A method for synthesizing axially chiral biaryl quinoline nitroxide compounds

Abstract

The application discloses a synthesis method of an axially chiral biaryl quinoline nitrogen oxygen compound and belongs to the field of organic chemistry. With racemic 1-aryl isoquinoline nitrogen oxide 1 and acrylic ester 2 as raw materials, palladium trifluoroacetate / N-acetyl-L-alanine as a catalyst, silver carbonate as an oxidant, 1,4-p-benzoquinone and trifluoroethanol as additives, asymmetric alkenylization reaction occurs in 1,2-dichloroethane / acetonitrile mixed solvents, and two types of axially chiral biaryl quinoline nitrogen oxygen compounds are obtained. The kinetic resolution method has the advantages of good resolution effect (up to 102.7), high yield and high enantioselectivity (up to 99%), and the like, and the remaining raw material can be derived through two steps to obtain a commercial (R)-QUINAP ligand.

Description

TECHNICAL FIELD

[0001] The application relates to a synthesis method of an axially chiral biaryl quinoline nitrogen oxide compound and belongs to the field of asymmetric synthesis in organic chemistry. BACKGROUND

[0002] The skeleton of the axially chiral biaryl quinoline and derivatives thereof is widely present in natural products, drugs, chiral ligands and catalyst structures, for example, Korupensamine A and Dioncophylline C with anti-malaria activity, HIV integrase inhibitor BI 224436, chiral ligand IAN, QUI NAP, QUINOX, chiral phosphoric acid catalyst and the like.

[0003] In recent years, the synthesis methods of the axially chiral biaryl compound mainly include coupling strategies, cyclization strategies, (dynamic) kinetic resolution strategies and desymmetrization strategies. The axially chiral biaryl quinoline nitrogen oxide is an important precursor of the axially chiral biaryl quinoline compound, but the synthesis method of the compound is relatively less reported.

[0004] Therefore, it is of important research significance to find a simple and efficient way to synthesize the compound with high enantioselectivity. SUMMARY

[0005] In order to solve the above technical problems, the application discloses a new method for synthesizing a series of axially chiral biaryl quinoline nitrogen oxide compounds by realizing kinetic resolution through asymmetric alkenylation reaction; the method has the advantages of good resolution effect (up to 102.7), high yield and enantioselectivity (up to 99% ee) and the like, and the remaining raw material can be derived through two steps to obtain a commercialized (R)-QUINAP ligand with good yield and basically unchanged ee value.

[0006] The synthesis method of the axially chiral biaryl quinoline nitrogen oxide compound comprises the following steps: taking racemic 1-aryl isoquinoline nitrogen oxide 1 and olefin compound 2 as raw materials, in the presence of an oxidant and an additive, under the catalysis of a metal palladium / N-substituted-L-amino acid in an organic solvent, alkenylation reaction occurs to obtain an axially chiral alkenylation product 3 and remaining raw material S-1. The reaction equation is as follows:

[0007]

[0008] R1, R2 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen; R3 is selected from C1-C4 alkyl, phenyl, benzyl,

[0009] Further, in the above technical solution, R1 is selected from hydrogen, methyl, isopropyl, methoxy, chlorine atom; R2 is selected from hydrogen, methyl, methoxy, fluorine atom; R3 is selected from methyl ester, ethyl ester, isopropyl ester, phenyl ester, benzyl ester, phenyl sulfone,

[0010] Further, in the above technical solution, the organic solvent is selected from one or more of 1,2-dichloroethane, acetonitrile, tetrahydrofuran, toluene or ethylene glycol dimethyl ether. Preferably, the organic solvent is a mixed solvent of 1,2-dichloroethane and acetonitrile.

[0011] Further, in the above technical solution, the palladium catalyst is selected from Pd(TFA)2, PdCl2, PdCl2(CH3CN)2, Pd(dppp)Cl2 or Pd(dba)2. Preferably, the palladium catalyst is Pd(TFA)2.

