A process for the preparation of an imino hydrazone intermediate

Abstract

The application discloses a preparation method of imino hydrazone intermediate, and the method comprises the step of reducing and hydrogenating a nitro hydrazone compound in the presence of a catalyst. The application determines suitable metal catalysts, relative proportions of the catalysts, reaction temperature, hydrogen pressure and reaction time through screening; and the method of the application overcomes the pollution problem caused by large amount of hazardous waste emissions in the prior art, and is a process for producing intermediate I with reduced three-waste emissions and green environmental protection.

Description

Technical Field

[0001] This invention belongs to the field of fine organic chemical synthesis, specifically relating to a method for preparing N'-(2,4-dichlorophenyl)acetimidinhydrazine, an intermediate of mesotrione, and N'-(4-chloro-2-fluorophenyl)acetimidinhydrazine, an intermediate of triadimefon. Background Technology

[0002] Mesotrione, also known as sulfadiazine, is a triazoline herbicide developed by FMC in 1985 and launched on the market in 1996. It is a protoporphyrinogen oxidase inhibitor and is mainly used in sugarcane, soybean, and sunflower fields for pre-sowing and pre-emergence application to control annual broadleaf weeds, grass weeds, and sedges. Triazine-methyl, also known as triazine-methyl, is also a highly effective and low-toxicity triazoline herbicide developed by FMC in 1988. Its effects are similar to those of mesotrione, but its efficacy is higher.

[0003] Both synthesize from similar intermediates I via fluoromethylation, nitration, reduction, followed by methanesulfonation or diazotization to yield mesotrione and triazine, respectively.

[0004]

[0005] Intermediate I is generally prepared using hydrazine as a starting material. Currently, the literature on the preparation of mesotrione intermediate Ia from 2,4-dichlorophenylhydrazine hydrochloride can be found in the synthesis of 4,5-dihydro-3-methyl-1-(2,4-dichlorophenyl)-1,2,4-triazol-5(1H)one, *Guangzhou Chemical Industry*, (2010), 38(1), 79-80, 95.

[0006]

[0007] In this method, the production of the raw material 2,4-dichlorophenylhydrazine requires a large amount of sodium sulfite to reduce the diazonium salt, generating a large amount of solid waste and causing serious pollution. The production of methyl acetylimine ester hydrochloride also requires a large amount of hydrochloric acid gas. The synthesis of Ia requires triethylamine as an acid-binding agent, which needs to be recycled and reused, increasing the post-processing steps.

[0008] The literature on the synthesis of triadimefon, Modern Pesticides (2010), 9(3), 28-30, 33, reports the preparation method of triadimefon.

[0009]

[0010] The synthesis of the intermediate acetylhydrazine also requires hydrazine as a raw material, and the production of the latter also generates a large amount of waste salt, while the use of phosphorus oxychloride generates a large amount of waste acid, resulting in significant environmental pressure.

[0011] Whether preparing mesotrione intermediate Ia from 2,4-dichloroaniline (hydrochloride) or preparing triazine-methyl intermediate Ib from 4-chloro-2-fluoroaniline (hydrochloride), both require preparation from hydrazine. The preparation of hydrazine uses a large amount of inorganic reducing agents such as sodium sulfite, and the synthesis of imine hydrazone generates a large amount of waste acid, resulting in significant environmental pressure and low atom economy. Summary of the Invention

[0012] In view of the shortcomings of the existing technology and in order to overcome the pollution problem caused by the large amount of hazardous waste emissions in the existing technology, the present invention provides a process for producing intermediate I that reduces the emissions of waste gas, wastewater, and solid waste and is environmentally friendly.

[0013] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0014] A method for preparing a compound with the structure of Formula I is provided, the method comprising the step of hydrogenating and reducing a nitrohydrazone compound represented by Formula A and / or Formula B in the presence of a catalyst:

[0015] and / or Where X = Y = Cl; or X = F, Y = Cl; or X = H, Y = Cl; or X = Cl, Y = H; or X = Y = H.

[0016] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the metal catalyst is selected from one or more of Ni, Pt, PtO2, and Rh.

[0017] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the catalyst is selected from one or more of Rh-C, Ranenickel, RaneCAT-8101, RaneCAT-1000, Pt-C, and Rh-C.

[0018] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the catalyst is selected from one or more of Ranenickel, RaneCAT-8101, and RaneCAT-1000; preferably, the catalyst is selected from RaneCAT-8101.

[0019] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the amount of catalyst added is 5-20% of the mass of the nitrohydrazone compound, preferably 8-20%, and more preferably 8-15%.

