A chiral oxazoline diester derivative and its preparation method and application

Abstract

The present invention discloses chiral oxazoline diester derivatives, their preparation methods, and applications, belonging to the fields of organic synthesis and medicinal chemistry. The present invention utilizes a one-pot method to design and synthesize a series of chiral oxazoline diester derivatives. The method first catalyzes an asymmetric Adol addition reaction of a racemic oxazoline ester derivative with paraformaldehyde, followed by an esterification reaction with various pharmacophore-containing carboxylic acids to ultimately obtain the target compound. The present invention prepares chiral diester compounds with oxazoline structures and provides their chemical structures. Antifungal and antioomycete activity results demonstrate that these compounds exhibit excellent antifungal and antioomycete activity and significant enantioselective activity.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis and medicinal chemistry, in particular to a chiral oxazoline diester derivative and a preparation method and application thereof. Background Art

[0002] Oxazolines, as important oxygen- and nitrogen-containing five-membered heterocyclic compounds, have broad application prospects in natural products, material synthesis, asymmetric catalysis, anticancer, antibacterial, antiviral, antifungal, and acaricides / insecticides. However, relatively little research has been conducted on the biological activities of chiral oxazolines.

[0003] The reported oxazoline natural product yanglingmycin exhibits good antibacterial activity as an S-configuration, but its enantiomeric R-configuration compound spoxazomicins C / nocazoline A shows some anti-trypanosomal activity but no obvious antibacterial or antifungal activity. Summary of the Invention

[0004] The object of the present invention is to provide a method for preparing chiral oxazoline diester derivatives to solve the problems raised in the above background technology.

[0005] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0006] A chiral oxazoline diester derivative is an optically active compound, including a levorotatory or dextrorotatory isomer as shown in the following structural formula:

[0007] or ;

[0008] In the formula, * represents a chiral carbon atom; R 1 is any one of an aryl group and a heteroaryl group; R 2 is any one of an alkyl group, an aryl group and a heteroaryl group.

[0009] Preferably, the structural formula of the chiral oxazoline diester derivative is any one of the following formulae:

[0010] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; .

[0011] Another object of the present invention is to provide a method for preparing the chiral oxazoline diester derivative, which comprises the following steps:

[0012] The invention uses racemic oxazoline ester derivatives and polyformaldehyde compounds as starting materials, tetraacetonitrile copper tetrafluoroborate as catalyst, and chiral ferrocene reagent as ligand. With the assistance of base, the reaction undergoes Adol reaction. After removing the solvent, the reaction is reacted with formaldehyde or polyformaldehyde in the presence of an activating reagent, an acyl transfer reagent and a base in a one-pot method to prepare chiral oxazoline diester compounds.

[0013] Preferably, the method specifically includes the following steps:

[0014] Under nitrogen protection, tetraacetonitrile copper tetrafluoroborate, a chiral ligand, and an anhydrous solvent are mixed and stirred, and a racemic oxazoline ester derivative, formaldehyde or paraformaldehyde, a base, and an anhydrous solvent are added in sequence, and stirring is continued to carry out a reaction; after the reaction is completed, the solvent is removed under reduced pressure; then, a carboxylic acid, an activation reagent, an acyl transfer reagent, a base, and an organic solvent are added in sequence, and stirring is carried out to react; after the reaction is completed, the reaction solution is filtered through diatomaceous earth, and the filtrate is then concentrated under reduced pressure, and finally purified by silica gel column chromatography to obtain the chiral oxazoline diester derivative;

[0015] Among them, the structural formula of the racemic oxazoline ester derivative is:

[0016] .

[0017] Preferably, the method for synthesizing the racemic oxazoline ester derivative comprises the following steps:

[0018] Ethanol and benzonitrile are mixed, and then acetyl chloride is slowly added dropwise in an ice bath to react; the solvent is then removed under reduced pressure to obtain a white solid; the white solid is washed with ether, and then a saturated sodium bicarbonate solution is added until the gas disappears; the resulting mixed solution is extracted with ethyl acetate, and the organic phase is collected, dried, and concentrated under reduced pressure to obtain an imidate intermediate;

[0019] An imidate intermediate, chloroform, and serine ethyl ester hydrochloride are mixed, and then triethylamine is added dropwise to react to form a red solution; after the red solution is decompressed to remove the solvent, a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution are added respectively, and extraction is performed with ethyl acetate. The organic phase is collected, dried, decompressed, and the solvent is removed, and purified by silica gel column chromatography to obtain the racemic oxazoline ester derivative.

[0020] Preferably, the method for synthesizing the racemic oxazoline ester derivative comprises the following steps:

[0021] Carboxylic acid, serine ethyl ester hydrochloride, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and dichloromethane are mixed and stirred for reaction, followed by adding a saturated sodium bicarbonate solution to obtain a mixed solution, which is extracted with dichloromethane. The organic phase is collected, dried, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain an amide intermediate;

[0022] Under nitrogen protection, the amide intermediate and anhydrous dichloromethane are mixed, and diethylaminosulfur trifluoride is slowly added dropwise at -40°C with continuous stirring; the reaction is monitored by thin-layer chromatography until the starting material is completely consumed; a saturated sodium bicarbonate solution is then added to quench the reaction, and the mixture is extracted with dichloromethane. The organic phase is collected, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the racemic oxazoline ester derivative.

[0023] Preferably, the molar ratio of tetraacetonitrile copper tetrafluoroborate, the chiral ligand and the racemic oxazoline ester derivative is 0.1:0.12:1; the molar equivalent ratio of the racemic oxazoline ester derivative to formaldehyde or paraformaldehyde is 1:(1-10); the molar ratio of the racemic oxazoline ester derivative to the base is 1:(1-3); the molar ratio of the racemic oxazoline ester derivative to the carboxylic acid is 1:(1-2); and the molar ratio of the racemic oxazoline ester derivative, the activating reagent, the acyl transfer reagent and the base is 1:3:3:3.

[0024] Preferably, the base is at least one of potassium acetate, potassium carbonate, potassium phosphate, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, 1,8-diazobisspiro[5.4.0]undec-7-ene, cesium carbonate and triethylenediamine;

[0025] The anhydrous solvent is an anhydrous organic solvent; the organic solvent is independently at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, 1,4-dioxane, acetonitrile, acetone, ethyl acetate, methanol, ethanol, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide;

[0026] The activation reagent and the acyl transfer reagent are independently at least one of 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0027] The chiral ligand is any one of (2R)-1-[(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]-2-(diphenylphosphino)ferrocene, (4S)-tert-butyl-(2R)-[2-(diphenylphosphino)ferrocenyl]-2-oxazoline, (S)-1-(diphenylphosphino)-2-[(S)-4-isopropyloxazolin-2-yl]ferrocene and (S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)-phosphino)ferrocen-1-yl]oxazoline.

[0028] Another object of the embodiments of the present invention is to provide a use of the above-mentioned chiral oxazoline diester derivatives in the preparation of antifungal and / or oomycete drugs.

[0029] Preferably, the fungal and / or oomycete drugs include at least one of apple black rot fungus, sclerotinia sclerotiorum, Botrytis cinerea, Sclerotinia solani, Fusarium graminearum, Pythium graminearum, Trichoderma, Curvularia lunata and Phytophthora capsici.

[0030] The present invention provides a method for preparing chiral oxazoline diester derivatives, utilizing a one-pot process to design and synthesize a series of chiral oxazoline diester derivatives. The method first catalyzes an asymmetric Adol addition reaction of a racemic oxazoline ester derivative with paraformaldehyde or formaldehyde to establish an oxygen bridge, followed by an esterification reaction with various pharmacophore-containing carboxylic acids to ultimately obtain diester compounds containing an aromatic substituted oxazoline structure. The present invention prepares diester compounds with chiral oxazoline structures and provides their chemical structures. Antifungal / antiumomycete activity results demonstrate that these compounds exhibit excellent antifungal / antiumomycete activity and significant enantioselective activity, indicating that these compounds have broad agricultural application prospects and lay the foundation for the further development and application of pesticide molecules. DETAILED DESCRIPTION

[0031] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0032] In one embodiment of the present invention, a chiral oxazoline diester derivative is provided, which is an optically active compound, including a levorotatory or dextrorotatory isomer as shown in the following structural formula:

[0033] or ;

[0034] In the formula, * represents a chiral carbon atom; R 1 is any one of an aryl group and a heteroaryl group; R 2 is any one of an alkyl group, an aryl group and a heteroaryl group.

[0035] The present invention uses racemic oxazoline ester, formaldehyde / paraformaldehyde and carboxylic acid compounds as starting materials, copper tetrafluoroborate tetraacetonitrile as a catalyst, and a chiral ferrocene reagent as a ligand. With the assistance of a base and a condensing agent, a class of chiral oxazoline diester compounds are prepared in a precise and rapid manner with high yield and high enantioselectivity for the first time. The target compound is obtained by structural design of the aryl-substituted oxazoline ester and carboxylic acid and substrate amplification.

