A preparation method of a chiral sulfonamide synthesized by nickel-catalyzed asymmetric reduction and a chiral sulfonamide compound

Abstract

The application discloses a preparation method of chiral sulfonamide synthesized by nickel-catalyzed asymmetric reduction and a chiral sulfonamide compound. The preparation method comprises the following steps: using a proton as a hydrogen source, and under the action of a chiral nickel catalyst and a boron reagent, chiral sulfonamides with various substituents can be obtained, and the enantiomeric excess can reach 98%. The application has the advantages of simple and practical operation, high yield, high enantioselectivity, environmental friendliness, greenness, mild reaction conditions and potential practical application value.

Description

Technical Field

[0001] This application relates to a method for preparing chiral sulfonamides by nickel-catalyzed asymmetric reduction synthesis and a chiral sulfonamide compound, belonging to the field of asymmetric catalytic synthesis technology. Background Technology

[0002] Chiral sulfonamides are an important class of structural units, widely found in natural products and pharmaceutical active molecules. For example, the sulfonamide compound 3,5-difluorophenyl-γ-sulfonamide is a key starting material for the chiral compound MK-3207, used to treat migraines. Most routes for synthesizing sulfonamide compounds suffer from drawbacks such as low yields, large catalyst requirements, use of precious metals, and difficulty in controlling enantioselectivity. Therefore, developing a simple, efficient, high-yield, and highly enantioselective method for synthesizing chiral sulfonamides is a highly attractive research direction. Summary of the Invention

[0003] The purpose of this application is to provide a method for synthesizing chiral sulfonamides by nickel-catalyzed asymmetric reduction. Therefore, this application uses protons as the hydrogen source and successfully constructs chiral sulfonamides by nickel-catalyzed asymmetric reduction of sulfonylimide, providing an effective synthetic method for the synthesis of chiral sulfonamides.

[0004] This application is simple and practical to operate, the raw materials are readily available, the metal precursors are inexpensive, the yield is high, the enantioselectivity is high, and the reaction has the advantages of being green, atom-economical, and environmentally friendly.

[0005] To achieve the above objectives, this application uses protons as the hydrogen source, a chiral diphosphorus complex of nickel as the catalyst, and a sulfonamide compound as the substrate to synthesize chiral sulfonamides via nickel-catalyzed asymmetric reduction.

[0006] According to one aspect of this application, a method for preparing chiral sulfonamides by nickel-catalyzed asymmetric reduction is provided, the method comprising: reacting a mixture containing a compound of formula I, a nickel metal precursor, a catalyst, a hydrogen source, and a boron reagent to obtain a chiral sulfonamide of formula II;

[0007]

[0008]

[0009] Ar is selected from phenyl, naphthyl, and substituted phenyl groups;

[0010] R is selected from C1 to C2. 10 Alkyl, phenyl, naphthyl, substituted phenyl;

[0011] The substituents of the substituted phenyl group are independently selected from C1 to C6 alkyl, halogen, and methoxy groups;

[0012] X is selected from O or N.

[0013] Optionally, the hydrogen source is selected from at least one of water, methanol, ethanol, isopropanol, trifluoroethanol, and hexafluoroisopropanol.

[0014] Optionally, the molar ratio of the compound shown in Formula I to the hydrogen source is 1:1 to 1:50.

[0015] Optionally, the catalyst is a chiral bisphosphine ligand.

[0016] Optionally, the chiral bisphosphine ligand is selected from (R,S) p At least one of (S,S)-JosiPhos, (S,S)-f-Binaphane, (S)-SynPhos, (R,R)-Me-DuPhos, (R,S)-DuanPhos, (S,S)-Ph-BPE, (R,R)-QuinoxP*, and (S)-DifluorPhos.

[0017] Optionally, the nickel metal precursor is selected from at least one of nickel acetate, nickel trifluoromethanesulfonate, nickel chloride ethylene glycol dimethyl ether, nickel acetylacetone, nickel diiodide, and bis(1,5-cyclooctadiene) nickel.

