A method for synthesizing α-aryl-β-monofluoroalkyl ketone derivatives from olefin bifunctional groups

Abstract

The invention discloses a method for synthesizing α-aryl-β-monofluoroalkyl ketone derivatives from olefin bifunctional groups, characterized in that the method comprises: in a glove box, ethyl monofluorobromoacetate, arylethylene, aryl formaldehyde, azacarbene NHC catalyst, Mn(acac) 2 or Fe(OAc) 2 , cesium carbonate are placed in a test tube, the test tube is sealed with a rubber stopper, the test tube is taken out of the glove box, and then anhydrous THF is added under argon protection to react, and α-aryl-β-monofluoroalkyl ketone derivatives are obtained after post-treatment. This method has mild reaction conditions, simple preparation methods, high efficiency, and easy operation. The synthesized derivatives have a high yield and can be applied to the structural modification of drug molecules.

Description

Technical Field

[0001] The invention relates to an organic synthesis technology, in particular to a method for synthesizing alpha-aryl-beta-monofluoroalkyl ketone derivatives by using olefin bifunctional groups. Background Art

[0002] Introducing fluorine atoms or fluorine-containing groups into the molecular skeleton is one of the important research strategies for modifying the chemical structure of drugs. Fluorine-containing groups can affect the physicochemical properties of compounds, improve the pharmacokinetic properties of drug molecules, enhance metabolic stability and improve the selectivity of target proteins. Therefore, organic molecules containing fluorine groups are widely used in the fields of life sciences, agricultural sciences and materials sciences, making the development of new synthetic methods for constructing fluorine-containing groups particularly urgent. Unlike other fluoroalkylation (such as difluoroalkylation, trifluoromethylation, etc.), there are relatively few studies on monofluoroalkylation, so it is of great significance to develop an efficient synthesis of monofluoroalkyl derivatives with diverse structural types. Summary of the invention

[0003] The purpose of the present invention is to provide a method for synthesizing α-aryl-β-monofluoroalkyl ketone derivatives from olefin bifunctional groups in view of the deficiencies of the prior art. The method has mild reaction conditions, a simple preparation method, high efficiency, and easy operation. The synthesized derivatives have a high yield and can be applied to the structural modification of drug molecules.

[0004] The technical solution for achieving the purpose of the present invention is:

[0005] A method for synthesizing α-aryl-β-monofluoroalkyl ketone derivatives from olefin bifunctional groups, the method comprising:

[0006] In the glove box, ethyl bromofluoroacetate, aryl ethylene, aryl formaldehyde, azacarbene NHC catalyst, Mn(acac) 2 or Fe(OAc) 2 , cesium carbonate is placed in a test tube, and after the test tube is sealed with a rubber stopper, the test tube is taken out from the glove box, and then anhydrous THF is added under argon protection to react, and after post-treatment, ethyl acetate and water are added for extraction, drying, and concentration, the concentrate is gradient eluted with a volume ratio of petroleum ether / ethyl acetate = 100:1 to 4:1 as an eluent, and column chromatography is performed for purification to obtain an α-aryl-β-monofluoroalkyl ketone derivative, wherein the structural formula of ethyl monofluorobromoacetate is formula (I), the structural formula of arylethylene is formula (II), the structural formula of aryl formaldehyde is formula (III), and the structural formulas of azacarbene NHC catalyst are formulas (IV) and (V):

[0007]

[0008] Among them, R 1It is naphthyl or substituted phenyl, and the substituent in the substituted phenyl is one or more of hydrogen, fluorine, bromine, chlorine, trifluoromethyl, methoxy, methyl or phenyl.

[0009] During the reaction, a thin layer chromatography plate was used to track the reaction until the reaction was complete, wherein the reaction temperature was 60° C. and the reaction time was 12 h.

[0010] The R 1 When it is a substituted phenyl olefin, the substituent is selected from one or more of hydrogen, fluorine, bromine, chlorine, nitro, cyano, ester, trifluoromethyl, methoxy, methyl, phenyl, amino, pyridyl, thienyl, and aromatic olefins derived from estrone, ibuprofen and Tamiflu.

[0011] The molar ratio of the raw materials in the method is aromatic aldehyde: aromatic olefin: ethyl monofluorobromoacetate: cesium carbonate: NHC catalyst: Mn(acac) 2 or Fe(OAc) 2 =1:1.5:2.0:1.5:0.1:0.1.

[0012] This method has mild reaction conditions, a simple, efficient and easy-to-operate preparation method, and a high yield of the synthesized derivatives, which can be applied to the structural modification of drug molecules. DETAILED DESCRIPTION

[0013] The present invention will be further described with examples below, but they are not intended to limit the present invention.

[0014] Example:

[0015] Example 1: Preparation and Characterization of (S)-2-Fluoro-5-(naphthalen-2-yl)-5-carbonyl-4-phenylpentanoic acid ethyl ester:

[0016]

[0017] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), styrene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, the reaction was cooled to room temperature, the filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 30:1 as eluent, and finally a yellow oily liquid (51.1mg, yield 70%, 1:1dr) was obtained. The product is characterized as follows: 1H NMR(400MHz,CDCl 3 ):δ8.50(d,J=8.0Hz,1H),8.03-7.99(m,1H),7.90(d,J=8.0Hz,1H),7.83-7.79(m,2H),7.57-7.49(m,2H),7.42-7.28(m,4H),7.25-7.18(m,1H),5.18-5.11(m,1H),5.07-4.63(m,1H),4.24-4.08(m,2H),3.08-2.29(m,2H),1.29-1.25(m,3H)ppm;Data of one isomer: 13 C NMR(101MHz,CDCl 3 ):δ198.03,169.5(d,J=29.3Hz),138.2,135.3,133.2,132.1,130.5,129.43,129.0,128.4,128.21,128.0,127.4,127.3,126.49,124.0,87.1(d,J=183.8Hz),61.3,48.6(d,J=1.0Hz),36.3(d,J=21.2Hz),13.8ppm; 19 FNMR(376MHz,CDCl 3 ):δ-192.6ppm Data of the other isomer: 13 C NMR(101MHz,CDCl 3 ):δ197.97,169.2(d,J=28.3Hz),137.2,135.2,133.1,132.1,130.4,129.41,129.1,128.4,128.3,128.17,127.5,127.4,126.47,124.13,86.5(d,J=183.8Hz),61.4,48.1(d,J=4.0Hz),35.7(d,J=20.2Hz),13.8ppm; 19 F NMR(376MHz,CDCl 3 ):δ-192.7ppm.HRMS m / z(ESI):calculated for C 24 H 20 FNO 3 Na[M+Na] + :387.1367,found 387.1372。

[0018] Example 2: Preparation and Characterization of (S)-2-Fluoro-5-(naphthalen-2-yl)-4-(p-tolyl)-5-oxopentanoic acid ethyl ester:

[0019]

[0020] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-methyl-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 25:1 as eluent, and finally a yellow oily liquid (47.1mg, yield 62%, 1.2:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.51-8.48(m,1H),8.03-7.98(m,1H),7.92-7.89(m,1H),7.83-7.79(m,2H),7.58-7.48(m,2H),7.30-7.23( Data ofone isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.53,169.7(d,J=23.9Hz),137.4,135.6,135.56,134.3,133.7,132.5,130.83,130.0,129.83,128.7,12 8.55,128.2,126.84,124.5,87.5(d,J=183.2Hz),61.7,48.6(d,J=1.6Hz),36.7(d,J=20.4Hz),21.1,14.2ppm; 19 FNMR (376MHz, CDCl 3 ): δ-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl3 ): δ198.51,170.0(d,J=23.5Hz),137.6,135.6,135.60,134.3,133.5,132.5,130.77,130.2,129.81,128.6,12 8.52,127.8,126.82,124.6,86.9(d,J=183.6Hz),61.8,48.1(d,J=3.5Hz),36.1(d,J=20.3Hz),21.2,14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-193.2ppm.HRMS m / z(ESI):calculated for C 24 H 23 FO 3 Na[M+Na] + :401.1524, found 401.1532.

