Preparation method of axially chiral N-pyrazolyl sulfonamide compound

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a preparation method of an axially chiral N-pyrazolyl sulfonamide compound. The preparation method provided by the invention comprises the following step: by taking N-protected 5-aminopyrazole and allyl carbonate as initial raw materials, preparing the axially chiral N-pyrazolyl sulfonamide compound as shown in a general formula I under the action of a palladium catalyst and a chiral ligand. The synthesis method provided by the invention is simple and efficient, the used reagent is cheap and easy to obtain, the reaction atom economy is high, the vacancy of the existing method for synthesizing the axially chiral N-pyrazolyl sulfonamide compound is made up, and the pyrazole skeleton has certain medicinal potential.

Description

Technical Field

[0001] The invention relates to a preparation method of an axially chiral N-pyrazolyl sulfonamide compound, and relates to the technical field of organic synthesis. Background Art

[0002] Axial chirality, as an important stereoisomerism phenomenon, is widely distributed in active molecules, ligands, and catalysts, and is of great value in fields such as organic chemistry, medicinal chemistry, and asymmetric catalysis (Acc. Chem. Res., 2018, 51: 534-547). Among them, the CN axial chiral skeleton has become a research hotspot due to its unique conformational characteristics and chiral recognition ability. In recent years, significant progress has been made in the catalytic asymmetric synthesis of axially chiral aromatic heterocycles (Angew. Chem. Int. Ed. 2020, 59, 6775-6779), bis-heteroaromatic rings (Angew. Chem. Int. Ed. 2021, 60, 8391-8395), and aromatic amines (Org. Biomol. Chem., 2015, 13, 125-132), providing an efficient strategy for the construction of chiral molecules. However, compared with these studies, there are few reports on axially chiral molecules with CN-linked heteroaryl open-chain skeletons. Because such molecules typically possess low rotational barriers and weak conformational stability, their catalytic asymmetric synthesis is extremely challenging. Furthermore, existing synthetic strategies are relatively limited, and the further development of efficient and universal synthetic methods remains an important issue to be addressed in this field.

[0003] Pyrazole, a unique five-membered dinitrogen aromatic ring, is widely present in natural products, pharmaceutical molecules, and functional materials due to its excellent chemical properties and biological activity, showing important application value. In recent years, the pyrazole skeleton has attracted much attention due to its potential in medicinal chemistry and organic synthesis. This structure is widely distributed in a variety of biologically active compounds, such as the mGluR5 positive allosteric modulator CDPPB (J.Med.Chem. 2006, 49, 3332-3344), as well as drug molecules with antifungal and antibacterial activities (J.Med.Chem., 2004, 47, 5825-5828). In addition, pyrazole derivatives also show broad application prospects in anti-inflammatory, anti-tumor, neuromodulation and other fields, making them important molecular scaffolds for new drug development and biomedical research.

[0004] Although the asymmetric synthesis of CN-based open-chain aromatic compounds has been extensively studied, the construction of CN-based open-chain axially chiral heteroaryl compounds remains rare. In particular, there are currently no synthetic examples of CN-based open-chain axially chiral pyrazoles. Summary of the Invention

[0005] In order to overcome the shortcomings of the existing technology, the present invention focuses on the construction of axially chiral N-pyrazolylsulfonamide compounds. The invention provides a method for preparing axially chiral N-pyrazolylsulfonamide compounds; using N-protected 5-aminopyrazole and allyl carbonate as starting materials, under the action of palladium catalyst and chiral ligand, an axially chiral N-pyrazolylsulfonamide compound represented by general formula I is synthesized through N-allylation reaction. This strategy provides a new method and idea for the construction of CN open-chain axially chiral five-membered heterocycles. Through reasonable reaction design, the present invention develops an innovative and efficient method for synthesizing axially chiral N-pyrazolylsulfonamides, which has important theoretical significance and application value.

[0006] The above-mentioned object of the present invention is achieved through the following technical solutions:

[0007] A method for preparing an axially chiral N-pyrazolylsulfonamide compound, wherein the N-pyrazolylsulfonamide having a general structure of formula I is synthesized by N-allylation reaction of N-protected 5-aminopyrazole and allyl carbonate;

[0008]

[0009] Where: R 1 R is independently selected from p-toluenesulfonyl, p-chlorobenzenesulfonyl or thienylsulfonyl; 2 Independently selected from various aromatic groups; R 3 Independently selected from methyl, cyclohexyl or aromatic groups.

[0010] In the compound of the general formula I described in the present invention, R 2 The aromatic groups include 2-naphthyl, phenyl or substituted phenyl, and the substituents include methyl, methoxy, chlorine and bromine, and the substitution positions include the 3rd and 4th positions of the benzene ring.

