Preparation methods for iminoaryl compound and intermediate

Abstract

The present invention belongs to the field of organic chemical synthesis, and particularly relates to preparation methods for an iminoaryl compound and an intermediate. The preparation of the intermediate comprises the following step: subjecting compound III and a chlorination reagent to a chlorination reaction to obtain compound IV, wherein reaction formula I is as described below. Intermediate compound IV is subjected to subsequent reactions to obtain an iminoaryl compound. The preparation methods of the present application are, as a whole, simplified in terms of process flow and reduced in process difficulty, and have the advantages of a high yield, a high product purity and being conducive to industrial production.

Description

Preparation method of imino aryl compound and intermediate TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemical synthesis, and particularly relates to a preparation method of an imino aryl compound and an intermediate. BACKGROUND

[0002] There are various types of herbicides on the market, such as CN113105405A discloses a carboxylic acid derivative substituted imino aryl compound, which has excellent herbicidal effect, but it still has problems such as complicated production process, high production difficulty, low yield and product purity, and it is urgent to develop a synthesis method suitable for industrial large-scale production. SUMMARY

[0003] To solve the above problems in the prior art, the present application provides a preparation method of an imino aryl compound and an intermediate.

[0004] The technical scheme adopted by the present application is as follows:

[0005] A preparation method of an imino aryl compound intermediate, comprising the following steps:

[0006] Compound III is chlorinated with a chlorinating agent to obtain compound IV, and the reaction formula is as follows:

[0007] The present application also discloses a preparation method of an imino aryl compound, comprising the following steps:

[0008] (1) Compound III is chlorinated with a chlorinating agent to obtain compound IV;

[0009] (2) Compound IV is reacted with chloroformate compound IV-a to obtain compound V;

[0010] (3) Compound V is first ring-formed and then methylated with V-a1 to obtain compound VI, or compound V is ring-formed with V-a2 to obtain compound VI;

[0011] (4) Compound VI is reacted to obtain compound VII;

[0012] (5) Compound VII is reacted with hydroxylamine hydrochloride to obtain compound VIII;

[0013] (6) Compound VIII is reacted with VIII-a to obtain imino aryl compound IX;

[0014] The synthesis route is as follows:

[0015] wherein L represents halogen, R1is selected from alkyl or aryl, and R2is selected from alkyl or aryl; the aforementioned "aryl" is optionally substituted with at least one group selected from hydroxy, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, alkoxycarbonyl, alkylthio, or alkylsulfonyl.

[0016] Preferably, R1is selected from C1-C8alkyl or aryl, and R2is selected from C1-C8alkyl or aryl; the aforementioned "aryl" is optionally substituted with at least one group selected from hydroxy, halogen, cyano, nitro, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, haloC1-C8alkyl, haloC2-C8alkenyl, haloC2-C8alkynyl, C1-C8alkoxy, haloC1-C8alkoxy, C1-C8alkoxycarbonyl, C1-C8alkylthio, or C1-C8alkylsulfonyl.

[0017] More preferably, R1is selected from C1-C4alkyl or phenyl, and R2is selected from methyl, ethyl, isopropyl, or phenyl; the aforementioned "phenyl" is optionally substituted with at least one group selected from hydroxy, halogen, cyano, nitro, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6alkoxycarbonyl, C1-C6alkylthio, or C1-C6alkylsulfonyl.

[0018] In a particular embodiment, the preparation of compound IV is carried out in the presence of a chlorinating catalyst and a solvent; preferably, the chlorinating reagent is selected from at least one of thionyl chloride, sulfuryl chloride, or hydrogen peroxide / hydrochloric acid; the chlorinating catalyst is selected from one or more of ferric chloride / diphenyl sulfide, aluminum chloride / diphenyl sulfide, iodine, or copper chloride; and / or the solvent is selected from at least one of acetonitrile, dichloromethane, 1,2-dichloroethane, or chlorobenzene.

[0019] In a particular embodiment, compound III is obtained from compound II by a reduction reaction with a hydrogenation reagent, according to the following reaction scheme: 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, or isopropanol; and / or the hydrogenation catalyst is selected from at least one of iron powder, copper powder, Raney nickel, palladium on carbon, or platinum on carbon.

