A kind of preparation method of p-nitrobenzyl alcohol
By avoiding the use of bromine in the preparation of p-nitrobenzyl alcohol, using hydrogen bromide and amphiphilic activated carbon to promote the reaction, the problems of expensive bromine and slow hydrolysis reaction in the prior art were solved, and efficient and safe nitrobenzyl were achieved Alcohol preparation improves product yield and purity, and is suitable for industrial production.
Patent Information
- Application Number
- CN202310642418.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-06-01
- Publication Date
- 2024-12-31
- Estimated Expiration
- 2043-06-01
AI Technical Summary
In the existing preparation methods for nitrobenzyl alcohol, bromine is expensive and has low safety. The hydrolysis process is a two-phase reaction, and the reaction is slow. The product is dark under high temperature conditions, the yield and purity are relatively low, and the reaction route is long. The use of chlorine is not conducive to industrial production.
Avoid using bromine in the bromination reaction, use hydrogen bromide as the bromine source, add free radical initiator, add drip hydrogen peroxide to warm up the reaction to obtain p-nitrobenzene bromine, and add amphiphilic activated carbon to make the reaction in water The oil interface is carried out to reduce temperature, improve efficiency, and isolate and recycle the pyramidal activated carbon by simple filtration.
It achieves safe operation, simple steps, mild reaction conditions and fast reaction rate, improves product yield and purity, is suitable for industrial production, and saves production costs.
Smart Images
Figure BDA0004261960830000061
Abstract
Description
Technical Field
[0001] The present application belongs to the field of pharmaceutical chemical technology, and more specifically, relates to a method for preparing p-nitrobenzyl alcohol. Background Art
[0002] p-Nitrobenzyl alcohol is an important pharmaceutical intermediate that can form a benzyl ester protective group and is widely used in the synthesis of raw materials. p-Nitrobenzyl alcohol derivatives can inhibit the activity of trypsin and treat tumors. The currently reported preparation methods of p-nitrobenzyl alcohol mainly include two methods: (1) using p-nitrotoluene as a raw material and bromine as a bromine source, first preparing p-nitrobenzyl bromide, and then hydrolyzing p-nitrobenzyl bromide under alkaline conditions to prepare p-nitrobenzyl alcohol. (2) using p-nitrotoluene as a raw material, first chlorinating with chlorine to generate p-nitrobenzyl chloride, then reacting p-nitrobenzyl chloride with sodium acetate to obtain p-nitrobenzyl acetate, and then hydrolyzing p-nitrobenzyl acetate under alkaline conditions to obtain p-nitrobenzyl alcohol. The bromine used in the first method is expensive and has low safety. The hydrolysis process is a two-phase reaction, the reaction is slow at low temperature, and the product obtained under high temperature conditions is dark in color. The product yield and purity are both low. The second method has a long reaction route and a high reaction temperature. The use of chlorine makes the operation difficult, which is not conducive to industrial production. In addition, the hydrolysis reaction also has the problem of a two-phase reaction and a slow reaction rate. Therefore, it is necessary to develop a new preparation process for p-nitrobenzyl alcohol with simple operation, mild reaction conditions and fast reaction rate, which has important application prospects. Summary of the invention
[0003] The present invention is to solve the deficiencies of the above-mentioned background technology and provide a novel method for preparing p-nitrobenzyl alcohol. In the present invention, in the bromination reaction, the use of bromine to prepare the intermediate p-nitrobenzyl bromide is avoided, the operation is safe, and the steps are simple; in the hydrolysis reaction, amphiphilic activated carbon is added to make the reaction proceed at the water-oil interface, the reaction temperature is reduced, the reaction efficiency is improved, and the added amphiphilic activated carbon can be separated, recycled and reused by simple filtration, which greatly improves the product yield and purity.
[0004] To this end, the present invention provides a method for preparing p-nitrobenzyl alcohol.