[0011] In the compound of the general formula I described in the present invention, R 3 It is a methyl group, a cyclohexyl group or an aromatic group. Aromatic groups include 2-thienyl, phenyl and substituted phenyl groups. Substituents include methyl, methoxy, trifluoromethyl, fluorine, chlorine and bromine. The substitution position is 2 to 4 positions of the benzene ring.

[0012] The compounds having the general formula I described in the present invention are preferably the following compounds numbered 1 to 23:

[0013]

[0014] The compound having the general formula I is prepared from N-protected 5-aminopyrazole and allyl carbonate by the following process:

[0015]

[0016] The following steps are involved:

[0017] To a 25 mL Schlenk tube, add N-protected 5-aminopyrazole, a palladium catalyst, and a ligand. The N2 atmosphere is replaced. Allyl carbonate, DIPEA, and a solvent are then added under a N2 purge. The reaction system is stirred under N2 protection and allowed to react at 0°C for 0.7 hours. (Preferred conditions include 1 equivalent of N-protected 5-aminopyrazole, 1 equivalent of DIPEA, and 2 equivalents of allyl carbonate; Pd2dba3 as the palladium catalyst, 4.4 mol% of the N-protected 5-aminopyrazole; and N,N'-[(1R,2R)-1,2-diphenyl-1,2-ethanediyl]bis[2-diphenylphosphinamide] as the ligand, 6.6 mol% of the N-protected 5-aminopyrazole. Chloroform is the preferred solvent, and the molar concentration of the N-protected 5-aminopyrazole is preferably 0.1 M.) After completion of the reaction, the reaction is concentrated and purified by column chromatography to obtain the desired N-pyrazolylsulfonamide product.

[0018] The relevant physical properties and characterization data of each preferred compound are listed in Table 1.

[0019] Table 1. Structure, physical properties and characterization data of compound (I)

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026] The beneficial effects of the present invention are:

[0027] (1) A novel N-allylation method for preparing axially chiral pyrazoles was developed, and a series of novel axially chiral N-pyrazolylsulfonamides were synthesized, providing a new method and idea for the construction of open-chain axially chiral skeletons similar to five-membered heterocyclic compounds.

[0028] (2) Introducing chiral elements into the skeleton of 5-aminopyrazole provides more possibilities for the spatial configuration of this type of biologically active skeleton.

[0029] (3) The synthesis method involved in the present invention is simple and efficient, uses cheap and readily available reagents, and has high reaction atom economy, which fills the gap in the existing methods for synthesizing axially chiral N-pyrazolylsulfonamide compounds, and this type of pyrazole skeleton has certain medicinal potential. DETAILED DESCRIPTION

[0030] The following examples may enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way.

[0031] Example 1: Synthesis of axially chiral N-pyrazolylsulfonamide 1

[0032]

[0033] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (55.1 mg). The yield was 98%, and the ee value was 88%. 1 H NMR(400MHz,Chloroform-d)δ7.87-7.79(m,2H),7.77(d,J=8.1Hz,2H),7.40-7.34(m,2H),7.33-7.17(m,8H),6.50(d,J=1 5.7Hz,1H),6.20(ddd,J=15.4,8.2,6.5Hz,1H),4.59-4.47(m,1H),4.37(dd,J=13.6,8.2Hz,1H),2.41(s,3H),1.76(s,9H). 13 C NMR (101MHz, CDCl3) δ146.0,144.4,136.5,136.0,135.8,135.3,132.6,129.8,128.9,128.7,1 28.2,128.2,128.1,127.5,126.6,122.5,91.7,64.4,53.2,30.6,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C 29 H 30BrN3O2S, 564.1315; Found, 564.1317. HPLC: 88% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 240 nm, 30 ° C, 0.8 mL / min, t major =6.3min,t minor =8.5min).

[0034] Example 2: Synthesis of axially chiral N-pyrazolylsulfonamide 2

[0035]

[0036] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (53.2 mg). The yield was 96% and the ee value was 80%. 1 H NMR(400MHz,Chloroform-d)δ7.84(d,J=7.0Hz,2H),7.73-7.59(m,2H),7.43-7.36(m,2H),7.36-7.21(m,6H),7.13(dd,J=5.0,3.8Hz ,1H),6.57(d,J=15.7Hz,1H),6.27(ddd,J=15.4,8.2,6.6Hz,1H),4.62(ddd,J=13.5,6.7,1.3Hz,1H),4.53-4.39(m,1H),1.76(s,9H). 13 C NMR (101MHz, CDCl3) δ146.1,139.5,136.2,135.9,134.8,134.1,133.3,132.5,128.7,128. 3,128.2,128.1,127.9,127.5,126.6,122.1,91.4,64.4,53.6,30.5.HRMS(ESI)m / z:[M+Na] + Calculated value C 26 H 26BrN3O2S2, 578.0542; Found, 578.0544. HPLC: 80% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =7.9min,t minor =11.4min).

