Synthesis method of thioether compound

Abstract

The invention discloses a synthesis method of a thioether compound. The synthesis method comprises the following steps: reacting 3-fluorotoluene with chlorosulfonic acid to obtain 4-fluoro-2-methylbenzenesulfonyl chloride; the preparation method comprises the following steps: dissolving 4-fluoro-2-methylbenzenesulfonyl chloride with acetic acid, adding acetic anhydride and red phosphorus, heating to 80-90 DEG C, adding elemental iodine in batches, and reacting to obtain (2-methyl-4-fluorophenyl) thioacetate; the preparation method comprises the following steps: dissolving (2-methyl-4-fluorophenyl) thioacetate with methanol, adding sodium formaldehyde sulfoxylate and potassium carbonate under the protection of nitrogen, and reacting; cooling the system to room temperature, dropwise adding 2, 2, 2-trifluoroethyl trifluoromethanesulfonate, and reacting to obtain (4-fluoro-2-methylphenyl) (2, 2, 2-trifluoroethyl) sulfane; the preparation method comprises the following steps: dissolving (4-fluoro-2-methylphenyl) (2, 2, 2-trifluoroethyl) sulfane with concentrated sulfuric acid, adding NBS (N-bromosuccinimide), and reacting to obtain (4-fluoro-5-bromo-2-methylphenyl) (2, 2, 2-trifluoroethyl) sulfane.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis and relates to a new synthesis method of thioether compounds. Background Art

[0002] Thioether compounds are an important class of compounds containing trifluoroethylthio groups. Their structural skeletons widely appear in fields such as pesticides and have important biological activities. Although there have been many reports on the synthesis of such compounds (References: CN118344315 A, CN 116041232A, CN111100048A, CN 118239818A), thioether compounds are very important. Therefore, it is still very necessary to develop new synthesis methods for such compounds. In view of this, the present invention aims to disclose a new synthesis method of thioether compounds. Summary of the Invention

[0003] The object of the present invention is to provide a new method for preparing thioether compounds using m-fluorotoluene as the starting raw material.

[0004] The present invention is achieved through the following technical solutions:

[0005] A synthesis method of thioether compounds. When the thioether compound is (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl) sulfane with the structure shown in Formula I, the synthesis route is as follows:

[0006]

[0007] It includes the following steps:

[0008] Step (1), sulfonation reaction: At a temperature of 0 - 10 °C, 3-fluorotoluene undergoes a sulfonation reaction with chlorosulfonic acid to obtain 4-fluoro-2-methylbenzenesulfonyl chloride;

[0009] Step (2), acetylation reaction: 4-fluoro-2-methylbenzenesulfonyl chloride is dissolved in acetic acid, acetic anhydride and red phosphorus are added, heated to 80 - 90 °C, and elemental iodine is added in batches. After the addition is completed, keep the temperature for reaction; after the reaction ends, filter to remove the solid, evaporate acetic acid, add ethyl acetate and saturated sodium bisulfite solution, take the organic phase, wash it successively with saturated brine and dry it with anhydrous sodium sulfate, and concentrate to obtain (2-methyl-4-fluorophenyl) thioacetate (or S-(4-fluoro-2-methylphenyl) ethanesulfonate);

[0010] Step (3), substitution reaction: Dissolve (2-methyl-4-fluorophenyl)thioacetate in methanol. Under nitrogen protection, add sodium formaldehyde sulfoxylate (rongalite) and potassium carbonate, and react at a temperature of 30 - 80°C for 1 hour to 12 hours; then cool the system to room temperature, slowly dropwise add 2,2,2-trifluoroethyl trifluoromethanesulfonate. After the addition is complete, react at room temperature for 1 hour to 12 hours; after the reaction is completed, filter to remove the solid, evaporate methanol, dilute with ethyl acetate, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane;

[0011] Step (4), bromination reaction: Dissolve (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane in concentrated sulfuric acid, add NBS, and react at a temperature of 0 - 10°C for about 1 hour to 12 hours. After the reaction is completed, pour the reaction solution into ice water, add ethyl acetate for extraction. The organic phase is successively washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane.

