Preparation method of axially chiral aminopyrazole compound

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a preparation method of an axially chiral aminopyrazole compound, which comprises the following steps: by taking 1-azanaphthalene and 5-aminopyrazole derivatives as raw materials, adding into a dichloromethane solvent; the axial chiral aminopyrazole compound as shown in the general formula I is prepared under the action of a chiral Bronsted acid catalyst. The synthesis method provided by the invention is simple and efficient, the used reagent is cheap and easy to obtain, the condition is mild, the optical purity is high, and the industrial production prospect is wide.

Description

Technical Field

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

[0002] Axially chiral backbone molecules have become a key topic in asymmetric catalysis due to their greater versatility in construction methods, diverse product structures, wide application range, and excellent biological activity. Axial chirality is a ubiquitous chiral element found in a variety of natural products, pharmaceuticals, and other functional molecules. Furthermore, these backbones are also advantageous in asymmetric synthesis, being widely used in chiral auxiliary groups, ligands, and catalysts (Chemical Reviews. 2021, 121: 4805-4902). Significant progress has been made in the enantioselective construction of hexameric biaryl axial chiral structures, with key strategies including asymmetric coupling, asymmetric cyclization, asymmetric functionalization of heterobiaryl groups, and asymmetric ring-opening of bridged biaryl groups (Journal of Medicinal Chemistry. 2021, 64: 2339-2381; Chemical Communications. 2017, 53: 12385-12393). Compared to six-membered biaryl axial chiral structures, the synthesis of biaryl axial chiral structures containing five-membered heteroaromatic rings is more challenging. This is mainly due to the greater distance between the ortho-groups and the central axis of the five-membered heteroaromatic structure. Therefore, under the same conditions, the flip energy barrier is lower and the conformational stability is poorer. In recent years, people have been increasingly committed to developing novel biaryl compounds containing five-membered heteroaromatic rings, including indole structures, furan structures, and pyrrole structures of the CC, CN, and CO types (Angewandte Chemie International Edition. 2018, 58: 1494-1498; Org. Lett. 2007, 10(4), 629-631; Org. Lett. 2010, 12(21): 4872-4875; Chemical Communications. 2017, 53: 2272-2274; J. Am. Chem. Soc. 1982, 104: 3628-3635).

[0003] Nitrogen heterocycles are an important component of heterocyclic compounds. This type of structure is widely present in natural products and active molecules and is involved in the growth and metabolism of many organisms. It has a wide range of applications in organic, agricultural chemistry, medicine, and materials. Among the numerous heterocyclic compounds, pyrazoles are an important class of bioactive molecules. The unique biological and pharmaceutical activities exhibited by this type of structure have made it a focus of attention in modern organic synthesis (Journal of the American Chemical Society. 2018, 140: 8662-8666; Bioorganic & Medicinal Chemistry. 2017, 25: 5891-5903; Journal of Medicinal Chemistry. 2012, 55: 8630-8641). In recent years, there has been an increasing amount of research on the backbone construction of axially chiral pyrazole structures (Chemical Communications. 2019, 55: 12715-12718; Organic & Biomolecular Chemistry. 2024, 22: 4254-4263).

[0004] However, the current construction of axially chiral arylpyrazoles has primarily focused on the coupling reaction of 2-substituted naphthalene with pyrazole after activation of the C1 position. However, the addition of pyrazole to the corresponding six- to five-membered axially chiral pyrazole skeleton using 1-azonaphthalene as the starting substrate has not been reported. 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 aminopyrazole compounds. The invention provides a method for preparing axially chiral aminopyrazole compounds; 1-azonaphthalene and 5-aminopyrazole derivatives are used as raw materials, added to a dichloromethane solvent, and an axially chiral aminopyrazole compound as shown in the general formula I is prepared under the action of a chiral Bronsted acid catalyst. This strategy provides a new method and idea for the construction of axially chiral pyrazole heterocycles. Through reasonable reaction design, the present invention has developed an innovative and efficient method for synthesizing the axially chiral aminopyrazole structural skeleton. While synthesizing the 1,6-addition product of 1-azonaphthalene and 5-aminopyrazole, the axial chirality is controlled, and the axially chiral pyrazole structure is successfully constructed. This method 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 aminopyrazole compound, comprising synthesizing an aminopyrazole compound having a general structure of formula I by a 1,6-addition reaction between 1-azonaphthalene and a 5-aminopyrazole derivative;

[0008]

[0009] Where: R 1 R is independently selected from a cyclohexyl group or an aromatic group; 2 R is independently selected from chain alkyl, benzyl or pharmacophore; 3 are independently selected from hydrogen, triflate or p-chlorophenyl.