[0018] Optionally, the boron reagent is selected from at least one of tetrahydroxydiboron, pinacol diborate, and bis(catechol)borate.

[0019] Optionally, the molar ratio of the compound shown in Formula I to the nickel metal precursor is 1:0.01 to 1:0.2.

[0020] Optionally, the molar ratio of the compound represented by Formula I to the catalyst is 1:0.01 to 1:0.2.

[0021] Optionally, the molar ratio of the compound shown in Formula I to the boron reagent is 1:1 to 1:5.

[0022] Optionally, the mixture further includes a solvent selected from at least one of water, toluene, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, trifluoroethanol, hexafluoroisopropanol, trifluorotoluene, and ethyl acetate.

[0023] Optionally, the molar volume ratio of the compound represented by Formula I to the solvent is 1:5 to 1:20 mol / L.

[0024] Optionally, the reaction temperature is 30–100°C, and the reaction time is 24–72 h.

[0025] Optionally, the temperature of the reaction is selected from any value of 30°C, 50°C, 60°C, 70°C, 80°C, 100°C, or a range between any two of the above points.

[0026] Optionally, the reaction time is selected from any value among 24h, 36h, 48h, 60h, and 72h, or a range between any two of the above points.

[0027] According to another aspect of this application, a chiral sulfonamide compound prepared by the preparation method described above is provided, having the structure shown in Formula II;

[0028]

[0029] In Formula II:

[0030] Ar is selected from phenyl, naphthyl, and substituted phenyl groups;

[0031] R is selected from C1 to C2. 10 Alkyl, phenyl, naphthyl, substituted phenyl;

[0032] The substituents of the substituted phenyl group are independently selected from C1 to C6 alkyl, halogen, and methoxy groups;

[0033] X is selected from O or N.

[0034] Optionally, the chiral sulfonamide compound is selected from any one of the structures shown in 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, and 2r;

[0035]

[0036] As a specific implementation method, this application is achieved through the following technical solution:

[0037] A method for synthesizing chiral sulfonamides, wherein the method uses protons as a hydrogen source, a nickel metal precursor and a chiral diphosphorus ligand complex as a catalyst, and a sulfonylimide compound as a substrate, to synthesize chiral sulfonamides via nickel-catalyzed asymmetric reduction. The reaction formula of the method is as follows:

[0038]

[0039] The specific reaction steps of the method are as follows:

[0040] (1) Add sulfonylimide compound as substrate, nickel metal precursor, chiral diphosphorus ligand, hydrogen source and boron reagent to the sealed tube, replace with nitrogen and add solvent, and stir the reaction at 30-100℃ for 12-48h.

[0041] (2) The solvent was removed under reduced pressure, and the chiral sulfonamide was obtained by column chromatography;

[0042] The molar ratio of sulfonamide to nickel metal precursor is 1:0.01-1:0.2; the molar ratio of sulfonamide to chiral bisphosphine ligand is 1:0.01-1:0.2; the molar ratio of sulfonamide to boron reagent is 1:1-1:5; and the molar ratio of sulfonamide to hydrogen source is 1:1-1:50.

[0043] The reaction is a nickel-catalyzed asymmetric reduction synthesis of chiral sulfonamides, where R is phenyl, X is oxygen, Ar is phenyl, the nickel metal precursor is nickel acetate, the chiral ligand is (R,R)-QuinoxP*, the boron reagent is tetrahydroxydiboron, the hydrogen source and organic solvent are both hexafluoroisopropanol, the temperature is 80℃, the reaction time is 24h, and the enantiomeric excess is 95%.

[0044] In this application, C1~C6, C1~C 10 "etc." refers to the number of carbon atoms contained in the group.

[0045] In this application, the term "alkyl" refers to a group formed by the loss of any one hydrogen atom from an alkane molecule.