[0005] The specific steps include:
[0006] (1) Bromination reaction: In an organic solvent, p-nitrotoluene is used as the raw material, hydrogen bromide is used as the bromine source, a free radical initiator is added, hydrogen peroxide is added dropwise, and the temperature is raised to react to obtain the intermediate p-nitrobenzyl bromide;
[0007] (2) Hydrolysis reaction: the p-nitrobenzyl bromide obtained in step (1) is added to a mixed solvent of water and an organic solvent, amphiphilic activated carbon is added, and the temperature is raised to cause a hydrolysis reaction to obtain p-nitrobenzyl alcohol.
[0008] Preferably, in step (1), the free radical initiator is one or more of azobisisobutyronitrile, ferrous sulfate, and ascorbic acid.
[0009] Preferably, in step (1), the bromination reaction temperature is 35-80°C.
[0010] Preferably, in step (1), the bromination reaction temperature is 60-70°C.
[0011] Preferably, in step (1), hydrogen bromide is prepared by bromination reaction of sodium bromide and sulfuric acid.
[0012] Preferably, the molar ratio of sodium bromide to p-nitrotoluene is 1-1.4:1, the concentration of sulfuric acid is 20%-50%, and the molar ratio of sulfuric acid to sodium bromide is 0.5-1:1.
[0013] Preferably, in step (1), the mass fraction of hydrogen peroxide is 20%-50%, the molar ratio of hydrogen peroxide to sodium bromide is 1-1.4:1, and the dropping time of hydrogen peroxide is controlled to be 0.5-5h.
[0014] Preferably, in step (1), the bromination reaction system turns white and the reaction is stopped. The bromination reaction time is 3-8 hours.
[0015] Preferably, in step (2), the mass of the added amphiphilic activated carbon is 1%-10% of the mass of the p-nitrobenzyl bromide.
[0016] Preferably, in step (2), the mass of the added amphiphilic activated carbon is 3%-5% of the mass of the p-nitrobenzyl bromide.
[0017] Preferably, in step (2), the temperature of the hydrolysis reaction is 50-95°C
[0018] Preferably, in step (2), the temperature of the hydrolysis reaction is 50-95°C.
[0019] Preferably, in step (1), the organic solvent is dichloromethane or dichloroethane.
[0020] Preferably, in step (2), the organic solvent added to the hydrolysis reaction is one or more of dichloromethane, dichloroethane, and toluene.
[0021] Preferably, in step (2), the mass ratio of the organic solvent to water is 0.5-2:1.
[0022] Preferably, in step (2), during the reaction, sampling is performed for control, and when the p-nitrobenzyl bromide content is detected to be ≤2%, the reaction is stopped, and the hydrolysis reaction time is 3-10 hours.
[0023] Preferably, in step (2), the hydrogen bromide, organic solvent and amphiphilic activated carbon generated by the hydrolysis reaction are recovered for recycling, wherein the organic solvent and amphiphilic activated carbon can be reused 2-5 times, which is beneficial to improve the purity of p-nitrobenzyl alcohol.
[0024] Preferably, in step (2), the mixed solution of water and organic solvent is recrystallized, which is also beneficial to improve the purity of p-nitrobenzyl alcohol.
[0025] The beneficial effects of the present invention are:
[0026] In the method for preparing p-nitrobenzyl alcohol of the present invention, direct use of bromine to prepare the intermediate p-nitrobenzyl bromide is avoided in the bromination reaction, the operation is safe, and the steps are simple. In the hydrolysis reaction, amphiphilic activated carbon is used to promote hydrolysis, so that the hydrolysis reaction is carried out at the water-oil interface, the reaction temperature is reduced, the reaction efficiency is improved, and the product yield and purity are improved. In addition, the added amphiphilic activated carbon can be separated, recycled and reused by simple filtration, and the hydrogen bromide generated during the reaction can be recycled and reused, which saves production costs and is suitable for industrial production. DETAILED DESCRIPTION
[0027] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.
[0028] Example 1
[0029] A preparation method of p-nitrobenzyl alcohol, the specific steps are as follows:
[0030] (1) Bromination reaction: Add 68.6g of p-nitrotoluene, 56.6g of sodium bromide, 53.9g of 50% sulfuric acid, 140g of ethylene dichloride, and 1g of azobisisobutyronitrile to the reaction flask, stir and heat to 65°C; add 69.3g of 27.5% hydrogen peroxide dropwise, add dropwise for 3 hours, control the temperature to 65°C, keep warm for 4 hours, and the system turns white. After the insulation is completed, separate the layers, cool the organic layer to below 0°C for crystallization, and filter to obtain 103.6g of p-nitrobenzyl bromide with a purity of 98.00% and a yield of 94.01%.