[0020] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the pressure of the hydrogenation reduction reaction is 0.7-5 MPa, preferably 0.7-3 MPa or 1.5-2.5 MPa.

[0021] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the reaction temperature of the hydrogenation reduction reaction is 20–80°C, preferably 20–50°C.

[0022] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the hydrogenation reduction reaction is carried out in the presence of a reaction solvent, and the solvent that can be used for the hydrogenation reduction reaction is known, preferably selected from inert organic solvents.

[0023] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the hydrogenation reduction reaction is carried out in the presence of a reaction solvent selected from benzene, toluene, xylene, chlorobenzene, and halogenated hydrocarbons. 1-4 One or more of the following: alkyl alcohols, THF, dioxane, DMF, DMSO, and ethyl acetate.

[0024] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the hydrogenation reduction reaction is carried out in the presence of a reaction solvent, wherein the reaction solvent is selected from one or more of toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, and n-butanol.

[0025] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, the method further comprising the step of monitoring the reaction and determining the reaction end time.

[0026] Furthermore, the present invention provides a method for preparing a compound with the structure described in Formula I above, wherein the reaction time of the method is not less than 6 hours, preferably not less than 2 days, or not less than 3 days.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The method of the present invention overcomes the pollution problem caused by the large amount of hazardous waste discharge in the prior art, and is a process for reducing the discharge of three wastes and being green and environmentally friendly for production intermediate I.

[0029] 2. The post-processing method of the present invention is simple and produces fewer byproducts, making it particularly suitable for the industrial production of intermediate I. Attached Figure Description

[0030] Appendix Figure 1 The 1H NMR spectrum of (Z)-N'-(2,4-dichlorophenyl)-N”-hydroxyacetylimine hydrazide;

[0031] Appendix Figure 2The 1H NMR spectrum of (Z)-N'-(2,4-dichlorophenyl)-N-hydroxyacetylhydrazine;

[0032] Appendix Figure 3 The image shows a locally magnified 1H NMR spectrum of (Z)-N'-(2,4-dichlorophenyl)-N-hydroxyacetylhydrazine.

[0033] Appendix Figure 4 The 1H NMR spectrum of N'-(2,4-dichlorophenyl)acetylimine hydrazide;

[0034] Appendix Figure 5 The carbon NMR spectrum of N'-(2,4-dichlorophenyl)acetylimine hydrazide;

[0035] Appendix Figure 6 The 1H NMR spectrum of N'-(4-chloro-2-fluorophenyl)acetylimine hydrazide;

[0036] Appendix Figure 7 The 1H NMR spectrum of N'-(4-chlorophenyl)acetylimine hydrazide;

[0037] Appendix Figure 8 The 1H NMR spectrum of N'-(2-chlorophenyl)acetylimine hydrazide;

[0038] Appendix Figure 9 The image shows a locally magnified 1H NMR spectrum of N'-(2-chlorophenyl)acetylimine hydrazide.

[0039] Appendix Figure 10 The 1H NMR spectrum of N'-phenylacetylimine hydrazide; Detailed Implementation

[0040] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0041] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" shall be understood to include the stated elements or components without excluding other elements or other components.

[0042] The product content in the following examples was confirmed by liquid chromatography or gas chromatography. The yield was calculated using the area normalization method instead of the external standard method, and should differ slightly from the actual yield (the difference is very small).

[0043] LC-MS: Liquid chromatography mass spectrometry, liquid quality.

[0044] GC-MS: Gas chromatography mass spectrometry, temperament.

[0045] HPLC: High Performance Liquid Chromatography.

[0046] GC: Gas chromatography.

[0047] NMR: Nuclear magnetic resonance spectrometry.

[0048] The aniline, 4-chloroaniline, 2-chloroaniline, 2,4-dichloroaniline, and 4-chloro-2-fluoroaniline used in the following examples are commercially available. Unless otherwise specified, the reaction process and results were detected by high-performance liquid chromatography, and the purity and selectivity were determined by normalization. Unless otherwise specified, Rane Nickel was prepared using a nickel-aluminum alloy method in the examples. Other modified Rane Nickel catalysts, RaneCAT-8101 and RaneCAT-1000, are commercially available products.

[0049] Depending on the process conditions, the method of this invention may produce byproducts or intermediate products. Some reactions may generate isomers in different proportions. Taking 2,4-dichlorophenylhydroxylamine hydrazone as an example, the 1H NMR spectrum data of hydroxylamine hydrazone, the first step reduction product of nitrohydrazone, shows that there are mainly two isomers, A (including A') and B. Among them, the A-isomer is the main one, followed by the B-isomer, and the A'-isomer has the lowest content.