[0046] In this application, the term "halogen" refers to at least one of fluorine, chlorine, bromine, and iodine.

[0047] In this application, the term "phenyl" refers to a group formed by losing any one hydrogen atom from a benzene ring.

[0048] In this application, the term "naphthyl" refers to a group formed by losing any one hydrogen atom from a naphthalene ring.

[0049] The beneficial effects that this application can produce include:

[0050] 1) The raw materials for this application are simple and readily available, and the operation is simple.

[0051] 2) The nickel metal precursors used in this application are inexpensive and abundant.

[0052] 3) The reaction in this application has high reactivity, complete conversion of raw materials, and convenient separation, which can obtain high-purity products. The reaction has good enantioselectivity and can obtain a single enantiomeric product with high enantioselectivity. The reaction conditions are mild and environmentally friendly. Detailed Implementation

[0053] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0054] Unless otherwise specified, all raw materials used in the embodiments of this application were purchased through commercial channels.

[0055] The synthesis of sulfonamide compounds is described in references (Li, S.-S.; Wu, L.; Qin, L.; Zhu, Y.-Q.; Su, F.; Xu, Y.-J.; Dong, L. Org. Lett. 2016, 18, 4214-4217; Li, B.; Chen, J.; Zhang, Z.; Gridnev, ID; Zhang, W. Angew. Chem. Int. Ed. 2019, 58, 7329-7334; Zhou, B.; Li, K.; Jiang, C.; Lu, Y.; Hayashi, T. Adv. Synth. Catal. 2017, 359, 1969-1975.), and all other starting materials are commercially available.

[0056] The prepared chiral sulfonamide compounds were characterized using a BRUKER DRX 400 NMR spectrometer and an Agilent 1100 high-performance liquid chromatograph.

[0057] Examples 1-12

[0058] Optimization of conditions

[0059] The types of nickel metal precursor, chiral bisphosphine ligand, hydrogen source, boron reagent, solvent, and reaction temperature were changed.

[0060] A nickel metal precursor (0.004 mmol), a chiral bisphosphine ligand (0.0048 mmol), a sulfonamide (0.2 mmol), a hydrogen source (0.4 mmol), and a boron reagent (0.6 mmol) were added to a sealed tube. After nitrogen purging, 3.0 mL of solvent was added, and the mixture was stirred at 80 °C for 24 hours. The solvent was removed under reduced pressure, and column chromatography (eluent: dichloromethane) was performed to obtain the corresponding chiral sulfonamide. The molar ratio of the sulfonamide, nickel metal precursor, chiral bisphosphine ligand, hydrogen source, and boron reagent was 1:0.02:0.024:2:3. By changing the types of nickel metal precursor, chiral bisphosphine ligand, hydrogen source, boron reagent, solvent, and reaction temperature, the yield of the product was determined by NMR with 1,3,5-trimethylbenzene as an internal standard, and the ee value was the enantiomeric excess percentage. The results were shown in Table 1.

[0061]

[0062] Table 1. Optimization of conditions for the synthesis of chiral sulfonamides

[0063]

[0064]

[0065] Examples 13-30

[0066] A series of chiral sulfonamides were synthesized by nickel-catalyzed asymmetric reduction.

[0067] Nickel acetate (0.004 mmol), chiral bisphosphine ligand (R,R)-QuinoxP* (0.0048 mmol), sulfonylimide (0.2 mmol), hexafluoroisopropanol (0.4 mmol), and tetrahydroxydiboron (0.6 mmol) were added to a sealed tube. After nitrogen purging, 3.0 mL of solvent was added, and the reaction was stirred at 80 °C for 24 hours. The solvent was removed under reduced pressure, and column chromatography (eluent: dichloromethane) was performed to obtain the corresponding chiral sulfonamide. The molar ratio of sulfonylimide, nickel metal precursor, chiral bisphosphine ligand, hydrogen source, and boron reagent was 1:0.02:0.024:2:3. By changing the types of nickel metal precursor, chiral bisphosphine ligand, hydrogen source, boron reagent, solvent, and reaction temperature, the yield of the product was determined by NMR with 1,3,5-trimethylbenzene as an internal standard, and the ee value was the enantiomeric excess percentage, as determined by chiral liquid chromatography. Eighteen different examples were obtained by changing the type of sulfonamide compound substrate in the reaction, and the specific types of changes are shown in Table 2.