[0031] (2) Hydrolysis reaction: 103.6 g of p-nitrobenzyl bromide obtained in step (1) was put into a reaction kettle, 200 g of water and 200 g of toluene were added, 5.1 g of amphiphilic activated carbon was added, the temperature was stirred and raised, and the temperature was controlled to 75°C. After keeping warm for 6 hours, a central control test was performed. If the p-nitrobenzyl bromide content was ≤2%, the reaction was stopped. The hydrogen bromide was evaporated and absorbed by water, the content was tested, and the reaction was recovered and reused. After the reaction was completed, the amphiphilic activated carbon was filtered out while hot, washed and dried, the liquid layer was cooled to below 0°C for crystallization, suction filtered, and dried to obtain 61.2 g of p-nitrobenzyl alcohol with a purity of 99.36% and a yield of 85.05%.
[0032] Example 2
[0033] The difference from Example 1 is that in the bromination reaction of step (1), 54.5 g of sodium bromide is added, and the other steps are the same, to obtain 101.7 g of p-nitrobenzyl bromide with a purity of 98.21% and a yield of 92.47%.
[0034] Example 3
[0035] The difference from Example 1 is that in the bromination reaction of step (1), 72.0 g of sodium bromide is added, and the other steps are the same, to obtain 104.8 g of p-nitrobenzyl bromide with a purity of 97.90% and a yield of 95.00%.
[0036] Example 4
[0037] The difference from Example 1 is that in the bromination reaction of step (1), the temperature is controlled at 35° C. The other steps are the same, and 102.8 g of p-nitrobenzyl bromide is obtained with a purity of 98.11% and a yield of 93.38%.
[0038] Example 5
[0039] The difference from Example 1 is that in the bromination reaction of step (1), the temperature is controlled at 60° C. The other steps are the same, and 103.4 g of p-nitrobenzyl bromide is obtained with a purity of 98.29% and a yield of 94.11%.
[0040] Example 6
[0041] The difference from Example 1 is that in the bromination reaction of step (1), the temperature is controlled at 70° C. The other steps are the same, and 104.0 g of p-nitrobenzyl bromide is obtained with a purity of 97.71% and a yield of 94.08%.
[0042] Example 7
[0043] The difference from Example 1 is that in the bromination reaction of step (1), the temperature is controlled at 80°C. The other steps are the same, and 102.0 g of p-nitrobenzyl bromide is obtained with a purity of 98.19% and a yield of 92.47%.
[0044] Example 8
[0045] The difference from Example 1 is that in the bromination reaction of step (1), 75.4 g of 50% sulfuric acid is added, and the other steps are the same, to obtain 103.8 g of p-nitrobenzyl bromide with a purity of 98.10% and a yield of 94.29%.
[0046] Example 9
[0047] The difference from Example 1 is that in the bromination reaction of step (1), 107.8 g of 50% sulfuric acid is added, and the other steps are the same, to obtain 104.2 g of p-nitrobenzyl bromide with a purity of 98.29% and a yield of 94.84%.
[0048] Example 10
[0049] The difference from Example 1 is that in the bromination reaction of step (1), 63 g of hydrogen peroxide was added. The other steps were the same, and 102.8 g of p-nitrobenzyl bromide was obtained with a purity of 98.01% and a yield of 93.28%.
[0050] Embodiment 11
[0051] The difference from Example 1 is that in the bromination reaction of step (1), 88.2 g of hydrogen peroxide was added, and the other steps were the same, to obtain 103.9 g of p-nitrobenzyl bromide with a purity of 98.31% and a yield of 94.57%.
[0052] Example 12
[0053] The difference from Example 1 is that in the hydrolysis reaction of step (2), 1.0 g of amphiphilic activated carbon is added, and the other steps are the same, to obtain 103.9 g of p-nitrobenzyl bromide with a purity of 98.09% and a yield of 94.29%.
