Preparation method of (5S)-4-[5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-yl]-2-methyl benzoic acid

Abstract

The invention discloses a preparation method of (5S)-4-[5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-yl]-2-methyl benzoic acid, which comprises the following steps: by taking chiral guanidine as a catalyst, in the presence of an additive and a resolving agent, synthesizing (5S)-4-[5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-yl]-2-methyl benzoic acid through a one-step method. The preparation method comprises the following steps: carrying out kinetic resolution reaction on 4-[5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-yl]-2-methyl benzoic acid in a two-phase system consisting of water and a non-polar solvent to generate the (5S)-4-[5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-yl]-2-methyl benzoic acid. According to the method, the kinetic resolution of the (5RS)-4-[5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-yl]-2-methyl benzoic acid is successfully realized, and the enantiomeric excess and the yield of the (5S)-4-[5-(3, 5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3-yl]-2-methyl benzoic acid are improved.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid. Background Art

[0002] Fluphenazine is a synthetic insecticide with the chemical name (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-2-methylbenzamide.

[0003] (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid (IOBA) is a key intermediate in the synthesis of fluphenazine. Its structural formula is shown in Formula 1. It occupies an important position in the entire synthesis route of fluphenazine.

[0004]

[0005] Fluphenazine is a racemic compound. It is reported that the S configuration of fluphenazine is the key component that exerts the main insecticidal activity. The separation of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid plays a key role in the preparation and synthesis of (S)-fluphenazine. The structural formula of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid is shown in formula (1a).

[0006]

[0007] Therefore, how to effectively separate (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-2-methylbenzoic acid into (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-2-methylbenzoic acid to prepare (S)-fluphenazine and improve the yield of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-2-methyl-benzoic acid has become an urgent problem to be solved. Summary of the invention

[0008] The technical problem to be solved by the present invention is: to overcome the deficiencies of the prior art and provide a method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid, which successfully realizes the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid and improves the enantiomeric excess and yield of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid.

[0009] The technical solution adopted by the present invention to solve the technical problem is: a method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid, wherein chiral guanidine is used as a catalyst, in the presence of an additive and a resolving agent, (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as shown in formula 1 is subjected to a kinetic resolution reaction in a two-phase system consisting of water and a non-polar solvent to generate (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as shown in formula (1a), and the reaction formula is as follows:

[0010]

[0011] Furthermore, the chiral guanidine has a structure of formula (2A) or formula (2B),

[0012]

[0013] Furthermore, the molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the chiral guanidine is 1:0.1-0.5.

[0014] Further, the resolving agent has a structure of formula (3A) or formula (3B),

[0015]

[0016] Furthermore, the molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the resolving agent is 1:0.74-2.

[0017] Preferably, the molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the resolving agent is 1:1.

[0018] Furthermore, the additive includes an inorganic base and a surfactant, the inorganic base is lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide, and the surfactant is tetrabutylammonium bromide, tetrabutylammonium chloride, hexadecyltrimethylammonium bromide or hexadecyltrimethylammonium chloride.

[0019] Furthermore, the molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the inorganic base is 1:4-4.5, and the molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the surfactant is 1:1.0-2.0.

[0020] Furthermore, the non-polar solvent is isopropyl acetate, ethyl acetate, n-heptane, cyclopentane, cyclohexane, carbon tetrachloride, toluene, chlorobenzene, chloroform or dichloromethane, and the mass ratio of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the non-polar solvent is 1:3.0-6.0, and the molar ratio to water is 1:0.5-2.5.

[0021] Further, the preparation method of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid specifically comprises the following steps:

[0022] 1) subjecting (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to a kinetic resolution reaction in a two-phase system consisting of water and a non-polar solvent, with chiral guanidine, an inorganic base, a surfactant and a resolution agent, controlling the reaction temperature to 75-95° C., reacting for 2-5 hours and then standing at room temperature overnight to obtain a suspension;

[0023] 2) filtering or centrifuging the suspension to separate the precipitate and the supernatant and discarding the supernatant, washing the precipitate with a corresponding non-polar solvent, filtering or centrifuging the washing liquid again and collecting the precipitate, combining the precipitates, and drying the solid obtained by combining the precipitates overnight;

[0024] 3) suspending the dried solid in ethyl acetate, then adding water and potassium hydrogen sulfate to the resulting suspension, adjusting the pH value to 1, and stirring thoroughly until all the solids are completely dissolved to obtain a mixed solution;

[0025] 4) The mixed solution was allowed to stand for stratification, and the organic phase was collected. At the same time, the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid.

