Chiral oxazoline diester derivative as well as preparation method and application thereof

Abstract

The invention discloses chiral oxazoline diester derivatives as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis and medicinal chemistry, and a series of chiral oxazoline diester derivatives are designed and synthesized by adopting a one-pot method. The method comprises the following steps: firstly catalyzing a racemic oxazoline ester derivative and paraformaldehyde to carry out an asymmetric Adol addition reaction, and then carrying out an esterification reaction with various carboxylic acids containing pharmacophores to finally obtain a target compound. The invention prepares the diester compounds with chiral oxazoline structures, provides chemical structures of the compounds, and meanwhile, the antifungal / anti-oomycete activity results show that the compounds show excellent antifungal / anti-oomycete activity and have obvious enantioselective activity.

Description

Technical Field

[0001] The 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] Oxazoline compounds, 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, acaricide / insecticide, etc. However, there are relatively few studies on the biological activity of chiral oxazolines.

[0003] The reported oxazoline natural product nocazoline has good antibacterial activity as an S-configuration, but its R-configuration compound spoxazomicin C / nocazoline A shows some antitrypanosomal 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 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 derivatives, 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. After Adol reaction with the assistance of base, the solvent is removed and then reacted with formaldehyde or polyformaldehyde under the conditions of activating reagent, acyl transfer reagent and base in one pot to obtain chiral oxazoline diester compounds.

[0013] Preferably, the method specifically comprises 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 polyformaldehyde, a base and an anhydrous solvent are added in sequence, and stirring is continued to react; 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 the reaction is stirred; after the reaction is completed, the reaction solution is filtered with diatomaceous earth, and then the filtrate is concentrated under reduced pressure, and finally the chiral oxazoline diester derivative is purified by silica gel column chromatography;

[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 under ice bath conditions to react; then the solvent is 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 obtained mixed solution is extracted with ethyl acetate, the organic phase is collected, dried and concentrated under reduced pressure to obtain an imidate intermediate;

[0019] The 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 extracted with ethyl acetate, the organic phase is collected, dried and decompressed to remove the solvent, 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, and then a saturated sodium bicarbonate solution is added to obtain a mixed solution, which is extracted with dichloromethane, and 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 raw material is completely consumed; then a saturated sodium bicarbonate solution is added to quench it, and dichloromethane is used for extraction, and 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); the molar ratio of the racemic oxazoline ester derivative, the activating agent, the acyl transfer agent 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-diazobispiro[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 an embodiment of the present invention is to provide a use of the chiral oxazoline diester derivatives in the preparation of antifungal and / or oomycete drugs.

[0029] Preferably, the fungi and / or oomycete drugs include at least one of Psoralea corylifolia, Sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia solani, Fusarium graminearum, Pythium graminearum, Trichoderma, Curvularia lunulata and Phytophthora capsici.

[0030] The present invention provides a method for preparing a chiral oxazoline diester derivative, which adopts a one-pot method to design and synthesize a series of chiral oxazoline diester derivatives. The method first catalyzes a racemic oxazoline ester derivative to undergo an asymmetric Adol addition reaction with polyformaldehyde or formaldehyde to establish an oxygen bridge, and then undergoes an esterification reaction with various carboxylic acids containing pharmacophoric groups to finally obtain a diester compound containing an aromatic substituted oxazoline structure. The present invention prepares diester compounds with a chiral oxazoline structure and provides the chemical structures of these compounds. At the same time, the antifungal / anti-oomycete activity results show that this type of compound exhibits excellent antifungal / anti-oomycete activity and has obvious enantioselective activity, indicating that this type of compound has a wide range of agricultural application prospects, laying a foundation for 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 described embodiments 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 work 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 of an alkyl group, an aryl group and a heteroaryl group.

[0035] The embodiment of the present invention uses racemic oxazoline ester, formaldehyde / polyformaldehyde and carboxylic acid compounds as starting materials, copper metal tetrafluoroborate tetraacetonitrile as a catalyst, a chiral ferrocene reagent as a ligand, and an Adol reaction and an esterification reaction with the assistance of a base and a condensing agent to prepare a class of chiral oxazoline diester compounds in a precise and rapid manner with high yield and high enantioselectivity for the first time; and the target compound is obtained by structural design of aromatic 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 of an alkyl group, an aryl group and a heteroaryl group.

