Preparation method of substituted trifluoroethyl sulfide aniline

Abstract

The invention discloses a synthesis method of substituted trifluoroethyl sulfide aniline, which comprises the following steps: reacting a compound of formula VII with an acylation reagent to obtain a compound of formula VI, reacting the compound of formula VI with an X-containing reagent to obtain a compound of formula V, reacting the compound of formula V with a sulfonylation reagent to obtain a compound of formula IV, reacting the compound of formula IV with a reduction reagent to obtain a compound of formula III, reacting the compound shown in the formula III with a compound containing a trifluoroethyl group to obtain a compound shown in the formula II, and performing deacylation protection to obtain a compound shown in the formula I. According to the technical scheme, the synthetic route has the advantages of high yield and cheap raw materials, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of substituted trifluoroethyl sulfide aniline. Background Art

[0002] There are many types of harmful mites in agriculture, with more than 30,000 known species. Pest mites are tiny and attach to leaves to suck juice, causing the leaves to curl up, wither and fall off at best, or even a decrease in agricultural product yields at worst. Chemical control is an important means of controlling harmful mites. However, due to the long-term unscientific use of existing miticides, harmful mites have developed serious resistance to many existing agents. Therefore, it is urgent to develop new and efficient miticides, and the market prospects for miticides are broad.

[0003] Trifluoroethyl sulfide (sulfoxide) compounds are a new type of compound with good acaricidal activity. Many companies and scientific research institutions have conducted research on this basis and found that many compounds have excellent acaricidal activity. For example, Zhang Lixin's research group at Shenyang University of Chemical Technology introduced compound 1 in the paper "Design, Synthesis and Acaricidal Activity Research of Trifluoroethyl Sulfide (Sulfoxide) Compounds" reported in 2019, which has good acaricidal activity. Hailier Pharmaceutical Group Co., Ltd. reported in the patent CN114605297A that compound 2 also has very high acaricidal activity. In Example 2 of CN114957062A, if dichlorothionyl is not added, sulfonic acid derivatives will be generated as byproducts, affecting the yield and being difficult to purify, and the intermediate purity is low, affecting subsequent reactions; in Example 3, glacial acetic acid is used as a solvent, and glacial acetic acid has a pungent smell. The odor problem when used in large quantities is an important environmental hazard; and glacial acetic acid has a low freezing point, and it is easy to solidify and precipitate during the production condensation process, causing safety accidents.

[0004]

[0005] In the above study, intermediate 3 is the key intermediate.

[0006] In public reports, intermediate 3 is obtained by the following synthetic route:

[0007]

[0008] However, in this synthetic route, the starting material 2-fluoro-4-methylaniline is expensive and not suitable for industrial promotion and application.

[0009] The synthesis of 2-fluoro-4-methylaniline is difficult, and the following synthesis methods are reported in public:

[0010] Teacher Xu Danqian from Zhejiang University of Technology reported a route for synthesizing 2-fluoro-4-methylaniline from p-methylaniline in Chem. Commun., 2019, 55, 14458-14461 and the patent "A method for synthesizing 2-fluoroaniline compounds (CN109704987B)". This route requires the synthesis of unstable nitroso compounds first, then condensation to obtain diaryl diimine, and then under palladium catalysis, directing fluorine to the ortho position, and finally obtaining the product under reduction conditions. However, this route: a) The route is lengthy. Starting from p-methylaniline, four steps of reaction are required to obtain 2-fluoro-4-methylaniline; b) Due to the poor stability of nitroso compounds and the easy occurrence of self-condensation reactions, the reaction yield is low; c) Due to the use of large-group trimethylaniline as a protecting group, it needs to be removed after the reaction, resulting in low atom economy; d) The use of precious metal palladium catalysts has high synthesis costs.

[0011]

[0012] B. Langlois et al. (J Fluorine Chem, 2005, 126, pp. 661-667) reported a method for synthesizing 2-fluoro-4-methylaniline by direct electrophilic fluorination of aromatic groups on p-toluidine using fluorine gas. The method is simple and direct. However, the following aspects are mentioned in this route: a) fluorine gas has high activity but poor selectivity, with at least four products; b) the main product is 3-fluoro-4-methylaniline, and the yield of the target product is low; c) fluorine gas is dangerous and difficult to operate during use.

