A preparation method of paracetamol impurities

Abstract

The present invention discloses a preparation method of paracetamol impurities. The impurities are aromatic ether derivatives of paracetamol, which have not been reported at present and may be of important significance in terms of drug impurities and metabolites. The process design of the preparation method of this application is reasonable and the experimental operation is simple, laying a foundation for future industrial production. The prepared paracetamol impurities have high purity, providing an important basis for the scientific evaluation of the quality, safety and efficacy of paracetamol. The structure of the impurities is as follows:

Description

Technical Field

[0001] The present invention relates to a method for preparing a compound, and particularly to a method for preparing impurities of acetaminophen. Background Art

[0002] Acetaminophen, with the chemical name of N-(4-hydroxyphenyl)acetamide, CAS: 103-90-2, has the structural formula as follows:

[0003]

[0004] Acetaminophen is the most widely used antipyretic and analgesic drug in the world. With the increase in the years of clinical use, it has been found that there are obvious drawbacks such as significant hepatic first-pass effect. Therefore, the research on the impurities and metabolites of acetaminophen becomes particularly important. This patent provides a method for synthesizing impurities of acetaminophen.

[0005] With the progress of the times and the improvement of the scientific and technological level, people have a more full understanding of the importance of scientifically evaluating the quality, safety and efficacy of drugs before they are marketed. Among them, the control of drug impurities is closely related to the quality of drugs. Impurities are often directly related to the safety of drugs. Pharmacopoeias of various countries have strict regulations on the content and types of drug impurities.

[0006] The acetaminophen impurity (Compound VII) prepared in this application has the compound name of N-(4-(4-acetamido-2-hydroxyphenoxy)phenyl)acetamide, and the molecular formula is C 16 H 16 N2O4, and the structural formula is as follows:

[0007]

[0008] There is currently no literature report on the synthesis of this acetaminophen impurity. Its research on drug metabolism and impurities may have important research significance. There is an urgent need to study a preparation method for this compound with reasonable process design and strong operability. Summary of the Invention

[0009] Object of the Invention: The present invention aims to provide a method for preparing impurities of acetaminophen with reasonable process design and strong operability.

[0010] Technical Solution: The method for preparing impurities of acetaminophen according to the present invention comprises the following steps:

[0011] (1) Compound I is dissolved in methanol, a catalyst and a reducing agent are added, and the reaction yields Compound II:

[0012]

[0013] (2) Compound II is dissolved in pyridine, and an acetylation reagent is added, and the reaction gives Compound III:

[0014]

[0015] (3) Compound III is dissolved in methanol, and an aqueous solution of a base is added, and the reaction gives Compound IV:

[0016]

[0017] (4) Compounds IV and V are dissolved in DMSO, and a base is added, and the reaction gives Compound VI:

[0018]

[0019] (5) Compound VI is dissolved in THF, and a hydrogen chloride / methanol solution is added, and the reaction gives Compound VII:

[0020]

[0021] Furthermore, in step (1), the catalyst is selected from palladium on carbon and palladium on calcium carbonate, preferably palladium on carbon; the reducing agent is selected from hydrazine hydrate and hydrogen, preferably hydrazine hydrate.

[0022] Furthermore, in step (1), the Compound I is 1 equivalent, the catalyst is 0.05 - 0.3 equivalent, preferably 0.1 equivalent; the reducing agent is 2 - 30 equivalents, preferably 15 equivalents; the reaction temperature is 25 - 100 °C, preferably 75 °C; the reaction time is 1 - 24 hours, preferably 1 hour.

[0023] Furthermore, in step (2), the acetylation reagent is selected from acetic anhydride and acetyl chloride, preferably acetyl chloride.

[0024] Furthermore, in step (2), the Compound II is 1 equivalent, the acetylation reagent is 1 - 5 equivalents, preferably 3 equivalents; the reaction temperature is room temperature; the reaction time is 1 - 24 hours, preferably 1 hour.

[0025] Furthermore, in step (3), the organic solvent is methanol; the base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, and potassium hydroxide, preferably potassium carbonate.

[0026] Furthermore, in step (3), the Compound III is 1 equivalent, the base is 1 - 3 equivalents, preferably 1 equivalent; the temperature is room temperature; the reaction time is 1 - 24 hours, preferably 1 hour.

