Method for synthesizing 2, 4, 6-trifluorobenzylamine through one-pot method

Abstract

The invention provides a method for synthesizing 2, 4, 6-trifluorobenzylamine through a one-pot method, and relates to the technical field of chemical synthesis. According to the method, the 2, 4, 6-trifluorobenzylamine is synthesized by taking the 2, 4, 6-trifluoro-3, 5-dichlorobenzonitrile as a raw material through a one-pot method, so that the method is more beneficial to economy and environmental friendliness. Compared with organic carboxylic acid and organic sulfinic acid, the organic sulfonic acid disclosed by the invention is more favorable for enhancing the reducing capacity of palladium on carbon, so that the yield of 2, 4, 6-trifluorobenzylamine is higher.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and relates to a method for synthesizing 2,4,6-trifluorobenzylamine by a one-pot method. Background Art

[0002] 2,4,6-Trifluorobenzylamine is an important fine chemical with a wide range of uses in drug synthesis and other fields. It is a key intermediate in the synthesis of Bictegravir.

[0003] There are four main methods for preparing 2,4,6-trifluorobenzylamine disclosed so far:

[0004] (1) Chinese patent CN104610068A discloses the preparation of 2,4,6-trifluorobenzylamine using 1,3,5-trifluorobenzene as a raw material through lithiation, formylation, reduction, chlorination, amination and other reactions.

[0005]

[0006] This method has long reaction steps, complex operating conditions, expensive raw and auxiliary materials, and a large amount of three wastes, so it lacks industrial application value.

[0007] (2) Chinese patent CN106349083A discloses the preparation of 2,4,6-trifluorobenzylamine by one-step hydrogenation reduction using 2,4,6-trifluorobenzonitrile as raw material.

[0008]

[0009] Although this method only has one step reaction, the raw material 2,4,6-trifluorobenzonitrile is expensive and difficult to obtain, so it cannot be applied on a large scale.

[0010] (3) Chinese patent CN107778183A discloses the preparation of 2,4,6-trifluorobenzylamine using pentachlorobenzonitrile as raw material through fluorination, reduction and other steps.

[0011]

[0012] The raw materials of this method are cheap and readily available, and the reaction steps are short, but the reduction reaction has many side reactions and the reaction yield is not ideal, which limits the industrial application of this method.

[0013] (4) Chinese patent CN108586267A discloses a method for preparing 2,4,6-trifluorobenzylamine, comprising the following steps: (1) pentachlorobenzonitrile undergoes a fluorination reaction with a fluorinating agent in a polar aprotic solvent in the presence of a catalyst to obtain 2,4,6-trifluoro-3,5-dichlorobenzonitrile; (2) the 2,4,6-trifluoro-3,5-dichlorobenzonitrile obtained in step (1) is subjected to hydrogen reduction in the presence of an organic carboxylic acid and palladium carbon as a catalyst to obtain 2,4,6-trifluoro-3,5-dichlorobenzylamine; (3) the 2,4,6-trifluoro-3,5-dichlorobenzylamine obtained in step (2) is subjected to hydrogen reduction in a solvent in the presence of a catalyst to obtain 2,4,6-trifluorobenzylamine.

[0014]

[0015] After the hydrogenation reaction in step (2) of the method is completed, the reaction liquid needs to be filtered to recover the palladium carbon, distilled to recover the solvent and other simple post-treatment operations before the reaction in step (3) is carried out, which is cumbersome.

[0016] In view of this, in order to solve the shortcomings of the prior art synthesis method, the present invention provides a one-pot method for synthesizing 2,4,6-trifluorobenzylamine. Summary of the invention

[0017] The present invention aims at the problems existing in the prior art and provides a one-pot method for synthesizing 2,4,6-trifluorobenzylamine. The synthesis method disclosed by the present invention has low raw material cost, simple and continuous reaction operation, high reaction yield, and continuous reaction is more suitable for large-scale production, and has good industrial application prospects.

[0018] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0019] The present invention provides a method for synthesizing 2,4,6-trifluorobenzylamine by a one-pot method. The 2,4,6-trifluorobenzylamine uses 2,4,6-trifluoro-3,5-dichlorobenzonitrile as a raw material and is synthesized by the following method:

[0020]

[0021] Preferably, the one-pot method for synthesizing 2,4,6-trifluorobenzylamine comprises the following steps:

[0022] S1. Using 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) as a raw material, in a solvent, with palladium carbon as a catalyst, in the presence of an organic sulfonic acid, a hydrogenation reduction reaction is carried out to obtain 2,4,6-trifluoro-3,5-dichlorobenzylamine (II);

[0023] S2. After the hydrogenation reduction reaction is completed, triethylamine is directly added to the reaction system without post-treatment, and the reaction is continued for 10-20 hours to obtain 2,4,6-trifluorobenzylamine (III).

