Synthesis method of N-tert-butyl-4-aminobenzamide

Abstract

The present invention discloses a method for synthesizing N-tert-butyl-4-aminobenzamide, which uses p-nitrobenzaldehyde and tert-butylamine as starting materials. First, through a condensation reaction, the intermediate tert-butyl-(4-nitro-benzylidene)amine is obtained, then through a catalytic oxidation reaction, N-tert-butyl-4-nitrobenzamide is obtained, and finally through a catalytic hydrogenation reaction, N-tert-butyl-4-aminobenzamide is obtained. The raw material p-nitrobenzaldehyde in the present invention has better stability and higher safety compared with p-nitrobenzoyl chloride used in the prior art, which greatly improves the safety and reliability of the process, and also improves the quality of the product to a certain extent, reduces the manufacturing cost of the product, and enhances the market competitiveness of the product; and the condensation reaction is carried out in a closed manner under solvent-free conditions, which can not only obtain a higher reaction yield, but also reduce the material consumption, lower the emission level, and is more environmentally friendly.

Description

Technical Field

[0001] The present invention belongs to the technical field of fine chemical industry, and particularly relates to a method for synthesizing N-tert-butyl-4-aminobenzamide. Background Art

[0002] N-tert-butyl-4-aminobenzamide [CAS No. 93483-71-7, molecular formula C 11 H 16 N2O, molecular weight 192.26] is an important benzamide compound and can be used to treat dementia caused by HIV virus infection.

[0003] The central nervous pathological changes associated with HIV infection include demyelination, astrocyte increase, neuron loss, dendritic branch damage, and reduction in the presynaptic region. Administering benzamide drugs to patients at an early stage can delay neuronal damage, postpone the onset of dementia, protect the intellectual level of patients, enable the working ability and living ability of patients to be maintained at a relatively good level, improve the quality of life of patients, and thus save a large amount of social costs.

[0004] N-tert-butyl-4-aminobenzamide is an important intermediate for preparing benzamide anti-AIDS drugs. The research and optimization of its synthesis process are beneficial to improving the efficacy of related drugs and reducing the treatment cost of related diseases.

[0005] Currently, the synthesis methods of N-tert-butyl-4-aminobenzamide all use p-nitrobenzoyl chloride and tert-butylamine as starting materials, and are obtained through two steps of condensation and reduction (see patent documents CN1182416A, CN1218399A, CN110305032A, etc.).

[0006] The deficiencies of this synthesis method are as follows:

[0007] (1) The yield of the condensation reaction of p-nitrobenzoyl chloride and tert-butylamine is relatively low. The yield in patent documents CN1182416A and CN1218399A is less than 80%. Although the yield in patent document CN110305032A can reach more than 90%, a large amount of benzene solvents need to be used, which is not environmentally friendly.

[0008] (2) The raw material p-nitrobenzoyl chloride is prone to hydrolysis and deterioration, and its preparation, storage and transportation have certain safety risks, which affect the quality and cost of the product to a certain extent. Summary of the Invention

[0009] The purpose of the present invention is to solve the above problems and provide a method for synthesizing N-tert-butyl-4-aminobenzamide with high raw material safety, high reaction yield and environmental friendliness.

[0010] The technical solution for achieving the object of the present invention is as follows: A method for synthesizing N-tert-butyl-4-aminobenzamide, comprising the following steps:

[0011] ① Using p-nitrobenzaldehyde and tert-butylamine as starting materials, first obtaining the intermediate tert-butyl-(4-nitro-benzylidene)amine through a condensation reaction, and then obtaining N-tert-butyl-4-nitrobenzamide through a catalytic oxidation reaction;

[0012] ② The N-tert-butyl-4-nitrobenzamide obtained in step ① is subjected to a catalytic hydrogenation reaction to obtain N-tert-butyl-4-aminobenzamide.

[0013] The synthesis route is as follows:

[0014] .

[0015] In the above step ①, the molar ratio of the p-nitrobenzaldehyde to the tert-butylamine is 1:2 to 1:12, preferably 1:6 to 1:8.

[0016] In the above step ①, the condensation reaction is carried out under solvent-free conditions; the temperature of the condensation reaction is 70 to 150 °C, preferably 95 to 115 °C.

