 12 g of compound III was dissolved in 180 mL of tetrahydrofuran, and 172.1 mL of 1 mol / L hydrochloric acid solution was added under ice bath. The mixture was stirred under ice bath for 1 hour. After the reactants were completely reacted, 600 mL of water was added under ice bath. The mixture was extracted three times with 200 mL of ethyl acetate and washed once with saturated sodium chloride solution. The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and then purified by column chromatography to obtain 7.2 g of compound IV, with a yield of 89.26%.
[0050] Mass spectrometry Figure 5 See MRI Figure 6 .
[0051]
[0052] Preparation of compound V: 7.2 g of compound IV was dissolved in 90 mL of dichloromethane. 3.65 g of pyridine and 4.22 g of methanesulfonyl chloride were added under ice bath conditions. The reaction was carried out at 30°C for 3 hours. After the reaction was complete, 100 mL of dichloromethane and 120 mL of 0.2 mol / L sulfuric acid solution were added under ice bath conditions. The mixture was stirred under ice bath conditions for 15 min, and the organic phase was separated. The organic phase was washed once with saturated sodium bicarbonate solution and then once with saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 9.50 g of compound V, yield: 98.96%. Compound V is an active ester intermediate and was used for the next reaction after processing.
[0053]
[0054] Preparation of compound VII: 9.50 g of compound V was dissolved in 142.5 mL of acetonitrile. 19.82 g of cesium carbonate and 8.13 g of compound VI were added under ice bath conditions. The mixture was stirred at 85 °C for 16 hours until the reaction was complete. After returning to room temperature, the reaction solution was filtered and washed with ethyl acetate. The filtrate was diluted with 800 mL of water and extracted three times with 150 mL of ethyl acetate. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 21 g of crude product. Column chromatography purification yielded 12.8 g of compound VII, yield: 87.02%. Mass spectrometry results are shown below. Figure 7 See MRI Figure 8 .
[0055]
[0056] Preparation of compound VIII: 12.80 g of compound VII was dissolved in 89.6 mL of methanol. A pre-prepared aqueous solution of sodium hydroxide (2.12 g of sodium hydroxide dissolved in 38.4 mL of water) was added under ice bath conditions. The mixture was stirred at 85°C for 12 hours until the reaction was complete. The reaction solution was concentrated to remove most of the methanol, and the product precipitated from the water. The product was filtered, washed with water, and dried to obtain 15 g of crude product. Finally, it was purified by crystallization with acetonitrile to obtain 8.6 g of a white solid, compound VIII. Yield: 62.06%, HPLC: 99.1%. Mass spectrometry is shown below. Figure 9 See MRI Figure 10 .
[0057]
[0058] Example 2
[0059] Preparation of Compound II: 25.00 g of Compound I was suspended in 375 mL of dichloromethane. 48.28 g of sodium bicarbonate and 41.56 g of m-chloroperoxybenzoic acid were added under ice bath conditions, and the mixture was stirred for 3 hours under ice bath conditions. After the reaction was complete, the reaction solution was poured into 1.2 L of water under ice bath conditions, and most of the dichloromethane was evaporated. The mixture was extracted three times with 350 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 33 g of crude product. Column chromatography yielded 23.8 g of Compound II, with a yield of 90.45%.
[0060]
[0061] Preparation of Compound III: 23.8 g of Compound II was dissolved in 119 mL of tetrahydrofuran to prepare solution B. 9.8 g of NaH was suspended in 196 mL of tetrahydrofuran solution under ice bath conditions. Solution B was slowly added dropwise under ice bath conditions. After stirring for 20 minutes under ice bath conditions, 34.78 g of iodomethane was slowly added dropwise. The reaction was stirred at 30°C for 8 hours. After the reaction was completed, the reaction solution was slowly added dropwise to ~500 mL of crushed ice to quench the reaction, removing most of the tetrahydrofuran. The mixture was extracted three times with 220 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and rotary evaporation, 30 g of crude product was obtained. Column chromatography yielded 22.30 g of Compound III, with a yield of 86.15%.
[0062]
[0063] Preparation of compound IV: 22.3 g of compound III was dissolved in 223 mL of tetrahydrofuran. 639.8 mL of 1 mol / L sulfuric acid solution was added under ice bath conditions. The mixture was stirred at room temperature for 30 minutes until the reaction was complete. 800 mL of water was added under ice bath conditions. The mixture was extracted three times with 300 mL of ethyl acetate, washed once with saturated sodium chloride solution, and the organic layers were combined and dried over anhydrous sodium sulfate. The extract was filtered, evaporated to dryness, and then purified by column chromatography to obtain 13.2 g of compound IV, with a yield of 88.06%.
