Synthesis method of 5-nitro-2-aminophenol

Abstract

The invention discloses a synthesis method of 5-nitro-2-aminophenol, which comprises the following steps: by using 2-chloro-4-nitroaniline as a raw material, providing an amino protecting group by using di-tert-butyl dicarbonate ester to obtain a compound 3; carrying out hydrolysis reaction in an alkaline environment to hydrolyze chlorine groups on benzene rings into hydroxyl groups to obtain a compound 4; and removing an amino protecting group under an acidic condition to obtain the 5-nitro-2-aminophenol. According to the method, 2-chloro-4-nitroaniline is used as a starting raw material, compared with expensive ortho-aminophenol, the cost of the raw material can be remarkably reduced, use of expensive catalysts in the hydrolysis process is avoided through amino protection, generation of the byproduct 2-amino-4-nitrophenol is effectively reduced, and the yield of the 2-chloro-4-nitrophenol is increased. And the synthesized 5-nitro-2-aminophenol has relatively high purity (99.5%) and relatively high yield (-86%). The method has the advantages of conventional production steps and conventional process equipment, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 5-nitro-2-aminophenol. Background Technology

[0002] 5-Nitro-2-aminophenol (ANP) is a widely used organic intermediate, particularly prominent in the fields of dyes, pharmaceuticals, and pesticides. Especially in dyes, dozens of dyes have been synthesized using ANP, including acid dyes, disperse dyes, solvent dyes, and leather dyes. Therefore, 5-nitro-2-aminophenol is a very promising dye intermediate. According to literature reports, the main industrialized synthetic routes for 5-nitro-2-aminophenol are as follows: Route 1: o-hydroxyacetanilide method

[0003] Route 2: p-Nitroaniline method

[0004] Route 3: o-aminophenol method

[0005] Each of the three methods described above has its own drawbacks, which are manifested in the following aspects: Route 1: Although the process is easy to control, the operation is complicated. The product also contains about 25% of the byproduct 2-amino-4-nitrophenol, resulting in a low overall yield. Furthermore, the price of the raw material o-hydroxyacetanilide is high, making it unsuitable for large-scale industrial production.

[0006] Route 2: Although the raw materials for this method are readily available, the intermediate product "p-nitrotriazine" is a highly toxic, flammable, and explosive substance, making the synthesis process extremely dangerous.

[0007] Route 3: This method has a high overall yield, but the operation process is relatively complicated, including unit operations such as hydrogenation reduction, phosgenation and nitration. The product also contains 10% of the byproduct 2-amino-4-nitrophenol.

[0008] Therefore, a method for synthesizing 5-nitro-2-aminophenol with high yield and low cost is urgently needed. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention provides a method for synthesizing 5-nitro-2-aminophenol.

[0010] To solve the above-mentioned technical problems, the present invention provides the following technical solution: This invention provides a method for synthesizing 5-nitro-2-aminophenol, the synthetic route of which is shown below:

[0011] The specific synthesis steps are as follows: Step 1: Using 2-chloro-4-nitroaniline as a raw material, di-tert-butyl dicarbonate is used to provide an amino protecting group to obtain compound 3, namely (2-chloro-4-nitrophenyl)carbamate tert-butyl ester; Step 2: The compound 3 obtained in Step 1 is subjected to a hydrolysis reaction in an alkaline environment to hydrolyze the chlorine group on the benzene ring to a hydroxyl group, yielding compound 4, namely tert-butyl (2-hydroxy-4-nitrophenyl)carbamate. Step 3: Using compound 4 obtained in step 2, remove the amino protecting group under acidic conditions to obtain 5-nitro-2-aminophenol.

