Planar chiral oxazolyl pyrimidine ligand compound based on cycloarane skeleton as well as synthesis method and application of planar chiral oxazolyl pyrimidine ligand compound

Abstract

The invention provides a planar chiral oxazole pyrimidine ligand compound based on a cycloarane skeleton as well as a synthesis method and application of the planar chiral oxazole pyrimidine ligand compound. The planar chiral compound has a structure as shown in a formula I; in the # imgabs0 # formula I, ring A is a heteroaryl group containing at least two heteroatoms; the heteroatom is selected from N, O or S; r is selected from one of H, alkyl groups of C1-C3, halogenated alkyl groups of C1-C3, alkoxy groups of C1-C3 and phenyl groups of C1-C3. According to the invention, the planar chiral oxazole pyrimidine ligand based on the cycloarane skeleton can be effectively synthesized, and the planar chiral oxazole pyrimidine ligand based on the cycloarane skeleton can realize asymmetric 1, 2-reduction reaction of alpha, beta-unsaturated ketone.

Description

Technical Field

[0001] The invention relates to a type of planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton, a synthesis method and application thereof. Background Art

[0002] Transition metal-catalyzed asymmetric synthesis reactions occupy a pivotal position in the field of modern synthetic chemistry and are a direct and effective method for constructing chiral compounds. Since ligands affect the spatial and electronic properties of metal catalysts, the development of new and efficient chiral ligands is the core of asymmetric catalysis. Chiral dinitrogen compounds are an important class of chiral ligands and are widely used in various metal-catalyzed asymmetric syntheses. However, in some asymmetric reactions, there are still scientific problems such as the inability to accurately control elementary reactions and stereoselectivity. Therefore, it is necessary and urgent to develop new chiral dinitrogen ligands to achieve the regulation of elementary reaction types and high stereoselectivity control in asymmetric reactions. It has important theoretical significance and application value, and is also an important supplement to existing chiral dinitrogen ligands. Summary of the invention

[0003] The purpose of the present invention is to provide a type of planar chiral oxazole pyrimidine ligand based on a cyclophane skeleton, a synthesis method and application thereof.

[0004] To achieve the above object, the technical solution of the present invention is as follows:

[0005] In one aspect, the present invention provides a type of planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton, having a structure shown in Formula I,

[0006]

[0007] In Formula I:

[0008] Ring A is a heteroaryl group containing at least two heteroatoms, preferably ring A is a heteroaryl group containing 2 to 3 heteroatoms;

[0009] The heteroatom is selected from N, O or S;

[0010] R is selected from one of H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and phenyl.

[0011] As an optional technical solution, the ring A is a heteroaryl group containing 2 to 3 heteroatoms, preferably a heteroaryl group containing 2 heteroatoms.

[0012] Alternatively, the ring A is a heteroaryl group containing 2 N atoms.

[0013] As an optional technical solution, the heteroaryl group is a monocyclic heteroaryl group; the monocyclic heteroaryl group is a 6-membered heteroaryl group.

[0014] Further optionally, the monocyclic heteroaryl group is a pyrimidinyl group.

[0015] As an optional technical solution, the heteroaryl group is a condensed-ring heteroaryl group; the condensed-ring heteroaryl group is a 10-membered condensed bicyclic heteroaryl group.

[0016] Optionally, the fused-ring heteroaryl group is selected from quinazolinyl or isoquinazolinyl.

[0017] As an optional technical solution, the C1-C3 alkyl group is selected from methyl and trifluoromethyl.

[0018] As an optional technical solution, the C1-C3 alkoxy group is selected from methoxy group.

[0019] As an optional technical solution, the phenyl group is selected from phenyl groups with different substituents.

[0020] Further optionally, the planar chiral oxazole pyrimidine ligand compound is selected from one of Formula 1-1, Formula 2-1, Formula 2-2, Formula 2-3, Formula 3-1, Formula 3-2, Formula 3-3, Formula 4-1, Formula 5-1 and Formula 6-1;

[0021]

[0022]

[0023] Optionally, the planar chiral oxazole pyrimidine ligand compound is in R configuration or S configuration.

[0024] On the other hand, the present invention also provides a method for preparing the above-mentioned planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton.

[0025] One embodiment thereof is prepared by method 1;

[0026] The first method is to prepare a mixed solution a containing a compound represented by formula II, a compound represented by formula a1 and a solvent X, and to carry out a condensation reaction a in an inactive atmosphere to obtain a planar chiral oxazolidinone ligand compound represented by formula I;

[0027]

[0028] As an optional technical solution, in the method 1:

[0029] The molar ratio of the compound represented by formula II to the compound represented by formula a1 is 1:1.0 to 1:1.5;

[0030] The molar ratio of the compound represented by formula a1 to metallic sodium is 1:0.1 to 1:0.2;

[0031] The molar concentration of the compound represented by formula II in solvent X is 0.2-0.5 mol / L.

[0032] Optionally, the reaction conditions of the condensation reaction a are a temperature of 40 to 60°C and a reaction time of 24 to 72 hours; optionally, the temperature of the condensation reaction a is selected from any value of 40°C, 50°C, 60°C or any value between any two of the above points; optionally, the reaction time of the condensation reaction a is selected from any value of 24 hours, 48 ​​hours, 72 hours or any value between any two of the above points.

[0033] Optionally, the inactive atmosphere in the condensation reaction a is selected from at least one of nitrogen and argon.