[0026] Furthermore, the step 4) further comprises the step of recovering the chiral guanidine:

[0027] a) collecting the supernatant obtained by filtration or centrifugation in step 2), combining the supernatants as a mother liquor, adding water to the mother liquor, stirring, and then separating the liquids, and collecting the organic phase;

[0028] b) adding water to the organic phase obtained in step a), then slowly adding a sodium hydroxide solution dropwise, adjusting the pH value to 10-12, and then continuing to stir, separating the liquids, and collecting the organic phase;

[0029] c) adding ammonium chloride solution to the organic phase obtained in step b), adjusting the pH value to 8.5-9.0, and then continuing to stir, separate the liquids, and collect the aqueous phase;

[0030] d) adding dilute hydrochloric acid to the aqueous phase to adjust the pH value to 5.5-6.0, then adding dichloromethane to extract the aqueous phase, collecting the dichloromethane phase, adding anhydrous magnesium sulfate thereto to dry and remove water, filtering to remove the magnesium sulfate solid, and then concentrating the filtrate obtained by the filtration under reduced pressure to obtain a dichloromethane concentrate;

[0031] e) slowly passing dried HCl gas into the dichloromethane concentrate, and after continuous aeration for 2 hours, the obtained suspension is filtered, and the filter cake obtained by filtration is washed with dichloromethane, and finally the washed solid is dried under reduced pressure at room temperature to obtain chiral guanidine.

[0032] The beneficial effects of the preparation method of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid of the present invention are as follows:

[0033] The preparation method of the present invention is simple, does not require complex equipment, and also avoids the need for a chromatographic purification step. It uses chiral guanidine as a catalyst and in the cooperation of an inorganic base and a resolving agent, the chiral guanidine catalyst guanidine group has a strong alkalinity and can activate the substrate through a proton transfer process. In the catalytic reaction, the chiral guanidine can capture a proton from the substrate molecule, so that the substrate molecule forms an active intermediate. The chiral guanidine is combined with the substrate through non-covalent interactions (such as hydrogen bonds, electrostatic effects, π-π stacking, etc.). These interactions enable the substrate to be combined with the chiral guanidine in a specific orientation during the reaction. In this reaction, the chiral guanidine catalyst catalyzes the ring-opening of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid by an inorganic base to close the ring in a specific orientation and precipitate from the reaction system, continuously promoting the conversion of the racemic intermediate into the expected product of S configuration, and successfully achieving the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid. . The separation method can not only obtain the intermediate (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid which is of great value in synthesizing (S)-fluphenazine, but also can make the enantiomeric excess of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid reach 95% and the yield reach 87%, thereby greatly improving the yield of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 - Chromatogram of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid prepared in Example 1;

[0035] Figure 2 - Chromatogram of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid prepared in Example 2;

[0036] Figure 3 - Chromatogram of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid prepared in Example 3;

[0037] Figure 4- Chromatogram of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid prepared in Example 4;

[0038] Figure 5 — is the chromatogram of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid prepared in Comparative Example 1. DETAILED DESCRIPTION

[0039] The present invention is further described below in conjunction with the accompanying drawings and examples, but these specific implementation schemes do not limit the protection scope of the present invention in any way.