[0017] In the above step ①, the condensation reaction is carried out under airtight conditions; the pressure of the condensation reaction is 0.01 to 0.05 MPa, preferably 0.02 to 0.03 MPa.

[0018] In the above step ①, the oxidant used in the catalytic oxidation reaction is oxygen.

[0019] In the above step ①, the catalytic system used in the catalytic oxidation reaction is manganese acetate + cobalt acetate tetrahydrate + sodium bromide.

[0020] In the above step ①, the catalytic oxidation reaction is carried out in an acetic acid solvent.

[0021] In the above step ①, the temperature of the catalytic oxidation reaction is 50 to 100 °C, preferably 75 to 90 °C.

[0022] In the above step ②, the catalyst used in the catalytic hydrogenation reaction is a noble metal catalyst; preferably a Pd / C catalyst or a Pt / C catalyst.

[0023] In the above step ②, the temperature of the catalytic hydrogenation reaction is 80 to 160 °C, preferably 90 to 110 °C.

[0024] In the above step ②, the pressure of the catalytic hydrogenation reaction is 0.5 to 2.0 MPa, preferably 0.6 to 1.5 MPa.

[0025] The positive effects of the present invention are:

[0026] (1) Compared with p-nitrobenzoyl chloride used in the prior art, the raw material p-nitrobenzaldehyde of the present invention has better stability and higher safety, which greatly improves the safety and reliability of the process, to a certain extent improves the quality of the product, reduces the manufacturing cost of the product, and enhances the market competitiveness of the product.

[0027] (2) The condensation reaction of the present invention is carried out in a closed manner under solvent-free conditions, which can not only obtain a high reaction yield, but also reduce material consumption, lower the emission level, and is more friendly to the environment. Specific Embodiments

[0028] (Example 1)

[0029] The synthesis method of N-tert-butyl-4-aminobenzamide in this example is as follows:

[0030] ① Add 15.1 g of p-nitrobenzaldehyde (0.1 mol) and 70 mL of tert-butylamine (0.67 mol) to a high-pressure reactor, displace with nitrogen three times, adjust the pressure in the reactor to 0.02 MPa, raise the temperature in the reactor to 105 - 110 °C, and carry out the condensation reaction for 3 h under closed conditions.

[0031] After the reaction is completed, cool down to 30 °C, concentrate under reduced pressure to recover tert-butylamine, add 100 mL of acetic acid to the remaining material first, then add 0.4 g of manganese acetate, 0.5 g of cobalt acetate tetrahydrate and 1.1 g of sodium bromide, continuously introduce oxygen and slowly raise the temperature to 85 - 90 °C, and carry out the catalytic oxidation reaction for 5 h.

[0032] After the reaction is completed, cool down to 45 °C, concentrate under reduced pressure to recover acetic acid until the volume of the material is reduced to 1 / 3 of the original volume, then cool down to 5 °C, stir and crystallize, filter, wash the filter cake with a small amount of ethanol, and dry to obtain 19.2 g of light yellow solid N-tert-butyl-4-nitrobenzamide, with a yield of 86.5%, a purity of 99.1%, and a melting point of 160.4 - 161.5 °C.

[0033] ② Add 60 mL of ethyl acetate, 18.6 g of N-tert-butyl-4-nitrobenzamide obtained in step ① and 0.8 g of Pd / C catalyst with a mass fraction of 3 wt% to a high-pressure reactor, displace with nitrogen three times first, then displace with hydrogen three times, adjust the pressure in the reactor to 0.8 - 1.2 MPa, raise the temperature in the reactor to 95 - 105 °C, and maintain the temperature and pressure for reaction for 4 h.

[0034] After the reaction was completed, the Pd / C catalyst was recovered by filtration. The filtrate was evaporated under reduced pressure to recover the solvent to a certain volume, cooled, crystallized, filtered. The filter cake was washed with a small amount of ethyl acetate and then dried in vacuo at 80-85 °C to obtain 15.4 g of white powder N-tert-butyl-4-aminobenzamide, with a yield of 95.7%, a purity of 99.7%, and a melting point of 125.6-126.7 °C.

