Method for synthesizing Iclepertin

Abstract

The invention relates to a method for synthesizing Iclepertin, and belongs to the technical field of medicinal chemistry. The reaction route is shown in the specification. Comprising the following steps: (1) carrying out sulfonation reaction on p-fluoroiodobenzene and sodium methanesulfinate to obtain p-fluoromethylsulfonyl benzene; (2) carrying out a reaction on p-fluoromethylsulfonyl benzene and (R)-1, 1, 1-trifluoro-2-propanol to obtain a compound shown in a formula II; (3) reacting the compound shown in the formula IV with triphosgene to obtain a compound shown in a formula III; and (4) carrying out Friedel-Crafts acylation reaction on the compound in the formula II and a compound in a formula III to obtain a compound in a formula I. According to the synthesis method, the reaction route is shortened, high-risk reagents are prevented from being used, and industrial large-scale production is facilitated.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and in particular to a method for synthesizing Iclepertin. BACKGROUND

[0002] Iclepertin (CAS: 1421936-85-7) is a new type of Glycine transporter 1 (Gly-T1) inhibitor developed by Boehringer Ingelheim, which improves the hypofunction of N-methyl-D-aspartate (NMDA) receptors by inhibiting Gly-T1 and plays a therapeutic role. The structure of Iclepertin is as follows: .

[0003] The abnormality of glutamatergic pathway caused by low NMDA receptor function is one of the pathological reasons for the onset of schizophrenia. The results of phase II clinical trials show that the cognitive function of patients in the Iclepertin 2 mg~25 mg group is improved compared with the placebo, and the cognitive function of patients in the 10 mg and 25 mg groups is improved the most. The overall safety and tolerability of Iclepertin of all doses are good. Based on the positive results of phase II clinical trials, Iclepertin has been granted breakthrough therapy designation by FDA and National Medical Products Administration. At present, the drug is carrying out global phase III clinical trials for schizophrenia.

[0004] The existing method for synthesizing Iclepertin is mainly disclosed in patent US20240083889A1, which uses benzoic acid compounds, and the carboxyl on the benzene ring is prepared into acyl chloride, and then docked with the side chain containing a bridged ring to obtain the final product. The synthetic route of patent US20240083889A1 is as follows:

[0005] According to the reaction route, it can be seen that the synthetic route of patent US20240083889A1 is extremely complicated, and high-risk compounds such as methyl lithium, chlorosulfonic acid, and n-butyl lithium are used. It cannot be applied to actual industrial production, so a reasonable preparation route needs to be selected to obtain Iclepertin. SUMMARY

[0006] In view of the problems of long reaction route and use of high-risk reaction reagents in the existing method for preparing Iclepertin, the present application provides a method for synthesizing Iclepertin to solve the above problems.

[0007] The technical scheme of the present application is as follows: A method for synthesizing Iclepertin, the reaction route is as follows: ; comprising the following steps: (1) sulfonating p-fluoroiodobenzene with sodium methylsulfinic acid to obtain p-fluoromethylsulfonylbenzene; (2) reacting p-fluoromethylsulfonylbenzene with (R)-1,1,1-trifluoro-2-propanol to obtain a compound of formula II; (3) reacting the compound of formula IV with triphosgene to obtain a compound of formula III; (4) subjecting the compound of formula II to a Friedel-Crafts acylation reaction with the compound of formula III to obtain the compound of formula I; wherein the compound of formula I is Iclepertin, chemical name: [5-methylsulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[1-(5-trifluoromethyl-isoxazol-3-yl)-3-aza-bicyclo[3.1.0]hex-3-yl]-methanone; the compound of formula II is (R)-1-methylsulfonyl-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzene; the compound of formula III is (3R,4R)-1-(5-trifluoromethyl-isoxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl chloride; the compound of formula IV is (3R,4R)-1-(5-trifluoromethyl-isoxazol-3-yl)-3-azabicyclo[3.1.0]hexane.

