Efficient preparation method and application of optically pure beta-cyanone

Abstract

The invention relates to an efficient preparation method and application of optically pure beta-cyanone. The invention belongs to the technical field of fine chemical synthesis. The invention aims to solve the technical problems of low yield, long reaction time, harsh reaction conditions and unsuitability for industrial production of the existing method for preparing optically pure beta-cyanone through asymmetric conjugate cyanidation addition reaction. According to the method, an alpha, beta-unsaturated carbonyl compound is taken as a substrate, acetone cyanohydrin is taken as a cyanogen source, and under the action of a cinchona alkali derivative, alkali and an additive, the optically pure beta-cyanoketone is prepared by heating in a nitrogen atmosphere in one step without tedious operation. By screening cinchona alkaloid derivatives, alkali, additives, reaction temperature and reaction solvents and coordinating and controlling the optimal proportion of all the substances, side reactions are inhibited to the maximum extent, beta-cyanoketone is obtained with high stereoselectivity and yield, and possibility is provided for industrial production of optically pure beta-cyanoketone. The method is mild in condition, simple in operation process, short in reaction time and environmentally friendly, acetone cyanohydrin serves as a cyanogen source, substances such as highly toxic sodium cyanide, TMSCN low in atom utilization rate and high in price are replaced, the application range of a substrate is good, and the method can be widely applied to the fields of biochemistry and medicinal chemistry.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical synthesis, and specifically relates to a high-efficiency preparation method and application of optically pure beta-cyanoketone. Background Art

[0002] As an important organic functional group, cyano is widely present in fine chemicals such as natural products, medicines, pesticides, dyes, etc. It is a key active group and plays an irreplaceable role. Organic compounds containing cyano are collectively referred to as nitriles. In modern organic synthesis, nitriles are important multifunctional synthetic building blocks. As intermediates, they can be easily converted into amides, amines, carboxylic acids and their derivatives, aldehydes, ketones, alcohols, nitrogen-containing heterocycles, etc. Chiral nitriles are intermediates of many biologically active substances and drugs such as naproxen, ibuprofen, flurbiprofen, venlafaxine, etc. Therefore, studying the introduction of cyano groups in molecules, especially asymmetric introduction methods, has important practical significance and application value. Optically pure β-cyanoketone is an important chemical intermediate, which can be further converted into γ-aminobutyric acid (GABA, an important inhibitory neurotransmitter of the central nervous system) with important biological activity under reducing conditions. In addition, β-cyanoketone is also used in the total synthesis of natural products such as terpenes, alkaloids, and steroids.

[0003] The most commonly used method for preparing optically pure β-cyanoketones is the asymmetric conjugate addition reaction of cyaniding reagents to α,β-unsaturated carbonyl compounds. The reported methods for preparing optically pure β-cyanoketones have the following problems: 1. Most reactions must be carried out below 0°C, the reaction rate is too slow, and the reaction time is as long as 48 to 72 hours; 2. The catalytic system is complex, and the chiral induction effect can only be produced after the coordination of two ligands, which is not suitable for industrial scale-up production; 3. Special organic reagents such as diisopropyl ether are used as solvents to show their excellent chiral induction effect. Diisopropyl ether is a flammable liquid that easily forms peroxides and explodes when shaken. It is difficult to transport and has great harm to the environment and the health of operators; 4. Quaternary ammonium salts are used as organic small molecule catalysts to catalyze the reaction. Organic small molecule catalysts cannot be recycled and reused, and the production cost is high. At present, the most in-depth research is on the asymmetric addition reaction of TMSCN as a cyaniding reagent to prepare optically pure β-cyanoketone. However, TMSCN as a cyaniding reagent has low atomic utilization, high price, and is only suitable for laboratory tests, not suitable for industrial production. Acetone cyanohydrin, as a by-product of acrylonitrile production, is cheap, miscible with water and a variety of organic solvents, and the only by-product after the reaction is acetone, which is suitable for industrial production. Therefore, it is very meaningful to develop a method for preparing optically pure β-cyanoketone using acetone cyanohydrin as a cyaniding reagent in a green, safe, efficient and rapid manner. Summary of the invention

[0004] In order to overcome the above-mentioned deficiencies of the prior art, the present invention provides a highly efficient preparation method and application of optically pure β-cyanoketone.

[0005] The technical solution of the present invention is as follows:

[0006] One of the objects of the present invention is to provide an efficient method for preparing optically pure β-cyanoketone, which is carried out according to the following steps:

[0007] Optically pure β-cyanoketone is prepared by using α,β-unsaturated carbonyl compounds as substrates and reacting them with acetone cyanohydrin in the presence of cinchona alkaloid derivatives, bases and additives.