[0054] Embodiment 13
[0055] The difference from Example 1 is that in the hydrolysis reaction of step (2), 3.0 g of amphiphilic activated carbon is added, and the other steps are the same, to obtain 102.9 g of p-nitrobenzyl bromide with a purity of 98.49% and a yield of 93.85%.
[0056] Embodiment 14
[0057] The difference from Example 1 is that in the hydrolysis reaction of step (2), 10.2 g of amphiphilic activated carbon is added, and the other steps are the same, to obtain 104.0 g of p-nitrobenzyl bromide with a purity of 97.91% and a yield of 94.27%.
[0058] Embodiment 15
[0059] The difference from Example 1 is that in the hydrolysis reaction of step (2), the temperature is controlled at 50° C. The other steps are the same, and 103.5 g of p-nitrobenzyl bromide is obtained with a purity of 98.30% and a yield of 94.21%.
[0060] Example 16
[0061] The difference from Example 1 is that in the hydrolysis reaction of step (2), the temperature is controlled at 95° C. The other steps are the same, and 103.8 g of p-nitrobenzyl bromide is obtained with a purity of 98.21% and a yield of 94.38%.
[0062] The experimental data parameters and results of Examples 1 to 16 are summarized as follows, see Table 1:
[0063] In Table 1, sodium bromide is the molar ratio of sodium bromide to p-nitrotoluene, sulfuric acid is the molar ratio of sulfuric acid to sodium bromide, and hydrogen peroxide is the molar ratio of hydrogen peroxide to sodium bromide. In Table 1, amphiphilic activated carbon is the mass ratio of amphiphilic activated carbon to p-nitrobenzyl bromide.
[0064]
[0065] As shown in Table 1, in the bromination reaction, the reaction temperature is 35-80° C.; the molar ratio of sodium bromide to p-nitrotoluene is 1-1.4:1; the molar ratio of sulfuric acid to sodium bromide is 0.5-1:1; and the molar ratio of hydrogen peroxide to sodium bromide is 1-1.4:1. All of these can obtain p-nitrobenzyl bromide with high yield and high purity, thereby realizing the method for preparing p-nitrobenzyl alcohol with high yield and high purity of the present invention.
[0066] In the hydrolysis reaction, the mass of the added amphiphilic activated carbon is 1%-10% of the mass of the p-nitrobenzyl bromide; the temperature of the hydrolysis reaction is 50-95° C., and the method for preparing p-nitrobenzyl alcohol with high yield and high purity of the present invention can be realized.
[0067] Example 17 A method for preparing p-nitrobenzyl alcohol, the specific steps are as follows:
[0068] The hydrogen bromide recovered from the hydrolysis reaction in step (2) of Example 1 is applied. If the hydrogen bromide content is insufficient, new hydrogen bromide can be added. The dichloroethane and amphiphilic activated carbon recovered from the hydrolysis reaction in step (2) of Example 1 are applied to carry out the following steps:
[0069] (1) Bromination reaction: Add 61.7g of p-nitrotoluene to the reaction flask, add hydrogen bromide recovered from the hydrolysis reaction in step (2) of Example 1 (if the content is insufficient, fresh hydrogen bromide can be added), add 62g of 50% hydrogen bromide, apply the dichloroethane recovered from the hydrolysis reaction in step (2) of Example 1, add 1g of azobisisobutyronitrile, stir and heat to 65°C; add 69.3g of 27.5% hydrogen peroxide dropwise, add dropwise for 3h, control the temperature to 65°C, keep warm for 5h, and the system turns white. After the insulation is completed, separate the layers, cool the organic layer to below 0°C for crystallization, and filter to obtain 103.1g of p-nitrobenzyl bromide.