[0013]

[0014] Tomcufcik et al. reported a route for synthesizing 2-fluoro-4-methylaniline by nitration and reduction of m-fluorotoluene in J.Org.Chem.1961,26,9,3351–3356. However, this route: a) has poor nitration selectivity, with the main product being the byproduct 4-fluoro-2-methyl-nitrobenzene, and only 5% of the target product; b) although the byproduct 4-fluoro-2-methyl-nitrobenzene can be converted into the desired 2-fluoro-4-methyl-nitrobenzene through four steps of conversion, such as reduction of the nitro group to the amino group, re-nitration, reaction with sodium nitrite to obtain diazotization and re-reduction, the overall route is lengthy and the yield is low.

[0015]

[0016] Therefore, it is urgent to develop a process route for synthesizing 2-fluoro-4-methylaniline intermediates and intermediate 3 using industrially scalable products as starting materials in a more economical and efficient manner. Summary of the invention

[0017] In view of the shortcomings of the prior art described above, the present invention aims to provide a new method for preparing substituted trifluoroethyl sulfide aniline, starting from p-toluidine which is industrializable, cheap and readily available, by protecting the amino group with an acetyl group and selectively fluorinating the benzene ring with an electrophilic fluorine reagent, the same intermediate as publicly reported can be obtained, and then the desired substituted trifluoroethyl sulfide aniline intermediate can be obtained by sulfonation with chlorosulfonic acid, reduction and alkylation, and finally deprotection. Starting from p-toluidine, a key 2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)aniline intermediate is synthesized through 6 steps of reaction, and the method has the advantages of high yield, easy purification and simple route; using cheap and readily available reagents, starting from cheap and readily available p-toluidine, overcoming the problem that the raw material 2-fluoro-4-methylaniline is expensive and difficult to purchase in large quantities, and realizing a substantial reduction in cost; the route is not only suitable for preparing the desired fluorinated product, but also suitable for preparing the desired bromo or chloro product, and is suitable for large-scale industrial production.

[0018] To achieve the above-mentioned purpose and other related purposes, the present invention provides the following technical solution: a method for preparing substituted trifluoroethyl sulfide aniline, which is as follows:

[0019]

[0020] In formulas I to VII, R1 and R2 are independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl or C3-C6 cycloalkyloxy, and X is halogen or CN;

[0021] The compound of formula VII is reacted with an acylating agent to obtain a compound of formula VI, which is then reacted with a reagent containing X to obtain a compound of formula V. The compound of formula V is reacted with a sulfonylating agent to obtain a compound of formula IV, which is then reacted with a reducing agent to obtain a compound of formula III. The compound of formula III is reacted with a compound containing a trifluoroethyl group to obtain a compound of formula II, which is then deacylated to obtain a compound of formula I.

[0022] Furthermore, the specific operation steps are as follows: after adding an alkaline reagent and a solvent, an acylating reagent is added dropwise under ice-water bath conditions, and the reaction is carried out at room temperature for 1-5 hours; the acylating reagent is acetic anhydride or acetyl chloride, and the alkaline reagent is any one or more of an inorganic or organic weak base such as NaHCO3, Na2CO3, Na3PO4, NaH2PO4, DIPEA or triethylamine; and the solvent is any one or more of dichloromethane, dichloroethane, tetrahydrofuran, toluene, dioxane, and acetonitrile.

[0023] Further, when X is F, the X-containing reagent is 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate); when X is Br, the X-containing reagent is Br2, NBS, dibromohydantoin; when X is Cl, the X-containing reagent is Cl2 or NCS.

[0024] Furthermore, the sulfonylating agent is a mixture of chlorosulfonic acid or fuming sulfuric acid and thionyl chloride, and the reaction temperature of the compound of formula V and the sulfonylating agent is 50-80°C.

[0025] Furthermore, the reducing agent is a mixture of zinc powder, magnesium powder or iron powder and glacial acetic acid, dilute hydrochloric acid or dilute sulfuric acid, and the reaction temperature of the compound of formula IV and the reducing agent is 100-150°C.

[0026] Furthermore, the compound containing a trifluoroethyl group is any one or more of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 2-iodo-1,1,1-trifluoroethane, 2-bromo-1,1,1-trifluoroethane or 2-chloro-1,1,1-trifluoroethane; the compound of formula III is reacted with the compound containing a trifluoroethyl group in acetonitrile as a solvent and potassium carbonate is added, and the reaction temperature is room temperature.

