A process for the preparation of nitrophenols

Abstract

The application discloses a preparation method of nitrophenol, which comprises the following steps: taking a nitrous acid compound as a nitro source, and reacting the nitrous acid compound with a phenol compound in a solvent under the catalysis of an acyl chloride or an anhydride catalyst to generate the nitrophenol. The application has the advantages of wide application range of substrates, mild reaction condition, short reaction time, simple operation, no use of strong acid and metal catalyst, environmental friendliness, excellent yield, and the like, and the yield can reach 95%.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of nitrophenol. BACKGROUND

[0002] Nitro group is one of the common and unique functional groups in medicinal chemistry, which can be found in many antitumor drugs, antibiotics, antituberculosis drugs, antiparasitic drugs, tranquilizers, insecticides and herbicides. The nitro group can be used to design prodrugs by its reducing property, and the nitro drug can produce active drug molecules in vivo through enzymatic reduction and finally induce biological effects. Nitrophenol derivatives have significant biological activity, and some can be used as antibacterial drugs to interfere with the physiological metabolic process of bacteria through a specific mechanism, effectively inhibit the growth of various common pathogenic bacteria, and have potential significance for solving the problem of clinical drug-resistant bacterial infection.

[0003] In the research and development of anticancer drugs, some nitrophenol compounds can target key metabolic pathways or signal transduction pathways of tumor cells, induce tumor cell apoptosis or inhibit their proliferation, and some exhibit higher selectivity compared to traditional chemotherapy drugs, which is expected to reduce the toxic side effects on normal cells. In addition, nitrophenol also serves as an important intermediate in drug synthesis, participating in the construction of various complex drug molecules. By utilizing its active chemical properties, specific functional groups can be effectively introduced to promote the structural modification and optimization of drug molecules, laying a foundation for the development of new drugs with higher efficacy and lower toxicity.

[0004] In the past, there have been many methods for synthesizing nitrophenol, such as: (1) introducing a nitro functional group through concentrated sulfuric acid and nitric acid, but this method is prone to explosion and produces difficult-to-handle waste acid, which is harmful to the environment; (2) iodine (III) through NonBrønsted acid NO2 + to generate electrophilic nitration of catalytic phenol (Org. Lett. 2019, 21, 1315-1319); (3) using CuPcS as a recyclable catalyst and sodium nitrate as a nitro source for the nitration of aromatic compounds (Journal of Molecular Structure 1280 (2023) 135039). However, these methods inevitably use transition metals or hazardous reaction conditions. SUMMARY

[0005] In view of the problems of violent reaction and high hazard in the above-mentioned synthesis method of nitrophenol, the present application provides a preparation method of nitrophenol, which has a wide range of suitable substrates, mild conditions, short reaction time and simple operation.

[0006] To achieve the above object, the present application provides a preparation method of nitrophenol, which comprises: reacting a nitrous acid compound as a nitro source with a phenol compound in a solvent under the catalytic condition of an acyl chloride or an acid anhydride catalyst to generate nitrophenol, and the reaction formula is as follows:

[0007] ,

[0008] wherein R is C 6-8 aryl, heteroaryl, alkyl, alkoxy, F, Cl, Br, I.

[0009] In the above technical solution, the acyl chloride or the acid anhydride is used as the catalyst, first forms an intermediate A with the nitrous acid compound, the intermediate A is uniformly split to generate a nitroso radical under heating, the intermediate A forms an intermediate B with the phenol, the intermediate B is converted into a phenoxy group, the nitric oxide is rapidly oxidized with the molecular oxygen, and finally the phenoxy group is coupled with the nitrogen dioxide to obtain the final product. For example, acetyl chloride, sodium nitrite and phenol are used as raw materials, and the reaction process is as follows:

[0010] .

[0011] Preferably, the nitrous acid compound is sodium nitrite, potassium nitrite or tert-butyl nitrite, and preferably sodium nitrite.