[0012] Preferably, in step 1, 2-chloro-4-nitroaniline and di-tert-butyl dicarbonate are both fully dissolved in methanol as a solvent to form 2-chloro-4-nitroaniline methanol solution and di-tert-butyl dicarbonate methanol solution, respectively. The di-tert-butyl dicarbonate methanol solution is slowly added to the 2-chloro-4-nitroaniline methanol solution at 0-80 °C, and the mixture is stirred for the first time. Then, N1,N1-dimethylethylenediamine is added, and the mixture is stirred for the second time. The dissolved organic phase is washed with hydrochloric acid and saturated brine, respectively. After filtration through anhydrous sodium sulfate, the filtrate is concentrated to obtain amino-protected compound 3.

[0013] Preferably, in step 1, the molar ratio of 2-chloro-4-nitroaniline to ditert-butyl dicarbonate is 1:1 to 1:3.

[0014] Preferably, in step 1, the first stirring is carried out at 0~80 ℃ for 2~6 h, and the second stirring is carried out at 0~80 ℃ for 15~60 min.

[0015] Preferably, in step 2, compound 3 obtained in step 1 is dissolved in an ethanol / water solution, and then NaOH is added to carry out a hydrolysis reaction; after the reaction is completed, the ethanol in the reaction solution is evaporated to dryness, and deionized water and ethyl acetate are added to extract the aqueous phase twice. The combined organic phases are dried under vacuum to obtain compound 4.

[0016] Preferably, in step 2, the molar ratio of compound 3 to NaOH is 1:1 to 1:5, and the volume ratio of ethanol to water in the ethanol / water solution is 2:1 to 5:1.

[0017] Preferably, in step 2, the hydrolysis reaction temperature is 50~100 ℃ and the reaction time is 3~10 h.

[0018] Preferably, in step 3, compound 4 obtained in step 2 is dissolved in ethyl acetate, HCl / ethyl acetate solution is added, and the mixture is stirred for the third time. Subsequently, the organic layer is directly evaporated from the solvent under vacuum to obtain 5-nitro-2-aminophenol.

[0019] Preferably, in step 3, the molar ratio of compound 4 to HCl is 1:1 to 1:4, and the concentration of the HCl / ethyl acetate solution is 2 M to 5 M.

[0020] Preferably, the third stirring is carried out at room temperature for 1 to 6 hours.

[0021] Compared with the prior art, the present invention has the following beneficial effects: This invention utilizes di-tert-butyl dicarbonate as an amino protecting group to protect the amino group on 2-chloro-4-nitroaniline, effectively avoiding interference from the amino group in subsequent reactions and improving the reaction yield. Subsequently, a hydrolysis reaction is used to hydrolyze the chlorine group on the benzene ring to a hydroxyl group, simultaneously avoiding the formation of byproducts. Finally, the amino protecting group is removed under acidic conditions to obtain 5-nitro-2-aminophenol, effectively avoiding the formation of the byproduct 2-amino-4-nitrophenol, further improving the purity and yield of the product. The synthesis method of this invention provides a way to avoid the formation of the byproduct 2-amino-4-nitrophenol. The amino protection strategy avoids the drawback of requiring a metal catalyst for direct hydrolysis of the chlorine group. Furthermore, the raw material price of this method is more advantageous compared to the o-aminophenol method, which has the best synthetic effect. The product yield (~86%) and purity (99.5%) are also higher, the operation steps are more conventional, and the required equipment is conventional. Attached Figure Description

[0022] Figure 1 The HPLC chromatogram is for pure 5-nitro-2-aminophenol. Detailed Implementation

[0023] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention. Example 1

[0024] This embodiment provides a method for synthesizing 5-nitro-2-aminophenol, the specific steps of which include: Step 1: A methanol solution (250 mL) of di-tert-butyl dicarbonate (Boc₂O, 207 g, 1.2 mol) was slowly added to a methanol solution (350 mL) of 2-chloro-4-nitroaniline (172.5 g, 1.0 mol) at 10 °C. The resulting mixture was stirred at 25 °C for 2 h. After stirring, N₁,N₁-dimethylethylenediamine (26 g, 0.3 mol) was added, and stirring was continued at 25 °C for 15 min. After the reaction was complete, the methanol solvent was removed by vacuum distillation, and the remaining residue was dissolved in 750 mL of ethyl acetate. The combined organic phases were washed successively with 1 N hydrochloric acid (2 × 250 mL) and saturated brine (2 × 250 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 250.8 g of (2-chloro-4-nitrophenyl)carbamate, with a yield of 97% and a purity of 98%.