[0008] Further defined, the α,β-unsaturated carbonyl compound is chalcone, 1-(2-fluorophenyl)-3-phenyl-2-propene-1-one, 3-(4-fluorophenyl)-1-phenyl-2-propene-1-one, 3-(4-methoxyphenyl)-1-phenyl-2-propene-1-one, 3-(4-methoxyphenyl)-1-(4-nitrophenyl)-2-propene-1-one, 3-(3-methoxyphenyl)-1-phenyl-2-propene-1-one, 1-(3-fluorophenyl)-3-phenyl-2-propene-1-one, )-3-phenyl-2-propene-1-one, 3-(2-chlorophenyl)-1-phenyl-2-propene-1-one, 3-(4-bromophenyl)-1-phenyl-2-propene-1-one, 1-phenyl-3-(p-tolyl)-2-propene-1-one, 3-(3-fluorophenyl)-1-phenyl-2-propene-1-one, 1-(2-fluorophenyl)-3-(4-fluorophenyl)-2-propene-1-one, 3-(2-fluorophenyl)-1-phenyl-2-propene-1-one.

[0009] It is further defined that the cinchona alkaloid derivatives are quinine, O-desmethylquinine, 6'-methoxyquinine-9-amine, 9-aminoquinine-6'-ol; the above cinchona alkaloid derivatives are cinchona alkaloid derivatives I, II, III, and IV, respectively, and the structural formulas are as follows:

[0010]

[0011] It is further defined that the base is cesium carbonate, potassium carbonate, n-butyl lithium, sodium amide, lithium hydride, dibutyl magnesium, lithium amide.

[0012] It is further defined that the additive is 2-tert-butylphenol, 2,6-di-tert-butylphenol, and 1-naphthol.

[0013] It is further defined that the amount of acetone cyanohydrin used is 1.0-4.0 equivalents of the α,β-unsaturated carbonyl compound, the amount of cinchona alkaloid derivative used is 0.1-0.4 equivalents of the α,β-unsaturated carbonyl compound, the amount of base used is 0.1-1.6 equivalents of the α,β-unsaturated carbonyl compound, and the amount of additive used is 0.1-0.4 equivalents of the α,β-unsaturated carbonyl compound.

[0014] It is further defined that the amount of acetone cyanohydrin is 2.0-4.0 equivalents of the α,β-unsaturated carbonyl compound, the amount of cinchona alkaloid derivative is 0.2-0.4 equivalents of the α,β-unsaturated carbonyl compound, the amount of base is 0.8-1.6 equivalents of the α,β-unsaturated carbonyl compound, and the amount of additive is 0.2-0.4 equivalents of the α,β-unsaturated carbonyl compound.

[0015] Most preferably, the usage ratio of substrate to acetone cyanohydrin, cinchona alkaloid derivative, base and additive is 1:2:0.2:0.8:0.2.

[0016] It is further defined that the reaction temperature is 25-80°C.

[0017] Further limited, the solvent is toluene, dichloroethane, chloroform.

[0018] The second object of the present invention is to provide a β-cyanoketone prepared by the above method, wherein the β-cyanoketone has the general structural formula:

[0019]

[0020] In the formula, R1 represents phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-chlorophenyl, 4-bromophenyl, p-tolyl, 3-fluorophenyl, 2-fluorophenyl; R2 represents phenyl, 2-fluorophenyl, 4-nitrophenyl, 3-fluorophenyl.

[0021] The third object of the present invention is to provide an application of the product prepared by the above method in the fields of biochemistry and medicinal chemistry.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] The method of the present invention starts from α, β-unsaturated carbonyl compounds, uses cheap and easily available acetone cyanohydrin as a cyanide source, and under the action of cinchona alkali derivatives, bases, and additives, without complicated operations, heats in a nitrogen atmosphere to prepare optically pure β-cyanoketone in one step. By screening cinchona alkali derivatives, bases, additives, reaction temperature, and reaction solvents, and coordinating and controlling the optimal ratio of each substance, the side reaction is suppressed to the maximum extent, and the optically pure β-cyanoketone is obtained with high stereoselectivity and yield, which provides the possibility for the industrial production of optically pure β-cyanoketone. The method of the present invention has mild conditions, a simple operation process, a short reaction time, and is green and environmentally friendly. Acetone cyanohydrin is used as a cyanide source, replacing highly toxic sodium cyanide, TMSCN with low atomic utilization and high price, and other substances. The substrate has a good scope of application and can be widely used in the fields of biochemistry and medicinal chemistry. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a high performance liquid chromatogram of the optically pure 4-oxo-2,4-diphenylbutyronitrile obtained in Example 1;

[0025] Figure 2 It is the high performance liquid chromatogram of the racemic 4-oxo-2,4-diphenylbutyronitrile sample;

[0026] Figure 3 4-oxo-2,4-diphenylbutyronitrile prepared in Example 1 1 H NMR spectrum. DETAILED DESCRIPTION

[0027] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0028] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained through commercial channels by those skilled in the art.

