Method for the synthesis of 3,4-dimethyl-6-nitrophenol

Abstract

The application discloses a synthesis method of 3,4-dimethyl-6-nitrophenol, which comprises the following steps: S1, 3,4-dimethylphenol and silica gel are added into an organic solvent, after the 3,4-dimethylphenol is dissolved, heating and concentration are carried out at 50-80 DEG C, until the organic solvent is evaporated, and the silica gel containing 3,4-dimethylphenol is obtained; S2, cerium ammonium nitrate and silica gel are added into an organic solvent, after the cerium ammonium nitrate is dissolved, heating and concentration are carried out at 50-80 DEG C, until the organic solvent is evaporated, and the silica gel containing cerium ammonium nitrate is obtained; S3, a silica gel column is taken, the silica gel containing 3,4-dimethylphenol and the silica gel containing cerium ammonium nitrate are added into the silica gel column, and then mixed solvents are used for column pressing; yellow oil is obtained after concentration; S4, the yellow oil is passed through a silica gel column, elution is carried out by using an eluent, and after concentration, the product 3,4-dimethyl-6-nitrophenol is obtained. The synthesis method of 3,4-dimethyl-6-nitrophenol improves the reaction yield, reduces the cost, and is green and environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a synthesis method of 3,4-dimethyl-6-nitrophenol. BACKGROUND

[0002] 3,4-dimethyl-6-nitrophenol is an important intermediate in the synthesis of medicine, and its molecular weight is 167.06, and its structural formula is as follows:

[0003]

[0004] 3,4-dimethyl-6-nitrophenol can be prepared by nitration process from 3,4-dimethylphenol, for example, 3,4-dimethylphenol can be sulfonated first, then nitrated, and finally hydrolyzed to obtain 3,4-dimethyl-6-nitrophenol. However, the current nitration process has poor selectivity for the nitration position, resulting in low yield of the target product. SUMMARY

[0005] The purpose of the present application is to provide a new synthesis method of 3,4-dimethyl-6-nitrophenol, which solves the defect of poor selectivity of nitration position in the existing synthesis method, improves the yield of the reaction, reduces the cost, and the synthesis method is green and environmental protection.

[0006] Specifically, the present application provides the following technical scheme:

[0007] The present application provides a synthesis method of 3,4-dimethyl-6-nitrophenol, comprising the following steps:

[0008] S1. 3,4-dimethylphenol and silica gel are added to an organic solvent, and after 3,4-dimethylphenol is dissolved, heating and concentration are carried out at 50-80℃ until the organic solvent is evaporated to dryness to obtain silica gel containing 3,4-dimethylphenol;

[0009] S2. Ammonium ceric nitrate and silica gel are added to an organic solvent, and after ammonium ceric nitrate is dissolved, heating and concentration are carried out until the organic solvent is evaporated to dryness to obtain silica gel containing ammonium ceric nitrate;

[0010] S3. A silica gel column is taken, and the silica gel containing 3,4-dimethylphenol and the silica gel containing ammonium ceric nitrate are added to the column, and then mixed solvent is used for column compression; after concentration, yellow oil is obtained;

[0011] S4. The yellow oil is passed through a silica gel column and eluted with eluent, and after concentration, the product 3,4-dimethyl-6-nitrophenol is obtained.

[0012] The reaction chemical equation of the synthesis method of the present application is as follows:

[0013]

[0014] In the above reaction, cerium ammonium nitrate as a nitrating agent can nitrate the aromatic ring compound 3,4-dimethylphenol under certain conditions to obtain the ortho-nitration product 3,4-dimethyl-6-nitrophenol. However, due to the strong oxidizing property of cerium ammonium nitrate, multi-nitration reaction occurs during the reaction to form by-products such as 3,4-dimethyl-2-nitrophenol (Formula I), 3,4-dimethyl-2,6-dinitrophenol (Formula II), etc. This not only reduces the yield of the target product, but also makes it difficult to separate the target product due to the presence of these by-products, and even polymers formed between these by-products are difficult to separate.

