A simple method for preparing high-purity lotirana

Abstract

The present invention relates to a method for simply preparing high-purity lotirana, comprising the steps of: reacting 5-acetyl-3-methyl-2-thiophene carboxylic acid with 2,2,2-trifluoro-1-trichlorophenyl ethyl-1-ketone to obtain 3-methyl-5-(4,4,4-trifluoro-3-trichlorophenyl but-2-enoyl) thiophene-2-carboxylic acid; reacting it with hydroxylamine hydrochloride to obtain an isoxazole thiophene carboxylic acid compound; then reacting it with (R)-1-(p-tolyl) ethyl-1-amine to obtain 5-[(5S)-5-trichlorophenyl-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-3-methyl-thiophene-2-carboxylic acid; finally condensing the product with 2-amino-N-trifluoroethylacetamide hydrochloride to obtain a (5S)-configuration end product lotirana. The method has a short synthetic route, a simple process, a mild reaction, high chiral purity and HPLC purity, and is particularly suitable for scaled-up production.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to a method for preparing lotirana, in particular to a method for simply preparing high-purity lotirana. Background Art

[0002] Lotilan was developed by Eli Lilly in 2017. Its insecticidal effect is similar to that of Afolan and Frelan, with fast insecticidal speed and long-lasting effect. Its mechanism of action is to inhibit GABA chloride channels, causing arthropod nerves to become highly excited and cause death. It is a revolutionary and powerful insecticide. However, Afolan and Frelan are only used to kill insects in dogs, while Lotilan is used for both dogs and cats. Therefore, it is of great significance to study the synthesis of Lotilan.

[0003] Lotiranab is an S-configuration isomer, which may also be referred to as S-lotirana or other easily understood expressions in the present invention. Its chemical name is: 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid [(2,2,2-trifluoroethylcarbamoyl)-methyl]-amide. The chemical name given in the FDA-approved drug instructions is 5-[(5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid [(2,2,2-trifluoroethylcarbamoyl)-methyl]-amide. Lotiranab has a molecular formula of C20H14Cl3F6N3O3S, a molecular weight of 596.76 g / mol, and a chemical structure of 5-[(5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.

[0004]

[0005] There have been some reports on the preparation of lotiranaven. For example, the preparation method reported in Chinese Patent 2020113642416 (CN112457267B) is as follows:

[0006]

[0007] The disadvantage of the above-mentioned synthesis process is that the first step uses nitromethane with poor thermal stability and expensive catalyst Pd2(dba)3, which makes the entire process route costly and risky.

[0008] Chinese patent application 2023114640163 (CN117486869A) reports a synthesis process as follows:

[0009]

[0010] Although this route does not use chemical reagents for splitting, the chiral catalysts used are expensive, so this synthetic route is difficult to industrialize.

[0011] In addition, Chinese patent 2022113947771 (CN115504971B) reports a synthesis process as follows:

[0012]

[0013] Although this route has a simple preparation method, it only produces a racemic form, rather than the target product lotirana with a single S configuration.

[0014] Chinese patent application 2021800613761 (and its homologue WO2022020585) prepared the following compounds 1 to 7 in paragraphs

[0171] to

[0177] and prepared lotirana in paragraphs

[0151] to

[0156] :

[0015]

[0016] The above process has too long synthesis steps and uses expensive chiral catalytic reagents, making it difficult to achieve industrialization.

[0017] In addition, WO2014090918 discloses a method for preparing lotirana using 2-bromo-3-methyl-5-acetylthiophene as a starting material, but this method still has certain defects.

[0018] Those skilled in the art are eager to provide a method for preparing lotirana with a short synthetic route, simple operation, and suitable for factory-scale production. Summary of the invention

[0019] The object of the present invention is to provide a method for preparing lotirana with a short synthetic route, simple operation and suitable for factory-scale production. The object of the present invention also involves providing some aspects with excellent technical effects recorded in this specification.

[0020] To this end, the first aspect of the present invention provides a method for preparing Lotiranab, comprising the following steps:

[0021] Step (i): reacting 5-acetyl-3-methyl-2-thiophenecarboxylic acid with 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one in a solvent in the presence of triethylamine at elevated temperature, then adding a catalyst and acetic anhydride at room temperature and continuing the reaction to obtain the product (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxylic acid; the solvent is selected from toluene, tert-butyl methyl ether, dimethyl ether, and acetone; and the catalyst is selected from p-dimethylaminopyridine, imidazole, and N-methylmorpholine;

[0022] Step (ii): adding an alkaline aqueous solution containing hydroxylamine hydrochloride to the product solution of step (i) dissolved in an organic solvent under cooling conditions, continuing to heat and stir the reaction solution, adding acid to acidify, collecting the product, and obtaining a racemic product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid; the organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and ethanol;

[0023] Step (iii): reacting the racemic product obtained in step (ii) with (R)-1-(p-tolyl)eth-1-amine in a mixed solvent at an elevated temperature, slowly cooling the mixture and collecting the precipitate to obtain 5-[(5S)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid;

[0024] Step (iv): acidifying the mixed solution of the (5S)-enantiomeric carboxylic acid product obtained in step (iii) in an aqueous mixed solvent to a pH value of 2-3, collecting the organic phase by separation, adding triethylamine and a condensing agent in sequence, and adding 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride to carry out a condensation reaction to obtain a (5S)-enantiomeric final product, lotirana; wherein the condensing agent is selected from: N,N'-carbonyldiimidazole, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, N'N-dicyclohexylcarbodiimide, and 1-n-propyl phosphoric anhydride.

[0025] According to the method of the first aspect of the present invention, in step (i), the temperature rising condition is a temperature condition of 50°C to 70°C.

[0026] According to the method of the first aspect of the present invention, step (i) comprises the following operations: adding 1.0 mol of 5-acetyl-3-methyl-2-thiophenecarboxylic acid, 1.2 mol of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one, 1200-1300 g of toluene, and 1-3 mol of triethylamine to a reaction bottle, heating and stirring at 50-70° C. to react for 15-25 hours; cooling to room temperature, adding 0.08-0.12 mol of p-dimethylaminopyridine, and dripping 2-4 mol of acetic anhydride at a temperature of 20-25° C., maintaining the temperature and continuing to stir the reaction for 2 hours, and extracting with an aqueous solution and an organic solvent to obtain a product.