[0029] The terms "comprising," "including," "having," "containing," or any other variations thereof, as used in the following examples, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus comprising the listed elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.

[0030] Example 1: Synthesis of 4-oxo-2,4-diphenylbutyronitrile

[0031] To a round-bottom flask equipped with a magnetic stirrer, 30.9 mg of 9-aminoquinine-6'-ol, 9.2 mg of lithium amide and 5 mL of dichloroethane were added, and then 104 mg of chalcone and 15 mg of 2-tert-butylphenol were added. After heating to 60°C under a nitrogen atmosphere, 0.09 ml of acetone cyanohydrin was added, and the reaction time was 4 h. The reaction was monitored by TLC. After the raw materials reacted completely, water was added for washing, and then dichloromethane was added for extraction. The organic phase was washed with water and saturated brine in turn, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to column chromatography, and ethyl acetate: n-hexane (v:v) = 1:10 was used for column chromatography to obtain 4-oxo-2,4-diphenylbutyronitrile, 111 mg, white solid powder, with a yield of 95.2% and an ee value of 93.4%.

[0032] Product 4-oxo-2,4-diphenylbutyronitrile: 1 H NMR(300MHz,Chloroform-d)δ7.97–7.92(m,2H),7.66–7.57(m,1H),7.55–7.32(m,7H),4. 59(dd,J=7.9,6.0Hz,1H),3.75(dd,J=17.9,7.9Hz,1H),3.53(dd,J=17.9,6.0Hz,1H)ppm.

[0033] The ee value of the product 4-oxo-2,4-diphenylbutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=10.9min, t2(major)=13.6min.

[0034] Example 2

[0035] The difference between this embodiment and embodiment 1 is that the cinchona alkaloid derivative used is replaced by quinine by 9-aminoquinine-6'-ol, and the other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 35 mg, white solid powder, has a yield of 27.8% and an ee value of 0.0%.

[0036] Example 3

[0037] The difference between this embodiment and embodiment 1 is that the cinchona alkaloid derivative used is replaced by 9-aminoquinine-6'-ol with O-desmethylquinine, and the other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 67 mg, white solid powder, has a yield of 56.9% and an ee value of 4.2%.

[0038] Example 4

[0039] The difference between this embodiment and embodiment 1 is that the cinchona alkaloid derivative used is replaced by 9-aminoquinine-6'-ol with 6'-methoxyquinine-9-amine, and the other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 48 mg, white solid powder, has a yield of 40.8% and an ee value of 8.2%.

[0040] Example 5

[0041] The difference between this embodiment and embodiment 1 is that the reaction temperature is replaced by 25° C. from 60° C. The other steps and parameters are the same as those in embodiment 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 34 mg, white solid powder, has a yield of 28.9% and an ee value of 11.5%.

[0042] Example 6

[0043] The difference between this embodiment and embodiment 1 is that the reaction temperature is replaced by 45° C. from 60° C. The other steps and parameters are the same as those in embodiment 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 81 mg, white solid powder, has a yield of 68.9% and an ee value of 45.7%.

[0044] Example 7

[0045] The difference between this embodiment and embodiment 1 is that the reaction temperature is replaced by 50° C. from 60° C. The other steps and parameters are the same as those in embodiment 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 92 mg, white solid powder, has a yield of 78.2% and an ee value of 79.1%.

[0046] Example 8

[0047] The difference between this embodiment and embodiment 1 is that the reaction temperature is replaced by 80° C. from 60° C. The other steps and parameters are the same as those in embodiment 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 106 mg, white solid powder, has a yield of 90.6% and an ee value of 37.0%.

[0048] Example 9

[0049] The difference between this example and Example 1 is that the solvent used is replaced by toluene instead of dichloroethane. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 100 mg, white solid powder, has a yield of 85.0% and an ee value of 40.3%.

