High-yield synthesis method of elplerenone

Abstract

The invention discloses a high-yield synthesis method of elxalidone, and relates to the technical field of drug synthesis. 1-chloro-2-(trifluoromethyl) benzene and 4-(methylsulfonyl) aniline are used as initial raw materials; according to the present invention, the isaprorenone is obtained through the Grignard reaction, the addition reaction, the bromination reaction, the condensation reaction, the substitution reaction, the cyclization reaction, the reduction reaction, the substitution reaction and the chiral resolution, and the synthesis method has advantages of low raw material cost, short route, high yield and the like, and can be used for the quantitative production of the isaprorenone.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a method for synthesizing esaxerenone with high yield. Background Art

[0002] Esaxerenone is a third-generation non-steroidal MRA (mineralocorticoid receptor antagonist). Esaxerenone has been shown to be more effective than spironolactone and eplerenone in inhibiting MR (mineralocorticoid receptor)-induced transcription, and is also much more selective for MR. Esaxerenone was approved for the treatment of hypertension in Japan in January 2019. Due to its high membrane permeability, esaxerenone can be rapidly absorbed after oral administration and has a high bioavailability.

[0003] Currently, there have been many literature reports on the synthesis method of esaxerenone. The most important one is the synthesis method disclosed by Daiichi Sankyo (JP6240164) in Japan. This method uses inexpensive 2-chloro-benzotrifluoride as the starting material and synthesizes esaxerenone API through steps such as condensation, ring closure, and resolution. However, this method has disadvantages such as a long route and low resolution yield.

[0004] Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for synthesizing esaxerenone, using 1-chloro-2-(trifluoromethyl)benzene and 4-(methylsulfonyl)aniline as starting materials, and improving the yield of esaxerenone while reducing the preparation cost, improving the environmental friendliness and safety of the process.

[0006] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0007] The object of the present invention is to provide a method for synthesizing esaxerenone, comprising the following steps:

[0008] S1. 1-chloro-2-(trifluoromethyl)benzene reacts with magnesium to form a Grignard reagent, and the Grignard reagent reacts with propionic anhydride through an addition reaction to form intermediate 1;

[0009] S2. Intermediate 1 reacts with a brominating reagent through a bromination reaction to form intermediate 2;

[0010] S3. 4-(methylsulfonyl)aniline reacts with cyanoacetic acid through a condensation reaction to form intermediate 3;

[0011] S4. Intermediate 2 reacts with intermediate 3 through a substitution reaction to form intermediate 4;

[0012] S5. Intermediate 4 reacts with thionyl chloride through a cyclization reaction to form intermediate 5;

[0013] S6. Intermediate 5 is converted to Intermediate 6 through a reduction reaction;

[0014] S7. Intermediate 6 reacts with a hydroxyethyl introducing agent through a substitution reaction to form Intermediate 7;

[0015] S8. Intermediate 7 is subjected to chiral resolution to obtain isatidone.

[0016] The synthetic route is as follows:

[0017]

[0018] In step S1, the molar ratio of 1-chloro-2-(trifluoromethyl)benzene to magnesium and propionic anhydride is 1:(1 - 1.1):(1 - 1.1). 1-chloro-2-(trifluoromethyl)benzene first reacts with magnesium to form a Grignard reagent, and the Grignard reagent then reacts with propionic anhydride to form Intermediate 1.

[0019] In step S2, the brominating reagent includes but is not limited to any one of liquid bromine (Br2), N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBH), and pyridinium tribromide (PyHBr3). Further, the molar ratio of Intermediate 1 to the brominating reagent is 1:(1.05 - 1.2).

[0020] In step S3, the condensation reaction is carried out under the action of a condensing agent and a catalyst. Among them, the condensing agent includes but is not limited to one or more of 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDCI), and N,N-carbonyldiimidazole (CDI); the catalyst includes but is not limited to one or more of triethanolamine (TEA), DMAP (DMAP), and N,N-diisopropylethylamine (DIPEA). Further, the molar ratio of 4-(methylsulfonyl)aniline to cyanoacetic acid, the condensing agent, and the catalyst is 1:(1 - 1.1):(1 - 1.1):(0.1 - 0.5).

[0021] In step S4, the substitution reaction is carried out under the action of an acid-binding agent. Specifically, the acid-binding agent includes but is not limited to one or more of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide. Using a base as the acid-binding agent can accelerate the reaction rate. Further, the molar ratio of Intermediate 2 to Intermediate 3 and the acid-binding agent is 1:(1 - 1.2):(1 - 1.2).