[0027] According to the method of the first aspect of the present invention, step (i) comprises the following operations: adding 1.0 mol of 5-acetyl-3-methyl-2-thiophenecarboxylic acid, 1.2 mol of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one, 1200-1300 g of toluene and 1-3 mol of triethylamine to a reaction bottle, heating and stirring at 50-70°C to react for 15-25 hours; cooling to room temperature, adding 0.08-0.12 mol of p-dimethylaminopyridine, controlling the temperature at 20-25°C to dropwise add 2-4 mol of acetic anhydride, and maintaining the temperature for continuous stirring and reaction for 2 hours; the organic phase after the reaction solution is treated with 10% sodium chloride aqueous solution is concentrated under reduced pressure to dryness, dissolved with isopropyl acetate and n-heptane (1:5, v / v), stirred at low temperature (5±5°C) for 3 hours, filtered to collect the solid, and dried to obtain the product.

[0028] According to the method of the first aspect of the present invention, in step (i), after acetic anhydride is added dropwise and the stirring reaction is completed, the following operation is performed: 500 g of a 10% sodium chloride aqueous solution is added to the reaction solution, the mixture is stirred for 0.5 hour, the mixture is allowed to stand for 0.25 hour, the mixture is separated, 300 g of a 10% sodium chloride aqueous solution is added to the collected upper organic phase, the mixture is stirred for 0.5 hour, the mixture is allowed to stand for 0.25 hour, the mixture is separated, and the upper organic phase is collected; the organic phase is concentrated to dryness under reduced pressure at 40°C, 100 g of isopropyl acetate and 500 g of n-heptane are added, the mixture is stirred at 5±5°C for 3 hours, the mixture is filtered under reduced pressure, the solid is collected, and the mixture is dried with air at 45±5°C for 6 hours to obtain the product.

[0029] According to the method of the first aspect of the present invention, in step (ii), the aqueous alkali solution is an aqueous solution of sodium hydroxide.

[0030] According to the method of the first aspect of the present invention, in step (ii), the aqueous alkali solution is an aqueous solution of sodium hydroxide, and the amount of sodium hydroxide used is 1.0 to 5.0 equivalents of the product of step (i), preferably 3.5 equivalents.

[0031] According to the method of the first aspect of the present invention, in step (ii), the amount of hydroxylamine hydrochloride used is 1.0 to 4.0 equivalents of the product of step (i), preferably 2.0 equivalents.

[0032] According to the method of the first aspect of the present invention, in step (ii), the cooling condition is a temperature condition of 0-5°C.

[0033] According to the method of the first aspect of the present invention, in step (ii), the amount of the organic solvent is 3 to 7 times by weight, such as 4 to 6 times by weight, of the amount of the product added in step (i).

[0034] According to the method of the first aspect of the present invention, step (ii) comprises the following operations: dissolving 2.87 mol of sodium hydroxide in 500 g of water, cooling to 0-5°C, adding 1.64 mol of hydroxylamine hydrochloride in batches within 0.5 hour, stirring at 0-5°C for 10 minutes, and obtaining a mixed solution for standby use; adding 1825 g of N,N-dimethylformamide and 0.82 mol of the product of step (i) into a reaction bottle to dissolve the materials, cooling to 0-5°C and then dripping the above hydroxylamine hydrochloride mixed solution, and continuing to stir the reaction at 0-5°C for 2 hours after dripping; adding hydrochloric acid aqueous solution for acidification, collecting the product, and obtaining a racemic product.

[0035] According to the method of the first aspect of the present invention, step (ii) comprises the following operations: dissolving 2.87 mol of sodium hydroxide in 500 g of water, cooling to 0-5°C, adding 1.64 mol of hydroxylamine hydrochloride in batches within 0.5 hours, stirring at 0-5°C for 10 minutes, and obtaining a mixed solution for standby use; adding 1825 g of N,N-dimethylformamide and 0.82 mol of the product of step (i) into a reaction bottle, dissolving the materials, cooling to 0-5°C, and then dripping the above-mentioned hydroxylamine hydrochloride mixed solution, and after dripping, stirring at 0-5°C. Continue stirring the reaction at 5°C for 2 hours; add 1000 g of water, adjust the pH value to 2-3 with concentrated hydrochloric acid, then add 1200 g of isopropyl acetate, stir for 0.5 hour, let stand for 0.25 hour, separate the liquids, and collect the upper organic phase; add 300 g of water, stir for 0.5 hour, let stand for 0.25 hour, separate the liquids, and collect the upper organic phase; concentrate to dryness under reduced pressure at 40°C, add 350 g of n-heptane, stir at 20-25°C for 2 hours, filter under reduced pressure, collect the solid, and dry to obtain a racemic product.

[0036] According to the method of the first aspect of the present invention, in step (iii), the amount of (R)-1-(p-tolyl)eth-1-amine used is 0.5 to 0.8 equivalents of the racemic product of step (ii), preferably 0.6 equivalents.

[0037] According to the method of the first aspect of the present invention, in step (iii), the mixed solvent is a mixed solvent consisting of n-butanol, acetonitrile and water.

[0038] According to the method of the first aspect of the present invention, in step (iii), the mixed solvent is a mixed solvent composed of n-butanol, acetonitrile and water in a weight ratio of 500:2000:150.

[0039] According to the method of the first aspect of the present invention, in step (iii), the elevated temperature is 50-70°C, for example, 60°C.

[0040] According to the method of the first aspect of the present invention, step (iii) comprises the following operations: adding 0.74 mol of the racemic product of step (ii), 500 g of n-butanol, 2000 g of acetonitrile, 150 g of water, and 0.444 mol of (R)-1-(p-tolyl)ethyl-1-amine into a reaction bottle, heating to 60° C. and stirring for 2 hours, cooling to 20-25° C. within 4 hours, collecting the solid, and drying to obtain the product.

[0041] According to the method of the first aspect of the present invention, step (iii) comprises the following operations: adding 0.74 mol of the racemic product of step (ii), 500 g of n-butanol, 2000 g of acetonitrile, 150 g of water, and 0.444 mol of (R)-1-(p-tolyl)ethyl-1-amine into a reaction flask, heating to 60°C and stirring for 2 hours, cooling to 20-25°C within 4 hours, keeping warm for 0.5 hour, filtering under reduced pressure, collecting solids, washing with a mixed solution of acetonitrile / water (e.g., 9:1), and then recrystallizing twice with a mixed solution of acetonitrile / water (e.g., 9:1) at 60°C, collecting crystals, and drying to obtain a product.

