Preparation method of nitrophenol

Abstract

The invention discloses a preparation method of nitrophenol, which comprises the following step: reacting a nitrous acid compound serving as a nitro source with a phenol compound in a solvent under the catalytic condition of an acyl chloride or anhydride catalyst to generate the nitrophenol. The method is wide in substrate application range, mild in reaction condition, short in reaction time, easy to operate, free of strong acid and metal catalysts, environmentally friendly and excellent in yield, and the yield can reach 95%.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing nitrophenol. Background Art

[0002] The nitro group is a common and unique functional group in medicinal chemistry, found in many anti-tumor drugs, antibiotics, anti-tuberculosis drugs, anti-parasitic drugs, sedatives, pesticides, and herbicides. The reducibility of the nitro group can be exploited to design prodrugs. Nitro-based drugs undergo enzymatic reduction in vivo to produce active drug molecules, ultimately inducing biological effects. Nitrophenol derivatives possess significant biological activity, and some can be used as antibacterial agents. Through specific mechanisms, they interfere with bacterial metabolic processes, effectively inhibiting the growth of many common pathogens and holding potential for addressing the problem of drug-resistant bacterial infections in clinical practice.

[0003] In the development of anticancer drugs, certain nitrophenol compounds can target key metabolic pathways or signaling pathways in tumor cells, inducing apoptosis or inhibiting their proliferation. Compared to traditional chemotherapy drugs, some exhibit higher selectivity, potentially reducing toxic side effects on normal cells. Furthermore, nitrophenols serve as important intermediates in drug synthesis, participating in the construction of a variety of complex drug molecules. Their active chemical properties can effectively introduce specific functional groups, promoting the structural modification and optimization of drug molecules and laying the foundation for the development of new drugs with higher efficacy and lower toxicity.

[0004] In the past, there were many methods for synthesizing nitrophenols, such as: (1) introducing nitro functional groups through concentrated sulfuric acid and nitric acid, but this method is prone to explosion and produces waste acid that is difficult to handle, which is harmful to the environment; (2) iodine (III) is synthesized through NonBrønsted acidic NO2 + The electrophilic nitration of phenol was catalyzed (Org. Lett. 2019, 21, 1315−1319); (3) CuPcS was used as a recyclable catalyst and sodium nitrate as a nitro source to nitrate aromatic compounds (Journal of Molecular Structure 1280 (2023) 135039). However, these methods inevitably use transition metals or more hazardous reaction conditions. Summary of the Invention

[0005] In order to solve the problems of violent reaction and great harm in the above-mentioned nitrophenol synthesis method, the present invention provides a preparation method of nitrophenol, which has a wide range of substrate applicability, mild conditions, short reaction time and simple operation.

[0006] To achieve the above object, the present invention provides a method for preparing nitrophenol, which comprises: using a nitrite compound as a nitro source and reacting it with a phenol compound in a solvent under catalytic conditions of an acid chloride or an acid anhydride catalyst to produce nitrophenol. The general reaction formula is as follows: , Where R is C 6-8 Aryl, heteroaryl, alkyl, alkoxy, F, Cl, Br, I.

[0007] In the above technical solution, an acid chloride or an acid anhydride is used as a catalyst to first react with a nitrous compound to form an intermediate A. Intermediate A undergoes homolytic cleavage upon heating to form a nitroso radical. Intermediate A reacts with phenol to form intermediate B, which is then converted into a phenoxy radical. Nitric oxide is then rapidly oxidized with molecular oxygen, and finally the phenoxy radical is coupled with nitrogen dioxide to obtain the final product. For example, using acetyl chloride, sodium nitrite, and phenol as raw materials, the reaction process is as follows: .

[0008] Preferably, the nitrite compound is sodium nitrite, potassium nitrite or tert-butyl nitrite, preferably sodium nitrite.

[0009] Preferably, the acyl chloride is acetyl chloride, benzoyl chloride, sulfonyl chloride, oxalyl chloride, chloroacetyl chloride or trichloroacetyl chloride, and the acid anhydride is acetic anhydride, preferably acetyl chloride.

[0010] Preferably, the solvent is 1,4-dioxane, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, toluene, anhydrous ethyl ether or tert-butyl methyl ether, preferably anhydrous ethyl ether.

