A method for synthesizing chiral 1,4-dienylpyrazole derivatives

Abstract

The present invention discloses a method for synthesizing a chiral 1,4-dienylpyrazole derivative compound with high chemical, regio- and enantioselectivity. Specifically, it is a method for preparing a chiral 1,4-dienylpyrazole derivative compound by combining an iridium catalyst and a chiral ligand to catalyze a substitution reaction between racemic 1,4-dienyl allyl alcohol and a pyrazole derivative compound, and the method belongs to the field of organic synthesis. The specific operation steps are: under argon protection, an iridium catalyst and a chiral ligand are added to a reaction tube, followed by adding 1,4-dienyl allyl alcohol, a pyrazole derivative compound and an additive, and then reacting at 0°C. After the reaction is complete, the reaction is quenched and purified to obtain a chiral 1,4-dienylpyrazole derivative compound. The method has good substrate applicability and mild reaction conditions. It has the advantages of high chemical selectivity, regioselectivity and enantioselectivity.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing chiral 1,4-dienylpyrazole derivatives with high chemical, regio- and enantioselectivity. Background Art

[0002] Chiral pyrazole compounds are a common class of organic synthesis intermediates, found extensively in natural products and various pharmaceutical intermediates. Marketed small molecule drugs such as ruxolitinib, MK-0893, and zanubrutinib all contain chiral pyrazole backbone units. All reported syntheses of chiral pyrazoles are based on the strategy of catalytic asymmetric reductive hydroamination of olefins and pyrazoles (for details, see: (a) AM Haydl, K. Xu, B. Breit, Angew. Chem. Int. Ed. 2015, 54, 7149-7153; (b) LJ Hilpert, SV Sieger, AM Haydl, B. Breit, Angew. Chem. Int. Ed. 2019, 58, 3378-3381; (c) AY Jiu, HS S Locumb, C.S. Yeung, X.-H. Yang, VM Dong, Angew. Chem. Int. Ed. 2021, 60, 19660-19664). Among them, olefin substrates include compounds such as allenes and 1,3-dienes. Most of the allene and 1,3-diene substrates are difficult to synthesize and their types are extremely limited. The limitation of the substrates seriously restricts the synthesis and development of chiral pyrazole derivatives.

[0003] Catalytic asymmetric N-alkylation is an important method for constructing chiral amine compounds. However, due to the weak nucleophilicity of pyrazole derivatives, there is currently no precedent for the N-asymmetric alkylation of pyrazole derivatives. Summary of the Invention

[0004] In view of the limitations of the previously developed methods, the present invention utilizes an asymmetric catalytic allylation strategy to provide a method for synthesizing chiral 1,4-dienyl pyrazole compounds with high chemical, regio, and enantioselectivity from commercially available pyrazole compounds and readily available 1,4-dienyl alcohols as reaction raw materials.

[0005] In order to achieve the purpose of the present invention, the technical solution adopted is:

[0006] A method for synthesizing chiral 1,4-dienylpyrazole compounds with high chemical, regio- and enantioselectivity. Under the catalysis of an iridium catalyst, racemic 1,4-dienyl allyl alcohol and a pyrazole derivative undergo a substitution reaction to generate a series of chiral 1,4-dienylpyrazole compounds.

[0007] Furthermore, the method is carried out according to the following steps: under argon protection, the iridium catalyst and chiral ligand L are dissolved in dichloromethane solvent and placed in a sealed tube, and stirred for 5 minutes. Subsequently, 1,4-dienyl allyl alcohol, pyrazole derivatives, and additives are added to the sealed tube in sequence, the argon atmosphere is replaced, and the reaction is carried out at 0°C for 2 hours. The reaction is quenched and purified to obtain a chiral 1,4-dienylpyrazole compound.

[0008] The specific reaction equation is as follows (Scheme 1):

[0009]

[0010] Scheme 1. Reaction equation

[0011] The structural formula of the racemic 1,4-dienyl allyl alcohol is:

[0012] Among them, R 1 It can be an alkyl or aryl group.

