Chiral spiro phosphine-nitrogen-nitrogen ligand as well as preparation method and application thereof

Abstract

The invention discloses a chiral spiro phosphine-nitrogen-nitrogen ligand as well as a preparation method and application thereof, the preparation method comprises the following steps: in an argon atmosphere, in the presence of an organic solvent and a reducing reagent, stirring 7-diarylphosphino-7 '-amino-1, 1'-spiroindane and an aldehyde compound in a reactor to react for 2-24 hours, filtering, washing, and drying to obtain the chiral spiro phosphine-nitrogen-nitrogen ligand. Wherein the reducing reagent is sodium triacetoxyborohydride. The application comprises the following steps: preparing a chiral spiro phosphine-nitrogen-nitrogen ligand iridium catalyst by using the chiral spiro phosphine-nitrogen-nitrogen ligand; and under the protection of nitrogen, adding the chiral spiro phosphine-nitrogen-nitrogen ligand iridium catalyst into an organic solvent of a hydrogenation reactor, adding an organic solution of a diaryl ketone compound and alkali, and stirring and reacting for 10-80 hours in a hydrogen atmosphere of 1-150 atm to obtain the chiral diaryl methanol. The method has excellent enantioselectivity and high catalytic activity, and the preparation method is simple and high in practicability.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a chiral spirocyclic phosphine-nitrogen-nitrogen ligand and a preparation method thereof and application thereof in the asymmetric hydrogenation of para-substituted diaryl ketones. Background Art

[0002] Chiral alcohols are widely present in bioactive molecules and natural products, and are also commonly used raw materials for the synthesis of various functional chiral molecules. In the past few decades, the development of efficient chiral alcohol synthesis methods has been the focus of chemists. The asymmetric catalytic hydrogenation of ketones has been proven to be an effective method for the synthesis of chiral alcohols due to its advantages such as high atom economy, high enantioselectivity and easy availability of raw materials. However, among various types of ketone compounds, the asymmetric hydrogenation reaction of diaryl ketones still faces great challenges.

[0003] The steric hindrances on both sides of the carbonyl group of diaryl ketones are extremely close, and it is very difficult for the catalyst to recognize them. In order to improve the enantioselectivity of the asymmetric hydrogenation reaction of diaryl ketones, a common strategy is to introduce an ortho substituent, two meta substituents or an η substituent on one side of the diaryl ketone. 6 -Cr(CO) 3 Groups are added to increase the steric hindrance difference between the two aromatic groups in the diaryl ketone. Several examples of high enantioselectivity have been reported using this strategy. However, in para-substituted diaryl ketones, the two substituents are far away from the reaction center, and the steric hindrance of the two aromatic groups is very small, and it is difficult for the catalyst to recognize the two aromatic rings through steric hindrance differences. Therefore, the asymmetric hydrogenation reaction of para-substituted diaryl ketones has been rarely reported, and usually exhibits low enantioselectivity. Therefore, it is particularly important to develop efficient and highly selective catalysts to achieve a high enantioselective asymmetric hydrogenation method for para-substituted diaryl ketones. Summary of the invention

[0004] An object of the present invention is to provide a chiral spirocyclic phosphine-nitrogen-nitrogen ligand.

[0005] Another object of the present invention is to provide a method for preparing the chiral spirocyclic phosphine-nitrogen-nitrogen ligand.

[0006] Another object of the present invention is to provide an application of the above-mentioned chiral spirocyclic phosphine-nitrogen-nitrogen ligand in the asymmetric hydrogenation of para-substituted diaryl ketones, which has the characteristics of high yield, high enantioselectivity, wide substrate range, greenness and high efficiency.

[0007] To this end, the present invention adopts the following technical solutions:

[0008] A chiral spirocyclic phosphine-nitrogen-nitrogen ligand having the following structural formula:

[0009]

[0010] or its enantiomer, racemate, or catalytically acceptable salt thereof, wherein:

[0011] R 4 A group selected from C1-C10 hydrocarbon group, phenyl group, substituted phenyl group, 1-naphthyl group, 2-naphthyl group, heteroaryl group or benzyl group, wherein the substituent on the substituted phenyl group is C1-C10 hydrocarbon group or alkoxy group, and the number of the substituents is 1-5; the heteroaryl group is furanyl group, thienyl group or pyridyl group;

[0012] R 5 is H, C1-C8 fluoroalkyl, C1-C8 alkoxy, hydroxy, halogen, phenyl or substituted phenyl, the substituent on the substituted phenyl is C1-C8 hydrocarbon or alkoxy, and the number of substituents is 1-5; the heteroaryl is furyl, thienyl or pyridyl;

[0013] n = 0 to 3;

[0014] X 1 , X 2 , X 3 , X 4 All are CH, or X 1 , X 2 , X 3 , X 4 One of them is N and the rest are CH.

