Synthetic method of aromatic intermediate 1-bromo-2-methoxy-4-methyl-5-nitrobenzene

Abstract

The invention discloses a synthesis method of an aromatic intermediate, namely 1-bromo-2-methoxy-4-methyl-5-nitrobenzene. The synthesis method comprises the following steps: adding a catalyst into a reaction kettle; the method comprises the following steps: by taking o-toluidine as an initial raw material, acetylating and fluorinating, removing acetyl, reacting with sodium methoxide to obtain 4-methoxy-2-methylaniline, oxidizing amino into nitryl by using 30% hydrogen peroxide, and finally catalyzing by using methanesulfonic acid-thianthrene as a catalyst to obtain the 1-bromo-2-methoxy-4-methyl-5-nitrobenzene. The method for synthesizing the 1-bromo-2-methoxy-4-methyl-5-nitrobenzene, provided by the invention, is novel and has simple steps. The method is simple, mild, low in cost, high in product purity and stable in yield.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemicals, and in particular to a novel synthesis method of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene. Background Art

[0002] 1-Bromo-2-methoxy-4-methyl-5-nitrobenzene is an important chemical intermediate. The main existing synthesis process uses 5-fluoro-2-nitrotoluene as a raw material, methoxylates it, and then adds a bromine group to obtain the final product (Journal of Organic Chemistry (2009), 74(22), 8844-8847). This process has high raw material prices and the resulting product has low purity, which is not conducive to industrial production. Summary of the Invention

[0003] The present invention aims to provide a new synthesis method of an aromatic intermediate 1-bromo-2-methoxy-4-methyl-5-nitrobenzene.

[0004] The present invention uses o-toluidine as the starting material, acetylates the fluorine group and then removes the acetyl group. The acetyl group is then reacted with sodium methoxide to produce 4-methoxy-2-methylaniline. The amino group is then oxidized to a nitro group using 30% hydrogen peroxide. Finally, methylsulfonic acid-thianthrene is used as a catalyst to produce 1-bromo-2-methoxy-4-methyl-5-nitrobenzene. This method provides a novel, simple method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene.

[0005] The synthetic route of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene is as follows:

[0006] The present invention provides a method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene, which is carried out according to the following steps: (1) The raw material o-toluidine is dissolved in N , N - dimethylformamide (DMF), add acetic anhydride dropwise at a temperature of 50-60°C, keep warm at 60-70°C, detect the completion of the reaction of the raw materials by TLC, then add potassium fluoride in batches at a temperature of 60-80°C, detect the completion of the reaction of the intermediate by TLC, pour the reaction solution into ice water, wash with an aqueous solution of sodium hydrosulfite, filter, beat with methanol and dry to obtain the intermediate N-(4-fluoro-2-methylphenyl)acetamide; (2) The intermediate N-(4-fluoro-2-methylphenyl)acetamide was added in batches to 50% dilute sulfuric acid water at a temperature of 80-90°C, stirred, kept at 90-100°C, and controlled by TLC gas phase. After the reaction, the temperature was lowered, poured into water and stirred, and sodium hydroxide aqueous solution was added to adjust the pH value to alkaline (8-10). The mixture was filtered, slurried with methanol, and dried to obtain the intermediate 2-methyl-4-fluoroaniline; (3) The intermediate 2-methyl-4-fluoroaniline was dissolved in methanol, and liquid sodium methoxide was added dropwise at a temperature of 30-40°C. After the addition was completed, the temperature was raised to reflux with stirring, and the gas phase was controlled at the plate. After the raw materials reacted, the reaction solution was poured into ice water, hydrochloric acid was added to adjust the acidity, and suction was performed. The filter cake was dissolved in dichloroethane, and the solvent was removed by layer drying to obtain the intermediate 2-methyl-4-methoxyaniline; (4) Add the intermediate 2-methyl-4-methoxyaniline to water, add 30% hydrogen peroxide, keep warm at 20-30°C, and perform TLC and gas phase control. After the reaction of the raw materials is completed, cool down, pour out the reaction solution, add ethyl acetate and stir for half an hour, pour out the supernatant, filter with diatomaceous earth and activated carbon, repeat three times, combine the organic phases, dry and desolvate to obtain the intermediate 2-methyl-4-methoxynitrobenzene; (5) The intermediate 2-methyl-4-methoxynitrobenzene was dissolved in dichloroethane, and methanesulfonic acid (MSA) was added dropwise at a temperature of 20-30°C. After the addition was completed, thianthrene (TT) and N-bromosuccinimide (NBS) were added in batches. After the addition was completed, the temperature was kept high, and the gas phase was controlled by a plate. After the reaction was completed, the temperature was lowered and filtered, and the mother liquor was desolvated to obtain 1-bromo-2-methoxy-4-methyl-5-nitrobenzene.