[0068] Table 2. Synthesis of a series of chiral sulfonamides by nickel-catalyzed asymmetric reduction.

[0069]

[0070] (S)-(-)-4-Phenyl-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide(2a):

[0071] 3H),7.16-6.97(m,2H),6.82(d,J=7.8Hz,1H),5.90(d,J=8.7Hz,1H),4.82(d,J=8.7Hz,1H). 13 C10 NMR (100MHz, CDCl3) δ 151.6, 137.9, 129.8, 129.7, 129.6, 128.9, 128.7, 125.4, 122.1, 119.0, 62.1. High performance liquid chromatography: chiral AD-H column, 210 nm, 30 °C, n-hexane / isopropanol = 90 / 10, flow rate = 0.8 mL / min, retention times 16.5 min and 17.5 min (major).

[0072] (-)-4-(o-Tolyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide(2b):

[0073] 7.15-7.02(m,3H),6.83(d,J=7.7Hz,1H),6.18(d,J=8.9Hz,1H),4.65(d,J=8.9Hz,1H),2.48(s,3H). 13 C10 NMR (100MHz, CDCl3) δ 151.9, 137.6, 136.1, 131.5, 129.7, 129.6, 128.7, 128.4, 127.2, 125.4, 122.1, 119.1, 58.6, 19.3. High performance liquid chromatography: chiral IC column, 210 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.7 mL / min, retention times 10.0 min and 11.6 min (major).

[0074] (-)-4-(m-Tolyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide(2c):

[0075]

[0076] 7.18-7.01(m,4H),6.83(d,J=7.5Hz,1H),5.85(d,J=8.7Hz,1H),4.85-4.65(m,1H),2.37(s,3H). 13 C10 NMR (100MHz, CDCl3) δ 151.6, 139.5, 137.9, 130.4, 129.8, 129.5, 129.5, 128.7, 125.9, 125.4, 122.3, 118.9, 62.1, 21.5. High performance liquid chromatography: chiral IC column, 210 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.7 mL / min, retention times 12.4 min and 14.0 min (major).

[0077] (-)-4-(p-Tolyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide(2d):

[0078] 7.14-6.95(m,2H),6.82(d,J=8.3Hz,1H),5.86(d,J=8.6Hz,1H),4.75(d,J=8.6Hz,1H),2.39(s,3H). 13C10 NMR (100MHz, CDCl3) δ 151.6, 139.7, 135.0, 130.2, 129.8, 128.8, 128.7, 125.3, 122.4, 118.9, 61.9, 21.4. High performance liquid chromatography: chiral AD-H column, 210 nm, 30 °C, n-hexane / isopropanol = 85 / 15, flow rate = 0.7 mL / min, retention times 15.4 min and 17.0 min (major).

[0079] (-)-4-(4-Fluorophenyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide(2e):55.4mg,99%yield,white solid,known compound,R f =0.55(hexanes / dichloromethane 2 / 1),94%ee,[α] 20 D =-41.44(c 1.11,CH2Cl2),[lit.:

[0080] 250.0Hz), 151.6, 133.9 (d, J) C-F =3.0Hz), 130.9(d,J C-F =8.3Hz),130.1,128.6,125.5,121.8,119.1,116.7(d,J C-F =22.0Hz), 61.4. 19 F NMR (377MHz, CDCl3) δ-111.06. High performance liquid chromatography: chiral IC column, 210nm, 30℃, n-hexane / isopropanol = 90 / 10, flow rate = 1.0mL / min, retention times 13.6 min and 18.2 min (major).

