Efficient preparation of optically pure beta-cyanoketones and uses thereof

Abstract

The present application belongs to the technical field of fine chemical synthesis. The purpose of the present application is to solve the technical problems of low yield, long reaction time, harsh reaction conditions and unsuitable for industrial production of the existing asymmetric conjugate cyanation addition reaction method for preparing optically pure beta-cyanoketone. The method of the present application: taking alpha, beta-unsaturated carbonyl compound as the substrate, taking acetone cyanohydrin as the cyan source, under the action of cinchona alkaloid derivatives, alkali and additives, without complicated operation, optically pure beta-cyanoketone is prepared in one step under the heating of nitrogen atmosphere. By screening the cinchona alkaloid derivatives, alkali, additives, reaction temperature and reaction solvent, and coordinating the optimal proportion of each substance, the side reaction is maximally inhibited, and beta-cyanoketone is obtained with high stereoselectivity and yield. The method of the present application has mild conditions, simple operation process and short reaction time, and has wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical synthesis technology, specifically relating to an efficient preparation method and application of optically pure β-cyanoketone. Background Technology

[0002] The cyano group, as an important organic functional group, is widely found in natural products, pharmaceuticals, pesticides, dyes, and other fine chemicals, serving as a key active group and playing an irreplaceable role. Organic compounds containing cyano groups are collectively called nitriles. In modern organic synthesis, nitriles are important multifunctional building blocks, serving as intermediates that can be readily converted into amides, amines, carboxylic acids and their derivatives, aldehydes, ketones, alcohols, and nitrogen-containing heterocycles. Chiral cyanides are intermediates for many bioactive substances and drugs, such as naproxen, ibuprofen, flurbiprofen, and venlafaxine. Therefore, studying the introduction of cyano groups into molecules, especially asymmetric introduction methods, has significant practical and application value. Optically pure β-cyanoketone is an important chemical intermediate that can be further converted under reducing conditions into γ-aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, possessing significant biological activity. Furthermore, β-cyanoketone is also used in the total synthesis of natural products such as terpenes, alkaloids, and steroids.

[0003] The most common method for preparing optically pure β-cyanoketone is the asymmetric conjugation addition reaction of cyanide reagents to α,β-unsaturated carbonyl compounds. Reported methods for preparing optically pure β-cyanoketone have the following problems: 1. Most reactions must be carried out below 0°C, resulting in slow reaction rates and reaction times of 48 to 72 hours; 2. The catalytic system is complex, requiring coordination of two ligands to produce chiral induction, making it unsuitable for industrial-scale production; 3. Special organic reagents such as diisopropyl ether are needed as solvents to exhibit excellent chiral induction; however, diisopropyl ether is a flammable liquid that easily forms peroxides, which can explode upon shaking, making transportation difficult and posing significant hazards to the environment and operators; 4. The use of quaternary ammonium salt organic small molecule catalysts results in high production costs because these catalysts cannot be recovered and reused. Currently, the most in-depth research focuses on the asymmetric addition reaction for the preparation of optically pure β-cyanoketones using TMSCN as the cyaniding reagent. However, TMSCN as a cyaniding reagent suffers from problems such as low atom utilization, high cost, and suitability only for small-scale laboratory tests, making it unsuitable for industrial production. In contrast, acetone cyanohydrin, a byproduct of acrylonitrile production, is inexpensive, miscible with water and many organic solvents, and its only byproduct after the reaction is acetone, making it suitable for industrial production. Therefore, developing a green, safe, efficient, and rapid method for preparing optically pure β-cyanoketones using acetone cyanohydrin as the cyaniding reagent is of great significance. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, the present invention provides an efficient preparation method and application of optically pure β-cyanoketone.

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

[0006] One objective of this invention is to provide an efficient method for preparing optically pure β-cyanoketone, the method comprising the following steps:

[0007] Optically pure β-cyanoketone was prepared by reacting α,β-unsaturated carbonyl compounds with acetone cyanohydrin in the presence of cinchona alkali derivatives, bases, and additives.

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

[0009] Further specifying, the cinchona alkaloid derivatives are quinine, O-demethylquinine, 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, with the following structural formulas:

[0010]

[0011] Further specifying, the alkali is cesium carbonate, potassium carbonate, n-butyllithium, sodium aminoide, lithium hydride, dibutylmagnesium, or lithium aminoide.