[0015] Preferably, the chiral spirocyclic phosphine-nitrogen-nitrogen ligand has the following structure:

[0016]

[0017] Among them, DTB is:

[0018] The present invention also provides a method for preparing the chiral spirocyclic phosphine-nitrogen-nitrogen ligand, and the reaction formula and reaction process are as follows:

[0019]

[0020] In an argon atmosphere, in the presence of an organic solvent and a reducing agent, a racemic or optically active 7-diarylphosphino-7′-amino-1,1′-spirodihydroindene compound of Formula 2 and an aldehyde compound of Formula 3 are stirred and reacted in a reactor for 2 to 24 hours, wherein:

[0021] The reducing agent is sodium triacetoxyborohydride;

[0022] The molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 is 1:(1-2);

[0023] Preferably, the organic solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, benzene, anisole, toluene, xylene, methyl tert-butyl ether, ethyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, petroleum ether, and n-hexane, or a mixture of several thereof; in the above preparation method, the reaction temperature in the reactor is 0-100°C, preferably 20-50°C.

[0024] The application of the chiral spirocyclic phosphine-nitrogen-nitrogen tridentate ligand in the asymmetric hydrogenation of para-substituted diaryl ketones comprises the following steps:

[0025] S1, using the chiral spirocyclic phosphine-nitrogen-nitrogen ligand to prepare a chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst;

[0026] S2, using the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst to prepare chiral para-substituted diaryl methanol, the reaction formula and preparation steps are as follows:

[0027]

[0028] Under nitrogen protection, the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst is added to the organic solvent of the hydrogenation reactor, and an organic solution of a diaryl ketone compound and a base is added, and the mixture is stirred and reacted in a hydrogen atmosphere of 1 to 150 atm for 10 to 80 hours to obtain a chiral diaryl methanol;

[0029] in:

[0030] R 1 , R 2 , R 3 are independently selected from hydrogen, C1-C10 hydrocarbon group, C1-C10 fluoroalkyl group, alkoxy group, thioalkyl group, halogen group, alkenyl group, substituted silicon group, phenyl group, substituted aryl group, heteroaryl group, cyano group, substituted ester group or sulfone group; the substituent on the substituted aryl group is C1-C10 hydrocarbon group or alkoxy group, and the number of substituents is 1-5; the heteroaryl group is furanyl or thienyl; or the adjacent R 1 , R 2 and R 3 and C3~C7 and an aliphatic ring or an aromatic ring, R 1 , R 2 , R 3 Same or different;

[0031] The amount of the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst is 0.0002 to 1 mol% of the diaryl ketone;

[0032] The concentration of the diaryl ketone compound is 0.01 to 1.0 M;

[0033] The reaction temperature is -20 to 70°C.

[0034] Preferably, the hydrogen atmosphere is 10 to 100 atm and the reaction time is 20 to 40 hours.

[0035] In the above application, the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, triethylamine, tributylamine or N-methylmorpholine; the amount of the base is 1.1 to 4 equivalents of the diaryl ketone;

[0036] In the above application, the organic solvent is one of alcohol solvents, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide or a mixture of several thereof; the alcohol solvent is preferably methanol, ethanol, n-propanol, isopropanol or butanol.