[0081] (-)-4-(4-Chlorophenyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine

[0082]

[0083] 1H), 6.80 (d, J = 7.8Hz, 1H), 5.87 (d, J = 8.0Hz, 1H), 4.98 (d, J = 8.4Hz, 1H). 13CNMR (100MHz, CDCl3) δ 151.5, 136.3, 135.7, 130.4, 130.0, 129.8, 128.5, 125.5, 121.6, 119.0, 61.3. High performance liquid chromatography: chiral IC column, 210 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.7 mL / min, retention times 8.2 min and 10.5 min (major).

[0084] (-)-4-(3-Chlorophenyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide

[0085]

[0086] 7.12(t,J=7.6Hz,1H),7.06(d,J=8.3Hz,1H),6.82(d,J=7.8Hz,1H),5.86(d,J=8.6Hz,1H),4.90(d,J=8.6Hz,1H). 13 C10 NMR (100MHz, CDCl3) δ 151.5, 139.7, 135.3, 130.9, 130.1, 129.9, 129.1, 128.5, 127.2, 125.6, 121.3, 119.1, 61.4. High performance liquid chromatography: chiral IC column, 210 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.8 mL / min, retention times 10.8 min and 14.5 min (major).

[0087] (-)-6-Methyl-4-phenyl-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide

[0088]

[0089] 2H),7.12(d,J=8.2Hz,1H),6.94(d,J=8.4Hz,1H),6.60(s,1H),5.85(d,J=8.6Hz,1H),4.78(d,J=8.6Hz,1H),2.21(s,3H). 13C10 NMR (100MHz, CDCl3) δ 149.5, 138.1, 135.2, 130.5, 129.6, 129.6, 128.9, 128.8, 121.7, 118.7, 62.1, 20.8. High performance liquid chromatography: chiral AD-H column, 210 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.8 mL / min, retention times 9.3 min and 10.5 min (major). (-)-7-Methyl-4-phenyl-3,4-dihydrobenzo[e][1,2,3]oxathiazine

[0090]

[0091] CHCl3) for 95% ee]. 1 H NMR (400MHz, CDCl3) δ7.48-7.39(m,3H),7.38-7.29(m,2H),6.90(d,J=8.0Hz,1H),6.86( s,1H),6.69(d,J=7.9Hz,1H),5.85(d,J=8.7Hz,1H),4.79(d,J=8.7Hz,1H),2.34(s,3H). 13 C10 NMR (100MHz, CDCl3) δ 151.4, 140.4, 138.1, 129.6, 129.5, 128.9, 128.4, 126.3, 119.1, 119.0, 61.9, 21.1. HPLC: Chirapak AD-H column, 210nm, 30℃, n-Hexane / i-PrOH = 80 / 20, flow rate = 0.8mL / min, retention time 10.0min and 14.1min (major).

[0092] (-)-4-Methyl-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide(2j):

[0093]

[0094] (d,J=8.0Hz,1H),4.96-4.83(m,1H),4.67(d,J=9.4Hz,1H),1.71(d,J=6.9Hz,3H). 13C10 NMR (100MHz, CDCl3) δ 151.0, 129.6, 126.4, 125.5, 123.7, 118.8, 53.1, 20.2. HPLC: Chirapak AS-H column, 210nm, 30℃, n-Hexane / i-PrOH = 70 / 30, flow rate = 0.8mL / min, retention time 12.4min (major) and 14.8min.

