Synthetic method of hydroquinone compound

Abstract

The invention discloses a synthetic method of a hydroquinone compound, which comprises the following steps: adding a compound A, an initiator azodiisobutyronitrile and a catalyst into an organic solvent, introducing oxygen, reacting to obtain a precipitate, separating the precipitate, washing and drying to obtain a compound B or C; the raw materials are easy to obtain, the cost is low, the obtained product is high in purity and good in yield, the process is green and efficient, and the method has wide universality and good industrial application prospects.

Description

Technical Field

[0001] This invention relates to a method for synthesizing hydroquinone compounds, belonging to the field of chemical synthesis technology. Background Technology

[0002] Methylhydroquinones, as key chemical intermediates and bioactive molecules, play an irreplaceable role in many fields. Methylhydroquinone (THQ) and its derivatives are important organic intermediates with wide applications in polymer materials, pharmaceuticals and vitamin synthesis, antioxidants, and dyes. Among them, trimethylhydroquinone (TMHQ) is a key intermediate in the artificial synthesis of vitamin E. With the continuous growth in demand for vitamin E and its precursor TMHQ in the pharmaceutical, food, and cosmetic fields, research on efficient synthetic methods for TMHQ has shown significant industrial value.

[0003] In the pharmaceutical field, its unique molecular structure can be used to synthesize a variety of drugs, such as antioxidants and anti-tumor drugs, providing important support for related treatments. In the field of polymer materials, these compounds can serve as initiators or stabilizers in polymerization reactions, effectively improving the antioxidant and thermal stability properties of materials and promoting the development of high-performance materials. In the chemical industry, as an important synthetic intermediate, it is widely used in the preparation of dyes, fragrances, and other fine chemicals, promoting the diversification of the chemical industry. With its diverse chemical properties and broad application potential, methylhydroquinone compounds continue to provide important support for the development of related industries.

[0004] Early synthesis of methylhydroquinone typically used phenol as a starting material, introducing a sulfonic acid group through sulfonation, followed by an alkaline fusion reaction to generate hydroquinone, and then further methylation to obtain the target product (e.g., using p-cresol as a starting material via a similar sulfonation-alkaline fusion-methylation route). This method involves harsh reaction conditions (high temperature, strong alkaline environment), produces numerous byproducts, and generates a large amount of waste acid in the sulfonation step, resulting in a heavy environmental burden. Subsequent methods include chlorinating o-cresol to generate chloro-o-cresol, followed by hydrolysis to obtain methylhydroquinone, but this route involves highly toxic chlorine gas, causes severe equipment corrosion, is difficult to separate the product, and has a low yield, limiting its industrial application.

[0005] Currently, the main industrial method for synthesizing trimethylhydroquinone (TMHQ) is the pseudotrimethylbenzene method. This involves using H₂O₂ as an oxidant in the presence of a γ-Al₂O₃ / copper phthalocyanine composite catalyst to generate trimethylbenzoquinone (TMBQ) via reflux reaction, followed by further reduction to obtain TMHQ. However, this method is costly and has limited operability, making large-scale industrial production difficult in the short term. Recent studies have also explored the synthesis of TMHQ via a redox route using 2,3,6-trimethylphenol, but this method still has limitations, and further optimization and exploration of the synthesis process are needed. Summary of the Invention

[0006] The purpose of this invention is to provide an efficient, green, and economical method for synthesizing hydroquinone compounds, thereby overcoming the main shortcomings of existing technologies.

[0007] The implementation process of this invention is as follows.

[0008] A method for synthesizing a hydroquinone compound, comprising the following steps:

[0009]

[0010] R is selected from C1-C10 alkyl groups, C1-C10 alkoxy groups, C1-C5 haloalkyl groups, alkoxy groups, nitro groups, nitrile groups, sulfonic acid groups, carboxyl groups, trifluoromethyl groups, hydroxyl groups, and halogen groups; R is preferably selected from C1-C5 alkyl groups, C1-C5 alkoxy groups, C1-C3 haloalkyl groups, alkoxy groups, nitro groups, nitrile groups, sulfonic acid groups, carboxyl groups, trifluoromethyl groups, hydroxyl groups, and halogen groups.