[0042] According to the method of the first aspect of the present invention, in step (iv), the amount of triethylamine used is 1.0 to 4.0 equivalents of the (5S)-enantiomeric carboxylic acid product obtained in step (iii), preferably 2.0 equivalents.

[0043] According to the method of the first aspect of the present invention, in step (iv), the amount of the condensing agent used is 1.0 to 2.0 equivalents of the (5S)-enantiomeric carboxylic acid product obtained in step (iii), preferably 1.3 equivalents.

[0044] According to the method of the first aspect of the present invention, in step (iv), the amount of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride used is 1.05 to 1.2 equivalents, preferably 1.1 equivalents, of the (5S)-enantiomeric carboxylic acid product obtained in step (iii).

[0045] According to the method of the first aspect of the present invention, step (iv) comprises the following operations: adding 0.30 mol of the (5S)-enantiomer carboxylic acid product obtained in step (iii), 900 g of ethyl acetate and 300 g of water into a reaction flask, adjusting the pH value to 2-3 with concentrated hydrochloric acid under stirring, continuing stirring for 0.5 hour, standing, separating the liquids, collecting the upper organic phase, adding 200 g of anhydrous sodium sulfate to dry, filtering off the desiccant and adding 0.3-1.2 mol of triethylamine; then adding 0.3-0.6 mol of N,N'-carbonyldiimidazole in batches at 20-25°C, maintaining this temperature and continuing stirring for 0.5 hour, adding 0.315-0.36 mol of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, and continuing stirring at 20-25°C for 6 hours; extracting with water and ethyl acetate / n-heptane mixed solvent in turn to obtain the final product (5S)-enantiomer lotirana.

[0046] According to the method of the first aspect of the present invention, step (iv) comprises the following operations: adding 0.30 mol of the (5S)-enantiomer carboxylic acid product obtained in step (iii), 900 g of ethyl acetate and 300 g of water into a reaction bottle, adjusting the pH value to 2-3 with concentrated hydrochloric acid under stirring, continuing stirring for 0.5 hour, standing and separating the liquids, collecting the upper organic phase, adding 200 g of anhydrous sodium sulfate to dry, filtering off the desiccant and adding 0.3-1.2 mol of triethylamine; then adding 0.3-0.6 mol of N,N'-carbonyldiimidazole in batches at 20-25°C, maintaining the mixture for 3 hours. Stirring was continued at this temperature for 0.5 hour, 0.315-0.36 mol of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was added, and stirring was continued at 20-25°C for 6 hours; 300 g of water was added, stirring was continued for 0.5 hour, standing, separation was carried out, the upper organic phase was collected, and it was concentrated to dryness under reduced pressure at 40°C, 50 g of ethyl acetate and 300 g of n-heptane were added, stirring was continued at 40°C for 2 hours, the temperature was lowered to 10-15°C, stirring was continued for 1 hour, and the solid was collected by filtration under reduced pressure and dried to obtain the final product (5S)-enantiomer of lotirana.

[0047] Furthermore, the second aspect of the present invention provides lotirana, which is prepared by any method described in the first aspect of the present invention.

[0048] The lotirana prepared by the method of the present invention exhibits excellent effects in one or more aspects, such as short synthesis route, simple process, mild reaction, high chiral purity and HPLC purity, and is particularly suitable for factory scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 : HPLC purity chromatogram of the final product (5S)-lotirana in step (iv) of Example 2.

[0050] Figure 2: HPLC chromatogram of the chiral purity of the final product (5S)-Lotiranab in step (iv) of Example 2. DETAILED DESCRIPTION

[0051] The following examples provided by the present invention are only for explanation purposes and are not intended to be used for, nor should they be construed as limiting the present invention in any way. Those skilled in the art will recognize that conventional changes and modifications may be made to the following examples without exceeding the spirit or scope of the present invention. The present invention provides a general and / or specific description of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described in as much detail as possible. It is clear to those skilled in the art that, hereinafter, if not otherwise specified, the materials and operating methods used in the present invention are well known in the art. Various materials used in the present invention are all commercially available, and for example, the 5-acetyl-3-methyl-2-thiophenecarboxylic acid used in Example 2 of the present invention can be easily purchased from commercial sources.

[0052] Example 1: Preparation of Lotiranab

[0053] In this example, S-lotirana was prepared by referring to the method described in WO2014090918.

[0054] Step (i): Preparation of (E / Z)-1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,4,5-trichlorophenyl)-4,4,4- Trifluoro-but-2-en-1-one

[0055] 88 g (0.40 mol, Mr = 219.1) of 2-bromo-3-methyl-5-acetylthiophene, 113 g (0.40 mol, Mr = 277.5) of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one, 880 g of tert-butyl methyl ether and 121 g of triethylamine were added to the reaction flask, and the mixture was heated and stirred at 60°C to react for 2 hours; the reaction solution was cooled to below 5°C, and 67 g of thionyl chloride was slowly added; the reaction solution was heated to 40°C and stirred for 3 hours, and extracted with 10% sodium bicarbonate solution and water in turn, the combined aqueous phase was extracted twice with methyl tert-butyl ether, and the combined organic phase was extracted with water again. After removing the solvent methyl tert-butyl ether by distillation, crystallization was performed with 68% ethanol to obtain 148.8 g (0.31 mol, Mr = 478.5) of (E / Z) -1- (5-bromo-4-methyl-thiophen-2-yl) -3- (3,4,5-trichlorophenyl) -4,4,4-trifluoro-but-2-ene-1-one as a gray solid with a molar yield of 77.5%.

[0056] .

[0057] Step (ii): Preparation of 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]- 3-Methyl-thiophene-2-carboxylic acid

[0058] (iia) 90g (0.188mol) of the product of step (i) and 1000g of ethanol were cooled to below 5°C, and 15g (0.216mol, Mr=69.5) of hydroxylamine hydrochloride was added to the reaction mixture. After 55g of 30% sodium hydroxide was slowly added, the suspension was stirred for 3 hours. Then 1650g of water was added, and the reaction mixture was stirred for another 2 hours. The suspension was centrifuged, the precipitate was washed with water, and vacuum dried to obtain solid 3-(5-bromo-4-methyl-thiophene-2-yl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole 80.9g (0.164mol, Mr=493.5, HPLC purity 98.6%) as an off-white solid with a molar yield of 87.2%.

[0059] .