[0034] Optionally, the solvent X is selected from at least one of methanol, tetrahydrofuran, diethyl ether and dioxane.

[0035] Optionally, the mixed solution a further comprises a catalyst, the catalyst being sodium methoxide or a methanol solution of metallic sodium, the molar ratio of the compound represented by formula II to the sodium in the catalyst being 1:0.1 to 1:0.5. The methanol in the methanol solution of metallic sodium is in excess relative to the metallic sodium, for example, the ratio of metallic sodium to methanol is 0.1-0.2 mmol:4.0 mL.

[0036] Another embodiment is to prepare by method 2;

[0037] The method 2 comprises condensation reaction b and cyclization reaction;

[0038] The condensation reaction b is: a mixed solution b containing a compound represented by formula II, a compound represented by formula b1, a condensation agent and a solvent Y undergoes a condensation reaction b in an inert atmosphere to obtain a compound represented by formula b2;

[0039]

[0040] The cyclization reaction is as follows: a mixed solution c containing the compound represented by formula b2, an acid and a solvent Z undergoes a cyclization reaction in an inactive atmosphere to obtain a planar chiral oxazole pyrimidine ligand compound represented by formula I.

[0041] As an optional technical solution, in the cyclization reaction of the second method:

[0042] The molar ratio of the compound represented by formula II to the compound represented by formula b1 is 1:1.0 to 1:1.5;

[0043] The molar ratio of the compound represented by formula b1 to the condensing agent is 1:1 to 1:1.2;

[0044] The molar concentration of the compound represented by formula II in solvent Y is 0.1-0.3 mol / L.

[0045] Optionally, the reaction conditions of the condensation reaction b are 0-25°C, and the reaction time is 5-12 hours; optionally, the temperature of the condensation reaction b is selected from any value of 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or any value between any two of the above points; the reaction time of the condensation reaction b is selected from any value of 5 hours, 6 hours, 8 hours, 12 hours or any value between any two of the above points.

[0046] Optionally, after the compound represented by Formula II and the compound represented by Formula b1 are mixed with solvent Y, it is necessary to cool to 0° C. because of the exothermic reaction before adding the condensation agent.

[0047] Optionally, the inert atmosphere in the condensation reaction b is selected from at least one of nitrogen and argon.

[0048] Optionally, the condensing agent is selected from at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyl uronium hexafluorophosphate, diisopropylcarbodiimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

[0049] Optionally, the solvent Y is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide and acetonitrile.

[0050] As an optional technical solution, in the cyclization reaction of the second method:

[0051] Optionally, the molar ratio of the compound represented by formula b2 to the acid is 1:1.2-1:1.5.

[0052] The molar concentration of the compound represented by formula b2 in the solvent Z is 0.05-0.1 mol / L.

[0053] Optionally, the cyclization reaction conditions are 120-150°C, and the reaction takes 10-24 hours; optionally, the cyclization reaction temperature is selected from any value among 120°C, 130°C, 140°C, 150°C or any value between any two of the above points; the reaction time of the cyclization reaction is selected from any value among 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 24 hours or any value between any two of the above points.

[0054] Optionally, the inactive atmosphere in the cyclization reaction is selected from at least one of nitrogen and argon.

[0055] Optionally, the acid is selected from at least one of toluenesulfonic acid monohydrate, methanesulfonic acid and acetic acid.

[0056] Optionally, the solvent Z is selected from at least one of p-xylene, m-xylene and toluene.

[0057] In another aspect, the present invention also provides the use of the above-mentioned planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton, wherein the above-mentioned planar chiral oxazole pyrimidine ligand compound is used as a ligand for the asymmetric 1,2-reduction reaction of α,β-unsaturated ketones.

[0058] In another aspect, a method for asymmetric 1,2-reduction of an α,β-unsaturated ketone, wherein the raw materials contain an α,β-unsaturated ketone I and pinacol borane; a mixture containing the α,β-unsaturated ketone I, pinacol borane, a catalyst, and a base reacts to obtain an asymmetric 1,2-reduction product;

[0059] The structure of the α,β-unsaturated ketone I is Ar is selected from phenyl or phenyl containing a substituent, wherein the substituent in the phenyl containing a substituent is one of C1-C3 alkyl or alkoxy, and halogen (such as fluorine, chlorine); R 1 Selected from H or C1-C3 alkyl; R 2 is one of C1-C4 alkyl, phenyl or trifluoromethyl;

[0060] The product of the asymmetric 1,2-reduction reaction is

[0061] The catalyst is a metal-ligand complex, the metal is nickel, and the ligand is the planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton as described in any one of claims 1 to 3.

[0062] Optionally, the metal-ligand complex is formed by coordination of a metal precursor and a ligand in a solvent M;

[0063] The metal precursor is at least one of bis(1,5-cyclooctadiene)nickel and nickel acetate tetrahydrate;

[0064] The molar ratio of the metal precursor to the ligand is 1:1 to 1:1.5;

[0065] The concentration of the metal precursor in the solvent M is 0.001-0.02 mol / L, preferably 0.005 mol / L;

[0066] The temperature of the coordination reaction is 0-50°C, preferably 25°C;

[0067] The coordination reaction time is 5 to 30 minutes, preferably 10 minutes.

[0068] Optionally, the solvent M for the asymmetric 1,2-reduction reaction is at least one of an aromatic hydrocarbon solvent, an ester solvent, and a chlorinated solvent; an aromatic hydrocarbon solvent such as toluene, benzene, trifluorotoluene, etc.; an ester solvent such as ethyl acetate; a chlorinated solvent such as dichloromethane, dichloroethane, etc.