[0036] Specifically, the synthesis route of the chiral oxazoline diester derivatives is as follows:

[0037] ;

[0038] Wherein, * represents a chiral carbon atom; R 1 is any one of an aryl group and a heteroaryl group; R 2 is any one of an alkyl group, an aryl group and a heteroaryl group.

[0039] In practical applications, the preparation method of the above-mentioned chiral oxazoline diester derivatives comprises the following steps:

[0040] S1. Ethanol and benzonitrile (compound 1 in the above synthetic route) are mixed, and acetyl chloride is slowly added dropwise in an ice bath to react. The reaction mixture is stirred at room temperature; the solvent is then removed under reduced pressure to obtain a white solid; the white solid is washed with diethyl ether, and a saturated sodium bicarbonate solution is added until the gas disappears; the resulting mixed solution is extracted with ethyl acetate, and the organic phase is collected, dried, and concentrated under reduced pressure to obtain an imidate intermediate (compound 2 in the above synthetic route);

[0041] Alternatively, a carboxylic acid (compound 1' in the above synthetic route), ethyl serine hydrochloride, 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and dichloromethane are mixed and stirred for reaction, followed by addition of a saturated sodium bicarbonate solution to obtain a mixed solution, which is extracted with dichloromethane. The organic phase is collected, dried, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain an amide intermediate (compound 2' in the above synthetic route).

[0042] S2. The imidate intermediate, chloroform, and serine ethyl ester hydrochloride are mixed, and triethylamine is then added dropwise to react to form a red solution; after removing the solvent from the red solution under reduced pressure, a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution are added, respectively, and extracted with ethyl acetate. The organic phase is collected, dried, and the solvent is removed under reduced pressure, and purified by silica gel column chromatography to obtain a racemic oxazoline ester derivative (compound 3 in the above synthetic route);

[0043] Alternatively, under nitrogen protection, the amide intermediate and anhydrous dichloromethane are mixed, and diethylaminosulfur trifluoride (DAST) is slowly added dropwise at -40°C with continuous stirring; the reaction is monitored by thin-layer chromatography until the starting material is completely consumed; saturated sodium bicarbonate solution is then added to quench the reaction, and the mixture is extracted with dichloromethane. The organic phase is collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a racemic oxazoline ester derivative (compound 3 in the above synthetic route).

[0044] S3. Under nitrogen protection, add copper tetrafluoroborate tetraacetonitrile, a chiral ligand, and an anhydrous solvent to a dry reaction vessel, mix and stir at 20°C, and sequentially add the racemic oxazoline ester derivative, formaldehyde or paraformaldehyde, a base, and an anhydrous solvent, and continue stirring at 20°C to react; after the reaction is completed, remove the solvent under reduced pressure; then add carboxylic acid, an activating reagent, an acyl transfer reagent, a base, and an organic solvent in sequence, and stir and react at 20°C; after the reaction is completed, filter the reaction solution with diatomaceous earth, then concentrate the filtrate under reduced pressure, and finally purify by silica gel column chromatography to obtain a chiral oxazoline diester derivative (compound 4 in the above synthetic route);

[0045] The molar ratio of tetraacetonitrile copper tetrafluoroborate, the chiral ligand and the racemic oxazoline ester derivative is 0.1:0.12:1; the molar equivalent ratio of the racemic oxazoline ester derivative to formaldehyde or paraformaldehyde is 1:(1-10); the molar ratio of the racemic oxazoline ester derivative to the base is 1:(1-3); the molar ratio of the racemic oxazoline ester derivative to the carboxylic acid is 1:(1-2); and the molar ratio of the racemic oxazoline ester derivative, the activation reagent, the acyl transfer reagent and the base is 1:3:3:3.

[0046] In addition, the base is at least one of potassium acetate, potassium carbonate, potassium phosphate, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, 1,8-diazobisspiro[5.4.0]undec-7-ene, cesium carbonate and triethylenediamine;

[0047] The anhydrous solvent is an anhydrous organic solvent; the organic solvent is independently at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, 1,4-dioxane, acetonitrile, acetone, ethyl acetate, methanol, ethanol, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide;

[0048] The activation reagent and the acyl transfer reagent are independently at least one of 1-hydroxybenzotriazole (HOBT), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP) and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU);

[0049] The chiral ligand is any one of (2R)-1-[(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]-2-(diphenylphosphino)ferrocene, (4S)-tert-butyl-(2R)-[2-(diphenylphosphino)ferrocenyl]-2-oxazoline, (S)-1-(diphenylphosphino)-2-[(S)-4-isopropyloxazolin-2-yl]ferrocene, and (S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)-phosphino)ferrocen-1-yl]oxazoline.

[0050] The following embodiments are some specific implementation cases of the present invention in practical applications, but are not limited to them.

[0051] It should be noted that the column chromatography conditions in the examples of the present invention are: 200-300 mesh column chromatography silica gel powder. In addition, the molar numbers marked in the examples of the present invention represent the amount of the substance used in the reaction system.

[0052] Example 1: This example provides a method for preparing compound (R)-4a. The synthetic route of compound (R)-4a is as follows:

[0053] ;

[0054] Step 1: Combine ethanol and benzonitrile 1a and stir in a round-bottom flask. Then, slowly add acetyl chloride dropwise over 20 minutes in an ice bath. Stir the reaction mixture at room temperature for 4 hours. The solvent is then removed under reduced pressure to yield a white solid. Wash the solid with ether, then add saturated sodium bicarbonate solution until the gas disappears. The resulting mixture is extracted three times with ethyl acetate. The organic phase is collected, dried, and concentrated under reduced pressure to yield the desired imidate 2a.

[0055] Step 2: The above-mentioned imidate 2a, chloroform, and serine ethyl ester hydrochloride were mixed and stirred in a round-bottom flask. Triethylamine was then added dropwise and the reaction was continued for 15 hours to form a red solution. After the solvent was removed from the reaction mixture under reduced pressure, saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution were added, respectively, and extracted twice with ethyl acetate. The organic phase was collected, dried, and the solvent was removed under reduced pressure. The product was purified by silica gel column chromatography to obtain compound 3a.

[0056] Alternatively, Step 3: Benzoic acid 1a', ethyl serine hydrochloride, 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and dichloromethane were added to a round-bottom flask and stirred for 15 hours. Saturated sodium bicarbonate solution was then added to the resulting mixture, which was extracted three times with dichloromethane. The organic phase was collected, dried, and concentrated under reduced pressure. Purification by silica gel column chromatography afforded the amide intermediate 2a'.

[0057] Step 4: Under nitrogen, add the above-mentioned amide intermediate 2a' and anhydrous dichloromethane to a round-bottom flask. Slowly add diethylaminosulfur trifluoride (DAST) dropwise at -40°C with constant stirring. Monitor the reaction by thin-layer chromatography until the starting material is completely consumed. Then, saturated sodium bicarbonate solution is added to quench the reaction, and the product is extracted three times with dichloromethane. The organic phase is collected, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography affords product 3a.

[0058] Step 5: Under nitrogen, add the following reagents to a dry Schlenk flask: copper tetrafluoroborate (10 mol %, 0.015 mmol), the ligand (4S)-tert-butyl-(2R)-[2-(diphenylphosphino)ferrocenyl]-2-oxazoline (12 mol %, 0.018 mmol), and anhydrous toluene (0.5 mL). Stir at 20°C for 0.5 h. Then, add compound 3 (0.15 mmol), paraformaldehyde (1.5 mmol), potassium acetate (0.3 mmol), and anhydrous toluene (1 mL). Stir at 20°C for 24 h. After completion of the reaction, remove the solvent under reduced pressure. Subsequently, 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.45 mmol), 4-dimethylaminopyridine (DMAP) (0.45 mmol), triethylamine (0.45 mmol), and dichloromethane (2 mL) were added sequentially, and the mixture was stirred at 20°C for 15 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Compound (R)-4a was purified by silica gel column chromatography.

[0059] Compound (R)-4a is named: (R)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-2-phenyl-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and its structural formula is shown below:

[0060] ;

[0061] Compound (R)-4a was a brown liquid with a yield of 84%; 1 H NMR (400 MHz, Chloroform-d) δ8.03 - 7.95 (m, 2H, Ph-H), 7.92 (s, 1H, Ar-H), 7.59 - 7.48 (m, 1H, Ph-H),7.47 - 7.37 (m, 2H, Ph-H), 4.97 (d, J = 9.2 Hz, 1H, CH2), 4.83 (d, J = 11.1Hz, 1H, CH2), 4.56 - 4.42 (m, 2H, CH2), 4.35 - 4.22 (m, 2H, CH2), 3.93 (s, 3H,CH3), 1.30 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (101 MHz, Chloroform-d) δ 170.30,166.88, 160.19, 141.48 (q, J = 38.2 Hz), 136.99, 132.23, 128.87, 128.51,126.84, 120.29 (q, J = 269.6 Hz), 112.45, 77.10, 72.55, 66.97, 62.45, 40.02,14.17. 19 F NMR (376 MHz, Chloroform-d) δ -62.10. ESI MS: calculated[C 19 H 18 F3N3O5 + H] + : 426.1271, found: 426.1268. [α] 20 D = 87.7 (c = 0.39, CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee(CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flowrate: 1.0 mL / min), t1 (major) = 9.3 min, t2 (minor) = 10.2 min.