[0060] (iib) 18.5 g (37.5 mmol, Mr=493.5) of the product of step (iia) was dissolved in 80 g of tetrahydrofuran at ambient temperature. 18.6 g of ethylmagnesium chloride (25% THF solution) was slowly added, and then 5.8 g of CO2 was slowly added below the liquid level. The reaction mixture was then stirred at ambient temperature for about 30 minutes. A mixture of 8 g of sodium chloride, 64 g of water and 7.9 g of 37% hydrochloric acid was added. After phase separation, the organic layer was distilled to a minimum volume and heptane was added. After distillation to remove heptane, the residue was dissolved in 10 g of ethyl acetate, and 240 g of heptane was slowly added at 40°C to precipitate the product. The product suspension was cooled to 0°C, and 14.4 g (HPLC purity 97.7%, 31.4 mmol, Mr = 458.7, S / R enantiomeric ratio 49.91 / 50.09) of 5- [5- (3,4,5-trichlorophenyl) -5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -3-methyl-thiophene-2-carboxylic acid was isolated as an off-white solid with a molar yield of 83.7%.

[0061]

[0062] It should be noted that the total molar yield of the racemic product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid obtained in the above step (i) from 2-bromo-3-methyl-5-acetylthiophene to step (iib) is about 56.6%, and the reaction steps are long.

[0063] Step (iii): Preparation of 5-[(5S)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dichlorophenyl] [H-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid

[0064] A mixture of 100 g (0.218 mol) of the racemic product of step (ii), 170 g of 2-butanol, 680 g of acetonitrile and 45 g of water was stirred at ambient temperature to dissolve, and then a solution of 16 g (0.118 mol) of (R)-1-(p-tolyl)ethan-1-amine, 19 g of 2-butanol, 76 g of acetonitrile and 5 g of water was added to the mixture, and then the reaction mixture was slowly heated to 60° C. and maintained at this temperature for 2 hours; the reaction mixture was slowly cooled to room temperature and maintained at this temperature for 0.5 hour, the solid was collected by filtration, washed with a mixture of acetonitrile / water (9:1), and then recrystallized twice from acetonitrile / water (9:1) at 60° C., the crystals were collected, and dried at 50° C. for 5 hours to obtain 45.8 g (HPLC purity 98.5%, Mr=458.7, chiral purity 99.2%) of (5S)-enantiomeric carboxylic acid product, with a molar yield of 45.8%.

[0065]

[0066] Step (iv): Preparation of the (5S)-enantiomer of lotirana

[0067] 13.8 g (0.030 mol) of the (5S)-enantiomeric carboxylic acid product obtained in step (iii) was heated to 60° C. in 150 g of toluene and extracted three times with 56 g of 1M hydrochloric acid; about 50% of the organic layer was distilled off under vacuum, 60 g of toluene was added, the mixture was heated to 110° C., and then 8 g of thionyl chloride was slowly added to the reaction mixture. After stirring for 1 hour, about 95 g of toluene was removed under vacuum, the reaction mixture was cooled to ambient temperature, and 95 g of dichloromethane was added;

[0068] The reaction solution was added to a mixture of 6.4 g (0.033 mol) of 2-amino-2',2',2'-trifluoroethylacetamide hydrochloride and 9.8 g of triethylamine in 95 g of dichloromethane at 5°C; the reaction mixture was stirred for another 5 hours, and then extracted with 4% hydrochloric acid, 8% sodium bicarbonate and water in sequence; most of the organic layer was removed by vacuum from the collected organic phase, 50 g of toluene was added, the reaction mixture was kept at 40°C and stirred for 2 hours, 290 g of heptane was slowly added, and then cooled to below 5°C, and stirring was continued for 1 hour, and the solid was filtered off under reduced pressure, collected, washed with 25 g of heptane, and dried at 45±5°C for 6 hours to obtain 13.9 g of lotirana (HPLC purity 99.2%, 23.3 mmol, Mr=596.8, chiral purity 98.1%) of the final product (5S)-enantiomer as a white solid with a molar yield of 77.7%.

[0069]

[0070] Example 2: Preparation of Lotiranab

[0071] Step (i): Preparation of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl) Thiophene-2-carboxylic acid

[0072] Add 184.2g (1.0mol) of 5-acetyl-3-methyl-2-thiophenecarboxylic acid, 332.9g (1.2mol) of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one, 1289g of toluene, and 151.5g (1.5mol) of triethylamine to the reaction bottle, heat and stir at 60°C to react for 20 hours; cool to room temperature, add 12.2g (0.1mol) of p-dimethylaminopyridine (DMAP), control the temperature at 20-25°C, add 306g (3.0mol) of acetic anhydride dropwise, keep this temperature and continue stirring and reacting for 2 hours. Add 500g of 10% sodium chloride aqueous solution, stir for 0.5 hour, stand for 0.25 hour, separate the liquids, add 300g of 10% sodium chloride aqueous solution to the collected upper organic phase, stir for 0.5 hour, stand for 0.25 hour, separate the liquids, and collect the upper organic phase. The organic phase was concentrated to dryness under reduced pressure at 40°C, 100 g of isopropyl acetate and 500 g of n-heptane were added, and the mixture was stirred at 5±5°C for 3 hours. The solid was collected by filtration under reduced pressure and dried by air at 45±5°C for 6 hours to obtain 367.8 g (HPLC purity 98.3%, 0.829 mol, Mr=443.7) of the product (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxylic acid as a yellow solid with a molar yield of 82.9%.

[0073]

[0074] Step (ii): Preparation of 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]- 3-Methyl-thiophene-2-carboxylic acid

[0075] 114.8 g (2.87 mol) of sodium hydroxide was dissolved in 500 g of water, and the temperature was lowered to 0-5°C. 114 g (1.64 mol) of hydroxylamine hydrochloride was added in batches within 0.5 hours, and the mixture was stirred at 0-5°C for 10 minutes to obtain a mixed solution for standby use; 1825 g of N,N-dimethylformamide (DMF) and 363.8 g (0.82 mol) of the product of step (i) were added to a reaction flask to dissolve the materials, and the mixture was added dropwise after the temperature was lowered to 0-5°C. After the addition was completed, the mixture was stirred and reacted at 0-5°C for 2 hours; 1000 g of water was added, and the pH value was adjusted to 2-3 with concentrated hydrochloric acid, and then 1200 g of isopropyl acetate was added, stirred for 0.5 hours, and allowed to stand for 0.25 hours. , separate the liquids, and collect the upper organic phase; add 300 g of water, stir for 0.5 hour, let stand for 0.25 hour, separate the liquids, and collect the upper organic phase; concentrate to dryness under reduced pressure at 40° C., add 350 g of n-heptane, stir at 20-25° C. for 2 hours, filter under reduced pressure, collect the solid, and dry with air at 50° C. to obtain 344.3 g (HPLC purity 98.1%, 0.751 mol, Mr=458.7, S / R enantiomeric ratio 49.94 / 50.06) of the racemic product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid) as an off-white solid with a molar yield of 91.5%.