[0021] Example 3: Preparation and Characterization of (S)-2-Fluoro-4-(4-methoxyphenyl)-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0022]

[0023] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-methoxy-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (40.0mg, yield 51%, 2:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ8.50-8.47(m,1H),8.02-7.97(m,1H),7.93-7.89(m,1H),7.84-7.80(m,2H),7.59-7.48(m,2H),7.33-7.26(m,2H),6. 88-6.79(m,2H),5.07-4.62(m,2H),4.26-4.08(m,2H),3.82-3.72(m,3H),3.03-2.25(m,2H),1.30-1.24(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.6,169.7(d,J=23.7Hz),159.1,135.7,133.7,132.5,130.8,130.5,129.83,129.5,128.72,128.6,12 7.8,126.9,124.5,114.7,87.5(d,J=183.3Hz),61.7,55.3,47.7(d,J=3.6Hz),36.7(d,J=20.6Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.6,170.0(d,J=23.4Hz),159.2,135.6,133.5,132.5,130.7,130.5,129.80,129.3,128.67,128.5,12 7.8,126.8,124.6,114.9,86.9(d,J=183.6Hz),61.8,55.3,48.1(d,J=1.4Hz),36.1(d,J=20.3Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-193.3ppm.HRMS m / z(ESI):calculated for C 24 H 23 FO 4 Na[M+Na] + :417.1473,found417.1472.

[0024] Example 4: Preparation and Characterization of (S)-4-(4-acetoxyphenyl)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0025]

[0026] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 4-vinylphenyl acetate (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 5:1 as eluent, and finally a yellow oily liquid (36.3mg, yield 43%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.49(d,J=12.0Hz,1H),8.01-7.97(m,1H),7.91(d,J=8.0Hz,1H),7.84- 7.81(m,2H),7.59-7.55(m,1H),7.54-7.50(m,1H),7.43-7.37(m,2H),7.08 Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.1,169.2(d,J=26.2Hz),169.0,150.0,135.6,135.4,133.2,132.2,130.54,129.53,129.4,128.54,128.39, 127.5, 126.64, 124.12, 122.3, 87.0 (d, J = 185.5Hz), 61.53, 47.8 (d, J = 1.0Hz), 36.4 (d, J = 20.2Hz), 20.92, 13.9ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-193.0ppm; Data of the other isomer: 13C NMR (101 MHz, CDCl 3 ): δ198.0,169.4(d,J=27.3Hz),169.0,149.8,135.37,134.5,133.0,132.2,130.47,129.51,129.1,128.49,128.36, 127.5, 126.61, 124.09, 122.1, 86.4 (d, J = 184.8Hz), 61.49, 47.3 (d, J = 3.0Hz), 35.8 (d, J = 20.2Hz), 20.89, 13.88ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-193.1ppm.HRMS m / z(ESI):calculated for C 25 H 23 FO 5 Na[M+Na] + :445.1422,found445.1416.

[0027] Example 5: Preparation and Characterization of Ethyl 4-(4-aminophenyl)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoate:

[0028]

[0029] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 4-vinylaniline (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 3:1 as eluent, and finally a yellow oily liquid (20.5mg, yield 27%, 1.5:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ8.47(d,J=8.0Hz,1H),8.01-7.98(m,1H),7.90(d,J=8.0Hz,1H),7.82-7.80(m,2H),7.57-7.49(m,2H),7.17-7.11(m, Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.6,170.0(d,J=24.2Hz),145.9,135.4,133.5,132.4,130.58,129.68,129.6,128.47,128.3,127.7, 126.8, 126.66, 124.51, 115.9, 86.9 (d, J = 183.8Hz), 61.62, 48.1 (d, J = 1.0Hz), 36.0 (d, J = 20.2Hz), 14.1ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.6,169.7(d,J=24.2Hz),145.8,135.5,133.7,132.4,130.63,129.7,129.3,128.52,128.4,128.0,1 27.7,126.69,124.47,115.7,87.4(d,J=183.8Hz),61.57,47.6(d,J=4.0Hz),36.5(d,J=20.2Hz),14.1ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-193.4ppm.HRMS m / z(ESI):calculated for C 23 H 22 FNO 3 Na[M+Na] + :402.1476,found402.1474.

[0030] Example 6: Preparation and Characterization of (S)-2-Fluoro-4-(4-fluorophenyl)-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0031]

[0032] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-fluoro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 25:1 as eluent, and finally a yellow oily liquid (53.4mg, yield 69%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.47(d,J=8.0Hz,1H),8.01-7.97(m,1H),7.92(d,J=8.0Hz),7.85-7.82(m,2H),7.60-7.51(m,2H),7.39-7.31(m,2H), 7.05-6.96(m,2H),5.09-5.03(m,1H),5.02-4.61(m,1H),4.25-4.09(m,2H),3.04-2.26(m,2H),1.29-1.26(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.1,169.4(d,J=24.2Hz),161.9(d,J=247.5Hz),135.4,134.0,133.1,132.9,132.2,130.5,130.0(d,J=8.1Hz),129.5(d,J=3.0 Hz), 128.6, 127.5, 126.7, 124.09, 116.1 (d, J = 23.2Hz), 87.0 (d, J = 183.8Hz), 61.54, 47.7 (d, J = 2.0Hz), 36.3 (d, J = 21.2Hz), 13.9ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-114.2,-192.9ppm; Data of the other isomer: 13C NMR (101 MHz, CDCl 3 ): δ198.0,169.2(d,J=25.3Hz),161.9(d,J=247.5Hz),135.3,133.9,132.94,132.87,132.2,130.4,129.7(d,J=8.1Hz),128.5,128.4( d,J=3.0Hz),127.5,126.6,124.06,115.9(d,J=23.2Hz),86.4(d,J=183.8Hz),61.45,47.3(d,J=4.0Hz),35.8(d,J=20.2Hz),13.9ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-114.5,-193.1ppm.HRMS m / z(ESI):calculated forC 23 H 20 F 2 O 3 Na[M+Na] + :405.1273, found 405.1289.

[0033] Example 7: Preparation and Characterization of Ethyl 4-(4-chlorophenyl)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoate:

[0034]

[0035] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-chloro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 30:1 as eluent, and finally a yellow oily liquid (64.0mg, yield 80%, 1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ8.46(d,J=8.0Hz,1H),8.01-7.96(m,1H),7.90(d,J=8.0Hz,1H),7.83-7.79(m,2H),7.57-7.48(m,2H) ,7.36-7.24(m,4H),5.09-4.61(m,2H),4.24-4.10(m,2H),3.05-2.26(m,2H),1.28-1.24(m,3H)ppm; Data of one isomer: 13 CNMR (101MHz, CDCl 3 ): δ198.0,169.6(d,J=24.2Hz),137.0,135.64,133.8,133.3,132.4,130.8,129.9,129.73,129.7,128.77, 128.6, 127.8, 126.89, 124.29, 87.2 (d, J = 183.8Hz), 61.8, 48.1 (d, J = 2.0Hz), 36.4 (d, J = 20.2Hz), 14.1ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-192.8ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.9,169.4(d,J=24.2Hz),135.9,135.59,133.6,133.1,132.4,130.7,129.68,129.6,129.4,128.82, 128.7, 127.8, 126.92, 124.25, 86.6 (d, J = 183.8Hz), 61.7, 47.7 (d, J = 4.0Hz), 35.9 (d, J = 21.2Hz), 14.1ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-192.9ppm.HRMS m / z(ESI):calculated forC 23 H 20 ClFO 3 Na[M+Na] + :421.0978,found 421.0985.