[0040] Example 1

[0041] A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid comprises: using chiral guanidine (having the structural formula of formula (2A)) as a catalyst, in the presence of an inorganic base, a surfactant and a resolving agent (having the structural formula of formula (3C)), in a two-phase system consisting of water and a non-polar solvent, a kinetic resolution reaction is performed to generate (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as shown in formula (1a), wherein the reaction formula is as follows:

[0042]

[0043] The specific steps are as follows:

[0044] 1) In a 1000 mL round-bottom flask, (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid (130.00 g, 1.00 molar equivalent), a chiral guanidine catalyst (Formula (2A), 28.08 g, 0.10 molar equivalent), lithium hydroxide (29.78 g, 4.00 molar equivalent), a resolving agent (Formula (3B), 51.35 g, 1.00 molar equivalent), isopropyl acetate (520.00 g, 4.00 times the weight), tetrabutylammonium bromide (15.32 g, 1.50 molar equivalent) and water (130.00 g, 1.00 molar equivalent) were added in sequence, the reaction temperature in the round-bottom flask was controlled to be 85° C., the reaction was heated for 5 hours and then allowed to stand at room temperature overnight to obtain a suspension;

[0045] 2) filtering or centrifuging the suspension to separate the precipitate and the supernatant and discarding the supernatant, washing the precipitate with isopropyl acetate, filtering or centrifuging the washing liquid again and collecting the precipitate, combining the precipitates, and drying the solid obtained by combining the precipitates overnight;

[0046] 3) suspending the dried solid in ethyl acetate, then adding water and potassium hydrogen sulfate to the resulting suspension, adjusting the pH value to 1, and stirring thoroughly until all the solids are completely dissolved to obtain a mixed solution;

[0047] 4) The mixed solution was allowed to stand for stratification, and the organic phase was collected. At the same time, the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain 113.10 g of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid. The chromatogram is shown in Figure 1 As shown, the peak area (purity) is 97.51%, the yield is 87%, and the enantiomeric excess (ee value) is 95%.

[0048] Example 2

[0049] The difference between this example and Example 1 is that a resolving agent having the structural formula (3A) is used. The chromatogram of 113.10 g of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid obtained in this example is shown in FIG. Figure 2 As shown, the purity is 96.13%.

[0050] Example 3

[0051] The difference between this embodiment and embodiment 1 is that a chiral guanidine catalyst having the structural formula (2B) is used. The chromatogram of 113.10 g of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid obtained in this embodiment is shown in FIG. Figure 3 As shown, the purity is 96.97%.

[0052] Example 4

[0053] The difference between this embodiment and embodiment 3 is that a chiral guanidine catalyst having the structural formula (3A) is used. The chromatogram of 113.10 g of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid obtained in this embodiment is shown in FIG. Figure 4 As shown, the purity is 95.57%.

[0054] Example 5

[0055] The difference between this embodiment and embodiment 1 is that: the step 4) further includes a step of recovering chiral guanidine, and the operation steps of recovering chiral guanidine are as follows:

[0056] a) collecting the supernatant obtained by filtration or centrifugation in step 2), combining the supernatants as a mother liquor, adding 390 g of water to the mother liquor, stirring for 0.5 h, and then separating the liquids to collect the isopropyl acetate phase;

[0057] b) adding 520 g of water to the isopropyl acetate phase obtained in step a), and then slowly adding a 4M sodium hydroxide solution dropwise, adjusting the pH value to 10-12 and continuing stirring for 0.5 h, separating the liquids, and collecting the isopropyl acetate phase;

[0058] c) adding 1M ammonium chloride solution to the isopropyl acetate phase obtained in step b), adjusting the pH value to 8.5-9.0, and continuing stirring for 0.5h, separating the liquids, and collecting the aqueous phase;

[0059] d) adding 2M dilute hydrochloric acid to the aqueous phase to adjust the pH value to 5.5-6.0, then adding 260g of dichloromethane, extracting the aqueous phase, collecting the dichloromethane phase, adding anhydrous magnesium sulfate to dry and remove water, filtering to remove magnesium sulfate solid, and then concentrating the filtrate obtained by filtering under reduced pressure to concentrate the dichloromethane solution to about 140g to obtain a dichloromethane concentrate;

[0060] e) Slowly passing dried HCl gas into the dichloromethane concentrate, and after continuous ventilation for 2 hours, the obtained suspension was filtered, and the filter cake obtained by filtration was washed with dichloromethane. Finally, the washed solid was placed at room temperature and dried under reduced pressure to obtain 17.9 g of light yellow crystalline chiral guanidine with a purity of 95% and a yield of 64%.

