Preparation method for iminoaryl compound and intermediate
By employing selective dechlorination reactions and optimized synthetic routes, the problems of low purity and yield in the synthesis of iminoaryl compounds have been solved, enabling efficient industrial production.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- SHANDONG KINGAGROOT CROPSCIENCE CO LTD
- Filing Date
- 2025-11-04
- Publication Date
- 2026-05-15
AI Technical Summary
Existing synthetic processes for iminoaryl compounds suffer from problems such as low product purity, low reaction yield, and high cost, making them unsuitable for industrial production.
Intermediate compound IV was prepared by selective dechlorination, then reacted with chloroformate compounds, cyclized and methylated, and further reacted with hydroxylamine hydrochloride to finally obtain iminoaryl compounds. The reaction efficiency was improved by optimizing the selection of solvent and catalyst.
This improved the yield and purity of intermediate compounds, making them suitable for industrial production and reducing costs.
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Abstract
Description
Preparation methods of iminoaryl compounds and intermediates Technical Field
[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a method for preparing iminoaryl compounds and intermediates. Background Technology
[0002] In recent years, my country's pesticide innovation has developed rapidly, and the variety of herbicides has also increased. Iminoaryl compounds are a new type of herbicide disclosed in CN113105405A, which have the characteristics of broad weed-killing spectrum, high activity, fast weeding speed, and environmental friendliness. However, their synthesis process still has problems such as low product purity, low reaction yield, and high cost, and scientists still need to further develop synthesis processes more suitable for industrial production. Summary of the Invention
[0003] To address the aforementioned problems in the prior art, this invention provides a method for preparing iminoaryl compounds and intermediates.
[0004] The technical solution adopted in this invention is as follows:
[0005] A method for preparing an iminoaryl compound intermediate includes the following steps:
[0006] Compound III undergoes a selective dechlorination reaction to yield compound IV, as shown in the following reaction formula:
[0007] This application also discloses a method for preparing iminoaryl compounds, comprising the following steps:
[0008] (1) Compound III undergoes a selective dechlorination reaction to give compound IV;
[0009] (2) Compound IV reacts with chloroformate compound IV-a to give compound V;
[0010] (3) Compound V first forms a ring with V-a1 and then undergoes methylation to obtain compound VI, or compound V forms a ring with V-a2 to obtain compound VI;
[0011] (4) Compound VI reacts to give compound VII;
[0012] (5) Compound VII reacts with hydroxylamine hydrochloride to give compound VIII;
[0013] (6) Compound VIII reacts with VIII-a to give iminoaryl compound IX;
[0014] The synthesis route is as follows:
[0015] Wherein, L represents halogen, R1 is selected from alkyl or aryl, and R2 is selected from alkyl or aryl; the aforementioned "aryl" is optionally replaced by at least one group selected from hydroxyl, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, alkoxycarbonyl, alkylthio or alkylsulfonyl.
[0016] Preferably, R1 is selected from C1-C8 alkyl or aryl, and R2 is selected from C1-C8 alkyl or aryl; the aforementioned "aryl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halo-C1-C8 alkyl, halo-C2-C8 alkenyl, halo-C2-C8 alkynyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, C1-C8 alkoxy carbonyl, C1-C8 alkylthio or C1-C8 alkylsulfonyl.
[0017] More preferably, R1 is selected from C1-C4 alkyl or phenyl, and R2 is selected from methyl, ethyl, isopropyl or phenyl; the aforementioned "phenyl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxy carbonyl, C1-C6 alkylthio or C1-C6 alkylsulfonyl.
[0018] In one specific embodiment, the dechlorination reaction is carried out in the presence of an alkaline solution and a dechlorination catalyst; more preferably, the alkaline solution is selected from at least one of aqueous solutions of alkali metal hydroxides (such as aqueous solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.); and / or the dechlorination catalyst is zinc or aluminum.
[0019] In one specific embodiment, step (2) is carried out in the presence of a solvent; preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene, or dichlorobenzene. High yields can be achieved in step (2) without the addition of alkali.
[0020] In one specific embodiment, the reaction temperature of step (3) is between 0 and 120°C.
