Synthetic method of 4-amino-N-tert-butylbenzamide

Abstract

The invention discloses a synthesis method of 4-amino-N-tert-butylbenzamide, which comprises the following steps: by taking p-aminobenzonitrile and tert-butyl acetate as initial raw materials, carrying out Ritter reaction in an acidic system to prepare the 4-amino-N-tert-butylbenzamide in one step; the acidic system is composed of an acidic solvent and an acidic catalyst; the acidic solvent is acetic acid; the acid catalyst is p-toluenesulfonic acid or sulfuric acid. The method provided by the invention not only solves the problem that the tert-butylamine and other raw materials with pungent smell need to be adopted in the prior art and are not friendly to human bodies and environment, but also avoids the problems of low safety caused by a high-risk process and high production cost caused by the need of adopting an expensive palladium catalyst in the prior art; particularly, the method is short in reaction step, simpler and more convenient to operate, more stable in process and suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a synthesis method of 4-amino-N-tert-butylbenzamide. Background Art

[0002] 4-Amino-N-tert-butylbenzamide, white powdery solid, molecular formula: C 11 H 16 N2O, relative molecular weight: 192.26, CAS number: 93483-71-7, is the main starting material for synthesizing new ultraviolet absorbers such as HEB. This type of ultraviolet absorber has the characteristics of high absorption efficiency, non-toxicity, no teratogenic side effects, good light and thermal stability, etc. It is the most commonly used light stabilizer at present. This is a type of substance that can strongly and selectively absorb high-energy ultraviolet light, convert energy, and release or consume energy in the form of heat energy or harmless low-energy radiation. It is mainly used in water-soluble chemical sunscreens, sunscreens, and lotions. It can also improve the color durability of dyed textiles, prevent wool textiles from yellowing, and prevent synthetic fiber fabrics from fading. At the same time, it can be used in hair products such as hair spray and mousse to prevent hair damage and whitening caused by ultraviolet radiation. It is widely used.

[0003] The synthesis methods of 4-amino-N-tert-butylbenzamide disclosed in the prior art mainly include the following: (i) Using p-nitrobenzoyl chloride and tert-butylamine as starting materials, 4-amino-N-tert-butylbenzamide is obtained through a two-step reaction of condensation and catalytic hydrogenation [see Chinese patent documents CN1182416A, CN1218399A, CN110305032A, etc.].

[0004] The synthetic route is as follows: .

[0005] The shortcomings of this method are: (1) both p-nitrobenzoyl chloride and tert-butylamine have pungent odors and are not friendly to humans and the environment; (2) catalytic hydrogenation is a high-risk process and requires the use of expensive palladium catalysts, resulting in high production costs.

[0006] (ii) Using p-nitrobenzaldehyde and tert-butylamine as starting materials, 4-amino-N-tert-butylbenzamide is obtained through three steps of condensation, catalytic oxidation and catalytic hydrogenation [see Chinese patent document CN116283642A].

[0007] The synthetic route is as follows: .

[0008] The shortcomings of this method are: (1) the synthesis route is long and requires three steps of reaction; (2) tert-butylamine is still required, which still has the problem of being unfriendly to the human body and the environment; (3) catalytic oxidation and catalytic hydrogenation are both high-risk processes, and the catalyst cost is also high. Summary of the invention

[0009] The purpose of the present invention is to solve the above problems and provide a method for synthesizing 4-amino-N-tert-butylbenzamide to solve the problems of the prior art that it is unfriendly to the environment, has a high production cost, and especially contains high-risk processes.

[0010] The technical scheme for achieving the purpose of the present invention is: a method for synthesizing 4-amino-N-tert-butylbenzamide, which uses p-aminobenzonitrile and tert-butyl acetate as starting materials, and obtains 4-amino-N-tert-butylbenzamide in one step through a Ritter reaction in an acidic system.

[0011] The synthetic route is as follows: .

[0012] The molar ratio of the p-aminobenzonitrile to the tert-butyl acetate is 1:1 to 1:1.5.

