Preparation method of o-hydroxybenzamide

Abstract

The invention discloses a preparation method of o-hydroxybenzamide, which comprises the following steps: adding methyl salicylate, ammonia gas, a porous base catalyst, an antioxidant and a solvent into a reaction kettle, introducing nitrogen into the reaction kettle, pressurizing, heating, reacting until no methyl salicylate is detected in the reaction liquid, and after the reaction is finished, cooling to room temperature to obtain the o-hydroxybenzamide. And filtering and recovering the catalyst, and distilling to remove ammonia gas and the solvent to obtain an o-hydroxybenzamide product. The method disclosed by the invention can effectively reduce the consumption of ammonia gas and improve the reaction yield, and the product is high in content, stable in color, free of wastewater and solid waste and environment-friendly.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing o-hydroxybenzamide. Background Art

[0002] o-Hydroxybenzamide (salicylamide), also known as salicylamide, has a molecular formula of C7H7NO2, CAS number 65-45-2, and is a white to slightly pink crystal. o-Hydroxybenzamide is an important chemical intermediate in the fields of chemical industry, medicine, pesticide, fragrance, liquid crystal, etc. It has a wide range of uses and can be used to synthesize organic chemicals such as nitrothiophene, o-ethoxyformamide, o-hydroxybenzonitrile, etc. It is also a widely used antipyretic and analgesic drug that can be used to treat fever, headache, neuralgia, joint pain and active rheumatism. In recent years, according to the strict requirements of the national environmental protection policy, the production cost of o-hydroxybenzamide has increased and the environmental protection pressure has been great, resulting in a shortage of o-hydroxybenzamide in the market and large price fluctuations. Therefore, it is urgent for production enterprises to develop a new process technology for the synthesis of o-hydroxybenzamide with high quality, high yield and low three wastes.

[0003] At present, the mainstream industrial production process of o-hydroxybenzamide widely uses the ammonolysis of methyl o-hydroxybenzoate in an ammonia solution to obtain o-hydroxybenzamide. There are some problems in this process that need to be solved: the amination reaction of methyl o-hydroxybenzoate is carried out in excess ammonia water, and the post-reaction treatment produces a large amount of ammonia-containing wastewater, which does not meet environmental protection requirements; hydrolysis side reactions will occur in the ammonia system to generate o-hydroxybenzoic acid, resulting in a low yield. In response to these problems, some literature reports use organic solvent systems for amination reactions. Chinese patent document CN102304061A discloses a method for synthesizing o-hydroxybenzamide by continuously passing ammonia gas into toluene with methyl o-hydroxybenzoate, and the product yield is 95%; Patent document WO2016114668A1 reports the process of synthesizing o-hydroxybenzamide by reacting methyl o-hydroxybenzoate with liquid ammonia in methanol, with a yield of 94%, but it is only a trace synthesis. Regarding the method for synthesizing o-hydroxybenzamide by reacting methyl o-hydroxybenzoate with ammonia in an organic solvent, the applicant has verified that when methyl o-hydroxybenzoate and ammonia are synthesized by ammoniation in organic solvents such as methanol and toluene, excessive ammonia consumption (more than 6 times the equivalent) occurs, and the product yield needs to be improved. Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for preparing o-hydroxybenzamide with high yield, low ammonia consumption, simple process flow and environmental friendliness.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions.

[0006] A method for preparing o-hydroxybenzamide comprises the following steps:

[0007] Methyl o-hydroxybenzoate, ammonia, a porous base catalyst, an antioxidant and a solvent are added into a reaction kettle, wherein the molar ratio of methyl o-hydroxybenzoate to ammonia is 1:1.5-3. Nitrogen is introduced into the reaction kettle and pressurized to 0.4MPa-0.8MPa. The temperature is raised to 50°C-65°C to react until no methyl o-hydroxybenzoate is detected in the reaction liquid. After the reaction is completed, the catalyst is filtered and recovered, and the ammonia and the solvent are distilled off to obtain an o-hydroxybenzamide product.

