CN115772105B - Synthesis method of 4-nitroanisole - Google Patents

Abstract

The present invention provides a method for synthesizing 4-nitrothioanisole. Using p-nitrochlorobenzene, potassium fluoride and dimethyl sulfoxide as raw materials, under the action of a catalyst, 4-nitrothioanisole is reacted. All raw materials of the 4-nitrothioanisole synthesis process of the present invention are widely available and inexpensive, the reaction conditions are mild, the process is relatively simple, each step of the reaction is a conventional operation, and the product yield is high. The method meets the basic requirements for the industrial production of 4-nitrothioanisole.

Description

A kind of synthetic method of 4-nitrothioanisole

Technical Field

The invention belongs to the technical field of fine chemicals, and particularly relates to a method for synthesizing 4-nitrothioanisole by reacting p-nitrochlorobenzene and potassium fluoride as raw materials in dimethyl sulfoxide.

Background technique

4-Nitrothioanisole, also known as p-methylthionitrobenzene and p-nitrotoluene thioether, is a light yellow to brown solid at room temperature and is easily soluble in organic solvents such as ethyl acetate. Its structural formula is shown in Formula S-1. 4-Nitrothioanisole has a wide range of uses and is a commonly used intermediate in fine chemicals such as medicine, pesticides, and veterinary drugs. For example, 4-nitrothioanisole is hydrogenated to produce 4-aminothioanisole, which is one of the important raw materials for the non-steroidal drug esalidonate (patent CN 114456098).

The literature (Journal of Fluorine Chemistry, 245, 109778; 2021) reported that 4-nitroanisole was prepared by the reaction of p-nitrofluorobenzene with dimethyl disulfide; the literature (Tetrahedron Letters, 56(37), 5199-5202; 2015) reported that 4-nitroanisole was prepared by the reaction of p-nitroiodobenzene or p-nitrobromobenzene with dimethyl sulfoxide under the catalysis of cuprous iodide/triethylenediamine; the literature (Tetrahedron Letters, 56(38), 5323-5326; 2014) reported that 4-nitroanisole was prepared by the reaction of p-nitrofluorobenzene or p-nitrochlorobenzene or p-dinitrobenzene with dimethyl sulfoxide under the catalysis of N,N-diisopropylethylamine, wherein the yield of the target product in the reaction with p-nitrochlorobenzene as the substrate was only 49%. In this synthetic route, the raw materials nitrobenzene derivatives (p-fluoronitrobenzene, p-bromonitrobenzene, p-iodinitrobenzene and p-dinitrobenzene) and catalysts used are expensive, the cost is high, or the product yield is very low (such as using p-chloronitrobenzene as a substrate). The literature (Phosphorus, Sulfur and Silicon and the Related Elements, 190 (7), 1169-1176; 2015) uses 1-methylsulfonyl 4-nitrobenzene to synthesize 4-nitrothioanisole, and the raw materials used are expensive and not suitable for industrial production. The literature also reports other methods for preparing 4-nitrothioanisole by reacting p-nitroiodobenzene, p-nitrobromobenzene or p-nitrochlorobenzene with dimethyl sulfoxide. In this type of synthetic route, p-nitroiodobenzene or p-nitrobromobenzene is expensive and the cost is high, so it is not suitable for industrial production; when p-nitrochlorobenzene is used as a raw material, the yield is low and the reaction time is long, which is also not conducive to its industrial production.

In summary, the current synthesis schemes of 4-nitrothioanisole all have certain defects and shortcomings. Therefore, developing a synthesis process with high yield, low cost and simple process is of great significance for the industrial production of 4-nitrothioanisole.

Summary of the invention

The technical problem to be solved by the present invention is to provide a new method for synthesizing 4-nitrothioanisole.

The technical solution of the present invention is:

A method for synthesizing 4-nitrothioanisole comprises the following steps: using p-nitrochlorobenzene, potassium fluoride and dimethyl sulfoxide as raw materials, reacting in the presence of a catalyst to generate 4-nitrothioanisole.

Preferably, in terms of mass ratio, the ratio of nitrochlorobenzene, potassium fluoride and dimethyl sulfoxide is 10-15 parts of potassium fluoride: 10-20 parts of p-nitrochlorobenzene: 30-100 parts of dimethyl sulfoxide.

