A preparation method of 9-dichloromethylene-5-amino-benzonorbornene

Abstract

The present invention relates to a preparation method of 9-dichloromethylene-5-amino-benzonorbornene. The reaction product of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole is subjected to bromination reaction and Favorskii rearrangement reaction to obtain 5-nitro-8-carboxyl-benzonorbornene, and the reaction of the 5-nitro-8-carboxyl-benzonorbornene and phosphorus pentachloride obtains 9-dichloromethylene-5-nitro-benzonorbornene, and the 9-dichloromethylene-5-nitro-benzonorbornene is subjected to hydrogenation reduction reaction to obtain the 9-dichloromethylene-5-amino-benzonorbornene. The 9-dichloromethylene-5-amino-benzonorbornene reaction route of the preparation method of the present invention is shorter, and the reaction time is shorter, so that the overall yield of the reaction is greatly increased. Moreover, the cost is reduced, the three wastes are reduced, the practical value is high, and it is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 9-dichloromethylene-5-amino-benzonorbornene. Background Technology

[0002] Benzovindiflupyr is a highly effective SDHI fungicide developed by Syngenta. It is effective against soybean rust, wheat leaf blight, and peanut black and white leaf spot, and is particularly effective against wheat powdery mildew, soybean rust, corn leaf spot, and gray mold. Furthermore, it can be used in combination with various fungicides without cross-resistance. Benzovindiflupyr is typically composed of two modules, one of which is 9-dichloromethylene-5-amino-benzonorbornene.

[0003] Its chemical structural formula is as follows:

[0004]

[0005] Currently, there are three main methods for synthesizing 9-dichloromethylene-5-amino-benzonorbornene.

[0006] The first method uses cyclopentadiene and 2-amino-6-nitrobenzoic acid as starting materials, undergoing condensation addition, Diels-Alder reaction, hydrogenation reduction, ozonation, and chlorination reactions to ultimately produce 9-dichloromethylene-5-amino-benzonorbornene, as reported in Syngenta-CN101296913A and Syngenta-CN101677558. This preparation method has the following drawbacks:

[0007] (1) The reaction requires two selective reduction hydrogenation processes, resulting in low yield and significantly increased catalyst usage.

[0008] (2) The high-risk process of ozonation fracture involved in this route increases the difficulty of scale-up and actual operation.

[0009] The second day, also using cyclopentadiene and 2-amino-6-nitrobenzoic acid as starting materials, involved a free radical addition reaction between cyclopentadiene and carbon tetrachloride, followed by removal of hydrogen chloride under sodium hydroxide conditions. The final product, 9-dichloromethylene-5-amino-benzonorbornene, was obtained through a Diels-Alder reaction and hydrogenation reduction. This is reported in Syngenta CN102197016 and Syngenta CN103068780. This preparation method has the following drawbacks:

[0010] The free radical addition reaction between cyclopentadiene and carbon tetrachloride results in a low yield, requiring significant manpower and resources for material accumulation and generating excessive amounts of waste. This makes it unsuitable for industrial production due to its limited benefits.

[0011] The third method uses 6,6-dimethyl-5-methylene-1,3-cyclopentadiene as a starting material. It first undergoes a Diels-Alder reaction with 2,6-dichlorofluorobenzene, followed by selective reduction, ozonolysis, chlorination, and finally palladium-catalyzed amino insertion to yield 9-dichloromethylene-5-amino-benzonorbornene, as publicly reported by Syngenta (CN102858749A). This preparation method has the following drawbacks:

[0012] (1) The Grignard reagent used in this step requires the Diels-Alder reaction to be carried out at extremely low temperatures, which is not conducive to industrial production.

[0013] (2) This route involves a high-risk process of ozonation fracture, which increases the difficulty of scale-up and actual operation.

[0014] (3) This route involves palladium-catalyzed amino insertion reaction. The yield of this step is low and the palladium catalyst is expensive. It is not significant for industrial production and is not suitable for industrial production. Summary of the Invention

[0015] The purpose of this invention is to provide a method for preparing 9-dichloromethylene-5-amino-benzonorbornene suitable for industrial production.