[0011] R1 is selected from hydrogen or hydroxyl;

[0012] R2 and R3 are selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C5 haloalkyl, alkoxy, nitro, nitrile, sulfonic acid, carboxyl, trifluoromethyl, hydroxy, and halogen; R2 and R3 are preferably selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C3 haloalkyl, alkoxy, nitro, nitrile, sulfonic acid, carboxyl, trifluoromethyl, hydroxy, and halogen; or, R2 and R3 form a benzene ring;

[0013] (1) Compound A, initiator azobisisobutyronitrile and catalyst are added to an organic solvent, and oxygen is introduced to react and a precipitate is obtained;

[0014] (2) After separating, washing and drying the precipitate, compound B or C is obtained.

[0015] The catalyst is selected from copper sulfate, sodium carbonate, potassium chloride, magnesium sulfate, sodium sulfate, sodium chloride, calcium carbonate, sodium carbonate, copper sulfate, and potassium chloride.

[0016] The organic solvent is selected from tetrahydrofuran, ethyl acetate, diethyl ether, dichloromethane, acetonitrile, and tert-butanol.

[0017] This invention has the following significant advantages:

[0018] (1) Raw materials are readily available and the cost is low.

[0019] Toluene is used as a starting material. It is a common bulk chemical product with wide availability, stable price, and easy large-scale procurement and storage.

[0020] (2) The product has high purity and good yield.

[0021] By precisely controlling the reaction conditions, the obtained p-aminophenol has high purity and excellent yield, which can meet the stringent quality requirements of most industrial applications.

[0022] (3) Green and efficient process

[0023] This method features a simple reaction route, eliminating the need for complex ligands and multi-step post-processing, thus reducing solvent use and waste generation at the source. The product boasts high purity and complete conversion, reducing environmental impact and enhancing market competitiveness. Detailed Implementation

[0024] To better illustrate the embodiments of the present invention, the following will further describe them in conjunction with specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Experimental methods not specifically specified in the examples are generally performed under conventional operating conditions or with reference to the recommended conditions provided by the manufacturers of the reagents and instruments used.

[0025] Example 1

[0026]

[0027] Add 1 mol of toluene, 1000 g of sodium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of ethyl acetate to a round-bottom flask. Then, purge oxygen into the solution and react at approximately 35°C for 12 hours. A small amount of precipitate will appear in the solution, turning it pale yellow (or yellow). After removing the ethyl acetate by rotary evaporation, a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtering and air-drying the solid for a period of time, the product methylhydroquinone is obtained, with a yield of 82%. 1 H NMR (400 MHz, CDCl3) δ 7.75 (s,0H), 7.67 (s, 0H), 6.65 (d, J = 8.6 Hz, 0H), 6.53 (dd, J = 2.2, 0.6 Hz, 0H), 6.52-6.48 (m, 0H), 2.08 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 149.73, 148.37, 124.79, 117.35, 115.37, 113.36, 15.83.

[0028] Example 2

[0029]

[0030] Add 1 mol of 1,2,4-trimethylbenzene, 1000 g of potassium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of dichloromethane to a round-bottom flask. Then, bubble oxygen through the solution and react at approximately 35°C for 12 hours. A small amount of precipitate will appear, and the solution will turn pale yellow (or yellow). Rotary evaporation will remove the dichloromethane, and a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of dichloromethane to obtain a relatively pure product. After filtration for a period of time and air-drying the solid, trimethylhydroquinone is obtained in 75% yield. 1 H NMR (400 MHz, CDCl3)δ 6.39 (d, J = 0.8 Hz, 1H), 6.03 (s, 1H), 5.68 (s, 1H), 2.13-22.07 (m, 9H). 13 C NMR (100 MHz, CDCl3) δ 148.13, 145.72, 124.69, 122.31, 121.00, 113.98,16.75, 12.73, 12.09.