[0069] Optionally, the molar concentration of the α,β-unsaturated ketone I in the solvent M is 0.05 to 0.1 mol / L.

[0070] The molar ratio of the α,β-unsaturated ketone I to pinacol borane is 1:1 to 1:2;

[0071] The molar ratio of the metal ligand complex to the α,β-unsaturated ketone I is 0.02:1 to 0.10:1, and the metal ligand complex is calculated based on the molar number of the metal precursor;

[0072] The base is at least one of 1,4-diazabicyclo[2.2.2]octane (DABCO), potassium tert-butoxide, triethylamine and diisopropylethylenediamine;

[0073] The molar ratio of the base to the α,β-unsaturated ketone I is 1:1 to 2:1;

[0074] The reaction temperature of the asymmetric 1,2-reduction reaction is -40 to 25°C, preferably -40 to 10°C, more preferably -25°C;

[0075] The reaction time of the asymmetric 1,2-reduction reaction is 0.5 to 24 hours, and the reaction time is selected from any value of 0.5 hours, 1 hour, 2 hours, 4 hours, 24 hours, or any value between any two of the above points.

[0076] The present invention uses cyclophane o-aminophenol as the initial raw material, and can obtain a planar chiral oxazole pyrimidine ligand with a cyclophane skeleton by two methods: one method is to obtain it by condensation reaction with a methyl pyrimidine imine methyl ester derivative; the other method is to react with a 2-pyrimidinecarboxylic acid derivative to form an amide, and then undergo a cyclization reaction under the promotion of an acid to obtain the target compound. The present invention can synthesize a novel planar chiral oxazole pyrimidine ligand based on a cyclophane skeleton.

[0077] The present invention has the following advantages

[0078] 1. Few reaction steps and easy operation.

[0079] 2. The synthesized planar chiral oxazole pyrimidine ligand based on the cyclophane skeleton is a chirally pure reagent.

[0080] 3. The synthesized planar chiral oxazolidinone ligand based on the cyclopentane skeleton is relatively stable and resistant to acid, alkali and high temperature.

[0081] 4. The synthesized planar chiral oxazole pyrimidine ligand based on the cyclophane skeleton can realize the asymmetric 1,2-reduction reaction of α,β-unsaturated ketones. DETAILED DESCRIPTION

[0082] The groups in the aforementioned formula I, formula a1, formula b1, and formula b2 are explained as follows.

[0083] The term "C1-C3 alkyl" used herein refers to a straight or branched alkyl group having 1 to 3 carbon atoms; preferred "C1-C3 alkyl" includes methyl, trifluoromethyl and the like.

[0084] The term "C1-C3 alkoxy" as used herein refers to an alkoxy group wherein the alkyl portion is as defined above in the "C1-C3 alkyl group"; preferred "C1-C3 alkoxy groups" include methoxy groups.

[0085] The term "phenyl" as used herein refers to a benzene ring containing various substituents.

[0086] The term "ring A" used herein may be a 6-membered heteroaryl group. "6-membered heteroaryl group" refers to a 6-membered monocyclic aromatic heterocyclic ring containing one or more (e.g., 1 to 3) nitrogen atoms, oxygen atoms, or sulfur atoms in addition to carbon atoms, such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.

[0087] The term "ring A" used herein may be further fused to form an optionally substituted fused heteroaryl. "Further fused" means that an aromatic ring is further fused at a position capable of fusion in ring A. For example, when ring A is a "6-membered heteroaryl", a 10-membered fused bicyclic heteroaryl in which a 6-membered heteroaryl is fused to a phenyl group is formed.

[0088] Among them, examples of the 10-membered condensed bicyclic heteroaryl group include quinazolinyl, isoquinazolinyl and the like.

[0089] The present invention is described in detail below by examples; however, the present invention is not limited to the following examples.

[0090] The present invention provides the design and synthesis of a type of planar chiral oxazole pyrimidine ligand based on a cyclophane skeleton, and the synthesis route thereof is as follows:

[0091]

[0092] The reaction steps are:

[0093] Method 1: One-step condensation reaction

[0094] Under nitrogen protection, add the compound represented by formula II and the compound represented by formula a1 and solvent X into a Schlenk bottle, stir at 40-60° C., and react for 24-72 hours to obtain a planar chiral oxazole pyrimidine ligand based on a cyclopentane skeleton (compound represented by formula I).

[0095] Method 2: including one-step condensation reaction and one-step cyclization reaction

[0096] Step 1: Condensation reaction

[0097] Under nitrogen protection, add the compound represented by formula II, the compound represented by formula b1, a condensing agent and a solvent X into a Schlenk bottle, stir at 0 to 25° C., and react for 5 to 10 hours to obtain a compound represented by formula b2;

[0098] Step 2 Cyclization

[0099] Under nitrogen protection, add the compound shown in formula b2, acid and solvent Y into a Schlenk flask, stir at 120-150° C., and react for 10-20 hours to obtain a planar chiral oxazole pyrimidine ligand based on a cyclophane skeleton (compound shown in formula I).

[0100] Example 1: Synthesis of Compound 3a

[0101]

[0102] Under nitrogen protection, sodium metal (0.8 mmol) was added to methanol (16.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2a (8.0 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (1.920 g, 8.0 mmol), and the mixture was stirred at 50 ° C for 24 hours. TLC detection showed that the raw material reaction was complete, the reaction was stopped, and the solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted 3 times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1 as eluent to obtain a total of 1.460 g of planar chiral ligand 3a with a yield of 56%.