[0050] Example 10

[0051] The difference between this example and Example 1 is that the solvent used is replaced by chloroform instead of dichloroethane. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 98 mg, white solid powder, has a yield of 83.3% and an ee value of 0.0%.

[0052] Embodiment 11

[0053] The difference between this example and Example 1 is that the base used is replaced by cesium carbonate instead of lithium amide. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 101 mg, white solid powder, has a yield of 85.9% and an ee value of 0.0%.

[0054] Example 12

[0055] The difference between this example and Example 1 is that the base used is replaced by potassium carbonate instead of lithium amide. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 113 mg, white solid powder, has a yield of 96.1% and an ee value of 0.0%.

[0056] Example 13

[0057] The difference between this example and Example 1 is that the base used is replaced by n-butyl lithium instead of lithium amide. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 108 mg, white solid powder, has a yield of 91.8% and an ee value of 0.0%.

[0058] Embodiment 14

[0059] The difference between this example and Example 1 is that the base used is replaced by sodium amide instead of lithium amide. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 91 mg, white solid powder, has a yield of 77.4% and an ee value of 27.3%.

[0060] Embodiment 15

[0061] The difference between this example and Example 1 is that the base used is replaced by lithium hydride instead of lithium amide. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 75.3 mg, white solid powder, has a yield of 64.0% and an ee value of 72.3%.

[0062] Example 16

[0063] The difference between this example and Example 1 is that the base used is replaced by dibutyl magnesium instead of lithium amide. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 112 mg, white solid powder, has a yield of 95.2% and an ee value of 0.0%.

[0064] Embodiment 17

[0065] The difference between this example and Example 1 is that the additive used is replaced by 2,6-di-tert-butylphenol instead of 2-tert-butylphenol. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 82 mg, white solid powder, has a yield of 69.7% and an ee value of 80.0%.

[0066] Embodiment 18

[0067] The difference between this example and Example 1 is that the additive used is replaced by 1-naphthol instead of 2-di-tert-butylphenol. The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 75 mg, white solid powder, has a yield of 63.8% and an ee value of 53.9%.

[0068] Embodiment 19

[0069] The difference between this example and Example 1 is that the amount of lithium amide is adjusted to 5.2 mg (0.45 equivalents of the substrate chalcone). The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile, 50.6 mg, white solid powder, has a yield of 43.0% and an ee value of 54.2%.

[0070] Embodiment 20

[0071] The difference between this example and Example 1 is that the amount of lithium amide is adjusted to 8.6 mg (0.75 equivalent of the substrate chalcone). The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile is 83.5 mg, a white solid powder, with a yield of 71.0% and an ee value of 83.7%.

[0072] Embodiment 21

[0073] The difference between this example and Example 1 is that the amount of lithium amide is adjusted to 10.4 mg (0.9 equivalent of the substrate chalcone). The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile is 108 mg, a white solid powder, with a yield of 92.0% and an ee value of 81.1%.

[0074] Embodiment 22

[0075] The difference between this example and Example 1 is that the amount of lithium amide is adjusted to 11.5 mg (1.0 equivalent of the substrate chalcone). The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile is 113 mg, a white solid powder, with a yield of 96.1% and an ee value of 79.1%.

[0076] Embodiment 23

[0077] The difference between this example and Example 1 is that the amount of lithium amide is adjusted to 13.8 mg (1.2 equivalents of the substrate chalcone). The other steps and parameters are the same as those in Example 1, and the obtained product 4-oxo-2,4-diphenylbutyronitrile is 112 mg, a white solid powder, with a yield of 95.2% and an ee value of 74.3%.

[0078] Embodiment 24

[0079] The difference between this example and Example 1 is that the amount of acetone cyanohydrin is adjusted to 0.18 ml (4.0 equivalents of the substrate chalcone). The other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile is 107 mg, a white solid powder, with a yield of 90.9% and an ee value of 91.5%.

[0080] Embodiment 25

[0081] The difference between this example and Example 1 is that the amount of 9-aminoquinine-6'-ol is adjusted to 61.8 mg (0.4 equivalent of the substrate chalcone). The other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile is 108 mg, a white solid powder, with a yield of 91.8% and an ee value of 83.7%.

[0082] Embodiment 26

[0083] The difference between this example and Example 1 is that the amount of 2-tert-butylphenol is adjusted to 30 mg (0.4 equivalent of the substrate chalcone). The other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile is 106 mg, a white solid powder, with a yield of 90.1% and an ee value of 95.1%.