[0022] In step S5, the molar ratio of Intermediate 4 to thionyl chloride is 1:(1.2 - 1.5). The carbonyl and cyano groups form a pyrrole ring through a nucleophilic addition reaction, and concentrated sulfuric acid can be used as a dehydrating agent to accelerate the reaction.

[0023] In step S6, the reduction reaction uses one or more of Pd / C, palladium acetate, and Raney nickel as the catalyst, but the types of catalysts are not limited to this, and any catalyst known in the art that can be used for reductive dechlorination can be employed.

[0024] In step S7, the hydroxyethyl introducing agent includes but is not limited to any one of ethylene carbonate, diethyl carbonate, bromoethanol, and chloroethanol. Further, the molar ratio of the intermediate 6 to the hydroxyethyl introducing agent is 1:(1.2 - 1.5).

[0025] In step S8, the chiral resolution uses any one of quinine, binaphthylamine, and cinchonine as the resolving agent, but the types of resolving agents are not limited to this. Further, the molar ratio of the intermediate 7 to the resolving agent is 1:(0.1 - 0.5).

[0026] The beneficial effects of the present invention are as follows: The present invention uses 1-chloro-2-(trifluoromethyl)benzene and 4-(methylsulfonyl)aniline as starting materials, and obtains isatidone through Grignard reaction, addition reaction, bromination reaction, condensation reaction, substitution reaction, cyclization reaction, reduction reaction, substitution reaction, and chiral resolution. This synthesis method has the advantages of low raw material cost, short route, and high yield, and can be applied to the quantitative production of isatidone. Description of the Drawings

[0027] Figure 1 It is the mass spectrum of isatidone synthesized by the present invention. Detailed Embodiments

[0028] In order to make the technical means, creative features, achieved purposes, and functions of the present invention easy to understand, the present invention will be further described below in conjunction with specific embodiments and diagrams.

[0029] Example 1

[0030] Synthesis of Intermediate 1:

[0031] Under nitrogen protection, magnesium (13.2 g, 0.55 mol) was dissolved in 300 mL of tetrahydrofuran (THF), then 5.5 mL of a THF solution of ethylmagnesium bromide (1 mol / L) was added, and then a solution of 1-chloro-2-(trifluoromethyl)benzene (100 g, 0.55 mol) dissolved in 300 mL of THF was added dropwise. After the addition was completed, the reaction was stirred for 1 h to obtain a Grignard reagent.

[0032] Propionic anhydride (71.6 g, 0.55 mol) was added to 200 mL of THF, and then the above Grignard reagent was slowly added dropwise. After the addition was complete, the reaction mixture was stirred for 2 h. After the reaction was completed, 300 mL of saturated ammonium chloride solution was added to the reaction solution, stirred, extracted with ethyl acetate, the organic phase was concentrated to remove the solvent, and rectified to obtain a transparent oily substance, namely Intermediate 1. The yield was 92.36% and the purity was 95.48%.

[0033] Synthesis of Intermediate 2:

[0034] Intermediate 1 (100 g, 0.495 mol) was dissolved in 300 mL of methyl tert-butyl ether (MTBE), 33% hydrobromic acid acetic acid solution (1.19 g, 4.95 mmol of hydrobromic acid) was added, and then Br2 (83 g, 0.52 mol) dissolved in 200 mL of MTBE was slowly added dropwise at -5 to 0 °C. After the addition was complete, the reaction mixture was stirred for 1 h. After the reaction was completed, 300 mL of saturated sodium sulfite solution was added to the reaction solution, stirred, separated, the organic phase was washed with water and dried, MTBE was replaced with 500 mL of n-heptane, cooled to -5 to 0 °C, stirred and crystallized for 2 h, filtered, the filter residue was washed with n-heptane, and dried to obtain a white solid, namely Intermediate 2. The yield was 88.73% and the purity was 98.04%.

[0035] Synthesis of Intermediate 3:

[0036] Cyanoacetic acid (54.6 g, 0.642 mol) was dissolved in 300 mL of dichloromethane, then DCC (120.5 g, 0.584 mol) and DMAP (7.1 g, 58.4 mmol) were added, and then 4-(methylsulfonyl)aniline (100 g, 0.584 mol) dissolved in 300 mL of dichloromethane was added dropwise. After the addition was complete, the reaction mixture was stirred for 5 h. After the reaction was completed, the reaction solution was cooled to 0 °C, filtered, the filtrate was washed with water and concentrated, recrystallized with ethyl acetate, and dried to obtain Intermediate 3. The yield was 66.75% and the purity was 92.75%.