[0035] (Example 2)

[0036] The synthetic method of N-tert-butyl-4-aminobenzamide in this example is as follows:

[0037] ① 15.1 g of p-nitrobenzaldehyde (0.1 mol) and 68 mL of tert-butylamine (0.65 mol) were added to a high-pressure reactor. After purging with nitrogen three times, the pressure in the reactor was adjusted to 0.02 MPa, and the temperature in the reactor was raised to 100-105 °C. The condensation reaction was carried out for 3 h under closed conditions.

[0038] After the reaction was completed, the temperature was lowered to 32 °C, and tert-butylamine was recovered by concentration under reduced pressure. First, 95 mL of acetic acid was added to the remaining material, and then 0.5 g of manganese acetate, 0.5 g of cobalt acetate tetrahydrate, and 1.2 g of sodium bromide were added. Oxygen was continuously introduced and the temperature was slowly raised to 80-85 °C for the catalytic oxidation reaction for 5 h.

[0039] After the reaction was completed, the temperature was lowered to 45 °C, and acetic acid was recovered by concentration under reduced pressure until the volume of the material was reduced to 1 / 3 of the original volume. Then the temperature was lowered to 5 °C, and crystallization was carried out with stirring. After filtration, the filter cake was washed with a small amount of ethanol and then dried to obtain 19.4 g of light yellow solid N-tert-butyl-4-nitrobenzamide, with a yield of 87.4%, a purity of 99.2%, and a melting point of 160.5-161.6 °C.

[0040] ② 60 mL of ethyl acetate, 18.8 g of N-tert-butyl-4-nitrobenzamide obtained in step ①, and 0.9 g of 3 wt% Pd / C catalyst were added to a high-pressure reactor. After purging with nitrogen three times and then with hydrogen three times, the pressure in the reactor was adjusted to 0.9-1.3 MPa, and the temperature in the reactor was raised to 95-105 °C. The reaction was carried out under constant temperature and pressure for 4 h.

[0041] After the reaction was completed, the Pd / C catalyst was recovered by filtration. The filtrate was evaporated under reduced pressure to recover the solvent to a certain volume, cooled, crystallized, filtered. The filter cake was washed with a small amount of ethyl acetate and then dried in vacuo at 80-85 °C to obtain 15.7 g of white powder N-tert-butyl-4-aminobenzamide, with a yield of 96.6%, a purity of 99.6%, and a melting point of 125.5-126.6 °C.

[0042] (Example 3)

[0043] The synthesis method of N-tert-butyl-4-aminobenzamide in this example is as follows:

[0044] ① Add 15.1 g of p-nitrobenzaldehyde (0.1 mol) and 72 mL of tert-butylamine (0.69 mol) to a high-pressure reactor. Replace the gas with nitrogen three times, adjust the pressure in the reactor to 0.03 MPa, raise the temperature in the reactor to 95 - 100 °C, and carry out the condensation reaction for 4 h under closed conditions.

[0045] After the reaction is completed, cool down to 30 °C, concentrate under reduced pressure to recover tert-butylamine. First, add 100 mL of acetic acid to the remaining material, and then add 0.6 g of manganese acetate, 0.5 g of cobalt acetate tetrahydrate, and 1.2 g of sodium bromide. Continuously introduce oxygen and slowly raise the temperature to 78 - 83 °C, and carry out the catalytic oxidation reaction for 6 h.

[0046] After the reaction is completed, cool down to 45 °C, concentrate under reduced pressure to recover acetic acid until the volume of the material is reduced to 1 / 3 of the original volume, then cool down to 5 °C, stir to crystallize, filter, wash the filter cake with a small amount of ethanol, and then dry to obtain 19.4 g of light yellow solid N-tert-butyl-4-nitrobenzamide, with a yield of 87.4%, a purity of 99.3%, and a melting point of 160.5 - 161.5 °C.

[0047] ② Add 70 mL of ethyl acetate, 18.6 g of N-tert-butyl-4-nitrobenzamide obtained in step ①, and 0.9 g of 3 wt% Pt / C catalyst to a high-pressure reactor. First, replace the gas with nitrogen three times, then replace the gas with hydrogen three times, adjust the pressure in the reactor to 0.8 - 1.2 MPa, raise the temperature in the reactor to 90 - 100 °C, and carry out the reaction under constant temperature and pressure for 3 h.