[0036] Example 8: Preparation and Characterization of (S)-4-(4-bromophenyl)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0037]

[0038] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-bromo-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 30:1 as eluent, and finally a yellow oily liquid (68.1mg, yield 77%, 1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.47(d,J=8.0Hz,1H),8.01-7.81(m,1H),7.91(d,J=8.0Hz,1H),7.84-7.81(m,2H),7.59-7.50(m,2H),7.47-7.41(m,2H) ),7.30-7.24(m,2H),5.07-5.01(m,1H),5.0-4.62(m,1H),4.24-4.11(m,2H),3.04-2.26(m,2H),1.29-1.25(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.7,169.3(d,J=23.2Hz),137.2,135.4,130.0,132.3,132.11,130.5,130.0,129.48,128.6,128.4, 127.5, 126.68, 123.99, 121.4, 86.9 (d, J = 183.8Hz), 61.4, 47.9 (d, J = 2.0Hz), 36.1 (d, J = 20.2Hz), 13.9ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-192.8ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3): δ197.6,169.1(d,J=23.2Hz),136.2,135.35,132.8,132.3,132.14,130.4,129.8,129.46,128.5,128.38 ,127.5,126.65,124.03,121.7,86.4(d,J=184.8Hz),61.6,47.5(d,J=3.0Hz),35.6(d,J=20.2Hz),13.9ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-192.9ppm.HRMS m / z(ESI):calculated for C 23 H 20 BrF 3 Na[M+Na] + :465.0473,found465.0473.

[0039] Example 9: Preparation and Characterization of (S)-4-(4-cyanobenzene)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0040]

[0041] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 4-vinylbenzene-1-carbonitrile (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 8:1 as eluent, and finally a yellow oily liquid (58.2mg, yield 75%, 1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3):δ8.46(d,J=12.0Hz,1H),7.99-7.95(m,1H),7.92(d,J=8.0Hz,1H),7.86(m,2H),7.62-7.64(m,1H),7.61-7.57(m,2H),7.55-7.53(m,2H),7.51-7.49(m,1H),5.15-5.11(m,1H),5.07-4.6(m,1H),4.24-4.11(m,2H),3.08-2.27(m,2H),1.29-1.25(m,3H)ppm;Data of one isomer: 13 C NMR(101MHz,CDCl 3 ):δ197.1,168.9(d,J=23.2Hz),143.7,135.8,133.11,133.05,132.4,130.8,129.74,129.4,129.1,128.9,127.8,127.09,124.11,118.34,111.9,87.4(d,J=184.8Hz),61.7,42.3(d,J=2.0Hz),36.0(d,J=20.2Hz),13.87ppm; 19 FNMR(376MHz,CDCl 3 ):δ-192.6ppm;Data of theother isomer: 13 C NMR(101MHz,CDCl 3 ):δ197.0,169.0(d,J=24.2Hz),142.9,135.7,133.0,132.9,132.4,130.7,129.71,129.2,129.0,128.8,127.8,127.07,124.07,118.32,111.7,85.6(d,J=184.8Hz),61.6,48.0(d,J=3.0Hz),35.6(d,J=20.2Hz),13.85ppm; 19 FNMR(376MHz,CDCl 3 ):δ-192.7ppm.HRMS m / z(ESI):calculated for C 24 H 21 FNO 3 [M+H] + :390.1500,found 390.1497。

[0042] Example 10: Preparation and Characterization of (S)-2-Fluoro-5-(naphthalen-2-yl)-4-(4-trifluoromethylphenyl)-5-oxopentanoic acid ethyl ester:

[0043]

[0044] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-(trifluoromethyl)-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 25:1 as eluent, and finally a yellow oily liquid (40.3mg, yield 46%, 1.2:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.49-8.46(m,1H),8.02-7.97(m,1H),7.94-7.91(m,1H),7.86-7.81(m,2H),7.62-7.49( m,6H),5.19-4.60(m,2H),4.26-4.07(m,2H),3.09-2.28(m,2H),1.29-1.24(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.7,169.5(d,J=23.5Hz),141.6,135.77,133.1,132.5,130.8,129.8,129.1,128.99,128.8,127.9,127.08,12 6.5(q,J=3.6Hz),125.3,124.31,122.6,86.6(d,J=184.4Hz),62.0,48.5(d,J=1.8Hz),36.0(d,J=20.4Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-62.71,-192.9ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3): δ197.8,169.3(d,J=23.6Hz),142.5,135.82,133.3,132.5,130.9,129.9,129.0,128.99,128.9,127.9,127.11,12 6.3(q,J=3.7Hz),125.3,124.28,122.6,87.2(d,J=184.0Hz),61.9,48.2(d,J=3.5Hz),36.5(d,J=20.7Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-62.69,-192.9ppm.HRMS m / z(ESI):calculated for C 24 H 20 F 4 O 3 Na[M+Na] + :455.1241,found455.1247.

[0045] Example 11: Preparation and Characterization of (S)-2-Fluoro-5-(naphthalen-2-yl)-4-(4-nitrophenyl)-5-oxopentanoic acid ethyl ester:

[0046]

[0047] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-nitro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 8:1 as eluent, and finally a yellow oily liquid (30.3mg, yield 37%, 1:0.9dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ8.47(d,J=8.0Hz,1H),8.21-8.14(m,2H),7.99-7.95(m,1H),7.92(d,J=8.0Hz,1H),7.86-7.82(m,2H),7.61-7. 52(m,4H),5.24-5.18(m,1H),5.08-4.62(m,1H),4.24-4.12(m,2H),3.11-2.29(m,2H),1.30-1.25(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.1,169.0(d,J=23.2Hz),147.2,145.5,135.6,132.8,132.1,130.6,129.51,129.3,128.9,128.7,12 7.6,126.89,124.3,123.9,86.2(d,J=184.8Hz),61.71,48.07(d,J=1.0Hz),35.64(d,J=20.2Hz),13.85ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-192.6ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.9,168.8(d,J=24.2Hz),147.1,144.7,135.5,132.6,132.1,130.5,129.48,129.0,128.8,128.6,12 7.6, 126.86, 124.2, 123.8, 86.8 (d, J = 184.8Hz), 61.62, 47.81 (d, J = 4.0Hz), 36.06 (d, J = 20.2Hz), 13.87ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-192.6ppm.HRMS m / z(ESI):calculated for C 23 H 20 FNO 5 Na[M+Na] + :432.1218, found 432.1210.

[0048] Example 12: Preparation and characterization of (S)-methyl 4-(5-ethoxy-4-fluoro-1-(naphthalen-2-yl)-1,5-dioxolane-2-yl)benzoate:

[0049]

[0050] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), methyl 4-vinylbenzoate (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (38.0mg, yield 45%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.46(d,J=8.0Hz,1H),8.01-7.95(m,3H),7.9(d,J=8.0Hz,1H),7.83-7.80(m,2H),7.58-7.44(m,4H),5.16-5 .09(m,1H),5.08-4.6(m,1H),4.24-4.1(m,2H),3.86-3.85(m,3H),3.09-2.27(m,2H),1.29-1.24(m,3H)ppm; Data ofone isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.2,169.9(d,J=23.2Hz),166.9,144.0,143.0,136.1,133.7,132.8,131.2,131.13,130.13,129.9,129.3,1 29.1,128.1,127.32,124.64,87.6(d,J=183.8Hz),62.1,52.59,49.1(d,J=1.0Hz),36.7(d,J=20.2Hz),14.51ppm; 19 FNMR (376MHz, CDCl 3 ): δ-192.8ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3): δ198.1,169.7(d,J=24.2Hz),166.9,144.0,143.0,136.0,133.5,132.8,131.15,130.9.130.1,129.9,129.2 ,128.8,128.1,127.3,124.6,87.0(d,J=184.8Hz),62.2,52.6,48.5(d,J=4.0Hz),36.3(d,J=21.2Hz),14.5ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-192.8ppm.HRMS m / z(ESI):calculated for C 25 H 23 FO 5 Na[M+Na] + :445.1422,found445.1427.