[0062] Example 2: This example provides a method for preparing compound (R)-4b, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with p-fluorobenzonitrile or p-fluorobenzoic acid. The resulting compound (R)-4b is (R)-2-(4-fluorophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0063] ;

[0064] Compound (R)-4b was a brown liquid with a yield of 83%; 1H NMR (400 MHz, Chloroform-d) δ8.03 - 7.96 (m, 2H, Ph-H), 7.94 (s, 1H, Ar-H), 7.16 - 7.05 (m, 2H, Ph-H),4.96 (d, J = 9.2 Hz, 1H, CH2), 4.82 (d, J = 11.1 Hz, 1H, CH2), 4.56 - 4.43 (m,2H, CH2), 4.36 - 4.22 (m, 2H, CH2), 3.95 (s, 3H, CH3), 1.30 (t, J = 7.1 Hz,3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.25, 165.96, 165.24 (d, J =252.8 Hz), 160.22, 141.41 (q, J = 38.6 Hz), 137.03, 131.23 (d, J = 9.0 Hz),123.10 (d, J = 3.1 Hz), 120.28 (q, J = 269.6 Hz), 115.70 (d, J = 22.0 Hz),112.45, 72.67, 66.92, 62.49, 40.04, 14.16. 19 F NMR (376 MHz, Chloroform-d) δ -62.09, -106.77. ESI MS: calculated [C 19 H 17 F4N3O5 + H] + : 444.1177, found:444.1180. [α] 20 D = 76.0 (c = 0.30, CH2Cl2). The product was analyzed by HPLC todetermine the enantiomeric excess: 92% ee (CHIRALPAK AD-H, hexane / i-PrOH =85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 10.2min, t2 (minor) = 12.9 min.

[0065] Example 3: This example provides a method for preparing compound (R)-4c. The only difference from Example 1 is that the benzonitrile 1a in step 1 or the benzoic acid 1a' in step 3 is replaced with p-chlorobenzonitrile or p-chlorobenzoic acid. The resulting compound (R)-4c is (R)-2-(4-chlorophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0066] ;

[0067] Compound (R)-4c was a brown liquid with a yield of 96%; 1 H NMR (400 MHz, Chloroform-d) δ7.94 (s, 1H, Ar-H), 7.93 - 7.88 (m, 2H, Ph-H), 7.48 - 7.34 (m, 2H, Ph-H), 4.96 (d, J = 9.2 Hz, 1H, CH2), 4.81 (d, J = 11.1 Hz, 1H, CH2), 4.59 - 4.43 (m,2H, CH2), 4.37 - 4.21 (m, 2H, CH2), 3.95 (s, 3H, CH3), 1.30 (t, J = 7.1 Hz,3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.16, 165.99, 160.20, 141.38 (q,J = 38.5 Hz), 138.47, 137.03, 130.21, 128.83, 125.33, 120.27 (q,J = 269.6Hz), 112.41, 72.65, 66.84, 62.51, 40.03, 14.15. 19 F NMR (376 MHz, Chloroform-d) δ -62.08. ESI MS: calculated [C 19 H 17 ClF3N3O5 + H] + : 460.0882, found:460.0889. [α] 20 D= 81.9 (c = 0.49, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (CHIRALPAK AD-H, hexane / i-PrOH =85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 10.4min, t2 (minor) = 14.6 min.

[0068] Example 4: This example provides a method for preparing compound (R)-4d, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with p-bromobenzonitrile or p-bromobenzoic acid. The resulting compound (R)-4d is (R)-2-(4-bromophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0069] ;

[0070] Compound (R)-4d was a brown liquid with a yield of 96%; 1 H NMR (400 MHz, Chloroform-d) δ7.94 (s, 1H, Ar-H), 7.89 - 7.79 (m, 2H, Ph-H), 7.62 - 7.51 (m, 2H, Ph-H), 4.96 (d, J = 9.2 Hz, 1H, CH2), 4.80 (d, J = 11.1 Hz, 1H, CH2), 4.60 - 4.43 (m,2H, CH2), 4.37 - 4.20 (m, 2H, CH2), 3.95 (s, 3H, CH3), 1.30 (t, J = 7.1 Hz,3H, CH3). 13C NMR (101 MHz, Chloroform-d) δ 170.13, 166.09, 160.21, 141.38 (q,J = 38.5 Hz), 137.04, 131.81, 130.37, 127.03, 125.78, 120.27 (q,J = 269.7Hz), 112.41, 77.18, 72.66, 66.81, 62.52, 40.04, 14.16. 19 F NMR (376 MHz,Chloroform-d) δ -62.08. ESI MS: calculated [C 19 H 17 BrF3N3O5 + H] + : 504.0376, found: 504.0374. [α] 20 D = 73.9 (c = 0.56, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major)= 11.2 min, t2 (minor) = 15.9 min.

[0071] Example 5: This example provides a method for preparing compound (R)-4e. The only difference from Example 1 is that the benzonitrile 1a in step 1 or the benzoic acid 1a' in step 3 is replaced with p-methylbenzonitrile or p-methylbenzoic acid. The resulting compound (R)-4e is (R)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxyloyl)oxy)methyl)-2-(p-tolyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0072] ;

[0073] Compound (R)-4e was a brown liquid with a yield of 85%; 1H NMR (400 MHz, Chloroform-d) δ7.92 (s, 1H, Ar-H), 7.89 - 7.82 (m, 2H, Ph-H), 7.22 (d, J = 8.0 Hz, 2H, Ph-H), 4.95 (d, J = 9.2 Hz, 1H, CH2), 4.83 (d, J = 11.0 Hz, 1H, CH2), 4.52 - 4.42(m, 2H, CH2), 4.34 - 4.22 (m, 2H, CH2), 3.93 (s, 3H, CH3), 2.40 (s, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.39, 166.96, 160.18, 142.76, 141.49 (q, J= 38.6 Hz), 136.97, 129.22, 128.83, 124.03, 120.29 (q, J = 269.6 Hz), 112.47,77.04, 72.43, 67.02, 62.39, 40.00, 21.76, 14.16. 19 F NMR (376 MHz, Chloroform-d) δ -62.10. ESI MS: calculated [C20H20F3N3O5 + H]+: 440.1428, found:440.1427. [α]20D = 77.7 (c = 0.39, CH2Cl2). The product was analyzed by HPLCto determine the enantiomeric excess: 91% ee (CHIRALPAK AD-H, hexane / i-PrOH =85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 10.7min, t2 (minor) = 12.4 min.

[0074] Example 6: This example provides a method for preparing compound (R)-4f, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 3,4-difluorobenzonitrile or 3,4-difluorobenzoic acid. The resulting compound (R)-4f is (R)-2-(3,4-difluorophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0075] ;

[0076] Compound (R)-4f was a brown liquid with a yield of 57%; 1 H NMR (400 MHz, Chloroform-d) δ7.96 (s, 1H, Ar-H), 7.88 - 7.78 (m, 1H, Ph-H), 7.78 - 7.70 (m, 1H, Ph-H), 7.25 - 7.11 (m, 1H, Ph-H), 4.97 (d, J = 9.2 Hz, 1H, CH2), 4.79 (d, J = 11.1Hz, 1H, CH2), 4.57 - 4.43 (m, 2H, CH2), 4.36 - 4.22 (m, 2H, CH2), 3.96 (s, 3H,CH3), 1.31 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.07,165.02, 160.23, 153.01 (dd, J = 255.1, 12.7 Hz), 150.16 (dd, J = 249.6, 13.0Hz), 141.35 (q, J = 38.4 Hz), 137.09, 125.67 (dd, J = 7.3, 3.7 Hz), 123.90 (dd, J = 6.7, 3.5 Hz), 120.28 (q, J = 269.6 Hz), 118.26 (d, J = 19.1 Hz), 117.58 (d, J = 17.9 Hz), 112.41, 77.21, 72.85, 66.77, 62.57, 40.06, 14.16. 19FNMR (376 MHz, Chloroform-d) δ -62.09, -131.39 (d, J = 21.3 Hz), -136.62 (d, J= 21.3 Hz). ESI MS: calculated [C 19 H 16 F5N3O5 + H] + : 462.1083, found: 462.1081.[α] 20 D = 66.2 (c = 0.44, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 7.9 min, t2(minor) = 12.0 min.