[0037] Example 3: Synthesis of axially chiral N-pyrazolylsulfonamide 3

[0038]

[0039] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (56.5 mg). The yield was 97% and the ee value was 82%. 1 H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.9Hz,4H),7.52-7.45(m,2H),7.43-7.37(m,2H),7.36-7.23(m,6H),6.55(d, J=15.7Hz,1H),6.22(dt,J=15.4,7.5Hz,1H),4.53(dd,J=13.6,6.5Hz,1H),4.41(dd,J=13.6,8.3Hz,1H),1.78(s,9H). 13 C NMR (126MHz, CDCl3) δ146.1,140.1,138.0,136.2,135.8,135.0,132.4,130.3,129.5,128.7 ,128.4,128.3,128.2,127.4,126.6,122.0,91.6,64.5,53.6,30.5.HRMS(ESI,m / z):[M+Na] + Calculated value C 28 H 27BrClN3O2S, 606.0588 found, 606.0591. HPLC: 82% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =7.8min,t minor =11.4min).

[0040] Example 4: Synthesis of axially chiral N-pyrazolylsulfonamide 4

[0041]

[0042] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (57.9 mg). The yield was 97% and the ee value was 86%. 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J=8.0Hz,2H),7.47-7.18(m,11H),6.53(d,J=15.7Hz,1H),6.21(d dd,J=15.4,8.3,6.6Hz,1H),4.84-4.45(m,1H),4.38(dd,J=13.1,8.3Hz,1H),2.44(s,3H),1.78(s,9H). 13 C NMR (101MHz, CDCl3) δ146.5,144.4,136.3,136.1,136.0,134.5,134.3,132.0,131.7,129.9,129.8,1 29.7,128.8,128.6,128.2,126.6,126.5,121.9,93.8,64.4,52.7,30.6,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 29 H 29BrClN3O2S, 620.0745; Found, 620.0745. HPLC: 86% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =6.9min,t minor =9.1min).

[0043] Example 5: Synthesis of axially chiral N-pyrazolylsulfonamide 5

[0044]

[0045] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a colorless oily liquid (58.7 mg) in a 99% yield and an ee value of 86%. 1 H NMR(400MHz,Chloroform-d)δ7.80(d,J=8.2Hz,2H),7.49-7.41(m,2H),7.36-7.18(m,8H),7.00-6.81(m,1H),6.54(d,J=15.7Hz,1H),6.2 3(ddd,J=15.4,8.2,6.6Hz,1H),4.56(ddd,J=13.6,6.6,1.3Hz,1H),4.41(dd,J=13.5,8.2Hz,1H),3.85(s,3H),2.45(s,3H),1.80(s,9H). 13 C NMR (101MHz, CDCl3) δ159.5,145.7,144.4,136.5,136.0,135.8,135.4,133.9,129.8,129.3,128.9,128. 7,128.2,126.6,122.4,112.0,113.7,113.1,91.8,64.4,55.3,53.2,30.6,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 30 H 32BrN3O3S, 616.1240; Found, 616.1238. HPLC: 86% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 232 nm, 30 ° C, 0.8 mL / min, t major =8.1min,t minor =11.6min).

[0046] Example 6: Synthesis of axially chiral N-pyrazolylsulfonamide 6

[0047]

[0048] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a colorless oily liquid (56.7 mg) in a 95% yield and an ee value of 83%. 1 H NMR(400MHz,Chloroform-d)δ7.83(d,J=2.1Hz,1H),7.79-7.57(m,3H),7.32-7.20(m,9H),6.49(d,J=15.7Hz,1H),6.18( ddd,J=15.4,8.2,6.6Hz,1H),4.52(ddd,J=13.5,6.6,1.3Hz,1H),4.36(dd,J=13.6,8.2Hz,1H),2.42(s,3H),1.75(s,9H). 13 C NMR (101MHz, CDCl3) δ144.5,144.5,136.4,135.9,135.9,135.6,134.3,134.2,129.8,129.5,128.8,1 28.7,128.3,128.0,127.4,126.6,125.5,122.3,91.8,64.6,53.2,30.5,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 29 H 29BrClN3O2S, 620.0745; found, 620.0737. HPLC: 83% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 232 nm, 30 ° C, 0.8 mL / min, t major =7.6min,t minor =10.6min).