[0064]
[0065] Preparation of compound V: 13.2 g of compound IV was dissolved in 264 mL of dichloromethane. 17.1 g of triethylamine and 12.91 g of methanesulfonyl chloride were added under ice bath conditions. The reaction was carried out at 30°C for 1.5 hours until completion. 250 mL of dichloromethane and 320 mL of 0.2 mol / L sulfuric acid solution were added under ice bath conditions. The mixture was stirred under ice bath conditions for 25 min, and the organic phase was separated. The organic phase was washed once with saturated sodium bicarbonate solution and then once with saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 17.5 g of compound V, yield: 99.44%.
[0066]
[0067] Preparation of compound VII: 17.5 g of compound V was dissolved in 437.5 mL of acetonitrile. 29.69 g of sodium carbonate and 17.97 g of compound VI were added under ice bath conditions. The mixture was stirred at 60 °C for 20 hours until the reaction was complete. After returning to room temperature, the reaction solution was filtered and washed with ethyl acetate. The filtrate was diluted with 1.2 L of water and extracted three times with 350 mL of ethyl acetate. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 31 g of crude product. Column chromatography purification yielded 23.5 g of compound VII, with a yield of 86.73%.
[0068]
[0069] Preparation of compound VIII: 23.5 g of compound VII was dissolved in 470 mL of methanol. A pre-prepared aqueous solution of sodium hydroxide (7.78 g of sodium hydroxide dissolved in 117.5 mL of water) was added under ice bath conditions. The mixture was stirred at 60°C for 20 hours until the reaction was complete. The reaction solution was concentrated to remove most of the methanol, and the product precipitated from the water. The product was filtered, washed with water, and dried to obtain 18 g of crude product. Finally, it was purified by crystallization with acetonitrile to obtain 13.2 g of a white solid, compound VIII. Yield: 51.88%, HPLC: 98.9%.
[0070]
[0071] Example 3
[0072] Preparation of Compound II: 22.00 g of Compound I was suspended in 330 mL of dichloromethane. 33.38 g of sodium bicarbonate and 26.6 g of m-chloroperoxybenzoic acid were added under ice bath conditions, and the mixture was stirred for 3 hours under ice bath conditions. After the reaction was complete, the reaction solution was poured into 1 L of water under ice bath conditions, and most of the dichloromethane was evaporated. The mixture was extracted three times with 300 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 32 g of crude product. Column chromatography yielded 21.6 g of Compound II, with a yield of 93.28%.
[0073]
[0074] Preparation of compound III: 21.6 g of compound II was dissolved in 108 mL of tetrahydrofuran to prepare solution C. 7.01 g of NaH was suspended in 175.2 mL of tetrahydrofuran solution under ice bath conditions. Solution C was slowly added dropwise under ice bath conditions. After stirring for 15 minutes under ice bath conditions, 23.92 g of iodomethane was slowly added dropwise. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the reaction solution was slowly added dropwise to ~300 mL of crushed ice to quench the reaction, removing most of the tetrahydrofuran. The mixture was extracted three times with 150 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and rotary evaporation, 30 g of crude product was obtained. Column chromatography yielded 22.1 g of compound III, with a yield of 94.08%.
[0075]
[0076] Preparation of compound IV: 22.1 g of compound III was dissolved in 663 mL of tetrahydrofuran. 380.4 mL of 1 mol / L hydrochloric acid solution was added under ice bath conditions. The mixture was stirred under ice bath conditions for 3 hours until the reaction was complete. 500 mL of water was added under ice bath conditions. The mixture was extracted three times with 200 mL of ethyl acetate, washed once with saturated sodium chloride solution, and the organic layers were combined and dried over anhydrous sodium sulfate. The extract was filtered, evaporated to dryness, and then purified by column chromatography to obtain 12.9 g of compound IV, with a yield of 86.84%.
[0077]
[0078] Preparation of compound V: 12.9 g of compound IV was dissolved in 322.5 mL of dichloromethane. 21.35 g of N,N-diisopropylethylamine and 12.61 g of methanesulfonyl chloride were added under ice bath conditions. The reaction was carried out at 30°C for 2 hours, after which the reaction was complete. 300 mL of dichloromethane and 300 mL of 0.2 mol / L sulfuric acid solution were added under ice bath conditions. The mixture was stirred under ice bath conditions for 10 min, and the organic phase was separated. The organic phase was washed once with saturated sodium bicarbonate solution, and then once with saturated sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 15.8 g of compound V, yield: 91.87%.