[0008] Further, the step (1) is: adding p-fluoroiodobenzene into DMSO (dimethyl sulfoxide), then adding sodium methylsulfinic acid, L-proline and sodium hydroxide, and reacting at 80-90°C under nitrogen protection; after the reaction of p-fluoroiodobenzene is completed, cooling down, adding water and ethyl acetate for extraction, washing the organic phase with saturated brine, drying and concentrating to obtain p-fluoromethylsulfonylbenzene.

[0009] Further, in the step (1), the molar ratio of p-fluoroiodobenzene, sodium methylsulfinic acid, L-proline and sodium hydroxide is 1: (1.4-1.6): (1-1.1): (1-1.1).

[0010] Further, the step (2) is: adding 1,1,1-trifluoroisopropanol into DMSO (dimethyl sulfoxide), adding sodium hydroxide and stirring until uniform, then adding p-fluoromethylsulfonylbenzene and heating to 70-80°C for reaction; after the reaction of p-fluoromethylsulfonylbenzene is completed, cooling down, adding water for crystallization, filtering and drying to obtain the compound of formula II.

[0011] Further, in the step (2), the molar ratio of p-fluoromethylsulfonylbenzene to 1,1,1-trifluoroisopropanol is 1:1.1-1.3.

[0012] Further, the step (3) is: taking the compound of formula IV, dissolving in dichloromethane, and cooling to -10 ℃ to -5 ℃; taking another triphosgene, dissolving in dichloromethane; then adding the dichloromethane solution of triphosgene into the reaction system, then adding pyridine dropwise, and controlling the temperature of the reaction system ≤0 ℃; after the dropwise addition is completed, the reaction system is warmed to 20 ℃ to 30 ℃ for reaction; after the compound of formula IV is completely reacted, filtering; obtaining a reaction liquid containing the compound of formula III; and directly performing subsequent reactions on the reaction liquid.

[0013] Further, the water content of the reaction liquid obtained in the step (3) is <0.10 %.

[0014] Further, in the step (3), the molar ratio of the compound of formula IV, triphosgene and pyridine is 1:(0.35-0.38):(1.1-1.5).

[0015] Further, the step (4) is: taking the compound of formula II, dissolving in dichloromethane, then adding a Lewis acid, stirring uniformly, then adding the reaction liquid containing the compound of formula III, and heating to 35 ℃ to 40 ℃ for reaction; after the compound of formula III is completely reacted, cooling to 20 ℃ to 25 ℃, adding water or ammonia water to quench the reaction; filtering, adding water to the filtrate to wash the reaction liquid, separating the liquid, then concentrating the organic phase, adding n-heptane to crystallize, filtering, and drying to obtain the compound of formula I; and the Lewis acid is anhydrous aluminum chloride, titanium tetrachloride or boron trifluoride diethyl ether solution.

[0016] Further, in the step (4), the amount of the compound of formula II is 1.0-1.1 mol / mol based on the amount of the compound of formula IV; and the amount of anhydrous aluminum chloride is 1.2-1.4 mol / mol based on the amount of the compound of formula IV.

[0017] The present application has the following beneficial effects: The method for synthesizing Iclepertin provided by the present application, after acyl chlorination of the bridged ring nitrogen, directly connects to the benzene ring by using a Friedel-Crafts reaction, thereby shortening the reaction steps. Meanwhile, the benzene ring of the compound of formula II only has two substitution sites, according to the positioning rules of the benzene ring, the acyl chlorinated bridged ring side chain can only be substituted at the meta position of the methylsulfonyl group, thereby avoiding the generation of isomers. The synthesis method of the present application shortens the reaction route, avoids the use of high-risk reagents, and is conducive to industrialized scale production. BRIEF DESCRIPTION OF DRAWINGS

[0018] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, for those skilled in the art, other drawings can also be obtained from these drawings without any creative effort.

[0019] Figure 1 HPLC chromatogram of the compound of formula I prepared in Example 1 of the present application.

