Chiral alpha,alpha-diaryl ketone compounds, methods of making and using the same

Abstract

The application discloses a kind of chiral α, α-diaryl ketone compounds and its preparation method and application, it has the structure shown in formula I: Wherein, R1Selected from naphthyl, anthryl, quinolinyl, unsubstituted or substituted with one or more C 1～6 Alkyl, C 1～6 Alkoxy halogen, phenyl, C 2～10 Alkynyl, nitro, cyano, trifluoromethanesulfonic acid group, C 2～10 Ester group, aldehyde group, C 2～10 Ketone group, C 1～6 Halogenated alkyl-substituted phenyl;R2Selected from naphthyl, C 2～10 Ester group, C 2～15 Alkynyl, unsubstituted or substituted with one or more halogen, phenyl, dimethyl tert-butyl silyl ether group C 1～10 Alkyl, unsubstituted or substituted phenyl;R3Selected from H, C 1～6 Alkyl, halogen.The chiral α, α-diaryl ketone compound provided by the application can be used for the stereoselective synthesis of pyridine amide, diaryl epoxy propane and BRL-15572 analogues.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly to a chiral α, α-diaryl ketone compound, a preparation method and application thereof. BACKGROUND

[0002] The α, α-diaryl ketone molecular skeleton is widely present in many natural products with important biological activities, organic functional materials and artificially synthesized drug molecules. For example, Pauciflorol E isolated from the stems of Styrax benzoin, Penchinones C and Penchinones D isolated from the liver-protecting decoction of Radix Pteroxygoni Multifidi and Volixibat Pharmacophore used for treating tuberculosis. Limited to the difficulty in preparation of the product and the possible racemization during the carbonyl addition reaction or storage, there are few effective methods to construct this specific skeleton with enantioselectivity, because the α-H is affected by the carbonyl group and shows quite strong acidity, leading to enolization under alkaline or acidic conditions to initiate racemization, and this inherent property makes it extremely difficult to control the stereoselectivity.

[0003] Therefore, it is necessary to develop a series of new chiral α, α-diaryl ketone compounds. SUMMARY

[0004] The present application aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present application provides a chiral α, α-diaryl ketone compound, which can be used for the modification of natural product molecules or the stereoselective synthesis of florylpicoxamid, 2-(diarylmethyl) oxirane and human 5-HT1D receptor antagonist (BRL-15572) analogs.

[0005] The second aspect of the present application further provides a preparation method of the α, α-diaryl ketone compound.

[0006] The third aspect of the present application further provides an application of the α, α-diaryl ketone compound.

[0007] The chiral α, α-diaryl ketone compound provided by the first aspect of the present application has the structure shown in Formula I:

[0008]

[0009] wherein R1 is selected from naphthyl, anthryl, quinolinyl, unsubstituted or substituted with one or more C 1～6 alkyl, C 1～6 alkoxy halogen, phenyl, C 2～10alkynyl, nitro, cyano, trifluoromethylsulfonate, C 2～10 ester, aldehyde, C 2～10 ketone, C 1～6 halogenated alkyl-substituted phenyl;

[0010] R2is selected from naphthyl, C 2～10 ester, aldehyde, C 2～15 alkynyl, C 1～10 alkyl, C 1～6 alkyl, C 1～6 alkoxy, phenyl, C 2～6 alkenyl, halogen-substituted phenyl;

[0011] R3is selected from H, C 1～6 alkyl, halogen.

[0012] The chiral α,α-diaryl ketone compound according to the embodiments of the present application has at least the following beneficial effects:

[0013] The chiral α,α-diaryl ketone compound provided by the present application can be used for the modification of natural product molecules; or for the stereoselective synthesis of florylpicoxamid, 2-(diarylmethyl)oxirane and human 5-HT1D receptor antagonist (BRL-15572) analogues.

[0014] According to some embodiments of the present application, R2is selected from naphthyl, C 4～7 ester, aldehyde, C 7～15 alkynyl, C 1～10 alkyl, C 1～6 alkyl, C 1～6 alkoxy, phenyl, C 2～6 alkenyl, F, Cl, Br-substituted phenyl.

[0015] According to some embodiments of the present application, the chiral α,α-diaryl ketone compound is selected from one of the following structures:

[0016]

[0017]

[0018] The preparation method of the chiral α,α-diaryl ketone compound according to the second aspect of the embodiments of the present application comprises the following steps:

[0019] S1, reacting compound 1, compound 3 and a solvent under visible light irradiation to obtain an intermediate;

[0020] S2, mixing the intermediate, compound 2 and a chiral phosphoric acid catalyst to react, to obtain a chiral α, α-diaryl ketone compound;

[0021] wherein compound 1, compound 2 and compound 3 have the following structural formulas:

[0022]

[0023] R4 and R5 are independently selected from C 1～6 alkyl, benzyl.

[0024] The method for preparing a chiral α, α-diaryl ketone compound according to the embodiment of the present application has at least the following beneficial effects:

[0025] The prior art is difficult to prepare and racemization may occur in the process after the carbonyl addition reaction or the reaction is completed, and there are few effective methods to construct this specific skeleton with enantioselectivity, because the α-H is affected by the carbonyl group, which shows quite strong acidity, leading to enolization under basic or acidic conditions to initiate racemization, and this inherent property makes it extremely difficult to control stereoselectivity.

[0026] The present application provides a simple and practical strategy, using commercially available alkyne compound 1 and benzoquinone as raw materials, after the photocatalytic formation of quinone intermediate, compound 2 as hydrogen source, chiral phosphoric acid (CPA) catalyst to complete the preparation of chiral α, α-diaryl ketone compound, and the reaction has high yield and enantioselectivity.

[0027] According to some embodiments of the present application, the wavelength of the visible light is 400-600 nm.

[0028] According to some embodiments of the present application, the chiral phosphoric acid catalyst is selected from one of the following structural formulas:

[0029]

[0030] According to some embodiments of the present application, the compound 2 is selected from one of the following structures:

[0031]

[0032] According to some embodiments of the present application, in step S2, the temperature of the reaction is -78-25°C. Reducing the reaction temperature can improve the enantioselectivity, and the temperature cannot be too low, otherwise the reaction activity of the chiral phosphoric acid catalyst will be reduced. Therefore, the temperature of the reaction is -78-25°C.

[0033] According to some embodiments of the present application, the reaction time in step S2 is 60-300 min.

[0034] According to some embodiments of the present application, the reaction raw material further comprises a molecular sieve. The molecular sieve is added to reduce the water content of the system.

[0035] According to some embodiments of the present application, the molar ratio of compound 1, compound 2, benzoquinone and chiral phosphoric acid catalyst is 1:(0.5-4):(0.5-4):(0.01-1).

[0036] According to some embodiments of the present application, a solvent is further added in the reaction, and the solvent is at least one selected from chlorobenzene, dichloromethane, acetonitrile, toluene or dichloroethane.

[0037] The third aspect of the present application provides a use of a chiral α,α-diaryl ketone compound in the preparation of pyridalyl, a diaryl epoxypropane or a human 5-HT1D receptor antagonist analog.

[0038] Definitions and general terms

[0039] "C 1～6 alkyl" refers to an alkyl group having a total number of carbon atoms of 1-6, including C 1～6 linear alkyl, C 1～6 branched alkyl and C 3～6 cycloalkyl, for example, can be a linear alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched alkyl group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkyl group having a total number of carbon atoms of 3, 4, 5 or 6, for example, can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc. The "C 1～10 alkyl" has a similar explanation as this, except that the number of carbon atoms is different.

[0040] "C 1～6 alkoxy" refers to an alkoxy group having a total number of carbon atoms of 1-6, including C 1-6 linear alkoxy, C 1-6 branched alkoxy and C 2-6 cycloalkoxy, for example, can be a linear alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched alkoxy group having a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkoxy group having a total number of carbon atoms of 2, 3, 4, 5 or 6, for example, can be methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0041] "Halogen" includes any one or more than two of fluorine, chlorine, bromine, iodine.

[0042] "C 1～6 "Haloalkyl" is similar to the definition of "alkyl", except that any H atom in the alkyl group is replaced by any halogen. 1～6 "C 2～10 "Akynyl" means a straight or branched chain hydrocarbon group having one or more triple bonds, and the total number of carbon atoms in the akynyl group is 2-10, and the triple bond in the group can be at any position. 2～15 "Akynyl" has a similar explanation, except that the number of carbon atoms is different.

[0043] "C 2～6 "Alkenyl" means a straight or branched chain hydrocarbon group having one or more double bonds, and the total number of carbon atoms in the alkenyl group is 2-6, and the double bond in the group can be at any position.

[0044] "C 2～10 "Ester" means an ester group having a total number of carbon atoms of 2-10, and representative examples include methyl formate, ethyl formate, ethyl acetate, methyl acetate, etc.

[0045] "C 1 "Carboxylic acid" means a carboxylic acid group having a total number of carbon atoms of 2-10, and representative examples include formic acid, acetic acid, propionic acid, etc.

[0046] Other features and advantages of the present application will be set forth in the following description, and in part will become apparent to those skilled in the art from the description, or can be learned by practice of the present application. DETAILED DESCRIPTION

[0047] The following are specific examples of the present application, and the technical solutions of the present application are further described in conjunction with the examples, but the present application is not limited to these examples.