[0050]

[0051] Further hydrogenation reduction of the above isomers yielded only one product, IVa, of iminohydrazone, with δ 5.917 (s, 1H) and δ 4.768 (brs, 2H). This indicates that the NH atoms all shifted to the higher field, representing a typical five-membered ring hydrogen bond structure. Due to its lowest energy, this structure is the most stable. For the similar hydrogenation product IVb, δ 9.36 (brs., 1H), it is evident that the central NH atom formed an intramolecular hydrogen bond with the adjacent F atom on the benzene ring, resulting in a chemical shift to the lower field.

[0052]

[0053] Preparation of (Z)-N'-(2,4-dichlorophenyl)-N'-hydroxyacetylimine hydrazide and (Z)-N'-(2,4-dichlorophenyl)-N-hydroxyacetylhydrazide amide in Examples 1 and 2

[0054] Example 1

[0055] In a 100 mL autoclave, 1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine (1.30 g, 96.0%, 5.03 mmol), Pt-C (0.13 g, 5%), and methanol (20 mL) were added. The autoclave was then purged with hydrogen three times to raise the hydrogen pressure to 2 MPa. The mixture was stirred at room temperature for 6 hours until the hydrogen pressure no longer decreased. Pt-C was removed by filtration. The filtrate was concentrated, and ethyl acetate:n-hexane (5 mL, V / V = 1:3) was added and stirred. Filtration yielded 1.13 g of a pale yellow solid with a purity of 97.7% and a yield of 93.8%. The products were (Z)-N'-(2,4-dichlorophenyl)-N”-hydroxyacetylimine hydrazine and (Z)-N'-(2,4-dichlorophenyl)-N-hydroxyacetylhydrazine amide.

[0056] Analytical data on the structure of (Z)-N'-(2,4-dichlorophenyl)-N”-hydroxyacetylimine hydrazide (A-isomer) (see appendix) Figure 1 ):

[0057] LCMS:[M+H] + =234;

[0058] 1 H NMR(DMSO-d6,500MHz), δ(ppm):9.271(s,1H),7.704(s,1H),7.667(s,1H),7.382(d,J =2.0Hz,1H),7.258(dd,J1=2.5Hz,J2=9.0Hz,1H),6.821(d,J=8.5Hz,1H),1.635(s,3H)

[0059] Analytical data on the structure of (Z)-N'-(2,4-dichlorophenyl)-N-hydroxyacetylhydrazine (B-isomer) (see attached) Figure 2 and appendix Figure 3 ): LCMS:[M+H] + =234;

[0060] 1 H NMR (DMSO-d6, 500MHz), δ (ppm): 9.153 (s, 1H), 7.552 (s, 1H), 7.338 (d, J = 2.5Hz, 1H), 7. 202(dd,J1=2.5Hz,J2=9.0Hz,1H),6.997(s,1H),6.935(d,J=9.0Hz,1H),1.792(s,3H);

[0061] From the appendix Figure 1It can be seen that the product mainly consists of two isomers: A and A' and B. Among them, A and A' are the same compound, but they are formed by different hydrogen bonds. The A isomer, which is a six-membered ring with intramolecular hydrogen bonds, is the main one, followed by the B-isomer. The A' isomer, which is a five-membered ring with intramolecular hydrogen bonds, has the least content. This is reflected in the integral of the proton spectrum, where the molar ratio of the three isomers is approximately 1:0.1:0.03.

[0062]

[0063] For the A-isomer, due to H c The chemical shift of the intramolecular hydrogen bond formed by the six-membered ring moves to a lower field, reaching δ 9.271 (see appendix). Figure 1 For the B-isomer, H e The chemical shift of the intramolecular hydrogen bond formed with the hydrogen atom of hydroxylamine shifts to a lower field, reaching δ9.153 (see appendix). Figure 2 For the A'-isomer, H d The chemical shift of the intramolecular hydrogen bond formed with the oxime hydrogen atom in a five-membered ring moves to a higher field, reaching δ 7.919 (see appendix). Figure 1 Among them, the A-isomer is the stable conformation with the lowest energy, followed by the B-isomer, while the A'-isomer has the highest energy and the lowest content due to the intramolecular strain of the 5-membered ring.