[0076]

[0077] The total molar yield of the racemic product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid obtained in step (i) from the readily available raw material 5-acetyl-3-methyl-2-thiophenecarboxylic acid to step (ii) is about 75.9%. The reaction steps are long and the reaction conditions are mild, which has significant advantages over the process of step (i) to step (iib) in Example 1.

[0078] Step (iii): Preparation of 5-[(5S)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dichlorophenyl] [H-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid

[0079] 340.0 g (0.74 mol) of the racemic product of step (ii), 500 g of n-butanol, 2000 g of acetonitrile, 150 g of water, and 60 g (0.444 mol) of (R)-1-(p-tolyl)ethyl-1-amine were added to a reaction flask, the temperature was raised to 60° C. and stirred for 2 hours, the temperature was lowered to 20-25° C. within 4 hours, the temperature was kept for 0.5 hour, and the solid was collected by filtration under reduced pressure. The solid was washed with a mixed solution of acetonitrile / water (9:1), and then recrystallized twice with a mixed solution of acetonitrile / water (9:1) at 60° C., the crystals were collected, and dried at 50° C. for 5 hours to obtain 156.8 g (HPLC purity 98.4%, Mr=458.7, chiral purity 99.4%) of (5S)-enantiomer carboxylic acid product, and the molar yield ((5S)-enantiomer accounted for 46.1% of the total amount of racemate).

[0080]

[0081] Step (iv): Preparation of the (5S)-enantiomer of lotirana

[0082] Add 137.6 g (0.30 mol) of the (5S)-enantiomer carboxylic acid product obtained in step (iii), 900 g of ethyl acetate and 300 g of water into a reaction flask, adjust the pH value to 2-3 with concentrated hydrochloric acid while stirring, continue stirring for 0.5 hour, let stand, separate the liquids, collect the upper organic phase, add 200 g of anhydrous sodium sulfate and dry for 2 hours, filter out the desiccant and add 60.6 g (0.60 mol) of triethylamine.

[0083] Then, 63.24 g (0.39 mol) of N,N'-carbonyldiimidazole was added in batches at 20-25°C, and stirring was continued for 0.5 hour while maintaining this temperature. 63.55 g (0.33 mol) of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was added, and stirring was continued at 20-25°C for 6 hours. 300 g of water was added, stirred for 0.5 hour, allowed to stand, separated, the upper organic phase was collected, concentrated to dryness under reduced pressure at 40 ° C, 50 g of ethyl acetate and 300 g of n-heptane were added, stirred at 40 ° C for 2 hours, cooled to 10-15 ° C and continued to stir for 1 hour, filtered under reduced pressure, solids were collected, and dried at 45 ± 5 ° C for 6 hours to obtain the final product (5S) -enantiomer lotirana 163.5 g (HPLC purity 99.94%, 0.274 mol, Mr = 596.8, chiral purity 99.9%) as a white solid, with a molar yield of 91.3%.

[0084]

[0085] The molar yield of the final product in step (iv) of Example 2 is as high as 91.3%, which is significantly higher than the molar yield of only 77.7% in step (iv) of Example 1, and toluene can be avoided, so the reaction conditions are more environmentally friendly and green.

[0086] The hydrogen spectrum data of (5S)-lotiranab obtained in Example 2 was consistent with the theoretical value: H NMR (400 MHz, DMSO-d6) 8.03 (brs, 1H), 7.98 (brs, 1H), 7.28 (d, 2H), 6.93 (s, 1H), 3.85 (s, 2H), 3.73 (m, 2H), 2.67 (d, 1H), 2.45 (d, 1H), 2.40 (s, 3H).

[0087] The chromatographic conditions for determining the HPLC purity of the final product Lotiranab and the products of steps (ii) to (iii) of the present invention are: Apollo C18 chromatographic column (150mm×4.6mm, 5μm), mobile phase: 0.05M potassium dihydrogen phosphate buffer (containing 0.5% sodium octane sulfonate, adjusted to pH=3.5 with phosphoric acid)-acetonitrile (4:6), flow rate: 1.5mL / min; ultraviolet detection wavelength 210nm, column temperature 40°C, injection volume 20μL, theoretical plate number calculated based on the Lotiranab peak should be not less than 3000. When determining the HPLC purity of the product of step (i), the mobile phase ratio is appropriately adjusted to buffer-acetonitrile=25:75 and the detection wavelength is changed to 254nm. Typically, the HPLC purity chromatogram of the final product (5S)-Lotiranab in step (iv) of Example 2 is as shown in Figure 1 shown.

[0088] The HPLC conditions for determining the isomer ratio and / or purity of the products in step (ii) to step (iv) of the present invention are as follows: chromatographic column: normal phase chromatographic column Chiralpak AS-H (250 mm×4.6 mm, 5 μm), mobile phase: n-hexane-acetonitrile-triethylamine (75:25:0.1), flow rate: 1.0 ml / min, detection wavelength: 254 nm, column temperature: 35° C., injection volume: 20 μl. Typically, the chromatogram of the chiral purity of the final product (5S)-lotirana in step (iv) of Example 2 is as follows: Figure 2 As shown, rt=32.4min is (5R) isomer, and rt=35.1min is (5S)-lotirana.

[0089] Example 3: Preparation of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl) Thiophene-2-carboxylic acid

[0090] The step (i) of reference example 2 was carried out (each material was fed at 1 / 10 of the amount), except that the DMAP used was replaced by imidazole and N-methylmorpholine in an equimolar ratio, and the molar yields of the product (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxylic acid were 69.2% and 63.4%, respectively, based on 5-acetyl-3-methyl-2-thiophenecarboxylic acid. This indicates that the product yield using p-dimethylaminopyridine in step (i) of example 2 is significantly higher than that of the same reagent.

[0091] Example 4: Preparation of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl) Thiophene-2-carboxylic acid

[0092] The same method as in Example 2 was used for step (i) (each material was charged at 1 / 10 of the amount), except that the toluene solvent was replaced with tert-butyl methyl ether, Dimethyl ether, The molar yields of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxylic acid based on 5-acetyl-3-methyl-2-thiophenecarboxylic acid were 63.6%, 65.2% and 71.8%, respectively.