[0061] The differences between the preparation methods of the above Examples 1-4 and the yields and enantiomeric excess values ​​of the prepared products are shown in the following table:

[0062] Table 1 The differences between the preparation methods of Examples 1-4 and the yield and ee value of the prepared products

[0063]

[0064] Comparative Example 1

[0065] The difference between this comparative example 1 and embodiment 1 is that step 1) is different. The specific operation of step 1) is as follows:

[0066] In a 1000 mL round-bottom flask, (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (130.00 g, 1.00 molar equivalent), (S)-1-phenylethylamine (51.35 g, 1.00 molar equivalent), isopropyl acetate (520.00 g, 4.00 times weight) were added in sequence, and the reaction temperature in the round-bottom flask was controlled to be 85° C. After heating the reaction for 5 hours, the mixture was allowed to stand at room temperature overnight to obtain a suspension. The chromatogram of 113.10 g (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid obtained in this comparative example is shown in FIG. Figure 5 As shown, the purity is 69.66%.

[0067] Comparative Example 2

[0068] The difference between this comparative example 1 and example 1 is that the resolving agent in step 1) is (S)-1-phenylethylamine.

[0069] Comparative Example 3

[0070] The difference between Comparative Example 1 and Example 1 is that the catalyst in step 1) is quinine.

[0071] Comparative Example 4

[0072] The difference between this comparative example 1 and example 1 is that lithium hydroxide is not added in step 1).

[0073] Comparative Example 5

[0074] The difference between this comparative example 1 and example 1 is that no water is added in step 1).

[0075] Comparative Example 6

[0076] The difference between this comparative example and Example 3 is that the resolving agent in step 1) is (S)-1-phenylethylamine.

[0077] The yield and enantiomeric excess of the product ((5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid)) prepared in Example 1 and Comparative Examples 1-6 are shown in the following table:

[0078] Table 2 Yield and ee value of the products prepared in Example 1 and Comparative Examples 1-6

[0079] Yield / % ee value / % Example 1 87 95 Comparative Example 1 23.5 40 Comparative Example 2 24.2 62 Comparative Example 3 25 74 Comparative Example 4 23.8 50 Comparative Example 5 32 86 Comparative Example 6 24 55

[0080] As can be seen from the above table, the yields and ee values ​​corresponding to Comparative Examples 1-6 are significantly lower than those in Example 1. In Comparative Example 1, when performing the resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to prepare (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid, no catalyst, inorganic base, or solvent is used, and water is not used as the solvent. The resolution agent used is (S)-1-phenylethylamine, and the corresponding yields and ee values ​​are only 23.5% and 40%, which are lower than those of Comparative Examples 2-6;

[0081] Compared with Examples 1 and 3, Comparative Examples 2 and Comparative Examples 6 respectively use conventional resolving agents ((S)-1-phenylethylamine), and the corresponding yields and enantiomeric excess values ​​of the two are significantly lower than those of Examples 1 and 3, indicating that the combination of conventional resolving agents with chiral guanidine catalysts and inorganic bases cannot effectively achieve dynamic slow resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid into (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid. Only by using the resolving agent of formula (3A) and formula (3B) in combination with chiral guanidine and inorganic base in the present invention can the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid be achieved, so that the yield and enantiomeric excess of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid reach 80% and 90% or more, respectively;

[0082] Compared with Example 1, Comparative Example 3 uses a conventional catalyst (quinine) to replace the chiral guanidine catalyst, and the corresponding yield and enantiomeric excess values ​​are significantly lower than those of Example 1, indicating that the combination of conventional catalysts, resolving agents and inorganic bases cannot effectively achieve dynamic slow resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- Toluic acid, only by using the chiral guanidine catalyst of formula (2A) and formula (2B) in combination with the inorganic base as a resolving agent in the present invention can the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid be achieved, so that the yield and enantiomeric excess of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid reach 80% and 90% or more, respectively;