[0051] Example 13: Preparation and Characterization of (S)-2-Fluoro-4-(2-methoxyphenyl)-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0052]

[0053] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-methoxy-2-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 25:1 as eluent, and finally a yellow oily liquid (43.1mg, yield 55%, 1.1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3):δ8.58-8.56(m,1H),8.05-8.00(m,1H),7.88-7.84(m,1H),7.81-7.77(m,2H),7.57-7.46(m,2H),7.24-7.14(m,2H),6.91-6.81(m,2H),5.58-5.47(m,1H),5.15-4.65(m,1H),4.28-4.09(m,2H),3.98(d,J=7.6Hz,3H),3.03-2.18(m,2H),1.30-1.24(m,3H)ppm;Data of one isomer: 13 C NMR(101MHz,CDCl 3 ):δ199.1,169.8(d,J=23.9Hz),155.9,135.65,133.6,132.5,130.7,129.8,129.0,128.9,128.5,128,.4,128.3,127.8,126.7,124.40,121.2,111.2,87.7(d,J=183.1Hz),61.6,55.7,40.8(d,J=3.3Hz),35.4(d,J=20.6Hz),14.21ppm; 19 F NMR(376MHz,CDCl 3 ):δ-193.0ppm;Dataof the other isomer: 13 C NMR(101MHz,CDCl 3 ):δ199.2,170.1(d,J=23.5Hz),156.7,135.59,133.5,132.5,130.6,129.7,129.0,128.8,128.6,128.4,128.2,127.8,126.6,124.44,121.5,111.4,87.2(d,J=184.5Hz),61.7,55.8,41.5(d,J=2.2Hz),35.3(d,J=20.7Hz),14.19ppm; 19 F NMR(376MHz,CDCl 3 ):δ-191.4ppm.HRMS m / z(ESI):calculated forC 24 H 23 FO 4 Na[M+Na] + :417.1473,found 417.1488。

[0054] Example 14: Preparation and Characterization of (S)-2-Fluoro-4-(3-methoxyphenyl)-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0055]

[0056] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-methoxy-3-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (29.9mg, yield 38%, 1.1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.51-8.48(m,1H),8.03-7.99(m,1H),7.93-7.89(m,1H),7.84-7.8 0(m,2H),7.59-7.48(m,2H),7.25-7.19(m,1H),7.01-6.88(m,2H),6.7 Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.27,169.9(d,J=27.4Hz),160.3,140.1,135.7,133.6,132.5,130.9,130.4,129.9,128.8,128.59,127.8,126 .89,124.49,120.7,114.0,113.0,87.4(d,J=183.3Hz),61.7,55.4,49.0(d,J=1.5Hz),36.6(d,J=20.6Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3): δ-192.9ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.26,169.7(d,J=27.5Hz),160.4,139.0,135.6,133.5,132.5,130.8,130.5,129.8,128.7,128.56,127.8,126 .86,124.52,121.1,114.3,113.1,86.9(d,J=183.8Hz),61.8,55.4,48.6(d,J=3.6Hz),36.0(d,J=20.3Hz),14.1ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-193.0ppm.HRMS m / z(ESI):calculated for C 24 H 23 FO 4 Na[M+Na] + :417.1473,found417.1478.

[0057] Example 15: Preparation and Characterization of (S)-2-Fluoro-5-(naphthalen-2-yl)-4-(pyridin-3-yl)-5-oxopentanoic acid ethyl ester:

[0058]

[0059] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 3-vinylpyridine (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 3:1 as eluent, and finally a yellow oily liquid (19.7mg, yield 27%, 1.1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ8.74-8.70(m,1H),8.53-8.46(m,2H),8.01-7.92(m,2H),7.87-7.81(m,2H),7.76-7.69(m,1H),7.62-7.51(m,2H),7. 31-7.22(m,1H),5.17-5.09(m,1H),5.08-4.63(m,1H),4.24-4.08(m,2H),3.09-2.47(m,2H),1.29-1.24(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.6,169.4(d,J=23.5Hz),149.8,149.1,136.1,135.82,134.5,132.9,132.5,130.8,129.86,129.07,12 8.92,127.9,127.1,124.4,124.2,87.1(d,J=184.5Hz),62.0,46.0(d,J=1.8Hz),36.4(d,J=20.6Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-192.7ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.8,169.2(d,J=23.5Hz),150.1,148.8,135.9,135.86,133.6,133.1,132.5,130.9,129.88,129.12,12 8.94,127.9,127.2,124.4,124.3,86.6(d,J=184.9Hz),61.9,45.7(d,J=3.4Hz),36.0(d,J=20.4Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-192.8ppm.HRMS m / z(ESI):calculated for C 22 H 21 FNO 3 [M+H] + :366.1500,found366.1506.

[0060] Example 16: Preparation and Characterization of (R)-2-Fluoro-5-(naphthalen-2-yl)-4-(thiophene-2-yl)-5-oxopentanoic acid ethyl ester:

[0061]

[0062] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 2-vinylthiophene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 30:1 as eluent, and finally a yellow oily liquid (33.3mg, yield 45%, 1.4:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.57-8.54(m,1H),8.07-8.02(m,1H),7.97-7.94(m,1H),7.88-7.83(m,2H),7.62-7.51(m,2H),7.24-7.17(m,1H),7. 07-6.88(m,2H),5.42-5.34(m,1H),5.06-4.76(m,1H),4.28-4.13(m,2H),3.10-2.39(m,2H),1.32-1.25(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.2,169.7(d,J=23.5Hz),139.4,135.80,133.0,132.6,130.86,129.88,128.90,128.8,127.9,127.5, 127.1,127.00,126.1,124.48,86.8(d,J=184.0Hz),61.90,43.5(d,J=2.0Hz),36.9(d,J=20.5Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-193.2ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3): δ197.3,169.4(d,J=22.8Hz),140.6,135.85,133.2,132.6,130.95,129.91,128.94,128.8,127.9,127.4, 127.0, 126.48, 125.6, 124.46, 87.1 (d, J = 183.7Hz), 61.86, 43.0 (d, J = 4.1Hz), 36.0 (d, J = 20.4Hz), 14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-192.8ppm.HRMS m / z(ESI):calculated for C 21 H 19 FO 3 SNa[M+Na] + :393.0932,found393.0936.

[0063] Example 17: Preparation and Characterization of (S)-2-Fluoro-4-((8R,9S,13S,14S)-13-methyl-17-hydroxy-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopentadienyl[a]benzopyrene-2-yl)-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester:

[0064]

[0065] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst V (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 2-vinylestr-1(2),3(4),5(10)-triene-17-one (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, the reaction was cooled to room temperature, the filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 6:1 as eluent, and finally a white solid (46.5mg, yield 43%, 1.7:1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3):δ8.51(d,J=8.0Hz,1H),8.05-8.01(m,1H),7.92(d,J=8.0Hz,1H),7.84-7.81(m,2H),7.59-7.51(m,2H),7.25-7.05(m,3H),5.06-4.98(m,1H),4.96-4.65(m,1H),4.24-4.12(m,2H),2.91-2.83(m,2H),2.66-1.91(m,9H),1.59-1.35(m,6H),1.29-1.25(m,3H),0.87-0.85(m,3H)ppm; 13 C NMR(101MHz,CDCl 3):δ220.6(overlap,four isomers),198.11&198.08(overlap,fourisomers),169..7(d,J=24.2Hz)&169.4(d,J=24.2Hz)&169.3(d,J=24.2Hz)(overlap,four isomers),139.07&139.06&138.9(overlap,four isomers),137.4&137.3&137.2(overlap,four isomers),135.62&135.59(overlap,four isomers),135.31&135.25(overlap,four isomers),134.35(overlap,four isomers),133.3&133.15(overlap,fourisomers),133.2(overlap,four isomers),130.6&130.5(overlap,four isomers),129.5&129.47(overlap,four isomers),128.6&128.5&128.4&128.3(four isomers),128.24&128.21&128.2(overlap,four isomers),127.4(overlap,four isomers),126.5&126.48(overlap,four isomers),126.1&126.08&125.9&125.46(four isomers),126.01&125.99&128.8&125.5(four isomers),124.3&124.2(overlap,four isomers),87.15(d,J=182.8Hz)&87.13(d,J=182.8Hz)&86.6(d,J=182.8Hz)(overlap,four isomers),61.44&61.35(overlap,four isomers),50.21&50.18(overlap,four isomers),48.0(d,J=4.0Hz)&47.6(d,J=5.0Hz)(overlap,four isomers),47.7(overlap,four isomers),44.01&43.99(overlap,four isomers),37.7&37.6 (overlap, four isomers), 36.5 (d, J = 20.2 Hz) & 35.8 (d, J = 17.2 Hz) (overlap, four isomers), 35.6 (overlap, four isomers), 31.3 (overlap, four isomers), 29.14 & 29.13 & 29.1 & 29.0 (four isomers), 26.13 & 26.11 (overlap, four isomers), 25.32 & 25.29 (overlap, four isomers), 21.31 (overlap, four isomers), 13.91 & 13.88 (overlap, four isomers), 13.56 ppm (overlap, four isomers);. 19 F NMR (376 MHz, CDCl 3 ): δ -192.8 & -192.9 & -193.0 ppm (overlap, four isomers). HRMS m / z (ESI): calculated for C 35 H 37 FO 4 Na[M + Na] + : 563.2569, found 563.2565。