[0037] Synthesis of Intermediate 4:

[0038] Intermediate 3 (81.4 g, 0.342 mol) was dissolved in 240 mL of acetone, then potassium carbonate (47.3 g, 0.342 mol) was added, the temperature was raised to 50 °C and stirred for 2 h, cooled to 30 °C, and then Intermediate 2 (80 g, 0.285 mol) dissolved in 240 mL of acetone was added dropwise. After the addition was complete, the reaction mixture was stirred for 20 h. After the reaction was completed, the reaction solution was filtered, the filter residue was washed with acetone, the filtrate was concentrated to dryness, then 300 mL of ethyl acetate was added to dissolve, washed with water, the organic phase was taken, and dried with anhydrous magnesium sulfate to obtain an ethyl acetate solution of Intermediate 4 with a purity of 96.42%.

[0039] Synthesis of Intermediate 5:

[0040] Cool the ethyl acetate solution of Intermediate 4 (300 mL, 0.285 mol) to -5 to 0 °C, then add thionyl chloride (40.7 g, 0.342 mol) and concentrated sulfuric acid (13.9 g, 0.142 mol), and slowly add dropwise an ethyl acetate solution of 356 mL of 4 M hydrochloric acid. After the addition is complete, stir and react at 30 °C for 20 h. After the reaction is completed, wash the reaction solution successively with water, saturated potassium bicarbonate solution, and water. Concentrate the organic phase to dryness, add toluene, heat to 80 °C to dissolve, slowly cool to 0 °C, stir for 2 h, perform recrystallization, filter, and dry to obtain a light gray solid, which is Intermediate 5. The yield is 64.12% and the purity is 98.33%.

[0041] Synthesis of Intermediate 6:

[0042] Dissolve Intermediate 5 (80 g, 0.175 mol) in 400 mL of ethanol, then add triethylamine (21.2 g, 0.210 mol) and 5% Pd / C (4 g). Replace the air with hydrogen, introduce hydrogen, heat to 45 °C, and seal the reaction for 24 h. After the reaction is completed, filter the reaction solution, wash the filter cake with ethanol, concentrate the filtrate to dryness, add ethyl acetate to dissolve, wash with water, separate the layers, dry the organic phase with anhydrous magnesium sulfate, concentrate to remove the solvent to obtain Intermediate 6. The yield is 95.17% and the purity is 97.16%.

[0043] Synthesis of Intermediate 7:

[0044] Dissolve Intermediate 6 (70 g, 0.166 mol) in 350 mL of N,N-dimethylacetamide (DMAC), then add ethylene carbonate (17.5 g, 0.199 mol) and DMAP (2.03 g, 16.6 mmol), heat to 120 °C and react for 20 h. After the reaction is completed, cool the reaction solution to 25 °C, add 350 mL of ethyl acetate and 350 mL of water, stir, separate the layers, wash the organic phase with water, dry with anhydrous magnesium sulfate, concentrate to dryness, add isopropanol, heat to 80 °C to dissolve, slowly cool, crystallize at 0 to 5 °C for 2 h, wash with isopropanol, and dry to obtain Intermediate 7. The yield is 83.25% and the purity is 96.41%.

[0045] Synthesis of Esalithone:

[0046] Add quinine (20.86 g, 64.31 mmol) to 300 mL of ethyl acetate, then add 6 mL of water and 30 mL of DMAC, heat to 65 °C, and then slowly add dropwise an ethyl acetate solution of Intermediate 7 (60 g, 128.62 mmol). After the addition is complete, cool to 0 to 5 °C and stir for 1 h to precipitate a solid. Filter, pre-cool the filter cake to 0 °C, wash with ethyl acetate, and dry to obtain the quinine salt of esalithone.

[0047] Add esalione quinine salt to 300 mL of ethyl acetate, dropwise add 150 mL of 2N hydrochloric acid. After the addition is complete, stir for 0.5 h. Wash the organic phase with 150 mL of water twice. Concentrate the organic phase to 80 mL, cool to -5 to 0 °C and stir for 2 h. Solids will precipitate. Filter, wash the filter cake with water and dry to obtain esalione. The yield is 42.14%, the purity is 99.41%, and the chiral purity is 98.78%.