[0024] More preferably, in step S1, the solvent is an alcohol solvent.

[0025] More preferably, in step S1, the solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.

[0026] Further preferably, in step S1, the organic sulfonic acid is selected from at least one of methanesulfonic acid, trifluoromethylsulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid.

[0027] Further preferably, in step S1, the mass ratio of the 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) to the solvent is 1:5-10.

[0028] Further preferably, in step S1, the molar ratio of the 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) to the organic sulfonic acid is 1:1-1.2.

[0029] Further preferably, in step S1, the temperature of the hydrogenation reduction reaction is 50-100°C.

[0030] Further preferably, in step S1, the pressure of the hydrogenation reduction reaction is 1.0-3.0 MPa.

[0031] Further preferably, in step S2, the molar ratio of the 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) to triethylamine is 1:3-4.

[0032] Further preferably, in step S2, the reaction temperature is 90-110°C.

[0033] Further preferably, in step S2, the reaction pressure is 2.0-4.0 MPa.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] (1) The present invention uses 2,4,6-trifluoro-3,5-dichlorobenzonitrile as a raw material and directly obtains 2,4,6-trifluorobenzylamine without separation of an intermediate, which is more economical and environmentally friendly.

[0036] (2) Compared with organic carboxylic acids and organic sulfonic acids, the organic sulfonic acid disclosed in the present invention is more conducive to enhancing the reducing ability of palladium carbon, so that the yield of 2,4,6-trifluorobenzylamine is higher. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The peak area ratio of 2,4,6-trifluoro-3,5-dichlorobenzylamine was determined by HPLC in Example 1.

[0038] Figure 2 The peak area ratio of 2,4,6-trifluorobenzylamine was determined by HPLC in Example 1.

[0039] Figure 3 The peak area ratio of 2,4,6-trifluoro-3,5-dichlorobenzylamine was determined by HPLC in Example 2.

[0040] Figure 4 The peak area ratio of 2,4,6-trifluorobenzylamine was determined by HPLC in Example 2.

[0041] Figure 5 The peak area ratio of 2,4,6-trifluoro-3,5-dichlorobenzylamine was determined by HPLC in Example 3.

[0042] Figure 6 The peak area ratio of 2,4,6-trifluorobenzylamine was determined by HPLC in Example 3.

[0043] Figure 7 The peak area ratio of 2,4,6-trifluoro-3,5-dichlorobenzylamine was determined by HPLC in Example 4.

[0044] Figure 8 The peak area ratio of 2,4,6-trifluorobenzylamine was determined by HPLC in Example 4.

[0045] Fig. 9 This is the peak area ratio result of 2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC in Comparative Example 1.

[0046] Fig.10 The peak area ratio of 2,4,6-trifluorobenzylamine was measured by HPLC in Comparative Example 1.

[0047] Fig.11 This is the peak area ratio result of 2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC in Comparative Example 2.

[0048] Fig.12 The peak area ratio of 2,4,6-trifluorobenzylamine was measured by HPLC in Comparative Example 2. DETAILED DESCRIPTION

[0049] In order to make the purpose, technical scheme and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. However, the following embodiments are only preferred embodiments of the present invention, not all. For the sake of clarity, all features of the actual embodiments are not described. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention.

[0050] The present invention does not limit the sources of the raw materials used. Unless otherwise specified, the raw materials used in the present invention are common commercial products in the technical field.

[0051] Example 1

[0052] 2,4,6-Trifluorobenzylamine was prepared according to the following scheme:

[0053]

[0054] (1) 50 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile, 26.6 g (1.2 eq) of methanesulfonic acid, 5.0 g of 5% wet palladium carbon, and 400 g of isopropanol were added to a 1.5 L autoclave. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled at 1.7-2.0 MPa with hydrogen. The autoclave was subjected to hydrogenation reaction at 70-75° C. for 3 hours. The peak area of ​​2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC accounted for 97.74% (e.g. Figure 1 shown).