[0015]

[0016] To solve this problem, the present application uses silica gel as a carrier to adsorb cerium ammonium nitrate on the silica gel, thereby reducing the oxidizing property of cerium ammonium nitrate and reducing the generation of multi-nitro products. At the same time, 3,4-dimethylphenol is also adsorbed on the silica gel. The silica gel loaded with 3,4-dimethylphenol and cerium ammonium nitrate is added to a silica gel column, and after the column is pressed with a mixed solvent, the synthesis reaction is carried out, so as to control the reaction rate of nitration, improve the selectivity of the nitration position, increase the yield of the target product, and reduce the occurrence of side reactions.

[0017] In a preferred embodiment of the present application, in steps S1 and S2, the organic solvent includes but is not limited to acetonitrile.

[0018] In a preferred embodiment of the present application, in steps S1 and S2, the heating temperature is 50-80℃, for example, it can be 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, etc., and preferably 60℃; the heating time is not limited, and preferably 1h.

[0019] In a preferred embodiment of the present application, in steps S1 and S2, the heating and concentration are carried out in a forced air drying box, so as to timely remove the volatile organic solvent.

[0020] In a preferred embodiment of the present application, in step S1, the mass ratio of 3,4-dimethylphenol to silica gel is 1:1.

[0021] In a preferred embodiment of the present application, in step S2, the mass ratio of cerium ammonium nitrate to silica gel is 1:1.

[0022] In a preferred embodiment of the present application, in step S3, the silica gel containing cerium ammonium nitrate is first added to the silica gel column, and then the silica gel containing 3,4-dimethylphenol is added.

[0023] In a preferred embodiment of the present application, in step S3, the mixed solvent is a mixture of n-hexane and toluene; preferably, the volume ratio of n-hexane to toluene in the mixed solvent is 9:1.

[0024] In a preferred embodiment of the present application, in step S4, the eluent is a mixture of n-hexane and ethyl acetate (EA); further, the volume ratio of n-hexane to ethyl acetate in the eluent is 100:1 to 80:1, for example, can be 100:1, 98:1, 95:1, 92:1, 90:1, 88:1, 85:1, 82:1, 80:1, etc.

[0025] In a preferred embodiment of the present application, in step S4, the yield of the product 3,4-dimethyl-6-nitrophenol reaches more than 79%.

[0026] The present application has the following advantages:

[0027] 1. The present application provides a synthesis method of 3,4-dimethyl-6-nitrophenol, in which cerium ammonium nitrate is adsorbed on silica gel to reduce the oxidizability of cerium ammonium nitrate, thereby reducing the generation of multi-nitro products; at the same time, 3,4-dimethylphenol is also adsorbed on silica gel, and the silica gel loaded 3,4-dimethylphenol and cerium ammonium nitrate are added to a silica gel column, and then the synthesis reaction is carried out after the column is pressed with a mixed solvent, so as to control the reaction rate of nitration, improve the selectivity of nitration position, increase the yield of target product, and reduce the occurrence of side reactions.

[0028] 2. The synthesis method of 3,4-dimethyl-6-nitrophenol provided by the present application has a target product yield of up to 79%, which not only reduces the cost, but also is green and environmentally friendly. BRIEF DESCRIPTION OF DRAWINGS

[0029] The technical solutions and other beneficial effects of the present application will become apparent from the following detailed description of the specific embodiments of the present application, combined with the accompanying drawings.

[0030] Figure 1 Nuclear magnetic resonance spectrum of the product 3,4-dimethyl-6-nitrophenol synthesized in Example 1. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present application will be described clearly and completely in combination with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0032] In the description of the present application, it should be noted that, unless otherwise expressly specified and limited, the term "and / or" herein is merely a description of the association relationship of the associated objects, which means that there can be three relationships, for example, A and / or B can represent the three cases of A existing alone, A and B existing together, and B existing alone. In addition, the character " / " herein generally represents an "or" relationship between the front and rear associated objects without special explanation.

[0033] In the following examples and comparative examples, all the raw materials involved can be purchased.

[0034] Example 1

[0035] This example provides a method for synthesizing 3,4-dimethyl-6-nitrophenol, the specific steps are as follows:

[0036] S1. In a 250 mL single-necked round-bottom flask, 3,4-dimethylphenol (24 g, 196 mmol, 1.0 eq.) and silica gel (24 g) were added, then acetonitrile (40 mL) was added to completely dissolve the 3,4-dimethylphenol in acetonitrile; then the single-necked round-bottom flask was placed in a blast drying oven and heated at 60°C for 1 h, and then concentrated to dryness to obtain silica gel containing 3,4-dimethylphenol.

