Preparation method of 3-nitrophthalic acid

Abstract

The invention relates to a preparation method of 3-nitrophthalic acid, and belongs to the technical field of organic synthesis intermediates. According to the method, cheap and easily available 3-nitro-o-xylene is used as a raw material, the 3-nitrophthalic acid is efficiently synthesized through bromination and oxidation two-step reaction, the reaction selectivity is good, the product yield is high, aftertreatment is simple, meanwhile, use of strong acid in a traditional synthesis method is avoided, and the method is environmentally friendly and efficient.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis intermediates, in particular to a synthesis process of 3-nitrophthalic acid. Background Art

[0002] 3-Nitrophthalic acid is a light yellow crystalline powder, an important organic synthesis intermediate, and is widely used in medicine, pesticides, photosensitive materials, etc. For example: antihypertensive drug candesartan cilexetil, psoriasis drug apremilast, antitumor drug pomalidomide, photosensitive material luminol, pesticide flubendiamide, etc.

[0003] At present, the market price of 3-nitrophthalic acid is about 50,000 yuan / ton, and the market capacity is about 1000 tons. There are more than 600 manufacturers producing 3-nitrophthalic acid in the world, and in China, there are more than 500, which have undertaken 60% of the global output, and the demand is large and the prospects are broad. At present, the synthetic method of 3-nitrophthalic acid is mainly nitration and oxidation. For example, the patent document of publication number CN1405143A uses phthalic anhydride as raw material, and concentrated sulfuric acid is solvent to obtain 3-nitrophthalic acid by nitrification of fuming nitric acid, and the yield is about 30%. This method can generate a large amount of 4-nitrophthalic acid in the nitration process, resulting in a low yield of 3-nitrophthalic acid, and simultaneously produces a large amount of spent acid in the reaction, resulting in problems such as being difficult to handle. The patent document with publication number CN102603536B uses 3-nitro-o-xylene as raw material and reacts under the conditions of catalyst, water, 65% nitric acid and 0.5 MPa air. This method also requires the participation of nitric acid and has the problem of waste acid. It also requires cyanuric acid compounds and pressurized conditions, and the reaction conditions are harsh.

[0004] In summary, it is necessary to develop a new preparation method for 3-nitrophthalic acid to reduce the use and generation of harmful substances, improve the utilization rate of raw materials, and meet the requirements of safety and green chemical processes. Summary of the invention

[0005] Based on the shortcomings of the existing 3-nitrophthalic acid synthesis technology, the purpose of the present invention is to provide an efficient and green preparation method of 3-nitrophthalic acid. 3-nitro-o-xylene is used as a starting material, and 3-nitrophthalic acid is efficiently obtained through a two-step reaction of bromination at the benzyl position and halogen oxidation.

[0006] The technical solution of the present invention is a method for preparing 3-nitrophthalic acid, which comprises heating 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and sodium hypochlorite to obtain the product 3-nitrophthalic acid.

[0007]

[0008] In some specific synthesis methods, the solvent for the oxidation reaction is any one or more of water, methanol, acetonitrile, ethanol, and dimethyl sulfoxide.

[0009] Some specific synthesis methods, the molar ratio of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene to sodium hypochlorite is 1:3~40, the reaction temperature is 30~100°C, and the reaction time is 2~45 h.

[0010] Some specific synthesis methods, the molar ratio of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene to sodium hypochlorite is 1:5~35, the reaction temperature is 40~100°C, and the reaction time is 5~24 h.

[0011] In some specific synthesis methods, sodium hypochlorite is added dropwise to the reaction at least twice, and the concentration of sodium hypochlorite is 0.5 mol / L~1.4 mol / L.

[0012] The present invention also provides a method for preparing 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene, wherein 3-nitro-o-xylene is reacted under the conditions of a solvent, a brominating agent, an initiator and light to obtain 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene, and the specific synthetic reaction formula is:

[0013] In some specific synthesis methods, the brominating agent and the initiator are added to the reaction at least twice.

[0014] In some specific synthesis methods, the solvent is selected from at least one of carbon tetrachloride, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol and water.