[0049] Example 7: Synthesis of axially chiral N-pyrazolylsulfonamide 7

[0050]

[0051] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a colorless oily liquid (57.4 mg) in a 91% yield and an ee value of 83%. 1 H NMR(400MHz,Chloroform-d)δ8.10(s,1H),8.02(d,J=7.7Hz,1H),7.85-7.69(m,2H),7.55(d,J=7.8Hz,1H),7.52-7.45(m,1H),7.32-7.18(m ,7H),6.50(d,J=15.7Hz,1H),6.19(ddd,J=15.3,8.1,6.5Hz,1H),4.60-4.46(m,1H),4.37(dd,J=13.6,8.2Hz,1H),2.42(s,3H),1.77(s,9H). 13 C NMR (101MHz, CDCl3) δ144.5,144.5,136.4,135.9,135.8,133.3,130.8,130.6,130.5,129 .8,128.8,128.7,128.3,126.6,124.6,124.6,124.2,122.2,91.8,64.7,53.2,30.5,21.7. 19 F NMR(377MHz,CDCl3)δ-62.60.HRMS(ESI,m / z):[M+Na] +Calculated value C 30 H 29 BrF3N3O2S, 654.1008; found, 654.1006. HPLC: 83% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =7.1min,t minor =10.2min).

[0052] Example 8: Synthesis of axially chiral N-pyrazolylsulfonamide 8

[0053]

[0054] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (54.2 mg). The yield was 94% and the ee value was 87%. 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J=7.9Hz,2H),7.72(d,J=7.8Hz,2H),7.33-7.18(m,9H),6.53(d,J=15.7Hz,1H),6.23 (dt,J=15.3,7.4Hz,1H),4.54(dd,J=13.6,6.6Hz,1H),4.39(dd,J=13.6,8.2Hz,1H),2.45(s,3H),2.37(s,3H),1.78(s,9H). 13 C NMR (126MHz, CDCl3) δ146.1,144.3,137.9,136.5,136.0,135.7,135.9,129.8,128.9,128.9, 128.7,128.2,127.4,126.6,122.5,91.5,64.2,53.2,30.6,21.7,21.3.HRMS(ESI,m / z):[M+H] + Calculated value C 30 H 32BrN3O2S, 578.1471; found, 578.1456. HPLC: 87% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 232 nm, 30 ° C, 0.8 mL / min, t major =7.1min,t minor =9.6min).

[0055] Example 9: Synthesis of axially chiral N-pyrazolylsulfonamide 9

[0056]

[0057] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (56.3 mg). The yield was 95%, and the ee value was 85%. 1 H NMR(400MHz,Chloroform-d)δ7.88-7.66(m,4H),7.33-7.21(m,7H),6.93(d,J=8.3Hz,2H),6.52(d,J=15.7Hz,1H),6.22(d t,J=15.3,7.4Hz,1H),4.53(dd,J=13.7,6.6Hz,1H),4.38(dd,J=13.7,8.2Hz,1H),3.82(s,3H),2.44(s,3H),1.77(s,9H). 13 C NMR (101MHz, CDCl3) δ159.5,145.8,144.3,136.5,136.0,135.7,135.1,129.8,128.9,128.8,128. 7,128.2,126.6,125.7,122.5,113.7,91.3,64.2,55.3,53.2,30.6,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 30 H 32BrN3O3S, 616.1240; Found, 616.1240. HPLC: 85% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =8.5min,t minor =12.1min).

[0058] Example 10: Synthesis of axially chiral N-pyrazolylsulfonamide 10

[0059]

[0060] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (52.8 mg). The yield was 91% and the ee value was 85%. 1 H NMR(400MHz,Chloroform-d)δ7.82(dd,J=13.9,6.8Hz,4H),7.44-7.16(m,7H),7.15-6.99(m,2H),6.53(d,J=15.7Hz,1 H),6.22(dt,J=15.3,7.4Hz,1H),4.54(dd,J=13.6,6.6Hz,1H),4.39(dd,J=13.6,8.2Hz,1H),2.45(s,3H),1.79(s,9H). 13 C NMR (101MHz, CDCl3) δ145.7,144.4,136.5,136.0,135.8,135.5,129.8,129.3,129 .2,128.9,128.7,128.2,126.6,122.4,115.3,115.0,91.5,64.4,53.3,30.5,21.7. 19 F NMR(376MHz,CDCl3)δ-113.80.HRMS(ESI,m / z):[M+Na] + Calculated value C 29 H 29BrFN3O2S, 604.1040; Found, 604.1035. HPLC: 85% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 232 nm, 30 ° C, 0.8 mL / min, t major =7.4min,t minor =10.2min).