[0020] In a particular embodiment, compound II is obtained from compound I by a fluorination reaction with a fluorinating salt, according to the following reaction scheme: 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 at least one of quaternary phosphonium salt phase transfer catalysts (such as tetraphenylphosphonium bromide, tetrabutylphosphonium bromide, tetra-(diethylamino)phosphonium bromide, etc.); and the fluorination solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, sulfolane, or N-methylpyrrolidone; preferably, the fluorine salt is selected from at least one of potassium fluoride, sodium fluoride, cesium fluoride, amine fluoride, or tetrabutylammonium fluoride.

[0021] In a specific embodiment, the step (2) is reacted 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. Among them, high yield can be achieved without adding base in the step (2).

[0022] In a specific embodiment, the reaction temperature of the step (3) is between 0-120°C.

[0023] In a specific embodiment, the ring-forming reaction of the step (3) is carried out in the presence of a solvent, 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-imidazolidinone, 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 methylation reagent is selected from at least one of iodomethane, chloromethane, bromomethane, dimethyl sulfate, or dimethyl carbonate.

[0024] In a specific embodiment, the step (4) is reacted in the presence of a halogenating reagent, 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 reagent is selected from at least one of N-bromosuccinimide, dibromohydantoin, N-chlorosuccinimide, dichlorohydantoin, 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.

[0025] In one specific embodiment, the step (5) is reacted in the presence of a solvent; preferably, the solvent is an alcohol (such as methanol, ethanol, isopropanol, etc.).

[0026] In one specific embodiment, the step (6) is reacted in the presence of a base and a polar solvent; preferably, the base 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, N-methyl pyrrolidone; further preferably, the base is in a powder form, which can improve the catalytic effect, and thus improve the yield and purity of the product.

[0027] In another specific embodiment, the carbon atom to which the L group of the step (6) is attached is in the R configuration, and the reaction formula is as follows:

[0028] The present application has the following excellent effects: compared with the prior art, the preparation of the intermediate compound IV is a one-step reaction, which simplifies the process flow, and has a high reaction yield and a high purity of the obtained product. The preparation method of the present application simplifies the overall process flow, reduces the process difficulty, and has the advantages of high yield, high product purity, and easy industrial production. DETAILED DESCRIPTION

[0029] The following examples are used to illustrate the present application and should not be regarded as limiting the present application in any way. The scope of the rights claimed by the present application is described by the claims.

[0030] If the specific experimental steps or conditions are not specified in the examples, the operations or conditions can be performed according to the conventional experimental steps described in the literature in the art. If the reagents or instruments used are not specified by the manufacturer, they are all conventional reagent products that can be obtained by purchase.

[0031] Example 1

[0032] A preparation method of a compound IX, comprising the following steps:

[0033] 1) Preparation of compound II 4-fluoro-3-nitrotoluene

[0034] In a 2000 mL four-necked flask equipped with mechanical stirrer and thermometer, spray-dried anhydrous potassium fluoride (69.72 g), sulfolane (515 g) and tetraphenylphosphonium bromide (8.58 g, 0.02 mol) were charged and heated to 200-220 °C. Compound I, 4-chloro-3-nitrotoluene (MW 171.58, 173.31 g) was added dropwise and the reaction was stirred for 5 h at 200-220 °C until the starting material was consumed as determined by GC. The reaction was cooled to room temperature and the salt was removed by filtration. The filter cake was distilled under reduced pressure with sulfolane. The fraction was compound II, 4-fluoro-3-nitrotoluene (141.03 g, 99% purity, 90% yield).

[0035] 2) Preparation of compound III, 2-fluoro-5-methylaniline

[0036] Compound II, 4-chloro-3-nitrotoluene (MW 155.13, 70.51 g) was charged into a 500 mL hydrogenation reactor. Methanol (212 g) and Raney nickel (1.41 g, about 80 mesh) were added. The reactor was sealed and purged with nitrogen and hydrogen. The reaction was carried out at 50 °C and 0.8 MPa for 3 h. The catalyst was removed by filtration. The organic phase was distilled. The forefraction was methanol and water. The main fraction was compound III (55.74 g, colorless liquid, 99% purity, 98% yield).

[0037] 3) Preparation of compound IV, 2-fluoro-4-chloro-5-methylaniline

[0038] Compound III, 2-fluoro-5-methylaniline (MW 125.15, 109.77 g, 0.4545 mol) was charged into a 2000 mL reactor. 1,2-dichloroethane (1000 g), aluminum trichloride (5.5 g, 0.041 mol) and diphenyl sulfide (5.4 g, 0.025 mol) were added. The temperature was controlled at 0-5 °C. Sulfuryl chloride (73.61 g, 0.545 mol) was added dropwise for 5 h. The reaction was quenched by slowly pouring the reaction mixture into an ice water mixture. The organic phase was washed with water until neutral. The compound IV, 4-chloro-2-fluoro-5-methylaniline (white solid, 134.33 g, 98% purity, 95% yield) was obtained after concentration.