[0070] (2) Hydrolysis reaction: 103.1 g of p-nitrobenzyl bromide obtained in step (1) is put into a reactor, 200 g of water and 200 g of toluene are added, and the amphiphilic activated carbon recovered in step (2) of Example 1 is added, stirred and heated, and the temperature is controlled to 75°C. After keeping warm for 10 hours, a central control test is performed, and the benzyl bromide content is ≤2%, and the reaction is stopped. The hydrogen bromide is evaporated and absorbed by water, the content is tested, and the reaction is recovered and reused. After the reaction is completed, the amphiphilic activated carbon is filtered out while hot, washed and dried, the liquid layer is cooled to below 0°C for crystallization, suction filtered, and dried to obtain 61.2 g of p-nitrobenzyl alcohol fine product, with a purity of 99.36% and a yield of 85.50%. The total yield of Example 1 and Example 2 is 85.28%.
[0071] It is worth noting that in step (1), the organic solvent is dichloromethane or dichloroethane; in step (2), the organic solvent added to the hydrolysis reaction is dichloromethane, dichloroethane, toluene, any of which can realize the preparation method of p-nitrobenzyl alcohol of the present invention.
[0072] In summary, in the method for preparing p-nitrobenzyl alcohol of the present invention, bromine is avoided from being directly used to prepare the intermediate p-nitrobenzyl bromide in the bromination reaction, the operation is safe, and the steps are simple. In the hydrolysis reaction, amphiphilic activated carbon is used to promote hydrolysis, so that the hydrolysis reaction is carried out at the water-oil interface, the reaction temperature is reduced, the reaction efficiency is improved, and the product yield and purity are improved. In addition, the added amphiphilic activated carbon can be separated, recycled and reused by simple filtration, and the hydrogen bromide generated during the reaction can be recycled and reused, saving production costs, and being suitable for industrial production.
[0073] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims
1. A method for preparing p-nitrobenzyl alcohol, characterized in that: The following steps are involved: (1) Bromination reaction: In an organic solvent, p-nitrotoluene is used as the raw material, hydrogen bromide is used as the bromine source, a free radical initiator is added, hydrogen peroxide is added dropwise, and the temperature is raised to react to obtain the intermediate p-nitrobenzyl bromide; (2) Hydrolysis reaction: the p-nitrobenzyl bromide obtained in step (1) is added to a mixed solvent of water and an organic solvent, amphiphilic activated carbon is added, and the temperature is raised to cause a hydrolysis reaction to obtain p-nitrobenzyl alcohol.
2. The method for preparing p-nitrobenzyl alcohol according to claim 1, wherein: In step (1), the free radical initiator is one or more of azobisisobutyronitrile, ferrous sulfate, and ascorbic acid.
3. The method for preparing p-nitrobenzyl alcohol according to claim 1, wherein: In step (1), the bromination reaction temperature is 35-80°C.
4. The method for preparing p-nitrobenzyl alcohol according to claim 1, wherein: In step (1), hydrogen bromide is prepared by bromination reaction of sodium bromide and sulfuric acid.
5. The method for preparing p-nitrobenzyl alcohol according to claim 4, characterized in that: The molar ratio of sodium bromide to p-nitrotoluene is 1-1.4:1, and the molar ratio of sulfuric acid to sodium bromide is 0.5-1:
1.
6. The method for preparing p-nitrobenzyl alcohol according to claim 1, characterized in that: In step (1), the molar ratio of hydrogen peroxide to sodium bromide is 1-1.4:
1.
7. The method for preparing p-nitrobenzyl alcohol according to claim 1, characterized in that: In step (2), the mass of the added amphiphilic activated carbon is 1%-10% of the mass of the p-nitrobenzyl bromide.
8. The method for preparing p-nitrobenzyl alcohol according to claim 1, wherein: In step (2), the temperature of the hydrolysis reaction is 50-95°C.
9. The method for preparing p-nitrobenzyl alcohol according to claim 1, characterized in that: In step (1), the organic solvent added to the bromination reaction is dichloromethane or dichloroethane; in step (2), the organic solvent added to the hydrolysis reaction is one or more of dichloromethane, dichloroethane and toluene.
10. The method for preparing p-nitrobenzyl alcohol according to claim 1, characterized in that: In step (2), hydrogen bromide, organic solvent and amphiphilic activated carbon generated by the hydrolysis reaction are recovered for recycling.