[0020] Figure 2 HPLC chromatogram of the compound of formula I prepared in Example 2 of the present application.

[0021] Figure 3 HPLC chromatogram of the compound of formula I prepared in Example 3 of the present application. Figure 4 HPLC chromatogram of the compound of formula I prepared in Example 4 of the present application. Figure 5 HPLC chromatogram of the compound of formula I prepared in Example 5 of the present application. DETAILED DESCRIPTION

[0022] In order to make the person skilled in the art better understand the technical solutions in the present application, the technical solutions in the embodiments of the present application will be described clearly and completely below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by the person skilled in the art without creative work should belong to the protection scope of the present application. EMBODIMENT

[0023] A method for synthesizing Iclepertin, the reaction route is as follows: ; comprising the following steps: (1) 110 ml dimethyl sulfoxide was added to a 250 ml three-necked flask, and p-fluoroiodobenzene 22.2 g (0.1 mol) was added into the dimethyl sulfoxide, then sodium methylsulfinate 15.3 g (0.15 mol), L-proline 17.3 g (0.15 mol) and sodium hydroxide 4.4 g (0.11 mol) were added, and the reaction was carried out under nitrogen protection at 90 °C; 10 hours of TLC detection showed that the reaction of p-fluoroiodobenzene was complete; then the reaction system was cooled, 110 ml water and 150 ml ethyl acetate were added, and the extraction was carried out, the organic phase was washed twice with 100 ml x 2 saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain p-fluoromethylsulfonylbenzene 14.46 g, with a yield of 83.0 % and a purity of 97.28 % (area normalization method) detected by HPLC.

[0024] (2) Into a 250 ml three-necked flask, 70 ml dimethyl sulfoxide was added, 1,1,1-trifluoroisopropanol 10.95 g (96 mmol) was added into the dimethyl sulfoxide, then sodium hydroxide 3.52 g (88 mmol) was added and stirred uniformly, p-fluoromethylsulfonylbenzene 13.94 g (80 mmol) was added, heated to 75 ℃~80 ℃ and reacted; 3 hours of TLC detection showed that the reaction of p-fluoromethylsulfonylbenzene was complete; cooled to 25 ℃, 70 ml water was added to crystallize, after the dropwise addition was completed, stirred for 15 minutes, filtered and dried to obtain 19.80 g of the compound of formula II, with a yield of 88.2 %, and an HPLC detection purity of 98.33 % (area normalization method).

[0025] (3) Into a 250 ml three-necked flask, 100 ml dichloromethane was added, 19.64 g (70 mmol) of the compound of formula IV was added and stirred to dissolve, and cooled to -10 ℃; another 7.68 g (25.9 mmol) of triphosgene was dissolved in 35 ml dichloromethane; then the dichloromethane solution of triphosgene was added dropwise into the reaction system, 7.20 g (91 mmol) of pyridine was added dropwise, and the temperature of the reaction system was controlled to be ≤0 ℃; after the dropwise addition was completed, the temperature of the reaction system was -2 ℃, then the temperature was increased to 25 ℃~30 ℃ and reacted; 1 hour of TLC detection showed that the reaction of the compound of formula IV was complete; filtered; a dichloromethane filtrate containing the compound of formula III was obtained, and the filtrate was directly used for subsequent reaction; the moisture content of the filtrate was 0.07 %.