[0083] Compared with Example 1, Comparative Example 4 did not use an inorganic base. The results showed that the corresponding yield and enantiomeric excess value were not significantly different from those of Comparative Example 1, but were significantly lower than those of Example 1. This indicates that the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid cannot be achieved without adding an inorganic base during the resolution. This may be because the presence of an inorganic base can make (5RS)-4-[5-(3,5 The invention discloses a method for preparing (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid by ring-opening, and under the catalytic action of a chiral guanidine catalyst, the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid ring-opened by an inorganic base can be ring-closed in a specific orientation and precipitated from the reaction system, thereby continuously promoting the conversion of the racemic intermediate into the expected product of S configuration, thereby improving the yield and the enantiomeric excess value. The results show that the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid can be successfully achieved only in the presence of an inorganic base chiral guanidine catalyst.

[0084] Compared with Example 1, Comparative Example 5 does not use water in the solvent. Although the corresponding yield and enantiomeric excess values ​​are higher than those of Comparative Example 1, they are still significantly lower than those of Example 1, indicating that the kinetic resolution reaction of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid using a two-phase system consisting of water and a non-polar solvent can achieve better resolution effect than a single-phase system using only a non-polar solvent.

[0085] Experimental Example 1 Investigation of Resolving Agents and Non-polar Solvents

[0086] In this experimental example, (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid) was prepared by referring to the method of Example 1. In step 1), sodium hydroxide was used as an inorganic base, and different resolving agents (Formula (3A-F) and non-polar solvents (ethyl acetate, isopropyl acetate) were replaced respectively. The other steps were the same as those in Example 1. The effects of different resolving agents and non-polar solvents on enantiomeric excess and product yield were studied. The results are shown in Table 4:

[0087] The structural formulas of formula (3C), formula (3D), formula (3E), and formula (3F) are as follows:

[0088]

[0089] Table 4 Effect of different resolving agents and non-polar solvents on the yield and enantiomeric excess of the product ((5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid))

[0090]

[0091] As can be seen from the above table, the enantiomeric excess and yield corresponding to the resolving agents represented by formula (3B) and formula (3A) used in the present invention are significantly higher than those represented by formula (3C), formula (3D), formula (3E) and formula (3F), and the combination of the resolving agent formula (3B) and isopropyl acetate can achieve the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid with a higher enantiomeric excess value and yield.

[0092] Experimental Example 2 Investigation of Inorganic Bases

[0093] In this experimental example, (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid) was prepared by referring to the method of Example 1. Different inorganic bases (lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide) were used in step 1). The other steps were the same as those in Example 1. The effects of different resolving agents and non-polar solvents on enantiomeric excess and product yield were studied. The results are shown in Table 5:

[0094] Table 5 Effect of different inorganic bases on the yield and enantiomeric excess of the product ((5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid))

[0095] Yield / % ee value / % Lithium hydroxide 87 95 Sodium hydroxide 86 94 Potassium hydroxide 60 76 Cesium Hydroxide 55 70

[0096] As can be seen from the above table, with the increase of alkalinity, the yield and enantiomeric excess of the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid decreased. The use of lithium hydroxide and sodium hydroxide as inorganic bases can achieve the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid with higher enantiomeric excess and yield.

[0097] Experimental Example 2 Investigation of the amount of inorganic alkali used

[0098] In this experimental example, (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid) was prepared by referring to the method of Example 1. Different inorganic bases (lithium hydroxide and sodium hydroxide) were used in step 1). The effect of the molar ratio of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid to the inorganic base on the enantiomeric excess and product yield was shown in Table 6.

[0099] Table 6 Effect of the amount of inorganic base used on enantiomeric excess and product yield

[0100]

[0101] It can be seen from the above table that with the increase of the base content, the yield and enantiomeric excess of the kinetic resolution of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid both show a trend of first increasing and then decreasing, and when the molar ratio is 1:4-4.5, the corresponding enantiomeric excess is higher than 90%, and the yield is higher than 80%. Therefore, the preferred molar ratio of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the inorganic base is 1:4-4.5.

