Preparation method of 1-(3-chloro-5-(trifluoromethyl) phenyl)-2, 2, 2-trifluoroethanone

Abstract

The invention relates to a preparation method of a 1-(3-chloro-5-(trifluoromethyl) phenyl)-2, 2, 2-trifluoroethanone compound 4, and the reaction is as follows: # imgabs0 # comprises the following steps: (1) performing chlorination reaction on a compound 1 in hydrochloric acid in the presence of tert-butyl hydroperoxide and a copper catalyst to obtain a compound 2; (2) carrying out diazotization reaction on the compound 2 in an organic solvent in the presence of an acidic reagent and a nitrous acid reagent, and then reacting with hypophosphorous acid to obtain a compound 3; and (3) reacting the compound 3 with a Konchel type Grignard reagent, and carrying out nucleophilic reaction with trifluoroacetyl dimethylamine to obtain a compound 4. The method has the advantages of short reaction time, mild process conditions, simple operation, high yield, single-step yield of more than 90%, purity of more than 99%, simple post-treatment, reduction of three wastes, and suitableness for industrial production.

Description

Technical Field

[0001] The invention relates to a method for synthesizing 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanone, and belongs to the field of drug intermediate synthesis. Background Art

[0002] Afoxolaner, trade name NexGard, is developed and produced by Boehringer Ingelheim and belongs to the isoxazoline class of drugs. Its mechanism of action is to inhibit the GABA chloride channel of arthropods, thereby blocking the transmission of chloride ions from the presynaptic membrane to the postsynaptic membrane, resulting in increased activity of insect neurons and death due to excessive excitement. It is a revolutionary and powerful insecticide. It has the characteristics of rapid onset, high safety, convenient oral administration and delicious taste. NexGard can kill fleas quickly and has a longer-lasting effect. The drug was approved for marketing in China in August 2017. It is the first oral anthelmintic for dogs in China that kills both ticks and fleas. It can meet the needs of pet owners for "taking care of both inside and outside". Dogs only need to take it once a month to expel and prevent six major types of common parasites inside and outside the body, such as heartworms, roundworms, hookworms, whipworms, fleas, and ticks. In 2018, China approved the import of Afolanimamicilomycete chewable tablets for the treatment of flea and tick infections in dogs, as well as for the prevention of heartworm infections and the treatment of gastrointestinal nematode infections. Currently, the drug has a good market development in the field of pet anthelmintics.

[0003] 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanone is an important intermediate in the synthesis of afolanine, with a molecular formula of C9H3ClF6O and a molecular weight of 276.56. The specific structure is shown below:

[0004]

[0005] Patent CN113636919B discloses that the intermediate compound is prepared by using o-aminotrifluorotoluene as the starting material, brominating, chlorinating, diazotizing, and using magnesium chips to make a Grignard reagent, and then reacting with an acylating agent to undergo a nucleophilic reaction; the total yield is low at only 53%, and this method is not conducive to industrial scale-up. The preparation method is as follows:

[0006]

[0007] Taizhou Zhenzhi Biotechnology's patent CN112778109B discloses that the intermediate compound is prepared from para-aminotrifluorotoluene as the starting material through five steps of amidation, substitution, hydrolysis, chlorination and diazotization; only the last two steps give a yield of 79%. The method is long and not conducive to industrial scale-up. The preparation method is as follows:

[0008]

[0009] In the patent WO2011054436A1 of Bayer AG of Germany, 1-bromo-3-chloro-5-trifluorotoluene is used as the starting material, and a Grignard reagent reaction is carried out at low temperature, and finally the bromine group is replaced by a trifluoroacetyl group. 1-bromo-3-chloro-5-trifluorotoluene is expensive and difficult to obtain, and the reaction needs to be carried out at -80°C, with a yield of only 78%. This method is not conducive to industrial scale-up. Its preparation method is as follows:

[0010]

[0011] Rhodia Chemical's patent WO199802409A1 discloses that 1,3-dichloro-5-(trifluoromethyl)benzene is obtained by reaction at 25°C under the conditions of hypophosphorous acid, anhydrous copper sulfate, concentrated sulfuric acid and nitrous acid, with a yield of 74%. This method is not conducive to industrial scale-up. Its preparation method is as follows:

[0012] Summary of the invention

[0013] In view of the defects of the prior art, the present invention provides a method for preparing 1-(3-chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanone. The intermediate prepared by the method is simple, efficient and high in yield, which greatly reduces the cost and is conducive to large-scale commercial production.