[0031] Example 3

[0032]

[0033] Add 1 mol of ethylbenzene, 1000 g of calcium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of diethyl ether to a round-bottom flask. Then, purify the solution with oxygen and react at approximately 35°C for 12 hours. A small amount of precipitate will appear, and the solution will turn pale yellow (or yellow). After removing the ether by rotary evaporation, a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration and air-drying the solid for a period of time, the product 2-ethylhydroquinone is obtained, with a yield of 78%. 1 H NMR (400 MHz, CDCl3) δ 8.26 (s,1H), 7.08 (s, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.58 (dt, J = 2.0, 0.9 Hz, 1H), 6.54 (dd, J = 9.0, 2.3 Hz, 1H), 2.61 (qd, J = 7.2, 1.1 Hz, 2H), 1.21 (t, J =7.2 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 150.31, 149.67, 130.30, 115.83, 115.39, 115.30, 23.12, 14.49.

[0034] Example 4

[0035]

[0036] Add 1 mol of p-xylene, 1000 g of sodium chloride, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of acetonitrile to a round-bottom flask. Then, purge oxygen into the solution and react at approximately 30°C for 12 hours. A small amount of precipitate will appear in the solution, turning it pale yellow (or yellow). After removing the acetonitrile by rotary evaporation, a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration and air-drying the solid for a period of time, the product 2,5-dimethylhydroquinone is obtained, with a yield of 65%. 1 H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H), 6.41 (s, 1H), 2.18 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 147.79, 121.47, 116.91, 15.82.

[0037] Example 5

[0038]

[0039] Add 1 mol of m-xylene, 1000 g of copper sulfate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of ethyl acetate to a round-bottom flask. Then, purge oxygen into the solution and react at approximately 25°C for 12 hours. A small amount of precipitate will appear in the solution, turning it pale yellow (or yellow). After rotary evaporation to remove the ethyl acetate, a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration and air-drying the solid for a period of time, the product 2,6-dimethylhydroquinone is obtained, with a yield of 72%. 1 H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 6.48 (s, 1H), 6.42 (s, 2H), 2.06 (s, 7H). 13 C NMR (100MHz, CDCl3) δ 149.84, 145.83, 125.53, 115.15, 16.58.

[0040] Example 6

[0041]

[0042] Add 1 mol of tert-butylbenzene, 1000 g of potassium chloride, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of N,N-dimethylformamide to a round-bottom flask. Then, purge oxygen into the solution and react at approximately 35°C for 12 hours. A small amount of precipitate will appear, and the solution will turn pale yellow (or yellow). After removing the N,N-dimethylformamide by rotary evaporation, a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration for a period of time and air drying, the product tert-butylhydroquinone is obtained, with a yield of 67%. 1 H NMR(400 MHz, CDCl3) δ 7.93 (s, 1H), 7.81 (s, 1H), 6.71 (d, J = 8.6 Hz, 1H), 6.69(d, J = 2.2 Hz, 1H), 6.54 (dd, J = 8.6, 2.2 Hz, 1H), 1.39 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 149.44, 148.72, 138.67, 116.92, 116.01, 114.36, 34.57, 29.82.

[0043] Example 7

[0044]

[0045] 1 mol of 1,4-di-tert-butylbenzene, 1000 g of sodium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of methanol were added to a round-bottom flask. Oxygen was then bubbled through the solution, and the reaction was carried out at approximately 25°C for 12 hours. A small amount of precipitate appeared in the solution, turning it pale yellow (or yellow). After removing the methanol by rotary evaporation, a large amount of precipitate was observed. Distillation was then stopped, and the solid was obtained by suction filtration. The solid was washed three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration and air-drying the solid, the product 2,5-di-tert-butylhydroquinone was obtained, with a yield of 80%. 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 6.70 (s, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ148.09, 134.30, 115.20, 34.10, 29.49.

[0046] Example 8

[0047]

[0048] Add 1 mol of chlorobenzene, 1000 g of sodium sulfate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of tert-butanol to a round-bottom flask. Then, purge oxygen into the solution and react at approximately 30°C for 12 hours. A small amount of precipitate will appear in the solution, turning it pale yellow (or yellow). After removing the tert-butanol by rotary evaporation, a large amount of precipitate will be observed. At this point, stop distillation, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtering and air-drying the solid for a period of time, the product chlorohydroquinone is obtained, with a yield of 75%. 1 H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.75 (d, J = 9.1 Hz, 1H), 6.62 (dd, J = 9.1, 2.2Hz, 1H), 6.21 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 150.70, 145.69, 120.25, 117.39, 117.25, 115.27.