[0012] 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, and preferably acetyl chloride.

[0013] Preferably, the solvent is 1,4-dioxane, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, toluene, anhydrous diethyl ether or tert-butyl methyl ether, and preferably anhydrous diethyl ether.

[0014] Preferably, the molar ratio of the phenol compound, the nitrous acid compound and the catalyst is 1: (2-5): (2.5-5), and preferably 1:5:4.

[0015] Specifically, the reaction condition is 10-40 ℃, 12-15 h, preferably 30 ℃, and 12 h.

[0016] The specific preparation process of the method of the present application can be: adding a phenol compound, a nitrous acid compound, a catalyst and a solvent into a reaction bottle, heating to 10-40 ℃ under air condition, stopping stirring after reaction for 12-15 h. A certain amount of saturated sodium bicarbonate solution is added to the reaction system, and then extracted with ethyl acetate for multiple times. The obtained organic phase is combined, dried with anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure to obtain a crude product. The pure product is obtained through silica gel column chromatography.

[0017] Through the above technical solution, the present application achieves the following beneficial effects:

[0018] The application uses phenols as a single raw material, nitrous acid compounds as a nitro source, and acyl chloride or acid anhydride as a catalyst to prepare nitrophenol under mild conditions. The method has wide substrate application range, mild reaction conditions, short reaction time, simple operation, no use of strong acid and metal catalyst, environmental friendliness, and excellent yield, which can reach 95%. DETAILED DESCRIPTION

[0019] The specific embodiments of the application are described in detail below with reference to the examples. It should be understood that the specific embodiments described herein are only used to illustrate and explain the application, and are not used to limit the application.

[0020] Example 1

[0021] Phenol 18 mg, sodium nitrite 70 mg and acetyl chloride 56 μL were added to a reaction bottle, then anhydrous ether solution 1 mL was added, and the temperature was raised to 30°C under air condition. After the reaction was carried out for 12 h, the stirring was stopped. A certain amount of saturated sodium bicarbonate solution was added to the reaction system, and then extracted with ethyl acetate three times. The obtained organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product nitrophenol isomer was obtained by silica gel column chromatography as a yellow solid, and the total yield was 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).

[0022] Example 2

[0023] Phenol 18 mg, sodium nitrite 70 mg and acetic anhydride 47 μL were added to a reaction bottle, then anhydrous ether solution 1 mL was added, and the temperature was raised to 30°C under air condition. After the reaction was carried out for 12 h, the stirring was stopped. A certain amount of saturated sodium bicarbonate solution was added to the reaction system, and then extracted with ethyl acetate three times. The obtained organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The yield was 80%.

[0024] Example 3

[0025] To the reaction flask was added phenol 18 mg, sodium nitrite 35 mg and acetyl chloride 42 μL, followed by tetrahydrofuran solution 1 mL, under air condition, the temperature was raised to 40 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The yield was 85%.

[0026] Example 4

[0027] To the reaction flask was added phenol 18 mg, sodium nitrite 28 mg and acetyl chloride 35 μL, followed by tetrahydrofuran solution 1 mL, under air condition, the temperature was raised to 10 °C, and the reaction was allowed to proceed for 15 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The yield was 70%.

[0028] Example 5

[0029] To the reaction flask was added phenol 18 mg, sodium nitrite 42 mg and acetyl chloride 70 μL, followed by ethylene glycol dimethyl ether solution 1 mL, under air condition, the temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The yield was 83%.

[0030] Example 6

[0031] To the reaction flask was added phenol 18 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, followed by tert-butyl methyl ether solution 1 mL, under air condition, the temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The yield was 85%.

[0032] Example 7

[0033] To a reaction flask was added 4-bromophenol 34.6 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, followed by the addition of anhydrous diethyl ether solution 1 mL, air condition, temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The product was a yellow solid with a yield of 89%. 1 H NMR (CDCI3), δ: 7.05~7.07 (d, 1H), 7.63~7.66 (d, 1H), 8.22~8.23 (d, 1H), 10.47 (s, 1H).