[0066] Example 18: Preparation and Characterization of Ethyl (4S)-2-Fluoro-4-(4-(2-(4-Isobutylphenyl)Propanamido)phenyl)-5-(Naphthalen-2-Yl)-5-Oxopentanoate:

[0067]

[0068] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst V (0.02 mmol), Mn(acac) 2 (0.02 mmol), Cs 2 CO 3(0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 2-[4-(2-methylpropyl)phenyl]-N-(4-vinylphenyl)propionamide (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, the reaction was cooled to room temperature, the filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 6:1 as eluent, and finally a yellow oily liquid (88.5mg, yield 78%, 2:1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.35(d,J=8.0Hz,1H),7.88-7.84(m,1H),7.78(d,J=8.0Hz,1H),7.71-7.68(m,2H),7.47-7.38( m,2H),7.32-7.28(m,2H),7.21-7.15(m,2H),7.11-7.07(m,3H),7.01-6.99(m,2H),4.96-4.86(m,1 H),4.84-4.48(m,1H),4.12-4.02(m,2H),3.58-3.51(m,1H),2.91-2.46(m,1H),2.34-2.32(m,2H), 2.23-2.12(m,1H),1.76-1.69(m,1H),1.44-1.42(m,3H),1.18-1.13(m,3H),0.79-0.77(m,6H)ppm; 13 C NMR (101 MHz, CDCl 3):δ197.2(overlap,three isomers),171.7&171.6(overlap,three isomers),168.7(d,J=23.2Hz)&168.5(d,J=23.2Hz)(overlap,three isomers),140.0&140.1(overlap,three isomers),136.82&136.8&136.79(threeisomers),136.5&136.3(overlap,three isomers),134.5&134.4(overlap,threeisomers),132.9(overlap,three isomers),132.3(overlap,three isomers),132.1(overlap,three isomers),131.8(overlap,three isomers),131.3(overlap,threeisomers),129.64&129.6(overlap,three isomers),128.8&128.7&128.6(threeisomers),128.0&127.6&127.55(three isomers),127.7&127.44&127.4(three isomers),126.6(overlap,three isomers),126.(overlap,three isomers),125.73&125.7(overlap,three isomers),123.3&123.2(overlap,three isomers),119.4&119.2(overlap,three isomers),86.2(d,J=183.8Hz)&85.6(d,J=183.8Hz)(overlap,threeisomers),60.64&60.6(overlap,three isomers),47.2(d,J=2.0Hz)&46.8(d,J=4.0Hz)(overlap,three isomers),46.6(overlap,three isomers),43.9(overlap,threeisomers),35.4(d,J=20.2Hz)&34.9(d,J=20.2Hz)(overlap,three isomers),29.1(overlap,three isomers),21.3(overlap,three isomers),17.4(overlap,three isomers),13.0ppm(overlap,three isomers);. 19 FNMR (376MHz, CDCl 3 ):δ-192.77&-192.8&-193.2ppm(three isomers).HRMS m / z(ESI):calculated for C 36 H 38 FNO 4 Na[M+Na] + :590.2678,found 590.2681.

[0069] Example 19: Preparation and Characterization of Ethyl (3R, 4R, 5S)-4-acetylamino-5-(4-((S)-5-ethoxy-4-fluoro-1-(naphthalen-2-yl)-1,5-dioxolan-2-yl)benzamide)-3-(pentane-3-oxy)cyclohexene-1-carboxylate:

[0070]

[0071] In the glove box, 2-naphthaldehyde (0.2 mmol), NHC catalyst V (0.02 mmol), Mn(acac) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), ethyl (3R,4R,5S)-4-(acetylamino)-3-(pentan-3-yloxy)-5-{[(4-vinylphenyl)carbonyl]amino}cyclohex-1-ene-1-carboxylate (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, the reaction was cooled to room temperature, the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 2:1 as the eluent, and finally a yellow oily liquid (49.2mg, yield 35%, 2:1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3):δ8.44(d,J=8.0Hz,1H),7.97-7.93(m,1H),7.88(d,J=8.0Hz,1H),7.81-7.78(m,2H),7.73-7.67(m,2H),7.57-7.48(m,2H),7.45-7.39(m,3H),6.77(s,1H),6.40(s,1H),5.12-4.58(m,2H),4.22-4.14(m,7H),3.41-3.37(m,1H),3.02-2.18(m,4H),1.81-1.79(m,3H),1.53-1.46(m,4H),1.28-1.23(m,6H),0.89-0.83(m,6H)ppm; 13 C NMR(101MHz,CDCl 3):δ197.8&197.75&197.7&197.66(four isomers),172.1&172.04&172.0&171.97(four isomers),169.5(d,J=23.2Hz)&169.3(d,J=24.2Hz)(overlap,four isomers),166.9&166.85&168.8(overlap,four isomers),165.9(overlap,four isomers),142.3&141.3(overlap,four isomers),137.0(overlap,fourisomers),135.62&135.57(overlap,four isomers),133.4&133.3&133.26&133.24(fourisomers),133.2&133.1&133.07&133.0(four isomers),132.3(overlap,four isomers),130.8&130.77(overlap,four isomers),130.7&130.69(overlap,four isomers),129.93&129.89&129.72&129.7(four isomers),129.41&129.4&129.37(overlap,four isomers),128.9&128.8&128.77(overlap,four isomers),128.63&128.59&128.5(overlap,fourisomers),128.1&128.0(overlap,four isomers),127.7(overlap,four isomers),126.89(overlap,four isomers),124.23&124.2(overlap,four isomers),87.2(d,J=183.8Hz)&86.5(d,J=183.8Hz)(overlap,four isomers),82.3(overlap,four isomers),75.2(overlap,four isomers),61.8&61.7(overlap,four isomers),61.0(overlap,fourisomers),53.7(overlap,four isomers),49.7&49.66&49.6(overlap,four isomers),48.6(d,J=2.0Hz)&48.2(d,J=2.0Hz)(overlap,four isomers),36.33(d,J=20.2Hz)&36.34(d,J=20.2Hz)&35.8(d,J=20.2Hz)(overlap,four isomers),30.5&29.7(overlap,four isomers),26.3(overlap,four isomers),25.8(overlap,four isomers),23.2&23.1(overlap,four isomers),14.2(overlap,four isomers),14.11&14.08(overlap,fourisomers),9.6(overlap,four isomers),9.3ppm(overlap,four isomers);. 19 F NMR (376 MHz, CDCl 3 ):δ-192.6&-192.7&-192.8ppm(overlap,four isomers).HRMS m / z(ESI):calculated for C 40 H 47 FN 2 O 8 Na[M+Na] + :725.3209, found 725.3211.