[0011] Preferably, the molar ratio of the phenol compound, the nitrite compound, and the catalyst is 1:(2-5):(2.5-5), preferably 1:5:4.

[0012] Specifically, the reaction conditions are 10-40° C., 12-15 h, preferably 30° C., 12 h.

[0013] The specific preparation process for the method of the present invention can be as follows: add a phenol compound, a nitrite compound, a catalyst, and a solvent to a reaction flask, raise the temperature to 10-40°C under air, and after reacting for 12-15 hours, stop stirring. Add a certain amount of saturated sodium bicarbonate solution to the reaction system, and then extract with ethyl acetate multiple times. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to obtain a crude product. The purified product is then purified by silica gel column chromatography.

[0014] Through the above technical solution, the present invention achieves the following beneficial effects: The present invention uses phenols as a single raw material, nitrite compounds as a nitro source, and acid chlorides or acid anhydrides as catalysts to prepare nitrophenols under mild conditions. The method has a wide range of substrate applicability, mild reaction conditions, short reaction time, simple operation, does not use strong acids and metal catalysts, is environmentally friendly, and has an excellent yield of up to 95%. DETAILED DESCRIPTION

[0015] The following is a detailed description of the specific embodiments of the present invention in conjunction with the examples. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0016] Example 1 Add 18 mg of phenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride to the reaction flask, then add 1 mL of anhydrous ether solution, heat to 30 ° C under air conditions, and stop stirring after the reaction for 12 hours. Add a certain amount of saturated sodium bicarbonate solution to the reaction system, and then extract three times with ethyl acetate. After combining the obtained organic phases, dry them over anhydrous sodium sulfate, filter them, and remove the solvent under reduced pressure to obtain a crude product. Then, the pure product nitrophenol isomers were obtained by silica gel column chromatography as a yellow solid with an overall yield of 90%. (o-NO2): 1 H NMR (CDCl3), δ: 6.95~7.03(m,1H), 7.13~7.19(m,1H), 7.55~7.62(m,1H), 8.08~8.14(m,1H), 10.5(s,1H); (p-NO2): 1 H NMR (DMSO), δ: 6.88~6.92(m,2H), 8.06~8.10(m,2H), 11.00(s,1H).

[0017] Example 2 To a reaction flask, add 18 mg of phenol, 70 mg of sodium nitrite, and 47 μL of acetic anhydride, followed by 1 mL of anhydrous ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. Combine the resulting organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to yield the crude product. Purify the product by silica gel column chromatography. The yield is 80%.

[0018] Example 3 To a reaction flask, add 18 mg of phenol, 35 mg of sodium nitrite, and 42 μL of acetyl chloride, followed by 1 mL of acetonitrile solution. Heat to 40°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. Combine the resulting organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to yield the crude product. Purify the product by silica gel column chromatography. The yield is 85%.

[0019] Example 4 To a reaction flask, add 18 mg of phenol, 28 mg of sodium nitrite, and 35 μL of acetyl chloride, followed by 1 mL of tetrahydrofuran solution. Warm to 10°C under air and allow to react for 15 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is then purified by silica gel column chromatography. The yield is 70%.

[0020] Example 5 To a reaction flask, add 18 mg of phenol, 42 mg of sodium nitrite, and 70 μL of acetyl chloride, followed by 1 mL of ethylene glycol dimethyl ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is then purified by silica gel column chromatography. The yield is 83%.

[0021] Example 6 To a reaction flask, add 18 mg of phenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride, followed by 1 mL of tert-butyl methyl ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is then purified by silica gel column chromatography. The yield is 85%.

[0022] Example 7 To a reaction flask, add 34.6 mg of 4-bromophenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride. Then, add 1 mL of anhydrous ether solution. Heat to 30°C under air. After 12 hours of reaction, discontinue stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is obtained by silica gel column chromatography. The product is a yellow solid with a yield of 89%. 1H NMR (CDCl3), δ: 7.05~7.07(d,1H), 7.63~7.66(d,1H), 8.22~8.23(d,1H), 10.47(s,1H).

[0023] Example 8 To a reaction flask, add 25.7 mg of 4-chlorophenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride, followed by 1 mL of anhydrous ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is obtained by silica gel column chromatography as a yellow solid in a 93% yield. 1 H NMR (CDCl3), δ: δ: 7.11~7.14(d,1H), 7.51~7.54(d,1H), 8.08~8.09(m,1H), 10.46(d,1H).