[0061] Example 11: Synthesis of axially chiral N-pyrazolylsulfonamide 11

[0062]

[0063] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (54.9 mg). The yield was 92% and the ee value was 83%. 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=8.1Hz,4H),7.34(d,J=8.5Hz,2H),7.31-7.19(m,7H),6.50(d,J=15.7Hz,1 H),6.19(ddd,J=15.4,8.2,6.5Hz,1H),4.63-4.45(m,1H),4.37(dd,J=13.6,8.2Hz,1H),2.43(s,3H),1.76(s,9H). 13 C NMR (101MHz, CDCl3) δ144.9,144.4,136.5,136.0,135.8,135.6,134.0,131.0,129.8,128.9,1 28.7,128.7,128.4,128.3,126.6,122.3,91.6,64.5,53.3,30.5,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 29 H 29BrClN3O2S, 620.0745; Found, 620.0742. HPLC: 83% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 232 nm, 30 ° C, 0.8 mL / min, t major =7.5min,t minor =10.4min).

[0064] Example 12: Synthesis of axially chiral N-pyrazolylsulfonamide 12

[0065]

[0066] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (62.8 mg). The yield was 98%, and the ee value was 86%. 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J=7.9Hz,2H),7.73(d,J=8.1Hz,2H),7.51(d,J=8.1Hz,2H),7.37-7.16(m,7H),6.52(d,J= 15.7Hz, 1H), 6.21 (dt, J=15.3, 7.4Hz, 1H), 4.53 (dd, J=13.6, 6.6Hz, 1H), 4.38 (dd, J=13.6, 8.2Hz, 1H), 2.44 (s, 3H), 1.77 (s, 9H). 13 C NMR (126MHz, CDCl3) δ144.9,144.4,136.5,135.9,135.8,135.6,131.5,131.4,129.8,129.0,1 28.8,128.7,128.3,126.6,122.3,122.2,91.6,64.5,53.3,30.5,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 29 H 29Br2N3O2S, 664.0239; found, 664.0241. HPLC: 86% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 232 nm, 30 ° C, 0.8 mL / min, t major =7.6min,t minor =10.5min).

[0067] Example 13: Synthesis of axially chiral N-pyrazolylsulfonamide 13

[0068]

[0069] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (49.1 mg). The yield was 98%, and the ee value was 89%. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J=8.4Hz,2H),7.29-7.20(m,7H),6.44(d,J=15.8Hz,1H),6.13(ddd,J=15.7,8.2,6 .6Hz,1H),4.44(ddd,J=13.6,6.6,1.3Hz,1H),4.28(ddd,J=13.6,8.2,1.1Hz,1H),2.41(s,3H),2.11(s,3H),1.68(s,9H). 13 C NMR (101MHz, CDCl3) δ145.2,144.3,136.4,136.0,135.5,134.2,129.7,128.8,128. 6,128.2,126.6,122.5,92.9,63.4,53.2,30.5,21.7,12.9.HRMS(ESI,m / z):[M+Na] + Calculated value C 24 H 28BrN3O2S, 524.0978; Found, 524.0981. HPLC: 89% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =6.6min,t minor =8.6min).

[0070] Example 14: Synthesis of axially chiral N-pyrazolylsulfonamide 14

[0071]

[0072] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a colorless oily liquid (46.6 mg) in an 82% yield and an ee value of 89%. 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=8.3Hz,2H),7.32-7.18(m,7H),6.45(d,J=15.7Hz,1H),6.15(ddd,J=15.4,8.2,6.5Hz,1H),4.46(ddd,J=13.5 ,6.5,1.3Hz,1H),4.30(dd,J=13.5,8.2Hz,1H),2.56-2.47(m,1H),2.43(s, 3H),1.86-1.73(m,4H),1.68(s,9H),1.57-1.44(m,2H),1.43-1.02(m,4H). 13 C NMR (101MHz, CDCl3) δ152.1,144.2,136.4,136.2,135.5,133.6,129.7,128.8,128.6,128.1,126. 5,122.7,91.5,63.3,53.1,36.9,31.3,31.3,30.4,26.4,26.4,26.1,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 29 H 36BrN3O2S, 592.1604, found 592.1604. HPLC: 89% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =5.7min,t minor =7.1min).

[0073] Example 15: Synthesis of axially chiral N-pyrazolylsulfonamide 15

[0074]

[0075] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under a N2 purge, tert-butyl cinnamyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (56.3 mg). The yield was 99% and the ee value was 91%. 1 H NMR(400MHz,Chloroform-d)δ7.78(d,J=8.2Hz,2H),7.61(dd,J=3.7,1.2Hz,1H),7.35-7.19(m,8H),7.04(dd,J=5.1,3.6Hz,1H),6.51(d,J= 15.7Hz,1H),6.21(ddd,J=15.4,8.2,6.6Hz,1H),4.53(ddd,J=13.7,6.6,1.3Hz,1H),4.37(dd,J=13.7,8.1Hz,1H),2.44(s,3H),1.76(s,9H). 13 C NMR (101MHz, CDCl3) δ144.4,141.9,136.4,135.9,135.8,135.5,135.1,129.8,128.9,128.7,1 28.2,127.2,126.6,125.2,125.0,122.3,90.8,64.6,53.3,30.5,21.7.HRMS(ESI,m / z):[M+Na] + Calculated value C 27 H 28BrN3O2S2, 592.0699; found, 592.0703. HPLC: 91% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =7.9min,t minor =11.6min).