[0012] Further, in the above technical solution, the N-substituted-L-amino acid is selected from N-Boc-L-valine, N-Boc-L-phenylalanine, N-Boc-L-tert-leucine, N-Boc-L-alanine, N-acetyl-L-valine, N-acetyl-L-alanine, N-acetyl-L-phenylalanine or L-alanine. Preferably, the N-substituted-L-amino acid is N-acetyl-L-alanine.

[0013] Further, in the above technical solution, the oxidant is selected from copper acetate, silver chloride, silver trifluoroacetate, silver acetate or silver carbonate. Preferably, the oxidant is silver carbonate.

[0014] Further, in the above technical solution, the additive includes additive 1 and additive 2, wherein: additive 1 is selected from 1,4-benzoquinone, 1,4-naphthoquinone, methyl-p-benzoquinone, 2,6-dimethyl-p-benzoquinone or 2,6-dimethoxy-p-benzoquinone; additive 2 is selected from methanol, ethanol, isopropanol, trifluoroethanol or hexafluoroisopropanol. Preferably, the additive is selected from 1,4-benzoquinone and trifluoroethanol.

[0015] Further, in the above technical solution, the recovered high ee value raw material can be further derived into commercial (R)-QUINAP ligand.

[0016] For example: the recovered high ee value raw material 1a reacts with NIS to obtain iodinated product 4, and then reacts with diphenylphosphine to obtain product, which is commercial (R)-QUINAP ligand. The reaction equation is as follows:

[0017]

[0018] Inventive beneficial effects:

[0019] The application provides a new method for synthesizing axially chiral biaryl quinoline nitrogen oxide compounds, and has good reaction resolution effect and generally high enantioselectivity, and the high ee value raw material recovered after further derivation can obtain expensive commercial (R)-QUINAP ligand. DETAILED DESCRIPTION

[0020] Example 1

[0021] rac-1-naphthyl isoquinoline nitrogen oxide 1a and n-butyl acrylate 2a as raw materials, the reaction equation is as follows:

[0022]

[0023] The specific reaction results are shown in the following table:

[0024]

[0025] [a] Unless otherwise specified, the reaction conditions are as follows: (rac)-1a (0.1 mmol), 2a (0.3 mmol), metal palladium (10 mol%), ligand (15 mol%), silver carbonate (2 eq), solvent (0.1 M), and reaction temperature is 80°C.[b] The ee value is determined by high performance liquid chromatography.[c] Conversion C = ee 1a + ee 1a + ee 3aa ).[d] Resolution factor s = ln[(1-C)(1-ee 1a ) / ln[(1-C)(1+ee 1a )].[e] BQ (20 mol%) is added.[f] BQ (20 mol%) and TFE (5 eq) are added.

[0026] In the reaction condition screening process, first, the effects of different organic solvents on the reaction are investigated (entry 1-4). Then, the effects of different metal palladium, ligand and additive on the reaction are investigated, and finally Pd(TFA)2(10 mol%) / L8(15 mol%) is determined as the catalyst, silver carbonate (2 eq) is determined as the oxidant, 1,4-benzoquinone (20 mol%) and trifluoroethanol (5 eq) are determined as the additive, and DCE / CH3CN (3:2) is determined as the solvent.