[0024] Example 9 To a reaction flask, add 22.4 mg of 4-fluorophenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride, followed by 1 mL of anhydrous ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is obtained by silica gel column chromatography. The product is a pale yellow solid with a yield of 91%. 1 H NMR (CDCl3), δ: 7.13~7.17(d,1H), 7.33~7.38(d,1H), 7.78~7.81(d,1H), 10.34(s,1H).

[0025] Example 10 To a reaction flask, add 24.4 mg of 2-ethylphenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride, followed by 1 mL of anhydrous ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is obtained by silica gel column chromatography. The product is a yellow solid with a yield of 89%. 1H NMR (CDCl3), δ: 1.22~1.26(d,3H), 2.72~2.77(d,2H), 6.88~6.92(d,1H), 7.44~7.46(m,1H), 7.94~7.96(m,1H), 10.94(s,1H).

[0026] Example 11 To a reaction flask, add 21.6 mg of 4-methylphenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride, followed by 1 mL of anhydrous ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is obtained by silica gel column chromatography. The product is a yellow solid with a yield of 95%. 1 H NMR (CDCl3), δ: 2.34(s,3H), 7.04~7.06(d,1H), 7.37~7.40(d,1H), 7.88~7.89(d,1H), 10.43(s,1H).

[0027] Example 12 To a reaction flask, add 24.4 mg of 4-ethylphenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride, followed by 1 mL of anhydrous ether solution. Heat to 30°C under air and allow to react for 12 hours before stopping stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is obtained by silica gel column chromatography. The product is a yellow solid with a yield of 93%. 1 H NMR (CDCl3), δ: 1.21~1.25(d,3H), 2.60~2.66(d,2H), 7.05~7.07(d,1H), 7.40~7.43(d,1H), 7.89~7.90(d,1H), 10.44(s,1H).

[0028] Example 13 To a reaction flask, add 35.3 mg of 4-cyclohexylphenol, 70 mg of sodium nitrite, and 56 μL of acetyl chloride. Then, add 1 mL of anhydrous ether solution. Heat to 30°C under air. After 12 hours of reaction, discontinue stirring. Add a saturated sodium bicarbonate solution to the reaction system, then extract three times with ethyl acetate. The resulting organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the crude product. Purified product is obtained by silica gel column chromatography. The product is a yellow solid with an 85% yield. 1H NMR (CDCl3), δ: 1.17~1.43(d,5H), 1.71~1.86(d,5H), 2.45~2.50(d,1H), 7.03~7.06(d,1H), 7.41~7.44(d,1H), 7.88~7.89(d,1H), 10.43(s,1H).

[0029] Table 1 Comparative table of example compounds

[0030] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0031] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0032] In addition, the various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A method for preparing nitrophenol, characterized in that: include: Nitrophenol is generated by reacting nitrite compounds as nitro sources with phenol compounds in a solvent under the catalytic conditions of acyl chloride or acid anhydride catalysts. The general reaction formula is as follows: ， Where R is C 6-8 One or more of aryl, heteroaryl, alkyl, alkoxy, F, Cl, Br, and I.

2. The preparation method according to claim 1, characterized in that: The nitrite compound is sodium nitrite, potassium nitrite or tert-butyl nitrite.

3. The preparation method according to claim 1, characterized in that: The acid chloride is acetyl chloride, benzoyl chloride, sulfonyl chloride, oxalyl chloride, chloroacetyl chloride or trichloroacetyl chloride, and the acid anhydride is acetic anhydride.

4. The preparation method according to claim 1, characterized in that: The solvent is 1,4-dioxane, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, toluene, anhydrous ether or tert-butyl methyl ether.

5. The preparation method according to claim 1, characterized in that: The molar ratio of phenol compounds, nitrite compounds and catalyst is 1:(2-5):(2.5-5).

6. The preparation method according to claim 5, characterized in that: The molar ratio of the phenol compound, the nitrite compound and the catalyst is 1:5:

4.

7. The preparation method according to claim 1, characterized in that The reaction conditions are 10~40 ℃, 12~15 h.

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