[0064] Example 2

[0065] In a 100 mL autoclave, 1-(2,4-dichlorophenyl)-2-(1-nitroethylene)hydrazine (5.2 g, 96.0%, 20 mmol), Ru-C (0.5 g, 5%), and methanol (50 mL) were added. The mixture was then purged with hydrogen three times, and the hydrogen pressure was increased to 2 MPa. The mixture was heated to 50 °C and stirred for 7 days, during which hydrogen was added to bring the pressure to 20 kg / cm². The reaction solution was filtered to remove Ru-C. The filtrate was concentrated to obtain a mixture of (Z)-N'-(2,4-dichlorophenyl)-N”-hydroxyacetylimine hydrazine and (Z)-N'-(2,4-dichlorophenyl)-N-hydroxyacetylhydrazine amide, which was a pale yellow solid, 4.8 g in weight, with a purity of 94.4%. 4.3% of the product was dechlorinated, resulting in a yield of 96.8%.

[0066] Preparation of N'-(2,4-dichlorophenyl)acetylimine hydrazide (Ⅰa) in Examples 3 to 9

[0067] Example 3

[0068] In a 1L autoclave, 51.7 g (96.0%, 0.2 mmol) of 1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine, 5 g (5%) of Pt-C, and 500 ml of methanol were added. Hydrogen gas was then purged three times to bring the pressure to 2 MPa. The mixture was stirred at room temperature for 6 hours until the hydrogen pressure no longer decreased. After the raw materials were completely eliminated, hydrogen gas was introduced into the autoclave to 2 MPa, and the reaction was carried out at 50°C for 6 days. The reaction solution was filtered to recover platinum carbon. The filtrate was concentrated by rotary evaporation and crystallized to obtain 41.7 g of N'-(2,4-dichlorophenyl)acetylimine hydrazine, a pale hydrazone-black solid. Dechlorination byproducts accounted for approximately 3.7%, the product purity was 95.5%, and the yield was 91.3%.

[0069] Analytical data on the structure of N'-(2,4-dichlorophenyl)acetylimine hydrazide:

[0070] LCMS:[M+H] + =218;

[0071] 1 H NMR (CDCl3, 500MHz), δ (ppm): 7.258 (dd, J1=2.5Hz, J2=7.0Hz, 1H), 7.130 (dd, J1=2.0Hz ,J2=9.0Hz,1H),7.070(d,J=9.0Hz,1H),5.917(s,1H),4.768(brs,2H),2.043(s,3H)(see attached Figure 4 ) 13 C NMR (CDCl3, 126MHz), δ: 155.76, 142.94, 128.25, 127.75, 123.80, 119.47, 115.75, 19.54 (see appendix) Figure 5 );

[0072] From the appendix Figure 4 It can be seen that NH all emerge from the high field, indicating the formation of intramolecular hydrogen bonds in a five-membered ring. NH shifts to the high field, reaching δ4.768, where it forms a broad single peak; [further details omitted]. Figure 5 The carbon spectrum at δ155.76 shows the presence of C=N bonds within the molecule. Therefore, intermediate Ia theoretically has two possible isomers: a C-imine isomer and a D-amide isomer. The C-isomer has two hydrogen bond forms, with the two hydrogens being more acidic (free hydrogens), thus forming a broad singlet at δ4.768. In the D-amide isomer, the two amide hydrogens are magnetically unequal and less acidic, resulting in three different NH groups. Therefore, the structure of intermediate Ia should be C-type.

[0073]

[0074] Example 4

[0075] 1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine (5.2 g, 96.0%, 20 mmol), PtO2 (0.025 g), and ethanol (50 mL) were added to a 100 mL autoclave. The hydrogen gas was then purged three times to bring the pressure to 2 MPa. The mixture was heated to 50 °C and stirred for 3 days, with hydrogen added to bring the pressure to 20 kg / cm². The reaction solution was filtered to remove the catalyst. The filtrate was concentrated to obtain N'-(2,4-dichlorophenyl)acetylimine hydrazine, which was then crystallized to give 4.1 g of a black solid with a purity of 95.7%. The dechlorination product accounted for approximately 3.7%, resulting in a yield of 89.4%.

[0076] Example 5

[0077] 1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine (5.2 g, 96.0%, 20 mmol), Rh-C (10%, 0.025 g), and ethanol (50 mL) were added to a 100 mL autoclave. The hydrogen gas was then purged three times to bring the pressure to 2 MPa. The mixture was heated to 35 °C and stirred for two days, with hydrogen added to bring the pressure to 2 MPa during this period. The reaction solution was filtered, and the filtrate was concentrated to obtain N'-(2,4-dichlorophenyl)acetylimine hydrazine, which was then crystallized to give 4.2 g of a black solid with a purity of 96.3%. The dechlorination product accounted for 2.2%, and the yield was 92.2%.