[0016] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0017] A method for preparing 9-dichloromethylene-5-amino-benzonorbornene involves subjecting the reaction product of isoamyl nitrite, 6-nitro-o-aminobenzoic acid, and anisole to a bromination reaction and a Favorskii rearrangement reaction to obtain 5-nitro-8-carboxy-benzonorbornene. The 5-nitro-8-carboxy-benzonorbornene is then reacted with phosphorus pentachloride to obtain 9-dichloromethylene-5-nitro-benzonorbornene. Finally, the 9-dichloromethylene-5-nitro-benzonorbornene is subjected to a hydrogenation reduction reaction to obtain the 9-dichloromethylene-5-amino-benzonorbornene.

[0018] Preferably, the isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole react in the presence of a catalyst, wherein the catalyst is trifluoroacetic acid.

[0019] Preferably, the isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole are reacted in 2-methyltetrahydrofuran.

[0020] Preferably, the reaction temperature of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole is 75℃-85℃, and the reaction time is 2h-3h.

[0021] Preferably, the mass ratio of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole is (0.5-1.5):1:(0.5-1.5).

[0022] More preferably, the mass ratio of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole is (0.8-1.2):1:(0.8-1.2).

[0023] Preferably, the 6-nitro-o-aminobenzoic acid and the anisole are mixed with a portion of the reaction solvent and then added dropwise, with the temperature of the dropwise addition controlled at 40℃-55℃ and the addition completed in 30-60 minutes.

[0024] Preferably, the reaction solvent for the bromination reaction is 2-methyltetrahydrofuran.

[0025] Preferably, the bromination reaction is carried out at a temperature of 5°C-35°C for 2-3 hours.

[0026] Preferably, the mass ratio of the reaction product of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole to liquid bromine is (0.5-1.5):1.

[0027] More preferably, the mass ratio of the reaction product of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole to liquid bromine is (1-1.2):1.

[0028] And / or, liquid bromine and part of the reaction solvent are mixed and added dropwise, with the temperature of the dropwise addition controlled at 15℃-25℃ and the addition completed in 30-60 minutes.

[0029] Preferably, the Favorskii rearrangement reaction is carried out in the presence of an alkaline substance, wherein the alkaline substance is potassium hydroxide, and the mass ratio of the reaction product of the bromination reaction to the alkaline substance is (2.5-6.5):1.

[0030] More preferably, the mass ratio of the reaction product of the bromination reaction to the alkaline substance is (4.5-5.5):1.

[0031] Preferably, the reaction solvent for the Favorskii rearrangement reaction is ethanol.

[0032] Preferably, the Favorskii rearrangement reaction is carried out at a temperature of 55°C-90°C for 3-7 hours.

[0033] Preferably, the mass ratio of 5-nitro-8-carboxy-benzonorbornene to phosphorus pentachloride is 1:(1-3).

[0034] More preferably, the mass ratio of 5-nitro-8-carboxy-benzonorbornene to phosphorus pentachloride is 1:(1.5-2).

[0035] Preferably, the 5-nitro-8-carboxy-benzonorbornene and the phosphorus pentachloride are reacted in diphenyl ether.

[0036] Preferably, the reaction temperature of the 5-nitro-8-carboxy-benzonorbornene and the phosphorus pentachloride is 175℃-225℃, and the reaction time is 7h-11h.

[0037] More preferably, the reaction temperature of the 5-nitro-8-carboxy-benzonorbornene and the phosphorus pentachloride is 205℃-215℃.

[0038] Preferably, the hydrogenation reduction reaction uses Raney nickel as a catalyst, and the mass ratio of 9-dichloromethylene-5-nitro-benzonorbornene to Raney nickel is 1:(0.01-0.5).

[0039] More preferably, the hydrogenation reduction reaction uses Raney nickel as a catalyst, and the mass ratio of 9-dichloromethylene-5-nitro-benzonorbornene to Raney nickel is 1:(0.05-0.25).

[0040] Preferably, the reaction solvent for the hydrogenation reduction reaction is 2-methyltetrahydrofuran.