[0048] After the reaction is completed, filter to recover the Pd / C catalyst, evaporate the filtrate under reduced pressure to recover the solvent to a certain volume, cool, crystallize, filter, wash the filter cake with a small amount of ethyl acetate, and then dry in vacuum at 80 - 85 °C to obtain 15.6 g of white powder N-tert-butyl-4-aminobenzamide, with a yield of 97.0%, a purity of 99.8%, and a melting point of 125.5 - 126.6 °C.

[0049] (Example 4)

[0050] The synthesis method of N-tert-butyl-4-aminobenzamide in this example is as follows:

[0051] ① Add 15.1 g of p-nitrobenzaldehyde (0.1 mol) and 80 mL of tert-butylamine (0.76 mol) to a high-pressure reactor. Replace the gas with nitrogen three times, adjust the pressure in the reactor to 0.02 MPa, raise the temperature in the reactor to 105 - 110 °C, and carry out the condensation reaction for 3 h under closed conditions.

[0052] After the reaction is completed, cool down to 30°C, concentrate under reduced pressure to recover tert-butylamine, add 110 mL of acetic acid to the remaining material first, and then add 0.4 g of manganese acetate, 0.8 g of cobalt acetate tetrahydrate, and 1.3 g of sodium bromide. Continuously introduce oxygen and slowly heat up to 85 - 90°C, and carry out the catalytic oxidation reaction for 5 h.

[0053] After the reaction is completed, cool down to 45°C, concentrate under reduced pressure to recover acetic acid until the volume of the material is reduced to 1 / 3 of the original volume, then cool down to 5°C, stir to crystallize, filter, wash the filter cake with a small amount of ethanol, and then dry to obtain 19.9 g of light yellow solid N-tert-butyl-4-nitrobenzamide, with a yield of 89.6%, a purity of 99.4%, and a melting point of 160.5 - 161.6°C.

[0054] ② Add 60 mL of tetrahydrofuran, 18.8 g of N-tert-butyl-4-nitrobenzamide obtained in step ①, and 0.8 g of 3 wt% Pt / C catalyst to the high-pressure reactor. First, displace with nitrogen three times, then displace with hydrogen three times. Adjust the pressure in the reactor to 0.8 - 1.2 MPa, raise the temperature in the reactor to 95 - 105°C, and keep the temperature and pressure constant for 4 h.

[0055] After the reaction is completed, filter to recover the Pd / C catalyst, evaporate the filtrate under reduced pressure to recover the solvent until the volume of the original material is reduced to 1 / 3, then add 50 mL of toluene, cool, crystallize, filter, wash the filter cake with a small amount of toluene, and dry it in vacuum at 80 - 85°C to obtain 15.8 g of white powder N-tert-butyl-4-aminobenzamide, with a yield of 97.2%, a purity of 99.8%, and a melting point of 125.6 - 126.7°C.

[0056] (Example 5)

[0057] The synthesis method of N-tert-butyl-4-aminobenzamide in this example is as follows:

[0058] ① Add 30.2 g of p-nitrobenzaldehyde (0.2 mol) and 138 mL of tert-butylamine (1.32 mol) to the high-pressure reactor, displace with nitrogen three times, adjust the pressure in the reactor to 0.02 MPa, raise the temperature in the reactor to 103 - 112°C, and carry out the condensation reaction for 3 h under closed conditions.

[0059] After the reaction is completed, cool down to 30°C, concentrate under reduced pressure to recover tert-butylamine, add 180 mL of acetic acid to the remaining material first, and then add 0.9 g of manganese acetate, 1.0 g of cobalt acetate tetrahydrate, and 2.3 g of sodium bromide. Continuously introduce oxygen and slowly heat up to 85 - 90°C, and carry out the catalytic oxidation reaction for 5.5 h.