[0103] 1 H NMR (400MHz, CDCl3) δ9.05 (d, J = 4.9Hz, 2H), 7.47 (t, J = 4.9Hz, 1H), 6.77-6.64 (m, 2H), 6.50 (d, J = 7.9Hz, 1H), 6.45 (d, J = 7.8Hz, 1H), 6.25-6.09 (m, 2H), 3.92-3.87 (m, 1H), 3.67-3.63 (m, 1H), 3.15-2.87 (m, 6H). 13 C{ 1H}NMR (100MHz, CDCl3) δ158.2,157.9,155.9,151.7,143.8,138.9,138.5,134.7,132.9,13 2.7,132.2,130.5,127.4,125.2,124.1,121.8,34.6,34.0,30.7,23.0.HRMS(ESI-TOF)m / z Calculated for C 21 H 18 N3O[M+H] + 328.1444,found:328.1444.

[0104] Example 2: Synthesis of Compound 3b

[0105]

[0106] Under nitrogen protection, sodium metal (0.2 mmol) was added to methanol (4.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2b (2.0 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (2.0 mmol), and the mixture was stirred at 50 ° C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain a total of 0.248 g of planar chiral ligand 3b with a yield of 48%.

[0107] 1 H NMR(400MHz, CDCl3)δ8.89(d,J=5.1Hz,1H),7.33(d,J=5.1Hz,1H),6.75-6.65(m,2H),6.51(d,J=8.0Hz,1H),6 .46(d,J=7.9Hz,1H),6.28-6.09(m,2H),4.00-3.83(m,1H),3.68-3.64(m,1H),3.16-2.86(m,6H),2.77(s,3H). 13 C{ 1H}NMR (100MHz, CDCl3) δ168.8,158.2,157.5,155.6,151.6,143.8,138.9,138.5,134.5,132.8,1 32.4,132.1,130.4,127.4,125.2,124.0,121.5,34.6,34.0,30.7,30.0,24.7.HRMS(ESI-TOF)m / z Calculatedfor C 22 H 20 N3O[M+H] + 342.1601, found:342.1602.

[0108] Example 3: Synthesis of Compound 3c

[0109]

[0110] Under nitrogen protection, sodium metal (0.14 mmol) was added to methanol (4.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2c (1.4 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (1.4 mmol), and the mixture was stirred at 50 ° C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain a total of 0.355 g of planar chiral ligand 3c with a yield of 74%.

[0111] 1 H NMR (400MHz, CDCl3) δ8.87 (s, 2H), 6.75-6.66 (m, 2H), 6.50 (d, J = 7.8Hz, 1H), 6.46 (d, J = 8.8Hz, 1H),6.21-6.10(m,2H),3.97-3.83(m,1H),3.71-3.60(m,1H),3.14-2.87(m,6H),2.48(s,3H). 13 C{ 1H}NMR (100MHz, CDCl3) δ158.3,158.1,153.6,151.6,143.7,138.9,138.4,134.5,132.8,132. 4,132.2,131.9,130.4,127.4,125.1,124.0,34.6,34.0,30.7,30.0,16.1.HRMS(ESI-TOF)m / z Calculated for C 22 H 20 N3O[M+H] + 342.1601, found:342.1600.

[0112] Example 4: Synthesis of Compound 3d

[0113]

[0114] Under nitrogen protection, sodium metal (0.17 mmol) was added to methanol (4.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2d (1.7 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (1.7 mmol), and the mixture was stirred at 50 ° C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted 3 times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain a total of 0.343 g of planar chiral ligand 3d with a yield of 56%.

[0115] 1 H NMR (400MHz, CDCl3) δ8.72(d,J=5.7Hz,1H),6.88(d,J=5.7Hz,1H),6.72-6.66(m,2H),6.50(d,J=8.0Hz,1H),6 .45(d,J=7.8Hz,1H),6.21-6.11(m,2H),4.23(s,3H),3.92-3.82(m,1H),3.66-3.60(m,1H),3.15-2.86(m,6H). 13 C{ 1H}NMR (100MHz, CDCl3) δ169.9,157.7,155.2,151.3,143.5,138.6,138.1,134.2,132.5,132. 0,131.8,130.0,127.1,124.9,123.6,108.8,54.1,34.3,33.8,30.4,29.7.HRMS(ESI-TOF)m / z Calculatedfor C 22 H 20 N3O2[M+H] + 358.1550, found:358.1551.

[0116] Example 5: Synthesis of Compound 3e

[0117]

[0118] Under nitrogen protection, sodium metal (0.4 mmol) was added to methanol (10.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2d (4.0 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (4.0 mmol), and the mixture was stirred at 50 ° C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain a total of 0.528 g of planar chiral ligand 3e with a yield of 40%.

[0119] 1 H NMR (400MHz, CDCl3) δ8.67(s,2H),6.67(s,2H),6.49(d,J=7.9Hz,1H),6.44(d,J=7.9Hz,1H ),6.15-6.08(m,2H),4.04(s,3H),3.91-3.83(m,1H),3.69-3.60(m,1H),3.11-2.85(m,6H). 13 C{ 1H}NMR (100MHz, CDCl3) δ158.0,153.8,151.5,148.6,144.2,143.8,138.9,138.4,134.3,132. 8,132.2,132.1,130.3,127.3,125.2,123.9,56.4,34.6,34.0,30.7,30.0.HRMS(ESI-TOF)m / z Calculated for C 22 H 20 N3O2[M+H] + 358.1565, found:358.1567.