[0013] Furthermore, the structural formula of the pyrazole derivative is:

[0014] Among them, R 2 It is alkyl, aryl, halogen and nitro.

[0015] Furthermore, the molar ratio of the 1,4-dienyl allyl alcohol to the pyrazole derivative is 1-2:1, and more preferably 1.5:1, as the yield is the highest at this molar ratio.

[0016] Furthermore, the solvent is dichloromethane, dichloroethane, toluene, or ether, wherein dichloromethane is the optimal solvent.

[0017] Furthermore, the iridium catalyst is 1,5-cyclooctadiene iridium chloride dimer; the amount of the iridium catalyst used is 2%-4% of the pyrazole derivative equivalent; preferably, the amount of the iridium catalyst used is 4% of the pyrazole derivative equivalent.

[0018] Furthermore, the chiral ligand L is a chiral phosphoramidite ligand, and its structural formula is:

[0019]

[0020] Furthermore, the chiral phosphoramidite ligand L is in S-configuration, and the amount of the chiral ligand used is 200-400% of the iridium catalyst equivalent; wherein, the yield is highest when the amount used is 400% of the molar amount of the iridium catalyst.

[0021] Furthermore, the additive is ytterbium trifluoromethanesulfonate Yb(OTf) 3，The equivalent amount is 10%-100% of the pyrazole derivative equivalent. The highest yield is achieved when the catalytic amount is 20%.

[0022] Beneficial effects:

[0023] The method of the present invention utilizes a designed catalytic system and screening conditions, using readily prepared 1,4-dienyl alcohols and commercially available pyrazole derivatives as starting materials to achieve asymmetric allylic substitution of pyrazole derivatives, resulting in the highly selective preparation of a series of chiral pyrazole compounds. This method offers the advantages of good substrate compatibility, mild reaction conditions, and high chemoselectivity, regioselectivity, and enantioselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the H NMR spectrum of 3aa;

[0025] Figure 2 This is the 3aa carbon nuclear magnetic resonance spectrum;

[0026] Figure 3 This is the chiral HPLC chromatogram of 3aa;

[0027] Figure 4 .This is a 3aa high-resolution analysis image. DETAILED DESCRIPTION

[0028] The present invention will be further described below with reference to the examples, but is not limited thereto.

[0029] In the following specific examples of the present invention, pyrazole raw materials 2a-2c were all purchased commercially. Other reagents in the present invention, unless otherwise specified, were all purchased commercially.

[0030] In the following specific examples, diene alcohols 1a-1f were prepared according to the following general method:

[0031]

[0032] Procedure: Dissolve 10 mmol of the corresponding unsaturated enal IV in 20 mL of dry tetrahydrofuran. Cool the reaction mixture to 0°C in an ice bath. Slowly add 12 mmol of vinylmagnesium chloride dropwise via syringe. After addition, continue stirring for 1 hour. Then, quench the mixture with saturated ammonium chloride solution, extract with 50 mL of ethyl acetate, evaporate to dryness, and separate on a silica gel column to obtain the desired product.

[0033] Example 1

[0034] Synthesis of (3aa):

[0035]

[0036] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), (S)-L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol, 27.3 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (12.4 mg, 0.02 mmol) were added. The tube was sealed and the reaction was allowed to proceed at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3aa (27.8 mg, 95% ee, yield: 76%). 1 H NMR (300MHz, CDCl3) δ7.94-7.74(m,2H),7.39(t,J=7.4Hz,3H),7.34-7.23( m,1H),7.14(s,1H),6.41(t,J=6.7Hz,1H),6.25(ddd,J=16.7,10.4,6.2Hz, 1H),5.89(dd,J=15.4,7.2Hz,1H),5.79-5.65(m,1H),5.24-5.14(m,2H),3. 90(s,3H),2.06(q,J=6.9Hz,2H),1.42-1.22(m,10H),0.86(t,J=6.6Hz,3H). 13 C NMR (75MHz, CDCl3) δ160.4,150.3,137.4,134.8,132.9,132.7,128.7,128.1,12 7.9,125.8,116.7,108.3,64.5,52.1,32.4,31.9,29.3,29.2,29.1,22.8,14.2.