[0015] Some specific synthesis methods are as follows: 3-nitro-o-xylene is added to a solvent, and then half of the brominating agent and initiator are added, and the reaction is carried out under heating and illumination for 2-12 hours, and then filtered. The other half of the brominating agent and initiator are added to the filtrate, and the reaction is continued under heating and illumination for 2~12 hours to obtain 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene.

[0016] The brominating agent used is any one or more of dibromohydantoin, liquid bromine, N-bromosuccinimide and carbon tetrabromide; the initiator is any one or more of azobisisobutyronitrile, dibenzoyl peroxide and dimethyl azobisisobutyrate.

[0017] Some specific synthesis methods, the molar ratio of 3-nitro-o-xylene to the brominating agent is 1:1-15, the mass ratio of 3-nitro-o-xylene to the initiator is 1:0.05-0.5, the temperature of the bromination reaction is 25-100°C, and the reaction time is 2-30h.

[0018] Some specific synthesis methods, the molar ratio of 3-nitro-o-xylene to the brominating agent is 1:2-10, the mass ratio of 3-nitro-o-xylene to the initiator is 1:0.1-0.4, the reaction temperature is 40-80°C, and the total reaction time is 6-24 h.

[0019] The preparation method of 3-nitrophthalic acid adopted in the present invention has the following advantages compared with the traditional synthesis method: A new preparation method is proposed, in which 3-nitrophthalic acid is prepared by highly selectively oxidizing 3-nitro-o-xylene in two steps of bromination and oxidation. The yield of 3-nitrophthalic acid in this method can reach 86.7%. The post-treatment of this method is simple, and the purity of the product can reach 99.9%. No strong acid and catalyst are required in the process, which avoids corrosion to pipelines and containers. Some solvents and reagents in this method can be recycled and reused, reducing process costs and environmental pollution. DETAILED DESCRIPTION

[0020] The present invention is further described in detail below in conjunction with examples, but the present invention is not limited to the following examples. Example 1

[0021] In a 1000 mL conical flask, add 40 g 3-nitro-o-xylene, 76 g dibromohydantoin and 2 g AIBN and 400 mL carbon tetrachloride, and stir and react under reflux and light conditions for 6 h. Then filter the solution, add the filtrate to the conical flask again, and add 76 g dibromohydantoin and 2 g AIBN to continue to react under reflux and light conditions for 6 h. Experimental treatment: Filter the reaction solution, take the filtrate, slowly add 500 mL saturated sodium sulfite solution, stir until the lower layer liquid changes from orange to yellow, separate the liquid, take the lower layer of clear liquid and evaporate it, dry it to obtain 101.2 g of light yellow solid 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene, with a yield of 98.6%. Example 2

[0022] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 35.5 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide were added and mixed with 200 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 35.5 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide were added to continue the reaction under reflux and illumination for 6 h. The post-treatment was performed with reference to Example 1, and the yield was 85.6%. Example 3

[0023] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 47.1 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide were added and mixed with 200 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 47.1 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide were added and continued to react under reflux and illumination for 6 h. The post-treatment was carried out with reference to Example 1, and the yield was 97.8%. Example 4

[0024] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 70.6 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide were added and mixed with 200 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 70.6 g of N-bromosuccinimide and 1 g of dibenzoyl peroxide were added to continue the reaction under reflux and illumination for 6 h. The post-treatment was performed with reference to Example 1, and the yield was 98.8%. Example 5

[0025] In a 1000 mL conical flask, 40 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 2 g of AIBN were added and mixed with 400 mL of carbon tetrachloride, and stirred for reaction under reflux and light conditions for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 2 g of AIBN were added to continue the reaction under reflux and light conditions for 6 h. The post-treatment was carried out according to Example 1, and the yield was 84.6%. Example 6

[0026] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 1 g of AIBN were added to 400 mL of carbon tetrachloride and stirred for reaction at 40°C under light for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 1 g of AIBN were added to continue the reaction at 40°C under light for 6 h. The post-treatment was performed according to Example 1, and the yield was 72.5%. Example 7

[0027] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 76 g of dibromohydantoin and 2 g of AIBN were added and mixed with 400 mL of carbon tetrachloride, and stirred for 12 h under reflux and light conditions. The post-treatment was carried out according to Example 1, and the yield was 82.3%. Example 8