[0037] In the above application, the preparation steps of the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst described in S1 are:

[0038] (1) reacting the chiral spirocyclic phosphine-nitrogen-nitrogen ligand with an iridium catalyst precursor in an organic solvent at a reaction temperature of 25 to 70° C. for 0.5 to 4 hours;

[0039] (2) stirring the reaction system in a hydrogen atmosphere of 0.1 to 50 atm for 0.1 to 12 hours to obtain a chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst;

[0040] in:

[0041] The iridium catalyst precursor is [Ir(COD)Cl] 2 、[Ir(COD) 2 ]BF 4 、[Ir(COD) 2 ]PF 6 、[Ir(COD) 2 ]SbF 6 or [Ir(COD) 2 ]OTf, wherein the COD = cyclooctadiene;

[0042] The molar ratio of the chiral spirocyclic phosphine-nitrogen-nitrogen ligand to the iridium catalyst precursor is (1-2):1;

[0043] In step (1), the organic solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, dichloromethane, DMF, DMSO or a mixed solvent of several thereof.

[0044] Preferably, the reaction temperature in step (1) is 25-40° C.; and the hydrogen pressure in step (2) is 0.1-12 atm.

[0045] The invention uses a complex formed in situ between a chiral spirocyclic phosphine-nitrogen-nitrogen tridentate ligand and a transition metal (iridium) (which may not be desolvated or may be prepared into a storable solid after desolvation) as a catalyst to catalyze an asymmetric hydrogenation reaction of a diaryl ketone in a hydrogen atmosphere and alkaline conditions to prepare a chiral diaryl methanol.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] 1. The chiral spirocyclic phosphine-nitrogen-nitrogen ligand of the present invention forms a complex with a transition metal salt and is used for the asymmetric hydrogenation reaction of carbonyl compounds such as para-substituted dialkyl ketones, and has excellent enantioselectivity and high catalytic activity.

[0048] 2. The preparation method of the chiral spirocyclic phosphine-nitrogen-phosphine ligand and its iridium catalyst of the present invention is simple, and is particularly suitable for asymmetric catalytic hydrogenation of carbonyl compounds. The preparation method has mild reaction conditions and high efficiency, and is suitable for large-scale production.

[0049] 3. The present invention provides a variety of chiral bis-aryl carbinols with important biological activities. These chiral bis-aryl carbinols are widely used in the industrial synthesis of drug molecules and have great practical value. DETAILED DESCRIPTION

[0050] The technical solution of the present invention is described in detail below in conjunction with embodiments. The listed implementations will help to understand the present invention, but cannot limit the content of the present invention.

[0051] The experimental methods in the following examples without specifying specific conditions were carried out according to conventional conditions and conditions described in the manual, or according to conditions recommended by the manufacturer. The equipment, materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial sources.

[0052] Example 1

[0053] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction steps are as follows:

[0054]

[0055] 1) In an argon atmosphere, (S)-7′-diphenylphosphino-7′-amino-1,1′-spirobidihydroindane (42 mg, 0.1 mmol), 2-pyridinecarboxaldehyde (21 mg, 0.12 mmol), sodium triacetoxyborohydride (34 mg, 0.16 mmol) and 5 mL 1,2-dichloroethane (DCE) were weighed into a 25 mL dry Schlenk tube. After stirring at room temperature for 12 hours, the raw materials were basically reacted.

[0056] 2) The reaction solution was desolvated on a rotary evaporator, and the residue was dissolved in 5 mL of anhydrous methanol and NaBH 4 (4 mg, 0.1 mmol), stirred at room temperature for 1 hour, and the unreacted 2-pyridinecarboxaldehyde was converted into 2-pyridinemethanol which is easier to separate. After the reaction was completed by TLC (thin layer chromatography), the reaction solution was desolventized on a rotary evaporator and chromatographed on a silica gel column (petroleum ether / ethyl acetate = 5:1) to obtain 53 mg of a white solid with a yield of 92%.

[0057] Product melting point: 123–124°C, (c 1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ8.14(s,1H),7.82(d,J=7.5Hz,1H),7.40(d,J=7.1Hz,1H),7.23(t,J=7.2Hz,1H),7 .18–7.04(d,J=24.9Hz,6H),7.00–6.78(m,7H),6.70(d,J=7.1Hz,1H),6.02(d,J=7.7H z,1H),5.07(s,1H),4.15(dd,J=17.0,4.8Hz,1H),3.32(d,J=17.1Hz,1H),3.16–2.99 (m,4H),2.60(q,J=10.1,9.6Hz,1H),2.49–2.32(m,2H),2.16(dd,J=11.8,7.3Hz,1H); 13 C NMR (101 MHz, CDCl 3)δ154.8,153.7,153.4,150.7,144.8,144.8,144.3,142.9,140.3,136.0,134.7,134.2,134.0,133.8,133.6,133.0,132.8,128.3,1 28.2,128.0,127.9,127.4,127.4,127.0,125.7,123.4,123.2,120.9,113.5,108.3,61.7,61.7,44.4,40.0,39.9,35.9,31.5,31.1; 31 P NMR (162 MHz, CDCl 3 )δ–22.7; 19 F NMR (376 MHz, CDCl 3 )δ–62.3; HR-MS(ESI-TOF)Calcd forC 36 H 30 F 3 N 2 P[M+H] + :579.2171;Found:579.2178.