[0027] Further, in step (4), the base is selected from cesium carbonate, potassium carbonate, and sodium carbonate, preferably cesium carbonate.

[0028] Further, in step (4), the compound IV is 1 equivalent, the compound V is 0.5 - 1.5 equivalents, preferably 0.8 equivalent; the amount of the selected base used is 1 - 3 equivalents, preferably 2 equivalents; the reaction temperature is 80 - 120 °C, preferably 100 °C; the reaction time is 4 - 48 hours, preferably 24 hours.

[0029] Further, in step (5), the mass - volume ratio of the compound VI to hydrogen chloride is 1 g: 1 - 10 ml; the reaction time is 1 - 48 hours, preferably 24 hours.

[0030] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages: The synthetic process design of the preparation method is reasonable and highly operable. Through characterization by NMR, MS, HPLC, etc., its purity can reach 98%. This impurity is an aromatic ether derivative of paracetamol, which has not been reported so far and has extremely important research significance in medicinal chemistry and organic synthesis. It can provide test and control samples for the quality control of the raw material drug paracetamol and has important application value in drug declaration. The preparation method of this application has a reasonable process design and simple experimental operation, laying a foundation for future industrial production. The prepared paracetamol impurity has high purity, providing an important basis for the scientific evaluation of the quality, safety, and efficacy of paracetamol. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the synthetic flow chart of the present invention;

[0032] Figure 2 is the 1 1H - NMR spectrum of the compound VI synthesized by the present invention;

[0033] Figure 3 is the 1 1H - NMR spectrum of the compound VII synthesized by the present invention;

[0034] Figure 4 is the MS spectrum of the compound VII synthesized by the present invention;

[0035] Figure 5 is the HPLC spectrum of the compound VII synthesized by the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0036] The technical solutions of the present invention will be further described below in conjunction with the embodiments.

[0037] Example 1

[0038] A preparation method of acetaminophen derivatives, comprising the following steps (the synthesis flow chart is as shown in Figure 1 ):

[0039] (1) Preparation of compound II

[0040]

[0041] Dissolve compound I (21.00 g, 0.105 mol) in methanol (210.0 mL), add 10% palladium on carbon (2.10 g) and hydrazine hydrate (79.16 g, 1.582 mol), stir at 75 °C for 1 hour, and detect the completion of the reaction by TLC. Filter by vacuum filtration, concentrate to dryness to obtain the crude product of compound II (17.50 g), with a yield of 98%.

[0042] (2) Preparation of compound III

[0043]

[0044] Dissolve compound II (17.00 g, 0.100 mol) in pyridine (85.0 mL), add acetic anhydride (30.78 g, 28.2 mL, 0.301 mmol). Stir at room temperature for 1 hour, and detect the completion of the reaction by TLC. Concentrate to dryness under reduced pressure to obtain the crude product of compound III (25.00 g), with a yield of 98%.

[0045] (3) Preparation of compound IV

[0046]

[0047] Dissolve compound III (24.00 g, 94.8 mmol) in methanol (240.0 mL), and add 1 M aqueous potassium carbonate solution (13.10 g, 94.8 mmol potassium carbonate dissolved in 94.8 mL water) under ice bath. Stir at room temperature for 1 hour, and detect the completion of the reaction by TLC. Concentrate the solution to remove methanol, filter by suction, and dry the filter cake to obtain compound IV (8.00 g), with a yield of 40%.

[0048] (4) Preparation of compound VI

[0049]

[0050] Dissolve compound IV (8.00 g, 37.9 mmol) and compound V (6.49 g, 30.3 mmol) in DMSO (56 mL), and add cesium phosphate (24.68 g). Stir at 100 °C for 24 hours, and detect that the reaction is basically completed by TLC. Extract with ethyl acetate and concentrate to dryness under reduced pressure to obtain the crude product.

[0051] The crude product was eluted with a mixed system of dichloromethane and methanol through silica gel column chromatography to obtain Compound VI (4.10 g), whose 1 1H-NMR is as Figure 2 shown, with a yield of 31%.