[0102] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technician familiar with this profession can make some changes or modifications to equivalent embodiments of equivalent changes using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid, characterized in that: With chiral guanidine as a catalyst, in the presence of an additive and a resolving agent, (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as shown in Formula 1 is subjected to a kinetic resolution reaction in a two-phase system consisting of water and a non-polar solvent to generate (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as shown in Formula (1a), and the reaction formula is as follows:

2. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as claimed in claim 1, characterized in that: The chiral guanidine has a structure of formula (2A) or formula (2B), 3. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as claimed in claim 2, characterized in that: The molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the chiral guanidine is 1:0.1-0.

5.

4. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as claimed in claim 1, characterized in that: The resolving agent has a structure of formula (3A) or formula (3B), 5. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as claimed in claim 4, characterized in that: The molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the resolving agent is 1:0.74-2.

6. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as claimed in claim 1, characterized in that: The additive comprises an inorganic base and a surfactant, wherein the inorganic base is lithium hydroxide or sodium hydroxide, and the surfactant is tetrabutylammonium bromide, tetrabutylammonium chloride, hexadecyltrimethylammonium bromide or hexadecyltrimethylammonium chloride.

7. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as claimed in claim 1, characterized in that: The molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the inorganic base is 1:4-4.5, and the molar ratio of the (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the surfactant is 1:1.0-2.

0.

8. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as claimed in claim 1, characterized in that: The non-polar solvent is isopropyl acetate, ethyl acetate, n-heptane, cyclopentane, cyclohexane, carbon tetrachloride, toluene, chlorobenzene, chloroform or dichloromethane, and the mass ratio of (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to the non-polar solvent is 1:3.0-6.0, and the molar ratio to water is 1:0.5-2.

5.

9. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid according to any one of claims 1 to 8, characterized in that: The specific steps include: 1) subjecting (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid to a kinetic resolution reaction in a two-phase system consisting of water and a non-polar solvent, with chiral guanidine, an inorganic base, a surfactant and a resolution agent, controlling the reaction temperature to 75-95° C., reacting for 2-5 hours and then standing at room temperature overnight to obtain a suspension; 2) filtering or centrifuging the suspension to separate the precipitate and the supernatant and discarding the supernatant, washing the precipitate with a corresponding non-polar solvent, filtering or centrifuging the washing liquid again and collecting the precipitate, combining the precipitates, and drying the solid obtained by combining the precipitates overnight; 3) suspending the dried solid in ethyl acetate, then adding water and potassium hydrogen sulfate to the resulting suspension, adjusting the pH value to 1, and stirring thoroughly until all the solids are completely dissolved to obtain a mixed solution; 4) The mixed solution was allowed to stand for stratification, and the organic phase was collected. At the same time, the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid.

10. A method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methylbenzoic acid as described in claim 9, characterized in that: The step 4) also includes a step of recovering chiral guanidine: a) collecting the supernatant obtained by filtration or centrifugation in step 2), combining the supernatants as a mother liquor, adding water to the mother liquor, stirring, and then separating the liquids, and collecting the organic phase; b) adding water to the organic phase obtained in step a), then slowly adding a sodium hydroxide solution dropwise, adjusting the pH value to 10-12, and then continuing to stir, separating the liquids, and collecting the organic phase; c) adding ammonium chloride solution to the organic phase obtained in step b), adjusting the pH value to 8.5-9.0, and then continuing stirring, separating the liquids, and collecting the aqueous phase; d) adding dilute hydrochloric acid to the aqueous phase to adjust the pH value to 5.5-6.0, then adding dichloromethane to extract the aqueous phase, collecting the dichloromethane phase, adding anhydrous magnesium sulfate thereto to dry and remove water, filtering to remove the magnesium sulfate solid, and then concentrating the filtrate obtained by the filtration under reduced pressure to obtain a dichloromethane concentrate; e) slowly passing dried HCl gas into the dichloromethane concentrate, and after continuous aeration for 2 hours, the obtained suspension is filtered, and the filter cake obtained by filtration is washed with dichloromethane, and finally the washed solid is dried under reduced pressure at room temperature to obtain chiral guanidine.

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