[0077] Example 7: This example provides a preparation of compound (R)-4g, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 3-chlorobenzonitrile or 3-chlorobenzoic acid. Compound (R)-2-(3-chlorophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester is obtained, and the structural formula is shown below:

[0078] ;

[0079] Compound (R)-4g was a brown liquid with a yield of 95%; 1H NMR (400 MHz, Chloroform-d) δ7.99 (s, 1H, Ph-H), 7.94 (s, 1H, Ar-H), 7.86 (d, J = 7.7 Hz, 1H, Ph-H), 7.49(d, J = 8.1 Hz, 1H, Ph-H), 7.36 (t, J = 7.9 Hz, 1H, Ph-H), 4.97 (d, J = 9.2Hz, 1H, CH2), 4.81 (d, J = 11.1 Hz, 1H, CH2), 4.56 - 4.45 (m, 2H, CH2), 4.36 -4.22 (m, 2H, CH2), 3.95 (s, 3H, CH3), 1.31 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR(101 MHz, Chloroform-d) δ 170.09, 165.71, 160.19, 141.42 (q, J = 38.8 Hz),137.03, 134.60, 132.25, 129.85, 128.91, 128.56, 126.95, 120.28 (q, J = 269.7Hz), 112.40, 72.71, 66.81, 62.57, 40.05, 14.17. 19 F NMR (376 MHz, Chloroform-d) δ -62.09. ESI MS: calculated [C 19 H 17 ClF3N3O5 + H] + : 460.0882, found:460.0880. [α] 20 D = 74.5 (c = 0.38, CH2Cl2). The product was analyzed by HPLC todetermine the enantiomeric excess: 90% ee (CHIRALPAK AD-H, hexane / i-PrOH =85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 7.7min, t2 (minor) = 9.9 min.

[0080] Example 8: This example provides a method for preparing compound (R)-4h, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 4-methoxybenzonitrile or 4-methoxybenzoic acid. The resulting compound is (R)-2-(4-methoxyphenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, the structural formula of which is shown below:

[0081] ;

[0082] Compound (R)-4h was a brown liquid with a yield of 67%; 1 H NMR (600 MHz, Chloroform-d) δ7.96 - 7.88 (m, 3H, Ar-H), 6.96 - 6.86 (m, 2H, Ph-H), 4.92 (d, J = 9.0 Hz,1H, CH2), 4.82 (d, J = 11.0 Hz, 1H, CH2), 4.52 - 4.41 (m, 2H, CH2), 4.33 -4.22 (m, 2H, CH2), 3.93 (s, 3H, CH3), 3.85 (s, 3H, CH3), 1.29 (t, J = 7.1 Hz,3H, CH3). 13 C NMR (151 MHz, Chloroform-d) δ 170.47, 166.65, 162.82, 160.18,141.55 (q, J = 38.7 Hz), 136.93, 130.71, 120.34 (q, J = 269.7 Hz), 119.35,113.86, 112.57, 77.10, 72.47, 67.08, 62.31, 55.51, 39.94, 14.15. 19 F NMR (376MHz, Chloroform-d) δ -62.10. ESI MS: calculated [C 20 H 20 F3N3O6 + H] + : 456.1377, found: 456.1374. [α] 20 D= 71.3 (c = 0.44, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee (CHIRALPAK IC, hexane / i-PrOH = 70 / 30, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major)= 7.5 min, t2 (minor) = 12.3 min.

[0083] Example 9: This example provides a method for preparing compound (R)-4i, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 4-trifluoromethylbenzonitrile or 4-trifluoromethylbenzoic acid. Compound (R)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxyloyl)oxy)methyl)-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester is obtained, and the structural formula is shown below:

[0084] ;

[0085] Compound (R)-4i was a brown liquid with a yield of 90%; 1 H NMR (500 MHz, Chloroform-d) δ8.10 (d, J = 8.0 Hz, 2H, Ph-H), 7.94 (s, 1H, Ar-H), 7.68 (d, J = 8.2 Hz, 2H,Ph-H), 4.99 (d, J = 9.2 Hz, 1H, CH2), 4.81 (d, J = 11.2 Hz, 1H, CH2), 4.59 -4.48 (m, 2H, CH2), 4.35 - 4.24 (m, 2H, CH2), 3.94 (s, 3H, CH3), 1.31 (t, J =7.1 Hz, 3H, CH3). 13C NMR (126 MHz, Chloroform-d) δ 170.04, 165.66, 160.25,141.42 (q, J = 38.3 Hz), 137.07, 133.77 (q, J = 32.7 Hz), 130.28, 129.29,125.50 (q, J = 3.8 Hz), 123.82 (q, J = 272.5 Hz), 120.31 (q, J = 269.7 Hz), 112.47, 77.34, 72.81, 66.77, 62.60, 40.05, 14.18. 19 F NMR (471 MHz, Chloroform-d) δ -62.08, -63.05. ESI MS: calculated [C 20 H 17 F6N3O5 + H] + :494.1145, found: 494.1148. [α] 20 D = 71.8 (c = 0.57, CH2Cl2). The product wasanalyzed by HPLC to determine the enantiomeric excess: 92% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 9.1 min, t2 (minor) = 12.6 min.

[0086] Example 10: This example provides a method for preparing compound (R)-4j, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 3,4-dichlorobenzonitrile or 3,4-dichlorobenzoic acid. Compound (R)-2-(3,4-dichlorophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester is obtained, and the structural formula is shown below:

[0087] ;

[0088] Compound (R)-4j was a brown liquid with a yield of 76%; 1H NMR (400 MHz, Chloroform-d) δ8.09 (d, J = 1.9 Hz, 1H, Ph-H), 7.96 (s, 1H, Ar-H), 7.80 (dd, J = 8.4, 2.0Hz, 1H, Ph-H), 7.51 (d, J = 8.4 Hz, 1H, Ph-H), 4.97 (d, J = 9.2 Hz, 1H, CH2),4.79 (d, J = 11.1 Hz, 1H, CH2), 4.58 - 4.45 (m, 2H, CH2), 4.36 - 4.22 (m, 2H,CH2), 3.96 (s, 3H, CH3), 1.31 (t, J = 7.2 Hz, 3H, CH3). 13 C NMR (101 MHz,Chloroform-d) δ 169.99, 165.01, 160.22, 141.37 (q, J = 38.5 Hz), 137.08,136.65, 133.01, 130.72, 130.66, 127.92, 126.75, 120.28 (q, J = 269.5 Hz),112.39, 77.24, 72.82, 66.72, 62.63, 40.07, 14.17. 19 F NMR (376 MHz,Chloroform-d) δ -62.08. ESI MS: calculated [C 19 H 16 Cl2F3N3O5 + H] + : 494.0492,found: 494.0493. [α] 20 D = 68.3 (c = 0.77, CH2Cl2). The product was analyzed byHPLC to determine the enantiomeric excess: 88% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major)= 8.5 min, t2 (minor) = 14.2 min.

[0089] Example 11: This example provides a method for preparing compound (R)-4k, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 3,5-dichlorobenzonitrile or 3,5-dichlorobenzoic acid. The resulting compound is (R)-2-(3,5-dichlorophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, having the structural formula shown below:

[0090] ;

[0091] Compound (R)-4k was obtained as a brown solid with a yield of 82%; 1 H NMR (400 MHz, Chloroform-d) δ7.95 (s, 1H, Ar-H), 7.87 (d, J = 1.9 Hz, 2H, Ph-H), 7.50 (t, J = 2.0 Hz, 1H, Ph-H), 4.97 (d, J = 9.2 Hz, 1H, CH2), 4.79 (d, J = 11.1 Hz, 1H, CH2), 4.57 -4.46 (m, 2H, CH2), 4.34 - 4.24 (m, 2H, CH2), 3.96 (s, 3H, CH3), 1.31 (t, J =7.1 Hz, 3H, CH3). 13 C NMR (151 MHz, Chloroform-d) δ 169.87, 164.64, 160.17,141.44 (q, J = 38.5 Hz), 137.03, 135.38, 132.04, 129.74, 127.23, 120.32 (q, J= 269.8 Hz), 112.42, 77.32, 72.93, 66.66, 62.61, 40.01, 14.15. 19 F NMR (376MHz, Chloroform-d) δ -62.09. ESI MS: calculated [C 19 H 16 Cl2F3N3O5 + H] + :494.0492, found: 494.0492. [α] 20 D= 58.4 (c = 0.29, CH2Cl2). The product wasanalyzed by HPLC to determine the enantiomeric excess: 86% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 5.8 min, t2 (minor) = 9.0 min.