[0048] The reagents, methods and equipment used in the present application are all conventional reagents, methods and equipment in the technical field, unless otherwise specified.

[0049] The ee value of the product prepared by the present application is determined by high performance liquid chromatography (HPLC) analysis.

[0050] Example 1

[0051] Example 1 provides a chiral α, α-diaromatic ketone compound, its reaction equation and preparation method are as follows:

[0052]

[0053] S1, at room temperature, compound 1 (0.20 mmol), benzoquinone (0.10 mmol), dichloromethane (2 mL), 2x35W blue LEDs irradiation at room temperature for 4h; to form quinone intermediate;

[0054] S2, then compound 2-1 (0.15 mmol) and chiral phosphoric acid catalyst (S)-C4 (5 mol%) were added, and the reaction was carried out at room temperature for 30 min to obtain a chiral α,α-diaryl ketone compound (yield 99%, ee value 52%).

[0055] Examples 2-8

[0056] Examples 2-8 provide a series of chiral α,α-diaryl ketone compounds, whose reaction equation and preparation method are the same as those of Example 1, and the difference is that the chiral phosphoric acid catalysts of Examples 2-8 are different, and the structural formula of the chiral phosphoric acid catalyst is as follows: the yield and ee value are shown in Table 1.

[0057]

[0058] Table 1

[0059]

[0060] Examples 9-13

[0061] Examples 9-13 provide a series of chiral α,α-diaryl ketone compounds, whose reaction equation and preparation method are the same as those of Example 1, and the difference is that the structural formula of compound 2 of Examples 9-13 is different, and the structural formula is as follows, and the yield and ee value are shown in Table 2.

[0062] Table 2:

[0063]

[0064] Table 2

[0065]

[0066] Examples 14-16

[0067] Examples 14-16 provide a series of chiral α,α-diaryl ketone compounds, whose reaction equation and preparation method are the same as those of Example 13, and the difference is that the reaction temperature and additive of step S2 are different, which are shown in Table 3.

[0068] Table 3

[0069]

[0070]

[0071] Example 17

[0072] Example 17 provides a chiral a,a-diaryl ketone compound, whose reaction equation and preparation method are the same as those of Example 15, except that a chiral phosphoric acid catalyst (R)-C11 is used instead of a chiral phosphoric acid catalyst (S)-C4; and a chiral a,a-diaryl ketone compound is prepared (the yield is 99%, and the ee value is 90%).

[0073] Examples 18-60

[0074] Examples 18-60 provide a series of chiral a,a-diaryl ketone compounds, whose structural formulas are as follows, and the preparation method is the same as that of Example 17, except that the structural formula of compound 1 is different; and the yield and ee value of the prepared chiral a,a-diaryl ketone compound are shown in Table 4.

[0075] Table 4

[0076]

[0077]

[0078]

[0079]

[0080]

[0081] The characterization data of Example 1 and Examples 18-60 are as follows:

[0082] Example 1; 1 H NMR (500 MHz, CDCl3) δ 7.30 (t, J = 7.4 Hz, 2H), 7.27-7.21 (m, 1H), 7.21-7.15 (m, 2H), 7.02 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 6.35 (s, 1H), 5.05 (s, 1H), 2.22 (s, 3H). 13 C{1H}NMR (126 MHz, CDCl3) δ 208.5, 155.1, 138.3, 130.1, 129.7, 128.8, 128.7, 127.2, 115.7, 64.2, 29.9. HRMS (ESI) m / z: [M+Na] + Calcd forC 15 H 14O2Na 241.1223; Found 241.1224. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 12.6 min, t major = 11.3 min).

[0083] Example 18; 1 H NMR (500 MHz, CDCI3) δ 7.13 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 5.01 (s, 1 H), 2.31 (s, 3H), 2.22 (s, 3H). 13 C{1H} NMR (126 MHz, CDCI3) δ 208.2, 155.0, 136.9, 135.4, 130.1, 129.4, 128.7, 115.6, 63.9, 29.9, 21.0. HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 17 O2241.1223; Found 241.1224. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 12.6 min, t major = 11.3 min).

[0084] Example 19; 1 H NMR (500 MHz, CDCI3) δ 7.28 (d, J = 8.5 Hz, 2H), 7.1 1 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 5.76 (s, 1 H), 5.02 (s, 1 H), 2.24 (s, 3H). 13C {1H} NMR (126 MHz, CDC13) δ 207.4, 155.2, 137.0, 133.1, 130.2, 130.1, 129.5, 128.8, 115.8, 63.4, 30.0. HRMS (ESI) m / z: [M + Na] + Calcd for C 15 H 13 ClO2Na283.0496; Found 283.0498. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 7.7 min, t major = 7.0 min).

[0085] Example 20; 1 H NMR (500 MHz, CDC13) δ 7.63 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 5.62 (s, 1H), 4.99 (s, 1H), 2.23 (s, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 207.2, 155.1, 138.2, 137.7, 130.8, 130.1, 129.5, 115.8, 92.9, 63.6, 30.0. HRMS (ESI) m / z: [M + Na] + Calcd for C 15 H 13 IO2Na374.9852; Found 374.9851. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 16.8 min, t major = 15.4 min).

[0086] Example 21; 1H NMR (500 MHz, CDC13) δ 7.31 (t, J = 7.3 Hz, 2H), 7.27 - 7.17 (m, 3H), 7.05 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 5.08 (s, 1H), 2.57 (q, J = 7.3 Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 210.7, 154.9, 138.7, 130.3, 130.1, 128.8, 128.6, 127.1, 115.6, 63.1, 36.1, 8.1. HRMS (ESI) m / z: [M + Na] + Calcd for C 16 H 16 O2Na 263.1043; Found 263.1044. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 95:5, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 20.8 min, t major = 22.8 min).

[0087] Example 22; melting point 175-176 °C, 1 H NMR (500 MHz, CDC13) δ 7.30 (t, J = 7.4 Hz, 2H), 7.27 - 7.16 (m, 3H), 7.00 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 5.42 (s, 1H), 5.20 (s, 1H), 2.06 - 1.95 (m, 1H), 1.13 - 1.07 (m, 2H), 0.90 - 0.83 (m, 2H). 13 C{1H} NMR (126 MHz, CDC13) δ 210.6, 155.2, 138.7, 130.2, 129.9, 129.1, 128.6, 127.1, 115.7, 64.5, 21.2, 12.3. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 17O2 253.1223; Found 253.1221. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 12.9 min, t major = 14.4 min).

[0088] Example 23; 1 H NMR (500 MHz, CDC13) δ 7.31 (t, J = 7.4 Hz, 2H), 7.27 - 7.16 (m, 3H), 7.04 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 5.07 (s, 1H), 2.54 (t, J = 7.4 Hz, 2H), 1.56 (dt, J = 20.6, 7.5 Hz, 2H), 1.32 - 1.18 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 210.2, 155.0, 138.6, 130.2, 130.1, 128.8, 128.6, 127.1, 115.6, 63.3, 42.6, 26.1, 22.2, 13.8. HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 21 O2 269.1536; Found 269.1537. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IC, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 245.0 nm; t minor = 12.1 min, t major = 10.7 min).

[0089] Example 24; 1H NMR (500 MHz, CDC13) δ 7.17 - 6.99 (m, 6 H), 6.73 (d, J = 8.5 Hz, 2 H), 5.03 (s, 1 H), 2.52 (t, J = 7.4 Hz, 2 H), 2.31 (s, 3 H), 1.55 (dt, J = 15.1, 7.5 Hz, 2 H), 1.33 - 1.18 (m, 2 H), 0.84 (t, J = 7.4 Hz, 3 H). 13 C{1H} NMR (126 MHz, CDC13) δ 210.2, 155.1, 140.6, 139.9, 137.7, 130.1, 129.2, 128.7, 127.3, 127.2, 127.0, 115.7, 62.9, 42.6, 26.1, 22.2, 13.8. HRMS (ESI) m / z: [M + H] + Calcd for C 19 H 23 O2 283.1698; Found 283.1696. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IC, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 230.0 nm; t minor = 11.8 min, t major = 12.9 min).

[0090] Example 25; 1 H NMR (500 MHz, CDC13) δ 7.60 - 7.49 (m, 4 H), 7.41 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.4 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.6 Hz, 2 H), 5.10 (s, 1 H), 2.56 (t, J = 7.4 Hz, 2 H), 1.66 - 1.48 (m, 2 H), 1.32 - 1.21 (m, 2 H), 0.84 (t, J = 7.4 Hz, 3 H). 13 C{1H} NMR (126 MHz, CDC13) δ 210.2, 155.1, 140.6, 139.9, 137.7, 130.1, 129.2, 128.7, 127.3, 127.2, 127.0, 115.7, 62.9, 42.6, 26.1, 22.2, 13.8. HRMS (ESI) m / z: [M + H] + Calcd for C24 H 25 O2 345.1849;Found 345.1847.The ee value wasdetermined by the chiral HPLC analysis(CHIRALPAK IA,n-hexane / 2-propanol=80:20,v=1mL / min -1 ,λ=254.0nm;t minor =8.6min,t major =7.3min).