[0052] (5) Preparation of Compound VII

[0053]

[0054] Compound VI (4.00 g, 11.6 mmol) was dissolved in THF (20.0 mL), and 4 M hydrogen chloride / methanol solution (20.0 mL) was slowly added dropwise under an ice bath. The reaction was stirred at room temperature overnight, and TLC was used to detect the completion of the reaction. After the methanol was evaporated to dryness, water was added, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was eluted with a mixed system of dichloromethane and methanol through silica gel column chromatography, and the obtained product was recrystallized with methanol to obtain Compound VII (3.10 g), whose 1 1H-NMR is as Figure 3 shown, and its MS is as Figure 4 shown, with a yield of 89%, as Figure 5 , and HPLC detection showed that its purity was over 98%.

[0055] Example 2

[0056] A preparation method of a paracetamol derivative, comprising the following steps:

[0057] (1) Preparation of Compound II

[0058]

[0059] Compound I (42.00 g, 0.105 mol) was dissolved in methanol (420.0 mL), 10% palladium on carbon (2.10 g) and hydrazine hydrate (10.55 g, 0.210 mol) were added, and the reaction was stirred at 75 °C for 2 hours. TLC was used to detect 50% of the reaction. The mixture was filtered under reduced pressure and concentrated to dryness to obtain the crude product.

[0060] The crude product was eluted with a mixed system of petroleum ether and ethyl acetate through silica gel column chromatography to obtain Compound II (17.20 g), with a yield of 48%.

[0061] (2) Preparation of Compound III

[0062]

[0063] Dissolve compound II (17.00 g, 0.100 mol) in pyridine (85.0 mL), and add acetic anhydride (41.04 g, 37.6 mL, 0.401 mmol). Stir the reaction at room temperature overnight, and monitor the completion of the reaction by TLC. Concentrate the reaction mixture under reduced pressure to dryness to obtain the crude product of compound III (25.05 g), with a yield of 98%.

[0064] (3) Preparation of compound IV

[0065]

[0066] Dissolve compound III (25.00 g, 98.7 mmol) in methanol (250.0 mL), and add 1 M aqueous potassium carbonate solution (prepared by dissolving 10.46 g, 98.7 mmol of potassium carbonate in 98.7 mL of water) under ice bath. Stir the reaction at room temperature for 1 hour, and monitor the completion of the reaction by TLC. Concentrate the solution to remove methanol, filter by suction, and dry the filter cake to obtain compound IV (8.02 g), with a yield of 38%.

[0067] (4) Preparation of compound VI

[0068]

[0069] Dissolve compound IV (8.00 g, 37.9 mmol) and compound V (8.11 g, 37.9 mmol) in DOSM (56 mL), and add cesium phosphate (24.68 g). Stir the reaction at 80 °C for 48 hours, and monitor the completion of the reaction by TLC. Dilute the reaction mixture with water and extract with ethyl acetate. Concentrate the extract under reduced pressure to dryness to obtain the crude product.

[0070] Use a mixed system of dichloromethane and methanol as the eluent to perform silica gel column chromatography on the crude product to obtain compound VI (3.5 g), with a yield of 27%.

[0071] (5) Preparation of compound VII

[0072]

[0073] Dissolve compound VI (3.00 g, 8.7 mmol) in THF (15.0 mL), and slowly add 4 M hydrogen chloride / methanol solution (6.0 mL) under ice bath. Stir the reaction at room temperature overnight, and monitor the completion of the reaction by TLC. Rotavapor to remove methanol, add water, extract with ethyl acetate, and concentrate the extract under reduced pressure to dryness to obtain the crude product. Use a mixed system of dichloromethane and methanol as the eluent to perform silica gel column chromatography on the crude product, and recrystallize the obtained product from methanol to obtain compound VII (2.1 g), with a yield of 60%.

[0074] Example 3

[0075] A method for preparing a paracetamol derivative, comprising the following steps:

[0076] (1) Preparation of Compound II

[0077]

[0078] Dissolve Compound I (30.00 g, 0.151 mol) in methanol (300.0 mL), add 10% palladium on carbon (4.20 g) and hydrazine hydrate (37.70 g, 0.753 mol), stir at 75 °C for 1 hour, and detect by TLC that the reaction is basically complete. Filter by suction under reduced pressure and concentrate to dryness to obtain the crude product.

[0079] Use a mixed system of petroleum ether and ethyl acetate as the eluent, and obtain Compound II (21.50 g) by silica gel column chromatography with a yield of 84.37%.