[0026] (4) Into a 250 ml three-necked flask, 85 ml dichloromethane was added, then 20.66 g (77 mmol) of the compound of formula II was added and stirred to dissolve, and the reaction system was replaced with nitrogen for 3 times; then 12.71 g (84 mmol) of anhydrous aluminum chloride was added into the solution under nitrogen protection, stirred for 15 minutes, then the dichloromethane solution containing the compound of formula III prepared in step (3) was added, and the whole reaction process was protected by nitrogen; then heated to 35 ℃~40 ℃ and reacted; 3.5 hours of TLC detection showed that the reaction of the compound of formula III was complete; the reaction liquid was cooled to 20 ℃, 10 ml ice water was added to quench the reaction; the reaction liquid was filtered, 100 ml×3 water was added to wash for 3 times, the organic phase was dried with anhydrous sodium sulfate and filtered, the organic phase was concentrated by using a rotary evaporator, when 180 ml of solvent was evaporated, the concentration was stopped, solid was precipitated in the reaction system, 45 ml n-heptane was added dropwise under stirring for 30 minutes, filtered, and a mixed solution of n-heptane:dichloromethane=1:1 was used to wash the filter cake, and dried to obtain 30.60 g of the compound of formula I, with a yield of 85.3 %, and an HPLC detection purity of 99.86 % (area normalization method). Example

[0027] Step (1), Step (2) and Step (3) are the same as Example 1. (4) 85 ml of dichloromethane was added to a 250 ml three-necked flask, then 20.66 g (77 mmol) of the compound of formula II was stirred and dissolved, and the reaction system was replaced with nitrogen for 3 times; then 15.93 g (84 mmol) of titanium tetrachloride was added dropwise to the solution under nitrogen protection, and stirred for 15 minutes, then the dichloromethane solution containing the compound of formula III prepared in Step (3) was added, and the whole reaction was protected by nitrogen; then heated to 35 ℃~ 40 ℃ for reaction; 3 hours of TLC detection showed that the reaction of the compound of formula III was complete; the reaction liquid was cooled to 20 ℃, and 10 ml of ice water was added dropwise to quench the reaction; the reaction liquid was filtered, 100 ml of water was added to the filtrate for washing 3 times, the organic phase was dried with anhydrous sodium sulfate, then filtered, and the organic phase was concentrated by using a rotary evaporator; when 180 ml of solvent was evaporated, the concentration was stopped, solid was precipitated in the reaction system, 45 ml of n-heptane was added dropwise under stirring, and stirred for 30 minutes, then filtered, and the filter cake was washed with a mixed solution of n-heptane and dichloromethane in a volume ratio of 1:1, and dried to obtain 28.56 g of the compound of formula I, with a yield of 79.6 %, and a purity of 99.84 % (area normalization method) detected by HPLC. Example

[0028] Step (1), Step (2) and Step (3) are the same as Example 1. (4) 85 ml of dichloromethane was added to a 250 ml three-necked flask, then 20.66 g (77 mmol) of the compound of formula II was stirred and dissolved, and the reaction system was replaced with nitrogen for 3 times; then 15.93 g (84 mmol) of titanium tetrachloride was added dropwise to the solution under nitrogen protection, and stirred for 15 minutes, then the dichloromethane solution containing the compound of formula III prepared in Step (3) was added, and the whole reaction was protected by nitrogen; then heated to 35 ℃~ 40 ℃ for reaction; 3 hours of TLC detection showed that the reaction of the compound of formula III was complete; the reaction liquid was cooled to 20 ℃, and 10 ml of ice water was added dropwise to quench the reaction; the reaction liquid was filtered, 100 ml of water was added to the filtrate for washing 3 times, the organic phase was dried with anhydrous sodium sulfate, then filtered, and the organic phase was concentrated by using a rotary evaporator; when 180 ml of solvent was evaporated, the concentration was stopped, solid was precipitated in the reaction system, 45 ml of n-heptane was added dropwise under stirring, and stirred for 30 minutes, then filtered, and the filter cake was washed with a mixed solution of n-heptane and dichloromethane in a volume ratio of 1:1, and dried to obtain 28.56 g of the compound of formula I, with a yield of 79.6 %, and a purity of 99.84 % (area normalization method) detected by HPLC. Example

[0029] A method for synthesizing Iclepertin (pilot test) comprises the following steps: (1) Prepare 5 L four-necked bottle, add 2.2 L dimethyl sulfoxide, then add p- fluorine iodobenzene 444.0 g (2.0 mol) into dimethyl sulfoxide, then add sodium methylsulfinyl 306.3 g (3.0 mol), L-proline 345.4 g (3.0 mol) and sodium hydroxide 88.0 g (2.2 mol), react under nitrogen protection at 90 ℃; 11 hours of TLC detection of p-fluoroiodobenzene reaction is complete; then cool down, add 2.2 L water and 3 L ethyl acetate to the reaction system, extract, wash the organic phase with 2 L x 2 saturated brine twice, dry with anhydrous sodium sulfate, concentrate to get p-fluoromethylsulfonylbenzene 294.7 g, yield 84.6 %, HPLC detection purity is 96.96% (area normalization method).