[0013] The acidic system is composed of an acidic solvent and an acidic catalyst.

[0014] The acidic solvent is acetic acid; the weight ratio of the p-aminobenzonitrile to the acetic acid is 1:1 to 1:5, preferably 1:1.5 to 1:2.5.

[0015] The acid catalyst is p-toluenesulfonic acid or sulfuric acid; the molar ratio of the p-aminobenzonitrile to the acid catalyst is 1:0.1 to 1:0.5.

[0016] When the acid catalyst is p-toluenesulfonic acid, the reaction temperature is 75-100° C., preferably 80-90° C.; the reaction time is 3-7 hours, preferably 4-5 hours.

[0017] When the acid catalyst is sulfuric acid, the reaction temperature is 15 to 30° C. and the reaction time is 2 to 6 hours.

[0018] The present invention has the positive effects: (1) The method of the present invention not only solves the problem that the prior art requires the use of raw materials with pungent odors such as tert-butylamine, which is unfriendly to the human body and the environment, but also avoids the problem that the prior art has high-risk processes resulting in low safety and the need to use expensive palladium catalysts resulting in high production costs. In particular, the present invention has a shorter reaction step, simpler operation, more stable process, and is suitable for large-scale industrial production.

[0019] (2) The method of the present invention uses acetic acid as a solvent, so that the raw material p-aminobenzonitrile can participate in the reaction in the form of acetate, thereby effectively avoiding the amine ester exchange side reaction between it and tert-butyl acetate, greatly reducing the generation of by-products, and having a higher product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The DSC spectrum of the final product obtained in Example 1 is shown in FIG.

[0021] Figure 2 The LC-MS spectrum of the final product obtained in Example 1 is shown in FIG. DETAILED DESCRIPTION

[0022] (Example 1) The synthetic method of 4-amino-N-tert-butylbenzamide of the present embodiment is as follows: Add 50 g of p-aminobenzonitrile (0.423 mol) and 100 g of acetic acid into a 1 L three-necked flask, then add 59 g of tert-butyl acetate (0.508 mol) and 14.5 g of p-toluenesulfonic acid (0.084 mol), heat to 80-85 °C and stir to react for 5 h.

[0023] After the reaction, the temperature was controlled below 85°C and part of the acetic acid (about 70 g) was concentrated under reduced pressure, then the temperature was lowered to 20-30°C, and a 15 wt% sodium carbonate aqueous solution (about 300 g) was added dropwise at a temperature controlled to adjust the system pH to 9. After the addition, stirring was continued for 30 min, filtered, the filter cake was rinsed with a small amount of water, returned to the above 1L three-necked flask, and then 480 mL of toluene was added, the temperature was raised to 85-90°C, stirred and dissolved, allowed to stand for stratification, the water layer was separated, the organic layer was cooled to 0-5°C within 2-3 h, and stirred for 30 min, filtered, the filter cake was rinsed with a small amount of toluene, and placed in a 70-80°C oven for reduced pressure drying for 10 h to obtain 69.3 g of a white solid product with a yield of 85.1%, a purity of 99.7% (HPLC), and a melting point of 127.7-130.0°C (see Figure 1 ).

[0024] The LC-MS spectrum of the final product is shown in Figure 2 ,Depend on Figure 2 It can be seen that its molecular weight is 192.2 (MS: M+H), which is basically consistent with 4-amino-N-tert-butylbenzamide.

[0025] (Example 2) The synthetic method of 4-amino-N-tert-butylbenzamide of the present embodiment is as follows: Add 50 g of p-aminobenzonitrile (0.423 mol) and 80 g of acetic acid into a 1.5 L three-necked flask, then add 57 g of tert-butyl acetate (0.490 mol) and 15 g of p-toluenesulfonic acid (0.087 mol), heat to 85-90 °C and stir to react for 4 h.