[0027] Further, in Formulas I to VII, R1 is methyl or ethyl, R2 is methyl or ethyl, and X is F, Cl or CN;

[0028] Furthermore, R1 is methyl, R2 is methyl, and X is F.

[0029] Furthermore, the deacylation reaction is carried out in a mixture of ethanol and water as a solvent.

[0030] Furthermore, the deacylation protection is specifically as follows: adding concentrated hydrochloric acid, heating to 70-90° C. for reaction, and adjusting the pH to neutral with an alkaline reagent after the reaction is complete.

[0031] Furthermore, the mixture of ethanol and water is a mixture with a volume ratio of 5:1.

[0032] Due to the adoption of the above technology, the present invention has the following significant advantages compared with the prior art:

[0033] 1) The problem that the raw material 2-fluoro-4-methylaniline is expensive and difficult to purchase in large quantities is overcome;

[0034] 2) Starting from p-toluidine, which is very cheap and can be purchased in large quantities and stably, the desired intermediate is obtained through several steps of transformation using cheap and readily available reagents, which greatly reduces the cost of synthesizing the intermediate and solves the scientific and technological problems of synthesizing 2-fluoro-4-methylaniline;

[0035] 3) This method can not only obtain the desired fluorinated product, but also the brominated or chlorinated product, which expands the scope of application of this type of substrate;

[0036] 4) Starting from p-toluidine, the key intermediate 2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)aniline was synthesized through 6 steps of reaction. The synthesis technology of this method has high yield, easy purification and simple route. DETAILED DESCRIPTION

[0037] In order to make the technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments, but the scope of the present invention is not limited thereby.

[0038] The present invention will be further described below in conjunction with the embodiments.

[0039] Example 1

[0040] Synthesis of N-(4-methylphenyl)acetamide:

[0041]

[0042] Weigh p-methylaniline (8.6 g, 80 mmol, 1.0 eq.) and sodium bicarbonate (13.4 g, 160 mmol, 2.0 eq.) in a bottle, add dichloromethane (200 mL) to dissolve, slowly drop acetic anhydride (8.57 g, 84 mmol, 1.05 eq.) in an ice-water bath, remove the ice-water bath after the dropwise addition, and react at room temperature for three hours. After TLC (PE:EA=5:1) confirms that the reaction is complete, filter the system by suction. Because the product is easy to solidify, the filter cake needs to be rinsed with dichloromethane several times. After the elution is completed, concentrate and desolventize to obtain reddish brown needle crystals (11.3 g, 76 mmol, 95%). LC-MS (ESI) [M+H] + =150.1.

[0043] Example 2

[0044] Synthesis of N-(2-fluoro-4-methylphenyl)acetamide:

[0045]

[0046] Take N-(4-methylphenyl)acetamide (11.3g, 76mmol, 1.0eq.) and dissolve it in acetonitrile (100mL), add 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (selectfluor, 32.2g, 91mmol, 1.2eq.), and heat to 80℃ for about 2 hours. After TLC (PE:EA=4:1) confirmed the completion of the reaction, pour the reaction solution into water, extract it with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate and remove the solvent, and purify it by silica gel column chromatography to obtain a light yellow oil (11.9g, 71mmol, 94%). LC-MS(ESI)[M+H] + =168.1; 1 H NMR (400MHz, Chloroform-d) δ8.10(t,J=8.3Hz,1H),7.34(s,1H),6.90(t,J=9.9Hz,2H),2.30(s,3H),2.20(s,3H).

[0047] Example 3

[0048] Synthesis of N-(2-fluoro-4-methylphenyl)acetamide:

[0049]

[0050] Dissolve N-(4-methylphenyl)acetamide (11.3 g, 76 mmol, 1.0 eq.) in acetonitrile (50 mL) and water (50 mL), add N-fluorobisbenzenesulfonamide (NFSI, 28.6 g, 91 mmol, 1.2 eq.), and heat to 80°C for about 8 hours. After TLC (PE:EA=4:1) confirmed the completion of the reaction, pour the reaction solution into water, extract with ethyl acetate three times, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate to remove the solvent, and purify by silica gel column chromatography to obtain a light yellow oil (7.8 g, 47.1 mmol, 62%). LC-MS (ESI) [M+H] + =168.1; 1 H NMR (400MHz, Chloroform-d) δ8.10(t,J=8.3Hz,1H),7.34(s,1H),6.90(t,J=9.9Hz,2H),2.30(s,3H),2.20(s,3H).