[0055] (2) The autoclave was cooled, vented, and 89.3 g (4.0 eq) of triethylamine was added at once. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled to be 2.5-3.0 MPa with hydrogen. The hydrogenation reaction was carried out at 100° C. for 12 hours. The peak area of ​​2,4,6-trifluorobenzylamine detected by HPLC accounted for 95.09% (e.g. Figure 2 40.0 g of water was added to the reaction solution to dissolve triethylamine hydrochloride, and palladium carbon was recovered by filtration. The organic phase was subjected to vacuum distillation to obtain 32.8 g of colorless transparent liquid, which was 2,4,6-trifluorobenzylamine, with a yield of 93.0%.

[0056] Example 2

[0057] 2,4,6-Trifluorobenzylamine was prepared according to the following scheme:

[0058]

[0059] (1) 50 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile, 36.5 g (1.1 eq) of trifluoromethanesulfonic acid, 2.5 g of 10% wet palladium carbon, and 350 g of ethanol were added to a 1.5 L autoclave. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled at 2.0-2.5 MPa with hydrogen. The autoclave was subjected to hydrogenation reaction at 80-85° C. for 3 hours. The peak area of ​​2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC accounted for 97.37% (e.g. Figure 3 shown).

[0060] (2) The autoclave was cooled, vented, and triethylamine (78.1 g (3.5 eq)) was added at once. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled to be 2.0-2.5 MPa with hydrogen. The autoclave was hydrogenated at 90° C. for 15 hours. The peak area of ​​2,4,6-trifluorobenzylamine detected by HPLC accounted for 96.49% (e.g. Figure 4 35.0 g of water was added to the reaction solution to dissolve triethylamine hydrochloride, and palladium carbon was recovered by filtration. The organic phase was subjected to vacuum distillation to obtain 32.2 g of colorless transparent liquid, which was 2,4,6-trifluorobenzylamine, with a yield of 93.5%.

[0061] Example 3

[0062] 2,4,6-Trifluorobenzylamine was prepared according to the following scheme:

[0063]

[0064] (1) 75 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile, 62.8 g (1.1 eq) of p-toluenesulfonic acid, 5.5 g of 5% wet palladium carbon, and 450 g of isopropanol were added to a 1.5 L autoclave. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled at 2.0-2.5 MPa with hydrogen. The autoclave was subjected to hydrogenation reaction at 95-100° C. for 3 hours. The peak area of ​​2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC accounted for 96.42% (e.g. Figure 5 shown).

[0065] (2) The autoclave was cooled, vented, and 117.3 g (3.5 eq) of triethylamine was added at once. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled to be 2.5-3.0 MPa with hydrogen. The hydrogenation reaction was carried out at 100° C. for 12 hours. The peak area of ​​2,4,6-trifluorobenzylamine detected by HPLC accounted for 93.51% (e.g. Figure 645 g of water was added to the reaction solution to dissolve triethylamine hydrochloride, palladium carbon was recovered by filtration, and the organic phase was subjected to vacuum distillation to obtain 48.8 g of colorless transparent liquid, which was 2,4,6-trifluorobenzylamine, with a yield of 91.5%.

[0066] Example 4

[0067] 2,4,6-Trifluorobenzylamine was prepared according to the following scheme:

[0068]

[0069] (1) 50 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile, 35.0 g (1.0 eq) of benzenesulfonic acid, 5 g of 5% wet palladium carbon, and 350 g of methanol were added to a 1.5 L autoclave. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled at 2.0-2.5 MPa with hydrogen. The autoclave was subjected to hydrogenation reaction at 70-75° C. for 3 hours. The peak area of ​​2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC accounted for 94.72% (e.g. Figure 7 shown).

[0070] (2) The autoclave was cooled, vented, and 89.4 g (4.0 eq) of triethylamine was added at once. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled to be 2.0-2.5 MPa with hydrogen. The hydrogenation reaction was carried out at 90° C. for 15 hours. The peak area of ​​2,4,6-trifluorobenzylamine detected by HPLC accounted for 93.53% (such as Figure 8 35.0 g of water was added to the reaction solution to dissolve triethylamine hydrochloride, and palladium carbon was recovered by filtration. The organic phase was subjected to vacuum distillation to obtain 32.3 g of colorless transparent liquid, which was 2,4,6-trifluorobenzylamine, with a yield of 90.9%.