[0014] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0015] The first aspect of the present invention provides a method for preparing compound 4, the reaction is as follows:

[0016]

[0017] The steps include:

[0018] (1) Compound 1 is subjected to a chlorination reaction in hydrochloric acid in the presence of tert-butyl hydroperoxide and a copper catalyst to obtain Compound 2;

[0019] (2) Compound 2 is subjected to a diazotization reaction in an organic solvent in the presence of an acidic reagent and a nitrous acid reagent, and then reacted with hypophosphorous acid to obtain compound 3;

[0020] (3) Compound 3 reacts with a Konchel-type Grignard reagent and then undergoes a nucleophilic reaction with trifluoroacetyl dimethylamine to obtain compound 4.

[0021] As a further improvement of the present invention, including but not limited to, the hydrochloric acid in step (1) is selected from concentrated hydrochloric acid;

[0022] As a further improvement of the present invention, including but not limited to, the copper catalyst in step (1) is selected from cuprous chloride, cupric chloride, and cupric chloride dihydrate, preferably cuprous chloride;

[0023] As a further improvement of the present invention, the molar ratio of compound 1 to copper catalyst in step (1) is 1:(0.01-0.5), preferably 1:(0.05-0.15);

[0024] As a further improvement of the present invention, the molar ratio of compound 1 to tert-butyl hydroperoxide in step (1) is 1:(1.01-5), preferably 1:(1.5-2.5);

[0025] As a further improvement of the present invention, including but not limited to, the volume of hydrochloric acid in step (1) is 3 to 10 times, preferably 4 to 6 times, the mass of compound 1;

[0026] As a further improvement of the present invention, the reaction temperature in step (1) is 20 to 50° C., preferably 25 to 45° C.;

[0027] As a further improvement of the present invention, the reaction time of step (1) is 5 to 24 hours, preferably 15 to 20 hours;

[0028] As a further improvement of the present invention, the reaction in step (2) comprises: performing a diazotization reaction on compound 2 in an organic solvent in the presence of an acidic reagent and an aqueous solution of a nitrous acid reagent at a first temperature, and then reacting with hypophosphorous acid at a second temperature to obtain compound 3;

[0029] As a further improvement of the present invention, the reaction in step (2) comprises: compound 2 and an acidic reagent in an organic solvent are subjected to a diazotization selective reaction with an aqueous solution of a nitrous acid reagent at a first temperature for a period of time, and then reacted with hypophosphorous acid at a second temperature to obtain compound 3;

[0030] As a further improvement of the present invention, the step (2) can be selectively reacted for a period of time selected from not less than 30 minutes, further not less than 40 minutes, not less than 50 minutes, not less than 60 minutes; for example, 40 to 80 minutes, such as 40 minutes, 50 minutes, 60 minutes, 70 minutes or 80 minutes.

[0031] As a further improvement of the present invention, in the reaction of step (2), preferably, the reaction time of the further reaction with hypophosphorous acid is not less than 1 hour, such as 1 to 5 hours, such as 1 hour, 2 hours, 3 hours, 4 hours or 5 hours.

[0032] As a further improvement of the present invention, including but not limited to, the hypophosphorous acid in step (2) is selected from hypophosphorous acid with a mass fraction of 45 to 55%;

[0033] As a further improvement of the present invention, including but not limited to, the acidic reagent in step (2) is selected from one or more of p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid, preferably p-toluenesulfonic acid;

[0034] As a further improvement of the present invention, including but not limited to, the nitrite reagent in step (2) is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite, and C1-C6 alkyl nitrite, preferably sodium nitrite;

[0035] As a further improvement of the present invention, the molar ratio of compound 2 to the acidic reagent in step (2) is 1:(1.01-2), preferably 1:(1.05-1.3);

[0036] As a further improvement of the present invention, the molar ratio of the acidic reagent to the nitrous acid reagent in step (2) is 1:(1-2), preferably 1:(1.05-1.2);

[0037] As a further improvement of the present invention, the molar ratio of compound 2 to hypophosphorous acid in step (2) is 1:(1.5-5), preferably 1:(2.5-3.5);

[0038] As a further improvement of the present invention, including but not limited to, the organic solvent in step (2) is selected from one or more of halogenated hydrocarbon solvents (such as 1,2-dichloroethane and / or dichloromethane), ketone solvents (such as acetone), nitrile solvents (such as acetonitrile), amide solvents (such as N,N-dimethylformamide) and sulfoxide solvents (such as dimethyl sulfoxide), preferably acetonitrile;

[0039] As a further improvement of the present invention, the volume of the organic solvent in step (2) is 1.5 to 5 times the mass of compound 2.