[0041] Preferably, the hydrogen pressure in the hydrogenation reduction reaction is 2-10 bar.

[0042] Preferably, the hydrogenation reduction reaction is carried out at a temperature of 40°C-50°C for 2-3 hours.

[0043] Preferably, the mass concentration of the isoamyl nitrite is 95% or higher.

[0044] Preferably, the mass concentration of the 6-nitro-o-aminobenzoic acid is 90% or higher.

[0045] Preferably, the mass concentration of the anisole is 90% or higher.

[0046] Preferably, the mass concentration of liquid bromine used in the bromination reaction is 90% or higher.

[0047] Preferably, the mass concentration of phosphorus pentachloride is 95% or higher.

[0048] This invention provides a method for preparing 9-dichloromethylene-5-amino-benzonorbornene, the method comprising the following steps:

[0049] Step 1: Isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole react in 2-methyltetrahydrofuran at 25℃-35℃ for 2-3 hours in the presence of trifluoroacetic acid;

[0050] Step 2: React the reaction product from Step 1 with liquid bromine in 2-methyltetrahydrofuran at 5℃-35℃ for 2-3 hours;

[0051] Step 3: The reaction product from Step 2 is reacted in ethanol at 55℃-90℃ for 3h-7h in the presence of potassium hydroxide to obtain 5-nitro-8-carboxy-benzonorbornene.

[0052] Step 4: React 5-nitro-8-carboxy-benzonorbornene from Step 3 with phosphorus pentachloride in diphenyl ether at 175℃-225℃ for 7h-11h to obtain 9-dichloromethylene-5-nitro-benzonorbornene;

[0053] Step 5: The 9-dichloromethylene-5-nitro-benzonorbornene from Step 4 and 2-10 bar of hydrogen gas are reacted in 2-methyltetrahydrofuran at 40-50°C for 2-3 hours in the presence of Raney nickel to obtain the 9-dichloromethylene-5-amino-benzonorbornene.

[0054] Specifically, steps one, two, three, and four are all carried out under the protection of an inert gas.

[0055] Specifically, in step one, the 6-nitro-o-aminobenzoic acid and the anisole are mixed with a portion of 2-methyltetrahydrofuran and then added dropwise. The temperature of the dropwise addition is controlled at 40℃-55℃, and the addition is completed in 30-60 minutes.

[0056] Specifically, in step two, the liquid bromine and a portion of 2-methyltetrahydrofuran are mixed and added dropwise, with the temperature of the dropwise addition controlled at 15℃-25℃ and the addition completed in 30-60 minutes.

[0057] Specifically, steps one and two, steps three, four, and five each include post-processing.

[0058] The post-treatment steps in steps one, two, and three are as follows: the reaction solution after the reaction is mixed with water and ethyl acetate, the pH is adjusted to 7-8, the organic phase is concentrated, and the desired compound is obtained by column chromatography.

[0059] The post-processing in step four involves mixing the reaction solution with ice water, adjusting the pH to 7-8, adding ethyl acetate for extraction, concentrating the organic phase, and then obtaining the desired compound by column chromatography.

[0060] The post-processing in step five involves mixing the reaction solution with water and ethyl acetate, concentrating the organic phase, and then obtaining the desired compound by column chromatography.

[0061] This invention also provides an intermediate compound for preparing 9-dichloromethylene-5-amino-benzonorbornene, said intermediate compound being... and / or Or the intermediate compound is

[0062] One or more of the following mixtures.

[0063] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0064] The method of this invention provides a shorter reaction route and shorter reaction time for 9-dichloromethylene-5-amino-benzonorbornene, resulting in a significant increase in overall yield. Furthermore, it reduces costs and waste, making it highly practical and suitable for industrial production. Detailed Implementation

[0065] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of the embodiments of the invention. Therefore, the drawings and description are considered to be exemplary in nature and not restrictive.

[0066] In this invention, the various processes and methods not described in detail are conventional methods known in the art.

[0067] In this invention, all the raw materials described can be obtained commercially or by known means, and unless otherwise specified, they all meet the requirements of standard chemical products.