[0010] In the compound of the general formula I described in the present invention, R 1 The aromatic group is naphthyl, phenyl or substituted phenyl, and the substituents include methyl, methoxy, nitro, chlorine and fluorine, and the substitution positions include the 2nd, 3rd and 4th positions of the benzene ring.

[0011] In the compound of the general formula I described in the present invention, R 2 The chain alkyl group includes methyl, n-propyl, isopropyl; R 2 The pharmacophores in the drug include cholesterol and menthol-modified ester groups.

[0012] The compounds having the general formula I described in the present invention are preferably the following compounds numbered 1 to 20:

[0013]

[0014] The compound having the general formula I is prepared from 1-azonaphthalene and 5-aminopyrazole derivatives by the following process:

[0015]

[0016] The following steps are involved:

[0017] In a 25 mL Schlenk tube, add a 1-azonaphthalene derivative, a 5-aminopyrazole derivative, and a catalyst to a solvent. The nitrogen atmosphere is replaced, and the reaction system is stirred under nitrogen protection at 25°C for 4-5 days. (Preferably, the 1-azonaphthalene derivative is 1 equivalent, the 5-aminopyrazole derivative is 1.2 equivalents, and the catalyst is (R)-3,3'-bis(1-pyrenyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, at a concentration of 10 mol% of the 1-azonaphthalene derivative. The preferred solvent is dichloromethane, and the molar concentration of the 1-azonaphthalene derivative is preferably 1 M.) After completion of the reaction, the reaction is concentrated and purified by column chromatography to obtain the desired axially chiral aminopyrazole 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 1,6-addition reaction of 1-azonaphthalene with aminopyrazole was developed to synthesize a series of novel axially chiral aminopyrazoles, providing a new method and idea for the construction of axially chiral skeletons of similar 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 of the present invention is simple and efficient, uses cheap and readily available reagents, operates under mild conditions, has high optical purity, and has broad prospects for industrial production. 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 aminopyrazole 1

[0032]

[0033] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2a (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After the reaction was completed (monitored by TLC), it was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 10 to 1 / 5) to obtain product 1 as a yellow solid with an isolated yield of 37.5 mg, a yield of 87%, and an ee value of 96%. 1HNMR(400MHz, CDCl3)δ7.89(d,J=8.1Hz,1H),7.76(dd,J=7.5,2.0Hz,1H),7.74-7.67(m,2H),7.53-7.38(m,5H ),7.33-7.27(m,1H),7.03(d,J=7.7Hz,1H),6.64(s,1H),6.47(s,1H),3.82(s,3H),3.35(s,2H),1.15(s,9H). 13 C NMR (101MHz, CDCl3) δ159.4,157.6,143.8,142.5,139.4,134.1,130.8,129.4,127.2,126. 5,126.3,125.5,124.6,123.3,123.3,120.1,106.6,101.6,53.1,33.8,30.2.HRMS(ESI)m / z Calcd.for C 25 H 28 N5O2 + ([M+H] + )430.2165, Found 430.2236; Enantiomeric excess was determined to be 96% (determined by HPLC using chiral AS-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =47.7min,t minor =35.1min).

[0034] Example 2: Synthesis of axially chiral aminopyrazole 2

[0035]

[0036] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2b (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After the reaction was completed (monitored by TLC), the product 2 was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 10 to 1 / 5) to obtain a yellow solid with an isolated yield of 29.7 mg, a yield of 67%, and an ee value of 90%. 1HNMR (500MHz, CDCl3) δ7.79(d,J=7.9Hz,1H),7.71-7.65(m,1H),7.48(d,J=7.9Hz,2H),7.42-7.35(m,2H),7.32(d,J=7.7Hz,1H) ,7.22-7.14(m,2H),6.93(d,J=7.8Hz,1H),6.77-6.53(m,1H),6.38(s,1H),3.72(s,3H),3.24(s,2H),2.31(s,3H),1.07(s,9H). 13 C NMR (101MHz, CDCl3) δ159.1,157.7,143.7,142.4,136.8,136.5,134.2,130.8,130.0,127.3,12 6.3,125.4,124.7,123.4,120.1,106.6,101.3,53.1,33.7,30.2,21.1.HRMS(ESI)m / zCalcd.for C 26 H 30 N5O2 + ([M+H] + )444.2321, Found 444.2392; Enantiomeric excess was determined to be 90% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=90 / 10, λ=254nm, 30℃, 0.8mL / min, t major =35.2min,t minor =29.6min).