[0078] Example 6

[0079] 1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine (1.04 g, 96.0%, 4.02 mmol, 1.0 eq), RaneCAT-1000 (150 mg, 15% wt), and toluene (10 mL) were added to an autoclave. The autoclave was purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 2 MPa. The autoclave was stirred at room temperature for 48 hours until the starting material disappeared. Concentration and crystallization yielded 0.84 g of a black product with a purity of 95.7%, containing 3.4% dechlorination byproducts, resulting in a yield of 91.7%.

[0080] Example 7

[0081] 1-(2,4-dichlorophenyl)-2-(1-nitroethylene)hydrazine (1.04 g, 96.0%, 4.02 mmol, 1.0 eq), NaF (33.8 mg, 0.81 mmol, 0.2 eq), Raney-Ni (150 mg, 15% wt), and methanol (10 mL) were added to an autoclave. The autoclave was purged with nitrogen three times, then with hydrogen three times, and the pressure was increased to 0.7 MPa. The autoclave was stirred at room temperature. After 110 minutes, LCMS analysis showed that the product comprised 9%. During this period, the autoclave was repeatedly purged with hydrogen to 0.7 MPa, and stirring continued at room temperature until the starting material disappeared. LCMS analysis showed a product selectivity of 95.45%. Concentration and crystallization yielded 0.83 g of a black product with a purity of 96.1%, and 3.2% of the dechlorinated product, resulting in a yield of 90.9%.

[0082] Example 8

[0083] 1-(2,4-dichlorophenyl)-2-(1-nitroethylidene)hydrazine (1.04 g, 96.0%, 4.02 mmol, 1.0 eq), Raney-Ni (150 mg, 15% wt), and 1,2-dichlorobenzene (10 mL) were added to an autoclave. The autoclave was purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 2.9 MPa. The autoclave was stirred at room temperature for 40 hours. LC-MS analysis confirmed complete reaction of the product and starting material. Concentration and crystallization yielded 820 mg of a black product with a purity of 97.3%, a dechlorination byproduct of 1.8%, and a yield of 91.0%.

[0084] Example 9

[0085] 1-(2,4-dichlorophenyl)-2-(1-nitroethylene)hydrazine (8.3 g, 95.9%, 32.1 mmol, 1.0 eq), Raney-Ni (1.2 g, 15% wt), and methanol (60 mL) were added to a high-pressure reactor. The reactor was purged with nitrogen three times, then with hydrogen three times, and the pressure was increased to 2.4 MPa. The reactor was stirred at 20°C for two days. A sample was taken and tested to determine the product content: 70% product and 24% feedstock remaining. The reactor was then purged with hydrogen to 2.9 MPa and stirred at 20°C for another 18 hours. The product conversion rate was 97.1%, indicating complete reaction of the feedstock. The Raney-Ni catalyst was recovered by centrifugation. The supernatant was filtered through diatomaceous earth and concentrated to obtain 6.6 g of a light brown solid product with a purity of 96.1%. Dechlorination byproducts accounted for 3.2%, and the yield was 90.6%.

[0086] Example 10

[0087] Dichloronitrohydrazone (10.0 g, 94.7%, 38 mmol, 1.0 eq), RaneCAT-8101 (1.4 g, 14% wt), and MeOH (70 mL) were added to an autoclave. The autoclave was purged with hydrogen three times, pressurized to 2.6 MPa, and stirred at 25°C for 7 hours. The pressure was then reduced to 7 kg / cm², and the pressure remained constant over this extended period. After depressurization, a sample was taken, and HPLC analysis showed a product content of 94%. The product was centrifuged and filtered to remove the catalyst. The mixture was concentrated until no more solvent evaporated, and petroleum ether (20 mL) was added. A solid precipitated out; this precipitate was crushed, stirred at room temperature for 0.5 hours, and allowed to stand for 0.5 hours. The precipitate was filtered, and the filter cake was concentrated to obtain 7.6 g of a light brown solid product with a purity of 97.2%, containing 1.1% dechlorination byproduct, resulting in a yield of 89.1%.

[0088] Example 11

[0089] Dichloronitrohydrazone (10.0 g, 94.7%, 38 mmol, 1.0 eq), RaneCAT-8101 (1.1 g, 11% wt), and MeOH (70 mL) were added to an autoclave. The autoclave was purged with hydrogen three times, pressurized to 2.9 MPa, and stirred at 25°C for 8 hours. The pressure was then reduced to 1.1 MPa, and the pressure remained constant over this extended period. After depressurization, a sample was taken, and HPLC analysis showed a product content of 94%. The product was centrifuged and filtered to remove the catalyst. The mixture was concentrated until no more solvent evaporated, and petroleum ether (30 mL) was added, resulting in solid precipitation. The precipitate was crushed, stirred at room temperature for 0.5 h, and allowed to stand for 0.5 h. The precipitate was filtered, and the filter cake was concentrated to obtain 7.7 g of a light brown solid product. The dechlorination byproduct accounted for 1.0%, with a purity of 97.1% and a yield of 90.2%.