[0068] Example 1

[0069] This embodiment provides a method for preparing 9-dichloromethylene-5-amino-benzonorbornene, the reaction route of which is as follows:

[0070]

[0071] The specific preparation method is as follows:

[0072] 1. Synthesize intermediate1 (intermediate 1)

[0073] Under N2 protection, 8.4 g of isoamyl nitrite and 20 g of 2-methyltetrahydrofuran were added sequentially to the reaction flask. The mixture was stirred at 40-50°C. 10 g of 6-nitro-o-aminobenzoic acid, 10 g of anisole, and 0.6 g of trifluoroacetic acid were dissolved in 25 g of 2-methyltetrahydrofuran and slowly added dropwise to the reaction flask over approximately 60 minutes. The temperature was then raised to 75°C, and the reaction was allowed to proceed for 3 hours. After TLC analysis confirmed the reaction was complete, ethyl acetate and purified water were added to the reaction mixture for extraction. The organic phase was dried and distilled under reduced pressure to remove the solvent and unreacted raw materials, yielding 9.7 g of intermediate 1 oil. This oil was used directly in the next step without further purification, with a yield of 82.2%.

[0074] MS-EI (m / z, %): 216 (M + +H + ).

[0075] 2. Synthesize intermediate2 (intermediate 2)

[0076] Under N2 protection, 9.7 g of intermediate 1 and 20 g of 2-methyltetrahydrofuran were added sequentially to the reaction flask. The mixture was stirred and kept at 15°C. A mixture of 8.7 g of liquid bromine and 20 g of 2-methyltetrahydrofuran was slowly added dropwise to the reaction system over 60 min. The reaction was then carried out at 15°C for 3 h. After the reaction was confirmed to be complete by TLC, ethyl acetate and purified water were added to the reaction solution and the pH was adjusted to approximately 7-8. The organic phase was dried and concentrated to obtain 11.7 g of intermediate 2 oil, which could be used directly in the next step without further purification, with a yield of 88.7%.

[0077] MS-EI (m / z, %): 293 (M + ); 295 (M) + +2H + ).

[0078] 3. Synthesis of 5-nitro-8-carboxy-benzonorbornene

[0079] Under N2 protection, 11.7 g of intermediate 2, 30 g of ethanol, and 2.4 g of potassium hydroxide were added sequentially to the reaction flask and stirred. The mixture was heated to 70 °C and reacted for 5 h. After the reaction was confirmed to be complete by TLC, ethyl acetate and purified water were added to the reaction solution and the pH was adjusted to approximately 7-8. The organic phase was dried and concentrated, and separated by column chromatography (150 g of 300 mesh silica gel). A linear gradient elution was performed using petroleum ether:ethyl acetate (v / v) = 1:3-1:1. Finally, 6.5 g of product was obtained, with a yield of 70.5%.

[0080] The synthesized compound was structurally analyzed and identified as 5-nitro-8-carboxy-benzonorbornene. The 1H NMR and mass spectrometry data are as follows:

[0081] The Bruker NMR spectrometer was selected, and the 1H NMR (300MHz, DMSO) results were: 11.019 (s, 1H), 8.092-8.052 (d, 1H, J = 12Hz), 7.621-7.581 (d, 1H, J = 12Hz), 7.441-7.399 (t, 1H), 5.620-5.580 (d, 2H, J = 12Hz), 4.175-4.135 (d, 2H, J = 12Hz), 2.877 (q, 1H).

[0082] MS-EI (m / z, %): 230 (M + -H + ); 232(M + +H + ).

[0083] 4. Synthesis of 9-dichloromethylene-5-nitro-benzonorbornene

[0084] Under N2 protection, 6.5 g of 5-nitro-8-carboxy-benzonorbornene, 20 g of diphenyl ether, and 11.7 g of phosphorus pentachloride were added sequentially to a sealed reaction flask and stirred. The mixture was heated to 205 °C and reacted for 9 h. After the reaction mixture disappeared as detected by TLC, the reaction solution was poured into ice water, the pH was adjusted to approximately 7-8, and ethyl acetate was added for extraction. The organic phase was dried and concentrated, and separated by column chromatography (150 g of 300-mesh silica gel). The eluent was a linear gradient elution with petroleum ether:ethyl acetate (v / v) = 1:3-1:1. 4.62 g of the solution was obtained, with a yield of 61.7%.