[0091] Example 26; 1 H NMR 1H NMR(500MHz,CDCl3)δ7.45–7.28(m,2H),7.11(d,J=8.2Hz,2H),7.02(d,J=8.5Hz,2H),6.73(d,J=8.6Hz,2H),5.68(s,1H),5.03(s,1H),2.52(t,J=7.4Hz,2H),2.39(t,J=7.1Hz,2H),1.66–1.40(m,6H),1.31–1.17(m,2H),0.93(t,J=7.3Hz,3H),0.84(t,J=7.4Hz,3H). 13 C{1H}NMR(126MHz,CDCl3)δ209.7,155.0,138.0,131.8,130.1,128.7,122.9,115.6,90.7,80.2,63.0,42.6,30.8,26.1,22.2,22.0,19.1,13.8,13.6.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 29 O2 349.2162;Found349.2159.The ee value was determined by the chiral HPLC analysis(CHIRALPAKIA,n-hexane / 2-propanol=90:10,v=1mL / min -1 ,λ=240.0nm;t minor =10.0min,t major =11.0min).

[0092] Example 26; 1H NMR (500 MHz, CDC13) δ 7.42 (d, J = 8.2 Hz, 2H), 7.05 (dd, J = 12.7, 8.4 Hz, 4H), 6.75 (d, J = 8.3 Hz, 2H), 5.64 (s, 1H), 5.02 (s, 1H), 2.65 - 2.41 (m, 2H), 1.70 - 1.48 (m, 2H), 1.39 - 1.12 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 209.5, 155.1, 137.8, 131.6, 130.5, 130.0, 129.7, 121.1, 115.8, 62.5, 42.6, 26.0, 22.1, 13.8. HRMS (ESI) m / z: [M+H] + Calcd for C 18 H 20 O2Br 347.0647; Found 347.0651. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IC, n-hexane / 2-propanol = 95:5, v = 1 mL / min-1, λ = 254.0 nm; λ = 254.0 nm; t minor = 16.6 min, t major = 15.4 min).

[0093] Example 28; 1 H NMR (500 MHz, CDC13) δ 7.27 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 5.04 (s, 1H), 2.63 - 2.45 (m, 2H), 1.63 - 1.47 (m, 2H), 1.33 - 1.17 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 209.7, 155.1, 137.2, 133.0, 130.2, 130.0, 129.8, 128.7, 115.8, 62.5, 42.6, 26.0, 22.1, 13.8. HRMS (ESI) m / z: [M+H] + Calcd for C 18 H 20CI02 303.1146; Found 303.1144. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 6.5 min, t major = 5.8 min).

[0094] Example 29; 1 H NMR (500 MHz, CDC13) δ 7.15 (dd, J = 8.6, 5.4 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.99 (t, J = 8.7 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 5.64 (s, 1H), 5.05 (s, 1H), 2.60 - 2.47 (m, 2H), 1.61 - 1.50 (m, 2H), 1.31 - 1.18 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 209.8, 161.9 (d, 1 J C-F = 245.9 Hz), 155.0, 134.5, 134.5, 130.4, 130.3, 130.1, 130.0, 115.7, 115.5, 115.3, 62.4, 42.5, 26.1, 22.2, 13.8. 19 F NMR (471 MHz, CDC13) δ -115.6. HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 20 FO2 287.1442; Found 287.1440. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IC, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 225.0 nm; t minor = 8.0 min, t major = 7.4 min).

[0095] Example 30; 1H NMR (500 MHz, CDC13) δ 7.25 (dd, J = 14.0, 7.9 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.99 - 6.84 (m, 3H), 6.76 (d, J = 8.6 Hz, 2H), 6.02 (s, 1H), 5.06 (s, 1H), 2.67 - 2.46 (m, 2H), 1.66 - 1.47 (m, 2H), 1.33 - 1.17 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 209.7, 162.8 (d, 1 J C-F = 246.2 Hz), 155.2, 141.2, 141.1, 130.1, 130.0, 129.9, 129.4, 124.5, 124.5, 116.0, 115.8, 115.8, 114.1, 113.9, 62.8, 42.6, 26.0, 22.1, 13.7. 19 F NMR (471 MHz, CDC13) δ -112.7. HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 20 FO 287.1442; Found 287.1439. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IC, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 235.0 nm; t minor = 7.2 min, t major = 7.9 min).

[0096] Example 31; 1 H NMR (500 MHz, CDC13) 7.24 - 7.17 (m, 1H), 7.13 - 6.94 (m, 5H), 6.79 (d, J = 8.6 Hz, 2H), 6.18 (s, 1H), 5.31 (s, 1H), 2.69 - 2.44 (m, 2H), 1.68 - 1.48 (m, 2H), 1.36 - 1.17 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 209.4, 160.3 (d, 1 J C-F= 245.4 Hz), 155.4, 130.6, 130.1, 130.1, 128.8, 128.7, 127.7, 126.7, 126.5, 124.0, 124.0, 115.9, 115.2, 115.0, 56.2, 56.1, 42.2, 26.0, 22.1, 13.7. 19 F NMR (471 MHz, CDC13) δ -116.3. HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 20 FO2 287.1442; Found 287.1440. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 98:2, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 47.1 min, t major = 49.5 min).

[0097] Example 32; 1 H NMR (500 MHz, CDC13) δ 7.07 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.75 - 6.64 (m, 3H), 5.53 (s, 1H), 5.02 (s, 1H), 2.68 - 2.44 (m, 2H), 1.65 - 1.47 (m, 2H), 1.34 - 1.18 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.6, 163.0 (d, 1 J C-F = 248.4 Hz), 162.8 (d, 1 J C-F = 248.4 Hz), 155.3, 142.6, 130.1, 128.9, 116.0, 111.9, 111.9, 111.8, 111.7, 102.7, 102.5, 102.3, 62.5, 42.7, 26.0, 22.1, 13.7. 19 F NMR (471 MHz, CDC13) δ -109.7. HRMS (ESI) m / z: [M - H] - Calcd for C 18 H 17F2O2303.1202; Found 303.1197. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 5.1 min, t major = 5.7 min).

[0098] Example 33; 1 H NMR (500 MHz, CDC13) δ 7.13 - 6.96 (m, 4H), 6.93 - 6.85 (m, 1H), 6.78 (d, J = 8.6 Hz, 2H), 5.92 (s, 1H), 5.02 (s, 1H), 2.64 - 2.45 (m, 2H), 1.67 - 1.47 (m, 2H), 1.37 - 1.15 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 209.4, 155.3, 149.8 (dd, 1 J C-F = 248.1, 93.5 Hz), 149.7 (dd, 1 J C-F = 248.0, 93.3 Hz), 135.8, 135.8, 135.7, 130.0, 129.3, 124.8, 124.7, 124.7, 124.7, 117.9, 117.8, 117.2, 117.0, 115.9, 62.1, 42.6, 26.0, 22.1, 13.7. 19 F NMR (471 MHz, CDC13) δ -137.27, -137.32, -140.1, -140.2. HRMS (ESI) m / z: [M+H] + Calcd for C 18 H 19 F2O2303.1202; Found 303.1197. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 6.7 min, t major= 7.6 min).

[0099] Example 34; 1 H NMR (500 MHz, CDC13) δ 7.36 (d, J = 8.3 Hz, 1 H), 7.29 - 7.20 (m, 1 H), 7.11 - 6.98 (m, 3 H), 6.80 (d, J = 8.5 Hz, 2 H), 5.21 (s, 1 H), 5.00 (s, 1 H), 2.70 - 2.40 (m, 2 H), 1.63 - 1.50 (m, 2 H), 1.34 - 1.19 (m, 2 H), 0.85 (t, J = 7.3 Hz, 3 H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.4, 155.2, 139.1, 132.5, 131.2, 130.8, 130.3, 130.1, 129.3, 128.2, 116.0, 62.1, 42.6, 26.0, 22.2, 13.8. HRMS (ESI) m / z: [M - H] - Calcd for C 18 H 17 Cl2O2335.0611; Found 335.0609. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 9.8 min, t major = 9.0 min).

[0100] Example 35; 1 H NMR (500 MHz, CDC13) δ 7.36 (d, J = 8.3 Hz, 1 H), 7.29 - 7.20 (m, 1 H), 7.11 - 6.98 (m, 3 H), 6.80 (d, J = 8.5 Hz, 2 H), 5.21 (s, 1 H), 5.00 (s, 1 H), 2.70 - 2.40 (m, 2 H), 1.63 - 1.50 (m, 2 H), 1.34 - 1.19 (m, 2 H), 0.85 (t, J = 7.3 Hz, 3 H). 13C {1H} NMR (126 MHz, CDC13) δ 208.8, 155.5, 142.6, 132.7, 130.6, 130.1, 128.5, 122.9, 116.1, 62.2, 42.6, 25.9, 22.1, 13.7. HRMS (ESI) m / z: [M - H] - Calcd for C 18 H 17 Br2O2424.9580; Found 424.9574. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 5.2 min, t major = 5.9 min).