[0071] Comparative Example 1

[0072] 2,4,6-Trifluorobenzylamine was prepared according to the following scheme:

[0073]

[0074] (1) 50 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile, 19.5 g (1.0 eq) of isobutyric acid, 5 g of 5% wet palladium carbon, and 350 g of methanol were added to a 1.5 L autoclave. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled at 2.0-2.5 MPa with hydrogen. The autoclave was subjected to hydrogenation reaction at 70-75° C. for 3 hours. The peak area of ​​2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC accounted for 89.71% (e.g. Fig. 9 shown).

[0075] (2) The autoclave was cooled, vented, and 89.4 g (4.0 eq) of triethylamine was added at once. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled to be 2.0-2.5 MPa with hydrogen. The hydrogenation reaction was carried out at 90° C. for 15 hours. The peak area of ​​2,4,6-trifluorobenzylamine detected by HPLC accounted for 86.31% (such as Fig.10 35.0 g of water was added to the reaction solution to dissolve triethylamine hydrochloride, and palladium carbon was recovered by filtration. The organic phase was subjected to vacuum distillation to obtain 29.7 g of colorless transparent liquid, which was 2,4,6-trifluorobenzylamine, with a yield of 83.5%.

[0076] Comparative Example 2

[0077] 2,4,6-Trifluorobenzylamine was prepared according to the following scheme:

[0078]

[0079] (1) 50 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile, 31.4 g (1.0 eq) of benzenesulfinic acid, 5 g of 5% wet palladium carbon, and 350 g of methanol were added to a 1.5 L autoclave. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled at 2.0-2.5 MPa with hydrogen. The autoclave was subjected to hydrogenation reaction at 70-75° C. for 3 hours. The peak area of ​​2,4,6-trifluoro-3,5-dichlorobenzylamine detected by HPLC accounted for 83.54% (e.g. Fig.11 shown).

[0080] (2) The autoclave was cooled, vented, and 89.4 g (4.0 eq) of triethylamine was added at once. The autoclave was sealed, and the gas was replaced with nitrogen three times, and then replaced with hydrogen three times. The pressure in the autoclave was controlled to be 2.0-2.5 MPa with hydrogen. The autoclave was hydrogenated at 90° C. for 15 hours. The peak area of ​​2,4,6-trifluorobenzylamine detected by HPLC accounted for 80.43% (e.g. Fig.12 35.0 g of water was added to the reaction solution to dissolve triethylamine hydrochloride, and palladium carbon was recovered by filtration. The organic phase was subjected to vacuum distillation to obtain 27.8 g of colorless transparent liquid, which was 2,4,6-trifluorobenzylamine, with a yield of 77.9%.

[0081] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A one-pot method for synthesizing 2,4,6-trifluorobenzylamine, characterized in that: The 2,4,6-trifluorobenzylamine is synthesized using 2,4,6-trifluoro-3,5-dichlorobenzonitrile as a raw material by the following method:

2. The method according to claim 1, characterized in that The one-pot method for synthesizing 2,4,6-trifluorobenzylamine comprises the following steps: S1. Using 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) as a raw material, in a solvent, with palladium carbon as a catalyst, in the presence of an organic sulfonic acid, a hydrogenation reduction reaction is carried out to obtain 2,4,6-trifluoro-3,5-dichlorobenzylamine (II); S2. After the hydrogenation reduction reaction is completed, triethylamine is directly added to the reaction system without post-treatment, and the reaction is continued for 10-20 hours to obtain 2,4,6-trifluorobenzylamine (III).

3. The method according to claim 2, characterized in that In step S1, the solvent is an alcohol solvent.

4. The method according to claim 3, characterized in that In step S1, the solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol.

5. The method according to claim 2, characterized in that: In step S1, the organic sulfonic acid is selected from at least one of methanesulfonic acid, trifluoromethylsulfonic acid, p-toluenesulfonic acid and benzenesulfonic acid.

6. The method according to claim 2, characterized in that In step S1, the mass ratio of the 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) to the solvent is 1:5-10.

7. The method according to claim 2, characterized in that In step S1, the molar ratio of the 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) to the organic sulfonic acid is 1:1-1.

2.

8. The method according to claim 2, characterized in that: In step S1, the temperature of the hydrogenation reduction reaction is 50-100°C; the pressure of the hydrogenation reduction reaction is 1.0-3.0 MPa.

9. The method according to claim 2, characterized in that: In step S2, the molar ratio of the 2,4,6-trifluoro-3,5-dichlorobenzonitrile (I) to triethylamine is 1:3-4.

10. The method according to claim 2, characterized in that In step S2, the reaction temperature is 90-110°C; the reaction pressure is 2.0-4.0 MPa.

Images