[0027] After adding racemic 1-naphthylisoquinoline nitrogen oxide raw material 1a (0.1 mmol, 27.1 mg), N-acetyl-L-alanine (2.0 mg, 0.015 mmol), palladium trifluoroacetate (3.3 mg, 0.01 mmol), 1,4-benzoquinone (2.2 mg, 0.02 mmol) and silver carbonate (55.2 mg, 0.2 mmol) in a test tube in turn, the reaction tube was moved into the fume hood, 0.6 mL of 1,2-dichloroethane and 0.4 mL of acetonitrile solution were taken into the reaction tube with a pipette, then n-butyl acrylate 2a (43 μL, 0.3 mmol) and trifluoroethanol (36 μL, 0.5 mmol) were added with a pipette, and then the reaction tube was placed in an 80°C oil bath for 5 hours. After the reaction was completed, the reaction tube was taken out, the reaction solution was filtered through diatomite, concentrated under reduced pressure, and separated and purified by wet column to obtain the target product 3aa (45% yield, 93% ee) and the remaining raw material S-1a (46% yield, 95% ee) after resolution. The data of the target product 3aa are as follows: foam solid, 17.7 mg, m.p.: 77.2-79.6°C, R f = 0.52 (EtOAc / MeOH, 50 / 1, v / v). HPLC CHIRALCEL IA, n-hexane / 2-propanol = 70 / 30, flow rate = 0.8 mL / min, λ = 250 nm, retention time: 19.930 min, 23.317 min. [α] D 25 = -93.02 (c = 0.334, CH2Cl2). 1 H NMR (600 MHz, CDCl3) δ 8.37 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.58-7.45 (m, 2H), 7.41-7.29 (m, 2H), 7.24 (d, J = 16.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 4.09-3.97 (m, 2H), 1.59-1.46 (m, 2H), 1.32-1.18 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDC13) δ 166.5, 143.2, 141.1, 137.6, 134.4, 132.2, 131.6, 130.4, 130.3, 130.0, 129.8, 128.6, 128.6, 127.8, 127.5, 127.2, 125.6, 124.9, 124.4, 123.2, 121.2, 64.3, 30.6, 19.1, 13.7. HRMS (ESI): exact mass calcd for C 26 H 23 NNaO3 + (M+Na) + requires m / z 420.1570, found m / z 420.1565. The recovered starting material S-1a was characterized as follows: foamy solid, 12.4 mg, R f = 0.28 (EtOAc / MeOH, 25 / 1, v / v). HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 13.657 min, 18.048 min. [a] D 25 = +330.14 (c = 0.230, CH2Cl2). 1 HNMR (400 MHz, CDC13) δ 8.37 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.61 - 7.46 (m, 3H), 7.44 - 7.33 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 145.5, 137.5, 133.8, 131.4, 130.3, 130.0, 129.2, 128.9, 128.9, 128.7, 128.4, 128.4, 127.0, 126.9, 126.4, 125.6, 125.1, 123.8. HRMS (ESI): exact mass calcd for C 19 H 14 NO + (M+H) +found m / z 272.1071.

[0028] Example 2

[0029]

[0030] After adding racemic starting material 1b (0.1 mmol, 27.1 mg), palladium trifluoroacetate (3.3 mg, 0.01 mmol), N-acetyl-L-alanine (2.0 mg, 0.015 mmol), silver carbonate (55.2 mg, 0.2 mmol) and 1,4-benzoquinone (2.2 mg, 0.02 mmol) in a test tube in turn, the reaction tube was moved into a fume hood, 0.6 mL of 1,2-dichloroethane and 0.4 mL of acetonitrile solution were taken into the reaction tube by using a pipette, then n-butyl acrylate 2a (43 μL, 0.3 mmol) and trifluoroethanol (36 μL, 0.5 mmol) were added by using a pipette, and then the reaction tube was placed in an 80 °C oil bath for 5 hours. After the reaction was completed, the reaction tube was taken out, the reaction solution was filtered through diatomite, concentrated under reduced pressure, and then wet column separation and purification were carried out to obtain the target product 3ba (48% yield, 87% ee) and the remaining starting material S-1b (40% yield, 96% ee) after resolution. The data of the target product 3ba are as follows: foamy solid, 19.6 mg, m.p.: 192.7-194.3 °C, Rf = 0.52 (EtOAc / MeOH, 50 / 1, v / v). HPLC CHIRALCEL IA, n-hexane / 2-propanol = 70 / 30, flow rate = 0.8 mL / min, λ = 250 nm, retention time: 17.573 min, 25.713 min. [α] f = -102.37 (c = 0.394, CH2Cl2). D 25 = -102.37 (c = 0.394, CH2Cl2). 1H NMR (600 MHz, CDC13) δ 8.38 (d, J = 7.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.57 - 7.50 (m, 2H), 7.38 - 7.31 (m, 2H), 7.22 (d, J = 15.6 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 4.08 - 3.98 (m, 2H), 2.81 (s, 3H), 1.57 - 1.48 (m, 2H), 1.30 - 1.20 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). 13 C NMR (150 MHz, CDC13) δ 166.5, 143.4, 141.2, 137.6, 137.0, 133.8, 131.7, 131.6, 130.5, 129.7, 128.6, 128.4, 127.4, 127.4, 127.1, 126.2, 125.0, 124.8, 124.3, 123.8, 120.9, 64.3, 30.6, 19.9, 19.1, 13.7. HRMS (ESI): exact mass calcd for C 27 H 25 NNaO3 + (M+Na) + requires m / z 434.1727, found m / z 434.1723. Recovered starting material 1b was characterized as follows: foamy solid, 11.3 mg, R f = 0.26 (EtOAc / MeOH, 25 / 1, v / v). HPLC CHIRALCEL AD, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 7.667 min, 16.903 min. [a] D 25 = +356.46 (c = 0.222, CH2Cl2). 1H NMR (600 MHz, CDC13) δ 8.36 (d, J = 7.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.57 - 7.48 (m, 3H), 7.44 - 7.35 (m, 3H), 7.26 (dd, J = 18.0, 8.4 Hz, 2H), 2.81 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 145.9, 137.0, 136.8, 133.1, 131.4, 130.6, 129.2, 128.9, 128.4, 128.2, 127.3, 126.9, 126.8, 126.5, 125.9, 125.8, 124.9, 123.7, 19.8. HRMS (ESI): exact mass calcd for C 20 H 16 NO + (M+H) + requires m / z 286.1226, found m / z 286.1225.