[0084] Example 27: Synthesis of 4-(2-fluorophenyl)-4-oxo-2-phenylbutyronitrile

[0085] The difference between this example and example 1 is that the substrate is replaced by 1-(2-fluorophenyl)-3-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in example 1. The obtained product 4-(2-fluorophenyl)-4-oxo-2-phenylbutyronitrile, 97 mg, white solid powder, has a yield of 76.7% and an ee value of 83.3%.

[0086] Product 4-(2-fluorophenyl)-4-oxo-2-phenylbutyronitrile: 1 H NMR (300MHz, Chloroform-d) δ7.96 (td, J=7.6, 1.9Hz, 1H), 7.66–7.53 (m, 1H), 7.49–7.23 (m, 7H), 4.67–4.49 (m, 1H), 3.84–3.45 (m, 2H).

[0087] The ee value of the product 4-(2-fluorophenyl)-4-oxo-2-phenylbutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=8.4min, t2(major)=9.8min.

[0088] Example 28: Synthesis of 2-(4-fluorophenyl)-4-oxo-4-phenylbutyronitrile

[0089] The difference between this example and example 1 is that the substrate is replaced by 3-(4-fluorophenyl)-1-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in example 1. The obtained product 2-(4-fluorophenyl)-4-oxo-4-phenylbutyronitrile, 103 mg, white solid powder, has a yield of 81.4% and an ee value of 87.0%.

[0090] Product 2-(4-fluorophenyl)-4-oxo-4-phenylbutyronitrile: 1 H NMR (300MHz, Chloroform-d) δ8.09–7.87(m,2H),7.69–7.55(m,1H),7.56–7.33(m,4H),7.10(t,J=8.6Hz,2H),4.59(t,J=6.9Hz,1H),3.85–3.37(m,2H).

[0091] The ee value of the product 2-(4-fluorophenyl)-4-oxo-4-phenylbutyronitrile was determined by using a CHIRALCEL OD-H chiral column for analysis, with a mobile phase of n-hexane / 2-propanol = 90:10 and a flow rate of 1.0 mL min –1 , detection wavelength 254nm, retention time: t1(major)=31.2min, t2(minor)=35.1min.

[0092] Example 29: Synthesis of 2-(4-methoxyphenyl)-4-oxo-4-phenylbutyronitrile

[0093] The difference between this example and example 1 is that the substrate is replaced by 3-(4-methoxyphenyl)-1-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in example 1. The obtained product 2-(4-methoxyphenyl)-4-oxo-4-phenylbutyronitrile, 111 mg, white solid powder, has a yield of 83.7% and an ee value of 65.0%.

[0094] Product 2-(4-methoxyphenyl)-4-oxo-4-phenylbutyronitrile: 1 H NMR(300MHz,Chloroform-d)δ8.01–7.84(m,2H),7.66–7.54(m,1H),7.47(t,J=7.6Hz,2H),7 .41–7.30(m,2H),6.99–6.83(m,2H),4.52(t,J=7.0Hz,1H),3.80(s,3H),3.75–3.40(m,2H).

[0095] The ee value of the product 2-(4-methoxyphenyl)-4-oxo-4-phenylbutyronitrile was determined by using a CHIRALCELOD-H chiral chromatographic column for analysis, with a mobile phase of n-hexane / 2-propanol = 90:10 and a flow rate of 1.0 mL min –1 , detection wavelength 254nm, retention time: t1(major)=15.4min, t2(minor)=18.1min.

[0096] Example 30: Synthesis of 2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4-oxobutyronitrile

[0097] The difference between this example and example 1 is that the substrate is replaced by 3-(4-methoxyphenyl)-1-(4-nitrophenyl)-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in example 1. The obtained product 2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4-oxobutyronitrile, 133 mg, white solid powder, has a yield of 85.8% and an ee value of 59.3%.

[0098] Product 2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4-oxobutyronitrile: 1 H NMR(300MHz,Chloroform-d)δ8.35–8.28(m,2H),8.13–8.04(m,2H),7.39–7.30 (m,2H),6.97–6.88(m,2H),4.56–4.44(m,1H),3.80(s,3H),3.79–3.46(m,2H).

[0099] The ee value of the product 2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4-oxobutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mmL) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=17.1min, t2(major)=18.5min.

[0100] Example 31: Synthesis of 2-(3-methoxyphenyl)-4-oxo-4-phenylbutyronitrile

[0101] The difference between this example and Example 1 is that the substrate is replaced by 3-(3-methoxyphenyl)-1-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in Example 1. The obtained product 2-(3-methoxyphenyl)-4-oxo-4-phenylbutyronitrile, 115 mg, yellow solid powder, has a yield of 86.7% and an ee value of 82.5%.