[0095] (-)-4-Ethyl-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide(2k):41.8mg,

[0096] (400MHz, CDCl3) δ7.35-7.27(m,1H),7.25-7.14(m,2H),6.97(d,J=8.1Hz,1H), 4.79-4.57(m,2H),2.28-2.11(m,1H),2.10-1.93(m,1H),1.10(t,J=7.4Hz,3H). 13 C10 NMR (100MHz, CDCl3) δ 151.3, 129.5, 126.5, 125.5, 122.7, 118.9, 58.6, 27.0, 9.7. HPLC: Chirapak AD-H column, 210nm, 30℃, n-Hexane / i-PrOH = 80 / 20, flow rate = 0.8mL / min, retention time 7.4min (major) and 8.2min.

[0097] (-)-4-Methyl-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazine

[0098] CH2Cl2) for 95% ee]. 1H NMR(400MHz,Chloroform-d)δ7.24-7.11(m,2H),7.09-7.01(m,1H),6.98(br s,1H),6.68(d,J=7.9Hz,1H),4.86-4.67(m,1H),4.40(d,J=10.5Hz,1H),1.66(d,J=6.9Hz,3H). 13 C10 NMR (100MHz, CDCl3) δ 137.5, 128.8, 126.0, 124.7, 123.5, 118.3, 53.4, 19.6. High performance liquid chromatography: chiral AD-H column, 210 nm, 30℃, n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min, retention times 34.9 min and 49.2 min (major).

[0099] (S)-(+)-3-Phenyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide(2m):47.8mg,97%yield,white solid,known compound,R f =0.20(dichloromethane),87%ee, 5.72(d,J=4.1Hz,1H),5.08(d,J=4.2Hz,1H). 13 C10 NMR (100MHz, CDCl3) δ 139.9, 138.8, 134.9, 133.5, 129.6, 129.4, 129.2, 127.7, 125.5, 121.3, 61.5. High performance liquid chromatography: chiral OJ-H column, 210 nm, 30 °C, n-hexane / isopropanol = 70 / 30, flow rate = 0.8 mL / min, retention times 17.7 min and 19.2 min (major).

[0100] (-)-3-Methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide(2n):34.2mg,93% =7.5Hz,1H),7.52(t,J=7.6Hz,1H),7.39(d,J=7.8Hz,1H),4.90(br s,1H),4.84-4.74(m,1H),1.61(d,J=6.7Hz,3H). 13C10 NMR (100MHz, CDCl3) δ 141.8, 135.6, 133.3, 129.3, 124.0, 121.3, 53.5, 21.5. High performance liquid chromatography: chiral OD-H column, 210 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.8 mL / min, retention times 14.0 min and 18.1 min (major).

[0101] (-)-3-Ethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide(2o):37.2mg,94% 7.8Hz,1H),7.62(td,J=7.6,1.2Hz,1H),7.52(t,J=7.6Hz,1H),7.38(d,J=7.8Hz,1H),4.86(br s,1H),4.73-4.54(m,1H),2.13-1.98(m,1H),1.89-1.75(m,1H),1.03(t,J=7.4Hz,3H). 13 C10 NMR (100MHz, CDCl3) δ 140.3, 135.8, 133.2, 129.3, 124.2, 121.4, 59.1, 28.8, 10.0. HPLC: Chiracel AD-H column, 210nm, 30℃, n-Hexane / i-PrOH = 80 / 20, flow = 0.8mL / min, retention time 12.1min (major) and 14.1min.

[0102] (-)-3-Butyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide(2p):42.6mg,94%

[0103] 1H),7.38(d,J=7.7Hz,1H),4.90(d,J=4.1Hz,1H),4.75-4.60(m,1H),2.10 -1.90(m,1H),1.86-1.69(m,1H),1.55-1.29(m,4H),0.91(t,J=7.0Hz,3H). 13C10 NMR (100MHz, CDCl3) δ 140.8, 135.7, 133.2, 129.3, 124.2, 121.4, 58.0, 35.6, 28.0, 22.5, 14.0. High performance liquid chromatography: chiral IC column, 210 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.8 mL / min, retention times 20.2 min and 30.6 min (major).