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

[0040] S1, ethanol and benzonitrile (compound 1 in the above synthetic route) are mixed, and then acetyl chloride is slowly added dropwise in an ice bath to react, and the reaction mixture is stirred at room temperature; then the solvent is 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 obtained mixed solution is extracted with ethyl acetate, the organic phase is collected, and it is dried and concentrated under reduced pressure to obtain an imidate intermediate (compound 2 in the above synthetic route);

[0041] Alternatively, carboxylic acid (compound 1' in the above synthetic route), serine ethyl ester hydrochloride, 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and dichloromethane are mixed and stirred for reaction, and then a saturated sodium bicarbonate solution is added to obtain a mixed solution, which is extracted with dichloromethane, and the organic phase is collected, dried, and 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, mixing the imidate intermediate, chloroform and serine ethyl ester hydrochloride, and then adding triethylamine dropwise to react to form a red solution; after removing the solvent from the red solution under reduced pressure, adding saturated ammonium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, extracting with ethyl acetate, collecting the organic phase, drying and removing the solvent under reduced pressure, and purifying 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 raw material is completely consumed; then a saturated sodium bicarbonate solution is added to quench it, 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 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, add the racemic oxazoline ester derivative, formaldehyde or polyformaldehyde, a base and an anhydrous solvent in sequence, 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 with silica gel column chromatography to obtain a chiral oxazoline diester derivative (compound 4 in the above synthetic route);

[0045] Among them, the molar ratio of tetraacetonitrile copper tetrafluoroborate, chiral ligand and 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); 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-diazobispiro[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 thereto.

[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: Mix ethanol and benzonitrile 1a and stir in a round-bottom flask, then slowly add acetyl chloride dropwise in an ice bath over 20 minutes, and stir the reaction mixture at room temperature for 4 hours. Then remove the solvent under reduced pressure to obtain a white solid. Wash the white solid with ether, and then add saturated sodium bicarbonate solution until the gas disappears. The resulting mixed solution is extracted three times with ethyl acetate, and the organic phase is collected, dried, and concentrated under reduced pressure to obtain the desired product, 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. Then triethylamine was added dropwise and the reaction was continued for 15 hours to form a red solution. After the reaction mixture was decompressed to remove the solvent, 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 decompressed to remove the solvent, and purified by silica gel column chromatography to obtain compound 3a.

[0056] Alternatively, step 3: Add benzoic acid 1a', serine ethyl ester hydrochloride, 1-hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and dichloromethane into a round-bottom flask and stir for 15 hours. Then add saturated sodium bicarbonate solution to obtain a mixed solution, and extract it three times with dichloromethane. Collect the organic phase, dry it, and concentrate it under reduced pressure. Then purify it by silica gel column chromatography to obtain amide intermediate 2a'.

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

[0058] Step 5: Under nitrogen protection, add the following reagents to a dry Schlenk flask: tetraacetonitrile copper tetrafluoroborate (10 mol %, 0.015 mmol), 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 hour, then add compound 3 (0.15 mmol), paraformaldehyde (1.5 mmol), potassium acetate (0.3 mmol) and anhydrous toluene (1 mL), and stir at 20 °C for 24 hours. After the reaction is completed, reduce the pressure and remove the solvent. 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 in sequence and stirred at 20 °C for 15 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. Compound (R)-4a was obtained by purification 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 the 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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by p-fluorobenzonitrile or p-fluorobenzoic acid. The obtained 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, and its structural formula is 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, which is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by p-chlorobenzonitrile or p-chlorobenzoic acid. The obtained 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, and its structural formula is 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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by p-bromobenzonitrile or p-bromobenzoic acid. The obtained 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, and its structural formula is 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, which is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by p-methylbenzonitrile or p-methylbenzoic acid. The obtained compound (R)-4e is (R)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate)oxy)methyl)-2-(p-tolyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is 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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by 3,4-difluorobenzonitrile or 3,4-difluorobenzoic acid. The obtained 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, and the structural formula is 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 is different 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 is 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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by 4-methoxybenzonitrile or 4-methoxybenzoic acid. Compound (R)-2-(4-methoxyphenyl)-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:

[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 is different 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-carboxylate)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 is different 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 is different 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. Compound (R)-2-(3,5-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:

[0090] ;