[0048] Example 2

[0049] Synthesis of Intermediate 1:

[0050] Under nitrogen protection, dissolve magnesium (14.5 g, 0.605 mmol) in 300 mL of THF, then add 5.5 mL of a THF solution of ethylmagnesium bromide (1 mol / L), and then dropwise add a solution of 1-chloro-2-(trifluoromethyl)benzene (100 g, 0.55 mmol) dissolved in 300 mL of THF. After the addition is complete, stir and react for 1 h to obtain a Grignard reagent.

[0051] Add propionic anhydride (75.5 g, 0.58 mol) to 200 mL of THF, and then slowly dropwise add the above Grignard reagent. After the addition is complete, stir and react for 2 h. After the reaction is completed, add 300 mL of saturated ammonium chloride solution to the reaction solution, stir, extract with ethyl acetate, concentrate the organic phase to remove the solvent, and rectify to obtain a transparent oily substance, which is Intermediate 1. The yield is 93.08%, and the purity is 95.53%.

[0052] Synthesis of Intermediate 2:

[0053] Dissolve Intermediate 1 (100 g, 0.495 mol) in 300 mL of DMF, and then slowly dropwise add NBS (92.44 g, 0.519 mol) dissolved in 200 mL of DMF at -5 to 0 °C. After the addition is complete, stir and react for 3 h. After the reaction is completed, add 500 mL of water and 500 mL of ethyl acetate to the reaction solution, stir, separate the layers, wash the organic phase with saturated brine and concentrate to dryness, dissolve it in 500 mL of n-heptane by heating, cool to -5 to 0 °C, stir and crystallize for 2 h, filter, wash the filter residue with n-heptane, and dry to obtain a white solid, which is Intermediate 2. The yield is 90.14%, and the purity is 98.33%.

[0054] Synthesis of Intermediate 3:

[0055] Dissolve cyanoacetic acid (49.7 g, 0.584 mol) in 300 mL of dichloromethane, then add DCC (132.5 g, 0.642 mol) and DMAP (35.7 g, 0.292 mol), and then dropwise add 4-(methylsulfonyl)aniline (100 g, 0.584 mol) dissolved in 300 mL of dichloromethane. After the addition is complete, stir and react for 5 h. After the reaction is completed, cool the reaction solution to 0 °C, filter, wash the filtrate with water and concentrate it, recrystallize with ethyl acetate, and dry it to obtain Intermediate 3. The yield is 71.42% and the purity is 93.86%.

[0056] Synthesis of Intermediate 4:

[0057] Dissolve Intermediate 3 (81.4 g, 0.342 mol) in 240 mL of acetone, then add potassium carbonate (39.4 g, 0.285 mol), heat to 50 °C and stir for 2 h. After cooling to 30 °C, dropwise add Intermediate 2 (80 g, 0.285 mol) dissolved in 240 mL of acetone. After the addition is complete, stir and react for 20 h. After the reaction is completed, filter the reaction solution, wash the filter residue with acetone, concentrate the filtrate to dryness, add 300 mL of ethyl acetate to dissolve it, wash it with water, take the organic phase, and dry it with anhydrous magnesium sulfate to obtain an ethyl acetate solution of Intermediate 4 with a purity of 96.83%.

[0058] Synthesis of Intermediate 5:

[0059] Cool the ethyl acetate solution of Intermediate 4 (300 mL, 0.285 mol) to -5 to 0 °C, then add thionyl chloride (40.7 g, 0.342 mol) and concentrated sulfuric acid (13.9 g, 0.142 mol), and dropwise add an ethyl acetate solution of 356 mL of 4 M hydrochloric acid. After the addition is complete, stir and react at 30 °C for 20 h. After the reaction is completed, wash the reaction solution successively with water, saturated potassium bicarbonate solution, and water. Concentrate the organic phase to dryness, add toluene, heat to 80 °C to dissolve it, slowly cool to 0 °C, stir for 2 h, recrystallize, filter, and dry to obtain a light gray solid, which is Intermediate 5. The yield is 63.84% and the purity is 98.25%.