[0040] As a further improvement of the present invention, the volume of water in step (2) is 0.5 to 1 times the mass of compound 2.

[0041] As a further improvement of the present invention, the first reaction temperature in step (2) is -10 to 10°C, preferably -10 to 5°C;

[0042] As a further improvement of the present invention, the second reaction temperature in step (2) is 15 to 40° C., preferably 15 to 35° C.;

[0043] As a further improvement of the present invention, the reaction in step (2) is about 20% higher than that disclosed in the prior art WO199802409A1 under the conditions of hypophosphorous acid, anhydrous copper sulfate, concentrated sulfuric acid and nitrous acid, and the reaction is carried out at 25°C to obtain 1,3-dichloro-5-(trifluoromethyl)benzene. The present invention preferably uses p-toluenesulfonic acid as the acidifying agent, first performs low-temperature diazotization and then reacts at room temperature to obtain compound 3, and the yield can reach 94.7% and the purity is above 99%, which is more conducive to industrial production.

[0044] As a further improvement of the present invention, the reaction in step (3) comprises: compound 3 reacts with a Konchel-type Grignard reagent in an organic solvent, and then reacts with trifluoroacetyl dimethylamine to obtain compound 4 by a nucleophilic reaction.

[0045] As a further improvement of the present invention, the reaction in step (3) comprises: compound 3 reacts with a Konchel-type Grignard reagent in an organic solvent for a period of time, and then reacts with trifluoroacetyl dimethylamine to obtain compound 4 by a nucleophilic reaction.

[0046] As a further improvement of the present invention, the reaction time of step (3) is selected from not less than 0.5 hours, further not less than 1 hour, not less than 1.5 hours; for example, 0.5 to 3 hours, such as 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours.

[0047] As a further improvement of the present invention, in the reaction of step (3), preferably, the reaction time for the nucleophilic reaction with trifluoroacetyl dimethylamine is not less than 1 hour, such as 1 to 5 hours, such as 1 hour, 2 hours, 3 hours, 4 hours or 5 hours.

[0048] As a further improvement of the present invention, including but not limited to, the Konchel-type Grignard reagent in step (3) is selected from 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride, 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride, isopropylmagnesium chloride lithium chloride, diisopropylmagnesium chloride lithium chloride, preferably 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride;

[0049] As a further improvement of the present invention, including but not limited to, the organic solvent in step (3) is selected from one or more of 1,2-dichloroethane, dichloromethane, acetone, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, preferably tetrahydrofuran;

[0050] As a further improvement of the present invention, the molar ratio of compound 3 to Konchel-type Grignard reagent in the reaction of step (3) is 1:(1-1.5), preferably 1:(1.01-1.1);

[0051] As a further improvement of the present invention, the molar ratio of compound 3 to trifluoroacetyl dimethylamine in the reaction of step (3) is 1:(1-1.5), preferably 1:(1.01-1.1);

[0052] As a further improvement of the present invention, the reaction temperature of the step (3) with the Konchel-type Grignard reagent is -45 to -15°C, preferably -40 to -20°C;

[0053] As a further improvement of the present invention, the reaction temperature of the nucleophilic reaction in step (3) is 5 to 35°C, preferably 15 to 30°C.

[0054] As a further improvement of the present invention, after the reaction in step (3) is completed, the internal temperature is controlled at -20 to 0°C and concentrated hydrochloric acid is added dropwise. After the addition is completed, the mixture is stirred at -5 to 0°C for 1 hour, and the mixture is allowed to stand for separation. Anhydrous sodium sulfate is added to the organic phase for drying, and the mixture is concentrated under reduced pressure at 40°C to obtain a light yellow oily liquid. The oily liquid compound 4 is obtained by distillation under reduced pressure.

[0055] As a further improvement of the present invention, including but not limited to, the reaction in step (3) is compared with the prior art CN113636919B which uses Mg chips as Grignard reagent and then reacts with acylating agent to produce compound 4 by nucleophilic reaction, and the yield is increased by about 15%, which greatly reduces the production cost and is more conducive to industrial production.

[0056] The third aspect of the present invention also provides a method for preparing afoxolane, comprising preparing compound 4 using the method for preparing compound 4 according to the first aspect of the present invention, and further preparing afoxolane using compound 4.