[0058] Example 2

[0059] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0060]

[0061] The operation process and reaction conditions were the same as those in Example 1. 32 mg of white solid was obtained with a yield of 62%.

[0062] Product melting point: 121–123°C, –209(c 1,CHCl 3 ). 1 H NMR(400MHz,Chloroform-d)δ9.29(s,1H),8.03(d,J=4.5Hz,1H),7.42–7.18(m, 8H),7.08(dt,J=28.4,8.4Hz,5H),7.01–6.92(m,3H),6.88(d,J=7.3Hz,1H),6.23 (d,J=7.8Hz,1H),3.94(d,J=15.6Hz,1H),3.73(d,J=15.8Hz,1H),3.62(s,1H),3. 13(t,J=7.2Hz,2H),3.03(d,J=8.5Hz,2H),2.63–2.44(m,1H),2.39–2.20(m,3H);13 C NMR (101 MHz, CDCl 3 )δ153.4,153.1,149.9,144.6,144.5,144.4,144.4,143.3,143.3,139.6,1 39.5,136.6,136.5,135.5,134.6,134.5,134.4,134.3,134.2,134.1,133. 3,133.3,133.1,128.6,128.4,128.2,128.2,128.2,127.8,127.6,126.2,125.4,122.4,114.4,108.8,61.8,61.7,47.3,39.7,39.6,36.3,31.4,31.0; 31 P NMR (162 MHz, CDCl 3 )δ–23.1.HR-MS(ESI-TOF)Calcd for C 35 H 31 N 2 OP[M+H] + :527.2247;Found:527.2249.

[0063] Example 3

[0064] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0065]

[0066] The operation process and reaction conditions were the same as those in Example 1. 46 mg of white solid was obtained with a yield of 87%.

[0067] Product melting point: 52.9–54.1°C, –190(c 1,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3)δ7.88(d,J=4.6Hz,1H),7.37(d,J=7.4Hz,1H),7.27–7.02(m,8H),6.98–6. 83(m,7H),6.69(d,J=7.3Hz,1H),6.05(d,J=7.9Hz,1H),4.77–4.71(m,1H), 4.01(dd,J=16.5,5.8Hz,1H),3.24(d,J=16.5Hz,1H),3.17–3.02(m,4H),2. 56(q,J=10.5Hz,1H),2.48–2.32(m,2H),2.15(ddd,J=12.8,6.3,2.7Hz,1H); 13 C NMR (101 MHz, CDCl 3 )δ157.8,155.3,153.5,153.3,145.6,145.5,144.7,144.6,144.2,144.2,143.9,143. 2,143.1,140.2,140.1,136.3,136.2,134.7,134.7,134.2,134.0,133.8,133.6,133. 5,133.4,133.0,132.8,128.3,128.1,128.0,127.9,127.5,127.4,127.1,125.9,122.5,122.5,121.8,121.6,113.4,108.3,108.2,61.7,61.6,41.9,40.0,36.0,31.4,31.0; 31 PNMR (162MHz, CDCl 3 )δ–22.6; 19 FNMR (376MHz, CDCl 3 )δ–127.7.HR-MS(ESI-TOF)Calcd for C 35 H 30 FN 2 P[M+H] + :529.2203;Found:529.2208.

[0068] Example 4

[0069] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0070]

[0071] The operation process and reaction conditions were the same as those in Example 1. 46 mg of white solid was obtained with a yield of 80%.