[0101] Example 36; 1 H NMR (500 MHz, CDC13) δ 7.26 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 5.91 (s, 1H), 5.09 (s, 1H), 2.65 - 2.46 (m, 2H), 1.66 - 1.47 (m, 2H), 1.33 - 1.17 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 209.3, 155.4, 148.5, 139.4, 130.6, 130.1, 129.2, 121.3, 118.7 (q, 1 J C-F = 320.7 Hz), 116.0, 62.3, 42.6, 26.0, 22.1, 13.7. 19 F NMR (471 MHz, CDC13) δ -72.9. HRMS (ESI) m / z: [M + H] + Calcd for C 19 H 20F3O5S 417.0938; Found 417.0972. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 240.0 nm; t minor = 10.3 min, t major = 8.7 min).

[0102] Example 37; 1 H NMR (500 MHz, CDC13) δ 8.14 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.55 (s, 1H), 5.16 (s, 1H), 2.70 - 2.46 (m, 2H), 1.69 - 1.49 (m, 2H), 1.35 - 1.15 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.3, 155.5, 146.8, 146.3, 130.1, 129.7, 128.8, 123.6, 116.1, 62.8, 42.7, 26.0, 22.1, 13.7. HRMS (ESI) m / z: [M - H] - Calcd for C 18 H 18 NO4 312.1241; Found 312.1239. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 235.1 nm; t minor = 22.3 min, t major = 24.1 min).

[0103] Example 38; 1H NMR (500 MHz, CDC13) δ 7.57 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.12 (s, 1H), 2.70 - 2.46 (m, 2H), 1.69 - 1.48 (m, 2H), 1.33 - 1.18 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 208.6, 155.6, 144.4, 132.2, 130.1, 129.6, 128.6, 118.7, 116.1, 110.6, 63.0, 42.7, 25.9, 22.1, 13.7. HRMS (ESI) m / z: [M - H] - Calcd for C 19 H 18 NO2 292.1343; Found 292.1340. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 85:15, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 11.6 min, t major = 12.8 min).

[0104] Example 39; 1 H NMR (500 MHz, CDC13) δ 7.97 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 5.11 (s, 1H), 3.89 (s, 3H), 2.64 - 2.46 (m, 2H), 1.66 - 1.49 (m, 2H), 1.33 - 1.18 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 209.2, 209.1, 167.2, 167.2, 155.5, 155.4, 144.2, 130.1, 129.8, 128.9, 128.6, 115.8, 63.1, 52.2, 42.6, 26.0, 22.1, 13.7. HRMS (ESI) m / z: [M + H] + Calcd for C 20H 23 O4 327.1591 ; Found 327.1589. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 43.3 min, t major = 38.6 min).

[0105] Example 40; 1 H NMR (500 MHz, CDC13) δ 9.96 (s, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.14 (s, 1H), 2.65 - 2.48 (m, 2H), 1.63 - 1.50 (m, 2H), 1.34 - 1.19 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.7, 192.2, 155.4, 146.0, 135.0, 130.1, 130.0, 129.5, 129.1, 115.9, 63.2, 42.7, 26.0, 22.1, 13.8. HRMS (ESI) m / z: [M - H] - Calcd for C 19 H 19 O3 295.1340; Found 295.1335. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 9.0 min, t major = 10.2 min).

[0106] Example 41; 1H NMR 1H NMR δ 7.84 - 7.69 (m, 4H), 7.63 - 7.52 (m, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.65 (s, 1H), 5.15 (s, 1H), 2.71 - 2.46 (m, 2H), 1.68 - 1.48 (m, 2H), 1.35 - 1.17 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 209.2, 196.9, 155.6, 143.9, 137.3, 136.0, 132.6, 130.4, 130.1, 130.0, 129.0, 128.8, 128.3, 115.9, 63.1, 42.7, 26.0, 22.1, 13.8. HRMS (ESI) m / z: [M - H] - Calcd for C 25 H 23 O3 371.1653; Found 371.1648. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 12.3 min, t major = 14.1 min).

[0107] Example 42; 1 H NMR (500 MHz, CDC13) δ 7.82 (dd, J = 8.2, 5.6 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.21 - 7.03 (m, 4H), 6.81 (d, J = 8.4 Hz, 2H), 5.82 (s, 1H), 5.14 (s, 1H), 2.65 - 2.48 (m, 2H), 1.69 - 1.50 (m, 2H), 1.37 - 1.15 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.9, 195.2, 165.4 (d, 1 J C-F= 254.3 Hz), 155.4, 143.8, 136.0, 133.6, 133.6, 132.7, 132.6, 130.2, 130.1, 129.4, 128.9, 115.9, 115.5, 115.4, 63.1, 42.7, 26.0, 22.2, 13.8. 19 F NMR (471 MHz, CDC13) δ -105.7. HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 24 FO3 391.1704; Found 391.1700. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 13.3 min, t major = 16.7 min).

[0108] Example 43; 1 H NMR (500 MHz, CDC13) δ 7.72 (dd, J = 8.4, 6.2 Hz, 4H), 7.43 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.98 (s, 1H), 5.14 (s, 1H), 2.70 - 2.46 (m, 2H), 1.64 - 1.52 (m, 2H), 1.32 - 1.19 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). 13 C{1H}NMR (126 MHz, CDC13) δ 209.2, 195.6, 155.6, 144.1, 139.0, 135.7, 135.6, 131.4, 130.2, 130.1, 129.0, 128.9, 128.6, 115.9, 63.1, 42.7, 26.0, 22.1, 13.8. HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 24CIO3 407.1408; Found 407.1407. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 9.0 min, t major = 12.1 min).

[0109] Example 44; 1 H NMR (500 MHz, CDC13) δ 7.72 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.61 - 6.41 (m, 2H), 5.79 (s, 1H), 5.11 (s, 1H), 3.86 (s, 3H), 3.69 (s, 3H), 2.65 - 2.45 (m, 2H), 1.63 - 1.49 (m, 2H), 1.36 - 1.15 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.8, 195.4, 163.4, 159.6, 155.3, 143.6, 137.4, 132.3, 130.1, 130.1, 129.6, 128.6, 121.2, 115.8, 104.4, 98.8, 63.2, 55.6, 55.5, 42.6, 26.0, 22.2, 13.8. HRMS (ESI) m / z: [M + H] + Calcd for C 27 H 29 O5 433.2010; Found 433.2007. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 44.7 min, t major = 60.9 min).

[0110] Example 44; 1H NMR (500 MHz, CDC13) δ 7.95 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 15.7 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.49 (d, J = 15.7 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.33 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.36 (s, 1H), 5.14 (s, 1H), 2.65 - 2.47 (m, 2H), 1.66 - 1.48 (m, 2H), 1.35 - 1.19 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). 13 C{1H}NMR (126 MHz, CDC13) δ 209.0, 190.6, 155.5, 145.2, 144.2, 136.7, 134.7, 130.7, 130.1, 129.2, 129.8, 128.9, 128.8, 128.5, 121.9, 115.9, 63.1, 42.7, 26.0, 22.1, 13.8. HRMS (ESI) m / z: [M + H] + Calcd for C 27 H 27 O3 399.1955; Found 399.1953. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 23.4 min, t major = 26.9 min).

[0111] Example 46; 1 H NMR (500 MHz, CDC13) δ 7.90 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.12 (s, 1H), 2.63 - 2.49 (m, 5H), 1.63 - 1.50 (m, 2H), 1.32 - 1.21 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13C {1H} NMR (126 MHz, CDC13) δ 208.8, 198.3, 155.4, 144.5, 135.7, 130.1, 129.3, 129.1, 128.6, 115.9, 63.1, 42.7, 26.6, 26.0, 22.2, 13.8. HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 23 O3 311.1642; Found 311.1638. The ee value was determined by the chiral HPLC analysis (CHIRALPAK ID, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 12.1 min, t major = 10.9 min).

[0112] Example 47; 1 H NMR (500 MHz, CDC13) δ 7.96 - 7.87 (m, 1H), 7.84 (dd, J = 6.2, 3.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.53 - 7.37 (m, 3H), 7.20 (d, J = 7.1 Hz, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 5.86 (s, 1H), 5.79 (s, 1H), 2.70 - 2.51 (m, 2H), 1.67 - 1.52 (m, 2H), 1.33 - 1.17 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 210.6, 155.0, 134.5, 134.1, 131.8, 130.4, 129.5, 129.0, 128.1, 126.5, 126.4, 125.7, 125.3, 123.3, 115.6, 59.6, 42.6, 26.3, 22.2, 13.8. HRMS (ESI) m / z: [M - H] - Calcd for C 22 H 21O2 317.1547; Found 317.1541. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IC, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 230.0 nm; t minor = 6.6 min, t major = 7.5 min).

[0113] Example 48; 1 H NMR (500 MHz, CDC13) δ 7.81 - 7.72 (m, 3H), 7.61 (s, 1H), 7.47 - 7.40 (m, 2H), 7.31 (dd, J = 8.5, 1.8 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 5.93 (s, 1H), 5.22 (s, 1H), 2.57 (t, J = 7.4 Hz, 2H), 1.58 (dt, J = 20.7, 7.5 Hz, 2H), 1.34 - 1.19 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 210.4, 155.0, 136.2, 133.4, 132.4, 130.2, 130.1, 128.3, 127.8, 127.6, 127.4, 127.1, 126.2, 125.9, 115.6, 63.3, 42.7, 26.1, 22.2, 13.8. HRMS (ESI) m / z: [M - H] - Calcd for C 22 H 21 O2 317.1547; Found 317.1542. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IC, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 6.6 min, t major = 7.5 min).