[0012] In step (1), the molar ratio of the 3-fluorotoluene to chlorosulfonic acid is 1:1 to 1:10, preferably 1:3 to 1:4.

[0013] Specifically, the molar ratio of the 3-fluorotoluene to chlorosulfonic acid can be 1:4.

[0014] Preferably, the sulfonation reaction includes: at a temperature of 0 - 10°C, add 3-fluorotoluene to chlorosulfonic acid in batches. After the addition is complete, maintain the temperature at 0 - 10°C. Under stirring, the 3-fluorotoluene and chlorosulfonic acid undergo a sulfonation reaction to obtain 4-fluoro-2-methylbenzenesulfonyl chloride.

[0015] More preferably, the sulfonation reaction includes: in an ice-water bath, add 3-fluorotoluene to chlorosulfonic acid in batches. After the addition is complete, in the ice-water bath, under stirring, the 3-fluorotoluene and chlorosulfonic acid undergo a sulfonation reaction to obtain 4-fluoro-2-methylbenzenesulfonyl chloride.

[0016] After the sulfonation reaction is completed, pour the reaction solution into ice water, add ethyl acetate for extraction. The organic phase is successively washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 4-fluoro-2-methylbenzenesulfonyl chloride.

[0017] In step (2), the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to acetic anhydride is 1:1 to 1:10, preferably 1:4.5 to 1:5.

[0018] Specifically, the molar ratio of the 3-fluorotoluene to chlorosulfonic acid can be 1:4.9.

[0019] Red phosphorus is used as a reducing agent and is in excess. The molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to red phosphorus is 1:1 to 1:10, preferably 1:4.5 to 1:5.

[0020] Specifically, the molar ratio of the 3-fluorotoluene to chlorosulfonic acid can be 1:4.7.

[0021] Elemental iodine is used as a catalyst. The molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to elemental iodine ranges from 10:1 to 50:1, preferably 22:1 to 23:1.

[0022] Specifically, the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to elemental iodine can be 22.5:1, 22.8:1, 23:1.

[0023] Preferably, the temperature is maintained at 80 - 90 °C, and elemental iodine is added in batches within 15 - 30 minutes, and the amount of elemental iodine added each time is 1 / 4 - 1 / 10 of the total amount of elemental iodine.

[0024] More preferably, the temperature is maintained at 80 - 90 °C, and elemental iodine is added in batches within 15 minutes, and the amount of elemental iodine added each time is 1 / 5 of the total amount of elemental iodine.

[0025] Preferably, after the addition is completed, the reaction is carried out at a temperature of 80 - 90 °C.

[0026] In step (3), the molar ratio of the 4-fluoro-2-methylphenyl thioacetate to sodium formaldehyde bisulfite is 1:1 to 10:1, preferably 1.5 - 2:1.

[0027] The molar ratio of the 4-fluoro-2-methylphenyl thioacetate to potassium carbonate is 1:1 to 1:10, preferably 1:1.7 - 1:1.8.

[0028] The molar ratio of the 4-fluoro-2-methylphenyl thioacetate to 2,2,2-trifluoroethyl trifluoromethanesulfonate is 1:1 to 1:10, preferably 1:2.

[0029] Specifically, the substitution reaction includes: dissolving (2-methyl-4-fluorophenyl) thioacetate in methanol, adding sodium formaldehyde bisulfite and potassium carbonate under nitrogen protection, and reacting at a temperature of 50 °C for about 2 hours; then cooling the system to room temperature, slowly dropping 2,2,2-trifluoroethyl trifluoromethanesulfonate, and after the dropping is completed, reacting at room temperature for 2 hours.

[0030] In step (4), the molar ratio of the (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl) sulfide to NBS is 1:1 to 1:10, preferably 1:1 to 1:1.2.