[0072] Example 20: Preparation and Characterization of (S)-4-(4-chlorophenyl)-2-fluoro-5-oxo-5-phenylpentanoic acid ethyl ester:

[0073]

[0074] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3(0.3mmol), ethyl monofluorobromoacetate (0.4mmol), benzaldehyde (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (36.9mg, yield 53%, 1.1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ7.90-7.85(m,2H),7.48-7.42(m,1H),7.37-7.31(m,2H),7.25-7.15(m,4H),4. 96-4.50(m,2H),4.18-4.01(m,2H),2.92-2.10(m,2H),1.23-1.18(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.13,169.4(d,J=23.6Hz),136.9,135.8,133.7,133.6,129.7,129.48,128.91 ,128.83,87.2(d,J=183.7Hz),61.8,48.1(d,J=1.9Hz),36.4(d,J=20.5Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.07,169.6(d,J=23.6Hz),136.0,135.9,133.9,133.5,130.0,129.69,128.89 ,128.80,86.6(d,J=184.2Hz),61.9,47.7(d,J=3.6Hz),35.9(d,J=20.4Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.1ppm.HRMS m / z(ESI):calculated for C 19 H 18 ClFO 3 Na[M+Na] +:371.0821, found 371.0825.

[0075] Example 21: Preparation and Characterization of (S)-4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(p-tolyl)pentanoic acid ethyl ester:

[0076]

[0077] In the glove box, 4-methylbenzene-1-carboxaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-chloro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (27.5mg, yield 38%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ7.85-7.82(m,2H),7.29-7.24(m,4H),7.21-7.18(m,2H),5.01 -4.86(m,1H),4.85-4.55(m,1H),4.23-4.07(m,2H),2.96-2.41(m,2H),2.35(s,3H),1.28-1.24(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.4,169.4(d,J=23.2Hz),144.2,136.8,133.5,133.3,129.7,129.3,129.21,128 .74,86.9(d,J=183.8Hz),61.5,47.6(d,J=2.0Hz),36.1(d,J=20.2Hz),21.4,13.9ppm; 19 FNMR (376MHz, CDCl 3 ): δ-193.1ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3): δ197.3,169.2(d,J=23.2Hz),144.1,135.8,133.2,133.0,129.4,129.18,129.1,128 .72,86.3(d,J=183.8Hz),61.45,47.2(d,J=3.0Hz),35.6(d,J=20.2Hz),21.4,13.9ppm; 19 FNMR (376MHz, CDCl 3 ):δ-193.2ppm HRMS m / z(ESI):calculated for C 20 H 20 ClFO 3 Na[M+Na] + :385.0978,found385.0983.

[0078] Example 22: Preparation and Characterization of (S)-5-([1,1'-biphenyl]-4-yl)-4-(4-chlorophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester:

[0079]

[0080] In the glove box, 4-phenylbenzene-1-carboxaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-chloro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, the reaction was cooled to room temperature, the filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 30:1 as eluent, and finally a yellow oily liquid (52.9mg, yield 62%, 1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ8.04-8.01(m,2H),7.63-7.61(m,2H),7.57(d,J=8.0Hz,2H),7.46-7.38(m,3H),7.40(d,J=16.0Hz,4H ),5.05-4.92(m,1H),4.91-4.59(m,1H),4.25-4.11(m,2H),3.01-2.22(m,2H),1.29-1.26(m,3H)ppm; Data ofone isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.3,169.3(d,J=23.2Hz),145.9,139.4,136.7,135.6,134.3,133.6,129.7,129 .43,129.2,128.13,127.13,127.0,86.9(d,J=183.8Hz),61.54,47.8,36.1,13.86ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-192.9ppm; Data of the otherisomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.25,169.1(d,J=23.2Hz),145.8,139.9,136.7,135.6,134.2,133.4,129.7,129.38,128.7, 128.11, 127.1, 127.0, 86.3 (d, J = 183.8Hz), 61.5, 47.4 (d, J = 3.0Hz), 35.6 (d, J = 21.2Hz), 13.86ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-193.0ppm.HRMS m / z(ESI):calculated for C 25 H 22 ClFO 3 Na[M+Na] + :447.1134,found447.1129.

[0081] Example 23: Preparation and Characterization of (S)-5-(4-(tert-butyl)phenyl)-4-(4-chlorophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester:

[0082]

[0083] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 4-(tert-butyl)benzaldehyde (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 60:1 as eluent, and finally a yellow oily liquid (46.1mg, yield 57%, 1.1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ7.92-7.85(m,2H),7.44-7.38(m,2H),7.33-7.23(m,4H),5.00-4.55( m,2H),4.24-4.07(m,2H),2.97-2.17(m,2H),1.30-1.23(m,12H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.61,169.5(d,J=23.9Hz),157.4,137.2,133.6,133.4,130.0,129.7,129.4,128.92,125 .81,87.2(d,J=183.6Hz),61.75,47.9(d,J=1.8Hz),36.5(d,J=20.4Hz),35.24,31.1,14.19ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.57,169.7(d,J=23.6Hz),157.3,136.1,133.8,133.2,130.0,129.6,129.4,128.88,125 .78,86.7(d,J=184.1Hz),61.83,47.5(d,J=3.4Hz),36.0(d,J=20.5Hz),35.22,31.1,14.2ppm; 19 F NMR (376 MHz, CDCl3 ):-193.1ppm.HRMS m / z(ESI):calculated forC 23 H 26 ClFO 3 Na[M+Na] + :427.1447,found427.1451.

[0084] Example 24: Preparation and Characterization of (S)-4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(4-trifluoromethylphenyl)pentanoic acid ethyl ester:

[0085]

[0086] In the glove box, 4-(trifluoromethyl)benzene-1-carboxaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-chloro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 25:1 as eluent, and finally a yellow oily liquid (40.0mg, yield 48%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.02-7.99(m,2H),7.66-7.63(m,2H),7.32-7.19(m,4H),5.02-4.57(m,2H),4.22-4.08(m,2H),2.97-2.20(m,2H),1.27-1.23(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.13,169.4(d,J=23.2Hz),138.6,136.0,134.7(d,J=8.1Hz),134.2,129.84,129.62,129.11,125.8(d, J=4.0Hz), 123.4 (q, J=273.7Hz), 86.9 (d, J=183.8Hz), 61.83, 48.4 (d, J=2.0Hz), 36.1 (d, J=21.2Hz), 14.1ppm;19 F NMR (376 MHz, CDCl 3 ): δ-63.25,-193.0ppm; Data of the otherisomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.06,169.2(d,J=23.2Hz),138.5,135.1,134.4(d,J=8.1Hz),134.0,129.8,129.6,129.09,125.75(d,J =3.0Hz), 123.4 (q, J = 273.7Hz), 86.3 (d, J = 183.8Hz), 61.76, 48.1 (d, J = 4.0Hz), 35.6 (d, J = 20.2Hz), 14.1ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-63.7,-193.1ppm.HRMS m / z(ESI):calculated for C 20 H 17 CIF 4 O 3 Na[M+Na] + :439.0695,found 439.0689.

[0087] Example 25: Preparation and Characterization of (S)-4,5-bis(4-chlorophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester:

[0088]

[0089] In the glove box, 4-chlorobenzene-1-carboxaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-chloro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (55.8mg, yield 73%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ7.88-7.85(m,2H),7.38-7.35(m,2H),7.32-7.21(m,4H),5.02-4.82(m,1H),4.81-4.56(m,1H),4.23-4.09(m,2H),2.96 -2.19(m,2H),1.28-1.25(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.82,169.5(d,J=23.2Hz),140.0,136.5,134.2,134.1,130.2,129.8,129.6, 129.1, 87.0 (d, J = 183.8Hz), 61.8, 48.0 (d, J = 2.0Hz), 36.2 (d, J = 21.2Hz), 14.1ppm; 19 F NMR (376 MHz, CDCl 3 ): δ-193.1ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.76,169.2(d,J=24.3Hz),139.9,135.5,133.8,134.0,130.19,129.7,129.5 ,129.0,86.4(d,J=183.8Hz),61.7,47.7(d,J=4.0Hz),35.7(d,J=20.2Hz),14.1ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-193.1ppm.HRMS m / z(ESI):calculated for C 19 H 17 Cl 2 FO 3 Na[M+Na] + :405.0431, found 405.0430.