[0114] Example 48; 1H NMR (500 MHz, CDC13) δ 8.72 (d, J = 8.1 Hz, 1H), 8.64 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.71 - 7.52 (m, 4H), 7.45 (s, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 5.79 (s, 1H), 5.39 (s, 1H), 2.80 - 2.53 (m, 2H), 1.67 - 1.58 (m, 2H), 1.33 - 1.21 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13 C{1H}NMR (126 MHz, CDC13) δ 210.1, 155.0, 132.8, 131.2, 131.1, 130.8, 130.5, 130.0, 129.4, 128.8, 127.5, 126.9, 126.9, 126.9, 126.5, 124.1, 123.4, 122.4, 115.6, 59.9, 42.8, 26.3, 22.2, 13.8. HRMS (ESI) m / z: [M - H] - Calcd for C 26 H 23 O2 367.1704; Found 367.1699. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 7.7 min, t major = 6.2 min).

[0115] Example 50; 1 H NMR (500 MHz, CDC13) δ 8.83 (dd, J = 4.3, 1.6 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.84 - 7.79 (m, 2H), 7.48 - 7.38 (m, 2H), 7.07 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.25 (s, 1H), 2.64 - 2.49 (m, 2H), 1.68 - 1.48 (m, 2H), 1.36 - 1.17 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 209.2, 157.0, 149.5, 147.1, 142.2, 136.8, 130.3, 128.6, 127.8, 127.7, 127.3, 127.1, 121.1, 116.2, 63.4, 42.5, 26.1, 22.2, 13.8. HRMS (ESI) m / z: [M+H] + Calcd for C 21 H 22 NO2 320.1645; Found 320.1643. The ee value was determined by the chiral HPLC analysis (CHIRALPAK ID, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 18.1 min, t major = 16.6 min).

[0116] Example 51; 1 1H NMR (500 MHz, CDCl3) δ 7.36–7.24 (m, 3H), 7.24–7.16 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.33 (s, 1H), 4.19 (s, 2H). 13 C{1H} NMR (126 MHz, CDCl3) δ 201.0, 155.2, 137.4, 130.2, 129.0, 128.9, 128.8, 127.6, 115.8, 60.0, 48.0. HRMS (ESI) m / z: [M–H] - Calcd for C 15 H 12 ClO2 259.0531; Found 259.0529. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 280.0 nm; t minor = 15.3 min, t major = 14.1 min).

[0117] Example 52; 1H NMR (500 MHz, CDC13) δ 7.57 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 5.24 (s, 1H), 5.13 (s, 1H), 3.67 - 3.39 (m, 2H), 2.85 - 2.62 (m, 2H), 2.17 - 1.97 (m, 2H). 13 C{1H} NMR (126 MHz, CDC13) δ 207.6, 155.3, 142.5, 130.1, 129.5, 129.3, 129.2, 129.1, 125.5, 125.5, 124.0 (q, 1 J C-F = 272.1 Hz), 116.0, 63.1, 44.2, 39.5, 26.4. 19 F NMR (471 MHz, CDC13) δ -62.5. HRMS (ESI) m / z: [M - H] - Calcd for C 18 H 15 ClF302 355.0718; Found 355.0713. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 6.8 min, t major = 7.4 min).

[0118] Example 53; 1 H NMR (500 MHz, CDC13) δ 7.55 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 5.12 (s, 1H), 2.64 - 2.49 (m, 2H), 1.66 - 1.50 (m, 2H), 1.32 - 1.18 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 209.3, 155.3, 142.8, 130.1, 129.4, 129.3, 129.2, 125.4, 125.4, 124.1 (q, 1 J C-F= 272.0 Hz), 115.9, 62.9, 42.7, 26.0, 22.1, 13.7. 19 19F NMR (471 MHz, CDCl3) δ -62.5. HRMS (ESI) m / z: [M–H] - Calcd for C 19 H 18 F3O2 335.1264; Found 335.1262. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 215.0 nm; t minor = 8.9 min, t major = 9.8 min).

[0119] Example 54; 1 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 5.54 (s, 1H), 5.12 (s, 1H), 2.66–2.45 (m, 2H), 1.68–1.49 (m, 2H), 1.35–1.12 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H). 13 13C{1H} NMR (126 MHz, CDCl3) δ 209.3, 155.3, 142.8, 130.1, 129.4, 129.3, 129.2, 129.2, 125.5, 125.5, 125.4, 125.4, 124.1 (q, 1 J C-F = 272.1 Hz), 115.9, 62.9, 43.0, 31.4, 28.7, 23.9, 22.4, 14.0. 19 19F NMR (471 MHz, CDCl3) δ -62.5. HRMS (ESI) m / z: [M–H] - Calcd for C 21 H 22F3O2 363.1577; Found 363.1574. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 5.1 min, t major = 5.8 min).

[0120] Example 55; 1 H NMR (500 MHz, CDC13) δ 7.55 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.08 (s, 1H), 2.42 (d, J = 6.8 Hz, 2H), 1.96 - 1.78 (m, 1H), 1.77 - 1.49 (m, 5H), 1.33 - 1.17 (m, 2H), 1.09 (dt, J = 15.6, 8.3 Hz, 1H), 0.97 - 0.77 (m, 2H). 13 C {1H} NMR (126 MHz, CDC13) δ 208.7, 155.3, 142.7, 130.2, 129.4, 129.2, 129.2, 125.4, 124.1 (q, 1 J C-F = 272.2 Hz), 115.9, 63.4, 50.5, 33.9, 33.1, 32.9, 26.1, 25.0, 25.9. 19 F NMR (471 MHz, CDC13) δ -62.5. HRMS (ESI) m / z: [M - H] - Calcd for C 22 H 22 F3O2 363.1577; Found 363.1574. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 5.3 min, t major = 6.5 min).

[0121] Example 55; 1 H NMR (500 MHz, CDC13) δ 7.64 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.27 (s, 1H), 4.38 - 3.52 (m, 2H), 2.96 - 2.70 (m, 2H), 0.96 (s, 9H), 0.133 (s, 3H), 0.131 (s, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 207.6, 155.2, 145.7, 142.6, 136.4, 130.4, 129.4, 129.3, 129.2, 129.1, 128.4, 125.4, 125.4, 124.1 (q, 1 J C-F = 271.9 Hz), 119.5, 115.9, 63.7, 59.0, 45.3, 25.9, 18.3, -5.5. HRMS (ESI) m / z: [M - H] - Calcd for C 23 H 28 F3O3Si 437.1765; Found 437.1759. 19 FNMR (471 MHz, CDC13) δ -62.5. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 85:15, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 4.3 min, t major = 3.8 min).

[0122] Example 57; 1 H NMR (500 MHz, CDC13) δ 7.55 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 5.37 (s, 1H), 5.11 (s, 1H), 3.56 (t, J = 6.3 Hz, 2H), 2.65 - 2.50 (m, 2H), 1.68 - 1.60 (m, 2H), 1.52 - 1.39 (m, 2H), 0.87 (s, 9H), 0.02 (s, 6H). 13C {1H} NMR (126 MHz, CDC13) δ 208.6, 155.3, 142.8, 130.1, 129.4, 129.3, 129.2, 125.5, 125.4, 124.1 (q, J = 271.9 Hz), 115.9, 62.8, 62.8, 42.7, 31.9, 25.9, 20.4, 18.3, -5.4. 1 J C-F = 271.9 Hz), 115.9, 62.8, 62.8, 42.7, 31.9, 25.9, 20.4, 18.3, -5.4. 19 F NMR (471 MHz, CDC13) δ -62.5. HRMS (ESI) m / z: [M - H] - Calcd for C 25 H 32 F3O3Si 465.2078; Found 465.2072. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IG, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 5.0 min, t major = 4.5 min).

[0123] Example 58; 1 H NMR (500 MHz, CDC13) δ 7.55 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 6.05 (s, 1H), 5.17 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.86 (t, J = 6.5 Hz, 2H), 2.71 - 2.50 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 207.2, 174.3, 173.1, 155.5, 142.6, 130.2, 129.5, 129.2, 129.2, 128.9, 125.5, 125.48, 125.45, 125.42, 125.40, 124.1 (q, J = 271.9 Hz), 115.9, 106.3, 63.0, 61.0, 37.2, 28.4, 14.1. 1 J C-F = 271.9 Hz), 115.9, 106.3, 63.0, 61.0, 37.2, 28.4, 14.1. 19 F NMR (471 MHz, CDC13) δ -62.5. HRMS (ESI) m / z: [M + H]+ Calcd for C 20 H 20 F3O4 381.1308; Found 381.1306. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 13.9 min, t major = 16.6 min).