[0072] Product melting point: 116–118°C, –222(c 1,CHCl 3 ). 1 H NMR (600 MHz, CDCl 3 )δ8.47–8.43(m,1H),7.33(d,J=6.8Hz,1H),7.29–7.12(m,7H),7.10–6.92(m,8H),6.72(d,J=7.0Hz,1H),5.96(d,J=7.5Hz,1H),4.02 (s,1H),3.96–3.90(m,1H),3.54(d,J=15.8Hz,1H),3.15–2.96(m,4H),2.46(dq,J=32.6,10.4Hz,2H),2.35(s,1H),2.24–2.13(m,1H); 13 C NMR (151 MHz, CDCl 3 )δ160.4,153.2,153.0,149.7,144.5,144.4,143.0,139.7,139.6,138.5(q,J=33 .9Hz),136.4,136.3,134.5,134.2,134.0,133.9,133.6,133.6,133.0,132.9,12 8.4,128.3,128.0,128.0,127.9,127.9,127.6,127.5,126.1,122.81(q,J=273.3 Hz),117.2,116.5,114.3,108.5,61.7,61.7,48.2,39.7,39.6,36.1,31.3,31.0; 31 P NMR (243 MHz, CDCl 3 )δ–22.7; 19 F NMR (376 MHz, CDCl 3 )δ–64.7; HR-MS(ESI-TOF)Calcd for C 36 H 30 F 3 N 2 P[M+H] + :579.2171;Found:579.2168.

[0073] Example 5

[0074] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0075]

[0076] The operation process and reaction conditions were the same as those in Example 1. 43 mg of white solid was obtained with a yield of 85%.

[0077] Product melting point: 162–164°C, –233(c 1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ8.41(d,J=4.8Hz,2H),7.37(d,J=7.4Hz,1H),7.21(t,J=7.5Hz,1H),7.16(q,J=5.1,3.6Hz,4H),7.07(t,J=7.6 Hz,1H),7.03(t,J=4.9Hz,1H),6.95(ddt,J=10.4,7.3,3.9Hz,3H),6.91–6.88(m,4H),6.69(d,J=7.4Hz,1H),6.0 2(d,J=7.9Hz,1H),4.63(d,J=3.6Hz,1H),4.09(dd,J=17.3,5.9Hz,1H),3.43(d,J=17.4Hz,1H),3.08(td,J=10.5 ,10.1,4.1Hz,4H),2.64–2.51(m,1H),2.54–2.41(m,1H),2.42–2.32(m,1H),2.17(ddd,J=13.1,6.9,2.6Hz,1H); 13 C NMR (101 MHz, CDCl 3 )δ167.0,156.4,153.6,153.3,144.7,144.7,144.2,144.2,143.1,143.0,1 40.1,140.0,136.3,136.1,134.6,134.6,134.1,133.9,133.8,133.3,133. 3,133.0,132.8,128.3,128.1,127.9,127.9,127.5,127.5,127.4,127.0,125.8,118.7,113.5,108.2,61.7,61.7,48.3,39.9,39.9,36.1,31.4,31.0; 31 P NMR (162 MHz, CDCl 3 )δ–22.5; HR-MS(ESI-TOF)Calcd for C 34 H 30 N 3 P[M+H] +:512.2250;Found:512.2249.

[0078] Example 6

[0079] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0080]

[0081] The operation process and reaction conditions were the same as those in Example 1. 45 mg of a white solid was obtained with a yield of 88%.

[0082] Product melting point: 83–85°C, –242(c 1,CHCl 3 ); 1 H NMR (600 MHz, CDCl 3 )δ8.40–8.17(m,3H),7.46–6.87(m,14H),6.72(s,1H),5.95(s,1H),4.03( s,1H),3.86(s,1H),3.63–3.37(m,1H),3.04(brs,4H),2.68–2.08(m,4H). 13 C NMR (151 MHz, CDCl 3 )δ154.1,144.5,143.4,143.3,142.9,142.6,139.8,139.7,136.4,136.3,135.3,135.2,135.0,134.6,134.2,134.1,133.9,133.6 ,133.0,132.8,128.4,128.3,128.0,128.0,127.9,127.8,127.6,127.4,126.1,114.3,108.5,61.6,46.0,39.7,36.1,31.3,31.0. 31 P NMR (243 MHz, CDCl 3 )δ-22.8.

[0083] Example 7

[0084] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0085]

[0086] The operation process and reaction conditions were the same as those in Example 1. 45 mg of a white solid was obtained with a yield of 88%.