[0021] In one specific embodiment, the cyclization reaction in step (3) is carried out in the presence of a solvent and a base; preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone; the base is selected from at least one of inorganic bases (such as K2CO3, Na2CO3, Cs2CO3, NaHCO3, KF, CsF, K3PO4, NaOH, KOH, NaH, KH, etc.) or organic bases (such as AcOK, AcONa, t-BuONa, MeONa, EtONa, DMAP, pyrazole, triethylamine, DIEA, etc.); and / or the methylating agent is selected from at least one of iodomethane, chloromethane, bromomethane, dimethyl sulfate, or dimethyl carbonate.
[0022] In one specific embodiment, step (4) is carried out in the presence of a halogenating agent, a catalyst, and a solvent; preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, ethyl acetate, isopropyl acetate, or benzene; the halogenating agent is selected from at least one of N-bromosuccinimide, dibromohexene, N-chlorosuccinimide, dichlorohexene, chlorine, bromine, hydrogen peroxide / hydrobromic acid, or sodium bromide / sodium bromate / sulfuric acid; and / or the catalyst is selected from at least one of azobisisobutyronitrile or benzoyl peroxide.
[0023] In one specific embodiment, step (5) is carried out in the presence of a solvent; preferably, the solvent is an alcohol (such as methanol, ethanol, isopropanol, etc.).
[0024] In one specific embodiment, step (6) is carried out in the presence of an alkali and a polar solvent; preferably, the alkali is selected from at least one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, or potassium bicarbonate; and / or the polar solvent is selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, and N-methylpyrrolidone; more preferably, the alkali is in powder form, which can improve the catalytic effect, thereby improving the yield and product purity.
[0025] Compound III is obtained by the reduction reaction of compound II with a hydride reagent, as shown in the following reaction formula: Preferably, the reduction reaction is carried out in the presence of a hydrogenation solvent and a hydrogenation catalyst; more preferably, the hydrogenation solvent is selected from at least one of methanol, ethanol, isopropanol or water; and / or the hydrogenation catalyst is selected from at least one of iron powder, copper powder, Raney nickel, palladium on carbon, platinum on carbon or ferric chloride.
[0026] Compound II is obtained by nitration of compound I with nitric acid, as shown in the following reaction formula: Preferably, the nitration reaction is carried out in the presence of a nitration solvent and a nitration catalyst; more preferably, the nitration solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, water, acetic acid, or trifluoroacetic acid; and / or the nitration catalyst is selected from at least one of concentrated sulfuric acid, acetic anhydride, or trifluoroacetic anhydride.
[0027] Compound II is obtained by first nitrifying compound I' with nitric acid and then fluorinating it with a fluoride salt, as shown in the following reaction formula:
[0028] Preferably, the nitration reaction is carried out in the presence of a nitration solvent and a nitration catalyst; more preferably, the nitration solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, water, acetic acid, or trifluoroacetic acid; and / or the nitration catalyst is selected from at least one of concentrated sulfuric acid, acetic anhydride, or trifluoroacetic anhydride.
[0029] Preferably, the fluorination reaction is carried out in the presence of a fluorination catalyst and a fluorination solvent; more preferably, the fluorination catalyst is selected from quaternary phosphine salt phase transfer catalysts (such as tetraphenylphosphine bromide, tetrabutylphosphine bromide, tetra-(diethylamino)phosphine bromide, etc.), quaternary ammonium salt phase transfer catalysts (such as tetrabutylammonium bromide, tetrabutylammonium chloride, TEBA, TBAB, etc.), crown ethers (such as 18-crown-6, 15-crown-5, etc.), CNC... + and PNC + At least one of the following: the fluorinated solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone; preferably, the fluoride salt is selected from at least one of potassium fluoride, sodium fluoride, cesium fluoride, amine fluoride, or tetrabutylammonium fluoride.
[0030] Among them, CNC + and PNC + The structural formulas are as follows:
[0031] In another specific embodiment, the carbon atom attached to the L group in step (6) has an R configuration, and its reaction formula is as follows:
[0032] This application also discloses an intermediate compound as shown in Formula III.
[0033] This application also discloses an intermediate compound as shown in Formula II.