[0076] Example 16: Synthesis of axially chiral N-pyrazolylsulfonamide 16

[0077]

[0078] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (54.8 mg). The yield was 95%, and the ee value was 83%. 1 H NMR(400MHz,Chloroform-d)δ7.96-7.77(m,4H),7.45-7.38(m,2H),7.38-7.29(m,3H),7.22-7.15(m,1H),7.14-7.01(m,3H),6.51(d,J=15.7Hz,1H) ,6.22(ddd,J=15.6,8.2,6.5Hz,1H),4.56(ddd,J=13.5,6.6,1.3Hz,1H),4 .40(ddd,J=13.5,8.2,1.0Hz,1H),2.46(s,3H),2.32(s,3H),1.81(s,9H). 13 C NMR (101MHz, CDCl3) δ146.0,144.4,138.2,136.5,136.0,135.9,135.4,132.6,129.8,129.0,128.9,128 .6,128.3,128.0,127.5,127.5,123.6,122.2,91.6,64.4,53.3,30.6,21.7,21.4.HRMS(ESI,m / z):[M+H] + Calculated value C 30 H32 BrN3O2S, 578.1471; found, 578.1497. HPLC: 83% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =6.6min,t minor =9.0min).

[0079] Example 17: Synthesis of axially chiral N-pyrazolylsulfonamide 17

[0080]

[0081] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (48.6 mg). The yield was 82%, and the ee value was 75%. 1 H NMR(400MHz,Chloroform-d)δ7.92-7.74(m,4H),7.40(dd,J=8.2,6.5Hz,2H),7.33(dd,J=11.9,7.6Hz,3H),7.23-7.15(m,1H),6.91-6.73(m,3H),6.50( d,J=15.7Hz,1H),6.22(ddd,J=15.3,8.2,6.6Hz,1H),4.54(dd,J=13.6,6.6H z,1H),4.39(dd,J=13.6,8.2Hz,1H),3.77(s,3H),2.45(s,3H),1.79(s,9H). 13 C NMR (101MHz, CDCl3) δ159.8,146.0,144.4,137.4,136.5,135.6,135.3,132.6,129.8,129.7,128.9,128 .2,128.0,127.5,122.8,119.2,113.8,112.0,91.7,64.4,55.2,53.2,30.6,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C30 H 32 BrN3O3S, 594.1421; found, 594.1431. HPLC: 75% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =8.0min,t minor =17.3min).

[0082] Example 18: Synthesis of axially chiral N-pyrazolylsulfonamide 18

[0083]

[0084] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a colorless oily liquid (56.7 mg) in a 95% yield and an ee value of 84%. 1 H NMR(400MHz,Chloroform-d)δ7.89-7.74(m,4H),7.43-7.37(m,2H),7.33(dd,J=13.0,7.5Hz,3H),7.25-7.17(m,3H),7.13(dd,J=6.0,3.1Hz,1H), 6.46(d,J=15.8Hz,1H), 6.25(ddd,J=15.4,8.2,6.4Hz,1H), 4.52(dd,J=13.8,6.4Hz,1H), 4.39(dd,J=13.8,8.2Hz,1H), 2.45(s,3H), 1.79(s,9H). 13 C NMR (101MHz, CDCl3) δ146.0,144.5,137.8,136.4,135.4,134.6,134.2,132.5,129.9,129.8,128.9,1 28.3,128.2,128.1,127.5,126.6,124.6,124.3,91.7,64.4,53.2,30.5,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C29 H 29 BrClN3O2S, 598.0925; found, 598.0936. HPLC: 84% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =6.8min,t minor =10.8min).

[0085] Example 19: Synthesis of axially chiral N-pyrazolylsulfonamide 19

[0086]

[0087] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a colorless oily liquid (55.4 mg) in a yield of 96% and an ee value of 81%). 1 H NMR(400MHz,Chloroform-d)δ7.96-7.69(m,4H),7.51-7.28(m,5H),7.18(d,J=7.9Hz,2H),7.10(d,J=7.8Hz,2H),6.51(d,J=15.7Hz,1H) ,6.19(ddd,J=15.3,8.1,6.5Hz,1H),4.56(dd,J=13.4,6.3Hz,1H),4.40(dd,J=13.5,8.2Hz,1H),2.46(s,3H),2.33(s,3H),1.81(s,9H). 13 CNMR (101MHz, CDCl3) δ146.0,144.3,138.2,136.6,135.8,135.3,133.2,132.6,129.8,129.4,128 .9,128.2,128.1,127.5,126.5,121.3,91.7,64.4,53.3,30.6,21.7,21.3.HRMS(ESI,m / z):[M+H] + Calculated value C 30 H 32BrN3O2S, 578.1471; Found, 578.1478. HPLC: 81% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =6.1min,t minor =7.4min).