[0091] Compound (R)-4k was 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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by 3-bromobenzonitrile or 3-bromobenzoic acid. Compound (R)-2-(3-bromophenyl)-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:

[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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by 3-thiophenecarbonitrile or 3-thiophenecarboxylic acid. The obtained 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, and the structural formula is shown below:

[0096] ;

[0097] Compound (R)-4m was 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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by 3-furancarbonitrile or 3-furancarboxylic acid. The obtained 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, and its structural formula is 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 is different from Example 1 only in that benzonitrile 1a in step 1 or benzoic acid 1a' in step 3 is replaced by 2-bromobenzonitrile or 2-bromobenzoic acid. The obtained 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, and its structural formula is 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 is different from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced by 1-methyl-3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid. The obtained compound (R)-4p is (R)-2-(4-bromophenyl)-4-(((3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is 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 is different from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced by 2-trifluoromethylbenzoic acid, and triethylamine is replaced by triethylenediamine. The obtained compound (R)-4q is (R)-2-(4-bromophenyl)-4-(((2-(trifluoromethyl)benzoyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is 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, 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, and 4-dimethylaminopyridine (DMAP) is replaced by 1-hydroxybenzotriazole (HOBT). The obtained compound (R)-4r is (R)-2-(4-bromophenyl)-4-(((2-chloronicotinyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is 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 is different from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced by 1-methylcyclohexane-1-carboxylic acid. The obtained compound (R)-4s is (R)-2-(4-bromophenyl)-4-(((1-methylcyclohexane-1-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and its structural formula is 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 product wasanalyzed by HPLC to determine the enantiomeric excess: 94% ee (CHIRALPAK IC,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 is different 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 obtained 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, and the structural formula is shown below:

[0117] ;

[0118] Compound (R)-4t was 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 is different 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 obtained compound (R)-4u is (R)-2-(4-bromophenyl)-4-(((3-methylthiophene-2-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is shown below:

[0120] ;

[0121] Compound (R)-4u was 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 is different 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 obtained compound (R)-4v is (R)-2-(4-bromophenyl)-4-(((2-methylfuran-3-carboxylate)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and its structural formula is 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 a compound (R)-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). The obtained compound (R)-4w is (R)-2-(4-bromophenyl)-4-(((2-methylnicotinoyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is 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 wasanalyzed by HPLC to determine the enantiomeric excess: 93% ee (CHIRALPAK IC,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 is different from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced by 3-methylthiophene-2-carboxylic acid, 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)-4u is (S)-2-(4-bromophenyl)-4-(((3-methylthiophene-2-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is shown below:

[0129] ;

[0130] Compound (S)-4u was 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 is different from Example 4 only in that 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in step 5 is replaced by 2-methylfuran-3-carboxylic acid, 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)-4v is (S)-2-(4-bromophenyl)-4-(((2-methylfuran-3-carboxyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the structural formula is 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 method for preparing 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)-2-(4-bromophenyl)-4-(((2-methylnicotinoyl)oxy)methyl)-4,5-dihydrooxazole-4-carboxylic acid ethyl ester, and the 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 wasanalyzed by HPLC to determine the enantiomeric excess: 93% ee (CHIRALPAK IC,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 examples.

[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 mycelium linear growth rate method was used to determine 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 pathogenic fungi, including Valsamali, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani, Fusarium graminicola, Pythium graminicola, Trichoderma viride, Curvularialunata and Phytophthora capsici. The selected 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 medium containing drug solution with a mass concentration of 50 mg / L. Then, it was poured into sterilized culture dishes while hot, 10 mL per dish, and cooled for use. The plant pathogenic fungi (5 mm in diameter) were inoculated into the above culture dishes, with 3 parallels for each test group; after culturing them in a constant temperature incubator at 25 °C for 72 h, the colony diameter (mm) was measured by the cross method, with 1% DMSO aqueous solution as the blank control, and the commercially available antifungal agent Tebuconazole and anti-oomycete agent Dimethomorph as the positive control. The mycelium growth inhibition rate (I1) was calculated according to the following formula:

[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 mycelium-containing 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 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 or thiophene-3-yl, the fungicidal activity is significantly reduced. 2 When R 2 When it is an aromatic acid, the fungicidal activity of the aromatic ring containing heteroatoms is significantly better than that of the benzene ring. In addition, the introduction of a methyl group at the ortho position of the aromatic ring will also significantly improve the fungicidal activity of the compound, but if other substituents are introduced at the non-ortho position of the benzene ring, the fungicidal activity of the compound may be reduced.