[0037] Example 3: Synthesis of axially chiral aminopyrazole 3

[0038]

[0039] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2c (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) gave product 3 as an orange solid in an isolated yield of 26.1 mg, a yield of 55%, and an ee value of 92%. 1HNMR (400MHz, CDCl3) δ8.33(d,J=8.9Hz,2H),8.03(d,J=8.9Hz,2H),7.90(d,J=8.1Hz,1H),7.70(d,J=8.1Hz,1H),7.55-7.42 (m,2H),7.39(d,J=7.7Hz,1H),7.05(d,J=7.8Hz,1H),6.64(s,1H),6.53-6.48(m,1H),3.82(s,3H),3.40(s,2H),1.14(s,8H). 13 C NMR (101MHz, CDCl3) δ161.4,157.6,145.0,144.7,144.4,142.9,133.9,130.9,126.9,1 26.5,125.7,125.1,123.4,121.5,120.2,106.5,104.4,53.1,34.0,29.9.HRMS(ESI)m / z Calcd.forC 25 H 27 N6O4 + ([M+H] + )475.2016, Found 475.2090; Enantiomeric excess was determined tobe 92% (determined by HPLC using chiral OD-H column, hexane / 2-propanol=70 / 30, λ=254nm, 30℃, 0.8mL / min, t major =31.3min,t minor =19.8min).

[0040] Example 4: Synthesis of axially chiral aminopyrazole 4

[0041]

[0042] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2d (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After the reaction was completed (monitored by TLC), it was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) to obtain product 4 as a yellow solid with an isolated yield of 32.1 mg, a yield of 70%, and an ee value of 90%. 1HNMR(500MHz, CDCl3)δ7.87(d,J=8.0Hz,1H),7.78-7.72(m,1H),7.61-7.55(m,2H),7.50-7.42(m,2H),7.40(d,J=7.7Hz,1 H),6.99(dd,J=15.7,8.2Hz,3H),6.72(s,1H),6.46(d,J=2.6Hz,1H),3.83(s,3H),3.80(s,3H),3.27(s,2H),1.14(s,9H). 13 C NMR (101MHz, CDCl3) δ158.9,158.4,157.6,143.7,142.4,134.2,132.4,130.8,128.9,127.3,126.2,12 5.4,125.3,124.9,120.1,114.6,106.6,101.1,77.4,77.1,76.7,55.6,53.1,33.7,30.3.HRMS(ESI)m / z Calcd.for C 26 H 30 N5O3 + ([M+H] + )460.2270, Found 460.2340; Enantiomeric excess was determined to be 90% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =19.0min,t minor =16.5min).

[0043] Example 5: Synthesis of axially chiral aminopyrazole 5

[0044]

[0045] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2e (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) gave product 5 as a yellow solid in an isolated yield of 33.3 mg, a yield of 72%, and an ee value of 91%. 1HNMR(400MHz, CDCl3)δ7.87(d,J=8.0Hz,1H),7.73(dd,J=7.7,2.0Hz,1H),7.70-7.64(m,2H),7.52-7 .35(m,5H),7.02(d,J=7.7Hz,1H),6.69(s,1H),6.47(s,1H),3.80(s,3H),3.31(s,2H),1.13(s,9H). 13 C NMR (101MHz, CDCl3) δ159.8,157.6,143.8,142.6,138.0,134.1,131.9,130.8,129.5,127. 1,126.4,125.5,124.3,124.2,123.3,120.1,106.6,102.3,53.1,33.8,30.1.HRMS(ESI)m / z Calcd.for C 25 H 27 ClN5O2 + ([M+H] + )464.1775, Found 464.1851; Enantiomeric excess was determined to be 91% (determined by HPLC using chiralOD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =24.8min,t minor =20.2min).