[0034] This application offers the following advantages: Compared with existing technologies, the preparation of intermediate compound IV utilizes selective dechlorination with polychlorinated benzene compounds, resulting in superior selective dechlorination, high reaction yield, and high product purity. Overall, the preparation method of this application boasts advantages such as high yield, high product purity, and ease of industrial production. Detailed Implementation
[0035] The following examples are for illustrative purposes only and should not be construed as limiting the invention in any way. The scope of protection of this invention is defined by the claims.
[0036] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.
[0037] Example 1
[0038] A method for preparing compound IX includes the following steps:
[0039] 1) Preparation of Compound II 2,4-dichloro-6-fluoro-3-methylnitrobenzene
[0040] In a 500 mL four-necked flask equipped with a mechanical stirrer and thermometer, 66.3 g of concentrated sulfuric acid and 70 g of 1,2-dichloroethane (MW 179.02, 24.22 g) of compound I were added. The mixture was stirred and cooled to 0-5 °C, and 14.14 g of 65% nitric acid was added dropwise over 0.5 h. After the addition was completed, the mixture was brought to room temperature and stirred at room temperature for 2 h until the reaction was complete. The reaction solution was poured into an ice-water mixture, and the mixture was separated. The aqueous phase was extracted with 70 g of 1,2-dichloroethane. The two organic phases were combined and washed successively with saturated sodium bicarbonate solution and purified water. The organic phase was dried and concentrated to give 29.39 g of solid, with a purity of 97% and a yield of 96%.
[0041] 2) Preparation of compound III 2,4-dichloro-6-fluoro-3-methylaniline
[0042] Compound II (MW 224.01, 29.39 g) was added to a 500 mL hydrogenation reactor, along with 100 g of methanol and 1.47 g of Raney nickel. The reactor was sealed, purged with nitrogen and hydrogen, and maintained at 30 °C and 0.8 MPa for 3 h. The catalyst was removed, and the organic phase was distilled. The foredistillate was methanol and water, and the main distillate was compound III, yielding a total of 24.69 g of gray solid with a purity of 98% and a yield of 98%.
[0043] 3) Preparation of compound IV, 4-chloro-2-fluoro-5-methylaniline
[0044] The prepared compound III, 2,4-dichloro-6-fluoro-3-methylaniline (MW 194.03, 24.69 g), was added to a 500 mL reaction flask, followed by 125 g of 10% sodium hydroxide solution. The mixture was heated to 90 °C, and then 16.25 g of zinc powder was added in three batches over 2 hours. The mixture was then kept at this temperature for 5 hours to complete the reaction. The reaction solution was cooled to room temperature, and the pH was adjusted to 3.0 with concentrated hydrochloric acid. The mixture was extracted twice with dichloromethane, and the organic phases were combined and concentrated to give 19.5 g of a white solid, namely 4-chloro-2-fluoro-5-methylaniline, with a purity of 98% and a yield of 96%.
[0045] 4) Preparation of compound V (2-fluoro-4-chloro-5-methylphenyl)carbamate
[0046] Compound IV, 2-fluoro-4-chloro-5-methylaniline (MW 159.59, 19.5 g), obtained in the previous step, was added to a 500 mL reaction flask, along with 117 g of 1,2-dichloroethane. The mixture was heated to reflux, and phenyl chloroformate (MW 156.57, 24.87 g) was added dropwise over 5 hours. The reaction was then maintained at this temperature with stirring for 3 hours until completion. The mixture was cooled to room temperature, quenched with purified water, separated, and the organic phase was concentrated to give 33.49 g of intermediate V, with a purity of 98% and a yield of 98%.