[0090] Example 12

[0091] Dichloronitrohydrazone (10.0 g, 94.7%, 38 mmol, 1.0 eq), RaneCAT-8101 (1.0 g, 10% wt), and MeOH (70 mL) were added to an autoclave. The autoclave was purged with hydrogen three times, pressurized to 2.8 MPa, and stirred at 25°C for 6 h. The pressure was then reduced to 1.2 MPa, and the pressure remained constant over the extended time. After depressurization, a sample was taken, and HPLC analysis showed that the product was 97% pure. The catalyst was recovered by centrifugation, and residual catalyst was removed by filtration. The mixture was concentrated until no solvent was distilled off, and 20 mL of petroleum ether was added. A solid precipitated out; this precipitate was crushed, stirred at room temperature for 0.5 h, and allowed to stand for 0.5 h. The precipitate was filtered, and the filter cake was concentrated to obtain 7.9 g of a light brown solid product with a purity of 97.8%, including 0.8% dechlorination byproducts, resulting in a yield of 92.8%.

[0092] Example 13

[0093] Dichloronitrohydrazone (10.0 g, 94.7%, 38 mmol, 1.0 eq), RaneCAT-8101 (0.8 g, 8% wt), and ethanol (70 mL) were added to an autoclave. The autoclave was purged with hydrogen three times, reaching a pressure of 2.9 MPa, and stirred at 25°C for 6.5 hours. The pressure was then reduced to 1.1 MPa, and the reaction time was extended for another 4 hours while maintaining the pressure. After depressurization, a sample was taken, and HPLC analysis showed that the product was 94%. The catalyst was recovered by centrifugation, and residual catalyst was removed by filtration. The mixture was concentrated to a final volume of 20 mL of ethanol, and 30 mL of petroleum ether was added. A solid precipitated out; this precipitate was crushed, stirred at room temperature for 0.5 hours, and allowed to stand for 0.5 hours. The precipitate was filtered, and the filter cake was concentrated to obtain 7.6 g of a light brown solid product. The dechlorination byproduct accounted for 0.9%, with a purity of 97.4% and a yield of 89.3%.

[0094] Table 1: Effect of metal catalyst hydrogenation on deproducts in Examples 3-13

[0095] Example catalyst quantity(%) Temperature (°C) Dechlorination products (%) purity(%) Yield (%) 3 Pt-C 5 50 3.7 95.5 91.3 4 PtO2 0.05 50 3.7 95.7 89.4 5 Rh-C 10 35 2.2 96.3 92.2 6 RaneCAT-1000 15 rt 3.4 95.7 91.7 7 Raney-Ni 15 rt 3.2 96.1 90.9 8 Raney-Ni 15 rt 1.8 97.3 91 9 Raney-Ni 15 rt 3.2 96.1 90.6 10 RaneCAT-8101 14 rt 1.1 97.2 89.1 11 RaneCAT-8101 11 rt 1 97.1 90.2 12 RaneCAT-8101 10 rt 0.8 97.8 92.8 13 RaneCAT-8101 8 rt 0.9 97.7 89.3

[0096] The above experimental data show that the activity of RaneNi varies greatly due to differences in processing methods and activation methods. Generally, smaller particle size, higher activity, and larger amounts of RaneNi or RaneCAT-1000 are more likely to produce dechlorination byproducts. For example, the dechlorination byproducts in Examples 6 to 9 are generally higher than 3%, with less dechlorination byproducts in Example 8 because 1,2-dichlorobenzene is used as the reaction solvent. On the other hand, larger particle size, lower activity, and smaller amounts of RaneCAT-8101 are directly reduced to iminohydrazones by pressurized hydrogenation, reducing the dechlorination byproducts to about 1%. Generally, the more catalyst added, the more dechlorination byproducts are produced, but if too little RaneCAT-8101 is added, the reaction time will be prolonged.