[0046] Example 6: Synthesis of axially chiral aminopyrazole 6

[0047]

[0048] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2f (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After the reaction was completed (monitored by TLC), it was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 10 to 1 / 5) to obtain product 6 as a yellow solid with an isolated yield of 33.5 mg, a yield of 75%, and an ee value of 94%. 1HNMR (500MHz, CDCl3) δ7.88(d,J=8.0Hz,1H),7.76-7.72(m,1H),7.70-7.64(m,2H),7.51-7.42(m,2H),7.39(d,J=7.7Hz ,1H),7.18-7.11(m,2H),7.02(d,J=7.8Hz,1H),6.69(s,1H),6.52-6.42(m,1H),3.81(s,3H),3.29(s,2H),1.13(s,9H). 19 F NMR (377MHz,CDCl3)δ-115.34. 13 C NMR (101MHz, CDCl3) δ159.4,157.6,143.7,142.5,135.5,134.1,130.8,127.2,126.3,125. 5,125.2,125.1,124.5,120.1,116.3,116.1,106.6,101.8,53.1,33.7,30.2.HRMS(ESI)m / z Calcd.for C 25 H 27 FN5O2 + ([M+H] + )448.2071, Found 448.2144; Enantiomeric excess was determined to be 94% (determined by HPLC using chiralAD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =14.6min,t minor =12.5min).

[0049] Example 7: Synthesis of axially chiral aminopyrazole 8

[0050]

[0051] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2h (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 10 to 1 / 5) gave product 8 as an orange solid in an isolated yield of 23.9 mg, a yield of 54%, and an ee value of 84%.1 HNMR (400MHz, CDCl3) δ7.88 (d, J = 7.6Hz, 1H), 7.77-7.71 (m, 1H), 7.56-7.39 (m, 5H), 7.36-7.27 (m, 3H) ,7.02(d,J=7.7Hz,1H),6.68(s,1H),6.45(s,1H),3.81(s,3H),3.09(s,2H),2.26(s,3H),1.14(s,9H). 13 C NMR (101MHz, CDCl3) δ158.8,157.7,144.5,142.3,137.3,137.1,134.2,131.4,130.8,129.1,128.0,12 7.1,126.8,126.2,125.4,120.1,106.6,99.6,77.4,77.1,76.7,53.1,33.7,30.4,17.8.HRMS(ESI)m / z Calcd.for C 26 H 30 N5O2 + ([M+H] + )444.2321, Found 444.2395; Enantiomeric excess was determined to be 84% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =13.1min,t minor =10.3min).

[0052] Example 8: Synthesis of axially chiral aminopyrazole 9

[0053]

[0054] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2i (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) gave product 9 as a yellow solid in an isolated yield of 32.4 mg, a yield of 73%, and an ee value of 94%. 1HNMR (500MHz, CDCl3) δ7.88(d,J=8.0Hz,1H),7.76(d,J=8.0Hz,1H),7.52(s,1H),7.51-7.42(m,3H),7.40(d,J=7.7Hz,1H),7.37-7.30(m ,1H),7.11(d,J=7.6Hz,1H),7.02(d,J=7.7Hz,1H),6.85-6.54(m,1H),6.46(s,1H),3.81(s,3H),3.35(s,2H),2.41(s,3H),1.15(s,9H). 13 C NMR (101MHz, CDCl3) δ159.2,157.6,143.8,142.4,139.6,139.2,134.2,130.8,129.2,127.5,127.3,1 26.3,125.5,124.7,124.3,123.3,120.3,120.1,106.6,101.4,53.1,33.7,30.2,21.5.HRMS(ESI)m / z Calcd.for C 26 H 30 N5O2 + ([M+H] + )444.2321, Found444.2389; Enantiomeric excess was determined to be 94% (determined by HPLC using chiral OD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =18.5min,t minor =15.7min).

[0055] Example 9: Synthesis of axially chiral aminopyrazole 10

[0056]

[0057] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2j (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) gave product 10 as an orange solid in an isolated yield of 37.5 mg, a yield of 87%, and an ee value of 96%.1 HNMR(500MHz, CDCl3)δ7.88(d,J=8.4Hz,1H),7.80-7.72(m,1H),7.51-7.43(m,2H),7.40(d,J=7.7Hz,1H),7.38-7.33(m,1H),7.30-7.2 6(m,2H),7.03(d,J=7.8Hz,1H),6.86-6.80(m,1H),6.66(s,1H),6.51-6.43(m,1H),3.86(s,3H),3.81(s,3H),3.38(s,2H),1.14(s,9H). 13 CNMR (101MHz, CDCl3) δ160.5,159.4,157.6,143.8,142.5,140.5,134.1,130.8,130.1,127.3,126 .3,125.5,124.6,120.1,115.2,112.5,109.0,106.6,101.6,55.5,53.1,33.8,30.2.HRMS(ESI)m / z Calcd.for C 26 H 30 N5O3 + ([M+H] + )460.2270, Found 460.2342; Enantiomeric excess was determined to be 92% (determined by HPLC using chiralID-H column, hexane / 2-propanol=70 / 30, λ=254nm, 30℃, 0.8mL / min, t major =23.3min,t minor =15.2min).