[0007] Wherein, in step (1), the volume of DMF is generally 2.5-3.5 times the mass volume, preferably 3 times the mass volume; the molar ratio of o-toluidine to acetic anhydride and potassium fluoride is 1:1.2:1; In step (2), the volume of dilute sulfuric acid is generally 4-5 times the mass volume, preferably 5 times the mass volume; the insulation temperature is 90-100°C; In step (3), the volume of methanol is generally 2.5-3.5 times the mass volume, preferably 3 times the mass volume; the molar ratio of 2-methyl-4-fluoroaniline to liquid sodium methoxide is 1:3-4, and the reflux temperature is 60-70°C; In step (4), the volume of water is generally 10 times the mass volume, and the molar ratio of 2-methyl-4-methoxyaniline to hydrogen peroxide is 1:1-1:5; preferably 1:1.9-:1:2.

[0008] Wherein, in step (5), the volume of dichloroethane is generally 3 times the mass volume, and the molar ratio of 3-methyl-4-nitroanisole:methanesulfonic acid:thianthrene:N-bromosuccinimide is 1:0.05:0.05:1-1.1; The present invention discloses a novel method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene. The method utilizes the inexpensive raw material o-methylaniline and undergoes five steps, including acetylation, to obtain the target product. This method eliminates the need for precious metal catalysts and requires no special reaction equipment. The method also features simple and mild reaction conditions, low cost, and a high-purity, stable product yield. DETAILED DESCRIPTION

[0009] The present invention is described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0010] Unless otherwise specified, the raw materials and reagents used in the following examples of the present invention can be purchased commercially.

[0011] Example 1

[0012] Step 1. Add o-toluidine (10 g, 0.09 mol) and DMF 30 mL to the reaction flask, start stirring, and after dissolving, add acetic anhydride (11.4 g, 0.11 mol) dropwise at 50-60 degrees. After the addition is complete, stir and heat to 60-70 degrees and continue to react for 2 hours. After the reaction of the raw materials, add potassium fluoride (5.4 g, 0.09 mol) in batches for fluorination, keep warm at 60-80 degrees, and continue to react for 3 hours. After the reaction is completed, cool the reaction solution, pour it into 150 g of water, add 30 mL of hydrosulfite aqueous solution (10% w / v) and stir, filter, and slurry the filter cake with methanol and dry it to obtain 10.3 g of N-(4-fluoro-2-methylphenyl)acetamide with a purity of 98% and a molar yield of 66%, which is directly used for the next step reaction.

[0013] Step 2: Add 50 mL of dilute sulfuric acid aqueous solution (sulfuric acid: water = 1:1, v / v) to the reaction flask, start stirring, add 10 g of N-(4-fluoro-2-methylphenyl)acetamide in batches between 80-90 degrees, stir and heat to 90-100 degrees, continue the reaction for 2 hours, after the reaction is completed, cool, pour the reaction solution into 200 g of water, add 60 mL of sodium hydroxide aqueous solution and stir, adjust the pH value to 8-9, filter, pulp the filter cake with methanol, and dry to obtain 6.2 g of 2-methyl-4-fluoroaniline with a purity of 98% and a molar yield of 82%.

[0014] Step 3. Add 2-methyl-4-fluoroaniline (10 g, 0.08 mol) and 30 mL of methanol to the reaction flask, start stirring, and after dissolving, add liquid sodium methoxide (14.3 g, 0.265 mol) dropwise at 30-40 degrees. After the addition is complete, stir and heat to 60-70 degrees and reflux, continue the reaction for 2 hours. After the reaction is completed, cool the reaction solution, pour it into 100 g of water, add 40 ml of hydrochloric acid to adjust the pH to 2-3, filter, dissolve the filter cake in dichloroethane, dry the layer by layer to remove moisture, and desolvate the organic layer to obtain 9.3 g of 2-methyl-4-methoxyaniline with a purity of 99% and a molar yield of 84.9%, which is directly used in the next step.

[0015] Step 4, 10 g of 2-methyl-4-methoxyaniline and 100 mL of water were added to the reaction flask, stirring was started, the temperature was raised to 30 degrees, 16 g of 30% w / w hydrogen peroxide was added, and the reaction was continued for 2 h after the addition. After the reaction was completed, the temperature was lowered, and the reaction solution was added to 200 mL of ethyl acetate. After stirring at 30-40 degrees for 10 min, the supernatant was poured out, and the mixture was repeated three times. The supernatants were combined, filtered through diatomaceous earth activated carbon, and dried to obtain 8.7 g of 3-methyl-4-nitroanisole with a purity of 98% and a molar yield of 71.3%.