[0097] Example 14

[0098] 1-(2,4-dichlorophenyl)-2-(1-nitroethylene)hydrazine (1.04 g, 96.0%, 4.03 mmol, 1.0 eq), palladium on carbon (100 mg, 10%, 10% wt), and methanol (10 mL) were added to an autoclave. The autoclave was purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 0.7 MPa. The autoclave was stirred at room temperature for 2 days until the product disappeared, with hydrogen continuously added to maintain the pressure at 0.7 MPa. LC-MS analysis showed that the product accounted for 9%, with 32% and 17% of the product after removal of monochlorination, and 38% after removal of dichlorination. The experiment demonstrated that the hydrogenation reaction of palladium on carbon yielded only a small amount of product, with the dechlorination product being the primary outcome.

[0099] Example 15 Preparation of N'-(4-chloro-2-fluorophenyl)acetylimine hydrazide (Ib)

[0100] In a 250 ml autoclave, (E)-1-(4-chloro-2-fluorophenyl)-2-(1-nitroethylidene)hydrazine and (Z)-1-(4-chloro-2-fluorophenyl)-2-(1-nitroethylidene)hydrazine (3.0 g, 99.6%, 12.9 mmol), ethanol (30 ml), and RaneCAT-8101 (0.3 g, 10% wt) were added. The autoclave was purged with hydrogen three times, and the pressure was increased to 3 MPa. The mixture was stirred at 30 °C for 16 hours. When the pressure was reduced to 2.4 MPa, the reaction was checked after depressurization. The reaction of the raw materials was complete, and the product yield was 86.9%. After centrifugation and filtration, the mother liquor was concentrated and crystallized to obtain 2.2 g of dark brown solid with a purity of 96.4% and a yield of 81.6%.

[0101] Analytical data on the structure of N'-(4-chloro-2-fluorophenyl)acetylimine hydrazide:

[0102] LCMS:[M+H] + =202;

[0103] 1 H NMR(DMSO-d6,400MHz), δ(ppm):11.645(s,1H),9.359(brs.,1H),8.680(s,1H),7.40 4(d,J=10.8Hz,1H),7.168(d,J=7.6Hz,1H),6.971(t,J=7.6Hz,1H),2.309(s,3H)(see attachment Figure 6 ).

[0104] Example 16 Preparation of N'-(4-chlorophenyl)acetylimine hydrazide (Ⅰc)

[0105] (Z)-1-(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine and (E)-1-(4-chlorophenyl)-2-(1-nitroethylidene)hydrazine (3.0 g, 98.4%, 13.8 mmol), ethanol (70 ml), and RaneCAT-8101 (0.3 g, 10% wt) were added to a 250 ml autoclave. The autoclave was purged with hydrogen three times, and the pressure was increased to 1.5 MPa. The autoclave was stirred at 20 °C for one day. Pressure testing after depressurization showed that the reaction was complete, with 2.8% dechlorination product and 95.5% product. The mixture was centrifuged and filtered, the mother liquor was concentrated, and the residue was purified by column chromatography to obtain 2.8 g of a white solid with a purity of 80.7% and a yield of 89.5%.

[0106] Analytical data on the structure of N'-(4-chlorophenyl)acetylimine hydrazide:

[0107] LCMS:[M+H] + =184;

[0108] 1H NMR (DMSO-d6, 400MHz), δ (ppm): 11.42 (brs., 1H), 9.13 (brs., 1H), 8.67 (s, 1H), 7.29 (d, J = 8.0Hz, 2H), 6.86 (d, J = 8.0Hz, 2H), 2.27 (s, 3H) (see attachment Figure 7 ).

[0109] Example 17 Preparation of N'-(2-chlorophenyl)acetylimine hydrazide (Id)

[0110] In a 250 ml autoclave, (E)-1-(2-chlorophenyl)-2-(1-nitroethylidene)hydrazine and (Z)-1-(2-chlorophenyl)-2-(1-nitroethylidene)hydrazine (3.0 g, 97.1%, 13.6 mmol), RaneCAT-8101 (0.3 g, 10% wt), and ethanol (70 ml) were added to replace hydrogen gas. The autoclave was pressurized to 2.1 MPa and reacted at 30 °C for 16 hours. Pressure testing upon depressurization indicated complete reaction of the reactants, with approximately 3.9% dechlorination byproducts and a product content of 93.7%. The catalyst was removed by filtration, and the filtrate was concentrated and purified by column chromatography to obtain 2.3 g of a white solid with a purity of 98.2% and a yield of 90.8%.