[0037] S2. In another 250 mL single-necked round-bottom flask, cerium ammonium nitrate (54 g, 99 mmol, 0.5 eq.) and silica gel (54 g) were added, then acetonitrile (80 mL) was added to completely dissolve the cerium ammonium nitrate in acetonitrile; then the single-necked round-bottom flask was placed in a blast drying oven and heated at 60°C for 1 h, and then concentrated to dryness to obtain silica gel containing cerium ammonium nitrate.

[0038] S3. 200 g of silica gel was weighed as a silica gel column, and then silica gel containing cerium ammonium nitrate and silica gel containing 3,4-dimethylphenol were added to the silica gel column, and then mixed solvent (n-hexane:toluene = 9:1, v / v) was quickly pressed through the column, and after concentration, about 30.4 g of yellow oil was obtained; the sample was directly spotted on a plate, and TLC detection showed that the raw materials were completely reacted.

[0039] S4. The above yellow oil was mixed with 30.4 g of silica gel, and then passed through a 250 g silica gel column, and then eluted with eluent (n-hexane:EA = 100:1, v / v) to elute the product, and after concentration, about 26 g of yellow solid was obtained, with a yield of 79%.

[0040] Figure 1 The product was a nuclear magnetic resonance spectrum. As can be seen from the figure, the method of this example successfully synthesized the target product 3,4-dimethyl-6-nitrophenol.

[0041] Comparative Example 1

[0042] The present comparative example provides a synthesis method of 3,4-dimethyl-6-nitrophenol, the specific steps are as follows:

[0043] S1. Under the condition of magnetic stirring, 3,4-dimethylphenol (30.2 g, 247.22 mmol, 1 eq.) and trifluoroacetic acid (300 mL) were added into a 500 mL single-necked round-bottom flask, and the solution was stirred and dissolved at room temperature to obtain a light brown transparent solution, which was cooled in an ice water bath.

[0044] S2. Then NaNO2(30.8 g, 446.38 mmol, 1.8 eq.) was added into the single-necked round-bottom flask in batches, and obvious bubbles were generated, and brown gas was observed to escape from the bottle mouth. It took about 1 h to complete the addition, and a dark brown reaction solution was obtained. The system was naturally warmed to room temperature, and the stirring reaction was carried out for about 19 h. The reaction solution was still dark brown. TLC detection showed that the raw material disappeared.

[0045] S2. The reaction solution was concentrated to remove trifluoroacetic acid, and ether (400 mL) and H2O (500 mL) were added into the obtained crude product, and the organic phase was separated. The organic phase was dried and concentrated to obtain 40 g of dark brown crude product, and 1.1 g of yellow solid was obtained by silica gel column chromatography, with a yield of 2.6%.

[0046] Comparative Example 2

[0047] The present comparative example provides a synthesis method of 3,4-dimethyl-6-nitrophenol, the specific steps are as follows:

[0048] S1. Under the condition of magnetic stirring, 3,4-dimethylphenol (30.2 g, 247.22 mmol, 1 eq.) and dichloromethane (150 ml) were added into a 500 mL single-necked round-bottom flask, and the 3,4-dimethylphenol was dissolved in dichloromethane, and the temperature was lowered to 0°C in an ice water bath.

[0049] S2. Nitric acid (15.6 g, 247.22 mmol, 1 eq.) was added dropwise into the single-necked round-bottom flask, and the temperature was slowly raised to about 20°C after the addition was completed. The reaction was carried out for 2 hours, and TLC detection showed that the raw material disappeared.

[0050] S3. Water was added to the system for extraction, and the organic phase was washed with saturated brine. Then the organic phase was dried and concentrated, and the crude product was mixed and passed through a silica gel column to obtain 6 g of yellow solid product, with a yield of 14.5%.

[0051] From the results of Example 1 and Comparative Examples 1-2, it can be seen that in Comparative Example 1, NaNO2 is used as the nitration reagent, and the reaction time is relatively long (19 h), and the yield is very low, only 2.6%. In Comparative Example 2, nitric acid is used as the nitration reagent, and the yield is also very low, only 14.5%. At the same time, a large amount of strong acid-nitric acid is consumed in the reaction process, and the waste acid is difficult to recover, and a large amount of water is also consumed, which is poor in safety and economy.