[0008] In the above-mentioned method for preparing o-hydroxybenzamide, preferably, the porous base catalyst is porous hydroxyapatite, and the mass ratio of the o-hydroxybenzoic acid methyl ester to the porous base catalyst is 1:0.01-0.05.

[0009] In the above-mentioned method for preparing o-hydroxybenzamide, preferably, the mass ratio of the o-hydroxybenzoic acid methyl ester, the antioxidant and the solvent is 1:0.001-0.05:0.5-3.

[0010] In the above-mentioned method for preparing o-hydroxybenzamide, preferably, the mass ratio of the o-hydroxybenzoic acid methyl ester, the antioxidant and the solvent is 1:0.002-0.01:1-2.

[0011] In the above-mentioned method for preparing o-hydroxybenzamide, preferably, the antioxidant is one or more of sodium sulfite, sodium bisulfite, ammonium sulfite, sodium pyrosulfite and sodium thiosulfate.

[0012] In the above-mentioned method for preparing o-hydroxybenzamide, preferably, the solvent is one or more of methanol, ethanol, toluene and xylene, preferably methanol.

[0013] In the above-mentioned method for preparing o-hydroxybenzamide, preferably, the reaction time is 6 h to 10 h.

[0014] In the above-mentioned method for preparing o-hydroxybenzamide, preferably, the content of the o-hydroxybenzamide product is ≥ 99%, and the yield is ≥ 99%.

[0015] Compared with the prior art, the advantages of the present invention are:

[0016] In the method for preparing o-hydroxybenzamide of the present invention, methyl o-hydroxybenzoate and ammonia are subjected to an amination reaction in an organic solvent in the presence of a porous base catalyst and an antioxidant to synthesize o-hydroxybenzamide. Compared with the high conversion rate and low reaction selectivity (85-96%) of the reaction of methyl o-hydroxybenzoate and aqueous ammonia, the reaction selectivity of the present invention is higher than 99%, the reaction yield is high, the product purity is high, and the product is white crystals because no hydrolysis side reaction occurs.

[0017] In the method for preparing o-hydroxybenzamide of the present invention, porous hydroxyapatite is used as a solid base catalyst to catalyze the ammoniation of methyl o-hydroxybenzoate to synthesize o-hydroxybenzamide. The porous hydroxyapatite can be used as a base catalyst and has good adsorption properties for ammonia, thereby promoting the enrichment of ammonia in the reaction solution, making the catalytic reaction efficient, having a high conversion rate (>99.5%) and a high selectivity (>99.5%). The solid catalyst can also be recovered by simple filtration separation.

[0018] In the reported prior art, excess ammonia is usually used, such as using more than 6 times the equivalent of ammonia, to increase the concentration of ammonia in the organic solvent, increase the amination reaction rate, and increase the reaction conversion rate. After the reaction, the ammonia needs to be recovered and processed by an additional process. In the method for preparing o-hydroxybenzamide of the present invention, low equivalent ammonia (1 to 3 times the equivalent) is designed, and the catalytic reaction is carried out in combination with a porous base catalyst. The low equivalent ammonia (1 to 3 times the equivalent) not only has a higher reaction efficiency in organic solvents such as methanol and toluene, but also can greatly reduce the consumption of ammonia, simplify the recovery and treatment process of ammonia, and at the same time, the product content of the method of the present invention is as high as more than 99%, the yield is as high as more than 99%, the color is stable, and no wastewater and solid waste are generated. It is an environmentally friendly production method, easy to operate, mild reaction conditions, recoverable catalysts, simple process, and easy to industrialize. DETAILED DESCRIPTION

[0019] The present invention is further described below in conjunction with specific preferred embodiments, but the scope of protection of the present invention is not limited thereby. The materials and instruments used in the following examples are all commercially available, among which porous hydroxyapatite is purchased from Li Ke Pharmaceutical Technology Co., Ltd. The purity of the product in the example is detected by high performance liquid chromatography (HPLC), and the yield of the product is calculated after measuring the external standard content of o-hydroxybenzamide in the solution by HPLC. The addition of ammonia can be directly introduced into the pressure reactor or first introduced into low temperature (-10°C to -5°C) methanol and then added to the pressure reactor.