[0026] After the reaction, the temperature was controlled below 90°C to concentrate part of the acetic acid (about 50 g) under reduced pressure, and then 500 mL of toluene was added, followed by cooling to 45-55°C, and a 15 wt% aqueous sodium carbonate solution (about 250 g) was added dropwise at a temperature controlled to adjust the system pH to 9. After the addition, the temperature was raised to 85-90°C, and stirring was continued for 30 min. The mixture was allowed to stand for stratification, and the water layer was separated. The organic layer was cooled to 0-5°C within 2-3 h, and stirred for 30 min. The filter cake was rinsed with a small amount of toluene, and then placed in an oven at 70-80°C and dried under reduced pressure for 10 h to obtain 66.7 g of a white solid product 4-amino-N-tert-butylbenzamide with a yield of 81.9% and a purity of 99.4% (HPLC).

[0027] (Example 3) The synthetic method of 4-amino-N-tert-butylbenzamide of the present embodiment is as follows: Add 50g of p-aminobenzonitrile (0.423mol) and 80g of acetic acid into a 500mL three-necked flask, then add 60g of tert-butyl acetate (0.516mol), and then slowly add 15g of 98wt% concentrated sulfuric acid (0.153mol) at a temperature of 20-25℃. After the addition, stir and react at 20-25℃ for 3h.

[0028] After the reaction, 590 g of a 15 wt% sodium carbonate aqueous solution was added to another 1L three-necked flask, and the temperature was controlled at 20 to 30 ° C. The system after the reaction was slowly added, stirred for 30 minutes after the addition, filtered, and the filter cake was rinsed with a small amount of water and returned to the 1L three-necked flask. Then 500 mL of toluene was added, the temperature was raised to 90 to 95 ° C. and stirred to dissolve, and the layers were allowed to stand for stratification. The water layer was separated, and the organic layer was cooled to 0 to 5 ° C within 2 to 3 hours and stirred for 30 minutes, filtered, and the filter cake was rinsed with a small amount of toluene, and then placed in a 70 to 80 ° C oven for reduced pressure drying for 10 hours to obtain 70.4 g of a white solid product 4-amino-N-tert-butylbenzamide, with a yield of 86.5% and a purity of 99.6% (HPLC).

Claims

1. A method for synthesizing 4-amino-N-tert-butylbenzamide, characterized in that: The method uses p-aminobenzonitrile and tert-butyl acetate as starting materials, and 4-amino-N-tert-butylbenzamide is prepared in one step through Ritter reaction in an acidic system.

2. The synthetic method of 4-amino-N-tert-butylbenzamide according to claim 1, characterized in that: The molar ratio of the p-aminobenzonitrile to the tert-butyl acetate is 1:1 to 1:1.

5.

3. The synthetic method of 4-amino-N-tert-butylbenzamide according to claim 1, characterized in that: The Ritter reaction is carried out in the presence of an acidic solvent.

4. The synthetic method of 4-amino-N-tert-butylbenzamide according to claim 3, characterized in that: The acidic solvent is acetic acid; the weight ratio of the p-aminobenzonitrile to the acetic acid is 1:1 to 1:

5.

5. The synthetic method of 4-amino-N-tert-butylbenzamide according to claim 1, characterized in that: The Ritter reaction is carried out in the presence of an acidic catalyst.

6. The method for synthesizing 4-amino-N-tert-butylbenzamide according to claim 5, characterized in that: The acid catalyst is p-toluenesulfonic acid or sulfuric acid; the molar ratio of the p-aminobenzonitrile to the acid catalyst is 1:0.1 to 1:0.

5.

7. The method for synthesizing 4-amino-N-tert-butylbenzamide according to claim 5 or 6, characterized in that: The acid catalyst is p-toluenesulfonic acid, the reaction temperature is 75-100° C., and the reaction time is 3-7 hours.

8. The method for synthesizing 4-amino-N-tert-butylbenzamide according to claim 5 or 6, characterized in that: The acid catalyst is sulfuric acid, the reaction temperature is 15-30° C., and the reaction time is 2-6 hours.

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