[0087] Product melting point: 62–64°C, –261(c 1,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ8.96(s,1H),8.50(d,J=5.2Hz,1H),7.38(d,J=7.4Hz,1H),7.31–7.19(m,5H),7.16 (t,J=7.4Hz,2H),7.13–7.03(m,4H),6.99(t,J=7.1Hz,3H),6.77(d,J=7.4Hz,1H),5. 89(d,J=7.9Hz,1H),3.96(d,J=4.3Hz,1H),3.79(dd,J=17.8,4.8Hz,1H),3.55(dd,J= 17.8,4.8Hz,1H),3.16–3.03(m,4H),2.57–2.32(m,3H),2.23(dd,J=12.6,7.0Hz,1H); 13 C NMR (101MHz, CDCl3) δ167.8,158.1,156.7,153.2,153.0,144.6,144.6,144.5,1 44.4,142.7,139.6,139.4,136.4,136.3,134.6,134.6,134.2,134.2,134.0,13 4.0,133.5,133.4,133.1,132.9,128.5,128.3,128.1,128.0,128.0,127.7,127.6,126.2,118.4,114.5,108.5,61.7,61.7,47.7,39.6,39.6,36.2,31.3,31.0; 31 P NMR (162 MHz, CDCl 3 )δ-22.6.

[0088] Example 8

[0089] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0090]

[0091] The operation process and reaction conditions were the same as those in Example 1. 40 mg of a white solid was obtained with a yield of 78%.

[0092] Product melting point: 62–64°C, –260(c 1,CHCl 3 ); 1 H NMR (600 MHz, CDCl 3)δ8.98(s,1H),7.48–6.85(m,16H),6.72(s,1H),5.90(s,1H),4.03(s 1H),3.86(s,1H),3.48(s,1H),3.16–2.91(m,4H),2.56–2.14(m,4H). 13 C NMR (151 MHz, CDCl 3 )δ162.1,153.1,152.9,150.0,144.7,144.2,144.2,142.8,139.4,139.3,136.4,136.3,134.5,134.2,134.0,133.3,133.1,13 3.0,128.7,128.4,128.2,128.2,128.1,127.8,127.7,126.7,126.2,124.7,114.7,108.7,61.7,47.0,39.5,36.1,31.3,30.9. 31 P NMR (243 MHz, CDCl 3 )δ-22.6.

[0093] Example 9

[0094] A method for preparing a chiral spirocyclic phosphine-nitrogen-nitrogen ligand, the reaction formula and reaction process are as follows:

[0095]

[0096] In an argon atmosphere, (S)-7′-di(3,5-di-tert-butylphenyl)phosphino-7′-amino-1,1′-spirobihydroindane (64 mg, 0.1 mmol), 2-pyrimidinecarboxaldehyde (21 mg, 0.12 mmol), acetic acid (7.8 mg, 0.13 mmol) and 5 mL of methanol were weighed into a 25 mL dry Schlenk tube. After stirring at room temperature for 3 hours, NaBH 3 CN (20 mg, 0.3 mmol), heated in an oil bath to 40 ° C, reacted for 15 hours. Remove the solvent methanol with a rotary evaporator, add dichloromethane and saturated sodium bicarbonate solution. Extract with dichloromethane three times, combine the organic phases and dry with anhydrous magnesium sulfate, then filter to remove the desiccant, and remove the solvent from the filtrate with a rotary evaporator. The residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 20: 1) to obtain 70 mg of a white solid 1h, with a yield of 95%.