[0085] The synthesized compound was structurally analyzed and identified as 9-dichloromethylene-5-nitro-benzonorbornene. The 1H NMR and mass spectrometry data are as follows:

[0086] The Bruker NMR spectrometer was selected. ¹H NMR (300MHz, CDCl₃) showed the following spectral signatures: 7.947-7.907 (d, ¹H, J = 12Hz), 7.482-7.442 (d, ¹H, J = 12Hz), 7.359-7.301 (t, ¹H), 4.823-4.715 (m, ¹H), 4.051-3.932 (m, ¹H), 2.229-2.121 (m, 2H), 1.480-1.397 (m, ¹H), and 1.351-1.221 (m, ¹H).

[0087] MS-EI (m / z, %): 268 (M + +H + ).

[0088] 5. Synthesis of 9-dichloromethylene-5-amino-benzonorbornene

[0089] 4.0 g of 9-dichloromethylene-5-nitro-benzonorbornene, 30 g of 2-methyltetrahydrofuran, and 0.5 g of Raney nickel were added sequentially to a high-pressure reactor. The reactor was sealed, and stirring was initiated. The reactor was purged three times with nitrogen to remove oxygen, followed by three purgings of nitrogen with hydrogen. The reactor was pressurized to 5 bar with hydrogen, and the reactor was heated to 40 °C. The reaction was allowed to proceed for 3 hours. After TLC analysis confirmed the reaction was complete, ethyl acetate and purified water were added to the reaction solution. The organic phase was dried and concentrated, and then separated by column chromatography (150 g of 300-mesh silica gel). A linear gradient elution was performed using petroleum ether:ethyl acetate (v / v) = 1:3-1:1. 3.45 g of the solution was obtained, with a yield of 96.2%.

[0090] The synthesized compound was structurally analyzed and identified as 9-dichloromethylene-5-amino-benzonorbornene. The 1H NMR and mass spectrometry data are as follows:

[0091] The Bruker NMR spectrometer was selected. ¹H NMR (300MHz, CDCl₃) showed the following spectral signatures: 6.972-6.851 (t, ¹H), 6.663-6.623 (d, ¹H, J = 12Hz), 6.623 (d, ¹H, J = 12Hz), 3.912-3.901 (m, ¹H), 3.872-3.832 (m, ¹H), 3.597 (br, ²H), 2.061-1.965 (m, ²H), 1.375-1.321 (m, ²H).

[0092] MS-EI (m / z, %): 240 (M + +H + ); 262(M + +Na + ).

[0093] Example 2

[0094] This embodiment provides a method for preparing 9-dichloromethylene-5-amino-benzonorbornene, and the reaction route is the same as in Example 1. The specific preparation method is as follows:

[0095] 1. Synthesize intermediate1 (intermediate 1)

[0096] Under N2 protection, 8.4 g of isoamyl nitrite and 20 g of 2-methyltetrahydrofuran were added sequentially to the reaction flask. The mixture was stirred at 50-55°C. 10 g of 6-nitro-o-aminobenzoic acid, 10 g of anisole, and 0.6 g of trifluoroacetic acid were dissolved in 25 g of 2-methyltetrahydrofuran and slowly added dropwise to the reaction flask over approximately 30 minutes. The temperature was then raised to 85°C, and the reaction was allowed to proceed for 2 hours. After TLC analysis confirmed the reaction was complete, ethyl acetate and purified water were added to the reaction mixture for extraction. The organic phase was dried and distilled under reduced pressure to remove the solvent and unreacted raw materials, yielding 10.9 g of intermediate 1 oil. This oil was used directly in the next step without further purification, with a yield of 92.3%.

[0097] MS-EI (m / z, %): 216 (M + +H + ).