[0104] (-)-3-Isobutyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide(2q):44.3mg,98%

[0105] yield,colorlessoil,known compound,R f =0.60 (dichloromethane), Hz,1H),7.60(td,J=7.5,1.3Hz,1H),7.50(t,J=7.5Hz,1H),7.36(dd,J=7.7,0.9Hz,1H),4.96(d,J=5.2Hz, 1H),4.76-4.64(m,1H),1.97-1.82(m,1H),1.79-1.64(m,2H),1.03(d,J=6.6Hz,3H),0.99(d,J=6.6Hz,3H). 13 C10 NMR (100MHz, CDCl3) δ 141.5, 135.7, 133.1, 129.3, 124.2, 121.4, 56.2, 45.3, 25.6, 23.5, 21.5. High performance liquid chromatography: chiral AD-H column, 210 nm, 30 °C, n-hexane / isopropanol = 80 / 20, flow rate = 0.8 mL / min, retention times 10.4 min and 22.8 min (major).

[0106] 0.50(dichloromethane),98%ee,[α] 20 D =-48.96(c 0.87,CHCl3),[lit.:[α] 20 D =-48.6(c1.00,CHCl3)for 97%ee]. 1H NMR (400MHz, CDCl3) δ7.76(d,J=7.7Hz,1H),7.61(t,J=7.5Hz,1H),7.51(t,J=7.5Hz,1H),7.37(d,J=7.8H z,1H),4.84(d,J=5.1Hz,1H),4.68-4.55(m,1H),1.99-1.76(m,3H),1.74-1.58(m,2H),1.37-1.01(m,6H). 13 C NMR (100MHz, CDCl3) δ 139.1, 135.8, 133.1, 129.3, 124.5, 121.5, 63.0, 42.8, 30.8, 26.4, 26.0, 25.9, 25.8. High performance liquid chromatography: chiral IC column, 210nm, 30℃, n-hexane / isopropanol = 70 / 30, flow rate = 0.7mL / min, retention times 18.1 min and 42.5 min (major). The above descriptions are merely several embodiments of this application and are not intended to limit the application in any way. Although preferred embodiments are disclosed above, they are not intended to limit the application. Any modifications or variations made by those skilled in the art without departing from the scope of the technical solution disclosed above are equivalent to equivalent implementations and fall within the scope of the technical solution.

Claims

1. A method for preparing chiral sulfonamides by nickel-catalyzed asymmetric reduction, characterized in that, The preparation method includes: reacting a mixture containing the compound shown in Formula I, a nickel metal precursor, a catalyst, a hydrogen source, and a boron reagent to obtain the chiral sulfonamide shown in Formula II; Equation I; Formula II; Ar is selected from phenyl, naphthyl, and substituted phenyl groups; The substituents of the substituted phenyl group are independently selected from C1-C6 alkyl, halogen, and methoxy groups; R is selected from C1~C 10 Alkyl, phenyl, naphthyl, substituted phenyl; The substituents of the substituted phenyl group are independently selected from C1-C6 alkyl, halogen, and methoxy groups; X is selected from O or NH; The nickel metal precursor is nickel acetate; The boron reagent is tetrahydroxydiboron; The catalyst is ; The hydrogen source and solvent are hexafluoroisopropanol; The reaction temperature is 50~80℃.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the hydrogen source is 1:1 to 1:

50.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the nickel metal precursor is 1:0.01 to 1:0.2; The molar ratio of the compound represented by Formula I to the catalyst is 1:0.01 to 1:0.2; The molar ratio of the compound shown in Formula I to the boron reagent is 1:1 to 1:

5.

4. The preparation method according to claim 1, characterized in that, The molar volume ratio of the compound represented by Formula I to the solvent is 1:5 to 1:20 mol / L.

5. The preparation method according to claim 1, characterized in that, The reaction time is 24~72 h.

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