[0028] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 1 g of AIBN were added to 400 mL of carbon tetrachloride and stirred for reaction at 40°C under light for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 1 g of AIBN were added to continue the reaction at 40°C under light for 6 h. The post-treatment was performed according to Example 1, and the yield was 72.5%. Example 9

[0029] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 4 g of AIBN were added and mixed with 400 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 4 g of AIBN were added to continue the reaction under reflux and illumination for 6 h. The post-treatment was carried out with reference to Example 1, and the yield was 96.7%. Example 10

[0030] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 190 g of dibromohydantoin and 1 g of AIBN were added and mixed with 400 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 190 g of dibromohydantoin and 1 g of AIBN were added to continue the reaction under reflux and illumination for 6 h. The post-treatment was carried out with reference to Example 1, and the yield was 98.2%. Embodiment 11

[0031] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 1 g of AIBN were added and mixed with 400 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 3 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 1 g of AIBN were added to continue the reaction under reflux and illumination for 3 h. The post-treatment was carried out according to Example 1, and the yield was 57.3%. Example 12

[0032] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 1 g of AIBN were added and mixed with 400 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 12 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 1 g of AIBN were added to continue the reaction under reflux and illumination for 12 h. The post-treatment was carried out with reference to Example 1, and the yield was 97.9%. Embodiment 13

[0033] In a 500 mL conical flask, 20 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 1 g of AIBN were added to 400 mL of carbon tetrachloride and stirred for reaction at room temperature and light for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 1 g of AIBN were added to continue the reaction for 6 h under reflux and light conditions. The post-treatment was performed with reference to Example 1, and the yield was 65.8%. Embodiment 14

[0034] 20 g of 3-nitro-o-xylene, 38 g of dibromohydantoin and 2 g of AIBN were added to a 500 mL conical flask and mixed with 400 mL of carbon tetrachloride, and stirred for reaction under reflux and illumination for 6 h. The solution was then filtered, the filtrate was added to the conical flask again, and 38 g of dibromohydantoin and 2 g of AIBN were added to continue the reaction under reflux and illumination for 6 h. The post-treatment was performed with reference to Example 1, and the yield was 97.6%. Embodiment 15

[0035] Add 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mL of acetonitrile to a 100 mL reaction bottle, stir and mix, and heat to 60°C. Add 33 mL of sodium hypochlorite (1 mol / L) dropwise to the reaction system. After 6 h of reaction, add another 33 mL of sodium hypochlorite dropwise. Continue the reaction at 60°C for 6 h before stopping. Experimental treatment: Filter the reaction solution, spin dry the filtrate, then add hot water to dissolve the solid, filter, add hydrochloric acid to acidify to pH 1, spin dry the water, add ethyl acetate to dissolve the product, filter, spin dry the filtrate to obtain a white solid, and dry to obtain 472 mg of the product, with an actual yield of 86.7%. Example 16

[0036] Add 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mL of acetonitrile to a 100 mL reaction bottle, stir and mix, and heat to 60°C. Add 4 mL of sodium hypochlorite (1 mol / L) dropwise to the reaction system. After 6 h of reaction, add another 4 mL of sodium hypochlorite dropwise. After 6 h of reaction, stop the reaction. Post-treatment was performed according to Example 15. The actual yield was 35.6%. Embodiment 17

[0037] Add 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mL of acetonitrile to a 100 mL reaction bottle, stir and mix, and heat to 60°C. Add 45 mL of sodium hypochlorite (1 mol / L) dropwise to the reaction system. Continue to react at 60°C for 6 hours, then add 45 mL of sodium hypochlorite dropwise. Stop the reaction after 6 hours. Post-treatment was performed with reference to Example 15, and the actual yield was 88.9%. Embodiment 18

[0038] 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mL of acetonitrile were added to a 100 mL reaction bottle, stirred and mixed, and 33 mL of sodium hypochlorite (1 mol / L) was added dropwise to the reaction system under reflux conditions. After 6 h of reaction, 33 mL of sodium hypochlorite was added dropwise, and the reaction was stopped after 6 h. The post-treatment was performed according to Example 15, and the actual yield was 56.8%. Embodiment 19