Preferably, the reaction temperature is 185-220° C., and the reaction time is 12 to 15 hours.

Preferably, the catalyst is tetramethylammonium chloride or polyethylene glycol 2000.

Preferably, the catalyst is used in an amount of 1-30 parts.

Another technical solution of the present invention is:

A method for synthesizing 4-nitrothioanisole comprises the following steps:

10-15 parts of potassium fluoride, 10-20 parts of p-nitrochlorobenzene, 1-30 parts of catalyst and 30-100 parts of dimethyl sulfoxide are added into a reactor for reaction at a temperature of 185-220° C. for 12-15 hours to generate the target product 4-nitrothioanisole.

Preferably, after the target product 4-nitrothioanisole is generated, the process further includes a product extraction step and a purification step.

Preferably, the product extraction step comprises:

After the reaction is completed, the remaining dimethyl sulfoxide in the reaction solution is evaporated under reduced pressure, and then appropriate amounts of water and ethyl acetate are added thereto for washing and extraction, and the ethyl acetate in the obtained organic phase is removed to obtain a crude 4-nitrothioanisole product;

Preferably, the purification step is to purify the obtained crude 4-nitrothioanisole product to obtain the product 4-nitrothioanisole.

Preferably, the purification method is recrystallization or distillation.

In the present invention, in a dimethyl sulfoxide solvent, under the catalysis of a catalyst, p-nitrochlorobenzene and potassium fluoride react to generate a fluorine-containing intermediate (the intermediate does not need to be separated), and the intermediate further reacts with dimethyl sulfoxide to obtain the target product 4-nitrothioanisole. The reaction equation is shown in S-2.

The synthetic product of the present invention can be analyzed by NMR.

Compared with the prior art, the present invention has the following beneficial effects:

The method of the present invention is used to prepare 4-nitrothioanisole. With p-nitrochlorobenzene and potassium fluoride as main raw materials and dimethyl sulfoxide as a thiomethylation reagent and solvent, 4-nitrothioanisole can be obtained with a high yield under mild reaction conditions. The process has low raw material cost, simple reaction and post-processing processes, and the yield of the target product is close to 90% under better process conditions. Compared with the prior art, the present invention has the advantages of low raw material cost, convenient operation, high yield, simple post-processing process, etc., and is an efficient and low-cost method for preparing 4-nitrothioanisole sulfide.

BRIEF DESCRIPTION OF THE DRAWINGS

The specific embodiments of the present invention are further described in detail below with reference to the accompanying drawings.

FIG1 is a hydrogen nuclear magnetic spectrum of 4-nitrothioanisole of Example 3 of the present invention.

FIG. 2 is a carbon NMR spectrum of 4-nitrothioanisole of Example 3 of the present invention.

Detailed ways

The invention discloses a method for synthesizing 4-nitrothioanisole, which comprises the following steps: taking p-nitrochlorobenzene, potassium fluoride and dimethyl sulfoxide as raw materials, and reacting in the presence of a catalyst to generate 4-nitrothioanisole.

Preferably, in terms of mass ratio, the ratio of nitrochlorobenzene, potassium fluoride and dimethyl sulfoxide is 10-15 parts of potassium fluoride: 10-20 parts of p-nitrochlorobenzene: 30-100 parts of dimethyl sulfoxide.

Example 1

(1) Weigh 1.0 g of potassium fluoride, 1.2 g of p-nitrochlorobenzene, 0.18 g of tetramethylammonium chloride, and 5.5 g of dimethyl sulfoxide in a heatable pressure-resistant reactor, heat to 220° C. in an oil bath, and stir to react for 15 hours;

(2) After the reaction was completed and the temperature was lowered, the remaining dimethyl sulfoxide in the reaction solution was evaporated under reduced pressure, and then 50 ml of water and 15 ml of ethyl acetate were added thereto for washing and extraction. The obtained aqueous phase was extracted twice with ethyl acetate (15 ml of ethyl acetate was used each time), and the solvent ethyl acetate in the obtained organic phase was removed to obtain 1.3 g of crude 4-nitrothioanisole. After further purification, 1.15 g of product 4-nitrothioanisole was obtained, with a yield of 89.2%;

The reactants are extracted and rotary evaporated to remove ethyl acetate and cooled to room temperature to obtain a colloidal mixture, which can be further purified by distillation or recrystallization.