[0016] Step 5. Add 3-methyl-4-nitroanisole (20 g, 0.12 mol) and 60 mL of dichloroethane to the reaction flask, start stirring, add methanesulfonic acid (0.57 g, 0.006 mol) dropwise at a temperature of 20-30 degrees, stir for 10 minutes, add thianthrene (1.292 g, 0.006 mol) and N-bromosuccinimide (23.4 g, 0.131 mol) in batches, and react for 3 hours. After the reaction is completed, cool and filter, rinse the filter cake with 30 ml of dichloroethane, combine the organic layers, dry and desolventize to obtain 22 g of a crude product, which is then purified by flash column chromatography (0-30% ethyl acetate / petroleum ether) to obtain 15 g of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene with a purity of 82% and a molar yield of 50.9%.

[0017] The total molar yield of the entire synthetic route was 16.6%.

[0018] Example 2

[0019] The amount of DMF used in step 1 was 35 mL, the amount of hydrogen peroxide used in step 4 was 20 g, and other conditions were the same as in Example 1. The total molar yield of the entire synthetic route was 22.1%.

[0020] Example 3

[0021] The amount of dilute sulfuric acid used in step 2 was 40 mL, the amount of hydrogen peroxide used in step 4 was 12 g, and other conditions were the same as in Example 1. The total molar yield of the entire synthetic route was 15.1%.

[0022] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene, characterized in that: The following steps are involved: (1) Using o-benzylamine as the starting material, N , N -dimethylformamide as solvent, acetic anhydride as acylating agent, acylation reaction; after the reaction is completed, potassium fluoride is added in batches at a temperature of 60-80°C. After the reaction is completed, the intermediate N-(4-fluoro-2-methylphenyl)acetamide is obtained by post-treatment; (2) Deacetylation of the intermediate N-(4-fluoro-2-methylphenyl)acetamide to obtain the intermediate 2-methyl-4-fluoroaniline; (3) Dissolve the intermediate 2-methyl-4-fluoroaniline in methanol, add sodium methoxide dropwise at 30-40°C, and heat and reflux to react with stirring to obtain the intermediate 2-methyl-4-methoxyaniline; (4) Add the intermediate 2-methyl-4-methoxyaniline to water, add hydrogen peroxide, and keep the temperature at 20-30 degrees to react to obtain the intermediate 2-methyl-4-methoxynitrobenzene; (5) The intermediate 2-methyl-4-methoxynitrobenzene was dissolved in dichloroethane, and methanesulfonic acid was added dropwise. After the addition was completed, thianthrene and N-bromosuccinimide were added in batches. The reaction was kept warm to obtain 1-bromo-2-methoxy-4-methyl-5-nitrobenzene.

2. The method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene according to claim 1, wherein In step (1), o-toluidine and N , N -The mass volume ratio of dimethylformamide is 1g:2.5-3.5mL; the molar ratio of o-toluidine to acetic anhydride and potassium fluoride is 1:1.2:

1.

3. The method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene according to claim 1, wherein: In step (1), acetic anhydride is added dropwise at a temperature of 50-60°C, and after the addition is completed, the temperature is raised to 60-70°C and kept warm to carry out the acylation reaction.

4. The method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene according to claim 1, wherein The post-treatment in step (1) is as follows: pouring the reaction solution into ice water, washing with sodium dithionite aqueous solution, filtering, beating with methanol and drying to obtain the intermediate N-(4-fluoro-2-methylphenyl)acetamide.

5. The method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene according to claim 1, wherein The deacetylation reaction in step (2) is as follows: the intermediate N-(4-fluoro-2-methylphenyl)acetamide is added in batches to 50% dilute sulfuric acid water at a temperature of 80-90°C, stirred, and kept at 90-100°C. After the reaction is completed, the temperature is lowered, poured into water, stirred, and sodium hydroxide aqueous solution is added to adjust the pH value to alkaline. The mixture is filtered, slurried with methanol, and dried to obtain the intermediate 2-methyl-4-fluoroaniline.

6. The method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene according to claim 1, wherein: The molar ratio of 2-methyl-4-fluoroaniline to liquid sodium methoxide in step (3) is 1:3-4, and the reflux temperature is 60-70°C.

7. The method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene according to claim 1, wherein: The molar ratio of 2-methyl-4-methoxyaniline to hydrogen peroxide in step (4) is 1:1-5.

8. The method for synthesizing 1-bromo-2-methoxy-4-methyl-5-nitrobenzene according to claim 1, wherein: The molar ratio of 3-methyl-4-nitroanisole:methanesulfonic acid:thianthrene:N-bromosuccinimide in step (5) is 1:0.05:0.05:1-1.1.

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