[0092] Example 12: This example provides a preparation of compound (R)-41, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 3-bromobenzonitrile or 3-bromobenzoic acid. The resulting compound is (R)-2-(3-bromophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, the structural formula of which is shown below:

[0093] ;

[0094] Compound (R)-4l was a brown liquid with a yield of 78%; 1 H NMR (400 MHz, Chloroform-d) δ8.15 (t, J = 1.8 Hz, 1H, Ph-H), 7.94 (s, 1H, Ar-H), 7.90 (dt, J = 7.8, 1.3Hz, 1H, Ph-H), 7.70 - 7.58 (m, 1H, Ph-H), 7.30 (t, J = 7.9 Hz, 1H, Ph-H), 4.97 (d, J = 9.2 Hz, 1H, CH2), 4.81 (d, J = 11.1 Hz, 1H, CH2), 4.57 - 4.45 (m,2H, CH2), 4.36 - 4.22 (m, 2H, CH2), 3.95 (s, 3H, CH3), 1.31 (t, J = 7.1 Hz,3H, CH3). 13C NMR (101 MHz, Chloroform-d) δ 170.08, 165.58, 160.18, 141.43 (q,J = 38.5 Hz), 137.03, 135.17, 131.78, 130.09, 128.78, 127.40, 122.55, 120.28(q, J = 269.6 Hz), 112.40, 72.72, 66.81, 62.57, 40.05, 14.17. 19 F NMR (376MHz, Chloroform-d) δ -62.09. ESI MS: calculated [C 19 H 17 BrF3N3O5 + H] + : 504.0376, found: 504.0380. [α] 20 D = 65.6 (c = 0.47, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 90% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major)= 8.0 min, t2 (minor) = 10.3 min.

[0095] Example 13: This example provides a method for preparing compound (R)-4m, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 3-thiophenecarbonitrile or 3-thiophenecarboxylic acid. The resulting compound (R)-4m is (R)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl)oxy)methyl)-2-(thiophen-3-yl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0096] ;

[0097] Compound (R)-4m was obtained as a brown solid with a yield of 89%; 1H NMR (400 MHz, Chloroform-d) δ8.01 - 7.96 (m, 1H, Ar-H), 7.93 (s, 1H, Ar-H), 7.60 - 7.49 (m, 1H, Ar-H),7.39 - 7.30 (m, 1H, Ar-H), 4.93 (d, J = 9.1 Hz, 1H, CH2), 4.82 (d, J = 11.1Hz, 1H, CH2), 4.53 - 4.40 (m, 2H, CH2), 4.36 - 4.18 (m, 2H, CH2), 3.94 (s, 3H,CH3), 1.30 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.27,163.06, 160.18, 141.48 (q, J = 38.5 Hz), 137.00, 130.36, 128.99, 127.58,126.45, 120.29 (q, J = 269.7 Hz), 112.45, 77.04, 72.35, 66.97, 62.47, 40.03,14.17. 19 F NMR (376 MHz, Chloroform-d) δ -62.10. ESI MS: calculated[C 17 H 16 F3N3O5S + Na] + : 454.0655, found: 454.0662. [α] 20 D = 85.4 (c = 0.44,CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 92% ee (CHIRALPAK AD-H, hexane / i-PrOH = 95 / 5, detector: 254 nm, T =40 ℃, flow rate: 1.0 mL / min), t1 (major) = 34.7 min, t2 (minor) = 36.8 min.

[0098] Example 14: This example provides a method for preparing compound (R)-4n, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 3-furancarbonitrile or 3-furancarboxylic acid. The resulting compound (R)-4n is (R)-2-(furan-3-yl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0099] ;

[0100] Compound (R)-4n was a brown liquid with a yield of 66%; 1 H NMR (400 MHz, Chloroform-d) δ8.02 – 7.96 (m, 2H, Ar-H), 7.95 (s, 1H, Ar-H), 7.45 (t, J = 1.7 Hz, 1H, Ar-H), 6.88 – 6.75 (m, 1H, Ar-H), 4.90 (d, J = 9.1 Hz, 1H, CH2), 4.80 (d, J =11.1 Hz, 1H, CH2), 4.50 – 4.38 (m, 2H, CH2), 4.35 – 4.21 (m, 2H, CH2), 3.96(s, 3H, CH3), 1.30 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ170.21, 162.23, 160.19, 145.99, 143.99, 141.47 (q, J = 38.6 Hz), 137.02,120.29 (q, J = 269.3 Hz), 114.86, 112.45, 109.67, 76.88, 72.20, 66.91, 62.50,40.05, 14.16. 19 F NMR (376 MHz, Chloroform-d) δ -62.11. ESI MS: calculated[C 17 H 16 F3N3O6 + H] + : 416.1064, found: 416.1062. [α] 20 D= 20.5 (c = 0.68, CH2Cl2).The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee(CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flowrate: 1.0 mL / min), t1 (major) = 9.1 min, t2 (minor) = 10.4 min.

[0101] Example 15: This example provides a method for preparing compound (R)-4o, which differs from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced with 2-bromobenzonitrile or 2-bromobenzoic acid. The resulting compound (R)-4o is (R)-2-(2-bromophenyl)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0102] ;

[0103] Compound (R)-4o was a brown liquid with a yield of 61%; 1 H NMR (500 MHz, Chloroform-d) δ7.98 (s, 1H, Ar-H), 7.70 (dd, J = 7.5, 2.0 Hz, 1H, Ph-H), 7.64 (dd, J = 7.7,1.4 Hz, 1H, Ph-H), 7.41 - 7.28 (m, 2H, Ph-H), 4.98 (d, J = 9.2 Hz, 1H, CH2), 4.83 (d, J = 11.1 Hz, 1H, CH2), 4.59 - 4.51 (m, 2H, CH2), 4.36 - 4.24 (m, 2H,CH2), 3.95 (s, 3H, CH3), 1.31 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (126 MHz, Chloroform-d) δ 169.96, 166.70, 160.13, 141.67 (q, J = 38.6 Hz), 136.96,134.01, 132.41, 131.83, 129.00, 127.31, 121.98, 120.36 (q, J = 269.6 Hz), 112.44, 77.31, 72.79, 66.59, 62.51, 40.03, 14.19. 19 F NMR (471 MHz,Chloroform-d) δ -62.04. ESI MS: calculated [C 19 H 17 BrF3N3O5 + H] + : 504.0376, found: 504.0386. [α] 20 D = 55.8 (c = 0.47, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 95% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major)= 8.8 min, t2 (minor) = 11.0 min.

[0104] Example 16: This example provides a method for preparing compound (R)-4p, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 1-methyl-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid. The resulting compound (R)-4p is (R)-2-(4-bromophenyl)-4-(((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0105] ;

[0106] Compound (R)-4p was a brown liquid with a yield of 97%; 1H NMR (500 MHz, Chloroform-d) δ7.88 - 7.85 (m, 1H, Ar-H), 7.85 - 7.81 (m, 2H, Ph-H), 7.62 - 7.50 (m, 2H, Ph-H), 6.91 (t, J = 53.8 Hz, 1H, CH), 4.92 (d, J = 9.2 Hz, 1H, CH2), 4.73 (d, J= 11.1 Hz, 1H, CH2), 4.57 - 4.47 (m, 2H, CH2), 4.35 - 4.23 (m, 2H, CH2), 3.92(s, 3H, CH3), 1.31 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR (126 MHz, Chloroform-d) δ170.27, 165.96, 161.10, 146.20 (t, J = 25.3 Hz), 135.74, 131.84, 130.35,127.09, 125.73, 112.33 (t, J = 2.6 Hz), 109.47 (t, J = 237.0 Hz), 77.32,72.62, 66.65, 62.53, 39.85, 14.18. 19 F NMR (471 MHz, Chloroform-d) δ -115.61,-115.64. ESI MS: calculated [C 19 H 18 BrF2N3O5 + H] + : 486.0471, found: 486.0478.[α] 20 D = 61.2 (c = 1.74, CH2Cl2). The product was analyzed by HPLC to determinethe enantiomeric excess: 93% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15,detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 13.3 min, t2(minor) = 17.8 min.