[0039] 4) Preparation of compound V-1, propyl (4-chloro-2-fluoro-5-methylphenyl)carbamate

[0040] Compound IV, 2-fluoro-4-chloro-5-methylaniline was charged into a 1000 mL reactor. 1,2-dichloroethane (340 g) was added. Compound IV-a-1, propyl chloroformate (MW 122.55, 53.07 g) was added dropwise for 5 h. The reaction was stirred for 2 h at room temperature. The reaction was quenched with purified water. The organic phase was concentrated to give compound V-1 (101.83 g, 98% purity, 97.5% yield).

[0041] 5) Preparation of compound VI 3-(4-chloro-2-fluoro-5-methylphenyl)-6- trifluoromethyl-1-methyluracil

[0042] V-1 (MW 245.68, 101.83 g) prepared in the previous step was added into a 1000 mL reaction flask, 305 g of N,N-dimethylformamide, 112.28 g of potassium carbonate and compound V-a 1-13-amino-4,4,4-trifluorobutenoic acid ethyl ester (MW 183.13, 89.22 g) were added, the temperature was raised to 110 °C, and the reaction was stirred for 5 h. The reaction was monitored by HPLC. When the reaction was completed, the temperature was lowered to room temperature.

[0043] 56.14 g of potassium carbonate was added, dimethyl sulfate (MW 126.13, 76.81 g) was added, and the reaction was maintained for 3 h. The reaction was quenched by slowly pouring the reaction mixture into water, toluene was added, and the mixture was stirred for 1 h. The organic phase was washed, concentrated, and compound VI (131.10 g, 98% purity, 94% yield) was obtained as a yellow solid.

[0044] 6) Synthesis of compound VII

[0045] Compound VI (MW 336.67, 262.9 g) prepared in the previous step was added into a 2000 mL reaction flask, 1,2-dichloroethane (790 g) was added, and the temperature was raised to 70 °C. Bromine (367 g) was added dropwise, and azobisisobutyronitrile (13 g) was added in five portions with an interval of 0.5 h. The addition was completed in 3 h, and the reaction was continued for 2 h. The reaction was monitored by HPLC. When the reaction was completed, the temperature was lowered to room temperature, and the reaction was quenched by adding sodium sulfite solution. The organic phase was washed with water, concentrated, and 85% formic acid (1300 g) was added. The temperature was raised to 105 °C, and the reaction was maintained for 12 h. The formic acid was removed under reduced pressure, the residue was dissolved in 1,2-dichloroethane, and purified water was added. The pH value was adjusted to 7.5-8.0 with sodium hydroxide aqueous solution. The organic phase was washed with water, concentrated, and compound VII (254.92 g, 97% purity, 92.15% yield) was obtained as a white solid.

[0046] 7) Synthesis of compound VIII

[0047] Compound VII (MW 350.65, 254.92 g) prepared in the previous step was added into a 2000 mL reaction flask, 1275 kg of ethanol was added, and the temperature was raised to 50 °C. 63.7 g of hydroxylamine hydrochloride was added in three portions, and the reaction was stirred for 6 h. The reaction was monitored by HPLC. When the reaction was completed, the temperature was lowered to room temperature, and 5% sodium hydroxide aqueous solution was added dropwise to adjust the pH value to 7.0-7.5. The reaction was stirred for 0.5 h, filtered, and dried to obtain compound VIII (253.87 g, 97% purity, 95.5% yield) as a white solid.

[0048] 8) Synthesis of compound IX

[0049] Compound VIII (MW 365.67, 37.69 g) was added to a 1000 mL reaction bottle, N,N- dimethylformamide 147 g, anhydrous potassium carbonate powder 27.64 g and 2-chloropropionic acid methyl ester 24.51 g were added, stirred at 25-30 °C for 8 h, HPLC detection of raw material disappeared, the reaction was completed. The reaction solution was poured into water to quench, extracted with toluene, the organic phase was washed with purified water, concentrated under reduced pressure to give compound IX (43.82 g, content 98.1%, yield 97%).