[0060] Synthesis of Intermediate 6:

[0061] Dissolve Intermediate 5 (80 g, 0.175 mol) in 400 mL of ethanol, then add triethylamine (17.7 g, 0.175 mol) and 5% Pd / C (4 g), displace the air with hydrogen, introduce hydrogen, heat to 45 °C, and seal the reaction for 24 h. After the reaction is completed, filter the reaction solution, wash the filter cake with ethanol, concentrate the filtrate to dryness, add ethyl acetate to dissolve it, wash it with water, separate the layers, dry the organic phase with anhydrous magnesium sulfate, and concentrate to remove the solvent to obtain Intermediate 6. The yield is 94.38% and the purity is 97.25%.

[0062] Synthesis of Intermediate 7:

[0063] Dissolve Intermediate 6 (70 g, 0.166 mol) in 350 mL of DMAC, then add ethylene carbonate (21.9 g, 0.249 mol) and DMAP (2.03 g, 16.6 mmol), and raise the temperature to 120 °C for reaction for 20 h. After the reaction is completed, cool the reaction solution to 25 °C, add 350 mL of ethyl acetate and 350 mL of water, stir, separate the layers, wash the organic phase with water, dry it with anhydrous magnesium sulfate, concentrate to dryness, add isopropanol, raise the temperature to 80 °C to dissolve, cool slowly, crystallize at 0 - 5 °C for 2 h, wash with isopropanol, and dry to obtain Intermediate 7. The yield is 84.72% and the purity is 96.85%.

[0064] Synthesis of Ailsartan:

[0065] Add cinchonine (3.79 g, 12.86 mmol) to 300 mL of ethyl acetate, then add 10 mL of water and 30 mL of DMAC, raise the temperature to 65 °C, and then dropwise add a solution of Intermediate 7 (60 g, 128.62 mmol) in ethyl acetate. After the addition is completed, cool to 0 - 5 °C and stir for 2 h to precipitate a solid. Filter, pre-cool the filter cake to 0 °C and wash with ethyl acetate, then dry to obtain the cinchonine salt of ailsartan.

[0066] Add the cinchonine salt of ailsartan to 300 mL of ethyl acetate, dropwise add 150 mL of 2N hydrochloric acid, stir for 1 h after the addition is completed, wash the organic phase with 150 mL of water twice, concentrate the organic phase to 80 mL, cool to -5 - 0 °C and stir for 2 h to precipitate a solid. Filter, wash the filter cake with water and dry to obtain ailsartan. The yield is 34.58%, the purity is 99.21%, and the chiral purity is 97.83%.

[0067] Example 3

[0068] Synthesis of Intermediate 1:

[0069] Under nitrogen protection, dissolve magnesium (13.9 g, 0.58 mmol) in 300 mL of THF, then add 5.5 mL of a THF solution of ethylmagnesium bromide (1 mol / L), and then dropwise add a solution of 1-chloro-2-(trifluoromethyl)benzene (100 g, 0.55 mmol) dissolved in 300 mL of THF. After the addition is completed, stir and react for 1 h to obtain a Grignard reagent.

[0070] Propionic anhydride (78.7 g, 0.605 mol) was added to 200 mL of THF, and the above Grignard reagent was slowly added dropwise. After the addition was complete, the reaction mixture was stirred for 2 h. After the reaction was completed, 300 mL of saturated ammonium chloride solution was added to the reaction solution, stirred, extracted with ethyl acetate, the organic phase was concentrated to remove the solvent, and rectified to obtain a transparent oily substance, namely Intermediate 1. The yield was 93.67% and the purity was 95.62%.

[0071] Synthesis of Intermediate 2:

[0072] Intermediate 1 (100 g, 0.495 mol) was dissolved in 300 mL of MTBE, 33% hydrobromic acid acetic acid solution (1.19 g, 4.95 mmol of hydrobromic acid) was added, and then Br2 (95 g, 0.594 mol) dissolved in 200 mL of MTBE was slowly added dropwise at -5 to 0 °C. After the addition was complete, the reaction mixture was stirred for 1 h. After the reaction was completed, 300 mL of saturated sodium sulfite solution was added to the reaction solution, stirred, separated, the organic phase was washed with water and dried, MTBE was replaced with 500 mL of n-heptane, cooled to -5 to 0 °C, stirred and crystallized for 2 h, filtered, the filter residue was washed with n-heptane, and dried to obtain a white solid, namely Intermediate 2. The yield was 89.50% and the purity was 98.42%.