[0051] Example 4

[0052] Synthesis of N-(2-bromo-4-methylphenyl)acetamide:

[0053]

[0054] Take N-(4-methylphenyl)acetamide (11.3g, 76mmol, 1.0eq.) and dissolve it in glacial acetic acid (50mL), add liquid bromine (14.5g, 91mmol, 1.2eq.), heat to 50℃ and react for about 4 hours. After TLC (PE:EA=4:1) confirms that the reaction is complete, pour the reaction solution into ice water to precipitate a white solid, filter it, and dry the solid to obtain a white solid as the product (15.2g, 67mmol, 88%). LC-MS(ESI)[M+H] + =227.9; 1 H NMR (400MHz, CDCl3) δ8.12(d,J=8.2Hz,1H),7.51(s,1H),7.32(s,1H),7.06(d,J=8.2Hz,1H),2.26(s,3H),2.20(s,1H).

[0055] Example 5

[0056] Synthesis of N-(2-chloro-4-methylphenyl)acetamide:

[0057]

[0058] Take N-(4-methylphenyl)acetamide (11.3g, 76mmol, 1.0eq.) and dissolve it in acetonitrile (50mL), add N-chlorosuccinimide (NCS, 15.3g, 114mmol, 1.5eq.) and ferric chloride (18.5g, 114mmol, 1.5eq.), heat to 80℃ and react for about 4 hours. After TLC (PE:EA=4:1) confirms that the reaction is complete, part of the acetonitrile is spun out, and the reaction solution is poured into ice water to precipitate solids, filter, and dry the solids to obtain a beige solid as the product (10.6g, 58mmol, 76%). LC-MS(ESI)[M+H] + =184.1; 1 H NMR (400MHz, CDCl3) δ8.15(d,J=8.3Hz,1H),7.50(s,1H),7.14(s,1H),7.02(d,J=8.3Hz,1H),2.26(s,3H),2.20(s,3H).

[0059] Example 6

[0060] Synthesis of 5-acetylamino-4-fluoro-2-methylbenzenesulfonyl chloride:

[0061]

[0062] Weigh N-(2-fluoro-4-methylphenyl)-acetamide (10.0 g, 60 mmol, 1.0 eq.) in a bottle, slowly add 25 mL of chlorosulfonic acid, heat at 60°C for reaction, add thionyl chloride (SOCl2, 7.1 g, 60 mmol, 1.0 eq.) after 1 hour, react at 60°C for another 1 hour, monitor by TLC (DCM: MeOH = 10:1) that the raw material disappears, pour the reaction solution into ice water, filter, rinse the filter cake with water, and dry the filter cake to obtain a yellow solid (14.3 g, 54 mmol, 90%). LC-MS (ESI) [M+H] + =266.1,[M+Na] + =288.1.

[0063] Example 7

[0064] Synthesis of N-(2-fluoro-5-mercapto-4-methylphenyl)acetamide:

[0065]

[0066] Weigh 5-acetylamino-4-fluoro-2-methylbenzenesulfonyl chloride (9.3 g, 35 mmol, 1.0 eq.) in a bottle, add zinc powder (11.4 g, 175 mmol, 5.0 eq.), add dilute hydrochloric acid (3 mol / L, 100 mL), heat to 100 ° C and reflux for reaction. After about 2 hours of reaction, TLC monitoring (EA: PE = 1: 1) shows that the raw material disappears. After cooling to room temperature, remove excess zinc powder by suction filtration, add ice water (100 mL) and ethyl acetate (100 mL) for washing, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and remove the solvent to obtain a light yellow solid (6.1 g, 30.1 mmol, 87%). LC-MS (ESI) [M+H] + =200.1,[M+Na] + =222.1.