[0090] Example 26: Preparation and Characterization of (S)-4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(4-(trifluoromethoxy)phenyl)pentanoic acid ethyl ester:

[0091]

[0092] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence.2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 4-(trifluoromethoxy)benzaldehyde (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (34.5mg, yield 40%, 1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.00-7.95(m,2H),7.34-7.19(m,6H),5.01-4.56(m,2H),4.24-4.07(m,2H),2.97-2.19(m,2H),1.29-1.23(m,3H)ppm; Dataof one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.6,169.3(d,J=23.2Hz),152.9(d,J=2.0Hz),136.5,134.1,133.9,130.99,129.87,129.67,120 .5,120.3(q,J=260.2Hz),87.1(d,J=183.9Hz),61.86,48.2(d,J=2.0Hz),36.4(d,J=20.5Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-57.6,-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.5,169.6(d,J=23.0Hz),152.8(d,J=23.0Hz),135.5,134.2,134.0,130.96,129.93,129.69,120 .5,120.3(q,J=260.2Hz),86.5(d,J=184.3Hz),61.93,47.9(d,J=3.8Hz),35.9(d,J=20.4Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3):-57.6,-193.1ppm.HRMS m / z(ESI):calculated for C 20 H 17 CIF 4 O 4 Na[M+Na] + :455.0644,found 455.0642.

[0093] Example 27: Preparation and Characterization of (S)-4-(2-(4-chlorophenyl)-5-ethoxy-4-fluoro-5-oxopentanoyl)benzoic acid methyl ester:

[0094]

[0095] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), methyl 4-formylbenzoate (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, the reaction was cooled to room temperature, the filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 10:1 as eluent, and finally a yellow oily liquid (55.2mg, yield 68%, 1:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ8.10-8.05(m,2H),8.01-7.97(m,2H),7.36-7.23(m,4H),5.07-4.60(m,2H) ,4.27-4.10(m,2H),3.94(s,3H),3.02-2.23(m,2H),1.32-1.26(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.1,169.3(d,J=23.2Hz),166.1,139.2,136.3,134.1,133.9,130.0,129.7,129.6, 128.7, 87.1 (d, J = 184.0Hz), 61.8, 52.6, 48.5 (d, J = 1.8Hz), 36.2 (d, J = 20.5Hz), 14.2ppm; 19F NMR (376 MHz, CDCl 3 ):-193.1ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ197.6,169.5(d,J=22.9Hz),166.1,139.1,135.3,134.2,133.9,129.9,129.8,129.6, 128.7, 86.5 (d, J = 184.4Hz), 61.9, 52.6, 48.1 (d, J = 3.7Hz), 35.7 (d, J = 20.3Hz), 14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.0ppm.HRMS m / z(ESI):calculated for C 21 H 20 ClFO 5 Na[M+Na] + :429.0876,found429.0880.

[0096] Example 28: Preparation and Characterization of (S)-4-(4-chlorophenyl)-5-(4-cyanophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester:

[0097]

[0098] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 4-formylbenzonitrile (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, the reaction was cooled to room temperature, and the filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 10:1 as eluent, and finally a yellow oily liquid (49.2mg, yield 66%, 1.3:1dr) was obtained. The product is characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ8.01-7.96(m,2H),7.71-7.67(m,2H),7.34-7.17(m,4H),5.02-4.56(m,2H),4.23-4.07(m,2H),2.97-2.19(m,2H),1.29-1.24(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.8,169.4(d,J=23.2Hz),138.9,134.9,134.4,132.6,130.0,129.8,129.2,117 .8,116.6,86.4(d,J=184.4Hz),62.0,48.6(d,J=2.1Hz),35.7(d,J=20.2Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.1ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.9,169.2(d,J=23.0Hz),139.0,135.8,134.2,132.7,129.9,129.7,129.2,117 .8,116.7,87.0(d,J=184.1Hz),61.9,48.2(d,J=4.0Hz),35.6(d,J=20.6Hz),14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-192.9ppm.HRMS m / z(ESI):calculated for C 20 H 17 ClFNO 3 Na[M+Na] + :396.0774, found 396.0772.

[0099] Example 29: Preparation and Characterization of (S)-4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(thiophen-2-yl)pentanoic acid ethyl ester:

[0100]

[0101] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), thiophene-2-carboxaldehyde (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 20:1 as eluent, and finally a yellow oily liquid (49.8mg, yield 71%, 1.2:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ7.72-7.68(m,1H),7.62-7.58(m,1H),7.31-7.25(m,4H),7.07-7.03(m,1H),5. 01-4.53(m,2H),4.23-4.05(m,2H),2.96-2.18(m,2H),1.27-1.22(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ190.9,169.2(d,J=23.5Hz),143.1,136.9,134.7,133.8,133.1,129.6,129.36, 128.41, 87.0 (d, J = 184.0Hz), 61.8, 49.5 (d, J = 1.9Hz), 36.1 (d, J = 20.6Hz), 14.1ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ190.8,169.5(d,J=23.2Hz),142.9,135.8,134.5,134.0,133.0,129.9,129.59, 128.36, 86.5 (d, J = 184.4Hz), 61.9, 49.1 (d, J = 3.5Hz), 35.7 (d, J = 20.5Hz), 14.1ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.2ppm.HRMS m / z(ESI):calculated for C 17 H 16 ClFO 3 SNa[M+Na]+ :377.0385, found 377.0393.

[0102] Example 30: Preparation and characterization of (S)-ethyl 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(quinolin-3-yl)pentanoate:

[0103]

[0104] In the glove box, quinoline-3-carboxaldehyde (0.2 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 1-chloro-4-vinylbenzene (0.3mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 6:1 as eluent, and finally a yellow oily liquid (55.1mg, yield 69%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ9.38(d,J=8.0Hz,1H),8.70(d,J=4.0Hz,1H),8.08(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,1H),7.81-7.77(m,1H),7.60 -7.56(m,1H),7.32-7.29(m,4H),5.10-4.63(m,2H),4.24-4.10(m,2H),3.05-2.28(m,2H),1.29-1.25(m,3H)ppm; Data of one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.6,169.1(d,J=23.2Hz),149.44,149.0,137.7,135.8,133.9,132.1,126.62,129.4,129.19,12 9.1,127.9,127.4,126.4,86.7(d,J=183.8Hz),61.6,48.3(d,J=2.0Hz),35.7(d,J=20.2Hz),13.8ppm; 19 F NMR (376 MHz, CDCl 3): δ-192.8ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ196.5,168.9(d,J=23.2Hz),149.99,149.4,137.6,135.9,133.7,132.0,129.56,129.3,129.16,12 9.1,127.8,127.38,126.4,86.1(d,J=183.8Hz),61.5,47.9(d,J=4.0Hz),35.3(d,J=20.2Hz),13.8ppm; 19 F NMR (376 MHz, CDCl 3 ):δ-192.9ppm.HRMS m / z(ESI):calculated for C 22 H 20 ClFNO 3 [M+H] + :400.1111,found400.1113.

[0105] Example 31: Preparation and Characterization of (S)-4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(o-tolyl)pentanoic acid ethyl ester:

[0106]

[0107] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2 (0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 2-methylbenzaldehyde (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 30:1 as eluent, and finally a yellow oily liquid (38.5mg, yield 53%, 1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3): δ7.60-7.57(m,1H),7.32-7.13(m,7H),5.07-4.56(m,2H),4.24-4.08(m,2H),3.02-2.17(m,5H),1.29-1.24(m,3H)ppm; Data of oneisomer: 13 CNMR (101MHz, CDCl 3 ): δ201.7,169.6(d,J=23.5Hz),138.52,137.4,136.0,133.8,131.92,131.50,130.0,129.5,12 8.2, 125.71, 86.7 (d, J = 184.4Hz), 61.84, 50.9 (d, J = 2.0Hz), 35.3 (d, J = 20.4Hz), 21.0, 14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.0ppm; Dataof the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ201.8,169.4(d,J=23.9Hz),138.47,137.7,135.3,133.6,131.90,131.54,129.8,129.3,12 8.1, 125.74, 87.2 (d, J = 183.8Hz), 61.77, 50.5 (d, J = 3.7Hz), 35.6 (d, J = 20.4Hz), 20.9, 14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.1ppm.HRMS m / z(ESI):calculated for C 20 H 20 ClFO 3 Na[M+Na] + :385.0978,found385.0977.