[0025] Step 2: The obtained (2-chloro-4-nitrophenyl)carbamate tert-butyl ester (250.8 g, 0.92 g) was added to the solution. 1.84 mol of NaOH was dissolved in 750 mL of ethanol / water (2:1 / V:V), and 73.6 g of NaOH (1.84 mol) was added. The mixture was heated to 80 °C and stirred for 6 h. After the reaction was complete, the ethanol was evaporated to dryness, and the aqueous phase was extracted twice with 250 mL of deionized water and 300 mL x 2 ethyl acetate. The combined organic phases were dried and evaporated under vacuum to obtain the desired product. 210.5 g of tert-butyl (2-hydroxy-4-nitrophenyl)carbamate, yield 94%, purity 99%.

[0026] Step 3: Dissolve the obtained (2-hydroxy-4-nitrophenyl)carbamate tert-butyl ester (210.5 g, 0.828 mol) in 500 mL of ethyl acetate, add 920 mL of 2M HCl / ethyl acetate solution, and stir at room temperature for 2 h. Then add 2 L of deionized water to the reaction solution, separate the layers to obtain the ethyl acetate organic layer, and dry and evaporate the organic layer under vacuum to obtain 121.2 g of 5-nitro-2-aminophenol (HPLC chromatogram shown). Figure 1 The yield was 95%, the purity was 99.5%, and the overall yield after the three-step reaction was 86%. Example 2

[0027] This embodiment provides a method for synthesizing 5-nitro-2-aminophenol, the specific steps of which include: Step 1: A methanol solution (250 mL) of di-tert-butyl dicarbonate (Boc₂O, 241.5 g, 1.4 mol) was slowly added at 10 °C to a methanol solution (350 mL) of 2-chloro-4-nitroaniline (172.5 g, 1.0 mol). The resulting mixture was stirred at 40 °C for 2 h. After stirring, N₁,N₁-dimethylethylenediamine (43.3 g, 0.5 mol) was added, and stirring was continued at 40 °C for 30 min. After the reaction was complete, the methanol solvent was removed by vacuum distillation, and the remaining residue was dissolved in 900 mL of ethyl acetate. The combined organic phases were washed successively with 1 N hydrochloric acid (2 × 300 mL) and saturated brine (2 × 300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 254.95 g of (2-chloro-4-nitrophenyl)carbamate, with a yield of 94% and a purity of 98.5%.

[0028] Step 2: The obtained (2-chloro-4-nitrophenyl)carbamate tert-butyl ester (254.95 g, 0.94 mol) was dissolved in 900 mL of ethanol / water (3:1 / V:V), and NaOH (110.4 g, 2.82 mol) was added. The mixture was heated to 75 °C and stirred for 4 h. After the reaction was completed, the ethanol was evaporated to dryness, and the aqueous phase was extracted twice with 300 mL of deionized water and 300 mL x 2 ethyl acetate. The organic phases were combined and dried under vacuum to obtain compound 4 in a total of 209.5 g, with a yield of 90% and a purity of 96%.

[0029] Step 3: Dissolve the obtained (2-hydroxy-4-nitrophenyl) tert-butyl carbamate (209.5 g, 0.8 mol) in 500 mL of ethyl acetate, add 920 mL of 3M HCl / ethyl acetate solution, and stir at room temperature for 1 h. Then add 2 L of deionized water to the reaction solution, separate the layers to obtain the ethyl acetate organic layer, and then... The organic layer was dried and evaporated under vacuum to obtain 118.3 g of 5-nitro-2-aminophenol, with a yield of 94% and a purity of 98.9%.