[0107] Example 17: This example provides a method for preparing compound (R)-4q, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 2-trifluoromethylbenzoic acid, and triethylamine is replaced with triethylenediamine. The resulting compound (R)-4q is (R)-ethyl 2-(4-bromophenyl)-4-(((2-(trifluoromethyl)benzoyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0108] ;

[0109] Compound (R)-4q was a brown liquid with a yield of 68%; 1 H NMR (400 MHz, Chloroform-d) δ7.84 (d, J = 8.2 Hz, 2H, Ph-H), 7.73 (d, J = 7.3 Hz, 2H, Ph-H), 7.65 - 7.50(m, 4H, Ph-H), 4.96 (d, J = 9.2 Hz, 1H, CH2), 4.86 (d, J = 11.1 Hz, 1H, CH2), 4.64 - 4.48 (m, 2H, CH2), 4.37 - 4.23 (m, 2H, CH2), 1.31 (t, J = 7.2 Hz, 3H,CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.12, 166.25, 166.07, 131.97,131.81, 131.72, 130.72, 130.38, 130.28, 128.78 (q, J = 32.4 Hz), 127.05,126.86 (q, J = 5.3 Hz), 125.75, 123.34 (q, J = 273.7 Hz), 77.20, 72.62,67.80, 62.57, 14.16. 19 F NMR (376 MHz, Chloroform-d) δ -59.43. ESI MS:calculated [C 21 H 17 BrF3NO5 + H] + : 500.0315, found: 500.0316. [α] 20 D= 72.6 (c =0.79, CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 92% ee (CHIRALPAK IC, hexane / i-PrOH = 70 / 30, detector: 254 nm, T = 40℃, flow rate: 1.0 mL / min), t1 (major) = 4.7 min, t2 (minor) = 8.5 min.

[0110] Example 18: This example provides a method for preparing compound (R)-4r. The only difference from Example 4 is that in step 5, 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid is replaced with 2-chloronicotinic acid, triethylamine is replaced with triethylenediamine, and 4-dimethylaminopyridine (DMAP) is replaced with 1-hydroxybenzotriazole (HOBT). The resulting compound (R)-4r is (R)-ethyl 2-(4-bromophenyl)-4-(((2-chloronicotinyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0111] ;

[0112] Compound (R)-4r was a brown liquid with a yield of 88%; 1 H NMR (400 MHz, Chloroform-d) δ8.51 (dd, J = 4.8, 2.0 Hz, 1H, Ar-H), 8.11 (dd, J = 7.7, 2.0 Hz, 1H, Ar-H), 7.91 - 7.78 (m, 2H, Ph-H), 7.62 - 7.49 (m, 2H, Ph-H), 7.29 (dd, J = 7.7, 4.8Hz, 1H, Ar-H), 4.94 (d, J = 9.1 Hz, 1H, CH2), 4.82 (d, J = 11.2 Hz, 1H, CH2), 4.71 - 4.53 (m, 2H, CH2), 4.38 - 4.25 (m, 2H, CH2), 1.33 (t, J = 7.1 Hz, 3H,CH3). 13C NMR (101 MHz, Chloroform-d) δ 170.18, 166.14, 164.14, 152.40,150.18, 140.88, 131.89, 130.37, 127.18, 126.24, 125.66, 122.31, 77.24, 72.61,67.79, 62.67, 14.25. ESI MS: calculated [C 19 H 16 BrClN2O5 + H] + : 467.0004, found:467.0002. [α] 20 D = 63.7 (c = 0.57, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 92% ee (CHIRALPAK IC, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 18.4min, t2 (minor) = 19.8 min.

[0113] Example 19: This example provides a method for preparing compound (R)-4s, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 1-methylcyclohexane-1-carboxylic acid. The resulting compound (R)-4s is (R)-ethyl 2-(4-bromophenyl)-4-(((1-methylcyclohexane-1-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0114] ;

[0115] Compound (R)-4s was a brown liquid with a yield of 30%; 1H NMR (400 MHz, Chloroform-d) δ7.90 - 7.80 (m, 2H, Ph-H), 7.60 - 7.53 (m, 2H, Ph-H), 4.88 (d, J = 9.0 Hz,1H, CH2), 4.56 - 4.37 (m, 3H, CH2), 4.35 - 4.24 (m, 2H, CH2), 2.00 - 1.85 (m,2H, CH2), 1.57 - 1.38 (m, 4H, CH2), 1.33 (t, J = 7.1 Hz, 3H, CH3), 1.24 - 1.10(m, 4H, CH2), 1.07 (s, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 177.14,170.40, 165.66, 131.81, 130.32, 126.96, 125.86, 77.54, 72.46, 66.15, 62.47,43.52, 35.55, 25.68, 23.25, 19.32, 14.27. ESI MS: calculated [C 21 H 26 BrNO5 + H] + : 452.1067, found: 452.1077. [α] 20 D = -34.9 (c = 0.38, CH2Cl2). The productwas analyzed by HPLC to determine the enantiomeric excess: 94% ee (CHIRALPAKIC, hexane / i-PrOH = 85 / 15, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 5.3 min, t2(minor) = 9.5 min.

[0116] Example 20: This example provides a method for preparing compound (R)-4t, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with (E)-3-(thiophen-2-yl)acrylic acid. The resulting compound (R)-4t is (R,E)-2-(4-bromophenyl)-4-(((3-(thiophen-2-yl)acryloyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, with the structural formula shown below:

[0117] ;

[0118] Compound (R)-4t was obtained as a brown solid with a yield of 84%; 1 H NMR (400 MHz, Chloroform-d) δ7.93 - 7.81 (m, 2H, Ph-H), 7.74 (d, J = 15.7, 1H, CH), 7.62 - 7.51 (m, 2H, Ph-H), 7.45 - 7.34 (m, 1H, Ar-H), 7.25 - 7.15 (m, 1H, Ar-H), 7.10 - 6.98 (m,1H, Ar-H), 6.18 (d, J = 15.7 Hz, 1H, CH), 4.90 (d, J = 9.0 Hz, 1H, CH2), 4.66(d, J = 11.2 Hz, 1H, CH2), 4.55 - 4.42 (m, 2H, CH2), 4.39 - 4.24 (m, 2H, CH2),1.33 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.41,166.31, 165.79, 139.32, 138.32, 131.82, 131.53, 130.39, 129.07, 128.27,127.03, 125.79, 115.74, 72.57, 66.58, 62.49, 14.26. ESI MS: calculated[C 20 H 18 BrNO5S + H] + : 464.0162, found: 464.0165. [α] 20 D= 100.7 (c = 0.53,CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 94% ee (CHIRALPAK IC, hexane / i-PrOH = 70 / 30, detector: 254 nm, T = 40℃, flow rate: 1.0 mL / min), t1 (major) = 8.6 min, t2 (minor) = 13.6 min.

[0119] Example 21: This example provides a method for preparing compound (R)-4u, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 3-methylthiophene-2-carboxylic acid. The resulting compound (R)-4u is (R)-ethyl 2-(4-bromophenyl)-4-(((3-methylthiophene-2-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0120] ;

[0121] Compound (R)-4u was obtained as a brown solid with a yield of 96%; 1 H NMR (600 MHz, Chloroform-d) δ7.91 - 7.79 (m, 2H, Ph-H), 7.62 - 7.49 (m, 2H, Ph-H), 7.36 (d, J = 5.0 Hz,1H, Ar-H), 6.87 (d, J = 5.0 Hz, 1H, Ar-H), 4.92 (d, J = 9.1 Hz, 1H, CH2), 4.73 (d, J = 11.2 Hz, 1H, CH2), 4.57 - 4.51 (m, 2H, CH2), 4.39 - 4.23 (m, 2H,CH2), 2.46 (s, 3H, CH3), 1.32 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (151 MHz, Chloroform-d) δ 170.32, 165.87, 162.18, 146.82, 131.91, 131.80, 130.94,130.38, 126.95, 126.20, 125.95, 77.55, 72.61, 66.57, 62.48, 16.04, 14.25. ESIMS: calculated [C 19 H 18 BrNO5S + H] + : 452.0162, found: 452.0164. [α] 20 D = 66.1 (c= 0.83, CH2Cl2). The product was analyzed by HPLC to determine theenantiomeric excess: 92% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector:254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 8.0 min, t2 (minor) =9.4 min.

[0122] Example 22: This example provides a method for preparing compound (R)-4v, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 2-methylfuran-3-carboxylic acid. The resulting compound (R)-4v is (R)-ethyl 2-(4-bromophenyl)-4-(((2-methylfuran-3-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0123] ;

[0124] Compound (R)-4v was a brown liquid with a yield of 99%; 1H NMR (400 MHz, Chloroform-d) δ7.89 - 7.81 (m, 2H, Ph-H), 7.60 - 7.54 (m, 2H, Ph-H), 7.19 (d, J = 2.0 Hz,1H, Ar-H), 6.53 (d, J = 2.0 Hz, 1H, Ar-H), 4.92 (d, J = 9.0 Hz, 1H, CH2),4.70 (d, J = 11.1 Hz, 1H, CH2), 4.59 - 4.43 (m, 2H, CH2), 4.36 - 4.26 (m, 2H,CH2), 2.45 (s, 3H, CH3), 1.32 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz,Chloroform-d) δ 170.38, 165.74, 163.39, 159.79, 140.68, 131.85, 130.33,127.05, 125.77, 112.88, 110.77, 77.51, 72.50, 66.23, 62.52, 14.26, 13.93. ESIMS: calculated [C 19 H 18 BrNO6 + H] + : 436.0390, found: 436.0389. [α] 20 D = 32.7 (c =0.51, CH2Cl2). The product was analyzed by HPLC to determine the enantiomericexcess: 94% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector: 254 nm, T =40 ℃, flow rate: 1.0 mL / min), t1 (major) = 6.8 min, t2 (minor) = 7.4 min.