[0031] Specifically, the molar ratio of (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane to NBS can be 1:1.2.

[0032] The mass fraction of the concentrated sulfuric acid is ≥70%, preferably 98%.

[0033] The bromination reaction includes: dissolving (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane in concentrated sulfuric acid, cooling to about 0 °C in an ice-water bath, adding NBS, maintaining the temperature at 0 °C, and reacting for about 2 hours; pouring the reaction solution into ice water, adding ethyl acetate for extraction, taking the organic phase, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane.

[0034] A method for synthesizing a thioether compound. When the thioether compound is a thioether compound with the structure shown in Formula II, the synthesis route is as follows:

[0035]

[0036] Among them, R is selected from a substituted or unsubstituted phenyl group, a pyridyl group, and other heterocyclic groups; the substituents of the phenyl group are methoxy, cyano, methylthio, nitro, and fluorine, and the number of substituents is an integer from 1 to 5;

[0037] Specifically, the substituted phenyl group is selected from The other heterocyclic groups are selected from

[0038]

[0039] It includes:

[0040] Steps (1)-(4) are the same as steps (1)-(4) for preparing (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane;

[0041] Step (5): Dissolve (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane in a mixed solvent of toluene and water, add a boric acid compound with the structure shown in Formula as shown, bis(triphenylphosphine)palladium(II) dichloride, and potassium carbonate, and react at 30-100 °C for 3-12 hours under nitrogen protection; after the reaction is completed, add ethyl acetate for extraction, wash the organic phase with saturated brine and dry it with anhydrous sodium sulfate, and concentrate to obtain a thioether compound with the structure shown in Formula II.

[0042] In step (5), the molar ratio of (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane to the boric acid compound is 1:1-1:10, preferably 1:1-1:1.2.

[0043] The molar ratio of the (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane to the bis(triphenylphosphine)palladium(II) dichloride is 1:0.01 to 1:0.2, preferably 1:0.05 to 1:0.06.

[0044] The molar ratio of the (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane to the potassium carbonate is 1:1 to 1:10, preferably 1:1.5 to 1:2.

[0045] Preferably, the reaction temperature is 90 °C and the reaction time is about 4 hours.

[0046] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0047] The traditional preparation process of (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl) uses 4-bromo-3-fluorotoluene as the raw material, which is expensive and has many synthetic by-products.

[0048] The present invention uses m-fluorotoluene as the starting material, and successively undergoes sulfonation reaction, acetylation, substitution, and bromination to prepare (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl). The raw materials are cheap and easily available, the operation is simple, the reaction conditions are mild, the side reactions are few, the product selectivity is good, the post-treatment is simple, and the yield of each step is relatively high.

[0049] The present invention realizes the synthesis of benzothioether compounds from m-fluoroaniline as the raw material for the first time, and this route is reported for the first time.

[0050] The present invention can achieve large-scale synthesis of (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl), and the solvent can be recovered and reused. Detailed implementation mode

[0051] Example 1

[0052]

[0053] Take chlorosulfonic acid (46 g, 394.8 mmol) and place it in a 250 mL single-necked flask. In an ice-water bath, add 3-fluorotoluene (11 g, 100 mmol) to the reaction flask in batches within 30 minutes. After the addition is complete, continuously stir in the ice-water bath for 3 hours. At this time, the central control detects that the raw materials have completely reacted; slowly pour the reaction solution into ice water, mix evenly, then add ethyl acetate to the system for extraction, collect the organic phase, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, filter, and concentrate to obtain 18.7 grams of 4-fluoro-2-methylbenzenesulfonyl chloride, an oily substance, with a yield of about 90%.

[0054] 1 1H NMR (400 MHz, Chloroform-d) δ 8.10 (m, 1H), 7.10 (m, 2H), 2.79 (s, 3H).