[0050] Example 2

[0051] The difference from Example 1 is that steps 4) and 5) are different, steps 4) and 5) of this example are as follows:

[0052] 4) Synthesis of compound V-2 (phenyl 2-fluoro-4-chloro-5-methylphenylcarbamate)

[0053] IV 2-fluoro-4-chloro-5-methylaniline (MW 159.59, 67.16 g) prepared in the above step was added to a 1000 mL reaction bottle, 1,2-dichloroethane 340 g was added, heated to reflux, and compound IV-a-2 chloroformate (MW 156.57, 65.22 g) was added dropwise. The dropwise addition was completed in 5 h, and the reaction was completed after stirring for 3 h at constant temperature. The temperature was lowered to room temperature, quenched with purified water, and separated. The organic phase was concentrated to give intermediate compound V-2 (115.35 g, content 98%, yield 98%).

[0054] 5) Preparation of 3-(4-chloro-2-fluoro-5-methylphenyl)-6-trifluoromethyl-1- methyluracil (VI)

[0055] A 1000 mL reaction bottle was added with 300 g of N,N-dimethylformamide and compound V-a 1-13-amino-4,4,4-trifluorobutenoic acid ethyl ester (MW 183.13, 88.8 g), the temperature was lowered to 10-20 °C, sodium ethoxide (55 g) was added, stirred for 1 h, and then a solution of 50% intermediate V-2 in N,N-dimethylformamide (containing V-2 115.35 g) was added dropwise. After the dropwise addition was completed, the reaction was stirred for 3 h at constant temperature, and HPLC detection showed that the reaction was completed.

[0056] The temperature was raised to room temperature, 56.14 g of potassium carbonate was added, dimethyl sulfate (MW 126.13, 76.81 g) was added, and the reaction was completed after 2 h of constant temperature reaction. The reaction solution was slowly poured into water to quench, extracted with toluene, stirred for 1 h, separated, the organic phase was washed, concentrated to give light yellow solid compound VI (131.88 g, content 98%, yield 95%).

[0057] Example 3

[0058] The difference between this example and Example 1 is that step 8) is different, and step 8) of this example is as follows:

[0059] 8) Synthesis of compound IX (R)

[0060] Compound VIII (MW 365.67, 37.69 g) was added to a 1000 mL reaction bottle, N,N-dimethylformamide 147 g, anhydrous potassium carbonate powder 7.64 g and s-2-methyl chloropropionate 24.51 g were added, stirred at 25-30°C for 8 h, HPLC detection of raw material disappearance, reaction was completed. The reaction liquid was poured into water for quenching, extracted with toluene, the organic phase was washed with purified water, concentrated under reduced pressure to give compound IX (R) (43.68 g, content 97.5%, yield 96.1%).

[0061] Example 4

[0062] The difference between this example and Example 2 is that step 5) is different, and step 5) of this example is as follows:

[0063] 5) A 1000 mL reaction bottle was added with 300 g of N,N-dimethylformamide and compound V-a2-1 (0.485 mol, 95.6 g), cooled to 10-20°C, added with sodium ethoxide (55 g), stirred for 1 h, then added dropwise with N,N-dimethylformamide solution containing 50% intermediate V-2 (containing V-2 115.35 g), after dropwise addition, stirred for 3 h, HPLC detection showed that the reaction was completed, the reaction liquid was slowly poured into water for quenching, extracted with toluene, stirred for 1 h, separated, the organic phase was washed, concentrated to give light yellow solid compound VI (131.9 g, content 97.7%, yield 95%).

[0064] Comparative Example 1

[0065] The difference between this example and Example 1 is that the catalyst in step 1) is different, and an equal amount of quaternary ammonium salt catalyst tetrabutylammonium bromide is used instead of tetraphenylphosphonium bromide. The specific steps are as follows:

[0066] In a 2000ml four-necked flask equipped with mechanical stirrer and thermometer, spray-dried anhydrous potassium fluoride (69.72g), sulfolane (515g) and tetrabutylammonium bromide (6.60g, 0.02mol) were added, the temperature was raised to 200-220°C, and compound I 4-chloro-3-nitrotoluene (MW 171.58, 173.31g) was added dropwise. The reaction was stirred for 5h, and GC analysis showed that 30% of the starting material remained. The reaction was then stopped. The temperature was lowered to room temperature, and the salt was removed by filtration. The filter cake was washed with sulfolane, and the distillate was obtained by vacuum distillation. The distillate was compound II 4-chlorofluoro-3-nitrotoluene (94.5g, 98% purity, 65% yield).