[0125] Example 23: This example provides a preparation of compound (R)-4w, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 2-chloronicotinic acid, triethylamine is replaced with triethylenediamine, dichloromethane is replaced with acetonitrile, and 4-dimethylaminopyridine (DMAP) is replaced with 1-hydroxybenzotriazole (HOBT). The resulting compound (R)-4w is (R)-ethyl 2-(4-bromophenyl)-4-(((2-methylnicotinoyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0126] ;

[0127] Compound (R)-4w was a brown liquid with a yield of 89%; 1 H NMR (400 MHz, Chloroform-d) δ8.60 (dd, J = 4.9, 1.8 Hz, 1H, Ar-H), 8.07 (dd, J = 7.9, 1.9 Hz, 1H, Ar-H), 7.91 - 7.79 (m, 2H, Ph-H), 7.66 - 7.51 (m, 2H, Ph-H), 7.16 (dd, J = 7.9, 4.8Hz, 1H, Ar-H), 4.93 (d, J = 9.1 Hz, 1H, CH2), 4.76 (d, J = 11.2 Hz, 1H, CH2), 4.68 - 4.48 (m, 2H, CH2), 4.41 - 4.23 (m, 2H, CH2), 2.76 (s, 3H, CH3), 1.33(t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.32, 165.95,160.19, 152.33, 138.66, 131.90, 130.35, 127.19, 125.65, 124.72, 121.11,77.41, 72.59, 67.27, 62.63, 25.07, 14.27. ESI MS: calculated [C 20 H 19 BrN2O5 + H] + : 447.0550, found: 447.0554. [α] 20 D= 64.7 (c = 0.62, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (CHIRALPAKIC, hexane / i-PrOH = 70 / 30, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 7.8 min, t2 (minor) = 9.0 min.

[0128] Example 24: This example provides a method for preparing compound (S)-4u, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 3-methylthiophene-2-carboxylic acid, and (4S)-tert-butyl-(2R)-[2-(diphenylphosphino)ferrocenyl]-2-oxazoline is replaced with (S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)-phosphino)ferrocen-1-yl]oxazoline. The resulting compound (S)-4u is (S)-ethyl 2-(4-bromophenyl)-4-(((3-methylthiophene-2-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0129] ;

[0130] Compound (S)-4u was obtained as a brown solid with a yield of 98%; 1 H NMR (600 MHz, Chloroform-d) δ7.91 - 7.79 (m, 2H, Ph-H), 7.62 - 7.49 (m, 2H, Ph-H), 7.36 (d, J = 5.0 Hz,1H, Ar-H), 6.87 (d, J = 5.0 Hz, 1H, Ar-H), 4.92 (d, J = 9.1 Hz, 1H, CH2), 4.73 (d, J = 11.2 Hz, 1H, CH2), 4.57 - 4.51 (m, 2H, CH2), 4.39 - 4.23 (m, 2H,CH2), 2.46 (s, 3H, CH3), 1.32 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (151 MHz, Chloroform-d) δ 170.32, 165.87, 162.18, 146.82, 131.91, 131.80, 130.94,130.38, 126.95, 126.20, 125.95, 77.55, 72.61, 66.57, 62.48, 16.04, 14.25. ESIMS: calculated [C 19 H 18 BrNO5S + H] + : 452.0162, found: 452.0160. [α] 20 D = -72.8 (c= 0.87, CH2Cl2). The product was analyzed by HPLC to determine theenantiomeric excess: 92% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector:254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 8.0 min, t2 (minor) =9.4 min.

[0131] Example 25: This example provides a method for preparing compound (S)-4v, which differs from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced with 2-methylfuran-3-carboxylic acid, and (4S)-tert-butyl-(2R)-[2-(diphenylphosphino)ferrocenyl]-2-oxazoline is replaced with (S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)-phosphino)ferrocen-1-yl]oxazoline. The resulting compound (S)-4v is (S)-ethyl 2-(4-bromophenyl)-4-(((2-methylfuran-3-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, with the structural formula shown below:

[0132] ;

[0133] Compound (S)-4v was a brown liquid with a yield of 99%; 1H NMR (400 MHz, Chloroform-d) δ7.89 - 7.81 (m, 2H, Ph-H), 7.60 - 7.54 (m, 2H, Ph-H), 7.19 (d, J = 2.0 Hz,1H, Ar-H), 6.53 (d, J = 2.0 Hz, 1H, Ar-H), 4.92 (d, J = 9.0 Hz, 1H, CH2),4.70 (d, J = 11.1 Hz, 1H, CH2), 4.59 - 4.43 (m, 2H, CH2), 4.36 - 4.26 (m, 2H,CH2), 2.45 (s, 3H, CH3), 1.32 (t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz,Chloroform-d) δ 170.38, 165.74, 163.39, 159.79, 140.68, 131.85, 130.33,127.05, 125.77, 112.88, 110.77, 77.51, 72.50, 66.23, 62.52, 14.26, 13.93. ESIMS: calculated [C 19 H 18 BrNO6 + Na] + : 458.0210, found: 458.0210. [α] 20 D = -20.8 (c= 0.48, CH2Cl2). The product was analyzed by HPLC to determine theenantiomeric excess: 94% ee (CHIRALPAK AD-H, hexane / i-PrOH = 85 / 15, detector:254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 6.8 min, t2 (minor) =7.4 min.

[0134] Example 26: This example provides a preparation method for compound (S)-4w, which is different from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced by 2-chloronicotinic acid, triethylamine is replaced by triethylenediamine, dichloromethane is replaced by acetonitrile, and 4-dimethylaminopyridine (DMAP) is replaced by 1-hydroxybenzotriazole (HOBT), and (4S)-tert-butyl-(2R)-[2-(diphenylphosphino)ferrocenyl]-2-oxazoline is replaced by (S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)-phosphino)ferrocen-1-yl]oxazoline. The obtained compound (S)-4w is (S)-ethyl 2-(4-bromophenyl)-4-(((2-methylnicotinoyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylate, and its structural formula is shown below:

[0135] ;

[0136] Compound (S)-4w was a brown liquid with a yield of 88%; 1 H NMR (400 MHz, Chloroform-d) δ8.60 (dd, J = 4.9, 1.8 Hz, 1H, Ar-H), 8.07 (dd, J = 7.9, 1.9 Hz, 1H, Ar-H), 7.91 - 7.79 (m, 2H, Ph-H), 7.66 - 7.51 (m, 2H, Ph-H), 7.16 (dd, J = 7.9, 4.8Hz, 1H, Ar-H), 4.93 (d, J = 9.1 Hz, 1H, CH2), 4.76 (d, J = 11.2 Hz, 1H, CH2), 4.68 - 4.48 (m, 2H, CH2), 4.41 - 4.23 (m, 2H, CH2), 2.76 (s, 3H, CH3), 1.33(t, J = 7.1 Hz, 3H, CH3). 13 C NMR (101 MHz, Chloroform-d) δ 170.32, 165.95,160.19, 152.33, 138.66, 131.90, 130.35, 127.19, 125.65, 124.72, 121.11,77.41, 72.59, 67.27, 62.63, 25.07, 14.27. ESI MS: calculated [C 20 H 19 BrN2O5 + H] +: 447.0550, found: 447.0554. [α] 20 D = -51.6 (c = 0.62, CH2Cl2). The product was analyzed by HPLC to determine the enantiomeric excess: 93% ee (CHIRALPAKIC, hexane / i-PrOH = 70 / 30, detector: 254 nm, T = 40 ℃, flow rate: 1.0 mL / min), t1 (major) = 7.8 min, t2 (minor) = 9.0 min.

[0137] Example 27: This example provides a compound (rac)-4u, which is a racemic compound obtained by uniformly mixing the two enantiomers (R)-4u and (S)-4u prepared in the above example.

[0138] Example 28: This example provides a compound (rac)-4v, which is a racemic compound obtained by uniformly mixing the two enantiomers (R)-4v and (S)-4v prepared in the above example.

[0139] Example 29: This example provides a compound (rac)-4w, which is a racemic compound obtained by uniformly mixing the two enantiomers (R)-4w and (S)-4w prepared in the above example.

[0140] Effect verification example (Study on the antifungal activity of chiral oxazoline diester derivatives):

[0141] 1. Experimental subjects: Chiral oxazoline diester derivatives prepared in Examples 1-29, namely compounds (R)-4a to (R)-4w, (S)-4u, (S)-4v, (S)-4w, (rac)-4u, (rac)-4v and (rac)-4w.