[0037] HRMS (ESI) m / z calculated molecular weight C 23 H 31 N2O2[M+H] + :367.2380, measured:367.2382.HPLC: Enantiomeric excess was determined by high performance liquid chromatography. Specific conditions: Daicel Chiralpak OD column (mobile phase: n-hexane / isopropanol = 99:1), flow rate: 1.0 mL / min, λ = 254 nm, retention time: t R (major)=5.17min,t R (minor) = 4.17min.ee = 98%.

[0038] Example 2

[0039] Synthesis of (3ab):

[0040]

[0041] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), chiral ligand L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol, 27.3 mg), 2b (0.1 mmol, 13.3 mg), and Yb(OTf)3 (10 mg, 0.12 mmol) were added. The tube was sealed and the reaction was incubated at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3ab (18.1 mg, 97% ee, yield: 58%). 1 HNMR (300MHz, CDCl3) δ8.17(s,1H),8.11(s,1H),6.15-5.99(m,1H),5.82(dt,J=15.4,6.6Hz,1H),5.72-5.63(m,1H),5.40(d ,J=10.4Hz,1H),5.33(t,J=6.6Hz,1H),5.29-5.21(m,1H),2.13(q,J=6.9Hz,2H),1.50-1.24(m,10H),0.88(t,J=6.6Hz,3H). 13 C NMR (75 MHz, CDCl3) δ 138.1, 135.9, 134.5, 127.4, 125.0, 119.5, 67.4, 32.4, 31.9, 29.24, 29.18, 28.8, 22.8, 14.2. HRMS (ESI) m / z calculated molecular weight C 15 H 24 N3O2[M+H] + : 278.1863, measured: 278.1796 HPLC: Enantiomeric excess was determined by high performance liquid chromatography, specific conditions: Daicel Chiralpak IC column (mobile phase: n-hexane / isopropanol = 95:5), flow rate: 1.0 mL / min, λ = 225 nm, retention time: t R (major)=5.65min,t R (minor) = 5.33min.ee = 97%.

[0042] Example 3

[0043] Synthesis of (3ac):

[0044]

[0045] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), chiral ligand L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol, 27.3 mg), 2c (0.1 mmol, 14.4 mg), and Yb(OTf)3 (10 mg, 0.12 mmol) were added. The tube was sealed and the reaction was incubated at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3ac (22.1 mg, 96% ee, 72% yield). 1 H NMR (300MHz, CDCl3) δ7.86-7.76(m,2H),7.44-7.35(m,3H),7.31-7.25(m,1H),6.57(d,J=2.4Hz,1H),6.14(ddd,J=17.1,10.3,5.7Hz,1H),5.81-5. 64(m,2H),5.41(t,J=5.3Hz,1H),5.28(dd,J=10.3,1.1Hz,1H),5.21-5.11 (m,1H),2.10(q,J=6.8Hz,2H),1.44-1.25(m,10H),0.88(t,J=6.5Hz,3H). 13 C NMR (75 MHz, CDCl3) δ 151.4, 136.6, 135.6, 133.8, 129.1, 128.6, 127.6, 127.1, 125.8, 117.5, 102.9, 66.0, 32.5, 31.9, 29.26, 29.25, 29.1, 22.8, 14.2. HRMS (ESI) m / z calculated molecular weight C 21 H 29 N2[M+H] + :309.2331, measured: 309.2321. HPLC: Enantiomeric excess was determined by high performance liquid chromatography. Specific conditions: Daicel Chiralpak OD-H column (mobile phase: n-hexane / isopropanol = 90:10), flow rate: 1.0 mL / min, λ = 225 nm, t R (major) = 7.37 min, retention time: t R (minor) = 6.78min.ee = 97%.