[0067] As can be seen from Example 1 and Comparative Example 1, the use of a quaternary phosphonium salt catalyst in the fluorination reaction described herein can significantly improve the yield of the product, compared to conventional ammonium salt catalysts.

[0068] Obviously, the above examples are merely illustrative and not intended to limit the embodiments. Based on the above description, those skilled in the art can make other different forms of changes or variations. It is not necessary or possible to exhaust all the embodiments. The obvious changes or variations derived therefrom are still within the protection scope of the present application.

Claims

1. A method of preparing an imino aryl class intermediate, characterized by, comprising the following steps: Compound III is chlorinated with a chlorinating agent to obtain compound IV, as shown in the following reaction formula:

2. A method for producing an imino aryl compound, characterized by, comprising the following steps: (1) chlorination of compound III with a chlorinating reagent to obtain compound IV; (2) reaction of compound IV with a chloroformate compound IV-a to obtain compound V; (3) ring formation of compound V with V-a1 and then methylation to obtain compound VI, or ring formation of compound V with V-a2 to obtain compound VI; (4) reaction of compound VI to obtain compound VII; (5) reaction of compound VII with hydroxylamine hydrochloride to obtain compound VIII; (6) reaction of compound VIII with VIII-a to obtain imino aryl compound IX; The synthetic 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 substituted with 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 with at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, haloC1-C8 alkyl, haloC2-C8 alkenyl, haloC2-C8 alkynyl, C1-C8 alkoxy, haloC1-C8 alkoxy, C1-C8 alkoxycarbonyl, 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 with at least one group selected from hydroxyl, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloC1-C6 alkyl, haloC2-C6 alkenyl, haloC2-C6 alkynyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylthio, or C1-C6 alkylsulfonyl.

3. The production method according to claim 1 or 2, characterized by, The preparation of compound IV is carried out in the presence of a chlorination catalyst and a solvent; preferably, the chlorinating reagent is selected from at least one of thionyl chloride, sulfuryl chloride, or hydrogen peroxide / hydrochloric acid; the chlorination catalyst is selected from one or more of ferric chloride / diphenyl sulfide, aluminum chloride / diphenyl sulfide, iodine, or copper chloride; and / or the solvent is selected from at least one of acetonitrile, dichloromethane, 1,2-dichloroethane, or chlorobenzene.

4. The method according to any one of claims 1 to 3, characterized in that, The compound III is obtained from the compound II by a reduction reaction with a hydrogenation reagent, according to the following reaction scheme: 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 or isopropanol; and / or the hydrogenation catalyst is selected from at least one of iron powder, copper powder, Raney nickel, palladium on carbon or platinum on carbon.

5. The method of any one of claims 1-4, wherein, The compound II is obtained by fluorination reaction of compound I with a fluoride salt, and the reaction formula is as follows: 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 at least one of quaternary phosphonium salt phase transfer catalysts; the fluorination solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, sulfolane or N-methyl pyrrolidone; preferably, the fluoride salt is selected from at least one of potassium fluoride, sodium fluoride, cesium fluoride, amine fluoride or tetrabutylammonium fluoride.

6. The method of any one of claims 2-5, wherein, The 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.

7. The method of any one of claims 2-6, wherein, The reaction temperature of the step (3) is between 0-120 °C; and / or the cyclization reaction is carried out in the presence of a solvent, a base; preferably, the solvent is selected from at least one of acetonitrile, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, sulfolane or N-methylpyrrolidone; the base is selected from at least one of an inorganic base and an organic base; and / or the methylating agent is selected from at least one of iodomethane, chloromethane, bromomethane, dimethyl sulfate or dimethyl carbonate.

8. The method of any one of claims 2-7, wherein, The step (4) is reacted 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, trichloromethane, acetonitrile, ethyl acetate, isopropyl acetate or benzene; the halogenating agent is selected from at least one of N-bromosuccinimide, dibromohydantoin, N-chlorosuccinimide, dichlorohydantoin, 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.

9. The method of any one of claims 2-8, wherein, The step (5) is reacted in the presence of a solvent; preferably, the solvent is an alcohol.

10. The method of any one of claims 2-9, wherein, The step (6) is reacted in the presence of a base and a polar solvent; preferably, the base 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, dimethylsulfoxide, sulfolane, N-methylpyrrolidone; further preferably, the base is in a powder state.

11. The method of any one of claims 2-10, wherein, The carbon atom to which the L group of step (6) is attached is in the R configuration, and the reaction scheme is as follows:

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