[0049] Example 9

[0050]

[0051] In a round-bottom flask, add 1 mol of toluene, 1000 g of magnesium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of dichloromethane. Then, bubble oxygen through the solution and react at approximately 35°C for 12 hours. A small amount of precipitate will appear, and the solution will turn pale yellow (or yellow). After rotary evaporation to remove the dichloromethane, a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration for a period of time and air-drying the solid, the product methylbenzoquinone is obtained, with a yield of 68%. 1H NMR (400 MHz, CDCl3) δ 6.78 (d,J = 9.3 Hz, 1H), 6.71 (dd, J = 9.2, 2.2 Hz, 1H), 6.63 (d, J = 2.1 Hz, 1H), 2.54 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 189.14, 187.43, 145.90, 136.73, 134.75, 133.09, 16.00.

[0052] Example 10

[0053]

[0054] 1 mol of methylbenzoquinone, 1000 g of copper chloride, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of diethyl ether were added to a round-bottom flask. Oxygen was then bubbled through the solution, and the reaction was carried out at approximately 35°C for 12 hours. A small amount of precipitate appeared in the solution, turning it pale yellow (or yellow). After removing the ether by rotary evaporation, a large amount of precipitate was observed. Distillation was then stopped, and the solid was obtained by suction filtration. The solid was washed three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration for a period of time and air-drying, the product, methylbenzoquinone, was obtained with a yield of 62%. 1 H NMR (400 MHz, CDCl3) δ 9.25 (s,0H), 8.65 (s, 0H), 8.10 - 8.07 (m, 0H), 8.05 (dd, J = 7.9, 1.5 Hz, 0H), 7.48(td, J = 7.7, 1.5 Hz, 0H), 7.42 (td, J = 7.8, 1.5 Hz, 0H), 6.76 (d, J = 0.8Hz, 0H), 2.17 (d, J = 0.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 149.09, 147.69, 129.79, 126.96, 124.38, 123.91, 123.02 -122.87 (m), 112.09, 16.53.

[0055] Example 11

[0056]

[0057] In a round-bottom flask, 1 mol of 2,3,5-trimethylphenol, 1000 g of potassium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of tetrahydrofuran were added. Oxygen was then bubbled through the solution, and the reaction was carried out at approximately 30°C for 12 hours. A small amount of precipitate appeared, and the solution turned pale yellow (or yellow). After removing the tetrahydrofuran by rotary evaporation, a large amount of precipitate was observed. Distillation was then stopped, and the solid was obtained by suction filtration. The solid was washed three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration for a period of time and air-drying, the product 2,3,5-trimethylbenzoquinone was obtained, with a yield of 73%. 1 H NMR (400MHz, CDCl3) δ 6.56 (s, 1H), 2.19 (d, J = 0.6 Hz, 4H), 2.16 (q, J = 1.0 Hz, 4H), 2.11 (q, J = 1.0 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 187.94, 187.51, 145.42, 142.08, 138.93, 136.53, 15.86, 13.14, 12.47.

[0058] Example 12

[0059]

[0060] Add 1 mol of p-xylene, 1000 g of calcium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of acetonitrile to a round-bottom flask. Then, purge oxygen into the solution and react at approximately 35°C for 12 hours. A small amount of precipitate will appear in the solution, turning it pale yellow (or yellow). After removing the acetonitrile by rotary evaporation, a large amount of precipitate will be observed. Stop distillation at this point, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration and air-drying the solid for a period of time, the product 2,5-dimethyl-p-benzoquinone is obtained, with a yield of 78%. 1 H NMR (400 MHz, CDCl3) δ 6.61 (d, J = 0.7 Hz, 1H), 2.05 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 188.16, 146.54, 133.76, 15.69.