[0030] (2) Add 1.4 L dimethyl sulfoxide to a 3 L three-necked bottle, take (R)-1,1,1-trifluoro-2-propanol 225.8 g (1.98 mol) and add it to dimethyl sulfoxide, then add sodium hydroxide 72.8 g (1.82 mol) and stir uniformly, add p-fluoromethylsulfonylbenzene 287.4 g (1.65 mol), heat to 75 ℃~80 ℃ and react; 3 hours of TLC detection of p-fluoromethylsulfonylbenzene reaction is complete; cool down to 25 ℃, add 1.4 L water to crystallize, after dropwise addition, stir for 30 minutes, filter and dry to get compound II 410.3 g, yield 92.7 %, HPLC detection purity is 98.37% (area normalization method).

[0031] (3) Add dichloromethane 1.5 L to a 5 L four-necked bottle, add compound IV 283.6 g (1.30 mol) and stir to dissolve, cool down to -10 ℃; take another 700 ml dichloromethane solution of triphosgene 142.7 g (0.481 mol); then add the dichloromethane solution of triphosgene to the reaction system; then add pyridine 133.7 g (1.69 mol), control the temperature of the reaction system ≤0 ℃; after dropwise addition, the temperature of the reaction system is -3 ℃, then warm up to 25 ℃~30 ℃ and react; 1 hour of TLC detection of compound IV reaction is complete; filter; get dichloromethane filtrate containing compound III, the filtrate is directly used for subsequent reaction, the moisture content of the filtrate is 0.09 %.

[0032] (4) Into a 10 L four-necked flask, 1.9 L of dichloromethane was added, then 383.6 g (1.43 mol) of the compound of formula II was stirred and dissolved, and the reaction system was replaced with nitrogen for 3 times; then 236.1 g (1.56 mol) of anhydrous aluminum chloride was added to the solution under nitrogen protection, and stirred for 15 minutes, then the dichloromethane solution containing the compound of formula III prepared in step (3) was added, and the whole reaction was protected by nitrogen; then heated to 35 ℃-40 ℃ for reaction; 5 hours of TLC detection showed that the reaction of the compound of formula III was complete; the reaction liquid was cooled to 20 ℃; the reaction liquid was filtered, 1.9 L of water was added to the filtrate for washing three times, the organic phase was dried with anhydrous sodium sulfate, then filtered, and the organic phase was concentrated by using a rotary evaporator; when 3.3 L of solvent was evaporated, the concentration was stopped, solid was precipitated in the reaction system, 1 L of n-heptane was added dropwise under stirring, and stirred for 1 hour, then filtered, and the filter cake was eluted with a mixed solution of n-heptane and dichloromethane in a volume ratio of 1:1, and dried to obtain 577.5 g of the compound of formula I, with a yield of 86.7 %, and a purity of 99.91 % (area normalization method) detected by HPLC. Example

[0033] A method for synthesizing Iclepertin (production batch) comprising the following steps: (1) A 20 L glass kettle was prepared, 4.4 L of dimethyl sulfoxide was added, then 888.0 g (4.0 mol) of p-fluoroiodobenzene was added to the dimethyl sulfoxide, then 612.6 g (6.0 mol) of sodium methylsulfinate, 690.8 g (6.0 mol) of L-proline and 176.0 g (4.4 mol) of sodium hydroxide were added, and the reaction was carried out under nitrogen protection at 90 ℃; 14 hours of TLC detection showed that the reaction of p-fluoroiodobenzene was complete; then cooled, 4.4 L of water and 6 L of ethyl acetate were added to the reaction system for extraction, the organic phase was washed with 4 L of saturated brine twice, dried with anhydrous sodium sulfate, concentrated to obtain 588.4 g of p-fluoromethylsulfonylbenzene, with a yield of 84.4 %, and a purity of 96.85 % (area normalization method) detected by HPLC.