[0120] Example 6: Synthesis of Compound 3f Under nitrogen protection, sodium metal (0.25 mmol) was added to methanol (8.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2f (2.5 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (2.5 mmol), and the mixture was stirred at 50 °C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain a total of 0.508 g of planar chiral ligand 3f in a yield of 57%. 1 H NMR(400 MHz, CDCl3)δ7.34(s,1H),6.79-6.70(m,2H),6.59(d,J=7.9 Hz,1H),6.54(d,J=7.9Hz,1H),6.31-6.18(m,2H),4.05-3.94(m,1H),3.80-3.69(m,1H),3.26-2.93(m,6H),2.78(s,6H). 13 C{ 1 H}NMR(100 MHz, CDCl3) δ168.0,158.5,155.5,151.6,143.8,138.9,138.5,134.3,132.7,132.2,132 .1,130.2,127.5,125.3,123.9,121.1,34.6,34.0,30.8,30.1,24.4.HRMS(ESI-TOF)m / z Cal-culated for C 23 H22 N3O[M+H]+356.1757,found:356.1755. Example 7: Synthesis of Compound 3g Under nitrogen protection, sodium metal (0.2 mmol) was added to methanol (8.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2 g (2.0 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (2.0 mmol), and the mixture was stirred at 50 ° C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain 3 g of planar chiral ligand, a total of 0.525 g, with a yield of 68%. 1 H NMR (400MHz, CDCl3) δ6.73-6.62(m,2H),6.49(d,J=7.8 Hz,1H),6.44(d,J=7.8 Hz,1H),6.21(s,1H),6.17(s,2H),4.16(s,6H),3.87-3.77(m,1H),3.65-3.54(m,1H),3.14-2.84(m,6H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ171.7,157.8,154.4,151.2,143.6,138.5,138.1,134.1,132.4,131. 9,131.7,129.8,127.1,125.0,123.6,90.6,54.5,34.4,33.8,30.6,29.8.HRMS(ESI-TOF)m / z Calcu-lated for C 23 H 22 N3O3[M+H] + 388.1656, found:388.1655.

[0121] Example 8: Synthesis of Compound 3h

[0122]

[0123] Under nitrogen protection, sodium metal (0.2 mmol) was added to methanol (8.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2h (2.0 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (2.0 mmol), and the mixture was stirred at 50 ° C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted 3 times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain a total of 0.427 g of planar chiral ligand 3h with a yield of 52%.

[0124] 1 H NMR(400MHz, CDCl3)δ9.05(d,J=5.3Hz,1H),8.41-8.13(m,2H),7.84(d,J=5.3Hz,1H),7.76-7.53(m,3H),6.80-6.65(m,2H) ,6.52(d,J=7.8Hz,1H),6.47(d,J=7.8Hz,1H),6.34-6.07(m,2H),4.03-3.85(m,1H),3.78-3.60(m,1H),3.21-2.85(m,6H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ165.3,158.7,158.4,156.2,151.7,143.9,138.9,138.5,136.1,134.6,132.8,132.4 ,132.1,131.7,130.3,129.3,127.7,127.5,125.3,124.0,117.3,34.7,34.1,30.8,30.1.HRMS(ESI-TOF)m / z Calculated for C 27 H 22 N3O[M+H] + 404.1757,found:404.1774.

[0125] Example 9: Synthesis of Compound 3i

[0126]

[0127] Under nitrogen protection, sodium metal (0.22 mmol) was added to methanol (8.0 mL) cooled to 0°C. After the sodium metal was completely consumed, 2-cyanopyrimidine 2i (2.2 mmol) was added. The resulting reaction mixture was warmed to room temperature and stirred for 24 hours. Then, chiral [2.2]-cyclophane-derived aminophenol (R p )-1 (2.2 mmol), and the mixture was stirred at 50 ° C for 24 hours. The solvent was removed under reduced pressure. The crude residue was dissolved in dichloromethane and water was added. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10 / 1) as eluent to obtain a total of 0.377 g of planar chiral ligand 3i with a yield of 46%.

[0128] 1 H NMR (400MHz, CDCl3) δ9.68 (s, 1H), 8.37 (d, J = 8.4Hz, 1H), 8.12-7.94 (m, 2H), 7.84-7.71 (m, 1H), 6.76-6.66 (m, 2H), 6.5 2(d,J=7.7Hz,1H),6.47(d,J=7.8Hz,1H),6.25-6.11(m,2H),4.02-3.89(m,1H),3.79-3.65(m,1H),3.20-2.89(m,6H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ161.5,158.6,152.1,151.8,150.6,144.0,139.0,138.5,135.1,134.6,132.8,132.5 ,132.2,130.4,129.4,129.3,127.5,127.5,125.3,124.8,124.0,34.7,34.1,30.8,30.1.HRMS(ESI-TOF)m / z Calculated for C 25 H 19 N3ONa[M+Na] + 400.1420,found:400.1428.

[0129] Example 10: Synthesis of Compound 3j

[0130]

[0131] 4-Trifluoromethyl-2-cyanopyrimidine 2j (0.350 g, 2.0 mmol) was dissolved in hydrochloric acid solution (6 M, 10.0 mL) and heated at 120 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Toluene (10 mL) was then added and the mixture was concentrated under reduced pressure. Further concentration under reduced pressure using 1,4-dioxane and diethyl ether gave 0.410 g of crude pyrimidinecarboxylic acid as a white solid, which was used in the next step without further purification.