[0093] Example 5: Preparation of 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3- Methyl-thiophene-2-carboxylic acid

[0094] The step (ii) of Reference Example 2 was carried out (each material was charged at 1 / 10 of the amount), except that the solvent N,N-dimethylformamide was replaced with tetrahydrofuran, acetonitrile and ethanol in equal amounts, respectively. The molar yields of the product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid were 83.3%, 77.3% and 69.4%, respectively, based on the product of step (i) as the starting material.

[0095] Example 6: Preparation of the (5S)-enantiomer of Lotiranab

[0096] The step (iv) of Reference Example 2 was carried out (each material was fed at 1 / 10 of the amount), except that the N,N'-carbonyldiimidazole used was replaced by similar reagents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, N'N-dicyclohexylcarbodiimide, and 1-n-propylphosphoric anhydride in equimolar ratios thereof. The molar yields of the (5S)-enantiomeric carboxylic acid product obtained in step (iii) as the starting material to the product (5S)-lotiranab were 76.4%, 81.4%, 84.3%, and 78.4%, respectively. This indicates that the product yield is significantly higher when carbonyldiimidazole is used in the reaction environment of step (iv) of Example 2 than when similar reagents are used. The HPLC purity of the four batches of (5S)-lotirana products obtained was further determined to be 99.1%, 99.3%, 98.5% and 98.8%, respectively; the chiral purity of the four batches of (5S)-lotirana products was also determined to be 92.4%, 94.2%, 86.2% and 90.6%, respectively; unexpectedly, it was found that although the HPLC purity was good, the chiral purity of the product decreased when different condensing agents were used. In view of the fact that the chiral purity of the condensed precursor had reached more than 98%, it was shown that certain condensation conditions would cause configuration conversion, which is completely unacceptable. From this perspective, the use of N,N'-carbonyldiimidazole in step (iv) is beneficial for obtaining a product with high chiral purity.

[0097] In the present invention, if not otherwise specified, HPLC purity refers to the percentage of lotirana (including the sum of (5S)-lotirana and (5R)-lotirana) in all detected peaks containing impurities under specified HPLC detection conditions. Reverse HPLC conditions cannot separate the S isomer from the R isomer. Similar definitions apply to other materials. In the present invention, if not otherwise specified, chiral purity refers to the percentage of a certain target configuration in the total amount of racemates of the substance under specified HPLC detection conditions. For example, for lotirana, the chiral purity of the final product of step (iv) of Example 2 refers to the percentage of (5S)-lotirana in the total amount of the two isomers. Similar definitions apply to other materials involving chiral purity.

[0098] Example 7: Preparation of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl) Thiophene-2-carboxylic acid

[0099] Reference Example 2 Step (i) is carried out: 1.0 mol of 5-acetyl-3-methyl-2-thiophenecarboxylic acid, 1.2 mol of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl) ethyl-1-one, 1300 g of toluene, and 1.0 mol of triethylamine are added to the reaction bottle, and the mixture is heated and stirred at 70°C for 15 hours; the mixture is cooled to room temperature, 0.12 mol of p-dimethylaminopyridine (DMAP) is added, 4.0 mol of acetic anhydride is added dropwise at a temperature of 20 to 25°C, and the mixture is dripped and stirred at this temperature for 2 hours. 500 g of 10% sodium chloride aqueous solution is added, stirred for 0.5 hour, and separated after standing for 0.25 hour, and 300 g of 10% sodium chloride aqueous solution is added to the collected upper organic phase, stirred for 0.5 hour, and separated after standing for 0.25 hour, and the upper organic phase is collected. The organic phase was concentrated to dryness under reduced pressure at 40°C, 100 g of isopropyl acetate and 500 g of n-heptane were added, and the mixture was stirred at 5±5°C for 3 hours. The solid was collected by filtration under reduced pressure and dried with air at 45±5°C for 6 hours to obtain the product (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxylic acid (HPLC purity 98.5%, 0.832 mol) as a yellow solid with a molar yield of 83.2%.

[0100] Example 8: Preparation of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl) Thiophene-2-carboxylic acid

[0101] Reference Example 2 Step (i) is carried out: 1.0 mol of 5-acetyl-3-methyl-2-thiophenecarboxylic acid, 1.2 mol of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl) ethyl-1-one, 1200 g of toluene, and 3.0 mol of triethylamine are added to the reaction bottle, and the mixture is heated and stirred at 50 ° C for 25 hours; the mixture is cooled to room temperature, 0.08 mol of p-dimethylaminopyridine (DMAP) is added, 2.0 mol of acetic anhydride is added dropwise at a temperature of 20-25 ° C, and the mixture is dripped and stirred at this temperature for 2 hours. 500 g of 10% sodium chloride aqueous solution is added, stirred for 0.5 hour, and separated after standing for 0.25 hour, and 300 g of 10% sodium chloride aqueous solution is added to the collected upper organic phase, stirred for 0.5 hour, and separated after standing for 0.25 hour, and the upper organic phase is collected. The organic phase was concentrated to dryness under reduced pressure at 40°C, 100 g of isopropyl acetate and 500 g of n-heptane were added, and the mixture was stirred at 5±5°C for 3 hours. The solid was collected by filtration under reduced pressure and dried with air at 45±5°C for 6 hours to obtain the product (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxylic acid (HPLC purity 98.0%, 0.822 mol) as a yellow solid with a molar yield of 82.1%.

[0102] Example 9: Preparation of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl) Thiophene-2-carboxylic acid

[0103] Reference Example 2 Step (ii) is carried out: 2.0 mol of sodium hydroxide is dissolved in 500 g of water, cooled to 0-5 ° C, 2.4 mol of hydroxylamine hydrochloride is added in batches within 0.5 hours, and stirred at 0-5 ° C for 10 minutes to obtain a mixed solution for standby use; 1625 g of N, N-dimethylformamide (DMF) and 363.8 g (0.82 mol) of the product of step (i) are added to the reaction flask to dissolve the materials, and the above hydroxylamine hydrochloride mixed solution is added dropwise after cooling to 0-5 ° C. After the dropwise addition, the reaction is continued at 0-5 ° C with stirring for 2 hours; 1000 g of water is added, the pH value is adjusted to 2-3 with concentrated hydrochloric acid, and then 1200 g of isopropyl acetate is added, stirred for 0.5 hours, and then the mixture is stirred for 2 hours. The mixture was allowed to stand for 0.25 hours, separated, and the upper organic phase was collected; 300 g of water was added, stirred for 0.5 hours, allowed to stand for 0.25 hours, separated, and the upper organic phase was collected; the mixture was concentrated to dryness under reduced pressure at 40° C., 350 g of n-heptane was added, stirred at 20-25° C. for 2 hours, filtered under reduced pressure, and the solid was collected, and dried with air at 50° C. to obtain the racemic product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (HPLC purity 98.3%, 0.744 mol, S / R enantiomeric ratio 49.92 / 50.08) as an off-white solid with a molar yield of 90.7%.