[0098] 2. Synthesize intermediate2 (intermediate 2)

[0099] Under N2 protection, 9.7 g of intermediate 1 and 20 g of 2-methyltetrahydrofuran were added sequentially to the reaction flask. The mixture was stirred and kept at 25°C. A mixture of 8.7 g of liquid bromine and 20 g of 2-methyltetrahydrofuran was slowly added dropwise to the reaction system over approximately 30 minutes. The reaction was then carried out at 25°C for 2 hours. After the reaction was confirmed to be complete by TLC, ethyl acetate and purified water were added to the reaction solution to adjust the pH to approximately 7-8. The organic phase was dried and concentrated to obtain 12.3 g of intermediate 2 oil, which could be used directly in the next step without further purification, with a yield of 93.4%.

[0100] MS-EI (m / z, %): 293 (M + ); 295 (M) + +2H + ).

[0101] 3. Synthesis of 5-nitro-8-carboxy-benzonorbornene

[0102] Under N2 protection, 11.7 g of intermediate 2, 30 g of ethanol, and 2.4 g of potassium hydroxide were added sequentially to the reaction flask and stirred. The mixture was heated to 85 °C and reacted for 4 h. After the reaction was confirmed to be complete by TLC, ethyl acetate and purified water were added to the reaction solution and the pH was adjusted to approximately 7-8. The organic phase was dried and concentrated, and separated by column chromatography (150 g of 300 mesh silica gel). The eluent was a linear gradient elution with petroleum ether:ethyl acetate (v / v) = 1:3-1:1, yielding 7.9 g of product, with a yield of 85.5%.

[0103] The synthesized compound was structurally analyzed and identified as 5-nitro-8-carboxy-benzonorbornene. The 1H NMR and mass spectrometry data are as follows:

[0104] The Bruker NMR spectrometer was selected, and the 1H NMR (300MHz, DMSO) results were: 11.019 (s, 1H), 8.092-8.052 (d, 1H, J = 12Hz), 7.621-7.581 (d, 1H, J = 12Hz), 7.441-7.399 (t, 1H), 5.620-5.580 (d, 2H, J = 12Hz), 4.175-4.135 (d, 2H, J = 12Hz), 2.877 (q, 1H).

[0105] MS-EI (m / z, %): 230 (M + -H + ); 232(M + +H + ).

[0106] 4. Synthesis of 9-dichloromethylene-5-nitro-benzonorbornene

[0107] Under N2 protection, 6.5 g of 5-nitro-8-carboxy-benzonorbornene, 20 g of diphenyl ether, and 11.7 g of phosphorus pentachloride were added sequentially to a sealed reaction flask and stirred. The mixture was heated to 215 °C and reacted for 8 h. After the reaction mixture disappeared as detected by TLC, the reaction solution was poured into ice water, the pH was adjusted to approximately 7-8, and ethyl acetate was added for extraction. The organic phase was dried and concentrated, and separated by column chromatography (150 g of 300-mesh silica gel). The eluent was a linear gradient elution with petroleum ether:ethyl acetate (v / v) = 1:3-1:1. 6.5 g of the product was obtained, with a yield of 86.9%.

[0108] The synthesized compound was structurally analyzed and identified as 9-dichloromethylene-5-nitro-benzonorbornene. The 1H NMR and mass spectrometry data are as follows:

[0109] The Bruker NMR spectrometer was selected. ¹H NMR (300MHz, CDCl₃) showed the following spectral signatures: 7.947-7.907 (d, ¹H, J = 12Hz), 7.482-7.442 (d, ¹H, J = 12Hz), 7.359-7.301 (t, ¹H), 4.823-4.715 (m, ¹H), 4.051-3.932 (m, ¹H), 2.229-2.121 (m, 2H), 1.480-1.397 (m, ¹H), and 1.351-1.221 (m, ¹H).

[0110] MS-EI (m / z, %): 268 (M + +H + ).