[0088] Example 20: Synthesis of axially chiral N-pyrazolylsulfonamide 20

[0089]

[0090] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (54.5 mg). The yield was 92%, and the ee value was 83%. 1 H NMR(400MHz,Chloroform-d)δ7.91-7.74(m,4H),7.43-7.37(m,2H),7.37-7.27(m,3H),7.25-7.13(m,2H),6.90-6.76(m,2H),6.47(d,J=15.7Hz, 1H),6.08(ddd,J=15.4,8.2,6.7Hz,1H),4.54(ddd,J=13.4,6.7,1.3Hz,1 H), 4.38 (dd, J = 13.5, 8.2Hz, 1H), 3.79 (s, 3H), 2.45 (s, 3H), 1.79 (s, 9H). 13 CNMR(101MHz, CDCl3)δ159.7,145.9,144.3,136.6,135.4,132.6,129.8,128.8,128.8,128.2, 128.0,127.8,127.5,120.0,114.1,91.6,64.3,55.3,53.3,30.6,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C 30 H 32BrN3O3S, 594.1421; found, 594.1418. HPLC: 83% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =7.7min,t minor =9.7min).

[0091] Example 21: Synthesis of axially chiral N-pyrazolylsulfonamide 21

[0092]

[0093] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (55.5 mg). The yield was 93% and the ee value was 87%. 1 H NMR (400MHz, Chloroform-d) δ7.98-7.65(m,4H),7.44-7.37(m,2H),7.33(dd,J=14.9,7.7Hz,3H),7.26(d,J=8.4Hz,2H),7.19(d,J=8. 6Hz,2H),6.48(d,J=15.7Hz,1H),6.29-6.14(m,1H),4.54(ddd,J=13.7,6.6,1.4Hz,1H),4.45-4.32(m,1H),2.45(s,3H),1.79(s,9H). 13 C NMR (101MHz, CDCl3) δ146.0,144.4,136.5,135.3,134.5,134.4,134.0,132.5,129.8,128.9,1 28.9,128.3,128.1,127.8,127.5,123.3,91.7,64.4,53.2,30.5,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C 29 H 29BrClN3O2S, 598.0925; Found, 598.0924. HPLC: 87% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =7.0min,t minor =8.8min).

[0094] Example 22: Synthesis of axially chiral N-pyrazolylsulfonamide 22

[0095]

[0096] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (58.3 mg). The yield was 91% and the ee value was 85%. 1 H NMR(400MHz,Chloroform-d)δ7.93-7.75(m,4H),7.40(dd,J=8.2,6.5Hz,4H),7.33(dd,J=14.6,7.6Hz,3H),7.12(d,J=8.5Hz,2H),6.46(d,J=15 .8Hz,1H),6.24(ddd,J=15.8,8.2,6.5Hz,1H),4.53(ddd,J=13.7,6.5,1.3Hz,1H),4.39(ddd,J=13.7,8.2,1.0Hz,1H),2.45(s,3H),1.78(s,9H). 13 CNMR (101MHz, CDCl3) δ146.0,144.4,136.5,135.3,134.9,134.5,132.5,131.8,129.8,128.9, 128.3,128.1,128.1,127.5,123.4,122.1,91.7,64.4,53.2,30.5,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C 29 H 29Br2N3O2S, 642.0420; Found, 642.0419. HPLC: 85% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =7.0min,t minor =8.7min).

[0097] Example 23: Synthesis of axially chiral N-pyrazolylsulfonamide 23

[0098]

[0099] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (0.10 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then allyl carbonate b (0.40 mmol), DIPEA (0.10 mmol), and CHCl3 (1 mL) were added under a N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a colorless oily liquid (60.1 mg) in a 98% yield and an ee value of 82%. 1 H NMR(400MHz,Chloroform-d)δ7.94-7.71(m,7H),7.63-7.28(m,9H),6.70(d,J=15.6Hz,1H),6.37(dt,J= 15.3,7.3Hz,1H),4.61(dd,J=13.6,6.6Hz,1H),4.46(dd,J=13.4,7.9Hz,1H),2.45(s,3H),1.81(s,9H). 13 C NMR (101MHz, CDCl3) δ149.1,146.0,144.4,136.6,135.9,135.4,133.5,133.2,132.6,129.8,129.0,128.9,128.4,1 28.3,128.1,127.7,127.5,127.0,126.4,126.3,123.3,122.8,91.7,64.4,53.4,30.6,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C 33 H 32BrN3O2S, 614.1471; Found, 614.1488. HPLC: 82% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 254 nm, 30 ° C, 0.8 mL / min, t major =10.5min,t minor =15.8min).