[0057] Beneficial technical effects of the present invention:

[0058] 1) The present invention uses o-aminotrifluorotoluene as a starting material, and prepares compound 4 through three steps of chlorination, diazotization and nucleophilic reaction with an acylating agent; the total yield is 81.9%, and the purity can reach 99%, which is about 30% higher than the yield of the prior art CN113636919B. Compared with the prior art CN112778109B, compound 4 is prepared through five steps, which is shortened by two steps, thereby greatly reducing the production cost;

[0059] 2) The present invention uses o-aminotrifluorotoluene as a starting material, which is cheap, while the prior art WO2011054436A1 uses 1-bromo-3-chloro-5-trifluorotoluene as a raw material, which is expensive. Although compound 4 is prepared in only one step, it is not superior to the present invention in terms of yield and raw materials, and requires an ultra-low temperature of -80°C for reaction, which is not conducive to industrial scale-up;

[0060] 3) The inventors found that when tetrahydrofuran is used as a solvent in step (3), it is significantly better than other organic solvents. The conditions of the present invention can achieve a yield of 91% and a purity of more than 99%. In addition, compared with the prior art CN113636919B, which uses Mg chips as a Grignard reagent and then reacts with an acylating agent to produce compound 4, the yield of step (3) is increased by about 15%, which greatly reduces the production cost and is more conducive to industrial production.

[0061] 4) The inventors found that step (2) is significantly better than other organic solvents when acetonitrile is used as the solvent, and the reaction of step (2) is about 20% higher than that disclosed in the prior art WO199802409A1 under the conditions of hypophosphorous acid, anhydrous copper sulfate, concentrated sulfuric acid and nitrous acid, and the reaction at 25°C to obtain 1,3-dichloro-5-(trifluoromethyl)benzene. In the present invention, p-toluenesulfonic acid is preferably used as the acidifying agent, and low-temperature diazotization is first performed and then the reaction is performed at room temperature to obtain compound 3, with a yield of up to 94.7% and a purity of more than 99%, which is more conducive to industrial production.

[0062] 5) The present invention has short reaction time, mild process conditions, simple operation, high yield, single-step yield of more than 90%, purity of more than 99%, simple post-treatment, reduced "three wastes", and is suitable for industrial production.

[0063] 6) When step (1) of the present invention repeats the prior art hydrogen peroxide as the chlorinated oxidant, the yield is only 83%. When step (2) repeats the prior art sulfuric acid, cuprous chloride, sodium nitrite, hypophosphorous acid as reaction conditions, the yield is only about 82%. The use of the conditions of the present invention can increase the yield by about 12%, and the conditions of the present invention are more suitable for process scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 The HPLC spectrum of the product obtained in Example 1 of the present invention;

[0065] Figure 2 The HPLC spectrum of the product obtained in Example 3 of the present invention;

[0066] Figure 3 The HPLC spectrum of the product obtained in Example 12 of the present invention. DETAILED DESCRIPTION

[0067] The preparation method of the present invention will be described in further detail below in conjunction with specific examples. It should be understood that the following examples are only exemplary illustrations and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0068] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0069] Example 1: Preparation of Compound 2

[0070]

[0071] Under nitrogen protection, 36% hydrochloric acid (1500mL) and cuprous chloride (18g, 0.1eq) were added to the reaction bottle, and the internal temperature was controlled at 30-35°C and stirred for 30min. 2-(trifluoromethyl)aniline (300g, 1.0eq) was slowly added dropwise, and the internal temperature was controlled at 30-40°C. After the addition was completed, a small amount of solid did not dissolve in the reaction solution. 68% tert-butyl hydroperoxide (490.07g, 2.0eq) was continued to be added dropwise, and the internal temperature was controlled at 30-40°C. After the addition was completed, 30-40°C was added. The mixture was stirred at room temperature for 16 h, and the reaction was tracked by thin layer chromatography (TLC). After 16 h, the reaction was completed. The lower organic phase was retained by standing and separation. Dichloromethane (600 mL) was added to the upper aqueous phase for extraction. The organic phases were combined, and a 10% wt aqueous sodium bicarbonate solution was added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 406.86 g of a brown oily liquid with a yield of 95%. The HPLC purity was 99.54%, and the retention time RT was 7.748. The HPLC spectrum was as shown in FIG. Figure 1 shown.