[0047] 5) Preparation of compound VI 3-(4-chloro-2-fluoro-5-methylphenyl)-6-trifluoromethyl-1-methyluracil
[0048] Add 113 g of N,N-dimethylformamide and ethyl 3-amino-4,4,4-trifluorobutenoate (MW 183.13, 26.0 g) to a 500 mL reaction flask. Cool to 10-20 °C, add sodium hydroxide (8.3 g), stir for 1 h, then add dropwise a 50% solution of intermediate V in N,N-dimethylformamide (MW 279.70, containing 33.49 g of compound V). After the addition is complete, maintain the temperature and stir for 3 h. The reaction is confirmed by HPLC. Rise to room temperature, add 24.57 g of potassium carbonate and dimethyl sulfate (MW 126.13, 26.9 g), and maintain the temperature for 2 h. Slowly pour the reaction solution into water to quench, extract with toluene, stir for 1 h, separate the liquid, wash with the organic phase, concentrate, and give 38.29 g of a pale yellow solid with a purity of 98% and a yield of 95%.
[0049] 6) Synthesis of compound VII
[0050] Compound VI (MW 336.67, 38.29 g) obtained in the previous step was added to a 2000 mL reaction flask, followed by 115 g of 1,2-dichloroethane. The mixture was heated to 70 °C. Bromine (53.5 g) was added dropwise, and azobisisobutyronitrile (1.89 g) was added in three batches at 0.5 h intervals, for a total of 3 h. The reaction was continued for another 2 h. HPLC analysis showed that dibromide was 96% and monobromide was 2.3%. The mixture was cooled to room temperature, quenched with sodium sulfite solution, washed with water, and concentrated. Then, 190 g of 85% formic acid was added, and the mixture was heated to 105 °C and maintained at this temperature for 12 h. Formic acid was removed under reduced pressure, and the residue was dissolved in 1,2-dichloroethane. Purified water was added, and the pH was adjusted to 7.5-8.0 with sodium hydroxide aqueous solution. The mixture was separated, washed with water, and concentrated to dryness to obtain 37.13 g of a white solid with a purity of 97% and a yield of 93%.
[0051] 7) Synthesis of compound VIII
[0052] The compound VII (MW 350.65, 37.13 g) obtained in the previous step was added to a 500 mL reaction flask, along with 105 g of ethanol. The mixture was heated to 50 °C, and 9.21 g of hydroxylamine hydrochloride was added to the reaction flask in three batches. The mixture was kept warm and stirred for 6 h until the reaction was complete. The mixture was then cooled to room temperature, and 5% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the system to 7.0-7.5. The mixture was kept warm and stirred for 0.5 h, filtered, and dried to obtain 36.98 g of white solid with a purity of 97% and a yield of 95.5%.
[0053] 8) Synthesis of compound IX
[0054] Compound VIII (MW 365.67, 36.98 g) obtained in the previous step was added to a 1000 mL reaction flask, along with 148 g of N,N-dimethylformamide, 17.8 g of anhydrous potassium carbonate powder (300 mesh), and 48.33 g of methyl s-2-chloropropionate. The mixture was stirred at 25-30 °C for 8 h. The reaction was considered complete when the starting material disappeared as detected by HPLC. The reaction solution was quenched in water, extracted with toluene, and the organic phase was washed with purified water and concentrated under reduced pressure to obtain 42.98 g of compound IX, with a purity of 98.0% and a yield of 97%.
[0055] Example 2
[0056] The difference from Example 1 lies in the different synthetic route of compound II:
[0057] 1) Preparation of 2,4,6-trichloro-3-methylnitrobenzene
[0058] In a 500 mL four-necked flask equipped with a mechanical stirrer and thermometer, 60 g of concentrated sulfuric acid and 60 g of 1,2-dichloroethane (MW 195.47, 19.5 g) of compound I' were added. The mixture was stirred and cooled to 0-5 °C, and 10.66 g of 65% nitric acid was added dropwise over 1.0 h. After the addition was completed, the mixture was brought to room temperature and stirred at room temperature for 3 h until the reaction was complete. The reaction solution was poured into an ice-water mixture, and the mixture was separated. The aqueous phase was extracted with 60 g of 1,2-dichloroethane. The two organic phases were combined and washed successively with saturated sodium bicarbonate solution and purified water. The organic phase was dried and concentrated to give 23.55 g of solid, with a purity of 96% and a yield of 94%.