[0034] Example 8

[0035] To a reaction flask was added 4-bromophenol 34.6 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, followed by the addition of anhydrous diethyl ether solution 1 mL, air condition, temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The product was a yellow solid with a yield of 89%. 1 H NMR (CDCI3), δ: 7.05~7.07 (d, 1H), 7.63~7.66 (d, 1H), 8.22~8.23 (d, 1H), 10.47 (s, 1H).

[0036] Example 9

[0037] To a reaction flask was added 4-bromophenol 34.6 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, followed by the addition of anhydrous diethyl ether solution 1 mL, air condition, temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The product was a yellow solid with a yield of 89%. 1 H NMR (CDCI3), δ: 7.05~7.07 (d, 1H), 7.63~7.66 (d, 1H), 8.22~8.23 (d, 1H), 10.47 (s, 1H).

[0038] Example 10

[0039] To the reaction flask was added 2-ethylphenol 24.4 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, followed by the addition of anhydrous diethyl ether solution 1 mL, under air condition, the temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The product was a yellow solid with a yield of 89%. 1 H NMR (CDCI3), 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).

[0040] Example 11

[0041] To the reaction flask was added 2-ethylphenol 24.4 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, followed by the addition of anhydrous diethyl ether solution 1 mL, under air condition, the temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The product was a yellow solid with a yield of 89%. 1 H NMR (CDCI3), 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).

[0042] Example 12

[0043] To the reaction flask was added 2-ethylphenol 24.4 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, followed by the addition of anhydrous diethyl ether solution 1 mL, under air condition, the temperature was raised to 30 °C, and the reaction was allowed to proceed for 12 h, after which the stirring was stopped. To the reaction system was added a certain amount of saturated sodium bicarbonate solution, followed by extraction with ethyl acetate three times. The resulting organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. The pure product was obtained by silica gel column chromatography. The product was a yellow solid with a yield of 89%. 1 H NMR (CDCI3), 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).

[0044] Example 13

[0045] Into a reaction flask was added 4-cyclohexylphenol 35.3 mg, sodium nitrite 70 mg and acetyl chloride 56 μL, then added anhydrous ethyl ether solution 1 mL, air condition, temperature to 30°C, after the reaction to 12 h, stop stirring. A certain amount of saturated sodium bicarbonate solution was added to the reaction system, then extracted with ethyl acetate three times. The resulting organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the crude product. Further column chromatography on silica gel to obtain the pure product. The product was a yellow solid, the yield was 85%. 1 H NMR (CDCI3), 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).

[0046] Table 1 Example compound control table

[0047]

[0048] The above describes the preferred embodiments of the present application, but the present application is not limited to the specific details of the above-described embodiments, within the technical concept of the present application, various simple modifications can be made to the technical solutions of the present application, and these simple modifications all belong to the protection scope of the present application.

[0049] In addition, it should be noted that each specific technical feature described in the above specific embodiments can be combined in any appropriate manner without contradiction, in order to avoid unnecessary repetition, the present application will not be described again.

[0050] In addition, various different embodiments of the present application can also be combined in any manner, as long as it does not deviate from the idea of the present application, it should also be considered as disclosed by the present application.

Claims

1. A method for preparing nitrophenol, characterized in that, include: Using nitrite compounds as the nitro source, phenolic compounds react with phenolic compounds in a solvent under the catalytic conditions of acyl chloride or acid anhydride catalysts to produce nitrophenol. The general reaction formula is as follows: ， In the formula, 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 acyl 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 diethyl ether, or tert-butyl methyl ether.

5. The preparation method according to claim 1, characterized in that, The molar ratio of phenolic 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 phenolic compounds, nitrite compounds, and catalyst is 1:5:

4.

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

Images