[0055]

[0056] Dissolve 4-fluoro-2-methylbenzenesulfonyl chloride (18.7 g, 90 mmol) in 200 mL of acetic acid. Add acetic anhydride (45 g, 440 mmol) and red phosphorus (13 g, 420 mmol). Heat to 80 °C and maintain this temperature. Add elemental iodine (1 g, 4 mmol) to the reaction system in portions within 15 minutes (in 5 portions, 200 mg each time, with obvious heat release during the addition process). After the addition, continue to stir at the same temperature for 4 hours. At this time, the reaction is detected to be complete by in-process control. Filter to remove the solid, evaporate acetic acid. Dilute the residue with ethyl acetate, wash with saturated sodium bisulfite solution, extract and collect the organic phase. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 15.6 g of S-(4-fluoro-2-methylphenyl) ethanesulfonate, an oily substance, with a yield of approximately 94%.

[0057] 1 1H NMR (400 MHz, Chloroform-d): 7.46 (m, 1H), 7.23 (m, 1H), 7.07 (m, 1H), 2.41 (s, 3H), 2.27 (s, 3H).

[0058]

[0059] Dissolve S-(4-fluoro-2-methylphenyl) ethanesulfonate (15.6 g, 85 mmol) in methanol. Under nitrogen protection, add the reducing agent sodium formaldehyde sulfoxylate (rongalite, 5.8 g, 49 mmol) and potassium carbonate (20 g, 145 mmol). Heat to 50 °C and react for about 2 hours. At this time, the raw materials disappear as detected by TLC. Lower the temperature of the system to room temperature, and slowly add 2,2,2-trifluoroethyl trifluoromethanesulfonate (39.44 g, 170 mmol). After the addition, continue to react at room temperature for 2 hours. At this time, the reaction is detected to be complete by in-process control. Filter to remove the solid, evaporate methanol. Dilute the residue with ethyl acetate again, wash with saturated brine, extract and collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 13.3 g of (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl) sulfide, an oily substance, with a yield of approximately 70%.

[0060] 1H-NMR(400MHz, Chloroform-d): 7.28(m, 1H), 7.16(m, 1H), 6.92(m, 1H), 3.72(m, 2H), 2.33(s, 3H).

[0061]

[0062] (4-Fluoro-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (13.3 g, 59.4 mmol) was dissolved in 80 mL of concentrated sulfuric acid (mass fraction 98%). The temperature was lowered to about 0 °C in an ice-water bath, and NBS (12.7 g, 71 mmol) was added. The temperature was maintained at 0 °C and the reaction was carried out for about 2 hours. At this time, the reaction was detected to be complete by in-process control. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and 14.4 g of (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane, an oily substance, was obtained with a yield of about 80%.

[0063] 1 H-NMR(400MHz, DMSO-d6): 7.87(d, 1H), 7.36(d, 1H), 4.02(q, 2H), 2.35(s, 3H).

[0064] Example 2

[0065]

[0066] (4-Fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (7.2 g, 23.8 mmol) was dissolved in 200 mL of toluene and 50 mL of water. Phenylboronic acid (3 g, 24.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.8 g, 1.1 mmol), and potassium carbonate (4.8 g, 34.8 mmol) were added. Under nitrogen protection, the reaction was carried out at 90 °C for about 4 hours. At this time, the reaction was detected to be complete by in-process control. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1 V / V) to obtain 4.3 g of (6-fluoro-4-methyl-[1,1'-biphenyl]-3-yl)(2,2,2-trifluoroethyl)sulfane, a white solid, with a yield of about 60%.

[0067] 1 H-NMR(400MHz, DMSO-d6): 7.52(m, 1H), 7.49(m, 2H), 7.37(m, 2H), 7.28(m, 1H), 7.04(m, 1H), 3.64(m, 2H), 2.39(s, 3H).