[0142] 2. Experimental Methods: The in vitro inhibitory activities of 29 compounds (R)-4a to (R)-4w, (S)-4u, (S)-4v, (S)-4w, (rac)-4u, (rac)-4v, and (rac)-4w) against nine plant pathogens (Valsamali, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani, Fusarium graminicola, Pythium graminicola, Trichoderma viride, Curvularia lunata, and Phytophthora capsici) were determined using the mycelial linear growth rate method. The fungi were provided by the Plant Disease Control Laboratory of Anhui Agricultural University. All compounds were dissolved in dimethyl sulfoxide (DMSO) and then diluted into sterile PDA medium to obtain a drug-containing medium with a mass concentration of 50 mg / L. The medium was then poured into sterilized Petri dishes while still hot, with 10 mL per dish, and cooled for later use. The test plant pathogenic fungi (fungus cake diameter 5 mm) were inoculated into the above Petri dishes, with three replicates per test group. After incubation in a constant temperature incubator at 25°C for 72 hours, the colony diameter (mm) was measured using the cross-hatch method. A 1% DMSO aqueous solution was used as a blank control, and the commercially available antifungal agent tebuconazole and the anti-oomycete agent dimethomorph were used as positive controls. The mycelial growth inhibition rate (I1) was calculated as follows:

[0143] ;

[0144] Where D1 is the average colony diameter containing the compound; D NC is the average colony diameter of the negative control; D0 is the diameter of the mycelial culture medium used for inoculation.

[0145] 3. Experimental results: Twenty-nine oxazoline derivatives (i.e., compounds (R)-4a to (R)-4w, (S)-4u, (S)-4v, (S)-4w, (rac)-4u, (rac)-4v, and (rac)-4w) were screened for their partial in vitro antifungal activity against nine plant pathogenic fungi at a concentration of 50 mg / L. The results are shown in Table 1.

[0146] Table 1

[0147]

[0148] Note: a Values ​​are the means of three replicate experiments; b Vm:Valsa mali, c S. s: Sclerotiniascleotiorum, d B. c:Botrytis cinerea, e R. s:Rhizoctonia solani, f F. g:Fusarium graminicola, g P. g:Pythium graminicola, h T. v:Trichoderma viride, i C. l:Curvularia lunata, j P. c: Phytophthora capsici.

[0149] The preliminary screening results shown in Table 1 indicate that compounds 4u, 4v, and 4w exhibit significant enantioselective activity against apple black rot pathogen and pepper phytophthora, and the R-configured compounds of these three compounds have excellent biological activity in the preliminary screening.

[0150] Structure-activity relationship (SAR) analysis showed that when R 1 When R is a benzene ring, the introduction of halogen atoms can significantly improve the fungicidal activity of the compound (Br > F > Cl > other substituents, para ≈ meta > ortho). 1 When R is furan-3-yl and thiophen-3-yl, the fungicidal activity is significantly reduced. 2 When R is fatty acid, the bactericidal activity is significantly reduced. 2 In the case of aromatic acids, heteroatom-containing aromatic rings exhibit significantly better fungicidal activity than those containing benzene rings. Furthermore, the introduction of a methyl group at the ortho position of the aromatic ring significantly enhances the fungicidal activity of the compound, but the introduction of other substituents at non-ortho positions of the benzene ring may reduce the fungicidal activity.

[0151] In summary, the chiral oxazoline diester derivatives prepared by the asymmetric synthesis method in the examples of the present invention have certain antifungal / antiumomycete activities, especially excellent biological activities against apple black rot pathogen and pepper Phytophthora, and the prepared chiral compounds show significant enantioselective activity, which lays a foundation for the preparation of fungicides with chiral oxazoline derivatives as the main antifungal / antiumomycete active ingredients.

[0152] Based on the above-mentioned ideal embodiment of the present invention, and through the above description, relevant personnel can make various changes and modifications without departing from the scope of the technical concept of the present invention. The technical scope of the present invention is not limited to the contents of the specification.

Claims

1. A chiral oxazoline diester derivative, characterized in that: The structural formula of the chiral oxazoline diester derivative is any one of the following formulae: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。 2. The method for preparing a chiral oxazoline diester derivative according to claim 1, wherein: The specific steps include: Under nitrogen protection, tetraacetonitrile copper tetrafluoroborate, a chiral ligand, and an anhydrous solvent are mixed and stirred, and a racemic oxazoline ester derivative, formaldehyde or paraformaldehyde, a base, and an anhydrous solvent are added in sequence, and stirring is continued to carry out a reaction; after the reaction is completed, the solvent is removed under reduced pressure; then, a carboxylic acid, an activation reagent, an acyl transfer reagent, a base, and an organic solvent are added in sequence, and stirring is carried out to react; after the reaction is completed, the reaction solution is filtered through diatomaceous earth, and the filtrate is then concentrated under reduced pressure, and finally purified by silica gel column chromatography to obtain the chiral oxazoline diester derivative; Among them, the structural formula of the racemic oxazoline ester derivative is: ； R 1 The corresponding definitions in each structural formula of claim 1; The activation reagent and the acyl transfer reagent are independently at least one of 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, 4-dimethylaminopyridine and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; The chiral ligand is any one of (2R)-1-[(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]-2-(diphenylphosphino)ferrocene, (4S)-tert-butyl-(2R)-[2-(diphenylphosphino)ferrocenyl]-2-oxazoline, (S)-1-(diphenylphosphino)-2-[(S)-4-isopropyloxazolin-2-yl]ferrocene and (S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)-phosphino)ferrocen-1-yl]oxazoline.

3. The method for preparing a chiral oxazoline diester derivative according to claim 2, wherein: The synthesis method of the racemic oxazoline ester derivative comprises the following steps: Ethanol and compound 1 are mixed, and then acetyl chloride is slowly added dropwise in an ice bath to react; the solvent is then removed under reduced pressure to obtain a white solid; the white solid is washed with ether, and then a saturated sodium bicarbonate solution is added until the gas disappears; the resulting mixed solution is extracted with ethyl acetate, and the organic phase is collected, dried, and concentrated under reduced pressure to obtain an imidate intermediate; The structural formula of compound 1 is: ; The structural formula of the imidate intermediate is: ; An imidate intermediate, chloroform, and serine ethyl ester hydrochloride are mixed, and then triethylamine is added dropwise to react to form a red solution; after the red solution is decompressed to remove the solvent, a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, and a saturated sodium chloride solution are added respectively, and extraction is performed with ethyl acetate. The organic phase is collected, dried, decompressed, and the solvent is removed, and purified by silica gel column chromatography to obtain the racemic oxazoline ester derivative.

4. The method for preparing a chiral oxazoline diester derivative according to claim 2, wherein: The synthesis method of the racemic oxazoline ester derivative comprises the following steps: Compound 1', serine ethyl ester hydrochloride, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and dichloromethane were mixed and stirred for reaction, and then a saturated sodium bicarbonate solution was added to obtain a mixed solution, which was extracted with dichloromethane. The organic phase was collected, dried, and concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain an amide intermediate; The structural formula of compound 1' is: ; The structural formula of the amide intermediate is: ; Under nitrogen protection, the amide intermediate and anhydrous dichloromethane are mixed, and diethylaminosulfur trifluoride is slowly added dropwise at -40°C with continuous stirring; the reaction is monitored by thin-layer chromatography until the starting material is completely consumed; a saturated sodium bicarbonate solution is then added to quench the reaction, and the mixture is extracted with dichloromethane. The organic phase is collected, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the racemic oxazoline ester derivative.

5. The method for preparing a chiral oxazoline diester derivative according to claim 2, wherein: The molar ratio of tetraacetonitrile copper tetrafluoroborate, the chiral ligand and the racemic oxazoline ester derivative is 0.1:0.12:1; the molar equivalent ratio of the racemic oxazoline ester derivative to formaldehyde or paraformaldehyde is 1:(1-10); the molar ratio of the racemic oxazoline ester derivative to the base is 1:(1-3); the molar ratio of the racemic oxazoline ester derivative to the carboxylic acid is 1:(1-2); and the molar ratio of the racemic oxazoline ester derivative, the activation reagent, the acyl transfer reagent and the base is 1:3:3:

3.

6. The method for preparing a chiral oxazoline diester derivative according to claim 2 or 5, wherein: The base is at least one of potassium acetate, potassium carbonate, potassium phosphate, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, 1,8-diazobisspiro[5.4.0]undec-7-ene, cesium carbonate and triethylenediamine; The anhydrous solvent is an anhydrous organic solvent; the organic solvent is independently at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, 1,4-dioxane, acetonitrile, acetone, ethyl acetate, methanol, ethanol, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.

7. Use of the chiral oxazoline diester derivative according to claim 1 in the preparation of antifungal and / or oomycete drugs, characterized in that: The fungus and / or oomycete drug is at least one of apple black rot pathogen, sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia solani, Fusarium graminearum, Pythium graminearum, Trichoderma, Curvularia lunata and Phytophthora capsici.

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