[0111] Analytical data on the structure of N'-(2-chlorophenyl)acetylimine hydrazide:

[0112] LCMS:[M+H] + =184;

[0113] 1 ¹H NMR (DMSO-d⁶, 400MHz), δ (ppm): 7.211 (dt, J₁ = 0.8 Hz, J₂ = 7.2 Hz, 2H), 7.124 (t, J = 8.0 Hz, 1H), 6.834 (s, 1H), 6.625 (dt, J₁ = 1.6 Hz, J₂ = 7.6 Hz, 1H), 6.043 (s, 2H), 1.845 (s, 3H) (see appendix) Figure 8 and appendix Figure 9 ).

[0114] Example 18 Preparation of N'-phenylacetylimine hydrazide (Ie)

[0115] In a 250 ml autoclave, (Z)-1-(1-nitroethylidene)-2-phenylhydrazine and (E)-1-(1-nitroethylidene)-2-phenylhydrazine (6 g, 90.1%, 30.2 mmol), ethanol (80 ml), and RaneCAT-8101 (0.6 g) were added. Hydrogen was purged three times, and the pressure was increased to 2.9 MPa. The reaction was carried out at 30 °C for 3 days, with the hydrogen pressure maintained at approximately 30 kg / cm². Pressure testing confirmed complete reaction of the reactants and a product content of 61%. The catalyst was removed by centrifugation, and the filtrate was concentrated. The filtrate was then stirred with 2 N hydrochloric acid, separated, and extracted three times with dichloromethane. The aqueous phase was adjusted to pH 8-9 with sodium hydroxide solution and extracted three times with ethyl acetate to remove excess impurities. The pH was then adjusted to 14 with sodium hydroxide solution, followed by three extractions with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 2.7 g of a white solid with a purity of 87.0% and a yield of 52.2%.

[0116] Analytical data on the structure of N'-phenylacetylimine hydrazide:

[0117] LCMS:[M+H] + =150;

[0118] 1 ¹H NMR (DMSO-d⁶, 400MHz), δ (ppm): 7.511 (s, 1H), 7.062 (t, J = 7.2Hz, 2H), 6.825 (d, J = 8.0Hz, 2H), 6.543 (t, J = 7.2Hz, 1H), 5.664 (s, 2H), 1.705 (s, 3H) (see appendix) Figure 10 ).

[0119] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a compound with the structure described in Formula I, characterized in that, The method includes the step of hydrogenating and reducing the nitrohydrazone compound represented by Formula A and / or Formula B in the presence of a catalyst: ， Where X=Y=Cl; or X=F, Y=Cl; or X=H, Y=Cl; or X=Cl, Y=H; The catalyst is selected from RaneCAT-8101; The pressure of the hydrogenation reduction reaction is 1.5–3 MPa; The reaction temperature for the hydrogenation reduction reaction is 20~50℃; The amount of catalyst added is 5-20% of the mass of the nitrohydrazone compound.

2. The method for preparing the compound with the structure of Formula I according to claim 1, characterized in that, The amount of catalyst added is 8-20% of the mass of the nitrohydrazone compound.

3. The method for preparing the compound with the structure of Formula I according to claim 1, characterized in that, The amount of catalyst added is 8-15% of the mass of the nitrohydrazone compound.

4. The method for preparing the compound with the structure of Formula I according to claim 1, characterized in that, The pressure of the hydrogenation reduction reaction is 1.5–2.5 MPa.

5. The method for preparing the compound with the structure of Formula I according to claim 1, characterized in that... The hydrogenation reduction reaction is carried out in the presence of a reaction solvent.

6. The method for preparing the compound with the structure of Formula I according to claim 1, characterized in that, The hydrogenation reduction reaction is carried out in the presence of a reaction solvent, which is selected from inert organic solvents.

7. The method for preparing the compound with the structure of Formula I according to claim 1, characterized in that, The hydrogenation reduction reaction is carried out in the presence of a reaction solvent, which is selected from benzene, toluene, xylene, chlorobenzene, and halogenated hydrocarbons. 1-4 One or more of the following: alkyl alcohols, THF, dioxane, DMF, DMSO, and ethyl acetate.

8. The method for preparing the compound of formula I according to claim 1, characterized in that, The hydrogenation reduction reaction is carried out in the presence of a reaction solvent, which is selected from one or more of toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, n-propanol, isopropanol, and n-butanol.

9. The method for preparing the compound of formula I according to claim 1, characterized in that, The method further includes the step of monitoring the reaction and determining the reaction end time.

10. A method for preparing a compound with the structure of Formula I according to claim 1, characterized in that, The reaction time of the method is no less than 6 hours.

11. A method for preparing a compound with the structure of Formula I according to claim 1, characterized in that, The reaction time of the method is no less than 2 days.

12. The method for preparing the compound of formula I according to claim 1, characterized in that, The reaction time of the method is no less than 3 days.

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