[0031] Example 3

[0032]

[0033] From starting materials 1h and 2a, under the same reaction conditions as described above, the target product 3ha (45% yield, 94% ee) and the remaining starting material S-1h (52% yield, 82% ee) were obtained. The data of the target product 3ha are as follows: foam-like solid, 19.4 mg, m.p.: 203.5-204.7 °C, R f = 0.60 (EtOAc / MeOH, 50 / 1, v / v). HPLC CHIRALCEL AD, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 14.443 min, 21.577 min. [α] D 25 = -107.22 (c = 0.388, CH2Cl2). 1H NMR (400 MHz, CDC13) δ 8.39 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.93 (t, J = 8.4 Hz, 2H), 7.88 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.57 - 7.48 (m, 1H), 7.39 - 7.28 (m, 2H), 7.20 (d, J = 16.0 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 15.6 Hz, 1H), 4.13 - 3.96 (m, 2H), 1.61 - 1.48 (m, 2H), 1.35 - 1.19 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 166.5, 143.4, 140.9, 138.9, 135.0, 134.5, 132.4, 131.6, 130.8, 130.8, 129.3, 129.2, 128.9, 128.8, 128.0, 127.7, 126.6, 126.2, 125.5, 123.4, 123.3, 121.5, 64.5, 30.7, 19.2, 13.8. HRMS (ESI): exact mass calcd for C 26 H 22 ClNNaO3 + (M+Na) + requires m / z 454.1180, found m / z 454.1175. The recovered starting material S-1h was characterized as follows: foamy solid, 14.0 mg, Rf = 0.34 (EtOAc / MeOH, 25 / 1, v / v). HPLC CHIRALCEL AD, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 7.720 min, 9.473 min. [α] f = +239.09 (c = 0.278, CH2Cl2). D 25 = +239.09 (c = 0.278, CH2Cl2). 1H NMR (600 MHz, CDC13) δ 8.35 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.53 - 7.48 (m, 2H), 7.42 - 7.36 (m, 1H), 7.31 (dd, J = 9.0, 1.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H). 13 C NMR (150 MHz, CDC13) δ 145.6, 138.7, 134.6, 133.9, 131.3, 130.3, 130.1, 129.5, 128.8, 128.8, 128.5, 128.4, 127.3, 127.2, 126.6, 125.9, 125.6, 125.0, 122.8. HRMS (ESI): exact mass calcd for C 19 H 13 Cl NO + (M+H) + requires m / z 306.0680, found m / z 306.0679.