[0132] Planar chiral aminophenol (Rp)-1 (0.370 g, 1.5 mmol) and pyrimidinecarboxylic acid (0.240 g, 1.0 mmol) were dissolved in dichloromethane (5.0 mL). Then, 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 0.383 g, 2.0 mmol) and 1-hydroxy-benzotriazole (HOBt, 0.304 g, 2.0 mmol) were added under nitrogen and 0°C. The mixture was stirred at room temperature for 12 hours. Water (10 mL) was added to quench the reaction. The aqueous phase was extracted 3 times with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an amide intermediate.

[0133] The solution of the amide intermediate (0.487 g, 1.0 mmol) and p-toluenesulfonic acid monohydrate (0.285 g, 1.5 mmol) in p-xylene (10 mL) was stirred at 120 ° C (oil bath temperature) for 24 hours. After cooling to room temperature, a saturated sodium carbonate solution (10 mL) was added. The aqueous phase was extracted 3 times with ethyl acetate and washed with brine. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using hexane / dichloromethane / ethyl acetate = 10 / 1 / 1 as eluent to obtain a total of 0.265 g of planar chiral ligand 3j with a yield of 67%.

[0134] 1 H NMR(400MHz, CDCl3) δ9.28(d,J=5.0Hz,1H),7.78(d,J=5.0Hz,1H),6.75-6.70(m,2H),6.51(d,J=7.8 Hz,1H),6.46(d,J=7.8Hz,1H),6.13(s,2H),3.93-3.86(m,1H),3.69-3.62(m,1H),3.13-2.88(m,6H). 13 C{ 1H}NMR(100MHz, CDCl3)δ160.6,157.3(q,J=37.1Hz),156.8,156.4,151.8,143.7,138.8,138.4,134.8,133.1,132 .8,132.2,130.6,127.4,125.1,124.2,123.0(q,J=274.0Hz),117.5,117.3(q,J=2.5Hz),34.6,34.0,30.7,29.9. 19 F{ 1 H}NMR(376MHz,CDCl3)δ-69.41.HRMS(ESI-TOF)m / z Calculated for C 22 H 17 F3N3O[M+H] + 396.1318, found:396.1319.

[0135] Example 11: Asymmetric 1,2-reduction of α,β-unsaturated ketones

[0136]

[0137] Under nitrogen protection, bis(1,5-cyclooctadiene)nickel (Ni(COD)2, 2.2 mg, 0.008 mmol, 2.0 mol%), 3b (0.0096 mmol, 2.4 mol%) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 67.2 mg, 0.6 mmol, 1.5 equiv.) were added to a 10 mL Schlenk tube. Toluene (1.6 mL) was added at room temperature and the mixture was stirred for 10 minutes. Pinacol borane (HBpin, 70 μL, 0.48 mmol, 1.2 equiv.) was added. After stirring for 10 minutes in a -25 °C cold bath, a toluene solution of α,β-unsaturated ketone 4a (1.0 equiv. 0.4 mmol in 0.4 mL of toluene) was added. The reaction mixture was stirred at this temperature for 1 hour. TLC showed that the reaction of the starting material was complete, and the reaction was stopped and quenched by adding a saturated methanol solution of ammonium fluoride. After stirring at room temperature for 30 minutes, water and ethyl acetate were added, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Petroleum ether / ethyl acetate = 10 / 1 was used as the eluent and purified by silica gel chromatography. Enantioselectivity was determined by HPLC analysis using a chiral stationary phase.

[0138] 1H NMR (400MHz, CDCl3) δ7.35-7.16(m,5H),6.50(d,J=15.9Hz,1H),6.20(dd,J=15.9,6.4Hz,1H),4.52-4.36(m,1H),1.92(s,1H),1.32(d,J=6.4Hz,3H). 13 C{ 1 H}NMR (100MHz, CDCl3) δ136.8,133.7,129.4,128.7,127.7,126.5,69.0,23.5.HPLC: ChiralcelOD-H, 250nm, 30℃, n-Hexane / i-PrOH=90 / 10, flow=1.0mL / min, retention time 8.5min(major).

[0139] Example 12: Substrate applicability investigation

[0140] The same method and conditions as in Example 11 were used to prepare products of asymmetric 1,2-reduction reactions of different structures, with only the type of α,β-unsaturated ketone 4 being changed in the reaction, as follows:

[0141]

[0142] When the substrate is 4f, the chiral ligand of 3h is used as a catalyst for the reaction.

[0143] 5b: 1 H NMR (400MHz, CDCl3) δ7.56-7.39(m,1H),7.22-7.10(m,3H),6.79(d,J=15.8Hz,1H),6.16(d d,J=15.8,6.4Hz,1H),4.58-4.43(m,1H),2.36(s,3H),1.93(s,1H),1.39(d,J=6.4Hz,3H). 13 C{ 1 H}NMR(100MHz, CDCl3)δ135.9,135.7,135.2,130.5,127.7,127.3,126.3,125.8,69.3,23.7,20.0.HPLC:Chiralcel OD-H, 250nm, 30℃, n-Hexane / i-PrOH=90 / 10, flow=1.0mL / min, retention time 9.2min (major).