[0067] Example 8

[0068] Synthesis of N-(2-fluoro-5-mercapto-4-methylphenyl)acetamide:

[0069]

[0070] Weigh 5-acetylamino-4-fluoro-2-methylbenzenesulfonyl chloride (9.3 g, 35 mmol, 1.0 eq.) in a bottle, add iron powder (11.4 g, 175 mmol, 5.0 eq.), add dilute hydrochloric acid (3 mol / L, 100 mL), heat to 100 ° C and reflux for reaction. After about 2 hours of reaction, TLC monitoring (EA: PE = 1: 1) shows that the raw material disappears. After cooling to room temperature, remove excess zinc powder by suction filtration, add ice water (100 mL) and ethyl acetate (100 mL) for washing, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate and remove the solvent to obtain a light yellow solid (5.2 g, 26.3 mmol, 75%). LC-MS (ESI) [M+H] + =200.1,[M+Na] + =222.1.

[0071] Example 9

[0072] Synthesis of N-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)acetamide:

[0073]

[0074] Weigh N-(2-fluoro-5-mercapto-4-methylphenyl)acetamide (5.4 g, 27 mmol, 1.0 eq.) in a bottle, add acetonitrile (100 mL), potassium carbonate (5.6 g, 40.5 mmol, 1.5 eq.), under the protection of nitrogen atmosphere, dropwise add 2,2,2-trifluoroethyl trifluoromethanesulfonate (9.4 g, 40.5 mmol, 1.5 eq.), and stir at room temperature overnight. Monitor the reaction by TLC (PE:EA=2:1). After the raw material disappears, add water to quench, dilute with dichloromethane, wash with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate and desolventize to obtain a crude product. Silica gel column chromatography (PE:EA=4:1) obtains a white solid (7 g, 25 mmol, 92%). LC-MS(ESI)[M+H] + =282.1,[M+Na] + =304.1.

[0075] Example 10

[0076] Synthesis of N-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)acetamide:

[0077]

[0078] Weigh N-(2-fluoro-5-mercapto-4-methylphenyl)acetamide (5.4 g, 27 mmol, 1.0 eq.) in a bottle, add acetonitrile (100 mL), potassium carbonate (5.6 g, 40.5 mmol, 1.5 eq.), under the protection of nitrogen atmosphere, dropwise add 2-iodo-1,1,1-trifluoroethane (8.5 g, 40.5 mmol, 1.5 eq.), and stir at room temperature overnight. Monitor the reaction by TLC (PE:EA=2:1). After the raw material disappears, add water to quench, dilute with dichloromethane, wash with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate and desolventize to obtain a crude product. Silica gel column chromatography (PE:EA=4:1) obtains a white solid (6.1 g, 21.8 mmol, 81%). LC-MS(ESI)[M+H] + =282.1,[M+Na] + =304.1.

[0079] Embodiment 11

[0080] Synthesis of 2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)aniline:

[0081]

[0082] Weigh N-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)acetamide (7g, 25mmol, 1.0eq.) in a bottle, add ethanol (50mL) and water (10mL) to dissolve, add concentrated hydrochloric acid (50mL), heat to 85°C, react for about 4 hours, monitor the reaction by TLC (PE:EA=5:1), adjust the pH to neutral with 1NNaOH solution after the raw material disappears. Remove most of the methanol under reduced pressure, dilute with dichloromethane, wash with saturated brine, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate and desolventize to obtain a pink liquid (5.3g, 22mmol, 88%). LC-MS(ESI)[M+H] + =240.1,[M+Na] + =262.1.

[0083] Comparative Example 1

[0084] Synthesis of 5-acetylamino-4-fluoro-2-methylbenzenesulfonyl chloride:

[0085]

[0086] Weigh N-(2-fluoro-4-methylphenyl)-acetamide (10.0 g, 60 mmol, 1.0 eq.) in a bottle, slowly drop 25 mL of chlorosulfonic acid, heat at 60°C for reaction, and after 2 hours of TLC monitoring (DCM: MeOH = 10: 1) the raw material disappears, pour the reaction solution into ice water, filter, rinse the filter cake with water, and dry the filter cake to obtain a yellow solid (9.3 g, 35 mmol, 70%). LC-MS (ESI) [M+H] + = 266.1, [M+Na] + = 288.1.