[0034] Example 4

[0035]

[0036] Starting from the starting materials 1j and 2a under the same reaction conditions as described above, the target product 3ja (46% yield, 92% ee) and the remaining starting material S-1j (45% yield, 95% ee) were obtained. The data of the target product 3ja are as follows: foamy solid, 19.7 mg, m.p.: 169.6-171.2 °C, Rf = 0.44 (EtOAc / MeOH, 50 / 1, v / v). HPLC CHIRALCEL AD, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 254 nm, retention time: 10.784 min, 14.906 min. [α] f D 25 = -172.12 (c = 0.342, CH2Cl2). 1 ​H NMR (600 MHz, CDC13) δ 8.35 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.61 - 7.55 (m, 2H), 7.43 - 7.37 (m, 1H), 7.25 - 7.21 (m, 2H), 7.20 - 7.15 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 15.6 Hz, 1H), 4.11 - 3.97 (m, 2H), 2.49 (s, 3H), 1.57 - 1.49 (m, 2H), 1.30 - 1.20 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). 13 C NMR (150 MHz, CDC13) δ 166.3, 160.0, (d, J = 255.0 Hz), 142.4, 140.4, 139.4, 137.7, 133.3 (d, J = 4.5 Hz), 132.9 (d, J = 9.0 Hz), 132.2, 129.0, 128.8 (d, J = 9.0 Hz), 127.9, 126.5, 126.3 (d, J = 3.0 Hz), 125.7 (d, J = 3.0 Hz), 125.2, 125.1, 124.8, 124.0, 121.8, 121.4 (d, J = 4.5 Hz), 106.9 (d, J = 21.0 Hz), 64.5, 30.7, 21.8, 19.2, 13.8. 19 F NMR (565 MHz, CDC13) δ -120.0. HRMS (ESI): exact mass calcd for C 27 H 25 FNO3 + (M+H) + requires m / z 430.1813, found m / z 430.1812. The recovered starting material S-1j was characterized as follows: foamy solid, 13.7 mg, R f = 0.25 (EtOAc / MeOH, 25 / 1, v / v). HPLC CHIRALCEL AD, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 254 nm, retention time: 7.263 min, 9.643 min. [a] D 25 = +321.94 (c = 0.234, CH2CI2). 1H NMR (600 MHz, CDC13) δ 8.34 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.64 (s, 1H), 7.59 - 7.54 (m, 1H), 7.49 - 7.41 (m, 2H), 7.33 (dd, J = 10.2, 7.8 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.12 (d, J = 9.0 Hz, 1H), 2.49 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 159.8 (d, J = 253.5 Hz), 144.7, 139.1, 137.5, 132.9 (d, J = 4.5 Hz), 131.6, 129.3, 128.6, 128.6 (d, J = 9.0 Hz), 128.0, 126.8, 126.2, 125.4, 125.2 (d, J = 3.0 Hz), 125.0 (d, J = 4.5 Hz), 124.2 (d, J = 16.5 Hz), 123.4, 121.3 (d, J = 6.0 Hz), 109.5 (d, J = 21.0 Hz), 21.7. 19 F NMR (565 MHz, CDC13) δ -120.2. HRMS (ESI): exact mass calcd for C 20 H 15 FNO + (M+H) + requires m / z 304.1132, found m / z 304.1132.

[0037] Example 5

[0038]