[0097] Melting point: 202–204°C, –168(c 1,CHCl 3 ); 1 H NMR (600 MHz, CDCl3 )δ8.41(d,J=4.7Hz,2H),7.36(d,J=7.3Hz,1H),7.24–7.18(m,3H),7.16(t,J=7.5Hz,1H),7.11–7.07(m,1H),7.02(t,J=4.5Hz, 1H),6.77(d,J=7.8Hz,2H),6.74(d,J=7.2Hz,2H),6.71(d,J=7.3Hz,1H),6.19(d,J=7.8Hz,1H),4.85(d,J=5.8Hz,1H),4.21(dd ,J=16.9,6.6Hz,1H),3.63(d,J=16.8Hz,1H),3.11(q,J=12.6,9.1Hz,1H),3.00(ddd,J=34.2,16.4,9.0Hz,2H),2.85(dd,J=14. 8,8.2Hz,1H),2.46(q,J=11.2Hz,1H),2.23(q,J=12.5,11.5Hz,2H),2.13(dd,J=12.5,7.7Hz,1H),1.16(s,18H),1.02(s,18H). 13 C NMR (151 MHz, CDCl 3 )δ167.1,156.6,152.6,152.5,149.8,149.8,149.6,149.6,144.4,144.4,144. 3,144.2,143.7,143.7,138.7,138.6,136.1,136.0,134.9,134.8,133.8,132.8 ,132.8,128.4,128.1,128.0,127.9,127.8,126.5,125.4,122.0,121.3,118.9,113.5,108.2,61.6,61.6,48.6,38.9,38.8,36.0,34.7,34.6,31.3,31.2,31.0. 31 P NMR (243 MHz, CDCl 3 )δ-18.3.

[0098] Example 10

[0099] A method for asymmetric hydrogenation of diaryl ketones, the reaction formula and reaction process are as follows:

[0100]

[0101] The ligand (S)-1e (3.2 μmol) and [Ir(COD)Cl] 2(1.0mg, 1.5μmol) was added to a dry and clean 10mL Schlenk tube equipped with a magnetic stirrer, and 2mL of anhydrous n-propanol was added. Stir at room temperature for 0.5 hours. Under nitrogen protection, the solution was added to a hydrogenation reactor equipped with a glass inner tube and a magnetic stirrer by syringe, and the gas in the reactor was quickly replaced with hydrogen three times. The hydrogen pressure was adjusted to 12atm. After stirring and reacting at room temperature for 0.5 hours, the hydrogen in the reactor was slowly released. Under nitrogen protection, 0.3-15mmol substrate and 0.36-16.5mmol potassium tert-butoxide n-propanol solution (3mL (0.1mmol / mL) ~ 100mL (0.15mmol / mL)) were added to the reactor by syringe. The gas in the reactor was quickly replaced with hydrogen three times, and finally the hydrogen pressure was adjusted to 25-50atm. The reaction was stirred at 0℃ until the hydrogen pressure no longer decreased. The hydrogen in the reactor was slowly released, and the reactants were filtered through a short silica gel column to remove the catalyst and potassium tert-butoxide, and then the solvent was removed by rotary evaporation to obtain a crude product. The crude product was purified by column chromatography, and the reaction yield was calculated. The optical purity of the product was determined by high performance liquid chromatography. The obtained hydrogenation experimental results are shown in Table 1.

[0102] Table 1. Asymmetric catalytic hydrogenation of diaryl ketone compounds

[0103]

[0104]

[0105]

[0106]

[0107] Embodiment 11:

[0108] A method for asymmetric hydrogenation of diaryl ketones, the reaction formula and reaction process are as follows:

[0109]

[0110] The operation process is the same as that of Example 10. The hydrogenation test results are shown in Table 2.

[0111] Table 2. Asymmetric catalytic hydrogenation of heterocyclic substituted biaryl ketone compounds

[0112]

Claims

1. A chiral spirocyclic phosphine-nitrogen-nitrogen ligand having the following structural formula: or its enantiomer, racemate, or catalytically acceptable salt thereof, wherein: R 4 A group selected from C1-C10 hydrocarbon group, phenyl group, substituted phenyl group, 1-naphthyl group, 2-naphthyl group, heteroaryl group or benzyl group, wherein the substituent on the substituted phenyl group is C1-C10 hydrocarbon group or alkoxy group, and the number of the substituents is 1-5; the heteroaryl group is furanyl group, thienyl group or pyridyl group; R 5 is H, C1-C8 fluoroalkyl, C1-C8 alkoxy, hydroxy, halogen, phenyl or substituted phenyl, the substituent on the substituted phenyl is C1-C8 hydrocarbon or alkoxy, and the number of substituents is 1-5; the heteroaryl is furyl, thienyl or pyridyl; n＝0～3； X 1 , X 2 , X 3 , X 4 All are CH, or X 1 , X 2 , X 3 , X 4 One of them is N and the rest are CH.