[0102] Product 2-(3-methoxyphenyl)-4-oxo-4-phenylbutyronitrile: 1H NMR(300MHz,Chloroform-d)δ7.95(dd,J=7.7,2.6Hz,2H),7.62(dd,J=8.7,6.1Hz,1H),7.49(dd,J=9.2,6.6Hz,2H),7 .38–7.29(m,1H),7.07–6.94(m,2H),6.89(dd,J=8.6,2.4Hz,1H),4.66–4.47(m,1H),3.84(s,3H),3.79–3.44(m,2H).

[0103] The ee value of the product 2-(3-methoxyphenyl)-4-oxo-4-phenylbutyronitrile was determined by using a CHIRALPAKIE chiral chromatographic column (4.6 mm I.D. × 250 mmL) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=14.3min, t2(major)=17.0min.

[0104] Example 32: Synthesis of 4-(3-fluorophenyl)-4-oxo-2-phenylbutyronitrile

[0105] The difference between this example and Example 1 is that the substrate is replaced by 1-(3-fluorophenyl)-3-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in Example 1. The obtained product 4-(3-fluorophenyl)-4-oxo-2-phenylbutyronitrile, 100 mg, yellow solid powder, has a yield of 79.0% and an ee value of 50.1%.

[0106] Product 4-(3-fluorophenyl)-4-oxo-2-phenylbutyronitrile: 1 H NMR(300MHz,Chloroform-d)δ7.72(dt,J=7.7,1.3Hz,1H),7.63(ddt,J=9.2,2.7,1 .4Hz,1H),7.57–7.25(m,7H),4.57(ddd,J=7.3,5.9,1.2Hz,1H),3.85–3.42(m,2H).

[0107] The ee value of the product 4-(3-fluorophenyl)-4-oxo-2-phenylbutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1, detection wavelength 214nm, retention time: t1(minor)=7.7min, t2(major)=14.2min.

[0108] Example 33: Synthesis of 2-(2-chlorophenyl)-4-oxo-4-phenylbutyronitrile

[0109] The difference between this example and Example 1 is that the substrate is replaced by 3-(2-chlorophenyl)-1-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in Example 1. The obtained product 2-(2-chlorophenyl)-4-oxo-4-phenylbutyronitrile, 103 mg, white solid, has a yield of 76.6% and an ee value of 53.8%.

[0110] Product 2-(2-chlorophenyl)-4-oxo-4-phenylbutyronitrile: 1 H NMR(300MHz,Chloroform-d)δ8.06–7.90(m,2H),7.69(dd,J=7.3,2.1Hz,1H),7.65–7.57(m,1H),7.51(d,J=1.5Hz ,1H),7.49(d,J=1.3Hz,1H),7.47–7.41(m,1H),7.41–7.29(m,2H),4.93(dd,J=9.3,4.5Hz,1H),3.77–3.45(m,2H).

[0111] The ee value of the product 2-(2-chlorophenyl)-4-oxo-4-phenylbutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 70:30, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=13.2min, t2(major)=13.9min.

[0112] Example 34: Synthesis of 2-(4-bromophenyl)-4-oxo-4-phenylbutyronitrile

[0113] The difference between this example and example 1 is that the substrate is replaced by 3-(4-bromophenyl)-1-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in example 1. The obtained product 2-(4-bromophenyl)-4-oxo-4-phenylbutyronitrile, 120 mg, white solid powder, has a yield of 76.7% and an ee value of 50.0%.

[0114] Product 2-(4-bromophenyl)-4-oxo-4-phenylbutyronitrile: 1H NMR (300MHz, Chloroform-d) δ8.05–7.86(m,2H),7.67–7.59(m,1H),7.58–7.46(m,4H),7.43–7.30(m,2H),4.57(t,J=6.9Hz,1H),3.81–3.43(m,2H).

[0115] The ee value of the product 2-(4-bromophenyl)-4-oxo-4-phenylbutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=9.0min, t2(major)=10.3min.

[0116] Example 35: Synthesis of 4-oxo-4-phenyl-2-(p-tolyl)butyronitrile

[0117] The difference between this example and Example 1 is that the substrate is replaced by 1-phenyl-3-(p-tolyl)-2-propene-1-one instead of chalcone, and the other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-4-phenyl-2-(p-tolyl)butyronitrile, 113 mg, white solid powder, has a yield of 90.7% and an ee value of 69.5%.