[0034] (2) Into a 10 L four-necked flask, 2.9 L of dimethyl sulfoxide was added, (R)-1,1,1-trifluoro-2-propanol 451.6 g (3.96 mol) was added into the dimethyl sulfoxide, then sodium hydroxide 72.8 g (1.82 mol) was added and stirred uniformly, p-fluoromethylsulfonylbenzene 574.8 g (3.30 mol) was added, and heated to 75 ℃-80 ℃ for reaction; 4 hours of TLC detection showed that the reaction of p-fluoromethylsulfonylbenzene was complete; cooled to 25 ℃, 2.9 L of water was added for crystallization, after dropwise addition was completed, stirred for 30 minutes, filtered, and dried to obtain 821.1 g of the compound of formula II, with a yield of 92.8 %, and a purity of 98.31 % (area normalization method) detected by HPLC.

[0035] (3) Into a 10 L four-necked flask, 3 L of dichloromethane was added, the compound of formula IV 567.3 g (2.60 mol) was added and stirred to dissolve, and cooled to -10 ℃; another 285.4 g (0.962 mol) of triphosgene was added and dissolved in 1.4 L of dichloromethane; then the dichloromethane solution of triphosgene was added dropwise into the reaction system; then 267.4 g (3.38 mol) of pyridine was added, and the temperature of the reaction system was controlled to be ≤0 ℃; after dropwise addition was completed, the temperature of the reaction system was -1 ℃, then the temperature was increased to 25 ℃-30 ℃ for reaction; 1 hour of TLC detection showed that the reaction of the compound of formula IV was complete; filtered; a dichloromethane filtrate containing the compound of formula III was obtained, and the filtrate was directly used for subsequent reaction, and the moisture content of the filtrate was 0.09 %.

[0036] (4) Into a 10 L four-necked flask, 3.8 L of dichloromethane was added, then the compound of formula II 767.2 g (2.86 mol) was added and stirred to dissolve, and the reaction system was replaced with nitrogen for 3 times; then anhydrous aluminum chloride 472.2 g (3.12 mol) was added into the solution under nitrogen protection, stirred for 30 minutes, then the dichloromethane solution containing the compound of formula III prepared in step (3) was added, and the whole reaction process was protected by nitrogen; then heated to 35 ℃-40 ℃ for reaction; 5.5 hours of TLC detection showed that the reaction of the compound of formula III was complete; the reaction liquid was cooled to 20 ℃; the reaction liquid was filtered, 3.8 L of water was added and washed for 3 times, the organic phase was dried with anhydrous sodium sulfate, then filtered, and the organic phase was concentrated by using a rotary evaporator; when 6.5 L of solvent was evaporated, the concentration was stopped, solid was precipitated in the reaction system, 2 L of n-heptane was added dropwise under stirring for 1 hour, then filtered, and a mixed solution of n-heptane:dichloromethane=1:1 was used to wash the filter cake, and dried to obtain 1160.8 g of the compound of formula I, with a yield of 87.1 %, and a purity of 99.90 % (area normalization method) detected by HPLC.

[0037] Although the present application has been described in detail with reference to the preferred embodiments, it should be understood that the application is not limited to those preferred embodiments. Various modifications and equivalents can be made by those skilled in the art without departing from the spirit and scope of the application. Any and all modifications and equivalents are intended to be included within the scope of the present application.