Example 2

(1) Weigh 1.0 g of potassium fluoride, 1.2 g of p-nitrochlorobenzene, 0.18 g of tetramethylammonium chloride, and 5.5 g of dimethyl sulfoxide in a heatable pressure-resistant reactor, heat to 220° C. in an oil bath, and stir to react for 12 hours;

(2) After the reaction was completed and the temperature was lowered, the remaining dimethyl sulfoxide in the reaction solution was evaporated under reduced pressure, and then 50 ml of water and 15 ml of ethyl acetate were added thereto for washing and extraction. The obtained aqueous phase was extracted twice with ethyl acetate (15 ml of ethyl acetate was used each time), and the solvent ethyl acetate in the obtained organic phase was removed to obtain 1.3 g of crude 4-nitrothioanisole. After further purification, 1.06 g of product 4-nitrothioanisole was obtained, with a yield of 82.2%;

The reactants are extracted and rotary evaporated to remove ethyl acetate and cooled to room temperature to obtain a colloidal mixture, which can be further purified by distillation or recrystallization.

Example 3

(1) Weigh 0.9 g potassium fluoride, 1.2 g p-nitrochlorobenzene, 0.17 g tetramethylammonium chloride, and 5.5 g dimethyl sulfoxide in a heatable pressure-resistant reactor, heat to 220° C. in an oil bath, and stir to react for 12 hours;

(2) After the reaction was completed and the temperature was lowered, the remaining dimethyl sulfoxide in the reaction solution was distilled off under reduced pressure, and then 50 ml of water and 15 ml of ethyl acetate were added thereto for washing and extraction. The obtained aqueous phase was extracted twice with ethyl acetate (15 ml of ethyl acetate was used each time), and the solvent ethyl acetate in the obtained organic phase was removed to obtain 1.3 g of crude 4-nitrothioanisole. After further purification, 1.07 g of product 4-nitrothioanisole was obtained, with a yield of 83.0%;

The reactants are extracted and rotary evaporated to remove ethyl acetate and cooled to room temperature to obtain a colloidal mixture, which can be further purified by distillation or recrystallization.

Example 4

(1) Weigh 1.0 g of potassium fluoride, 1.2 g of p-nitrochlorobenzene, 0.18 g of tetramethylammonium chloride, and 5.5 g of dimethyl sulfoxide in a heatable pressure-resistant reactor, heat to 185° C. in an oil bath, and stir to react for 12 hours;

(2) After the reaction was completed and the temperature was lowered, the remaining dimethyl sulfoxide in the reaction solution was distilled off under reduced pressure, and then 50 ml of water and 15 ml of ethyl acetate were added thereto for washing and extraction. The obtained aqueous phase was extracted twice with ethyl acetate (15 ml of ethyl acetate was used each time), and the solvent ethyl acetate in the obtained organic phase was removed to obtain 1.0 g of crude 4-nitrothioanisole, which was further purified to obtain 0.62 g of product 4-nitrothioanisole, with a yield of 48.0%;

The reactants are extracted and rotary evaporated to remove ethyl acetate and cooled to room temperature to obtain a colloidal mixture, which can be further purified by distillation or recrystallization.

Example 5

(1) Weigh 1.0 g of potassium fluoride, 1.2 g of p-nitrochlorobenzene, 3.2 g of polyethylene glycol 2000, and 5.5 g of dimethyl sulfoxide in a heatable pressure-resistant reactor, heat to 220° C. in an oil bath, and stir to react for 15 hours;

(2) After the reaction was completed and the temperature was lowered, the remaining dimethyl sulfoxide in the reaction solution was evaporated under reduced pressure, and then 50 ml of water and 15 ml of ethyl acetate were added thereto for washing and extraction. The obtained aqueous phase was extracted twice with ethyl acetate (15 ml of ethyl acetate was used each time), and the solvent ethyl acetate in the obtained organic phase was removed to obtain 1.2 g of crude 4-nitrothioanisole, which was further purified to obtain 0.96 g of product 4-nitrothioanisole, with a yield of 74.5%;

The reactants are extracted and rotary evaporated to remove ethyl acetate and cooled to room temperature to obtain a colloidal mixture, which can be further purified by distillation or recrystallization.