[0058] Example 10: Synthesis of axially chiral aminopyrazole 11

[0059]

[0060] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2k (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). The N₂ atmosphere was replaced, and the reaction system was stirred under N₂ protection, maintaining the reaction solution at 25° C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) afforded product 11 as an orange solid in an isolated yield of 32.4 mg, a yield of 70%, and an ee value of 92%. 1 H NMR (500MHz, CDCl3) δ7.88(d,J=8.2Hz,1H),7.80-7.77(m,1H),7.75-7.70(m,1H),7.63(dd,J=7.7,2.0Hz,1H),7.52-7.43(m,2H ),7.41-7.35(m,2H),7.28-7.23(m,1H),7.03(d,J=7.8Hz,1H),6.66(s,1H),6.48(s,1H),3.81(s,3H),3.34(s,2H),1.13(s,9H). 13 C NMR (101MHz, CDCl3) δ160.0,157.6,143.9,142.6,140.6,135.1,134.1,130.8,130.3,127.1,126 .4,125.5,124.2,123.2,120.7,120.1,102.4,77.4,77.0,76.7,53.1,33.8,30.1.HRMS(ESI)m / z Calcd.for C 25 H 27 ClN5O2 + ([M+H] + )464.1775, Found 464.1849; Enantiomeric excess was determined to be 92% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =13.6min,t minor =11.3min).

[0061] Example 11: Synthesis of axially chiral aminopyrazole 13

[0062]

[0063] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (0.20 mmol), 5-aminopyrazole derivative 2m (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After the reaction was completed (monitored by TLC), the product 13 was purified by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 10 to 1 / 5) to obtain a yellow solid in an isolated yield of 34.5 mg, a yield of 72%, and an ee value of 92%. 1 H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.37(s,1H),8.25-8.13(m,2H),8.08-8.01(m,1H),8.01-7.91(m,3H),7.67-7.59(m,1H),7.54(q, J=8.1,7.6Hz,2H),7.49-7.41(m,2H),7.33(dd,J=7.8,2.0Hz,1H),6.78(dd,J=7.8,2.1Hz,1H),4.47(s,2H),3.68(s,3H),1.07(s,9H). 13 CNMR(101MHz,DMSO-d6)δ158.8,157.9,145.9,144.4,137.7,134.4,133.6,131.5,131.4,129.2,128.4,128.1,127 .1,126.9,126.3,126.2,124.7,122.8,122.6,122.3,121.9,119.6,104.8,101.7,52.4,33.9,30.5.HRMS(ESI)m / z Calcd.for C 29 H 30 N5O2 + ([M+H] + )480.2321, Found 480.2396; Enantiomeric excess was determined to be 92% (determined by HPLC using chiral IC-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =10.4min,t minor =8.3min).

[0064] Example 12: Synthesis of axially chiral aminopyrazole 14

[0065]

[0066] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1b (0.20 mmol), 5-aminopyrazole derivative 2a (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether=1 / 10 to 1 / 5) gave product 14 as an orange solid in an isolated yield of 29.3 mg, a yield of 64%, and an ee value of 94%. 1 HNMR (400MHz, CDCl3) δ7.89(d,J=7.9Hz,1H),7.80-7.66(m,3H),7.54-7.37(m,5H),7.32-7.27(m,1H),7.03(d,J=7.7H z,1H),6.63(s,1H),6.48(d,J=2.6Hz,1H),4.17(d,J=8.0Hz,2H),3.34(s,2H),1.71(s,2H),1.14(s,9H),0.99(s,3H). 13 C NMR (101MHz, CDCl3) δ159.4,157.4,143.8,142.7,139.4,134.1,130.9,129.4,127.2,126.5, 126.2,125.4,124.5,123.3,120.1,106.5,101.7,67.7,33.8,30.2,22.3,10.3.HRMS(ESI)m / z Calcd.forC 27 H 32 N5O2 + ([M+H] + )458.2478, Found 458.2546; Enantiomeric excess was determined tobe 94% (determined by HPLC using chiral AD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =13.0min,t minor =10.7min).