[0118] Product 4-oxo-4-phenyl-2-(p-tolyl)butyronitrile: 1 H NMR(300MHz,Chloroform-d)δ8.04–7.85(m,2H),7.69–7.56(m,1H),7.54–7.44(m,2H),7.39– 7.30(m,2H),7.26–7.17(m,2H),5.31(s,3H),4.55(dd,J=7.9,6.1Hz,1H),3.81–3.42(m,2H).

[0119] The ee value of the product 4-oxo-4-phenyl-2-(p-tolyl)butyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=11.8min, t2(major)=13.7min.

[0120] Example 36: Synthesis of 2-(3-fluorophenyl)-4-oxo-4-phenylbutyronitrile

[0121] The difference between this example and example 1 is that the substrate is replaced by 3-(3-fluorophenyl)-1-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in example 1. The obtained product 2-(3-fluorophenyl)-4-oxo-4-phenylbutyronitrile, 95 mg, white solid powder, has a yield of 75.1% and an ee value of 56.7%.

[0122] Product 2-(3-fluorophenyl)-4-oxo-4-phenylbutyronitrile: 1 H NMR (300MHz, Chloroform-d) δ7.93 (dt, J=8.5, 1.4Hz, 2H), 7.68–7.54 (m, 1H), 7.48 (ddd, J=8.6, 6.9, 1.4Hz, 2H), 7.37 (tdd, J=7 .8,5.9,1.3Hz,1H),7.26–7.13(m,2H),7.04(tdt,J=8.4,2.5,1.2Hz,1H),4.58(ddd,J=7.5,6.2,1.2Hz,1H),3.91–3.37(m,2H).

[0123] The ee value of the product 2-(3-fluorophenyl)-4-oxo-4-phenylbutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=8.4min, t2(major)=9.9min.

[0124] Example 37: Synthesis of 4-(2-fluorophenyl)-2-(4-fluorophenyl)-4-oxobutyronitrile

[0125] The difference between this embodiment and embodiment 1 is that the substrate is replaced by 1-(2-fluorophenyl)-3-(4-fluorophenyl)-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in embodiment 1. The obtained product 4-(2-fluorophenyl)-2-(4-fluorophenyl)-4-oxobutyronitrile, 118 mg, yellow oily liquid, has a yield of 87% and an ee value of 50%.

[0126] Product 4-(2-fluorophenyl)-2-(4-fluorophenyl)-4-oxobutyronitrile: 1H NMR(300MHz,Chloroform-d)δ7.90(td,J=7.7,1.8Hz,1H),7.55(q,J=7.2,6.6Hz,1H),7.45–7.33(m,2H), 7.23(d,J=7.4Hz,1H),7.18–7.09(m,1H),7.06(t,J=8.6Hz,2H),4.52(t,J=7.0Hz,1H),3.76–3.40(m,2H).

[0127] The ee value of the product 4-(2-fluorophenyl)-2-(4-fluorophenyl)-4-oxobutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 60:40, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=7.7min, t2(major)=8.6min.

[0128] Example 38: Synthesis of 2-(2-fluorophenyl)-4-oxo-4-phenylbutyronitrile

[0129] The difference between this example and example 1 is that the substrate is replaced by 3-(2-fluorophenyl 1)-1-phenyl-2-propene-1-one from chalcone, and the other steps and parameters are the same as those in example 1. The obtained product 2-(2-fluorophenyl)-4-oxo-4-phenylbutyronitrile, 102 mg, white solid powder, has a yield of 80.6% and an ee value of 65.9%.

[0130] Product 2-(2-fluorophenyl)-4-oxo-4-phenylbutyronitrile: 1 H NMR(300MHz,Chloroform-d)δ8.03–7.87(m,2H),7.65–7.52(m,2H),7.52–7.43(m,2H),7.35(dddd,J=8.2,7.2,5.3,1.8 Hz,1H),7.20(td,J=7.6,1.3Hz,1H),7.11(ddd,J=10.5,8.2,1.2Hz,1H),4.74(dd,J=8.5,5.3Hz,1H),3.85–3.45(m,2H).

[0131] The ee value of the product 2-(2-fluorophenyl)-4-oxo-4-phenylbutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L) for analysis, with a mobile phase of n-hexane / 2-propanol = 80:20, and a flow rate of 1.0 mL min –1 , detection wavelength 214nm, retention time: t1(minor)=20.2min, t2(major)=20.8min.