[0046] Example 4

[0047] Synthesis of (3ba):

[0048]

[0049] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), (S)-L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1b (0.15 mmol, 19.0 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (12.4 mg, 0.02 mmol) were added. The tube was sealed and the reaction was incubated at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3ba (22.5 mg, 99% ee, yield: 73%). 1 H NMR (300MHz, CDCl3) δ7.83-7.80(m,2H),7.44-7.36(m,2H),7.34-7.27(m,1H) ,7.14(s,1H),6.41(t,J=6.7Hz,1H),6.25(ddd,J=16.8,10.4,6.2Hz,1H),5.90 (ddt,J=15.4,7.1,1.2Hz,1H),5.71(dt,J=15.0,6.6Hz,1H),5.24-5.14(m,2H) ,3.90(s,3H),2.04(q,J=7.3Hz,2H),1.48-1.34(m,2H),0.89(t,J=7.3Hz,3H).

[0050] 13 C NMR (75MHz, CDCl3) δ160.4,150.3,137.5,134.5,132.9,132.7,128.8,128.2,128.1,125.8,116.7,108.3,64.6,52.1,34.5,22.3,13.8.

[0051] HRMS (ESI) m / z calculated molecular weight C 19 H 23 N2O2[M+H] + :311.1754, measured:311.1754.

[0052] HPLC: Enantiomeric excess was determined by high performance liquid chromatography. Specific conditions: Daicel Chiralpak IC column (mobile phase: n-hexane / isopropanol = 99:1), flow rate: 1.0 mL / min, λ = 254 nm, retention time: t R (major)=5.58min,t R (minor) = 4.00min.ee > 99%.

[0053] Example 5

[0054] Synthesis of (3ca):

[0055]

[0056] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), chiral ligand L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1c (0.15 mmol, 28.5 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (10 mg, 0.12 mmol) were added. The tube was sealed and the reaction was incubated at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3ca (31.7 mg, 90% ee, 85% yield). 1 H NMR (300MHz, CDCl3) δ7.85-7.81(m,2H),7.43-7.28(m,5H),7.16(s,1H),6.87-6.79(m,2H),6.65 -6.43(m,3H),6.35(ddd,J=17.3,10.1,6.1Hz,1H),5.32-5.23(m,2H),3.91(s,3H),3.79(s,3H). 13 C NMR (75MHz, CDCl3) δ160.4,159.6,150.5,137.0,132.82,132.78,132.4,129.3 ,128.8,128.14,128.06,125.8,125.4,117.3,114.1,108.4,64.7,55.4,52.1.

[0057] HRMS (ESI) m / z calculated molecular weight C 23 H 23 N2O3[M+H] + :375.1703, measured: 375.1703. HPLC: Enantiomeric excess was determined by high performance liquid chromatography. Specific conditions: Daicel Chiralpak IC column (mobile phase: n-hexane / isopropanol = 99:1), flow rate: 1.0 mL / min, λ = 254 nm, retention time: t R (major)=12.19min,t R (minor) = 8.28min.ee = 90%.

[0058] Example 6

[0059] Synthesis of (3da):

[0060]

[0061] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), chiral ligand L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1d (0.15 mmol, 25.0 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (10 mg, 0.12 mmol) were added. The tube was sealed and the reaction was incubated at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3da (24.5 mg, 98% ee, yield: 71%). 1 H NMR (300MHz, CDCl3) δ7.87-7.79(m,2H),7.45-7.26(m,3H),7.14(s,1H),6.43(t,J=6.7Hz,1H),6.32-6.18(m,1H),5.92(dd,J=15.4,7.2H z,1H),5.80-5.66(m,1H),5.43-5.27(m,2H),5.23-5.13(m,2H),3.89(s,3H),2.16-2.11(m,4H),2.07-1.95(m,2H),0.93(t,J=7.5Hz,3H).

[0062] 13 C NMR (75MHz, CDCl3) δ160.3,150.3,137.3,133.9,132.9,132.7,132.3,128.7, 128.4,128.2,128.1,125.8,116.8,108.3,64.4,52.0,32.5,26.7,20.7,14.4.