[0108] Example 32: Preparation and Characterization of (S)-4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(m-tolyl)pentanoic acid ethyl ester:

[0109]

[0110] In the glove box, 1-chloro-4-vinylbenzene (0.3 mmol), NHC catalyst IV (0.02 mmol), Fe(OAc) were added to the reaction tube in sequence. 2(0.02mmol), Cs 2 CO 3 (0.3mmol), ethyl monofluorobromoacetate (0.4mmol), 3-methylbenzaldehyde (0.2mmol) and anhydrous DCM (2.0mL), the reaction tube was sealed with a rubber stopper, taken out from the glove box, placed in a 60°C metal module for reaction for 12h, and the reaction was cooled to room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using petroleum ether: ethyl acetate = 30:1 as eluent, and finally a yellow oily liquid (32.7mg, yield 45%, 1.1:1dr) was obtained. The product was characterized as follows: 1 H NMR (400 MHz, CDCl 3 ): δ7.76-7.69(m,2H),7.33-7.22(m,6H),5.01-4.55(m,2H),4.24-4.07(m,2H),2.97-2.18(m,5H),1.26(t,J=7.2Hz,3H)ppm; Dataof one isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.3,169.4(d,J=23.6Hz),138.7,137.0,135.93,134.4,133.6,129.7,129.4,129.37,128 .64,126.12,87.2(d,J=183.6Hz),61.7,48.0(d,J=1.9Hz),36.4(d,J=20.5Hz),21.4,14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.0ppm; Data of the other isomer: 13 C NMR (101 MHz, CDCl 3 ): δ198.2,169.6(d,J=22.8Hz),138.6,136.1,135.89,134.3,133.8,130.0,129.6,129.35,128 .61,126.10,86.6(d,J=184.1Hz),61.8,47.6(d,J=3.6Hz),35.9(d,J=20.4Hz),21.4,14.2ppm; 19 F NMR (376 MHz, CDCl 3 ):-193.1ppm.HRMS m / z(ESI):calculated for C 20 H 20 ClFO3 In[M+In] + :385.0978, found 385.0984.

Claims

1. A method for synthesizing α-aryl-β-monofluoroalkyl ketone derivatives from olefin bifunctional groups, It is characterized in that The method comprises: in a glove box, ethyl bromofluoroacetate; arylethylene; aryl formaldehyde; azacarbene NHC catalyst; Mn(acac) 2 or Fe(OAc) 2 ; Cesium carbonate is placed in a test tube, and after the test tube is sealed with a rubber stopper, the test tube is taken out from the glove box, and then anhydrous THF is added under argon protection to react, and after post-treatment, ethyl acetate and water are added for extraction, drying, and concentration, the concentrate is gradient eluted with a volume ratio of petroleum ether / ethyl acetate = 100:1 to 4:1 as an eluent, and column chromatography purification is performed to obtain an α-aryl-β-monofluoroalkyl ketone derivative; the structural formula of the azacarbene NHC catalyst is formula (IV) or (V): The aromatic vinyl is styrene, 1-methyl-4-vinylbenzene, 1-methoxy-4-vinylbenzene, 4-vinylphenyl acetate, 4-vinylaniline, 1-fluoro-4-vinylbenzene, 1-chloro-4-vinylbenzene, 1-bromo-4-vinylbenzene, 4-vinylbenzene-1-carbonitrile, 1-(trifluoromethyl)-4-vinylbenzene, 1-nitro-4-vinylbenzene, methyl 4-vinylbenzoate, 1-methoxy-2-vinylbenzene, 1-methoxy-3-vinylbenzene, 3-vinylpyridine, 2-vinylthiophene, 1-chloro-4-vinylbenzene; The aromatic formaldehyde is 2-naphthaldehyde, benzaldehyde, 4-methylbenzene-1-carboxaldehyde, 4-phenylbenzene-1-carboxaldehyde, 4-(tert-butyl)benzaldehyde, 4-(trifluoromethyl)benzaldehyde-1-carboxaldehyde, 4-chlorobenzene-1-carboxaldehyde, 4-(trifluoromethoxy)benzaldehyde, 4-formylbenzoic acid methyl ester, 4-formylbenzonitrile, thiophene-2-carboxaldehyde, quinoline-3-carboxaldehyde, 2-methylbenzaldehyde, 3-methylbenzaldehyde; The α-aryl-β-monofluoroalkyl ketone derivatives are 2-fluoro-5-(naphthalene-2-yl)-5-carbonyl-4-phenylpentanoic acid ethyl ester, 2-fluoro-5-(naphthalene-2-yl)-4-(p-tolyl)-5-oxopentanoic acid ethyl ester, 2-fluoro-4-(4-methoxyphenyl)-5-(naphthalene-2-yl)-5-oxopentanoic acid ethyl ester, 4-(4-acetoxyphenyl)-2-fluoro-5-(naphthalene-2-yl)-5-oxopentanoic acid ethyl ester, 4-(4-aminophenyl)-2-fluoro-5-(naphthalene-2-yl)-5-oxopentanoic acid ethyl ester, 2-fluoro-4-(4-methoxyphenyl)-5-(naphthalene-2-yl)-5-oxopentanoic acid ethyl ester, Fluoro-4-(4-fluorophenyl)-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester, 4-(4-bromophenyl)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester, 4-(4-cyanobenzene)-2-fluoro-5-(naphthalen-2-yl)-5-oxopentanoic acid ethyl ester, 2-fluoro-5-(naphthalen-2-yl)-4-(4-trifluoromethylphenyl)-5-oxopentanoic acid ethyl ester, 2-fluoro-5-(naphthalen-2-yl)-4-(4- 2-Fluoro-4-(2-methoxyphenyl)-5-(naphthalene-2-yl)-5-oxopentanoic acid ethyl ester, 2-Fluoro-4-(3-methoxyphenyl)-5-(naphthalene-2-yl)-5-oxopentanoic acid ethyl ester, 2-Fluoro-5-(naphthalene-2-yl)-4-(pyridin-3-yl)-5-oxopentanoic acid ethyl ester, 2-Fluoro-5-(naphthalene-2-yl)-4-(thiophene-2-yl)- 5-oxopentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-phenylpentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(p-tolyl) pentanoic acid ethyl ester, 5-([1,1'-biphenyl]-4-yl)-4-(4-chlorophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester, 5-(4-(tert-butyl)phenyl)-4-(4-chlorophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(4-trifluoromethylphenyl) pentanoic acid ethyl ester, 4,5-bis(4-chlorophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(4-(trifluoromethoxy)phenyl)pentanoic acid ethyl ester, 4-(2-(4-chlorophenyl)-5-ethoxy-4-fluoro-5-oxopentanoyl)benzoic acid methyl ester, 4-(4-chlorophenyl)-5-(4-cyanophenyl)-2-fluoro-5-oxopentanoic acid ethyl ester Ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(thiophen-2-yl) pentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(quinolin-3-yl) pentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(o-tolyl) pentanoic acid ethyl ester, 4-(4-chlorophenyl)-2-fluoro-5-oxo-5-(m-tolyl) pentanoic acid ethyl ester.

2. The method for synthesizing α-aryl-β-monofluoroalkyl ketone derivatives from olefin bifunctional groups according to claim 1, It is characterized in that The molar ratio of the raw materials in the method is aryl formaldehyde: aryl ethylene: ethyl monofluorobromoacetate: cesium carbonate: NHC catalyst: Mn(acac) 2 or Fe(OAc) 2 =1:1.5:2.0:1.5:0.1:0.1.

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