[0052] In the embodiment 1, the cerium ammonium nitrate is used as the nitrating agent, compared with NaNO2 and nitric acid, the cerium ammonium nitrate is a green chemical product, high safety and green environmental protection; secondly, by using silica gel as the carrier, the reactants 3,4-dimethylphenol and cerium ammonium nitrate are adsorbed on the silica gel to carry out the reaction, the reaction rate of the nitration can be controlled, the selectivity of the nitration position is higher, the side reaction is less, the yield of the reaction is high, and reaches 79%.

[0053] To sum up, the application provides a new synthesis method of 3,4-dimethyl-6-nitrophenol, the synthesis method not only greatly improves the yield of the reaction (up to 79%), greatly reduces the production cost, and is more economical, and the synthesis method is high in safety and green environmental protection.

[0054] To sum up, although the application has been disclosed as above with preferred embodiments, the above preferred embodiments are not used to limit the application, and those skilled in the art can make various changes and decorations without departing from the spirit and scope of the application, therefore the protection scope of the application is subject to the range defined by the claims.

Claims

1. A process for the synthesis of 3,4-dimethyl-6-nitrophenol, characterized in that, The method comprises the following steps: S1. Adding 3,4-dimethylphenol and silica gel into an organic solvent, and heating and concentrating at 50-80℃ until the organic solvent is evaporated to dryness to obtain silica gel containing 3,4-dimethylphenol; S2. Adding cerium ammonium nitrate and silica gel into an organic solvent, and heating and concentrating until the organic solvent is evaporated to dryness to obtain silica gel containing cerium ammonium nitrate; S3. Adding the silica gel containing 3,4-dimethylphenol and the silica gel containing cerium ammonium nitrate into a silica gel column, and then performing column compression with a mixed solvent; and obtaining yellow oil after concentration; S4. Passing the yellow oil through a silica gel column and eluting with an eluent, and obtaining the product 3,4-dimethyl-6-nitrophenol after concentration; In step S3, the silica gel containing cerium ammonium nitrate is added into the silica gel column first, and then the silica gel containing 3,4-dimethylphenol is added; the mixed solvent is a mixed solvent composed of n-hexane and toluene; and / or the volume ratio of n-hexane to toluene in the mixed solvent is 9:

1.

2. The method of claim 1, wherein the 3,4-dimethyl-6-nitrophenol is synthesized by the reaction of 3,4-dimethylphenol with nitric acid in the presence of a catalyst. In steps S1 and S2, the organic solvent is acetonitrile.

3. The method of claim 1, wherein the 3,4-dimethyl-6-nitrophenol is synthesized by the reaction of 3,4-dimethylphenol with nitric acid in the presence of a catalyst. In steps S1 and S2, the heating and concentrating is performed at 60℃ for 1h; and / or The heating and concentrating is performed in a blast drying oven.

4. The method of claim 1, wherein the 3,4-dimethyl-6-nitrophenol is synthesized by the reaction of 3,4-dimethylphenol with nitric acid in the presence of a catalyst. In step S1, the mass ratio of 3,4-dimethylphenol to silica gel is 1:

1.

5. The method of claim 1, wherein the 3,4-dimethyl-6-nitrophenol is synthesized by the reaction of 3,4-dimethylphenol with nitronium tetrafluoroborate in the presence of a solvent. In step S2, the mass ratio of cerium ammonium nitrate to silica gel is 1:

1.

6. The method of claim 1, wherein the 3,4-dimethyl-6-nitrophenol is synthesized by the reaction of 3,4-dimethylphenol with nitronium tetrafluoroborate in the presence of a solvent. In step S4, the eluent is a mixture of n-hexane and ethyl acetate; and / or In the eluent, the volume ratio of n-hexane to ethyl acetate is 100:1-80:

1.

7. The method of claim 1, wherein the 3,4-dimethyl-6-nitrophenol is synthesized by the reaction of 3,4-dimethylphenol with nitronium tetrafluoroborate in the presence of a solvent. In step S4, the yield of the product 3,4-dimethyl-6-nitrophenol reaches more than 79%.

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