[0151] In summary, the chiral oxazoline diester derivatives prepared by the asymmetric synthesis method in the embodiments of the present invention have certain antifungal / anti-oomycete 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 / anti-oomycete active ingredients.

[0152] Based on the above-mentioned ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above-mentioned description. 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: It is an optically active compound, including the levorotatory or dextrorotatory isomer shown in the following structural formula: or ; 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 of an alkyl group, an aryl group and a heteroaryl group.

2. The chiral oxazoline diester derivative according to claim 1, characterized in that: The structural formula of the chiral oxazoline diester derivative is any one of the following formulas: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。 3. A method for preparing a chiral oxazoline diester derivative as claimed in claim 1 or 2, characterized in that: The following steps are involved: The invention uses racemic oxazoline ester derivatives and polyformaldehyde compounds as starting materials, tetraacetonitrile copper tetrafluoroborate as catalyst, and chiral ferrocene reagent as ligand. After Adol reaction with the assistance of base, the solvent is removed and then reacted with formaldehyde or polyformaldehyde under the conditions of activating reagent, acyl transfer reagent and base in one pot to obtain chiral oxazoline diester compounds.

4. The method for preparing a chiral oxazoline diester derivative according to claim 3, characterized in that: 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 polyformaldehyde, a base and an anhydrous solvent are added in sequence, and stirring is continued to react; 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 the reaction is stirred; after the reaction is completed, the reaction solution is filtered with diatomaceous earth, and then the filtrate is concentrated under reduced pressure, and finally the chiral oxazoline diester derivative is purified by silica gel column chromatography; Among them, the structural formula of the racemic oxazoline ester derivative is: 。 5. The method for preparing a chiral oxazoline diester derivative according to claim 4, characterized in that: The synthesis method of the racemic oxazoline ester derivative comprises the following steps: Ethanol and benzonitrile are mixed, and then acetyl chloride is slowly added dropwise under ice bath conditions to react; then the solvent is 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 obtained mixed solution is extracted with ethyl acetate, the organic phase is collected, dried and concentrated under reduced pressure to obtain an imidate intermediate; The 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 extracted with ethyl acetate, the organic phase is collected, dried and decompressed to remove the solvent, and purified by silica gel column chromatography to obtain the racemic oxazoline ester derivative.

6. The method for preparing a chiral oxazoline diester derivative according to claim 4, characterized in that: The synthesis method of the racemic oxazoline ester derivative comprises the following steps: Carboxylic acid, serine ethyl ester hydrochloride, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and dichloromethane are mixed and stirred for reaction, and then a saturated sodium bicarbonate solution is added to obtain a mixed solution, which is extracted with dichloromethane, and the organic phase is collected, dried, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain an amide intermediate; 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 raw material is completely consumed; then a saturated sodium bicarbonate solution is added to quench it, and dichloromethane is used for extraction, and 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.

7. The method for preparing a chiral oxazoline diester derivative according to claim 4, characterized in that: The molar ratio of tetraacetonitrile copper tetrafluoroborate, chiral ligand and racemic oxazoline ester derivative is 0.1:0.12:1; the molar equivalent ratio of racemic oxazoline ester derivative and formaldehyde or paraformaldehyde is 1:(1-10); the molar ratio of racemic oxazoline ester derivative and base is 1:(1-3); the molar ratio of racemic oxazoline ester derivative and carboxylic acid is 1:(1-2); the molar ratio of racemic oxazoline ester derivative, activation reagent, acyl transfer reagent and base is 1:3:3:

3.

8. The method for preparing a chiral oxazoline diester derivative according to claim 4 or 7, characterized in that: The base is at least one of potassium acetate, potassium carbonate, potassium phosphate, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, 1,8-diazobispiro[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; 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.

9. Use of the chiral oxazoline diester derivatives according to claim 1 or 2 in the preparation of antifungal and / or oomycete drugs.

10. The use according to claim 9, characterized in that: The fungi and / or oomycete drugs include at least one of apple black rot pathogen, sclerotinia sclerotiorum, Botrytis cinerea, Rhizoctonia solani, Fusarium graminearum, Pythium graminearum, Trichoderma, Curvularia lunulata and Phytophthora capsici.

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