[0068] Example 3

[0069]

[0070] Dissolve (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (3 g, 10 mmol) in 100 mL of toluene and 30 mL of water, add p-methoxyphenylboronic acid (1.7 g, 11.2 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.35 g, 0.5 mmol), potassium carbonate (2.8 g, 20 mmol), and react at 90 °C for about 3 hours under nitrogen protection. At this time, the reaction is detected to be complete by in-process control; cool the reaction solution to room temperature, pour the reaction solution into water, extract with ethyl acetate, take the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:3 V / V) to obtain 2.5 g of (6-fluoro-4'-methoxy-4-methyl-[1,1'-biphenyl]-3-yl)(2,2,2-trifluoroethyl)sulfane, a white solid, with a yield of about 75.8%.

[0071] 1 1H-NMR (400 MHz, DMSO-d6): 7.52 (m, 2H), 7.45 (m, 1H), 7.33 (m, 1H), 7.06 (m, 2H), 3.77 (s, 3H), 3.64 (m, 2H), 2.39 (s, 3H).

[0072] Example 4

[0073]

[0074] Dissolve (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (1.5 g, 5 mmol) in 60 mL of toluene and 20 mL of water, add m-cyanophenylboronic acid (850 mg, 5.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.26 mmol), potassium carbonate (1.4 g, 10 mmol), and react at 90 °C for about 5 hours under nitrogen protection. At this time, the reaction is detected to be complete by in-process control; cool the reaction solution to room temperature, pour the reaction solution into water, extract with ethyl acetate, take the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1 V / V) to obtain 1.1 g of 2'-fluoro-4'-methyl-5'-(2,2,2-trifluoroethyl)thio-[1,1'-biphenyl]-3-carbonitrile, a white solid, with a yield of about 68%.

[0075] 1H-NMR(400MHz, Chloroform-d): 7.80(s, 1H), 7.73(m, 1H), 7.65(m, 1H), 7.58(m, 1H), 7.55(t, 1H), 7.10(d, 1H), 3.35(m, 2H), 2.53(s, 3H).

[0076] Example 5

[0077]

[0078] Dissolve (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (1.5 g, 5 mmol) in 60 mL of toluene and 20 mL of water. Add m-methylthiophenylboronic acid (1 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.26 mmol), and potassium carbonate (1.4 g, 10 mmol). Under nitrogen protection, react at 90 °C for about 5 hours. At this time, monitor the reaction by TLC and find that the reaction is complete. Cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, take the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1 V / V) to obtain 1 g of (2'-fluoro-4'-methyl-5'-(2,2,2-trifluoroethyl)thio)-[1,1'-biphenyl]-3-yl)(methyl)sulfane, a white solid, with a yield of about 58%.

[0079] 1 H-NMR(400MHz, Chloroform-d): 7.62(d, 1H), 7.37(m, 2H), 7.28(m, 2H), 7.05(d, 1H), 3.35(m, 2H), 2.53(m, 6H).

[0080] Example 6

[0081]

[0082] (4-Fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (1.5 g, 5 mmol) was dissolved in 60 mL of toluene and 20 mL of water. m-Nitrophenylboronic acid (1 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.26 mmol), and potassium carbonate (1.4 g, 10 mmol) were added. Under nitrogen protection, the reaction was carried out at 90 °C for about 4 hours. At this time, the reaction was detected to be complete by in-process control. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (the eluent was ethyl acetate:petroleum ether = 1:1 V / V) to obtain 950 mg of (6-fluoro-4-methyl-3'-nitro-[1,1'-biphenyl]-3-yl)(2,2,2-trifluoroethyl)sulfane, a white solid, with a yield of about 55%.

[0083] 1 1H-NMR (400 MHz, Chloroform-d): 8.41 (d, 1H), 8.25 (s, 1H), 7.87 (m, 1H), 7.67 (d, 1H), 7.66 (m, 1H), 7.11 (d, 1H), 3.35 (m, 2H), 2.56 (m, 3H).