[0073] Synthesis of Intermediate 3:

[0074] Cyanoacetic acid (54.6 g, 0.642 mol) was dissolved in 300 mL of dichloromethane, then DCC (120.5 g, 0.584 mol) and DMAP (17.8 g, 0.146 mol) were added, and then 4-(methylsulfonyl)aniline (100 g, 0.584 mol) dissolved in 300 mL of dichloromethane was added dropwise. After the addition was complete, the reaction mixture was stirred for 5 h. After the reaction was completed, the reaction solution was cooled to 0 °C, filtered, the filtrate was washed with water and concentrated, recrystallized with ethyl acetate, and dried to obtain Intermediate 3. The yield was 69.28% and the purity was 93.04%.

[0075] Synthesis of Intermediate 4:

[0076] Intermediate 3 (81.4 g, 0.342 mol) was dissolved in 240 mL of acetone, then sodium carbonate (36.2 g, 0.342 mol) was added, the temperature was raised to 50 °C and stirred for 2 h, cooled to 30 °C, and Intermediate 2 (80 g, 0.285 mol) dissolved in 240 mL of acetone was added dropwise. After the addition was complete, the reaction mixture was stirred for 20 h. After the reaction was completed, the reaction solution was filtered, the filter residue was washed with acetone, the filtrate was concentrated to dryness, then 300 mL of ethyl acetate was added to dissolve, washed with water, the organic phase was taken, and dried with anhydrous magnesium sulfate to obtain an ethyl acetate solution of Intermediate 4 with a purity of 95.17%.

[0077] Synthesis of Intermediate 5:

[0078] Cool the ethyl acetate solution of Intermediate 4 (300 mL, 0.285 mol) to -5 to 0 °C, then add thionyl chloride (50.9 g, 0.428 mol) and concentrated sulfuric acid (13.9 g, 0.142 mol), and slowly add dropwise a 4M hydrochloric acid solution in ethyl acetate (356 mL). After the addition is complete, stir the reaction mixture at 30 °C for 20 h. After the reaction is completed, wash the reaction mixture successively with water, saturated potassium bicarbonate solution, and water. Concentrate the organic phase to dryness, add toluene, heat to 80 °C to dissolve, slowly cool to 0 °C, stir for 2 h, perform recrystallization, filter, and dry to obtain a light gray solid, which is Intermediate 5. The yield is 65.80% and the purity is 98.72%.

[0079] Synthesis of Intermediate 6:

[0080] Dissolve Intermediate 5 (80 g, 0.175 mol) in 400 mL of ethanol, then add triethylamine (17.7 g, 0.175 mol) and 5% Pd / C (5 g). Replace the air with hydrogen, introduce hydrogen, heat to 45 °C, and seal the reaction vessel for 24 h. After the reaction is completed, filter the reaction mixture, wash the filter cake with ethanol. Concentrate the filtrate to dryness, add ethyl acetate to dissolve, wash with water, separate the layers. Dry the organic phase with anhydrous magnesium sulfate, concentrate to remove the solvent to obtain Intermediate 6. The yield is 95.72% and the purity is 97.60%.

[0081] Synthesis of Intermediate 7:

[0082] Dissolve Intermediate 6 (70 g, 0.166 mol) in 350 mL of DMAC, then add bromoethanol (31.1 g, 0.249 mol) and DMAP (2.03 g, 16.6 mmol). Heat to 120 °C and react for 20 h. After the reaction is completed, cool the reaction mixture to 25 °C, add 350 mL of ethyl acetate and 350 mL of water, stir, separate the layers. Wash the organic phase with water, dry with anhydrous magnesium sulfate, concentrate to dryness, add isopropanol, heat to 80 °C to dissolve, slowly cool, crystallize at 0 - 5 °C for 2 h, wash with isopropanol, and dry to obtain Intermediate 7. The yield is 73.58% and the purity is 84.87%.

[0083] Synthesis of Esalithone:

[0084] Add binaphthylamine (18.29 g, 64.31 mmol) to 300 mL of ethyl acetate, then add 10 mL of water and 30 mL of DMAC. Heat to 65 °C, then slowly add dropwise an ethyl acetate solution of Intermediate 7 (60 g, 128.62 mmol). After the addition is complete, cool to 0 - 5 °C and stir for 2 h to precipitate a solid. Filter, pre-cool the filter cake to 0 °C, wash with ethyl acetate, and dry to obtain the esalithone binaphthylamine salt.