[0059] 2) Preparation of Compound II 2,4-dichloro-6-fluoro-3-methylnitrobenzene
[0060] The 2,4,6-trichloro-3-methylnitrobenzene (MW 240.46, 23.55 g) obtained in the previous step was added to a 500 mL reaction flask, along with spray-dried anhydrous potassium fluoride (6.55 g), N,N-dimethylacetamide (100 g), and tetraphenylphosphine bromide (1.2 g). The mixture was heated to 170 °C and stirred for 5 h. The reaction was considered complete when the remaining starting material was less than 1.0%. The mixture was cooled to room temperature, filtered to remove salt, and the filter cake was washed with N,N-dimethylacetamide. The filtrate was then distilled under reduced pressure, yielding compound II, 2,4-dichloro-6-fluoro-3-methylnitrobenzene, in the reactor. The yield was 19.74 g, with a purity of 96% and a yield of 90%.
[0061] Example 3
[0062] The difference from Example 1 lies in step 3), which is as follows:
[0063] Compound III, 2,4-dichloro-6-fluoro-3-methylaniline (MW 194.03, 24.69 g), was added to a 500 mL reaction flask, followed by 125 g of 10% sodium hydroxide solution. The mixture was heated to 90 °C, and then 10.3 g of aluminum powder was added in four batches over 2 hours. The mixture was then kept at this temperature for 3 hours to complete the reaction. The reaction solution was cooled to room temperature, and the pH was adjusted to 1.0-2.0 with concentrated hydrochloric acid. The mixture was extracted twice with dichloromethane, and the organic phases were combined and concentrated to give 18.9 g of compound IV, a white solid, namely 4-chloro-2-fluoro-5-methylaniline, with a purity of 97% and a yield of 93%.
[0064] Comparative Example 1
[0065] The difference from Examples 1 and 3 lies in the dechlorination method in step 3), where palladium on carbon catalytic hydrogenation is used. The specific steps are as follows:
[0066] The prepared compound III, 2,4-dichloro-6-fluoro-3-methylaniline (MW 194.03, 49.38 g), was added to a 500 mL hydrogenation reactor, along with 245 g of methanol and 77 g of triethylamine. 0.2 g of 5% wet palladium on carbon was added. The reactor was purged with nitrogen and hydrogen, and the hydrogen pressure was increased to 0.8-1.0 MPa. The temperature was raised to 60-80 °C, and the mixture was stirred under constant temperature and pressure for 10 h. A sample was taken for GC analysis. The reaction was then complete, yielding 22.1 g of compound IV (99% purity, 55% yield) after filtration. Sodium hydroxide aqueous solution was added to the mother liquor to release the free triethylamine. The solution was then distilled at atmospheric pressure followed by fractional distillation to separate compound IV.
[0067] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.
Claims
1. A method for preparing an iminoaryl compound intermediate, characterized in that, Includes the following steps: Compound III undergoes a selective dechlorination reaction to yield compound IV, as shown in the following reaction formula:
2. A method for preparing an iminoaryl compound, characterized in that, Includes the following steps: (1) Compound III undergoes a selective dechlorination reaction to give compound IV; (2) Compound IV reacts with chloroformate compound IV-a to give compound V; (3) Compound V first forms a ring with V-a1 and then undergoes methylation to obtain compound VI, or compound V forms a ring with V-a2 to obtain compound VI; (4) Compound VI reacts to give compound VII; (5) Compound VII reacts with hydroxylamine hydrochloride to give compound VIII; (6) Compound VIII reacts with VIII-a to give iminoaryl compound IX; The synthesis route is as follows: Wherein, L represents halogen, R1 is selected from alkyl or aryl, and R2 is selected from alkyl or aryl; the aforementioned "aryl" is optionally replaced by at least one group selected from hydroxyl, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, alkoxycarbonyl, alkylthio or alkylsulfonyl. Preferably, R1 is selected from C1-C8 alkyl or aryl, and R2 is selected from C1-C8 alkyl or aryl; the aforementioned "aryl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halo-C1-C8 alkyl, halo-C2-C8 alkenyl, halo-C2-C8 alkynyl, C1-C8 alkoxy, halo-C1-C8 alkoxy, C1-C8 alkoxy carbonyl, C1-C8 alkylthio or C1-C8 alkylsulfonyl. More preferably, R1 is selected from C1-C4 alkyl or phenyl, and R2 is selected from methyl, ethyl, isopropyl or phenyl; the aforementioned "phenyl" is optionally substituted by at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkoxy carbonyl, C1-C6 alkylthio or C1-C6 alkylsulfonyl.