[0087] Comparative Example 2

[0088] Synthesis of N-(2-fluoro-5-mercapto-4-methylphenyl)acetamide:

[0089]

[0090] Weigh 5-acetylamino-4-fluoro-2-methylbenzenesulfonyl chloride (9.3 g, 35 mmol, 1.0 eq.) in a bottle, add zinc powder (11.4 g, 175 mmol, 5.0 eq.) and glacial acetic acid (100 mL), heat to 120 ° C and reflux for reaction. After about 2 hours of reaction, TLC monitoring (EA: PE = 1: 1) shows that the raw material disappears. After cooling to room temperature, remove excess zinc powder by suction filtration, and then evaporate most of the glacial acetic acid under reduced pressure. Add ice water (100 mL) and ethyl acetate (100 mL) to wash. The organic phase is then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and desolventized to obtain a light yellow solid (5.4 g, 27 mmol, 77%). LC-MS (ESI) [M+H] + =200.1,[M+Na] + =222.1.

[0091] The above embodiments are only preferred technical solutions of the present invention and should not be regarded as limitations of the present invention. The protection scope of the present invention should be the technical solutions recorded in the claims, including equivalent replacement solutions of the technical features in the technical solutions recorded in the claims, that is, equivalent replacement improvements within this scope are also within the protection scope of the present invention.

Claims

1. A method for preparing substituted trifluoroethyl sulfide aniline, characterized in that: The details are as follows: In formulas I to VII, R1 and R2 are independently selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl or C3-C6 cycloalkyloxy, and X is halogen or CN; The compound of formula VII is reacted with an acylating agent to obtain a compound of formula VI, which is then reacted with a reagent containing X to obtain a compound of formula V. The compound of formula V is reacted with a sulfonylating agent to obtain a compound of formula IV, which is then reacted with a reducing agent to obtain a compound of formula III. The compound of formula III is reacted with a compound containing a trifluoroethyl group to obtain a compound of formula II, which is then deacylated to obtain a compound of formula I.

2. The preparation method according to claim 1, characterized in that The specific operation steps are as follows: after adding an alkaline reagent and a solvent, an acylating reagent is added dropwise under ice-water bath conditions, and the reaction is carried out at room temperature for 1-5 hours; the acylating reagent is acetic anhydride or acetyl chloride, the alkaline reagent is any one or more of an inorganic or organic weak base such as NaHCO3, Na2CO3, Na3PO4, NaH2PO4, DIPEA or triethylamine; the solvent is any one or more of dichloromethane, dichloroethane, tetrahydrofuran, toluene, dioxane, and acetonitrile.

3. The preparation method according to claim 1, characterized in that: When X is F, the X-containing reagent is 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate); when X is Br, the X-containing reagent is Br2, NBS, dibromohydantoin; when X is Cl, the X-containing reagent is Cl2 or NCS.

4. The preparation method according to claim 3, characterized in that: The sulfonylating agent is a mixture of chlorosulfonic acid or fuming sulfuric acid and thionyl chloride, and the reaction temperature of the compound of formula V and the sulfonylating agent is 50-80°C.

5. The preparation method according to claim 1, characterized in that: The reducing agent is a mixture of zinc powder, magnesium powder or iron powder and glacial acetic acid, dilute hydrochloric acid or dilute sulfuric acid. The reaction temperature of the compound of formula IV and the reducing agent is 100-150°C.

6. The preparation method according to claim 1, characterized in that: The compound containing a trifluoroethyl group is any one or more of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 2-iodo-1,1,1-trifluoroethane, 2-bromo-1,1,1-trifluoroethane or 2-chloro-1,1,1-trifluoroethane; the compound of formula III reacts with the compound containing a trifluoroethyl group in acetonitrile as a solvent and potassium carbonate is added, and the reaction temperature is room temperature.

7. The preparation method according to claim 1, characterized in that: In formulas I to VII, R1 is methyl or ethyl, R2 is methyl or ethyl, and X is F, Cl or CN; preferably, R1 is methyl, R2 is methyl, and X is F.

8. The preparation method according to claim 1, characterized in that: The deacylation reaction is carried out in a mixture of ethanol and water as a solvent.

9. The preparation method according to claim 8, characterized in that: The deacylation protection specifically comprises: adding concentrated hydrochloric acid, heating to 70-90° C. for reaction, and adjusting the pH to neutral with an alkaline reagent after the reaction is complete.

10. The preparation method according to claim 8, characterized in that: The mixture of ethanol and water is a mixture with a volume ratio of 5:1.

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