[0067] Example 13: Synthesis of axially chiral aminopyrazole 16

[0068]

[0069] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1d (0.20 mmol), 5-aminopyrazole derivative 2a (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) gave product 1 as a yellow solid in an isolated yield of 25.8 mg, a yield of 51%, and an ee value of 96%. 1 HNMR(400MHz, CDCl3)δ7.85(dd,J=6.5,3.1Hz,1H),7.78-7.73(m,1H),7.72-7.67(m,2H),7.50-7.42(m,5H),7.42-7.31(m ,5H),7.31-7.26(m,1H),6.98(d,J=7.7Hz,1H),6.78(s,1H),6.48(d,J=2.8Hz,1H),5.21(s,2H),3.33(s,2H),1.14(s,9H). 13 C NMR (101MHz, CDCl3) δ159.40,157.08,143.79,142.46,139.40,135.82,134.13,130.84,129.41,128.67,128.53 ,127.23,126.51,126.28,125.44,124.58,123.29,120.14,106.59,101.62,67.76,33.77,30.22.HRMS(ESI)m / z Calcd.for C 31 H 32 N5O2 + ([M+H] + )506.2478, Found 506.2549; Enantiomeric excess was determined to be 96% (determined by HPLC using chiralAD-H column, hexane / 2-propanol=70 / 30, λ=254nm, 30℃, 0.8mL / min, t major =12.5min,t minor =9.3min).

[0070] Example 14: Synthesis of axially chiral aminopyrazole 17

[0071]

[0072] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1e (0.20 mmol), 5-aminopyrazole derivative 2a (0.24 mmol) and catalyst (0.02 mmol) were added to DCM (2 mL). The N₂ was replaced, and the reaction system was stirred under N₂ protection, and the reaction solution was kept stirring at 25° C. After completion of the reaction (monitored by TLC), the product 17 was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) to obtain a yellow solid in an isolated yield of 47.8 mg, a yield of 61%, and an ee value of 93%. 1 HNMR(400MHz, CDCl3)δ7.94-7.86(m,1H),7.76(dd,J=8.2,1.6Hz,1H),7.73-7.68(m,2H),7.54-7.45(m,4H),7.41(d,J= 7.7Hz,1H),7.33-7.27(m,1H),7.03(d,J=7.7Hz,1H),6.57(s,1H),6.49(s,1H),5.39(s,1H),4.70-4.56(m,1H),3.36(s ,2H),2.42(s,2H),1.99(t,J=15.2Hz,3H),1.92-1.79(m,2H),1.57-1.43(m,6H),1.39-1.24(m,6H),1.14(s,9H),1.10- 1.07(m,2H),1.03(d,J=6.9Hz,2H),1.01-0.96(m,2H),0.91(d,J=6.5Hz,3H),0.86(dd,J=6.6,1.8Hz,6H),0.68(s,3H). 13 C NMR (101MHz, CDCl3) δ159.4,156.8,143.8,142.7,139.5,139.4,134.1,130.9,129 .4,127.2,126.5,126.3,125.4,123.3,122.9,120.1,106.7,101.7,75.9,56.7,56 .2,50.0,42.3,39.7,39.5,38.4,36.9,36.6,36.2,35.8,33.8,31.9,31.9,30.2,2 8.2,28.0,24.3,23.8,22.8,22.6,21.1,19.3,18.7,11.9.HRMS(ESI)m / zCalcd.for C 51 H 70 N5O2 + ([M+H] +)784.5451, Found 784.5522; Enantiomeric excess was determined to be 93% (determined by HPLC using chiral IC-H column, hexane / 2-propanol=70 / 30, λ=254nm, 30℃, 0.8mL / min, t major =11.8min,t minor =7.6min).