2. The chiral spirocyclic phosphine-nitrogen-nitrogen ligand according to claim 1, characterized in that Has the following structure: Where DTB is:

3. A method for preparing the chiral spirocyclic phosphine-nitrogen-nitrogen ligand according to claim 1, characterized in that: The reaction formula and reaction process are as follows: In an argon atmosphere, in the presence of an organic solvent and a reducing agent, the compounds represented by Formula 2 and Formula 3 are stirred and reacted in a reactor for 2 to 24 hours, wherein: The reducing agent is sodium triacetoxyborohydride; The molar ratio of the compound represented by Formula 2 to the compound represented by Formula 3 is 1:(1-2).

4. The preparation method according to claim 3, characterized in that: The organic solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, benzene, anisole, toluene, xylene, methyl tert-butyl ether, ethyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, petroleum ether, and n-hexane, or a mixture of several thereof; The reaction temperature in the reactor is 0 to 100°C.

5. The preparation method according to claim 4, characterized in that: The reaction temperature in the reactor is 20-50°C.

6. Use of the chiral spirocyclic phosphine-nitrogen-nitrogen tridentate ligand according to claim 1 in the asymmetric hydrogenation of para-substituted biaryl ketones, characterized in that The following steps are involved: S1, using the chiral spirocyclic phosphine-nitrogen-nitrogen ligand to prepare a chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst; S2, using the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst to prepare chiral para-substituted diaryl methanol, the reaction formula and preparation steps are as follows: Under nitrogen protection, the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst is added to the organic solvent of the hydrogenation reactor, and an organic solution of a diaryl ketone compound and a base is added, and the mixture is stirred and reacted in a hydrogen atmosphere of 1 to 150 atm for 10 to 80 hours to obtain a chiral diaryl methanol; in: R 1 , R 2 , R 3 are independently selected from hydrogen, C1-C10 hydrocarbon group, C1-C10 fluoroalkyl group, alkoxy group, thioalkyl group, halogen group, alkenyl group, substituted silicon group, phenyl group, substituted aryl group, heteroaryl group, cyano group, substituted ester group or sulfone group; the substituent on the substituted aryl group is C1-C10 hydrocarbon group or alkoxy group, and the number of substituents is 1-5; the heteroaryl group is furanyl or thienyl; or the adjacent R 1 , R 2 and R 3 and C3~C7 and an aliphatic ring or an aromatic ring, R 1 , R 2 , R 3 Same or different; The amount of the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst is 0.0002 to 1 mol% of the diaryl ketone; The concentration of the diaryl ketone compound is 0.01 to 1.0 M; The reaction temperature is -20 to 70°C.

7. The use according to claim 6, characterized in that: The hydrogen atmosphere is 10 to 100 atm; and the reaction time is 20 to 40 hours.

8. The use according to claim 6, characterized in that: The base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, triethylamine, tributylamine or N-methylmorpholine; the amount of the base is 1.1 to 4 equivalents of the diaryl ketone; The organic solvent is one of alcohol solvents, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, or a mixture of several thereof; Preferably, the alcohol solvent is methanol, ethanol, n-propanol, isopropanol or butanol.

9. The use according to claim 6, characterized in that: The preparation steps of the chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst described in S1 are: (1) reacting the chiral spirocyclic phosphine-nitrogen-nitrogen ligand with an iridium catalyst precursor in an organic solvent at a reaction temperature of 25 to 70° C. for 0.5 to 4 hours; (2) stirring the reaction system in a hydrogen atmosphere of 0.1 to 50 atm for 0.1 to 12 hours to obtain a chiral spirocyclic phosphine-nitrogen-nitrogen ligand iridium catalyst; in: The iridium catalyst precursor is [Ir(COD)Cl]2, [Ir(COD)2]BF4, [Ir(COD)2]PF6, [Ir(COD)2]SbF6 or [Ir(COD)2]OTf, wherein the COD=cyclooctadiene; The molar ratio of the chiral spirocyclic phosphine-nitrogen-nitrogen ligand to the iridium catalyst precursor is (1-2):1; In step (1), the organic solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, dichloromethane, DMF, DMSO or a mixed solvent of several thereof.

10. The use according to claim 6, characterized in that: The reaction temperature in step (1) is 25-40° C.; the pressure of hydrogen in step (2) is 0.1-12 atm.

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