[0144] 5c: 1H NMR(400MHz,CDCl3)δ7.47-7.39(m,1H),7.26-7.19(m,1H),6.97-6.81(m,3H),6.27(dd,J=16.1,6.6Hz,1H),4.59-4.40(m,1H),3.85(s,3H),1.68(s,1H),1.38(d,J=6.4Hz,3H). 13 C{ 1 H}NMR(100MHz,CDCl3)δ156.9,134.4,128.8,127.0,125.8,124.4,120.8,110.9,69.6,55.6,23.5.HPLC:Chiralcel OD-H,250nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0mL / min,retention time 12.4min(major).

[0145] 5d: 1 H NMR(400MHz,CDCl3)δ7.32-7.26(m,4H),6.52(d,J=15.9Hz,1H),6.23(dd,J=15.9,6.2Hz,1H),4.53-4.43(m,1H),1.66(s,1H),1.37(d,J=6.4Hz,3H). 13 C{ 1 H}NMR(100MHz,CDCl3)δ135.3,134.3,133.4,128.9,128.3,127.8,68.9,23.6.HPLC:ChiralcelOB-H,250nm,30℃,n-Hexane / i-PrOH=95 / 5,flow=1.0mL / min,retention time 8.1minand 9.4min(major).

[0146] 5e: 1 H NMR(400MHz,CDCl3)δ7.42-7.36(m,2H),7.35-7.27(m,2H),7.27-7.20(m,1H),5.86-5.74(m,1H),4.80-4.65(m,1H),2.07(d,J=1.4Hz,3H),2.01(s,1H),1.33(d,J=6.3Hz,3H). 13 C{ 1H}NMR(100MHz,CDCl3)δ143.0,136.1,132.0,128.3,127.3,125.9,65.3,23.6,16.2.HPLC:Chiralcel OD-H,250nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0mL / min,retention time 6.2min(major)and 12.1min.

[0147] 5f: 1 H NMR(400MHz,CDCl3)δ7.44-7.14(m,10H),6.63(d,J=15.9Hz,1H),6.33(dd,J=15.8,6.5Hz,1H),5.32(d,J=6.5Hz,1H),2.21(s,1H) 13 C{ 1 H}NMR(100MHz,CDCl3)δ142.9,136.6,131.6,130.6,128.7,128.7,127.9,126.7,126.5,77.1,75.2.HPLC:Chiralcel OD-H,250nm,30℃,n-Hexane / i-PrOH=90 / 10,flow=1.0mL / min,retentiontime 14.9min(major)and 18.8min.1,4-Reduction:20.2mg,24%yield, 1 H NMR(400MHz,CDCl3)δ8.06-7.86(m,2H),7.58-7.50(m,1H),7.50-7.40(m,2H),7.35-7.14(m,5H),3.38-3.25(m,2H),3.15-3.02(m,2H).

[0148] 5g: 1 H NMR(400MHz,CDCl3)δ7.44-7.29(m,5H),6.87(d,J=16.0Hz,1H),6.21(dd,J=16.0,6.5Hz,1H),4.70-4.63(m,1H),2.33(s,1H). 13 C{ 1 H}NMR(100MHz,CDCl3)δ136.2,135.2,128.9,128.6,126.7,125.5(q,J=280.2Hz),120.5(q,J=2.0Hz),71.6(q,J=32.0Hz). 19F{ 1 H}NMR (376MHz,CDCl3)δ-79.07.HPLC:Chiralpak OJ-H,220nm,30℃,n-Hexane / i-PrOH=95 / 5,flow=1.0mL / min,retention time 12.9min and 15.5min(major).Comparative Example 1

[0149] Under the same reaction conditions as in Example 11, only toluene was replaced by acetonitrile and the ligand was changed to 3a, the enantioselectivity of the target product was 14%.

[0150]

Claims

1. A type of planar chiral oxazolidinone ligand compound based on a cyclophane skeleton, characterized in that: The planar chiral oxazolidinone ligand compound has a structure shown in Formula I, In Formula I: Ring A is a heteroaryl group containing at least two heteroatoms, preferably ring A is a heteroaryl group containing 2 to 3 heteroatoms; The heteroatom is selected from N, O or S; R is selected from one of H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and phenyl.

2. The planar chiral oxazolidinone ligand compound according to claim 1, characterized in that: The ring A is a heteroaryl group containing 2 to 3 N atoms; R is selected from one of methyl, methoxy, trifluoromethyl and phenyl; The heteroaryl group is a monocyclic heteroaryl group, preferably a 6-membered heteroaryl group, and more preferably a pyrimidinyl group; Or the heteroaryl group is a fused-ring heteroaryl group, preferably a 10-membered fused-bicyclic heteroaryl group, preferably a quinazolinyl group or an isoquinazolinyl group.

3. The planar chiral oxazolidinone ligand compound according to claim 1, characterized in that: The planar chiral oxazolidinone ligand compound is selected from one of Formula 1-1, Formula 2-1, Formula 2-2, Formula 2-3, Formula 3-1, Formula 3-2, Formula 3-3, Formula 4-1, Formula 5-1 and Formula 6-1; Or the planar chiral oxazole pyrimidine ligand compound is in R configuration or S configuration.