[0085] Add esaliclone binaphthylamine salt to 300 mL of ethyl acetate, dropwise add 150 mL of 2N hydrochloric acid. After the addition is complete, stir for 1 h. Wash the organic phase with 150 mL of water twice. Concentrate the organic phase to 80 mL, cool down to -5 to 0 °C and stir for 2 h. Solids will precipitate. Filter, wash the filter cake with water and then dry it to obtain esaliclone. The yield is 45.38%, the purity is 99.47%, and the chiral purity is 98.83%.

[0086] It can be seen from Examples 1 to 3 that the last-step chiral resolution is the key factor affecting the yield of esaliclone. After successfully synthesizing esaliclone, the present invention also starts from the catalyst, hoping to improve the yield of esaliclone by using the catalyst.

[0087] In step S8, the chiral resolution is carried out under the action of a resolving agent and a catalyst. Further, the resolving agent includes but is not limited to any one of quinine, binaphthylamine, and cinchonine; the catalyst is 1-propyl-3-methylimidazolium hexafluorophosphate. Further, the molar ratio of intermediate 7 to the resolving agent and the catalyst is 1:(0.1 - 0.5):(0.01 - 0.05). 1-propyl-3-methylimidazolium hexafluorophosphate belongs to ionic liquid and is used as a chiral resolution catalyst in the present invention, which can improve the yield and purity of esaliclone.

[0088] Example 4

[0089] The synthesis steps of intermediates 1 to 7 are the same as those in Example 1, except that 1-propyl-3-methylimidazolium hexafluorophosphate is added when synthesizing esaliclone.

[0090] Synthesis of esaliclone:

[0091] Add quinine (20.86 g, 64.31 mmol) and 1-propyl-3-methylimidazolium hexafluorophosphate (1.74 g, 6.43 mmol) to 300 mL of ethyl acetate, then add 6 mL of water and 30 mL of DMAC. Heat up to 65 °C, and then dropwise add the ethyl acetate solution of intermediate 7 (60 g, 128.62 mmol). After the addition is complete, cool down to 0 to 5 °C and stir for 1 h. Solids will precipitate. Filter, pre-cool the filter cake to 0 °C and then wash it with ethyl acetate, and dry it to obtain esaliclone quinine salt.

[0092] Add esaliclone quinine salt to 300 mL of ethyl acetate, dropwise add 150 mL of 2N hydrochloric acid. After the addition is complete, stir for 0.5 h. Wash the organic phase with 150 mL of water twice. Concentrate the organic phase to 80 mL, cool down to -5 to 0 °C and stir for 2 h. Solids will precipitate. Filter, wash the filter cake with water and then dry it to obtain esaliclone. The yield is 56.83%, the purity is 99.74%, and the chiral purity is 98.95%.

[0093] Example 5

[0094] The synthesis steps of Intermediates 1 - 7 are the same as those in Example 1, except that 1 - propyl - 3 - methylimidazolium hexafluorophosphate is added during the synthesis of isatrone.

[0095] Synthesis of isatrone:

[0096] Add cinchonine (3.79 g, 12.86 mmol) and 1 - propyl - 3 - methylimidazolium hexafluorophosphate (0.35 g, 1.29 mmol) to 300 mL of ethyl acetate, then add 10 mL of water and 30 mL of DMAC. Heat the mixture to 65 °C, and then dropwise add the ethyl acetate solution of Intermediate 7 (60 g, 128.62 mmol). After the addition is complete, cool the mixture to 0 - 5 °C and stir for 2 h. A solid precipitates. Filter the solid, pre - cool the filter cake to 0 °C, wash it with ethyl acetate, and dry it to obtain the cinchonine salt of isatrone.

[0097] Add the cinchonine salt of isatrone to 300 mL of ethyl acetate, dropwise add 150 mL of 2N hydrochloric acid. After the addition is complete, stir for 1 h. Wash the organic phase with 150 mL of water twice. Concentrate the organic phase to 80 mL, cool it to - 5 - 0 °C and stir for 2 h. A solid precipitates. Filter the solid, wash it with water and dry it to obtain isatrone. The yield is 42.76%, the purity is 99.39%, and the chiral purity is 98.52%.

[0098] Example 6

[0099] The synthesis steps of Intermediates 1 - 7 are the same as those in Example 1, except that 1 - propyl - 3 - methylimidazolium hexafluorophosphate is added during the synthesis of isatrone.