[0084] Example 7

[0085]

[0086] (4-Fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (1.5 g, 5 mmol) was dissolved in 60 mL of toluene and 20 mL of water. (3,4,5-Trifluorophenyl)boronic acid (1.05 g, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.26 mmol), and potassium carbonate (1.4 g, 10 mmol) were added. Under nitrogen protection, the reaction was carried out at 90 °C for about 4 hours. At this time, the reaction was detected to be complete by in-process control. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (the eluent was ethyl acetate:petroleum ether = 1:3 V / V) to obtain 1.15 g of (3',4',5',6-tetrafluoro-4-methyl-[1,1'-biphenyl]-3-yl)(2,2,2-trifluoroethyl)sulfane, a white solid, with a yield of about 65%.

[0087] 1 1H-NMR (400 MHz, Chloroform-d): 7.41 (d, 1H), 7.25 (m, 2H), 7.87 (m, 1H), 3.35 (m, 2H), 2.37 (m, 3H).

[0088] Example 8

[0089]

[0090] (4-Fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane (1.5 g, 5 mmol) was dissolved in 60 mL of toluene and 20 mL of water. 3,5-Dimethylisoxazole-4-boronic acid (850 mg, 6 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.26 mmol), and potassium carbonate (1.4 g, 10 mmol) were added. Under nitrogen protection, the reaction was carried out at 90 °C for about 4 hours. At this time, the reaction was detected to be complete by in-process control. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate. The organic phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:5 V / V) to obtain 720 mg of 4-(2-fluoro-4-methyl-5-((2,2,2-trifluoroethyl)thio)phenyl)-3,5-dimethylisoxazole, a white solid product, with a yield of about 45%.

[0091] 1 H-NMR(400MHz,Chloroform-d):7.33(d,1H),7.12(d,1H),3.41(m,2H),2.56(s,3H),2.49(s,3H),2.37(s,3H).

[0092] The above is a description of the preferred embodiments of the present invention, so that those skilled in the art can implement or use the present invention. Some modifications to these embodiments are obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the scope or spirit of the present invention. Therefore, the scope of the present invention is not limited by the above specific embodiments.

Claims

1. A method for synthesizing a thioether compound, characterized in that: The thioether compound is (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl) sulfane with a structure as shown in Formula I, and the synthesis route is as follows: It includes the following steps: Step (1), sulfonation reaction: At a temperature of 0 - 10 °C, 3-fluorotoluene reacts with chlorosulfonic acid in a sulfonation reaction to obtain 4-fluoro-2-methylbenzenesulfonyl chloride; Step (2), acetylation reaction: 4-Fluoro-2-methylbenzenesulfonyl chloride is dissolved in acetic acid, acetic anhydride and red phosphorus are added, heated to 80 - 90 °C, and elemental iodine is added in batches. After the addition is complete, keep the temperature for reaction; after the reaction is completed, filter to remove the solid, evaporate acetic acid, add ethyl acetate and saturated sodium bisulfite solution, take the organic phase, wash successively with saturated brine and dry over anhydrous sodium sulfate, and concentrate to obtain (2-methyl-4-fluorophenyl) thioacetate; Step (3), substitution reaction: (2-Methyl-4-fluorophenyl) thioacetate is dissolved in methanol. Under nitrogen protection, sodium formaldehyde sulfoxylate and potassium carbonate are added, and the reaction is carried out at a temperature of 30 - 80 °C for 1 hour to 12 hours; then the system is cooled to room temperature, and 2,2,2-trifluoroethyl trifluoromethanesulfonate is added dropwise. After the addition is complete, react at room temperature for 1 hour to 12 hours; after the reaction is completed, filter to remove the solid, evaporate methanol, dilute with ethyl acetate, wash with saturated brine, and the organic phase is dried over anhydrous sodium sulfate and concentrated to obtain (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl) sulfane; Step (4), bromination reaction: (4-Fluoro-2-methylphenyl)(2,2,2-trifluoroethyl) sulfane is dissolved in concentrated sulfuric acid, NBS is added, and the reaction is carried out at a temperature of 0 - 10 °C for 1 hour to 12 hours. After the reaction is completed, pour the reaction solution into ice water, add ethyl acetate for extraction, and the organic phase is successively washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated to obtain (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl) sulfane.