[0030] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 5-nitro-2-aminophenol, characterized in that, The synthetic route is shown below: ； The specific synthesis steps are as follows: Step 1: Using 2-chloro-4-nitroaniline as a raw material, di-tert-butyl dicarbonate is used to provide an amino protecting group to obtain compound 3, namely (2-chloro-4-nitrophenyl)carbamate tert-butyl ester; Step 2: The compound 3 obtained in Step 1 is subjected to a hydrolysis reaction in an alkaline environment to hydrolyze the chlorine group on the benzene ring to a hydroxyl group, yielding compound 4, namely tert-butyl (2-hydroxy-4-nitrophenyl)carbamate. Step 3: Using compound 4 obtained in step 2, remove the amino protecting group under acidic conditions to obtain 5-nitro-2-aminophenol.

2. The method for synthesizing 5-nitro-2-aminophenol according to claim 1, characterized in that, In step 1, 2-chloro-4-nitroaniline and di-tert-butyl dicarbonate were both fully dissolved in methanol as a solvent to form 2-chloro-4-nitroaniline methanol solution and di-tert-butyl dicarbonate methanol solution, respectively. The di-tert-butyl dicarbonate methanol solution was slowly added to the 2-chloro-4-nitroaniline methanol solution at 0-80 °C, and the mixture was stirred for the first time. Then, N1,N1-dimethylethylenediamine was added, and the mixture was stirred for the second time. The dissolved organic phases were washed with hydrochloric acid and saturated brine, respectively. After filtration through anhydrous sodium sulfate, the filtrate was concentrated to obtain amino-protected compound 3.

3. The method for synthesizing 5-nitro-2-aminophenol according to claim 2, characterized in that, In step 1, the molar ratio of 2-chloro-4-nitroaniline to ditert-butyl dicarbonate is 1:1 to 1:

3.

4. The method for synthesizing 5-nitro-2-aminophenol according to claim 2, characterized in that, In step 1, the first stirring is carried out at 0~80 ℃ for 2~6 h, and the second stirring is carried out at 0~80 ℃ for 15~60 min.

5. The method for synthesizing 5-nitro-2-aminophenol according to claim 1, characterized in that, In step 2, compound 3 obtained in step 1 is dissolved in an ethanol / water solution, and then NaOH is added to carry out a hydrolysis reaction. After the reaction is completed, the ethanol in the reaction solution is evaporated to dryness, and deionized water and ethyl acetate are added to extract the aqueous phase twice. The organic phases are combined and dried under vacuum to obtain compound 4.

6. The method for synthesizing 5-nitro-2-aminophenol according to claim 5, characterized in that, In step 2, the molar ratio of compound 3 to NaOH is 1:1 to 1:5, and the volume ratio of ethanol to water in the ethanol / water solution is 2:1 to 5:

1.

7. The method for synthesizing 5-nitro-2-aminophenol according to claim 5, characterized in that, In step 2, the hydrolysis reaction is carried out at a temperature of 50-100 °C for 3-10 h.

8. The method for synthesizing 5-nitro-2-aminophenol according to claim 1, characterized in that, In step 3, compound 4 obtained in step 2 is dissolved in ethyl acetate, HCl / ethyl acetate solution is added, and the mixture is stirred for the third time. Subsequently, the organic layer is directly evaporated from the solvent under vacuum to obtain 5-nitro-2-aminophenol.

9. The method for synthesizing 5-nitro-2-aminophenol according to claim 8, characterized in that, In step 3, the molar ratio of compound 4 to HCl is 1:1 to 1:4, and the concentration of the HCl / ethyl acetate solution is 2 M to 5 M.

10. The method for synthesizing 5-nitro-2-aminophenol according to claim 8, characterized in that, The third stirring is carried out at room temperature for 1 to 6 hours.

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