[0020] Example 1

[0021] A method for preparing o-hydroxybenzamide of the present invention comprises the following steps:

[0022] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 0.9 g of porous hydroxyapatite, 0.1 g of sodium sulfite and 90 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa, and the temperature was raised to 50° C. After reacting for 10 h, no methyl o-hydroxybenzoate was detected in the reaction solution, and the reaction was terminated. The catalyst was recovered by filtration, and excess ammonia and all solvents (recoverable) were removed by reduced pressure distillation to obtain a white crystalline powder, which was the o-hydroxybenzamide product, with a content of 99.7% and a yield of 99.5%.

[0023] Example 2

[0024] A method for preparing o-hydroxybenzamide of the present invention comprises the following steps:

[0025] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 2.3 g of porous hydroxyapatite, 0.1 g of sodium sulfite and 90 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa, the reaction temperature was 50 ° C, and the reaction was carried out for 8 h. No methyl o-hydroxybenzoate was detected in the reaction solution, and the reaction was completed. The catalyst was filtered and recovered, and the excess ammonia and all solvents were distilled off under reduced pressure to obtain a white crystalline powder, which was the o-hydroxybenzamide product, with a content of 99.5% and a yield of 99.2%.

[0026] Example 3

[0027] A method for preparing o-hydroxybenzamide of the present invention comprises the following steps:

[0028] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 15.3 g of ammonia (0.9 mol), 0.9 g of porous hydroxyapatite, 0.1 g of sodium sulfite and 46 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa, the reaction temperature was 50 ° C, and the reaction was carried out for 8 h. No methyl o-hydroxybenzoate was detected in the reaction solution, and the reaction was completed. The catalyst was filtered and recovered, and the excess ammonia and all solvents were distilled off under reduced pressure to obtain a white crystalline powder, which was the o-hydroxybenzamide product, with a content of 99.8% and a yield of 99.8%.

[0029] Example 4

[0030] A method for preparing o-hydroxybenzamide of the present invention comprises the following steps:

[0031] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 0.9 g of porous hydroxyapatite, 0.1 g of sodium sulfite and 46 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.8 MPa, the reaction temperature was 65 ° C, and the reaction was carried out for 6 h. No methyl o-hydroxybenzoate was detected in the reaction solution, and the reaction was completed. The catalyst was filtered and recovered, and the excess ammonia and all solvents were removed by distillation under reduced pressure to obtain a white crystalline powder, which was the o-hydroxybenzamide product, with a content of 99.0% and a yield of 99.1%.

[0032] Example 5

[0033] A method for preparing o-hydroxybenzamide of the present invention comprises the following steps:

[0034] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 0.9 g of porous hydroxyapatite, 0.1 g of sodium sulfite and 90 g of toluene were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa, the reaction temperature was 60 ° C, and the reaction was carried out for 10 h. No methyl o-hydroxybenzoate was detected in the reaction solution, and the reaction was completed. The catalyst was filtered and recovered, and the excess ammonia and all solvents were removed by distillation under reduced pressure to obtain a white crystalline powder, which was the o-hydroxybenzamide product, with a content of 99.3% and a yield of 99.0%.

[0035] Example 6

[0036] A method for preparing o-hydroxybenzamide of the present invention comprises the following steps:

[0037] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 0.9 g of porous hydroxyapatite, 0.4 g of sodium sulfite and 46 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa, the reaction temperature was 60 ° C, and the reaction was carried out for 8 h. No methyl o-hydroxybenzoate was detected in the reaction solution, and the reaction was completed. The catalyst was filtered and recovered, and the excess ammonia and all solvents were removed by distillation under reduced pressure to obtain a white crystalline powder, which was the o-hydroxybenzamide product, with a content of 99.3% and a yield of 99.4%.