[0061] Example 13

[0062]

[0063] Add 1 mol of m-xylene, 1000 g of sodium chloride, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of dichloromethane to a round-bottom flask. Then, purge oxygen into the solution and react at approximately 35°C for 12 hours. Subsequently, a small amount of precipitate appears in the solution, and the solution turns pale yellow (or yellow). After removing the dichloromethane by rotary evaporation, a large amount of precipitate is observed. At this point, stop the distillation, filter to obtain a solid, and wash the solid three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtering and air-drying the solid for a period of time, the product 2,6-dimethylbenzoquinone is obtained, with a yield of 76%. 1 H NMR (400 MHz, CDCl3) δ 6.61 (s, 1H), 2.17 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 188.25, 187.67, 145.40, 134.07, 15.89.

[0064] Example 14

[0065]

[0066] In a round-bottom flask, 1 mol of p-tert-butyltoluene, 1000 g of sodium carbonate, 15 g of AIBN (azobisisobutyronitrile), and 0.5 L of ethyl acetate were added. Oxygen was then bubbled through the solution, and the reaction was carried out at approximately 30°C for 12 hours. A small amount of precipitate appeared in the solution, turning it pale yellow (or yellow). After rotary evaporation to remove the ethyl acetate, a large amount of precipitate was observed. Distillation was then stopped, and the solid was obtained by suction filtration. The solid was washed three times with 100 mL of ethyl acetate to obtain a relatively pure product. After filtration and air-drying, the product 2-isopropyl-5-methyl-1,4-benzoquinone was obtained, with a yield of 80%. 1 H NMR(400 MHz, CDCl3) δ 6.60 (d, J = 0.7 Hz, 1H), 6.55 (d, J = 0.6 Hz, 1H), 3.04(heptd, J = 6.7, 0.6 Hz, 1H), 2.05 (s, 3H), 1.22 (d, J = 6.6 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 188.15, 186.94, 153.00, 145.73, 133.82, 130.34, 27.27, 21.51, 15.44.

[0067] Example 15

[0068] Similar to the synthesis methods in Examples 1-14 above, the target compounds can still be synthesized by changing the substrate, catalyst and organic solvent type (R1, R2 and R3 are selected from hydrogen, as shown in Table 1).

[0069]

[0070] Within the scope of this invention, the above-described technical features and the technical features specifically described in the embodiments can be combined with each other to form new or preferred technical solutions. Furthermore, any feature disclosed in the specification can be replaced by an alternative feature capable of achieving the same, equivalent, or similar function.

Claims

1. A method for synthesizing a hydroquinone compound, characterized in that... Includes the following steps: ； R is selected from C1~C10 alkyl, C1~C10 alkoxy, C1~C5 haloalkyl, alkoxy, nitro, nitrile, sulfonic acid, carboxyl, trifluoromethyl, hydroxy, halogen. R1 is selected from hydrogen or hydroxyl; R2 and R3 are selected from hydrogen, C1-C10 alkyl, C1-C10 alkoxy, C1-C5 haloalkyl, alkoxy, nitro, nitrile, sulfonic acid, carboxyl, trifluoromethyl, hydroxy, halogen; or, R2 and R3 form a benzene ring. (1) Compound A, initiator azobisisobutyronitrile and catalyst are added to an organic solvent, and oxygen is introduced to react and a precipitate is obtained; (2) After separating, washing and drying the precipitate, compound B or C is obtained.

2. The method for synthesizing hydroquinone compounds according to claim 1, characterized in that: R is selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C3 haloalkyl, alkoxy, nitro, nitrile, sulfonic acid, carboxyl, trifluoromethyl, hydroxy, and halogen.

3. The method for synthesizing hydroquinone compounds according to claim 1, characterized in that: R2 and R3 are selected from hydrogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C3 haloalkyl, alkoxy, nitro, nitrile, sulfonic acid, carboxyl, trifluoromethyl, hydroxy, and halogen.

4. The method for synthesizing hydroquinone compounds according to claim 1, characterized in that: The catalyst is selected from copper sulfate, sodium carbonate, potassium chloride, magnesium sulfate, sodium sulfate, sodium chloride, calcium carbonate, sodium carbonate, copper sulfate, and potassium chloride.

5. The method for synthesizing hydroquinone compounds according to claim 1, characterized in that: The organic solvent is selected from tetrahydrofuran, ethyl acetate, diethyl ether, dichloromethane, acetonitrile, and tert-butanol.

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