[0072] Example 2: Preparation of Compound 2

[0073]

[0074] Under nitrogen protection, 36% hydrochloric acid (3000 mL) and cuprous chloride (37 g, 0.1 eq) were added to the reaction bottle, and the internal temperature was controlled at 30-35°C and stirred for 30 min. 2-(trifluoromethyl)aniline (600 g, 1.0 eq) was slowly added dropwise, and the internal temperature was controlled at 30-40°C. After the addition was completed, a small amount of solid did not dissolve in the reaction solution. 68% tert-butyl hydroperoxide (980.1 g, 2.0 eq) was continued to be added dropwise, and the internal temperature was controlled at 30 ~40℃, after the addition, keep warm and stir at 30~40℃ for 16h, track the reaction by thin layer chromatography (TLC), and the reaction is completed after 16h. Let the liquid stand and retain the lower organic phase. Add dichloromethane (1200mL) to the upper aqueous phase for extraction, combine the organic phases, add 10%wt sodium bicarbonate aqueous solution to wash the organic phase, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 813.82g of brown oily liquid with a yield of 95.02%.

[0075] Example 3: Preparation of Compound 3

[0076]

[0077] Compound 2 (230 g, 1.0 eq) was added to acetonitrile (460 mL), stirred to dissolve, p-toluenesulfonic acid (192.46 g, 1.1 eq) was added, and then sodium nitrite (82.8 g, 1.2 eq) was dissolved in water (170 mL) and the temperature in the system was controlled at -5 to 0 ° C and added dropwise. After the addition was completed, stirring was continued at -5 to 0 ° C for 1 h and stored for later use. Take another reaction bottle, add 50% hypophosphorous acid (384 g, 3.0 eq), control the temperature in the system to 20 to 30 ° C, and add the pre-prepared diazonium salt solution dropwise. After the addition was completed, stir for 25 to 30 ℃, stirred for 3 h, followed by thin layer chromatography (TLC). After 3 h, the reaction was completed. Dichloromethane (920 mL) was added and stirred for 30 min. The mixture was allowed to stand for separation. The lower organic phase was retained. Saturated sodium bicarbonate (920 mL) and saturated brine (230 mL) were added in sequence to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a light yellow oily liquid. 203.6 g of a colorless transparent liquid was obtained by distillation under reduced pressure. The yield was 94.7%. The HPLC purity was 99.38%. The retention time RT was 8.807. The HPLC spectrum was as shown in FIG. Figure 2 shown.

[0078] Example 4: Preparation of Compound 3

[0079]

[0080] Compound 2 (460 g, 1.0 eq) was added to acetonitrile (920 mL), stirred to dissolve, and p-toluenesulfonic acid (384.9 g, 1.1 eq) was added. Subsequently, sodium nitrite (165.6 g, 1.2 eq) was dissolved in water (370 mL) and added dropwise at a temperature of -5 to 0 ° C. After the addition was completed, the mixture was stirred at -5 to 0 ° C for 1 h and stored for later use. In another reaction bottle, 50% hypophosphorous acid (768 g, 3.0 eq) was added, and the temperature was controlled at 20 to 3 The pre-prepared diazonium salt solution was added dropwise at 0°C. After the addition was completed, the mixture was kept warm and stirred at 25-30°C for 3 hours. The reaction was tracked by thin layer chromatography (TLC). After 3 hours, the reaction was completed. Dichloromethane (1840 mL) was added and stirred for 30 minutes. The mixture was allowed to stand for separation. The lower organic phase was retained. Saturated sodium bicarbonate and saturated brine were added in sequence to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a light yellow oily liquid. 407 g of colorless transparent liquid was obtained by distillation under reduced pressure. The yield was 94.66%.

[0081] The preparation method of the compound of formula 3 in Example 5-7 is as described in Example 3-4, and different solvents are used in step 2. The results are shown in Table 2:

[0082] Table 2

[0083] Example Solvents result 3 Acetonitrile Yield 94.7%, HPLC purity 99.38% 4 Acetonitrile Yield: 94.66% 5 Tetrahydrofuran The reaction time is long and the residual raw materials in TLC control are obvious 6 Ethyl acetate The reaction time is long and the residual raw materials in TLC control are obvious 7 Ethanol TLC controls more impurities

[0084] The preparation method of the compound of formula 3 in Example 8-11 is as described in Example 3-4. In step 2, the compound 3 is obtained by reacting with hypophosphorous acid at different temperatures. The results are shown in Table 3:

[0085] Table 3

[0086]