3. The preparation method according to claim 1 or 2, characterized in that, The dechlorination reaction is carried out in the presence of an alkaline solution and a dechlorination catalyst; preferably, the alkaline solution is selected from at least one aqueous solution of an alkali metal hydroxide, and / or the dechlorination catalyst is zinc or aluminum.
4. The preparation method according to any one of claims 2-3, characterized in that, The reaction in step (2) is carried out in the presence of a solvent; more preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene or dichlorobenzene; The reaction temperature of step (3) is between 0 and 120°C; and / or the cyclization reaction is carried out in the presence of a solvent and a base; preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone; the base is selected from at least one of inorganic or organic bases; and / or the methylating agent is selected from at least one of iodomethane, chloromethane, bromomethane, dimethyl sulfate, or dimethyl carbonate; Step (4) is carried out in the presence of a halogenating agent, a catalyst, and a solvent; preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, ethyl acetate, isopropyl acetate, or benzene; the halogenating agent is selected from at least one of N-bromosuccinimide, dibromohexane, N-chlorosuccinimide, dichlorohexane, chlorine, bromine, hydrogen peroxide / hydrobromic acid, or sodium bromide / sodium bromate / sulfuric acid; and / or the catalyst is selected from at least one of azobisisobutyronitrile or benzoyl peroxide; The reaction in step (5) takes place in the presence of a solvent; preferably, the solvent is an alcohol. Step (6) is carried out in the presence of an alkali and a polar solvent; preferably, the alkali is selected from at least one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, or potassium bicarbonate; and / or the polar solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, or N-methylpyrrolidone; more preferably, the alkali is in the form of a powder.
5. The preparation method according to any one of claims 1-4, characterized in that, Compound III is obtained by the reduction reaction of compound II with a hydride reagent, as shown in the following reaction formula: Preferably, the reduction reaction is carried out in the presence of a hydrogenation solvent and a hydrogenation catalyst; more preferably, the hydrogenation solvent is selected from at least one of methanol, ethanol, isopropanol or water; and / or the hydrogenation catalyst is selected from at least one of iron powder, copper powder, Raney nickel, palladium on carbon, platinum on carbon or ferric chloride.
6. The preparation method according to claim 5, characterized in that, Compound II is obtained by nitration of compound I with nitric acid, as shown in the following reaction formula: Preferably, the nitration reaction is carried out in the presence of a nitration solvent and a nitration catalyst; more preferably, the nitration solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, water, acetic acid, or trifluoroacetic acid; and / or the nitration catalyst is selected from at least one of concentrated sulfuric acid, acetic anhydride, or trifluoroacetic anhydride.
7. The preparation method according to claim 5, characterized in that, Compound II is obtained by first nitrifying compound I' with nitric acid and then fluorinating it with a fluoride salt, as shown in the following reaction formula: Preferably, the nitration reaction is carried out in the presence of a nitration solvent and a nitration catalyst; more preferably, the nitration solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, water, acetic acid, or trifluoroacetic acid; and / or the nitration catalyst is selected from at least one of concentrated sulfuric acid, acetic anhydride, or trifluoroacetic anhydride. Preferably, the fluorination reaction is carried out in the presence of a fluorination catalyst and a fluorination solvent; more preferably, the fluorination catalyst is selected from quaternary phosphine salt phase transfer catalysts, quaternary ammonium salt phase transfer catalysts, crown ethers, and CNC. + or PNC + At least one of the following: the fluorinated solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, sulfolane, or N-methylpyrrolidone; preferably, the fluoride salt is selected from at least one of potassium fluoride, sodium fluoride, cesium fluoride, amine fluoride, or tetrabutylammonium fluoride.
8. The preparation method according to any one of claims 1-7, characterized in that, The carbon atom attached to the L group in step (6) has an R configuration, and its reaction formula is as follows:
9. An intermediate compound as described in claim 1, formula III or claim 5, formula II.