[0104] Example 10: Preparation of (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl 1-(2-Methyl)thiophene-2-carboxylic acid

[0105] Reference Example 2 Step (ii) is carried out: 3.5 mol of sodium hydroxide is dissolved in 500 g of water, cooled to 0-5 ° C, 1.2 mol of hydroxylamine hydrochloride is added in batches within 0.5 hours, and stirred at 0-5 ° C for 10 minutes to obtain a mixed solution for standby use; 2000 g of N, N-dimethylformamide (DMF) and 363.8 g (0.82 mol) of the product of step (i) are added to the reaction flask to dissolve the materials, and the above hydroxylamine hydrochloride mixed solution is added dropwise after cooling to 0-5 ° C. After the dropwise addition, the reaction is continued to stir at 0-5 ° C for 2 hours; 1000 g of water is added, the pH value is adjusted to 2-3 with concentrated hydrochloric acid, and then 1200 g of isopropyl acetate is added, stirred for 0.5 hours, and then the mixture is stirred for 2 hours. The mixture was allowed to stand for 0.25 hours, separated, and the upper organic phase was collected; 300 g of water was added, stirred for 0.5 hours, allowed to stand for 0.25 hours, separated, and the upper organic phase was collected; the mixture was concentrated to dryness under reduced pressure at 40° C., 350 g of n-heptane was added, stirred at 20-25° C. for 2 hours, filtered under reduced pressure, the solid was collected, and dried with air at 50° C. to obtain the racemic product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (HPLC purity 97.9%, 0.753 mol, S / R enantiomeric ratio 49.96 / 50.04) as an off-white solid with a molar yield of 91.8%.

[0106] Example 11: Preparation of 5-[(5S)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3- 3-Methyl-thiophene-2-carboxylic acid

[0107] Reference Example 2 Step (iii) was carried out: 340.0 g (0.74 mol) of the racemic product of step (ii), 500 g of n-butanol, 2000 g of acetonitrile, 150 g of water, and 0.385 mol of (R)-1-(p-tolyl)ethyl-1-amine were added to a reaction flask, the temperature was raised to 60 ° C and stirred for 2 hours, the temperature was lowered to 20-25 ° C within 4 hours, and the mixture was kept warm for 0.5 hour. The solid was collected by filtration under reduced pressure, washed with a mixed solution of acetonitrile / water (9:1), and then recrystallized twice at 60 ° C with a mixed solution of acetonitrile / water (9:1), the crystals were collected, and dried at 50 ° C for 5 hours to obtain a (5S)-enantiomeric carboxylic acid product with a molar yield of 45.9%, an HPLC purity of 98.2%, and a chiral purity of 99.3%.

[0108] Example 12: Preparation of 5-[(5S)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3- 3-Methyl-thiophene-2-carboxylic acid

[0109] Reference Example 2 Step (iii) was carried out: 340.0 g (0.74 mol) of the racemic product of step (ii), 500 g of n-butanol, 2000 g of acetonitrile, 150 g of water, and 0.59 mol of (R)-1-(p-tolyl)ethyl-1-amine were added to a reaction flask, the temperature was raised to 60 ° C and stirred for 2 hours, the temperature was lowered to 20-25 ° C within 4 hours, and the mixture was kept warm for 0.5 hour. The solid was collected by filtration under reduced pressure, washed with a mixed solution of acetonitrile / water (9:1), and then recrystallized twice at 60 ° C with a mixed solution of acetonitrile / water (9:1), the crystals were collected, and dried at 50 ° C for 5 hours to obtain a (5S)-enantiomeric carboxylic acid product with a molar yield of 46.4%, an HPLC purity of 98.3%, and a chiral purity of 99.5%.

[0110] Example 13: Preparation of the (5S)-enantiomer of Lotiranab

[0111] Reference Example 2 Step (iv) was performed: 137.6 g (0.30 mol) of the (5S)-enantiomeric carboxylic acid product obtained in step (iii), 900 g of ethyl acetate, and 300 g of water were added to the reaction flask, and the pH value was adjusted to 2-3 with concentrated hydrochloric acid under stirring, and the stirring was continued for 0.5 hour, and the mixture was allowed to stand for separation, and the upper organic phase was collected, and 200 g of anhydrous sodium sulfate was added to dry for 2 hours, and 0.45 mol of triethylamine was added after filtering off the desiccant. Then 0.6 mol of N,N'-carbonyldiimidazole was added in batches at 20-25°C, and the stirring was continued for 0.5 hour while maintaining the temperature, and 0.315 mol of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was added, and the stirring was continued at 20-25°C for 6 hours. Add 300g of water, stir for 0.5 hours, let stand, separate the liquids, collect the upper organic phase, concentrate to dryness under reduced pressure at 40°C, add 50g of ethyl acetate and 300g of n-heptane, stir at 40°C for 2 hours, cool to 10-15°C and continue stirring for 1 hour, filter under reduced pressure, collect the solid, and dry at 45±5°C for 6 hours to obtain the final product (5S)-enantiomer of lotirana as a white solid with a molar yield of 90.8%, HPLC purity of 99.95%, and chiral purity of 99.8%.

[0112] Example 14: Preparation of the (5S)-enantiomer of Lotiranab

[0113] Reference Example 2 Step (iv) was performed: 137.6 g (0.30 mol) of the (5S)-enantiomeric carboxylic acid product obtained in step (iii), 900 g of ethyl acetate, and 300 g of water were added to the reaction flask, and the pH value was adjusted to 2-3 with concentrated hydrochloric acid under stirring, and the stirring was continued for 0.5 hours, and the mixture was allowed to stand for separation, and the upper organic phase was collected, and 200 g of anhydrous sodium sulfate was added to dry for 2 hours, and 0.90 mol of triethylamine was added after filtering off the desiccant. Then, 0.3 mol of N,N'-carbonyldiimidazole was added in batches at 20-25°C, and the stirring was continued for 0.5 hours while maintaining the temperature, and 0.36 mol of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was added, and the stirring was continued at 20-25°C for 6 hours. Add 300g of water, stir for 0.5 hour, let stand, separate the liquids, collect the upper organic phase, concentrate to dryness under reduced pressure at 40°C, add 50g of ethyl acetate and 300g of n-heptane, stir at 40°C for 2 hours, cool to 10-15°C and continue stirring for 1 hour, filter under reduced pressure, collect the solid, and dry at 45±5°C for 6 hours to obtain the final product (5S)-enantiomer of lotirana as a white solid with a molar yield of 91.1%, HPLC purity of 99.91%, and chiral purity of 99.9%.