[0087]

[0088] The inventors have finally determined the appropriate solvent and temperature through creative labor. For example, it can be seen from Examples 3 to 7 in Table 2 that when other ether, lipid and alcohol solvents other than acetonitrile are used as solvents, the reaction is very complicated, more by-products are generated, or a large amount of raw materials remain and the reaction is not completed; for example, it can be seen from Examples 3 to 4, 8 to 11 in Table 3 that at 0-10° C., the reaction is slow and the product conversion is not obvious, and at 40-50° C., there are more reaction impurities. When the solvent acetonitrile of the present invention is used and the reaction temperature is 25 to 30° C., the yield is about 95%, and the HPLC purity is above 99%. It also has the advantages of simple post-processing and good reproducibility, and is suitable for industrial production.

[0089] Example 12: Preparation of Compound 4

[0090]

[0091] Under nitrogen protection, compound 3 (200 g, 1.0 eq) was dissolved in THF (1000 mL), the internal temperature was controlled at -35 to -25 ° C, 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1 mol / L in THF, 976 mL, 1.05 eq) was added dropwise, and the mixture was stirred at -35 to -25 ° C for 1 h. Then, trifluoroacetyl dimethylamine (124.12 g, 1.05 eq) was added dropwise at the same temperature, and stirring was continued for 30 min after the addition was completed. , heat to 10-20°C and stir for 2h, track the reaction with thin layer chromatography (TLC), and the reaction is completed after 2h. Control the internal temperature at -15--10°C and add 36% hydrochloric acid (300mL) dropwise. After the addition, stir at 0°C for 1h, stand and separate the liquids. Add anhydrous sodium sulfate to the organic phase and dry it. Concentrate under reduced pressure to obtain a light yellow oily liquid. Distill under reduced pressure to obtain 233.34g of a colorless oily liquid with a yield of 90.7%, HPLC purity of 99.09%, retention time RT=5.356, and HPLC spectrum as shown Figure 3 shown.

[0092] Example 13: Preparation of Compound 4

[0093]

[0094] Under nitrogen protection, compound 3 (400 g, 1.0 eq) was added to THF (200000 mL), and the internal temperature was controlled at -35 to -25 ° C. 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex (1 mol / L in THF, 1952 mL, 1.05 eq) was added dropwise. After the addition was completed, stirring was continued at -35 to -25 ° C for 1 h, and then trifluoroacetyl dimethylamine (248.23 g, 1 .05eq), after the addition, continue stirring for 30 minutes, raise the temperature to 10-20°C and stir for 2 hours, use thin layer chromatography (TLC) to track the reaction, and the reaction is completed after 2 hours. Control the internal temperature at -15 to -10°C and add 36% hydrochloric acid (600mL) dropwise. After the addition, stir at 0°C for 1 hour, let stand and separate the liquids, add anhydrous sodium sulfate to the organic phase, dry it, concentrate it under reduced pressure to obtain a light yellow oily liquid, and distill it under reduced pressure to obtain 468.22g of a colorless oily liquid with a yield of 91%.

[0095] The preparation method of the compound of formula 3 in Example 14-15 is as described in Example 12-13, and different solvents are used in step 3. The results are shown in Table 4 below:

[0096] Table 4

[0097] Example Solvents result 12 Tetrahydrofuran Yield 90.7%, HPLC purity 99.09% 13 Tetrahydrofuran Yield 91% 14 Acetonitrile TLC controls more impurities 15 Methyl tert-butyl ether TLC controls more impurities

[0098] The inventors have finally determined a suitable solvent through creative work. For example, it can be seen from Examples 12 to 15 in Table 4 that when acetonitrile and methyl tert-butyl ether other than tetrahydrofuran are used as solvents, the reaction is very complicated and more by-products are generated. When the tetrahydrofuran of the present invention is used as a solvent, the yield is about 91%, the HPLC purity is above 99%, and it also has the advantages of simple post-processing and good reproducibility, and is suitable for industrial production.