Example 6

(1) Weigh 1.0 g of potassium fluoride, 1.2 g of p-nitrochlorobenzene, 3.2 g of polyethylene glycol 2000, and 5.5 g of dimethyl sulfoxide in a heatable pressure-resistant reactor, heat to 220° C. in an oil bath, and stir to react for 12 hours;

(2) After the reaction was completed and the temperature was lowered, the remaining dimethyl sulfoxide in the reaction solution was evaporated under reduced pressure, and then 50 ml of water and 15 ml of ethyl acetate were added thereto for washing and extraction. The obtained aqueous phase was extracted twice with ethyl acetate (15 ml of ethyl acetate was used each time), and the solvent ethyl acetate in the obtained organic phase was removed to obtain 1.2 g of crude 4-nitrothioanisole, which was further purified to obtain 0.87 g of product 4-nitrothioanisole, with a yield of 67.5%;

The reactants are extracted and rotary evaporated to remove ethyl acetate and cooled to room temperature to obtain a colloidal mixture, which can be further purified by distillation or recrystallization.

Example 7

(1) Weigh 0.8 g potassium fluoride, 1.2 g p-nitrochlorobenzene, 0.6 g polyethylene glycol 2000, and 5.5 g dimethyl sulfoxide in a heatable pressure-resistant reactor, heat to 220° C. in an oil bath, and stir to react for 12 hours;

(2) After the reaction was completed and the temperature was lowered, the remaining dimethyl sulfoxide in the reaction solution was distilled off under reduced pressure, and then 50 ml of water and 15 ml of ethyl acetate were added thereto for washing and extraction. The obtained aqueous phase was extracted twice with ethyl acetate (15 ml of ethyl acetate was used each time), and the solvent ethyl acetate in the obtained organic phase was removed to obtain 1.2 g of crude 4-nitrothioanisole, which was further purified to obtain 0.89 g of product 4-nitrothioanisole, with a yield of 69.0%;

The reactants are extracted and rotary evaporated to remove ethyl acetate and cooled to room temperature to obtain a colloidal mixture, which can be further purified by distillation or recrystallization.

The above are only some specific examples of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by a person skilled in the art should be considered as the protection scope of the present invention.

Claims (8)

1. A synthetic method of 4-nitroanisole comprises the following steps: using paranitrochlorobenzene, potassium fluoride and dimethyl sulfoxide as raw materials, and reacting under the action of a catalyst to generate 4-nitroanisole; the catalyst is tetramethyl ammonium chloride or polyethylene glycol 2000.

2. The method for synthesizing 4-nitroanisole as claimed in claim 1, wherein the proportion of nitrochlorobenzene, potassium fluoride and dimethyl sulfoxide is 10-15 parts by mass: 10-20 parts of p-nitrochlorobenzene: 30-100 parts of dimethyl sulfoxide.

3. The method for synthesizing 4-nitroanisole as claimed in claim 1, wherein the reaction temperature is 185-220 ℃ and the reaction time is 12-15 h.

4. A synthetic method of 4-nitroanisole comprises the following steps:

10-15 parts of potassium fluoride, 10-20 parts of paranitrochlorobenzene, 1-30 parts of catalyst and 30-100 parts of dimethyl sulfoxide are added into a reactor for reaction, the reaction temperature is 185-220 ℃, and the reaction time is 12-15 h to generate the target product 4-nitroanisole; the catalyst is tetramethyl ammonium chloride or polyethylene glycol 2000.

5. The method for synthesizing 4-nitroanisole as defined in claim 4, wherein: after the target product 4-nitroanisole is generated, the method also comprises a product extraction step and a purification step.

6. The method for synthesizing 4-nitroanisole as defined in claim 5, wherein: the product extraction step comprises the following steps:

And after the reaction is finished, decompressing and steaming to remove the residual dimethyl sulfoxide in the reaction liquid, adding a proper amount of water and ethyl acetate into the reaction liquid for washing and extraction, and removing the ethyl acetate in the obtained organic phase to obtain a crude product of the 4-nitroanisole sulfide.

7. The method for synthesizing 4-nitroanisole as defined in claim 6, wherein: the purification step is to purify the obtained crude 4-nitroanisole product to obtain the product 4-nitroanisole.

8. The method for synthesizing 4-nitroanisole as defined in claim 5, wherein: the purification step is carried out by adopting recrystallization or rectification.