[0124] Example 59; 1 H NMR (500 MHz, CDC13) δ 7.54 (dd, J = 14.3, 8.2 Hz, 4H), 7.44 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.30 (s, 1H), 5.12 (s, 1H), 2.76 - 2.53 (m, 2H), 2.38 (t, J = 7.0 Hz, 2H), 1.92 - 1.66 (m, 2H), 1.63 - 1.45 (m, 2H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.2, 155.2, 142.7, 131.7, 130.1, 129.5, 129.5, 129.4, 129.2, 129.2, 129.1, 127.6, 125.5, 125.5, 125.4, 125.1, 125.1, 125.1, 124.04 (q, 1 J C-F = 270.1 Hz), 123.97 (q, 1 J C-F = 270.1 Hz), 115.9, 92.3, 79.92, 62.9, 42.2, 27.7, 23.1, 19.2. 19 F NMR (471 MHz, CDC13) δ -62.5, -62.7. HRMS (ESI) m / z: [M - H] - Calcd for C 28 H 21F6O2503.1451 ; Found 503.1447. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 6.7 min, t major = 8.0 min)

[0125] Example 60; 1 H NMR (500 MHz, CDC13) δ 7.51 (d, J = 8.2 Hz, 2H), 7.29 - 7.15 (m, 5H), 7.12 - 7.08 (m, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 5.61 (s, 1H), 5.01 (s, 1H), 2.99 - 2.80 (m, 4H). 13 C{1H} NMR (126 MHz, CDC13) δ 208.0, 155.2, 142.4, 140.4, 130.1, 129.2, 129.0, 128.5, 128.4, 126.2, 125.4, 125.4, 124.0 (q, 1 J C-F = 272.0 Hz), 63.3, 44.2, 30.0. 19 F NMR (471 MHz, CDC13) δ -62.5. HRMS (ESI) m / z: [M - H] - Calcd for C 23 H 18 F3O2383.1264; Found 383.1260. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 6.9 min, t major = 8.8 min).

[0126] Example 61

[0127] Example 61 provides a chiral α,α-diaryl ketone compound, its reaction equation and preparation method as follows:

[0128]

[0129] S1, compound 1 (0.20 mmol), benzoquinone (0.10 mmol), dichloromethane (2 mL), 2x35W blue LEDs irradiation at room temperature for 4 h; quinone intermediate was generated;

[0130] S2, then compound 2-6 (0.15 mmol) was added, MS (60 mg) and chiral phosphoric acid catalyst (R)-C2 (5 mol%), -60 °C for 3 h to give chiral α,α-diaryl ketone (yield 95%, ee value 91%).

[0131] Examples 62-67

[0132] Examples 62-67 provide a series of chiral α,α-diaryl ketones, which are prepared by the preparation method of Example 61 to prepare the following compounds, the structure, yield and ee value are as follows:

[0133]

[0134] The data of Examples 61-67 are characterized as follows:

[0135] Example 61; 1 H NMR (500 MHz, CDC13) δ 7.96 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.38 - 7.12 (m, 7H), 7.02 (d, J = 8.5 Hz, 2H), 6.82 (s, 1H), 6.67 (d, J = 8.5 Hz, 2H), 5.96 (s, 1H). 13 C{1H} NMR (126 MHz, CDC13) δ 199.9, 155.0, 139.1, 136.4, 133.2, 130.3, 130.1, 128.9, 128.6, 128.6, 127.0, 115.7, 58.5. HRMS (ESI) m / z: [M+H] + Calcd for C 20 H 17 O2 289.1223; Found 289.1222. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IF, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 7.3 min, tmajor = 8.1 min).

[0136] Example 62; 1 H NMR (500 MHz, CDC13) δ 7.97 (d, J = 8.9 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.85 (dd, J = 15.0, 8.8 Hz, 4H), 6.71 (d, J = 8.6 Hz, 2H), 5.88 (s, 1H), 5.83 (s, 1H), 3.81 (s, 3H), 3.74 (s, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 198.0, 163.4, 158.5, 154.8, 131.7, 131.5, 131.3, 130.1, 130.0, 129.6, 115.6, 114.1, 113.8, 57.4, 55.4, 55.2. HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 21 O4 349.1434; Found 349.1432. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 23.3 min, t major = 26.4 min).

[0137] Example 63; 1 H NMR (500 MHz, CDC13) δ 7.89 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.15 - 7.06 (m, 6H), 6.73 (d, J = 8.6 Hz, 2H), 5.91 (s, 1H), 5.11 (s, 1H), 2.36 (s, 3H), 2.29 (s, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 198.6, 154.6, 143.9, 136.7, 136.5, 134.2, 131.5, 130.3, 129.4, 129.3, 129.1, 128.9, 115.6, 58.1, 21.6, 21.0. HRMS (ESI) m / z: [M + H] +Caled for C 22 H 21 O2 317.1536; Found 317.1533. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 12.7 min, t major = 15.2 min).

[0138] Example 64; 1 H NMR (500 MHz, CDC13) δ 7.92 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.18 - 7.06 (m, 6H), 6.72 (d, J = 8.6 Hz, 2H), 5.93 (s, 1H), 5.91 - 5.75 (m, 2H), 5.34 (s, 1H), 5.09 - 4.90 (m, 4H), 2.75 - 2.69 (m, 2H), 2.69 - 2.61 (m, 2H), 2.41 - 2.28 (m, 4H). 13 C{1H} NMR (126 MHz, CDC13) δ 198.8, 154.7, 147.7, 140.6, 138.1, 137.4, 136.9, 134.6, 131.3, 130.3, 129.2, 128.9, 128.7, 128.7, 115.6, 115.4, 114.8, 58.1, 35.3, 35.3, 34.9, 34.9. HRMS (ESI) m / z: [M + H] + Caled for C 28 H 29 O2 397.2168; Found 397.2169. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IF, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 7.4 min, t major = 8.3 min).

[0139] Example 64; 1H NMR (500 MHz, DMSO) δ 9.42 (d, J = 9.5 Hz, 1H), 8.23 - 8.00 (m, 2H), 7.41 - 7.21 (m, 4H), 7.22 - 7.05 (m, 4H), 6.72 (dd, J = 13.3, 5.3 Hz, 2H), 6.30 (s, 1H), 3.41 (s, 1H). 13 C{1H} NMR (126 MHz, DMSO) δ 196.9, 165.9, 164.9 (d, 1 J C-F = 252.3 Hz), 161.0 (d, 1 J C-F = 243.2 Hz), 136.2, 136.2, 132.9, 132.9, 131.8, 131.8, 130.9, 130.9, 129.9, 129.2, 115.9, 115.7, 115.6, 115.1, 114.9, 56.0. 19 F NMR (471 MHz, DMSO) δ -105.7, -116.3. HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 14 F2O2Na 347.0854; Found 347.0857. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 8.9 min, t major = 11.1 min).

[0140] Example 66; melting point 213 - 214 °C, 1 H NMR (500 MHz, DMSO) δ 8.16 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.3 Hz, 2H), 7.62 (dd, J = 11.2, 7.8 Hz, 4H), 7.54 - 7.31 (m, 8H), 7.15 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.5 Hz, 2H), 6.35 (s, 1H). 13C{1H}NMR(126MHz,DMSO)δ197.9,144.6,139.9,139.4,138.8,138.5,135.2,130.0,129.6,129.6,129.1,128.9,128.4,127.4,127.0,127.0,126.7,126.6,115.6,56.6.HRMS(ESI)m / z:[M+H] + Calcd for C 32 H 25 O2 441.1849;Found 441.1848.The ee value was determined by the chiral HPLC analysis(CHIRALPAK IF,n - hexane / 2 - propanol=80:20,v=1mL / min -1 ,λ=254.0nm;t minor =18.4min,t major =17.0min).

[0141] Example 67; 1 1H NMR(500MHz,CDCl3)δ8.56(s,1H),8.07(dd,J=8.7,1.7Hz,1H),7.94–7.65(m,7H),7.61–7.36(m,5H),7.17(d,J=8.5Hz,2H),6.77(d,J=8.6Hz,2H),6.28(s,1H). 13 C{1H}NMR(126MHz,CDCl3)δ198.9,155.0,137.0,135.5,134.0,133.4,132.4,131.0,130.8,130.5,129.7,128.6,128.5,128.5,127.9,127.7,127.6,127.6,127.3,126.7,126.1,125.9,124.6,115.8,58.7.HRMS(ESI)m / z:[M+H] + Calcd for C 28 H 21 O2 389.1536;Found 389.1533.The ee value was determined by the chiral HPLC analysis(CHIRALPAK IF,n - hexane / 2 - propanol=80:20,v=1mL / min -1, λ = 254.0 nm; t minor = 12.3 min, t major = 14.1 min). Application Example 1

[0142] Synthesis of pyridinamide analogs

[0143] Florylpicoxamid is the second generation pyridinamide fungicide developed by Dow AgroSciences, which can be used for the prevention and treatment of diseases caused by Cylindrocarpon, Erysiphe, Monilinia, Alternaria fungi and powdery mildew, anthracnose, spot disease, etc. in cereals, grapes, fruit trees, nuts, vegetables, etc. It acts on the complex III Qi ubiquinone (i.e. coenzyme Q) bonding site of fungi, and inhibits mitochondrial respiration to produce effect.