[0079]
[0080] Preparation of compound VII: 15.8 g of compound V was dissolved in 474 mL of acetonitrile. 34.95 g of potassium carbonate and 20.29 g of compound VI were added under ice bath conditions. The mixture was stirred at 95 °C for 10 hours until the reaction was complete. After returning to room temperature, the reaction solution was filtered and washed with ethyl acetate. The filtrate was diluted with 600 mL of water and extracted three times with 260 mL of ethyl acetate. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 36 g of crude product. Column chromatography purification yielded 23.1 g of compound VII, with a yield of 94.43%.
[0081]
[0082] Preparation of compound VIII: 23.1 g of compound VII was dissolved in 231 mL of methanol. A pre-prepared aqueous solution of sodium hydroxide (11.47 g of sodium hydroxide dissolved in 231 mL of water) was added under ice bath conditions. The mixture was stirred at 85°C for 6 hours until the reaction was complete. The reaction solution was concentrated to remove most of the methanol, and the product precipitated from the water. The product was filtered, washed with water, and dried to obtain 18 g of crude product. Finally, it was purified by crystallization with acetonitrile to obtain 15.1 g of a white solid, compound VIII. Yield: 60.37%, HPLC: 98.7%.
[0083]
Claims
1. A method for preparing a fexofenadine isomer, characterized in that, Includes the following steps: (1) Compound I was suspended in dichloromethane, sodium bicarbonate and m-chloroperoxybenzoic acid were added, and the mixture was stirred to obtain intermediate product II: ； (2) Take the intermediate product II obtained in step (1), dissolve it in tetrahydrofuran, add the tetrahydrofuran suspension of sodium hydride in an ice bath, stir, and then add iodomethane to react and generate intermediate product III: ； (3) Dissolve intermediate product III obtained in step (2) in tetrahydrofuran, add acidic aqueous solution, and react to obtain intermediate product IV: ； (4) Dissolve intermediate IV obtained in step (3) in dichloromethane, add an organic base and methanesulfonyl chloride, and react to obtain intermediate V: ； (5) Dissolve intermediate V obtained in step (4) in acetonitrile, add inorganic base and compound VI, and react to obtain intermediate VII: ； (6) Dissolve the intermediate product VII obtained in step (5) in methanol, add an aqueous solution of sodium hydroxide, and react to obtain the isomer of compound VIII, fexofenadine: 。 2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound I to sodium bicarbonate and m-chloroperoxybenzoic acid is 1:3~10:1~3; the reaction time is 1~20h.
3. The preparation method according to claim 1, characterized in that, In step (1), after the stirring reaction is completed, the mixture is poured into water under an ice bath, evaporated by rotary evaporation, extracted with ethyl acetate, the organic layers are combined, dried, filtered, and evaporated by rotary evaporation to obtain intermediate product II.
4. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of intermediate product II to NaH and iodomethane is 1:2~10:2~10; the reaction is carried out at a temperature of 20~30℃ for 1-32h.
5. The preparation method according to claim 1, characterized in that, In step (3), the acidic aqueous solution is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution; the molar ratio of the intermediate product III to the acidic aqueous solution is 1:1~30; the reaction is carried out at a temperature of 0~50℃ and for a reaction time of 1~24h.
6. The preparation method according to claim 1, characterized in that, In step (4), the molar ratio of intermediate product IV to organic base and methanesulfonyl chloride is 1:1~5:1~5; the reaction is carried out at a temperature of 0-50℃ for 1~30h.
7. The preparation method according to claim 1, characterized in that, In step (4), the organic base is pyridine, triethylamine or N,N-diisopropylethylamine.
8. The preparation method according to claim 1, characterized in that, In step (5), the molar ratio of intermediate product V to inorganic base and compound VI is 1:2~10:1~2; the reaction is carried out at a temperature of 0-100℃ for 1~32h.
9. The preparation method according to claim 1, characterized in that, In step (5), the inorganic base is sodium carbonate, potassium carbonate or cesium carbonate.
10. The preparation method according to claim 1, characterized in that, The molar ratio of intermediate product VII to sodium hydroxide in step (6) is 1:1 to 20; the reaction is carried out at a temperature of 30-100℃ for 1 to 36 hours.