[0073] Example 15: Gram-scale synthesis of axially chiral aminopyrazoles

[0074]

[0075] In a 25 mL Schlenk tube, 1-azonaphthalene derivative 1a (3.00 mmol), 5-aminopyrazole derivative 2e (3.30 mmol) and catalyst (0.30 mmol) were added to DCE (30 mL). N2 was replaced, and the reaction system was stirred under N2 protection, and the reaction solution was kept stirring at 25°C. After completion of the reaction (monitored by TLC), purification by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10 to 1 / 5) gave 1.1 g of product 5 as a yellow solid in a yield of 79% and an ee value of 91%. 1 HNMR(400MHz, CDCl3)δ7.87(d,J=8.0Hz,1H),7.73(dd,J=7.7,2.0Hz,1H),7.70-7.64(m,2H),7.52-7 .35(m,5H),7.02(d,J=7.7Hz,1H),6.69(s,1H),6.47(s,1H),3.80(s,3H),3.31(s,2H),1.13(s,9H). 13 C NMR (101MHz, CDCl3) δ159.8,157.6,143.8,142.6,138.0,134.1,131.9,130.8,129.5,127. 1,126.4,125.5,124.3,124.2,123.3,120.1,106.6,102.3,53.1,33.8,30.1.HRMS(ESI)m / z Calcd.for C 25 H 27 ClN5O2 + ([M+H] +)464.1775, Found 464.1851; Enantiomeric excess was determined to be 91% (determined by HPLC using chiralOD-H column, hexane / 2-propanol=80 / 20, λ=254nm, 30℃, 0.8mL / min, t major =24.8min,t minor =20.2min).

[0076] Example 16: Conversion of axially chiral aminopyrazoles

[0077]

[0078] 5 (0.2 mmol) was dissolved in 3 mL of dichloromethane and PCC (52 mg, 0.24 mmol) was added. The mixture was stirred at room temperature until 5 was completely consumed (monitored by TLC). The reaction mixture was filtered through celite. Concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 20 to 1 / 10) to give 56.5 mg of a red oily product with a yield of 62% and an ee value of 88%. 1 HNMR (400MHz, CDCl3) δ8.91 (d, J=8.5Hz, 1H), 7.88 (dd, J=8.3, 6.4Hz, 2H), 7.73-7.65 (m,3H),7.65-7.57(m,2H),7.49-7.43(m,2H),4.14(s,3H),3.35(s,2H),1.15(s,9H). 13 C NMR (101MHz, CDCl3) δ162.9,159.2,146.6,143.1,139.5,137.7,134.2,132.4,132.1,130. 2,129.6,128.0,127.4,126.5,124.5,123.6,112.1,101.5,54.9,33.9,30.2.HRMS(ESI)m / z Calcd.for C 25 H 25 ClN5O2 + ([M+H] +)462.1619,Found 462.0687;Enantiomericexcess was determined to be 88%(determined by HPLC using chiral AD-H column,hexane / 2-propanol=80 / 20,λ=254nm,30℃,0.8mL / min,t major =9.0min,t minor =7.7min)。

Claims

1. An axially chiral aminopyrazole compound, characterized in that: An aminopyrazole having the general structure of formula I; Where: R 1 R is independently selected from a cyclohexyl group or an aromatic group; 2 R is independently selected from chain alkyl, benzyl or pharmacophore; 3 are independently selected from hydrogen, triflate or p-chlorophenyl.

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

3. The axially chiral aminopyrazole compound according to claim 1, characterized in that: A compound having the general formula I, R 2 The chain alkyl group includes methyl, n-propyl, isopropyl; R 2 The pharmacophores in the drug include cholesterol and menthol-modified ester groups.

4. A method for preparing an axially chiral aminopyrazole compound, characterized in that: The compound having the general formula I is prepared from a 1-azonaphthalene derivative (1) and a 5-aminopyrazole derivative (2) as raw materials by the following process: The method comprises the following steps: adding a 1-azonaphthalene derivative, a 5-aminopyrazole derivative and a catalyst into a solvent, replacing N2, stirring the reaction system under N2 protection, and reacting at 25°C for 4 to 5 days; concentrating after the reaction is completed, and purifying by column chromatography to obtain an axially chiral aminopyrazole target product.

5. The method for preparing an axially chiral aminopyrazole compound according to claim 4, wherein: The catalyst is (R)-3,3'-bis(1-pyrenyl)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthol phosphate, and the amount used is 10 mol% of the 1-azonaphthalene derivative.

6. The method for preparing an axially chiral aminopyrazole compound according to claim 4, wherein: The solvent was dichloromethane, and the molar concentration of the 1-azonaphthalene derivative was 1M.

7. The method for preparing an axially chiral aminopyrazole compound according to claim 5, wherein: The amount of the 1-azonaphthalene derivative is 1 equivalent, and the amount of the 5-aminopyrazole derivative is 1.2 equivalents.

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