[0144] The present application successfully realizes the asymmetric synthesis of the drug through a series of reactions, and the synthesis route is as follows:

[0145]

[0146] The preparation steps are as follows:

[0147] Under the protection of nitrogen at room temperature, aryl alkyne compound 1 (4 mmol, 2.0 equiv) and benzoquinone (2 mmol, 1.0 equiv) were dissolved in CH2Cl2(40 mL) solution, irradiated under blue LED (2x35W) for 4h, then the reaction mixture was cooled to-60℃, and MS (1.2g), (R)-C11 (0.1mmol, 5mol%) and compound 2-6 (3mmol, 1.5equiv) were added to the system in turn. The resulting mixture was stirred at-60℃ for 3h. After the reaction was completed, the mixture was concentrated under vacuum, and directly subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain compound I-102;

[0148] To the methanol (16mL) solution of compound I-102 (390.8mg, 1.6mmol) at 0℃, NaBH4 (90.8mg, 2.4mmol) was added. The reaction mixture was stirred at room temperature for 1h, and after the reaction was completed, DCM was extracted. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate / dichloromethane 3:1:3 to 1:1:1) to obtain products I-103 and I-103';

[0149] To a solution of compound I-103 (123.1 mg, 0.5 mmol) in CH2Cl2(5 mL) was added Et3N (105 ul, 0.75 mmol), 4-methylbenzenesulfonyl chloride (114.4 mg, 0.6 mmol) sequentially at 0 °C and stirred for 1 h at 0 °C. After the reaction was completed, the mixture was concentrated in vacuo and directly subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate 2:1) to give compound I-104.

[0150] To a solution of compound I-104 (195 mg, 0.49 mmol), DMAP (6 mg, 0.049 mmol), (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (111.3 mg, 0.588 mmol) in CH2Cl2(5 mL) was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (187.9 mg, 0.9 mmol) at 0 °C. The reaction was stirred at room temperature for 12 h. It was concentrated in vacuo and directly subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate 1:1) to give compound I-105;

[0151] To a solution of compound I-105 (171.5 mg, 0.3 mmol) in 1,4-dioxane (2 mL) was added HCl (1 mL, 4 mol, 4 N) at room temperature. The reaction was stirred overnight and then concentrated in vacuo to give a sticky material. After the addition of diethyl ether (10 mL), the mixture was stirred vigorously for 30 min. The mixture was filtered, rinsed with diethyl ether, and then rinsed with n-hexane. The crude product, alanine hydrochloride, was dried in vacuo. To a mixture of alanine hydrochloride, 3-hydroxy-4-methoxypicolinic acid I-106 (55.8 mg, 0.33 mmol) in DCM (3 mL) was added PyBOP (171.7 mg, 0.33 mmol) and N,N-diisopropylethylamine (183 uL, 10.5 mmol). The reaction was stirred at room temperature for 24 h. After it was concentrated in vacuo, it was directly subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate 1:2) to give the product I-107 as a white foamy solid.

[0152] To a 25 mL flask was added compound I-107 (62.3 mg, 0.1 mmol), triethylamine (0.5 mL), and acetic anhydride (0.5 mL, 5 mol). It was stirred at room temperature for 1 h. After it was concentrated in vacuo, it was directly subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate 1:1) to give the product I-108.

[0153] Product characterization:

[0154] Compound I-102; 1H NMR (500 MHz, CDC13) δ 7.21 - 7.10 (m, 2H), 7.10 - 6.91 (m, 4H), 6.77 (d, J = 8.5 Hz, 2H), 5.61 (s, 1H), 5.04 (s, 1H), 2.24 (s, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 207.7, δ 161.9 (d, 1 J C-F = 246.3 Hz), 155.1, 134.2, 134.2, 130.4, 130.4, 130.1, 115.8, 115.6, 115.4, 63.3, 29.9. 19 F NMR (471 MHz, CDC13) δ -115.4. HRMS (ESI) m / z: [M + Na] + Calcd for C 15 H 13 FO2Na 267.0792; Found 267.0789. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 90:10, v = 1 mL / min -1 , λ = 210.0 nm; t minor = 13.9 min, t major = 12.6 min).

[0155] Compound I-103; melting point 124-125 °C, 94% ee, 1 H NMR (500 MHz, DMSO) 1H NMR (500 MHz, DMSO) δ 9.11 (s, 1H), 7.29 (dd, J = 8.7, 5.7 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.05 (t, J = 8.9 Hz, 2H), 6.64 (d, J = 8.5 Hz, 2H), 4.48 (d, J = 5.3 Hz, 1H), 4.40 - 4.23 (m, 1H), 3.65 (d, J = 8.4 Hz, 1H), 0.96 (d, J = 6.1 Hz, 3H). 13 C{1H} NMR (126 MHz, DMSO) δ 160.5 (d, 1 J C-F = 241.8 Hz), 155.4, 140.9, 140.9, 133.5, 129.8, 129.8, 129.5, 114.9, 114.8, 7.18, 57.8, 22.8.19 F NMR (471 MHz, DMSO) δ -117.6. HRMS (ESI) m / z: [M-H] - Calcd for C 15 H 14 FO 2245.0983; Found 245.0981. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 6.6 min, t major = 5.4 min).

[0156] Compound I-104; 1 H NMR (500 MHz, CDC13) δ 7.70 (d, J = 8.3 Hz, 2H), 7.37 - 7.22 (m, 4H), 7.22 - 7.11 (m, 2H), 7.06 - 6.88 (m, 4H), 4.54 - 4.27 (m, 1H), 3.78 (d, J = 8.2 Hz, 1H), 2.44 (s, 3H), 1.15 (d, J = 6.2 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 161.5 (d, 1 J C-F = 245.5 Hz), 148.3, 145.4, 140.3, 137.7, 137.7, 132.4, 129.8, 129.7, 129.6, 129.6, 128.4, 122.6, 115.6, 115.4, 69.9, 58.6, 21.7, 21.6. 19 F NMR (471 MHz, CDC13) δ -115.9. HRMS (ESI) m / z: [M-H] - Calcd for C 22 H 20 FO4S 399.1072; Found 399.1072. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 80:20, v = 1 mL / min -1 , λ = 240.0 nm; t minor = 11.6 min, tmajor = 9.9 min).

[0157] Compound 1-105; 1 H NMR (500 MHz, CDC13) δ 7.67 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.24 - 7.14 (m, 4H), 6.98 (t, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.98 - 5.47 (m, 1H), 4.96 (d, J = 7.6 Hz, 1H), 4.18 - 4.05 (m, 1H), 4.01 (d, J = 10.1 Hz, 1H), 2.44 (s, 3H), 1.42 (s, 9H), 1.19 (d, J = 6.2 Hz, 3H), 0.78 (d, J = 7.2 Hz, 3H). 13 C{1H} NMR (126 MHz, CDC13) δ 172.6, δ 161.7 (d, 1 J C-F = 246.3 Hz), 154.9, 148.3, 145.3, 140.2, 136.3, 132.4, 129.7, 129.5, 129.4, 129.1, 128.3, 122.4, 115.8, 115.6, 79.7, 72.7, 56.3, 49.0, 28.2, 21.6, 19.1, 18.0. 19 F NMR (471 MHz, CDC13) δ -115.2. HRMS (ESI) m / z: [M + CI] - Calcd for C 30 H 34 FNO7S CI 606.1729; Found 606.1741.

[0158] Compound 1-107; 1 H NMR (500 MHz, CDC13) δ 7.67 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.24 - 7.14 (m, 4H), 6.98 (t, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.98 - 5.47 (m, 1H), 4.96 (d, J = 7.6 Hz, 1H), 4.18 - 4.05 (m, 1H), 4.01 (d, J = 10.1 Hz, 1H), 2.44 (s, 3H), 1.42 (s, 9H), 1.19 (d, J = 6.2 Hz, 3H), 0.78 (d, J = 7.2 Hz, 3H). 13C {1H} NMR (126 MHz, CDC13) δ 171.4, 168.5, 161.7 (d, J = 246.1 Hz), 155.3, 148.6, 148.2, 145.3, 140.4, 140.0, 136.1, 136.1, 132.3, 130.1, 129.7, 129.5, 129.4, 129.1, 128.3, 122.3, 115.7, 115.6, 109.4, 73.1, 56.2, 56.0, 47.7, 21.6, 18.9, 17.5. 1 J C-F = 246.1 Hz), 159.4, 148.3, 146.6, 145.3, 141.3, 140.1, 137.4, 136.3, 136.3, 132.3, 129.7, 129.6, 129.5, 129.2, 128.3, 122.4, 115.8, 115.6, 109.8, 72.9, 56.3, 56.2, 47.7, 21.6, 20.7, 19.0, 18.0. 19 F NMR (471 MHz, CDC13) δ -115.2. HRMS (ESI) m / z: [M + H] + Calcd for C 32 H 32 FN2O8S 623.1858; Found 623.1851.