[0039] Add 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mL of acetonitrile to a 100 mL reaction bottle, stir and mix, and heat to 40°C. Add 33 mL of sodium hypochlorite (1 mol / L) dropwise to the reaction system. After reacting for 6 h, add another 33 mL of sodium hypochlorite dropwise. Continue to react at 40°C for 6 h before stopping. Post-treatment was performed with reference to Example 15, and the actual yield was 19.8%. Embodiment 20

[0040] Add 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mL of water to a 100 mL reaction bottle, stir and mix, and heat to 60°C. Add 33 mL of sodium hypochlorite (1 mol / L) dropwise to the reaction system. After reacting for 6 h, add another 33 mL of sodium hypochlorite dropwise. Continue to react at 60°C for 6 h before stopping. Post-treatment was performed with reference to Example 15. The actual yield was 58.5%. Embodiment 21

[0041] Add 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mL of methanol to a 100 mL reaction bottle, stir and mix, and heat to 60°C. Add 33 mL of sodium hypochlorite (1 mol / L) dropwise to the reaction system. After reacting for 6 h, add another 33 mL of sodium hypochlorite dropwise. Continue to react at 60°C for 6 h before stopping. Post-treatment was performed with reference to Example 15. The actual yield was 85.1%. Embodiment 22

[0042] In a 100 mL reaction bottle, 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 380 mg of sodium hydroxide were added to 20 mL of methanol, stirred and mixed, and reacted at room temperature for 6 h, and then 10 mL of sodium hypochlorite (1 mol / L) was added dropwise to the reaction solution, and the reflux reaction was stopped after 12 h. The post-treatment was performed according to Example 15, and the actual yield was 41.8%. Embodiment 23

[0043] 1 g of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene and 20 mg of tetrabutylammonium bromide were added to a 100 mL reaction bottle, stirred and mixed in 20 mL of sodium hypochlorite (1 mol / L), and 30 mL of sodium hypochlorite (1 mol / L) was added dropwise, and the reaction was stopped after 12 h at 90°C. The post-treatment was performed according to Example 15, and the actual yield was 68.7%.

Claims

1. A method for preparing 3-nitrophthalic acid, characterized in that: The preparation method comprises the following steps: The product 3-nitrophthalic acid is obtained by reacting 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene with sodium hypochlorite.

2. The preparation method according to claim 1, characterized in that: The reaction solvent is any one or more of water, methanol, acetonitrile, ethanol and dimethyl sulfoxide; sodium hypochlorite is added dropwise into the reaction system at least twice.

3. The preparation method according to claim 1, characterized in that: The molar ratio of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene to sodium hypochlorite is 1:3-40, the reaction temperature is 30-100°C, and the reaction time is 2-45 h.

4. The preparation method according to claim 3, characterized in that: The molar ratio of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene to sodium hypochlorite is 1:5~35, the reaction temperature is 40~100℃, and the reaction time is 5~24 h.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The preparation steps of 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene are as follows: 3-Nitro-o-xylene reacts with a brominating agent and an initiator in carbon tetrachloride under stirring under light to obtain 2-(bromomethyl)-1-(dibromomethyl)-3-nitrobenzene.

6. The preparation method according to claim 5, characterized in that: The brominating agent is any one or more of dibromohydantoin, liquid bromine, N-bromosuccinimide, and carbon tetrabromide; the initiator is any one or more of azobisisobutyronitrile, dibenzoyl peroxide, and dimethyl azobisisobutyrate.

7. The preparation method according to claim 6, characterized in that: The temperature of the bromination reaction is 25~100℃, and the reaction time is 2~30 h.

8. The preparation method according to claim 7, characterized in that: The temperature of the bromination reaction is 40~80℃, and the reaction time is 6~24 h.

9. The preparation method according to claim 7, characterized in that: The molar ratio of 3-nitro-o-xylene to the brominating agent is 1:1-15, and the mass ratio of 3-nitro-o-xylene to the initiator is 1:0.05-0.

5.

10. The preparation method according to claim 7, characterized in that: The brominating agent and the initiator are added to the reaction at least twice. Except for the first time, the reaction solution is filtered before adding the brominating agent and the initiator.

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