[0111] 5. Synthesis of 9-dichloromethylene-5-amino-benzonorbornene

[0112] 4.0 g of 9-dichloromethylene-5-nitro-benzonorbornene, 30 g of 2-methyltetrahydrofuran, and 0.5 g of Raney nickel were added sequentially to a high-pressure reactor. The reactor was sealed, and stirring was initiated. The reactor was purged three times with nitrogen to remove oxygen, followed by three purgings of nitrogen with hydrogen. The reactor was pressurized to 3 bar with hydrogen, and the reactor was heated to 50 °C. The reaction was allowed to proceed for 2 hours. After the reaction was confirmed to be complete by TLC, ethyl acetate and purified water were added to the reaction solution. The organic phase was dried and concentrated, and then separated by column chromatography (150 g of 300-mesh silica gel). A linear gradient elution was performed using petroleum ether:ethyl acetate (v / v) = 1:3-1:1. 3.5 g of the solution was obtained, with a yield of 97.9%.

[0113] The synthesized compound was structurally analyzed and identified as 9-dichloromethylene-5-amino-benzonorbornene. The 1H NMR and mass spectrometry data are as follows:

[0114] The Bruker NMR spectrometer was selected. ¹H NMR (300MHz, CDCl₃) showed the following spectral signatures: 6.972-6.851 (t, ¹H), 6.663-6.623 (d, ¹H, J = 12Hz), 6.623 (d, ¹H, J = 12Hz), 3.912-3.901 (m, ¹H), 3.872-3.832 (m, ¹H), 3.597 (br, ²H), 2.061-1.965 (m, ²H), 1.375-1.321 (m, ²H).

[0115] MS-EI (m / z, %): 240 (M + +H + ); 262(M + +Na + ).

Claims

1. A method for preparing 9-dichloromethylene-5-amino-benzonorbornene, characterized in that: The reaction product of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole is subjected to bromination reaction and Favorskii rearrangement reaction to obtain 5-nitro-8-carboxyl-benzonorbornene, the 5-nitro-8-carboxyl-benzonorbornene is reacted with phosphorus pentachloride to obtain 9-dichloromethylene-5-nitro-benzonorbornene, and the 9-dichloromethylene-5-nitro-benzonorbornene is subjected to hydrogenation reduction reaction to obtain the 9-dichloromethylene-5-amino-benzonorbornene.

2. The preparation method according to claim 1, characterized in that: The isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole react in the presence of a catalyst, and the catalyst is trifluoroacetic acid; and / or, the isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole are reacted in 2-methyltetrahydrofuran; and / or, the reaction temperature of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole is 75° C.-85° C., and the reaction time is 2 h-3 h; And / or, the mass ratio of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole is (0.5-1.5):1:(0.5-1.5); And / or, the 6-nitro-o-aminobenzoic acid and the anisole are mixed with part of the reaction solvent and added dropwise, the temperature of the addition is controlled at 40° C.-55° C., and the addition is completed within 30-60 min.

3. The preparation method according to claim 1, characterized in that: The reaction solvent of the bromination reaction is 2-methyltetrahydrofuran; And / or, the reaction temperature of the bromination reaction is 5°C-35°C, and the reaction time is 2h-3h; and / or, the mass ratio of the reaction product of isoamyl nitrite, 6-nitro-o-aminobenzoic acid and anisole to liquid bromine is (0.5-1.5):1; And / or, liquid bromine and part of the reaction solvent are mixed and added dropwise, the temperature of the addition is controlled at 15° C.-25° C., and the addition is completed within 30-60 min.

4. The preparation method according to claim 1, characterized in that: The Favorskii rearrangement reaction is carried out in the presence of an alkaline substance, the alkaline substance is potassium hydroxide, and the mass ratio of the reaction product of the bromination reaction to the alkaline substance is (2.5-6.5):1; And / or, the reaction solvent of the Favorskii rearrangement reaction is ethanol; And / or, the temperature of the Favorskii rearrangement reaction is 55° C.-90° C., and the reaction time is 3 h-7 h.