[0159] Compound I-108; 1 H NMR (500 MHz, CDC13) δ 8.40 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 - 7.10 (m, 4H), 7.07 - 6.92 (m, 3H), 6.88 (d, J = 8.7 Hz, 2H), 5.80 - 5.58 (m, 1H), 4.65 - 4.40 (m, 1H), 4.02 (d, J = 9.8 Hz, 1H), 3.91 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H), 1.20 (d, J = 6.2 Hz, 3H), 0.92 (d, J = 7.2 Hz, 3H). 13 C {1H} NMR (126 MHz, CDC13) δ 171.4, 168.5, 161.7 (d, J = 246.1 Hz), 155.3, 148.6, 148.2, 145.3, 140.4, 140.0, 136.1, 136.1, 132.3, 130.1, 129.7, 129.5, 129.4, 129.1, 128.3, 122.3, 115.7, 115.6, 109.4, 73.1, 56.2, 56.0, 47.7, 21.6, 18.9, 17.5. 1 J C-F = 246.1 Hz), 159.4, 148.3, 146.6, 145.3, 141.3, 140.1, 137.4, 136.3, 136.3, 132.3, 129.7, 129.6, 129.5, 129.2, 128.3, 122.4, 115.8, 115.6, 109.8, 72.9, 56.3, 56.2, 47.7, 21.6, 20.7, 19.0, 18.0. 19F NMR (471 MHz, CDC13) δ -115.3. HRMS (ESI) m / z: [M + H] + Calcd for C 34 H 34 FN2O9S665.1964;Found 665.1954.

[0160] Example 2

[0161] Preparation of BRL-15572 analogues of Glaxo Group Ltd:

[0162]

[0163] S1, To a solution of compound (R)-I-51 or (S)-I-51' prepared in example 51 (208.6 mg, 0.8 mmol) in methanol (8 mL) was added NaBH4(45.4 mg, 1.2 mmol) and stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate / dichloromethane 5:1:5 to 2:1:2) to give the reduced product SI-51.

[0164]

[0165] S2, In a 25 mL round flask with magnetic stirring, SI-51 (26.3 mg, 0.1 mmol), piperazine 2-110 (29.5 mg, 25 uL, 0.15 mmol), K2CO3(55.3 mg, 0.2 mmol) and KI (3.3 mg, 0.02 mmol) were added successively in acetonitrile (1 mL) and the reaction mixture was stirred at 90 °C for 24 h. After concentration under vacuum, the product 2-111 was directly purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 2:1 to 1:1) to give the BRL-15572 analogue.

[0166] The characterization data of the BRL-15572 analogue are as follows:

[0167] Compound (R,S)-2-111 was obtained as a white foamy solid with an isolated yield of 93% (39.2 mg), 92% ee, 1H NMR (500 MHz, CDC13) δ 7.69 - 6.99 (m, 8H), 6.99 - 6.51 (m, 5H), 4.68 - 4.25 (m, 1H), 3.79 (d, J = 8.1 Hz, 1H), 3.44 - 2.96 (m, 4H), 2.92 - 2.65 (m, 2H), 2.62 - 2.44 (m, 2H), 2.43 - 2.22 (m, 2H). 13 C{1H} NMR (126 MHz, CDC13) δ 154.4, 152.1, 141.9, 134.9, 133.8, 130.0, 129.3, 128.6, 128.5, 126.5, 119.5, 115.8, 115.5, 113.9, 68.6, 62.5, 55.8, 52.9, 48.7. HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 28 ClN2O2 423.1834; Found 423.1826. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 9.1 min, t major = 10.8 min).

[0168] Compound (R,R)-2-111 was a white foamy solid with an isolated yield of 98% (41.4 mg), 92% ee, 1 H NMR (500 MHz, CDC13) δ 7.34 - 7.08 (m, 4H), 6.91 - 6.70 (m, 1H), 6.64 (d, J = 8.5 Hz, 1H), 4.57 - 4.33 (m, 1H), 3.78 (d, J = 8.4 Hz, 1H), 3.33 - 2.97 (m, 2H), 2.88 - 2.63 (m, 1H), 2.54 - 2.43 (m, 1H), 2.41 - 2.26 (m, 1H). 13C {1H} NMR (126 MHz, CDC13) δ 154.4, 152.1, 142.0, 134.9, 133.4, 130.0, 129.6, 128.7, 128.1, 126.6, 119.5, 115.8, 115.5, 113.9, 68.5, 62.5, 56.0, 52.9, 48.7. HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 28 ClN2O2 423.1834; Found 423.1826. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 13.4 min, t major = 7.7 min).

[0169] Compound (S,R)-2-111 was a white foamy solid with an isolated yield of 96% (40.4 mg), 92% ee, 1 H NMR (500 MHz, CDC13) δ 7.69 - 6.99 (m, 8H), 6.99 - 6.51 (m, 5H), 4.68 - 4.25 (m, 1H), 3.79 (d, J = 8.1 Hz, 1H), 3.44 - 2.96 (m, 4H), 2.92 - 2.65 (m, 2H), 2.62 - 2.44 (m, 2H), 2.43 - 2.22 (m, 2H). 13 C {1H} NMR (126 MHz, CDC13) δ 154.4, 152.1, 141.9, 134.9, 133.8, 130.0, 129.3, 128.6, 128.5, 126.5, 119.5, 115.8, 115.5, 113.9, 68.6, 62.5, 55.8, 52.9, 48.7. HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 28ClN2O2 423.1834; Found 423.1826. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 10.8 min, t major = 9.0 min).

[0170] Compound (S,S)-2-111 was a white foamy solid with an isolated yield of 98% (41.4 mg), 93% ee, 1 H NMR (500 MHz, CDC13) δ 7.34 - 7.08 (m, 4H), 6.91 - 6.70 (m, 1H), 6.64 (d, J = 8.5 Hz, 1H), 4.57 - 4.33 (m, 1H), 3.78 (d, J = 8.4 Hz, 1H), 3.33 - 2.97 (m, 2H), 2.88 - 2.63 (m, 1H), 2.54 - 2.43 (m, 1H), 2.41 - 2.26 (m, 1H). 13 C{1H} NMR (126 MHz, CDC13) δ 154.4, 152.1, 142.0, 134.9, 133.4, 130.0, 129.6, 128.7, 128.1, 126.6, 119.5, 115.8, 115.5, 113.9, 68.5, 62.5, 56.0, 52.9, 48.7. HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 28 ClN2O2 423.1834; Found 423.1826. The ee value was determined by the chiral HPLC analysis (CHIRALPAK IA, n-hexane / 2-propanol = 70:30, v = 1 mL / min -1 , λ = 254.0 nm; t minor = 7.7 min, t major = 13.5 min).

[0171] Thus, the chiral α,α-diaryl ketone compound prepared by the present application can be used to synthesize a fungicide of pyridinamide analog and an analog of BRL-15572 of GlaxoSmithKline Company. The application of the chiral α,α-diaryl ketone compound of the present application is not limited to the above, and can also be used for structural modification of natural products and preparation of 2-(diarylmethyl)oxirane.

[0172] The above is the detailed description of the embodiments of the present application, but the present application is not limited to the above-described embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present application.

Claims

1. A chiral α,α-diaryl ketone compound, characterized in that, It has the structure shown in Equation I: R1 is selected from naphthyl, anthracene, quinolinyl, unsubstituted or substituted with one or more methyl groups, methoxy groups, F, Cl, Br, I, phenyl, C 2～10 The alkynyl group, nitro group, cyano group, trifluoromethanesulfonic acid group, C 2～10 ester group, aldehyde group, C 2～10 ketone group, C 1～6 Halogenated alkyl-substituted phenyl groups; R2 is selected from naphthyl, C 4～7 ester group, C 7～15 C18, alkynyl, unsubstituted or substituted with one or more F, Cl, Br, phenyl, or dimethyl tert-butylsilyl ether groups. 1～10 Alkyl, unsubstituted or with one or more C 1～6 alkyl, C 1～6 alkoxy, phenyl, C 2～6 Alkenyl, F, Cl, Br-substituted phenyl groups; R3 is selected from H.

2. The chiral α,α-diaryl ketone compound according to claim 1, characterized in that, The chiral α,α-diaryl ketones are selected from the following structures:

3. The method for preparing chiral α,α-diaryl ketone compounds according to claim 1 or 2, characterized in that, Includes the following steps: S1. Compound 1, Compound 3 and solvent are reacted under visible light irradiation to obtain an intermediate; S2. The intermediate, compound 2 and chiral phosphoric acid catalyst are mixed and reacted to obtain chiral α,α-diaryl ketone compounds; The structural formulas of compounds 1, 2, and 3 are as follows: R4 and R5 are independently selected from C 1～6 Alkyl and benzyl groups; The solvent is selected from at least one of chlorobenzene, dichloromethane, tetrahydrofuran, acetonitrile, toluene, or dichloroethane; The chiral phosphoric acid catalyst is selected from one of the following structural formulas: The wavelength of the visible light is 400nm to 600nm.

4. The method for preparing chiral α,α-diaryl ketone compounds according to claim 3, characterized in that, Compound 2 is selected from one of the following structures:

5. The method for preparing chiral α,α-diaryl ketone compounds according to claim 3, characterized in that, The reaction temperature is -78℃ to 25℃.

6. The method for preparing chiral α,α-diaryl ketone compounds according to claim 3, characterized in that, In step S2, the raw materials for the preparation of the reaction also include Molecular sieves.

7. The use of the chiral α,α-diaryl ketone compound of claim 1 or 2 in the preparation of pyridoxine, diaryl propylene oxide or human 5-HT1D receptor antagonist analogues.

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