[0100] Synthesis of isatrone:

[0101] Add binaphthylamine (18.29 g, 64.31 mmol) and 1 - propyl - 3 - methylimidazolium hexafluorophosphate (0.95 g, 3.52 mmol) to 300 mL of ethyl acetate, then add 10 mL of water and 30 mL of DMAC. Heat the mixture to 65 °C, and then dropwise add the ethyl acetate solution of Intermediate 7 (60 g, 128.62 mmol). After the addition is complete, cool the mixture to 0 - 5 °C and stir for 2 h. A solid precipitates. Filter the solid, pre - cool the filter cake to 0 °C, wash it with ethyl acetate, and dry it to obtain the binaphthylamine salt of isatrone.

[0102] Add the binaphthylamine salt of isatrone to 300 mL of ethyl acetate, dropwise add 150 mL of 2N hydrochloric acid. After the addition is complete, stir for 1 h. Wash the organic phase with 150 mL of water twice. Concentrate the organic phase to 80 mL, cool it to - 5 - 0 °C and stir for 2 h. A solid precipitates. Filter the solid, wash it with water and dry it to obtain isatrone. The yield is 53.62%, the purity is 99.74%, and the chiral purity is 98.93%.

[0103] The foregoing has shown and described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and what is described in the above embodiments and the specification is only to illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will also have various changes and improvements, and these changes and improvements fall within the scope of the present invention claimed. The scope of the present invention claimed is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing isalidone, characterized in that: The following steps are involved: S1, 1-chloro-2-(trifluoromethyl)benzene reacts with magnesium to form a Grignard reagent, and the Grignard reagent reacts with propionic anhydride to form intermediate 1 through an addition reaction; S2, intermediate 1 and bromination reagent generate intermediate 2 through bromination reaction; S3, 4-(methylsulfonyl)aniline and cyanoacetic acid react to form intermediate 3; S4, intermediate 2 and intermediate 3 undergo substitution reaction to generate intermediate 4; S5, intermediate 4 and thionyl chloride undergo a cyclization reaction to generate intermediate 5; S6, intermediate 5 is reduced to generate intermediate 6; S7, intermediate 6 and a hydroxyethyl introducing agent undergo a substitution reaction to generate intermediate 7; S8, intermediate 7, was subjected to chiral resolution to obtain isalidone; The synthetic route is as follows:

2. The synthesis method according to claim 1, characterized in that: In step S1, the molar ratio of 1-chloro-2-(trifluoromethyl)benzene to magnesium and propionic anhydride is 1:(1-1.1):(1-1.1).

3. The synthesis method according to claim 1, characterized in that: In step S2, the brominating agent is any one of Br2, NBS, DBH, and PyHBr3; preferably, the molar ratio of the intermediate 1 to the brominating agent is 1:(1.05-1.2).

4. The synthesis method according to claim 1, characterized in that: In step S3, the condensation reaction is carried out under the action of a condensation agent and a catalyst; preferably, the condensation agent is one or more of DCC, EDCI, and CDI; the catalyst is one or more of TEA, DMAP, and DIPEA; preferably, the molar ratio of the 4-(methylsulfonyl)aniline to cyanoacetic acid, the condensation agent, and the catalyst is 1:(1-1.1):(1-1.1):(0.1-0.5).

5. The synthesis method according to claim 1, characterized in that: In step S4, the substitution reaction is carried out under the action of an acid binding agent; preferably, the acid binding agent is one or more of potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; preferably, the molar ratio of the intermediate 2 to the intermediate 3 and the acid binding agent is 1:(1-1.2):(1-1.2).

6. The synthesis method according to claim 1, characterized in that: In step S5, the molar ratio of the intermediate 4 to thionyl chloride is 1:(1.2-1.5).

7. The synthesis method according to claim 1, characterized in that: In step S6, the reduction reaction uses one or more of Pd / C, palladium acetate, and Raney nickel as catalysts.

8. The synthesis method according to claim 1, characterized in that: In step S7, the hydroxyethyl introducing agent is any one of ethylene carbonate, diethyl carbonate, bromoethanol and chloroethanol.

9. The synthesis method according to claim 8, characterized in that: The molar ratio of the intermediate 6 to the hydroxyethyl introducing agent is 1:(1.2-1.5).

10. The synthesis method according to claim 1, characterized in that: In step S8, the chiral resolution uses any one of quinine, dinaphthylamine and cinchonine as a resolving agent; preferably, the molar ratio of the intermediate 7 to the resolving agent is 1:(0.1-0.5).

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