[0039] The target product 3la (44% yield, 89% ee) and the remaining starting material S-ll (43% yield, 94% ee) after resolution were obtained from starting materials 11 and 2a under the same reaction conditions as described above. The target product 3la data were characterized as follows: foam-like solid, 20.6 mg, m.p.: 184.0-185.8 °C, Rf = 0.42 (EtOAc / MeOH, 50 / 1, v / v). HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 28.265 min, 48.893 min. [α] f D 25 ​= + 114.57 (c = 0.302, CH2Cl2). 1 H NMR (400 MHz, CDC13) δ 8.64 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.18 - 8.10 (m, 3H), 8.01 (t, J = 7.6 Hz, 1H), 7.98 - 7.86 (m, 3H), 7.59 - 7.47 (m, 2H), 7.38 - 7.28 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 15.6 Hz, 1H), 4.15 - 4.02 (m, 2H), 1.63 - 1.51 (m, 2H), 1.33 - 1.26 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 166.5, 143.8, 142.0, 137.8, 132.5, 132.1, 131.4, 131.1, 130.7, 130.3, 129.9, 129.4, 129.2, 128.7, 128.7, 127.4, 127.2, 126.9, 126.2, 126.1, 126.0, 125.8, 125.1, 124.5, 124.5, 124.4, 123.0, 121.7, 64.4, 30.7, 19.2, 13.8. HRMS (ESI): exact mass calcd for C 32 H 26 NO3 + (M+H) + requires m / z 472.1907, found m / z 472.1897. The recovered starting material S-1l was characterized as follows: foam-like solid, 15.0 mg, m.p.: 239.9-242.6 °C, R f = 0.18 (EtOAc / MeOH, 25 / 1, v / v). HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 21.883 min, 29.523 min. [α] D 25 = + 179.67 (c = 0.200, CH2Cl2). 1H NMR (400 MHz, CDC13) δ 8.45 (d, J = 7.2 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.21 - 8.14 (m, 3H), 8.08 - 7.98 (m, 3H), 7.86 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.37 - 7.31 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 145.9, 137.7, 132.5, 131.2, 131.0, 130.6, 129.9, 129.3, 129.0, 128.8, 128.6, 128.4, 127.9, 127.4, 127.0, 126.3, 125.8, 125.8, 125.7, 125.1, 124.8, 124.5, 123.9. HRMS (ESI): exact mass calcd for C 25 H 16 NO + (M+H) + requires m / z 346.1226, found m / z 346.1221.

[0040] Example 6

[0041]

[0042] Starting from the starting materials la and 2b under the same reaction conditions as described above, the target product 3ab (42% yield, 91% ee) and the remaining starting material S-la (44% yield, 94% ee) were obtained. The data of the target product 3ab are as follows: foamy solid, 15.0 mg, m.p.: 176.2-177.9 °C, Rf = 0.30 (EtOAc / MeOH, 50 / 1, v / v). HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 32.407 min, 39.073 min. [α] f D 24 = -92.22 (c = 0.300, CH2Cl2). 1 ​H NMR (400 MHz, CDC13) δ 8.38 (d, J = 7, 2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.95 - 7.80 (m, 4H), 7.57 - 7.46 (m, 2H), 7.39 - 7.30 (m, 2H), 7.27 (d, J = 16.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 3, 64 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 166.9, 143.1, 141.4, 137.6, 134.5, 132.2, 131.6, 130.5, 130.4, 130.0, 129.8, 128.7, 128.6, 128.6, 127.8, 127.6, 127.2, 125.7, 124.9, 124.5, 123.2, 120.8, 51.7. HRMS (ESI): exact mass calcd for C 23 H 17 NNaO3 + (M+Na) + requires m / z 378.1101, found m / z 378.1096. The recovered starting material S-1a was characterized as follows: foamy solid, 11.8 mg, HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 13.760 min, 18.122 min. [α] D 24 = +322.88 (c = 0.236, CH2CI2).

[0043] Example 7

[0044]