[0063] HRMS (ESI) m / z calculated molecular weight C 22 H 27 N2O2[M+H] + :351.2067, measured:351.2066.

[0064] HPLC: Enantiomeric excess was determined by high-performance liquid chromatography using a Daicel Chiralpak IA column (mobile phase: n-hexane / isopropanol = 99.5:0.5), flow rate: 1.0 mL / min, λ = 225 nm, retention time: tR(major) = 5.81 min, tR(minor) = 5.12 min, ee > 99%.

[0065] Example 7

[0066] Synthesis of (3ea):

[0067]

[0068] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), chiral ligand L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1e (0.15 mmol, 25 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (10 mg, 0.12 mmol) were added. The tube was sealed and the reaction was incubated at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3ea (26.5 mg, 99% ee, 76% yield). 1 H NMR (300MHz, CDCl3) δ7.85-7.79(m,2H),7.43-7.36(m,2H),7.34-7.27(m,1H ),7.13(s,1H),6.39(t,J=6.7Hz,1H),6.24(ddd,J=16.6,10.3,6.1Hz,1H),5 .85(ddd,J=15.6,7.2,0.9Hz,1H),5.67(dd,J=15.6,6.4Hz,1H),5.23-5.12( m,2H),3.89(s,3H),2.03-1.94(m,1H),1.74-1.63(m,5H),1.33-1.01(m,5H).

[0069] 13 C NMR (75MHz, CDCl3) δ160.3,150.3,140.3,137.6,132.9,132.7,128.7,128. 0,125.8,125.6,116.6,108.3,64.7,52.0,40.5,32.75,32.73,26.3,26.1.

[0070] HRMS (ESI) m / z calculated molecular weight C 22 H 27 N2O2[M+H] + :351.2067, measured:351.2066.

[0071] HPLC: Enantiomeric excess was determined by high performance liquid chromatography. Specific conditions: Daicel Chiralpak IC column (mobile phase: n-hexane / isopropanol = 90:10), flow rate: 1.0 mL / min, λ = 225 nm, retention time: t R (major)=3.99min,t R (minor) = 3.66min.ee = 99%.

[0072] Example 8

[0073] Synthesis of (3fa):

[0074]

[0075] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), chiral ligand L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1f (0.15 mmol, 28.2 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (10 mg, 0.12 mmol) were added. The tube was sealed and the reaction was incubated at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3fa (23.7 mg, 97% ee, yield: 64%). 1 H NMR (300MHz, CDCl3) δ7.84-7.79(m,2H),7.43-7.37(m,2H),7.34-7.21(m,3H),7.19-7.12(m,4H),6.42(t,J=6.6Hz,1H),6.29-6.16(m,1H) ,5.92(dd,J=15.5,7.2Hz,1H),5.75(dt,J=15.4,6.4Hz,1H),5.23-5.10(m,2H),3.90(s,3H),2.70(t,J=7.2Hz,2H),2.38(q,J=7.0Hz,2H).

[0076] 13 C NMR (75MHz, CDCl3) δ160.3,150.4,141.7,137.2,133.5,132.8,132.7,128.8,1 28.7,128.6,128.4,128.1,125.9,125.8,116.8,108.3,64.4,52.1,35.5,34.2.

[0077] HRMS (ESI) m / z calculated molecular weight C 24 H 25 N2O2[M+H] + :373.1911, measured:373.1909.

[0078] HPLC: Enantiomeric excess was determined by high-performance liquid chromatography (HPLC) using a Daicel Chiralpak IC column (mobile phase: n-hexane / isopropanol = 99:1), flow rate: 1.0 mL / min, λ = 234 nm, retention time: tR(major) = 7.88 min, tR(minor) = 5.42 min, ee = 97%.