2. The synthesis method of the thioether compound according to claim 1, wherein: In step (1), the molar ratio of the 3-fluorotoluene to chlorosulfonic acid is 1:1 - 1:10, preferably 1:3 - 1:

4.

3. The synthesis method of the thioether compound according to claim 1, wherein: In step (1), after the sulfonation reaction is completed, pour the reaction solution into ice water, add ethyl acetate for extraction, and the organic phase is successively washed with saturated brine and dried over anhydrous sodium sulfate, and concentrated to obtain 4-fluoro-2-methylbenzenesulfonyl chloride.

4. The synthesis method of the thioether compound according to claim 1, characterized in that: In step (2), the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to acetic anhydride is 1:1 - 1:10; the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to red phosphorus is 1:1 - 1:10; the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to elemental iodine is 10:1 - 50:

1.

5. The method for synthesizing a thioether compound according to claim 1 or 4, characterized in that: In step (2), the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to acetic anhydride is 1:4.5 - 1:5; the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to red phosphorus is 1:4.5 - 1:5; the molar ratio of the 4-fluoro-2-methylbenzenesulfonyl chloride to elemental iodine is 22:1 - 23:

1.

6. The synthesis method of the thioether compound according to claim 1, wherein: In step (2), maintain the temperature at 80 - 90 °C, and add iodine in batches within 15 - 30 minutes. The amount of iodine added each time is 1 / 4 - 1 / 10 of the total amount of iodine.

7. The synthetic method of the thioether compound according to claim 1, characterized in that: In step (3), the molar ratio of 4-fluoro-2-methylphenylthioacetate to sodium formaldehyde sulfoxylate is 1:1 - 10:1, preferably 1.5 - 2:1; the molar ratio of 4-fluoro-2-methylphenylthioacetate to potassium carbonate is 1:1 - 1:10, preferably 1:1.7 - 1:1.8; the molar ratio of 4-fluoro-2-methylphenylthioacetate to 2,2,2-trifluoroethyl trifluoromethanesulfonate is 1:1 - 1:10, preferably 1:

2.

8. The synthetic method of the thioether compound according to claim 1, characterized in that: In step (4), the molar ratio of (4-fluoro-2-methylphenyl)(2,2,2-trifluoroethyl) sulfide to NBS is 1:1 - 1:10, preferably 1:1 - 1:1.2; the mass fraction of concentrated sulfuric acid ≥ 70%, preferably 98%.

9. A method for synthesizing a thioether compound, characterized in that: The thioether compound is a thioether compound with a structure shown in formula II, and the synthesis route is as follows: Among them, R is selected from a substituted or unsubstituted phenyl group, a pyridyl group, or other heterocyclic groups; the substituents of the phenyl group are methoxy, cyano, methylthio, nitro, or fluorine, and the number of substituents is an integer from 1 to 5. Including: Synthesize (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane according to steps (1)-(4) of claim 1; dissolve (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl)sulfane in a mixed solvent of toluene and water, add a boronic acid compound shown in the formula , bis(triphenylphosphine)palladium(II) dichloride, and potassium carbonate, and react at 30-100 °C for 3-12 hours under nitrogen protection; after the reaction is completed, add ethyl acetate for extraction, wash the organic phase with saturated brine, dry it over anhydrous sodium sulfate, and concentrate to obtain a thioether compound shown in formula II.

10. The method for synthesizing a thioether compound according to claim 9, characterized in that: The molar ratio of (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl) sulfide to the boric acid compound is 1:1 - 1:10, preferably 1:1 - 1:1.2; the molar ratio of (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl) sulfide to bis(triphenylphosphine)palladium(II) dichloride is 1:0.01 - 1:0.2, preferably 1:0.05 - 1:0.06; the molar ratio of (4-fluoro-5-bromo-2-methylphenyl)(2,2,2-trifluoroethyl) sulfide to potassium carbonate is 1:1 - 1:10, preferably 1:1.5 - 1:2.

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