[0099] Comparative Example 1: Preparation of Compound 2

[0100]

[0101] Under nitrogen protection, 36% hydrochloric acid (2100 mL) and cuprous chloride (18 g, 0.1 eq) were added to the reaction bottle, the internal temperature was controlled at 30-35°C and stirred for 30 min, 2-(trifluoromethyl)aniline (300 g, 1.0 eq) was slowly added dropwise, the internal temperature was controlled at 30-40°C, after the addition, a small amount of solid did not dissolve in the reaction solution, 30% hydrogen peroxide (1266.7 g, 6.0 eq) was continued to be added dropwise, the internal temperature was controlled at 30-40°C, After the addition, the temperature was raised to 80-90°C and stirred for 20 hours. The reaction was tracked by thin layer chromatography (TLC). After 20 hours, the reaction was completed. The lower organic phase was retained by standing and separation. Dichloromethane (900 mL) was added to the upper aqueous phase for extraction. The organic phases were combined and a 10% wt aqueous sodium bicarbonate solution was added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily liquid. 355.47 g of a light yellow liquid was obtained by distillation, with a yield of 83%.

[0102] Comparative Example 2: Preparation of Compound 3

[0103]

[0104] Compound 2 (230 g, 1.0 eq) was added to 70% sulfuric acid (1380 mL), followed by cuprous chloride (4.94 g, 0.05 eq), stirred to dissolve, sodium nitrite (82.8 g, 1.2 eq) was dissolved in water (299 mL), and the internal temperature was controlled at 0-5 ° C. The mixture was added dropwise, and the mixture was stirred at 0-5 ° C for 1.5 h, and stored for later use; in another reaction bottle, 50% hypophosphorous acid (384 g, 3.0 eq) was added, and the internal temperature was controlled at 10-20 ° C. The mixture was added dropwise. Add the pre-prepared diazonium salt solution, stir at 25-30°C for 16h, track the reaction by thin layer chromatography (TLC), and the reaction is completed after 16h. Add dichloromethane (1840mL) and stir for 30min. Let stand and separate the liquids, retain the lower organic phase, add saturated sodium bicarbonate and saturated brine to wash the organic phase in turn, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow oily liquid. Distill under reduced pressure to obtain 177.37g of colorless transparent liquid with a yield of 82.5%.

Claims

1. A method for preparing compound 4, the reaction formula is as follows: The steps include: (1) Compound 1 is subjected to a chlorination reaction in hydrochloric acid in the presence of tert-butyl hydroperoxide and a copper catalyst to obtain Compound 2; (2) Compound 2 is subjected to a diazotization reaction in an organic solvent in the presence of an acidic reagent and a nitrous acid reagent, and then reacted with hypophosphorous acid to obtain compound 3; (3) Compound 3 reacts with a Konchel-type Grignard reagent and then undergoes a nucleophilic reaction with trifluoroacetyl dimethylamine to obtain compound 4.

2. The preparation method according to claim 1, characterized in that: The hydrochloric acid in step (1) is selected from concentrated hydrochloric acid; And / or, preferably, the copper catalyst in step (1) is selected from one of cuprous chloride, cupric chloride and cupric chloride dihydrate; Cuprous chloride is preferred; And / or, preferably, the molar ratio of compound 1 to the copper catalyst in step (1) is 1:(0.01-0.5), preferably 1: (0.05～0.15)； And / or, preferably, the molar ratio of compound 1 to tert-butyl hydroperoxide in step (1) is 1:(1.01-5), preferably 1:(1.5-2.5); And / or, preferably, the volume of hydrochloric acid in step (1) is 3 to 10 times, preferably 4 to 6 times, the mass of compound 1 in mL; And / or, preferably, the reaction temperature in step (1) is 20 to 50°C, preferably 25 to 45°C; And / or, preferably, the reaction time of step (1) is 5 to 24 hours, preferably 15 to 20 hours.

3. The preparation method according to claim 1, characterized in that: The reaction in step (2) comprises: performing a diazotization reaction on compound 2 in an organic solvent in the presence of an acidic reagent and an aqueous solution of a nitrous acid reagent at a first temperature, and then reacting with hypophosphorous acid at a second temperature to obtain compound 3.