[0060] After the reaction was completed, the temperature was lowered to 45 °C, and acetic acid was recovered by reduced-pressure concentration until the volume of the material was 1 / 3 of the original volume. Then the temperature was further lowered to 5 °C, and crystallization was carried out with stirring. After filtration, the filter cake was washed with a small amount of ethanol and then dried to obtain 38.5 g of light yellow solid N-tert-butyl-4-nitrobenzamide, with a yield of 86.7%, a purity of 99.3%, and a melting point of 160.6 - 161.7 °C.

[0061] ② 80 mL of ethanol, 20.0 g of the N-tert-butyl-4-nitrobenzamide obtained in step ①, and 1.0 g of a 5 wt% Pd / C catalyst were added to a high-pressure reactor. The reactor was purged with nitrogen three times and then with hydrogen three times. The pressure in the reactor was adjusted to 0.7 - 1.1 MPa, and the temperature in the reactor was raised to 95 - 105 °C, and the reaction was carried out under isothermal and isobaric conditions for 4 h.

[0062] After the reaction was completed, the Pd / C catalyst was recovered by filtration. The filtrate was evaporated under reduced pressure to recover the solvent to a certain volume, cooled, crystallized, and filtered. The filter cake was washed with a small amount of ethanol and then dried in vacuo at 90 - 95 °C to obtain 16.8 g of white powder N-tert-butyl-4-aminobenzamide, with a yield of 97.1%, a purity of 99.7%, and a melting point of 125.6 - 126.6 °C.

Claims

1. A method for synthesizing N-tert-butyl-4-aminobenzamide, characterized in that It has the following steps: ① Using p-nitrobenzaldehyde and tert-butylamine as starting materials, first obtain the intermediate tert-butyl-(4-nitro-benzylidene)amine through a condensation reaction, and then obtain N-tert-butyl-4-nitrobenzamide through a catalytic oxidation reaction; the oxidant used in the catalytic oxidation reaction is oxygen; the catalytic system used in the catalytic oxidation reaction is manganese acetate + cobalt acetate tetrahydrate + sodium bromide; ② The N-tert-butyl-4-nitrobenzamide obtained in step ① is subjected to a catalytic hydrogenation reaction to obtain N-tert-butyl-4-aminobenzamide.

2. The synthesis method of N-tert-butyl-4-aminobenzamide according to claim 1, wherein: In the above step ①, the molar ratio of the p-nitrobenzaldehyde to the tert-butylamine is 1:2 to 1:

12.

3. The synthesis method of N-tert-butyl-4-aminobenzamide according to claim 2, characterized in that: The molar ratio of the p-nitrobenzaldehyde to the tert-butylamine is 1:6 to 1:

8.

4. The synthesis method of N-tert-butyl-4-aminobenzamide according to any one of claims 1 to 3, characterized in that: In the above step ①, the condensation reaction is carried out under solvent-free conditions; the temperature of the condensation reaction is 95 to 115 °C.

5. The synthesis method of N-tert-butyl-4-aminobenzamide according to any one of claims 1 to 3, characterized in that: In the above step ①, the condensation reaction is carried out under closed conditions; the pressure of the condensation reaction is 0.02 to 0.03 MPa.

6. The synthesis method of N-tert-butyl-4-aminobenzamide according to any one of claims 1 to 3, characterized in that: In the above step ①, the catalytic oxidation reaction is carried out in an acetic acid solvent, and the temperature of the catalytic oxidation reaction is 75 to 90 °C.

7. The method for synthesizing N-tert-butyl-4-aminobenzamide according to any one of claims 1 to 3, characterized in that: In the above step ②, the catalyst used in the catalytic hydrogenation reaction is a Pd / C catalyst or a Pt / C catalyst.

8. The synthesis method of N-tert-butyl-4-aminobenzamide according to any one of claims 1 to 3, characterized in that: In the above step ②, the temperature of the catalytic hydrogenation reaction is 80 to 160 °C, and the pressure of the catalytic hydrogenation reaction is 0.5 to 2.0 MPa.

9. The synthesis method of N-tert-butyl-4-aminobenzamide according to claim 8, characterized in that: The temperature of the catalytic hydrogenation reaction is 90 to 110 °C, and the pressure of the catalytic hydrogenation reaction is 0.6 to 1.5 Mpa.