Claims

1. A method of synthesizing Iclepertin, characterized in that, The reaction route is as follows: ； The method comprises the following steps: (1) sulfonation of p-fluoroiodobenzene and sodium methanesulfinate to obtain p-fluoromethylsulfonylbenzene; (2) reaction of p-fluoromethylsulfonylbenzene and (R)-1,1,1-trifluoro-2-propanol to obtain the compound of formula II; (3) reaction of the compound of formula IV and triphosgene to obtain the compound of formula III; (4) Friedel-Crafts acylation of the compound of formula II and the compound of formula III to obtain the compound of formula I.

2. A process for the synthesis of Iclepertin according to claim 1, characterized in that, In step (1), p-fluoroiodobenzene is added to DMSO (dimethyl sulfoxide), and then sodium methanesulfinate, L-proline and sodium hydroxide are added, and the reaction is carried out at 80-90 DEG C under nitrogen protection; after the reaction of p-fluoroiodobenzene is completed, the temperature is lowered, water and ethyl acetate are added for extraction, and the organic phase is washed with saturated brine, dried and concentrated to obtain p-fluoromethylsulfonylbenzene.

3. A process for the synthesis of Iclepertin according to claim 2, characterized in that, In step (1), the molar ratio of p-fluoroiodobenzene, sodium methanesulfinate, L-proline and sodium hydroxide is 1: (1.4-1.6): (1-1.1): (1-1.1).

4. A process for the synthesis of Iclepertin according to claim 1, characterized in that, In step (2), 1,1,1-trifluoroisopropanol is added to DMSO (dimethyl sulfoxide), sodium hydroxide is added and stirred until uniform, and then p-fluoromethylsulfonylbenzene is added, and the reaction is carried out at 70-80 DEG C; after the reaction of p-fluoromethylsulfonylbenzene is completed, the temperature is lowered, water is added for crystallization, and the compound of formula II is obtained by filtration and drying.

5. A process for the synthesis of Iclepertin according to claim 4, characterized in that, In step (2), the molar ratio of p-fluoromethylsulfonylbenzene and 1,1,1-trifluoroisopropanol is 1:1.1-1.

3.

6. A process for the synthesis of Iclepertin as claimed in claim 1 wherein, In step (3), the compound of formula IV is dissolved in dichloromethane and cooled to -10 ℃ to -5 ℃; triphosgene is dissolved in dichloromethane; the dichloromethane solution of triphosgene is added to the reaction system, and then pyridine is added dropwise, and the temperature of the reaction system is controlled to be ≤0 ℃; after the dropwise addition is completed, the reaction system is warmed to 20-30 DEG C and reacted; after the reaction of the compound of formula IV is completed, the reaction system is filtered; The reaction liquid containing the compound of formula III is obtained.

7. A process for the synthesis of Iclepertin according to claim 6, characterized in that, The water content of the reaction liquid obtained in step (3) is <0.10 %.

8. A process for the synthesis of Iclepertin as claimed in claim 6 wherein, In step (3), the molar ratio of the compound of formula IV, triphosgene and pyridine is 1: (0.35-0.38): (1.1-1.5).

9. A process for the synthesis of Iclepertin according to claim 1, characterized in that, In step (4), the compound of formula II is dissolved in dichloromethane, and then a Lewis acid is added, and the reaction is carried out at 35-40 DEG C after the addition of the reaction liquid containing the compound of formula III; after the reaction of the compound of formula III is completed, the temperature is lowered to 20-25 DEG C, and water or ammonia is added dropwise to quench the reaction; the reaction liquid is washed with water after filtration, and the organic phase is concentrated, and then n-heptane is added for crystallization, and the compound of formula I is obtained by filtration and drying; the Lewis acid is anhydrous aluminum chloride, titanium tetrachloride or boron trifluoride ether solution.

10. A process for the synthesis of Iclepertin according to claim 9, characterized in that, In step (4), the amount of the compound of formula II is 1.0-1.1 mol / mol based on the amount of the compound of formula IV; the amount of anhydrous aluminum chloride is 1.2-1.4 mol / mol based on the amount of the compound of formula IV.

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