[0038] Comparative Example 1

[0039] A method for preparing o-hydroxybenzamide comprises the following steps:

[0040] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 0.1 g of sodium sulfite and 90 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa. The reaction temperature was 50 ° C. and the reaction was carried out for 10 h. After the reaction was completed, excess ammonia and all solvents were removed by distillation under reduced pressure to obtain a white crystalline powder, which was the o-hydroxybenzamide product, with a content of 85.4% and a yield of 86.0%.

[0041] Comparative Example 2

[0042] A method for preparing o-hydroxybenzamide comprises the following steps:

[0043] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 0.9 g of porous hydroxyapatite and 90 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa. The reaction temperature was 50 ° C. and the reaction was carried out for 10 h. No methyl o-hydroxybenzoate was detected in the reaction solution. After the reaction was completed, the catalyst was filtered and recovered, and the excess ammonia and all solvents were removed by distillation under reduced pressure to obtain a pink crystalline powder, which was the o-hydroxybenzamide product with a content of 98.1% and a yield of 98.4%.

[0044] Comparative Example 3

[0045] A method for preparing o-hydroxybenzamide comprises the following steps:

[0046] 45.6 g (0.3 mol) of methyl o-hydroxybenzoate, 10.2 g of ammonia (0.6 mol), 0.9 g of potassium carbonate, 0.1 g of sodium sulfite and 90 g of methanol were added to a 250 mL pressure reactor, which was sealed. Nitrogen was introduced into the pressure reactor until the pressure was 0.6 MPa. The reaction temperature was 50 ° C. and the reaction was carried out for 10 h. After the reaction was completed, the catalyst was filtered and recovered, and the excess ammonia and all solvents were removed by distillation under reduced pressure to obtain a light pink crystalline powder, which was the o-hydroxybenzamide product, with a content of 90.6% and a yield of 91.1%.

[0047] The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as above in the preferred embodiment, it is not used to limit the present invention. Any technician familiar with the art can make many possible changes and modifications to the technical solution of the present invention by using the methods and technical contents disclosed above without departing from the spirit and technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention, still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing o-hydroxybenzamide, characterized in that: The following steps are involved: Methyl o-hydroxybenzoate, ammonia, a porous base catalyst, an antioxidant and a solvent are added into a reaction kettle, wherein the molar ratio of methyl o-hydroxybenzoate to ammonia is 1:1.5-3. Nitrogen is introduced into the reaction kettle and pressurized to 0.4MPa-0.8MPa. The temperature is raised to 50°C-65°C to react until no methyl o-hydroxybenzoate is detected in the reaction liquid. After the reaction is completed, the catalyst is filtered and recovered, and the ammonia and the solvent are distilled off to obtain an o-hydroxybenzamide product.

2. The method for preparing o-hydroxybenzamide according to claim 1, characterized in that: The porous alkali catalyst is porous hydroxyapatite, and the mass ratio of the methyl o-hydroxybenzoate to the porous alkali catalyst is 1:0.01-0.

05.

3. The method for preparing o-hydroxybenzamide according to claim 1, characterized in that: The mass ratio of the methyl o-hydroxybenzoate, the antioxidant and the solvent is 1:0.001-0.05:0.5-3.

4. The method for preparing o-hydroxybenzamide according to claim 3, characterized in that: The mass ratio of the methyl o-hydroxybenzoate, the antioxidant and the solvent is 1:0.002-0.01:1-2.

5. The method for preparing o-hydroxybenzamide according to any one of claims 1 to 4, characterized in that: The antioxidant is one or more of sodium sulfite, sodium bisulfite, ammonium sulfite, sodium pyrosulfite and sodium thiosulfate.

6. The method for preparing o-hydroxybenzamide according to any one of claims 1 to 4, characterized in that: The solvent is one or more of methanol, ethanol, toluene and xylene.

7. The method for preparing o-hydroxybenzamide according to any one of claims 1 to 4, characterized in that: The reaction time is 6 h to 10 h.

8. The method for preparing o-hydroxybenzamide according to any one of claims 1 to 4, characterized in that: The content of the o-hydroxybenzamide product is ≥99%, and the yield is ≥99%.