[0045] The target product 3af (38% yield, 91% ee) and the remaining starting material S-1a (44% yield, 91% ee) were obtained under the same reaction conditions described above starting from 1a and 2f. The target product 3af was characterized as follows: foamy solid, 16.5 mg, m.p.: 197.2-198.8 °C, R f= 0.44 (EtOAc / MeOH, 50 / 1, v / v). HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 60 / 40, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 28.785 min, 35.675 min.[α] D 25 = -82.02 (c = 0.330, CH2Cl2). 1 H NMR (600 MHz, CDC13) δ 8.38 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.93 (t, J = 9.0 Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.41 - 7.28 (m, 6H), 7.24 (d, J = 7.2 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.59 (d, J = 15.6 Hz, 1H), 5.14 - 5.05 (m, 2H). 13 C NMR (150 MHz, CDC13) δ 166.2, 143.2, 141.8, 137.7, 136.0, 134.6, 132.1, 131.7, 130.5, 130.4, 130.2, 129.9, 128.7, 128.6, 128.6, 128.2, 128.0, 127.9, 127.6, 127.2, 125.7, 125.0, 124.5, 123.2, 120.7, 66.3. HRMS (ESI): exact mass calcd for C 29 H 21 NNaO3 + (M+Na) + requires m / z 454.1414, found m / z 454.1409. The recovered starting material S-la was characterized as follows: foam-like solid, 12.0 mg, HPLC CHIRALCEL OD-H, n-hexane / 2-propanol = 70 / 30, flow rate = 1.0 mL / min, λ = 256 nm, retention time: 12.788 min, 16.902 min.[α] D 25 = +287.22 (c = 0.240, CH2Cl2).

[0046] Example 8

[0047] According to the reaction conditions in Example 2 above, only the reaction substrates and the reaction time of individual substrates were changed, and the following reaction results were obtained:

[0048]

[0049]

[0050] The above examples describe the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the scope of the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of protection of the present application.

Claims

1. A method for synthesizing axially chiral biarylquinoline nitrogen oxide compounds, characterized in that, The process includes the following steps: using racemic 1-arylisoquinoline 1 and olefin compound 2 as raw materials, an alkenylation reaction occurs in an organic solvent in the presence of an oxidant and additives, catalyzed by palladium / N-substituted-L-amino acid, to obtain an axially chiral alkenylated product 3 and the remaining raw material S-1; the reaction equation is as follows: Wherein: R1 and R2 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and halogen; R3 is selected from C1-C4 alkyl, phenyl, benzyl, ... , The palladium catalyst is selected from Pd(dppp)Cl2, Pd(TFA)2, PdCl2(CH3CN)2, PdCl2, or Pd(dba)2; the N-substituted L-amino acid is selected from... N -Boc-L-valine, N -Boc-L-phenylalanine, N -Boc-L-tert-leucine, N -Boc-L-alanine, N -acetyl-L-valine, N -acetyl-L-alanine, N - Acetyl-L-phenylalanine or L-alanine; the additives include additive 1 and additive 2, wherein: additive 1 is selected from 1,4-benzoquinone, 1,4-naphthoquinone, methyl-p-benzoquinone, 2,6-dimethyl-p-benzoquinone or 2,6-dimethoxy-p-benzoquinone; additive 2 is selected from methanol, ethanol, isopropanol, trifluoroethanol or hexafluoroisopropanol.

2. The method for synthesizing axially chiral biarylquinoline nitroxide compounds according to claim 1, characterized in that: The organic solvent is selected from one or more of 1,2-dichloroethane, acetonitrile, tetrahydrofuran, toluene, and ethylene glycol dimethyl ether.

3. The method for synthesizing axially chiral biarylquinoline nitroxide compounds according to claim 2, characterized in that: The organic solvent is selected from a mixture of 1,2-dichloroethane and acetonitrile.

4. The method for synthesizing axially chiral biarylquinoline nitroxide compounds according to claim 1, characterized in that: The oxidizing agent is selected from copper acetate, silver chloride, silver trifluoroacetate, silver acetate, or silver carbonate.

5. The method for synthesizing axially chiral biarylquinoline nitroxide compounds according to claim 1, characterized in that: The molar ratio of racemic 1-arylisoquinoline nitrogen oxide 1 to olefin compound 2 is 1:2-3.

6. The method for synthesizing axially chiral biarylquinoline nitroxide compounds according to claim 1, characterized in that: The reaction temperature is 60-90℃.

7. A kind of ( R The method for synthesizing )-QUINAP ligands is characterized by, Includes the following steps: The recovered raw material S-1a is obtained by any one of claims 1-6, and then the raw material S-1a reacts with NIS to obtain iodide product 4, which is then reacted with diphenylphosphine to obtain ( R )-QUINAP.

Images