[0100] Example 24: Gram-Scale Synthesis of Axially Chiral N-Pyrazolylsulfonamide

[0101]

[0102] To a 25 mL Schlenk tube, N-protected 5-aminopyrazole a (2.5 mmol), Pd2dba3 (4.4 mol%), and L3 ligand (6.6 mol%) were added. The N2 atmosphere was replaced, and then, under an N2 purge, tert-butyl cinnamyl carbonate b (5.0 mmol), DIPEA (2.5 mmol), and CHCl3 (25 mL) were added. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After completion of the reaction (monitored by TLC), the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 70 to 1 / 50) to obtain the desired product c as a white solid (1.4 g) in a 97% yield and an ee value of 85%. 1 H NMR(400MHz,Chloroform-d)δ7.87-7.79(m,2H),7.77(d,J=8.1Hz,2H),7.40-7.34(m,2H),7.33-7.17(m,8H),6.50(d,J=1 5.7Hz,1H),6.20(ddd,J=15.4,8.2,6.5Hz,1H),4.59-4.47(m,1H),4.37(dd,J=13.6,8.2Hz,1H),2.41(s,3H),1.76(s,9H). 13 C NMR (101MHz, CDCl3) δ146.0,144.4,136.5,136.0,135.8,135.3,132.6,129.8,128.9,128.7,1 28.2,128.2,128.1,127.5,126.6,122.5,91.7,64.4,53.2,30.6,21.7.HRMS(ESI,m / z):[M+H] + Calculated value C 29 H 30BrN3O2S, 564.1315; Found, 564.1317. HPLC: 88% ee (HPLC analysis conditions: chiral OD-H column, hexane / 2-propanol = 7 / 3, absorption wavelength λ = 240 nm, 30 ° C, 0.8 mL / min, t major =6.3min,t minor =8.5min).

Claims

1. An axially chiral N-pyrazolylsulfonamide compound, characterized in that: N-pyrazolylsulfonamide compounds having the general structure of Formula I; Where: R 1 R is independently selected from p-toluenesulfonyl, p-chlorobenzenesulfonyl or thienylsulfonyl; 2 Independently selected from various aromatic groups; R 3 Independently selected from methyl, cyclohexyl or aromatic groups.

2. The axially chiral pyrazole compound according to claim 1, characterized in that: A compound having the general formula I, R 2 The aromatic groups include 2-naphthyl, phenyl or substituted phenyl, and the substituents include methyl, methoxy, chlorine and bromine, and the substitution positions include the 3rd and 4th positions of the benzene ring.

3. The axially chiral N-pyrazolylsulfonamide compound according to claim 1, characterized in that: A compound having the general formula I, R 3 The aromatic groups include 2-thienyl, phenyl and substituted phenyl, and the substituents include methyl, methoxy, trifluoromethyl, fluorine, chlorine and bromine, and the substitution positions are 2 to 4 positions of the benzene ring.

4. The axially chiral N-pyrazolylsulfonamide compound according to claim 1, characterized in that: The pyrazole compound is selected from any one of the following compounds numbered 1 to 23:

5. A method for preparing an axially chiral N-pyrazolylsulfonamide compound, characterized in that: The compound having the general formula I is prepared from N-protected 5-aminopyrazole and allyl carbonate by the following process: The following steps are involved: N-protected 5-aminopyrazole, palladium catalyst and ligand were added to replace N2, and then allyl carbonate, DIPEA and solvent were added under N2 purge. The reaction system was stirred under N2 protection and reacted at 0°C for 0.7 hours. After the reaction was completed, the reaction was concentrated and purified by column chromatography to obtain the target N-pyrazolylsulfonamide product.

6. The method for preparing the axially chiral N-pyrazolylsulfonamide compound according to claim 5, characterized in that: The palladium catalyst is Pd2dba3, and the amount used is 4.4 mol% of the N-protected 5-aminopyrazole.

7. The method for preparing the axially chiral N-pyrazolylsulfonamide compound according to claim 5, characterized in that: The ligand was N,N'-[(1R,2R)-1,2-diphenyl-1,2-ethanediyl]bis[2-diphenylphosphinamide], and the amount used was 6.6 mol% of the N-protected 5-aminopyrazole.

8. The method for preparing the axially chiral N-pyrazolylsulfonamide compound according to claim 5, characterized in that: The N-protected 5-aminopyrazole was 1 equivalent, DIPEA was 1 equivalent, and allyl carbonate was 2 equivalents.

9. The method for preparing the axially chiral N-pyrazolylsulfonamide compound according to claim 5, characterized in that: The solvent was chloroform, and the molar concentration of N-protected 5-aminopyrazole was 0.1M.

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