5. The preparation method according to claim 1, characterized in that: The mass ratio of the 5-nitro-8-carboxyl-benzonorbornene to the phosphorus pentachloride is 1:(1-3); and / or, the 5-nitro-8-carboxyl-benzonorbornene and the phosphorus pentachloride are reacted in diphenyl ether; And / or, the reaction temperature of the 5-nitro-8-carboxy-benzonorbornene and the phosphorus pentachloride is 175° C.-225° C., and the reaction time is 7 h-11 h.

6. The preparation method according to claim 1, characterized in that: The hydrogenation reduction reaction uses Raney nickel as a catalyst, and the mass ratio of the 9-dichloromethylene-5-nitro-benzonorbornene to the Raney nickel is 1:(0.01-0.5); And / or, the reaction solvent of the hydrogenation reduction reaction is 2-methyltetrahydrofuran; And / or, the hydrogen pressure of the hydrogenation reduction reaction is 2-10 bar; And / or, the reaction temperature of the hydrogenation reduction reaction is 40°C-50°C, and the reaction time is 2-3h.

7. The preparation method according to claim 1, characterized in that: The mass concentration of the isoamyl nitrite is 95% or more; And / or, the mass concentration of 6-nitroanthranilic acid is 90% or more; And / or, the mass concentration of anisole is 90% or more; And / or, the mass concentration of liquid bromine used in the bromination reaction is 90% or more; And / or, the mass concentration of the phosphorus pentachloride is 95% or above.

8. A method for preparing 9-dichloromethylene-5-amino-benzonorbornene, characterized in that: The preparation method comprises the following steps: Step 1: isopentyl nitrite, 6-nitro-o-aminobenzoic acid and anisole are reacted in 2-methyltetrahydrofuran at 75° C.-85° C. for 2 h-3 h in the presence of trifluoroacetic acid; Step 2: react the reaction product of step 1 and liquid bromine in 2-methyltetrahydrofuran at 5°C-35°C for 2h-3h; Step 3: reacting the reaction product of step 2 in ethanol at 55° C.-90° C. for 3 h-7 h in the presence of potassium hydroxide to obtain 5-nitro-8-carboxyl-benzonorbornene; Step 4: reacting the 5-nitro-8-carboxyl-benzonorbornene prepared in step 3 with phosphorus pentachloride in diphenyl ether at 175° C.-225° C. for 7 h-11 h to obtain 9-dichloromethylene-5-nitro-benzonorbornene; Step 5: reacting the 9-dichloromethylene-5-nitro-benzonorbornene prepared in step 4 with 2-10 bar of hydrogen in 2-methyltetrahydrofuran at 40° C.-50° C. for 2-3 h in the presence of Raney nickel to obtain the 9-dichloromethylene-5-amino-benzonorbornene.

9. The preparation method according to claim 8, characterized in that: Step 1, step 2, step 3 and step 4 are all carried out under the protection of inert gas; And / or, in step 1, the 6-nitro-o-aminobenzoic acid and the anisole are mixed with a portion of 2-methyltetrahydrofuran and added dropwise, the temperature of the addition is controlled at 40° C.-55° C., and the addition is completed within 30-60 min; And / or, in step 2, the liquid bromine and part of 2-methyltetrahydrofuran are mixed and added dropwise, the temperature of the addition is controlled at 15° C.-25° C., and the addition is completed within 30-60 min; and / or, step 1, step 2. Step 3, step 4 and step 5 respectively include post-treatment, wherein the post-treatment of step 1, step 2 and step 3 respectively comprises mixing the reaction solution after the reaction with water and ethyl acetate, adjusting the pH value to 7-8, concentrating the organic phase and subjecting it to column chromatography to obtain the desired compound; The post-treatment of step 4 is to mix the reaction solution with ice water, adjust the pH value to 7-8, add ethyl acetate for extraction, concentrate the organic phase and perform column chromatography to obtain the desired compound; The post-treatment of step 5 is to mix the reaction solution with water and ethyl acetate, and then concentrate the organic phase and perform column chromatography to obtain the desired compound.

10. An intermediate compound for preparing 9-dichloromethylene-5-amino-benzonorbornene, characterized in that: The intermediate compound is Or the intermediate compound is A mixture of one or more of.

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