4. The preparation method according to claim 3, characterized in that: The acidic reagent in step (2) is selected from one or more of p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid, preferably p-toluenesulfonic acid; And / or, preferably, the nitrite reagent in step (2) is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite, and C1-C6 alkyl nitrite, preferably sodium nitrite; And / or, preferably, the hypophosphorous acid in step (2) is selected from hypophosphorous acid having a mass fraction of 45 to 55%; And / or, preferably, the molar ratio of compound 2 to the acidic reagent in step (2) is 1:(1.01-2), preferably 1: (1.05～1.3)； And / or, preferably, the molar ratio of the acidic reagent to the nitrous acid reagent in step (2) is 1:(1-2), preferably 1: (1.05～1.2)； And / or, preferably, the molar ratio of compound 2 to hypophosphorous acid in step (2) is 1:(1.5-5), preferably 1:(2.5-3.5); and / or, preferably, the organic solvent in step (2) is selected from one or more of halogenated hydrocarbon solvents, ketone solvents, nitrile solvents, amide solvents and sulfoxide solvents; And / or, preferably, in step (2), the halogenated hydrocarbon solvent is selected from 1,2-dichloroethane and dichloromethane, the ketone solvent is selected from acetone, the nitrile solvent is selected from acetonitrile, the amide solvent is selected from N,N-dimethylformamide, and the sulfoxide solvent is selected from dimethyl sulfoxide, preferably acetonitrile; And / or, preferably, the volume of the organic solvent in step (2) is 1.5 to 5 times the mass of compound 2 in mL; And / or, preferably, the volume of water in step (2) is 0.5 to 1 times the mass of compound 2; And / or, preferably, the first reaction temperature in step (2) is -10 to 10°C, preferably -10 to 5°C; And / or, preferably, the second reaction temperature in step (2) is 15 to 40°C, preferably 15 to 35°C.

5. The preparation method according to claim 1 or claim 3, characterized in that: The reaction in step (2) comprises: compound 2 and an acidic reagent in an organic solvent are subjected to a diazotization selective reaction with an aqueous solution of a nitrous acid reagent at a first temperature for a period of time, and then reacted with hypophosphorous acid at a second temperature to obtain compound 3; and / or, preferably, the reaction may be selectively carried out for a period of time selected from not less than 40 minutes, preferably 40 to 80 minutes; And / or, preferably, the reaction time of the further reaction with hypophosphorous acid is not less than 1 hour, preferably 1 to 5 hours.

6. The preparation method according to claim 1, characterized in that: The reaction in step (3) comprises: reacting compound 3 with a Konchel-type Grignard reagent in an organic solvent, and then reacting with trifluoroacetyl dimethylamine for nucleophilic reaction to obtain compound 4.

7. The preparation method according to claim 1 or claim 6, characterized in that: The reaction in step (3) comprises: reacting compound 3 with a Konchel-type Grignard reagent in an organic solvent for a period of time, and then reacting with trifluoroacetyl dimethylamine for a nucleophilic reaction to obtain compound 4; and / or, preferably, the reaction time is selected from not less than 0.5 hours, preferably 0.5 to 3 hours; And / or, preferably, the reaction time for the nucleophilic reaction with trifluoroacetyl dimethylamine is not less than 1 hour, preferably 1 to 5 hours.

8. The preparation method according to claim 6 or claim 7, characterized in that: The Konchel-type Grignard reagent in step (3) is selected from 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride, 2,2,6,6-tetramethylpiperidinylzinc chloride lithium chloride, isopropylmagnesium chloride lithium chloride, and diisopropylmagnesium chloride lithium chloride, preferably 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride; And / or, preferably, the organic solvent in step (3) is selected from one or more of 1,2-dichloroethane, dichloromethane, acetone, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, preferably tetrahydrofuran; And / or, preferably, in the reaction of step (3), the molar ratio of compound 3 to Konchel-type Grignard reagent is 1:(1-1.5), Preferably 1:(1.01~1.1); And / or, preferably, in the reaction of step (3), the molar ratio of compound 3 to trifluoroacetyl dimethylamine is 1:(1-1.5), preferably 1:(1.01-1.1); And / or, preferably, the reaction temperature of the step (3) with the Konchel-type Grignard reagent is -45 to -15°C, preferably -40 to -20°C; And / or, preferably, the reaction temperature of the nucleophilic reaction in step (3) is 5 to 35°C, preferably 15 to 30°C.

9. The preparation method according to claim 1 or claim 6 or claim 7, characterized in that: After the reaction in step (3) is completed, the internal temperature is controlled at -20 to 0°C and concentrated hydrochloric acid is added dropwise. After the addition is completed, the mixture is stirred at -5 to 0°C for 1 hour, and the mixture is allowed to stand for separation. Anhydrous sodium sulfate is added to the organic phase for drying, and the mixture is concentrated under reduced pressure at 40°C to obtain a light yellow oily liquid. The oily liquid compound 4 is obtained by distillation under reduced pressure.

10. A method for preparing afoxolane, comprising preparing compound 4 by the method for preparing compound 4 according to claims 1 to 9, and further preparing afoxolane from compound 4.

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