[0080] (2) Preparation of Compound III

[0081]

[0082] Dissolve Compound II (21.00 g, 0.124 mol) in pyridine (105.0 mL), add acetic anhydride (27.88 g, 0.273 mmol). Stir at room temperature for 1 hour and detect by TLC that the reaction is complete. Concentrate to dryness under reduced pressure to obtain the crude product of Compound III (20.30 g) with a yield of 77%.

[0083] (3) Preparation of Compound IV

[0084]

[0085] Dissolve Compound III (20.00 g, 79.0 mmol) in methanol (200.0 mL), and add 1 M aqueous potassium bicarbonate solution (7.91 g of potassium carbonate dissolved in 79.0 mL of water) under ice bath. Stir at room temperature for 24 hours and detect by TLC that the reaction is complete. Concentrate the solution to remove methanol, filter by suction, and dry the filter cake to obtain Compound IV (5.60 g) with a yield of 38%.

[0086] (4) Preparation of Compound VI

[0087]

[0088] Dissolve Compound IV (8.00 g, 26.0 mmol) and Compound V (5.57 g, 26.0 mmol) in DOSM (38.5 mL), add potassium carbonate (7.20 g, 52.1 mmol). Stir at 100 °C for 24 hours and detect by TLC that the reaction is basically complete. Dilute with water and extract with ethyl acetate, and concentrate to dryness under reduced pressure to obtain the crude product.

[0089] The crude product was eluted with a mixed system of dichloromethane and methanol, and compound VI (2.14 g) was obtained by silica gel column chromatography with a yield of 24%.

[0090] (5) Preparation of compound VII

[0091]

[0092] Compound VI (2.00 g, 8.7 mmol) was dissolved in THF (10.0 mL), and 4 M hydrogen chloride / methanol solution (20.0 mL) was slowly added dropwise under an ice bath. The reaction was stirred at room temperature overnight, and TLC was used to detect that the reaction was basically completed. After evaporating methanol, water was added, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was eluted with a mixed system of dichloromethane and methanol, and the obtained product was recrystallized from methanol to obtain compound VII (2.01 g) with a yield of 87%.

Claims

1. A method for preparing paracetamol impurities, characterized in that, It includes the following steps: (1) Compound I is dissolved in methanol, a catalyst and a reducing agent are added, and the reaction gives Compound II: (2) Compound II is dissolved in pyridine, an acetylation reagent is added, and the reaction gives Compound III: (3) Compound III is dissolved in methanol, a base is added, and the reaction gives Compound IV: (4) Compound IV is dissolved in DMSO, a bromide raw material V and a base are added, and the reaction gives Compound VI: (5) Compound VI is dissolved in THF, a hydrogen chloride / methanol solution is added, and the reaction gives Compound VII:

2. The preparation method according to claim 1, characterized in that: In step (1), the catalyst is selected from palladium on carbon or palladium calcium carbonate; the reducing agent is selected from hydrazine hydrate or hydrogen.

3. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of Compound I, the catalyst and the reducing agent is 1:0.05 - 0.3:2 - 30, the reaction temperature is 25 - 100 °C, and the reaction time is 1 - 24 hours.

4. The preparation method according to claim 1, characterized in that: In step (2), the acetylation reagent is selected from acetic anhydride or acetyl chloride.

5. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of Compound II and the acetylation reagent is 1:1 - 5, the reaction temperature is room temperature, and the reaction time is 1 - 24 hours.

6. The preparation method according to claim 1, characterized in that: In step (3), the base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or potassium hydroxide.

7. The preparation method according to claim 1, wherein: In step (3), the molar ratio of Compound III and the base is 1:1 - 3, the reaction temperature is room temperature, and the reaction time is 1 - 24 hours.

8. The preparation method according to claim 1, characterized in that: In step (4), the base is selected from cesium carbonate, potassium carbonate or sodium carbonate.

9. The preparation method according to claim 1, characterized in that: In step (4), the molar ratio of Compound IV, Compound V and the base is 1:0.5 - 1.5:1 - 4, the reaction temperature is 80 - 120 °C, and the reaction time is 4 - 48 hours.

10. The preparation method according to claim 1, characterized in that: In step (5), the mass - volume ratio of Compound VI to hydrogen chloride is 1 g:1 - 10 ml, and the reaction time is 1 - 24 hours.

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