4. The method for preparing a planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton according to any one of claims 1 to 3, characterized in that: Prepared by method 1; The first method is to prepare a mixed solution a containing a compound represented by formula II, a compound represented by formula a1 and a solvent X, and to carry out a condensation reaction a in an inactive atmosphere to obtain a planar chiral oxazolidinone ligand compound represented by formula I; 5. The preparation method according to claim 4, characterized in that: In the method 1: The molar ratio of the compound represented by formula II to the compound represented by formula a1 is 1:1.0 to 1:1.5; The reaction conditions of the condensation reaction a are a temperature of 40 to 60° C. and a reaction time of 24 to 72 hours; The inert atmosphere in the condensation reaction a is selected from at least one of nitrogen and argon; The solvent X is selected from at least one of methanol, tetrahydrofuran, ether and dioxane; The molar concentration of the compound represented by formula II in solvent X is 0.2 to 0.5 mol / L; The mixed solution a also includes a catalyst, which is a methanol solution of sodium methoxide or metallic sodium. The molar ratio of the compound represented by formula II to the sodium in the catalyst is 1:0.1 to 1:0.

5.

6. The method for preparing a planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton according to any one of claims 1 to 3, characterized in that: Prepared by method 2; The method 2 comprises condensation reaction b and cyclization reaction; The condensation reaction b is: a mixed solution b containing a compound represented by formula II, a compound represented by formula b1, a condensation agent and a solvent Y undergoes a condensation reaction b in an inert atmosphere to obtain a compound represented by formula b2; The cyclization reaction is as follows: a mixed solution c containing the compound shown in formula b2, an acid and a solvent Z undergoes a cyclization reaction in an inactive atmosphere to obtain a planar chiral oxazole pyrimidine ligand compound shown in formula I.

7. The preparation method according to claim 6, characterized in that: In the condensation reaction b of the method 2: The molar ratio of the compound represented by formula II to the compound represented by formula b1 is 1:1.0 to 1:1.5; The molar ratio of the compound represented by formula b1 to the condensing agent is 1:1 to 1:1.2; The reaction conditions of the condensation reaction b are 0-25°C and the reaction time is 5-12 hours; The inert atmosphere in the condensation reaction b is selected from at least one of nitrogen and argon; The condensing agent is selected from at least two of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, diisopropylcarbodiimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; The solvent Y is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide and acetonitrile; The molar concentration of the compound represented by formula II in solvent Y is 0.1-0.3 mol / L. In the cyclization reaction of the method 2: The molar ratio of the compound represented by formula b2 to the acid is 1:1.2 to 1:1.5; The cyclization reaction conditions are 120-150° C. and 10-20 hours; The inactive atmosphere in the cyclization reaction is selected from at least one of nitrogen and argon; The acid is selected from at least one of p-toluenesulfonic acid monohydrate, methanesulfonic acid, and acetic acid; The solvent Z is selected from at least one of p-xylene, m-xylene and toluene; The molar concentration of the compound represented by formula b2 in the solvent Z is 0.05 to 0.1 mol / L.

8. The use of the planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton according to any one of claims 1 to 4, characterized in that: The planar chiral oxazolidinone ligand compound is used as a ligand for the asymmetric 1,2-reduction reaction of α,β-unsaturated ketone.

9. A method for the asymmetric 1,2-reduction of α,β-unsaturated ketones, characterized in that: The raw materials contain α,β-unsaturated ketone I and pinacol borane; a mixture containing α,β-unsaturated ketone I, pinacol borane, a catalyst and a base reacts to obtain a product of an asymmetric 1,2-reduction reaction; The structure of the α,β-unsaturated ketone I is Ar is selected from phenyl or phenyl containing a substituent, and the substituent in the phenyl containing a substituent is one of C1-C3 alkyl or alkoxy, and halogen; R 1 Selected from H or C1-C3 alkyl; R 2 is one of C1-C4 alkyl, phenyl or trifluoromethyl; The product of the asymmetric 1,2-reduction reaction is The catalyst is a metal-ligand complex, the metal is nickel, and the ligand is the planar chiral oxazole pyrimidine ligand compound based on a cyclophane skeleton as described in any one of claims 1 to 3.

10. The method according to claim 11, characterized in that The metal-ligand complex is formed by coordination of a metal precursor and a ligand in a solvent M; The metal precursor is at least one of bis(1,5-cyclooctadiene)nickel and nickel acetate tetrahydrate; The molar ratio of the metal precursor to the ligand is 1:1 to 1:1.5; The concentration of the metal precursor in the solvent M is 0.001 to 0.02 mol / L; The temperature of the coordination reaction is 0 to 50°C and the time is 5 to 30 minutes; The molar ratio of the α,β-unsaturated ketone I to pinacol borane is 1:1 to 1:2; The molar ratio of the metal ligand complex to the α,β-unsaturated ketone I is 0.02:1 to 0.10:1, and the metal ligand complex is calculated based on the molar number of the metal precursor; The base is at least one of 1,4-diazabicyclo[2.2.2]octane, potassium tert-butoxide, triethylamine and diisopropylethylenediamine; The molar ratio of the base to the α,β-unsaturated ketone I is 1:1 to 2:1; The solvent M is at least one of an aromatic hydrocarbon solvent, an ester solvent, and a chlorinated solvent; the aromatic hydrocarbon solvent is preferably at least one of toluene, benzene, and trifluorotoluene; the ester solvent is preferably ethyl acetate; the chlorinated solvent is preferably at least one of dichloromethane and dichloroethane; The molar concentration of the α,β-unsaturated ketone I in the solvent M is 0.05 to 0.1 mol / L; The reaction temperature of the asymmetric 1,2-reduction reaction is -40 to 25°C; The reaction time of the asymmetric 1,2-reduction reaction is 0.5 to 24 hours.

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