[0132]

[0133]

[0134] From Examples 1, 27-38, it can be seen that the method of the present invention starts from readily available α, β-unsaturated ketones, uses acetone cyanohydrin as a cyanide source, the cinchona alkaloid derivative is most preferably 9-aminoquinine-6'-ol, the base is most preferably lithium amide, the solvent is most preferably ethylene dichloride, and the additive is most preferably 2-tert-butylphenol. The mixture is heated to 60°C under a nitrogen atmosphere and reacted for 4 hours, which effectively realizes the Michael addition reaction of α, β-unsaturated carbonyl compounds to prepare optically pure β-cyanoketones. The method has good compatibility with functional groups on aromatic rings and is a new green and general method for preparing optically pure β-cyanoketones.

[0135] The above are only preferred specific embodiments of the present invention, which are all different implementations based on the overall concept of the present invention, and the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. An efficient method for preparing optically pure β-cyanoketone, characterized in that: The method: Optically pure β-cyanoketone is prepared by using α,β-unsaturated carbonyl compounds as substrates and reacting them with acetone cyanohydrin in the presence of cinchona alkaloid derivatives, bases and additives.

2. The method according to claim 1, characterized in that The α,β-unsaturated carbonyl compounds are chalcone, 1-(2-fluorophenyl)-3-phenyl-2-propene-1-one, 3-(4-fluorophenyl)-1-phenyl-2-propene-1-one, 3-(4-methoxyphenyl)-1-phenyl-2-propene-1-one, 3-(4-methoxyphenyl)-1-(4-nitrophenyl)-2-propene-1-one, 3-(3-methoxyphenyl)-1-phenyl-2-propene-1-one, 1-(3-fluorophenyl)-3 -phenyl-2-propene-1-one, 3-(2-chlorophenyl)-1-phenyl-2-propene-1-one, 3-(4-bromophenyl)-1-phenyl-2-propene-1-one, 1-phenyl-3-(p-tolyl)-2-propene-1-one, 3-(3-fluorophenyl)-1-phenyl-2-propene-1-one, 1-(2-fluorophenyl)-3-(4-fluorophenyl)-2-propene-1-one, 3-(2-fluorophenyl l)-1-phenyl-2-propene-1-one.

3. The method according to claim 1, characterized in that The cinchona alkaloid derivatives are quinine, O-desmethylquinine, 6'-methoxyquinine-9-amine, and 9-aminoquinine-6'-ol. The above-mentioned cinchona alkaloid derivatives are cinchona alkaloid derivatives I, II, III, and IV, respectively, and the structural formulas are as follows:

4. The method according to claim 1, characterized in that: The base is cesium carbonate, potassium carbonate, n-butyl lithium, sodium amide, lithium hydride, dibutyl magnesium, lithium amide; the additive is 2-tert-butylphenol, 2,6-di-tert-butylphenol, 1-naphthol.

5. The method according to claim 1, characterized in that The amount of acetone cyanohydrin used is 1.0-4.0 equivalents of the α, β-unsaturated carbonyl compound, the amount of cinchona alkaloid derivative used is 0.1-0.4 equivalents of the α, β-unsaturated carbonyl compound, the amount of base used is 0.1-1.6 equivalents of the α, β-unsaturated carbonyl compound, and the amount of additive used is 0.1-0.4 equivalents of the α, β-unsaturated carbonyl compound.

6. The method according to claim 5, characterized in that The dosage of acetone cyanohydrin is 2.0-4.0 equivalents of the α,β-unsaturated carbonyl compound, the dosage of cinchona alkaloid derivative is 0.2-0.4 equivalents of the α,β-unsaturated carbonyl compound, the dosage of base is 0.8-1.6 equivalents of the α,β-unsaturated carbonyl compound, the dosage of additive is 0.2-0.4 equivalents of the α,β-unsaturated carbonyl compound, and the dosage ratio of substrate to acetone cyanohydrin, cinchona alkaloid derivative, base and additive is 1:2:0.2:0.8:0.

2.

7. The method according to claim 1, characterized in that The reaction temperature is 25-80°C.

8. The method according to claim 1, characterized in that The solvents are toluene, dichloroethane and chloroform.

9. β-cyanoketone prepared by the method according to any one of claims 1 to 8, characterized in that The general structural formula of the β-cyanoketone is: In the formula, R1 represents phenyl, 4-fluorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-chlorophenyl, 4-bromophenyl, p-tolyl, 3-fluorophenyl, 2-fluorophenyl; R2 represents phenyl, 2-fluorophenyl, 4-nitrophenyl, 3-fluorophenyl.

10. Use of the optically pure β-cyanoketone according to claim 9 as an intermediate in the fields of chemistry, biology and medicine.

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