[0114] The present invention illustrates the detailed method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed method, that is, it does not mean that the present invention must rely on the above-mentioned detailed method to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing Lotiranab, comprising the steps of: Step (i): reacting 5-acetyl-3-methyl-2-thiophenecarboxylic acid with 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one in a solvent in the presence of triethylamine at elevated temperature, then adding a catalyst and acetic anhydride at room temperature and continuing the reaction to obtain the product (E / Z)-3-methyl-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxylic acid; the solvent is selected from toluene, tert-butyl methyl ether, dimethyl ether, and acetone; and the catalyst is selected from p-dimethylaminopyridine, imidazole, and N-methylmorpholine; Step (ii): adding an alkaline aqueous solution containing hydroxylamine hydrochloride to the product solution of step (i) dissolved in an organic solvent under cooling conditions, continuing to heat and stir the reaction solution, adding acid to acidify, collecting the product, and obtaining a racemic product 5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid; the organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and ethanol; Step (iii): reacting the racemic product obtained in step (ii) with (R)-1-(p-tolyl)eth-1-amine in a mixed solvent at an elevated temperature, slowly cooling the mixture and collecting the precipitate to obtain 5-[(5S)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid; Step (iv): acidifying the mixed solution of the (5S)-enantiomeric carboxylic acid product obtained in step (iii) in an aqueous mixed solvent to a pH value of 2 to 3, collecting the organic phase by separation, sequentially adding triethylamine and a condensing agent, and adding 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride to carry out a condensation reaction to obtain a final product, lotirana, of (5S)-enantiomeric configuration; wherein, The condensing agent is selected from: N,N'-carbonyldiimidazole, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, N'N-dicyclohexylcarbodiimide, and 1-n-propyl phosphoric anhydride.

2. according to the method for claim 1, in step (i), described heating condition is the temperature condition of 50 ℃ ~ 70 ℃.

3. According to the method of claim 1, step (i) comprises the following operations: adding 1.0 mol of 5-acetyl-3-methyl-2-thiophenecarboxylic acid, 1.2 mol of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethan-1-one, 1200-1300 g of toluene, and 1-3 mol of triethylamine to a reaction flask, heating and stirring at 50-70° C. to react for 15-25 hours; cooling to room temperature, adding 0.08-0.12 mol of p-dimethylaminopyridine, and adding 2-4 mol of acetic anhydride dropwise at a temperature of 20-25° C. After the addition is completed, the temperature is maintained and the reaction is continued with stirring for 2 hours, and the product is extracted with an aqueous solution and an organic solvent to obtain the product.

4. according to the method for claim 1, in step (ii), described alkaline aqueous solution is an aqueous solution of sodium hydroxide, described sodium hydroxide dosage is 1.0~5.0 equivalents of step (i) product; described hydroxylamine hydrochloride dosage is 1.0~4.0 equivalents of step (i) product; Or, described organic solvent dosage is 3~7 times weight of step (i) product addition amount.

5. According to the method of claim 1, step (ii) comprises the following operations: dissolving 2.87 mol of sodium hydroxide in 500 g of water, cooling to 0-5° C., adding 1.64 mol of hydroxylamine hydrochloride in batches over 0.5 hour, stirring at 0-5° C. for 10 minutes, and obtaining a mixed solution for standby use; adding 1825 g of N,N-dimethylformamide and 0.82 mol of the product of step (i) into a reaction flask to dissolve the materials, and dripping the above-mentioned hydroxylamine hydrochloride mixed solution after cooling to 0-5° C., and continuing to stir the reaction at 0-5° C. for 2 hours after dripping; acidifying with aqueous hydrochloric acid solution, collecting the product, and obtaining a racemic product.

6. The method according to claim 1, wherein in step (iii), the amount of (R)-1-(p-tolyl)eth-1-amine is 0.5 to 0.8 equivalents of the racemic product of step (ii); the mixed solvent is a mixed solvent consisting of n-butanol, acetonitrile and water; or the elevated temperature is 50 to 70°C.

7. According to the method of claim 1, step (iii) comprises the following operations: adding 0.74 mol of the racemic product of step (ii), 500 g of n-butanol, 2000 g of acetonitrile, 150 g of water, and 0.444 mol of (R)-1-(p-tolyl)ethyl-1-amine into a reaction flask, heating to 60° C. and stirring for 2 hours, cooling to 20-25° C. within 4 hours, collecting the solid, and drying to obtain the product.

8. The method according to claim 1, wherein in step (iv), the amount of triethylamine used is 1.0 to 4.0 equivalents of the (5S)-enantiomeric carboxylic acid product obtained in step (iii); the amount of the condensing agent used is 1.0 to 2.0 equivalents of the (5S)-enantiomeric carboxylic acid product obtained in step (iii); or the amount of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride used is 1.05 to 1.2 equivalents of the (5S)-enantiomeric carboxylic acid product obtained in step (iii).

9. The method according to claim 1, wherein step (iv) comprises the following operations: adding 0.30 mol of the (5S)-enantiomer carboxylic acid product obtained in step (iii), 900 g of ethyl acetate and 300 g of water to a reaction flask, adjusting the pH value to 2-3 with concentrated hydrochloric acid while stirring, continuing stirring for 0.5 hour, standing, separating the liquids, collecting the upper organic phase, adding 200 g of anhydrous sodium sulfate to dry, filtering off the desiccant and adding 0.3-1.2 mol of triethylamine; then adding 0.3-0.6 mol of N,N'-carbonyldiimidazole in batches at 20-25°C, maintaining this temperature and continuing stirring for 0.5 hour, adding 0.315-0.36 mol of 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, and continuing stirring at 20-25°C for 6 hours; extracting with water and ethyl acetate / n-heptane mixed solvent in turn to obtain the final product (5S)-enantiomer lotiranab.

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