[0079] Example 9

[0080] Synthesis of (3aa):

[0081] Under argon, 1,5-cyclooctadiene iridium chloride dimer (1.3 mg, 2 mol%), (S)-L (4.0 mg, 8 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol, 27.3 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (12.4 mg, 0.02 mmol) were added. The tube was sealed and the reaction was allowed to proceed at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3aa (18.3 mg, 95% ee, yield: 50%).

[0082] Example 10

[0083] Synthesis of (3aa):

[0084] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), (S)-L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol, 27.3 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (12.4 mg, 0.02 mmol) were added. The tube was sealed and the reaction was allowed to proceed at 25°C for 2 hours. The crude product was purified by preparative TLC to afford 3aa (27.8 mg, 92% ee, yield: 76%).

[0085] Example 11

[0086] Synthesis of (3aa):

[0087] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), (S)-L (8.0 mg, 16 mol%), and toluene (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1a (0.15 mmol, 27.3 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (12.4 mg, 0.02 mmol) were added. The tube was sealed and the reaction was allowed to proceed at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3aa (14.0 mg, 92% ee, yield: 38%).

[0088] Example 12

[0089] Synthesis of (3aa):

[0090] Under argon, 1,5-cyclooctadiene iridium chloride dimer (2.6 mg, 4 mol%), (S)-L (8.0 mg, 16 mol%), and dichloromethane (1.5 mL) were added to a reaction tube and stirred at room temperature for 5 minutes. Subsequently, 1a (0.2 mmol, 36.0 mg), 2a (0.1 mmol, 20.2 mg), and Yb(OTf)3 (12.4 mg, 0.02 mmol) were added. The tube was sealed and the reaction was allowed to proceed at 0°C for 2 hours. The crude product was purified by preparative TLC to afford 3aa (27.8 mg, 94% ee, yield: 76%).

[0091] The embodiments described are preferred implementations of the present invention, but the present invention is not limited to the above implementations. Any obvious improvements, substitutions or modifications that can be made by those skilled in the art without departing from the essence of the present invention are within the scope of protection of the present invention.

Claims

1. A method for synthesizing chiral 1,4-dienylpyrazole derivatives, characterized in that: The method is carried out according to the following steps: under argon protection, the iridium catalyst and the chiral ligand L are dissolved in an organic solvent and placed in a sealed tube; racemic 1,4-dienyl allyl alcohol, a pyrazole derivative, and an additive are then added to the sealed tube in sequence, the argon is replaced, and the racemic 1,4-dienyl allyl alcohol and the pyrazole derivative undergo a substitution reaction to obtain a chiral 1,4-dienyl pyrazole derivative; the reaction equation is as follows: , Among them, R 1 is an alkyl or aryl group, R 2 is one of alkyl, aryl, halogen or nitro; The iridium catalyst is 1,5-cyclooctadiene iridium chloride dimer; the additive is Yb(OTf)3; the chiral ligand L is S-configuration, and its structural formula is .

2. The method for synthesizing chiral 1,4-dienylpyrazole derivatives according to claim 1, characterized in that: The molar ratio of the 1,4-dienyl allyl alcohol to the pyrazole derivative is 1-2:

1.

3. The method for synthesizing chiral 1,4-dienylpyrazole derivatives according to claim 1, characterized in that: The organic solvent is one or more of dichloromethane, dichloroethane, toluene and ether.

4. The method for synthesizing chiral 1,4-dienylpyrazole derivatives according to claim 1, characterized in that: The amount of the iridium catalyst used is 2%-4% of the pyrazole derivative equivalent.

5. The method for synthesizing chiral 1,4-dienylpyrazole derivatives according to claim 1, characterized in that: The equivalent weight of the additive is 10-100% of the equivalent weight of the pyrazole derivative.

6. The method for synthesizing chiral 1,4-dienylpyrazole derivatives according to claim 1, characterized in that: The amount of the chiral ligand L is 200-400% of the iridium catalyst equivalent.

7. The method for synthesizing chiral 1,4-dienylpyrazole derivatives according to claim 1, characterized in that: The reaction temperature of the substitution reaction is 0° C., and the reaction time is 2 h.

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