[0012] Further specified, the additives are 2-tert-butylphenol, 2,6-di-tert-butylphenol, and 1-naphthol.

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

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

[0015] The optimal ratio of substrate to acetone cyanohydrin, cinchona alkaloid derivative, alkali, and additives is 1:2:0.2:0.8:0.2.

[0016] Further, the reaction temperature is limited to 25-80℃.

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

[0018] A second objective of this invention is to provide a β-cyanoketone prepared by the above method, wherein the general structural formula of the β-cyanoketone is:

[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] A third objective of this invention is to provide an application of the product obtained by the above method in the fields of biochemistry and medicinal chemistry.

[0022] The advantages of this invention compared to the prior art are:

[0023] This invention utilizes an α,β-unsaturated carbonyl compound as a cyanide source, employing readily available and inexpensive acetone cyanohydrin. With the aid of cinchona bark derivatives, a base, and additives, optically pure β-cyanoketone is prepared in a single step under nitrogen atmosphere with heating, eliminating the need for cumbersome procedures. By screening cinchona bark derivatives, bases, additives, reaction temperature, and reaction solvents, and by coordinating and controlling the optimal ratios of each substance to minimize side reactions, optically pure β-cyanoketone is obtained with high stereoselectivity and yield, making its industrial production possible. The method of this invention features mild conditions, simple operation, short reaction time, and is environmentally friendly. Using acetone cyanohydrin as the cyanide source replaces highly toxic sodium cyanide and expensive substances with low atom utilization, such as TMSCN. It also has a wide range of substrate applicability and can be widely applied in the fields of biochemistry and medicinal chemistry. Attached Figure Description

[0024] Figure 1 The high-performance liquid chromatogram of optically pure 4-oxo-2,4-diphenylbutyronitrile obtained in Example 1 is shown.

[0025] Figure 2 The high-performance liquid chromatogram of the racemic 4-oxo-2,4-diphenylbutyronitrile sample is shown.

[0026] Figure 3 The 4-oxo-2,4-diphenylbutyronitrile prepared in Example 1 1 H NMR spectrum. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials, reagents, methods, and instruments used are all conventional materials, reagents, methods, and instruments in the art, and can be obtained commercially by those skilled in the art.

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

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

[0031] 30.9 mg of 9-aminoquinine-6'-ol, 9.2 mg of lithium aminoacetate, and 5 mL of dichloroethane were added to a round-bottom flask equipped with a magnetic stirrer. Then, 104 mg of chalcone and 15 mg of 2-tert-butylphenol were added. The mixture was heated to 60 °C under a nitrogen atmosphere, and then 0.09 mL of acetone cyanohydrin was added. The reaction time was 4 h. The reaction was monitored by TLC. After the starting materials had reacted completely, the mixture was washed with water and then extracted with dichloromethane. The organic phase was washed successively with water and saturated brine. After drying with anhydrous magnesium sulfate, the mixture was concentrated to obtain the crude product. The crude product was subjected to column chromatography with ethyl acetate:n-hexane (v:v) = 1:10 to obtain 111 mg of 4-oxo-2,4-diphenylbutyronitrile, a 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 using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL / min. –1 The detection wavelength is 214nm, and the retention times are: t1(minor) = 10.9min, t2(major) = 13.6min.

[0034] Example 2

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

[0036] Example 3

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

[0038] Example 4

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

[0040] Example 5

[0041] The difference between this embodiment and Example 1 is that the reaction temperature is changed from 60℃ to 25℃. Other steps and parameters are the same as in Example 1. The obtained product, 4-oxo-2,4-diphenylbutyronitrile, 34 mg, is a white solid powder with a yield of 28.9% and an ee value of 11.5%.

[0042] Example 6

[0043] The difference between this embodiment and Example 1 is that the reaction temperature is changed from 60℃ to 45℃. Other steps and parameters are the same as in Example 1. The obtained product is 81 mg of 4-oxo-2,4-diphenylbutyronitrile, a white solid powder, with a yield of 68.9% and an ee value of 45.7%.

[0044] Example 7

[0045] The difference between this embodiment and Example 1 is that the reaction temperature is changed from 60℃ to 50℃. Other steps and parameters are the same as in Example 1. The obtained product, 4-oxo-2,4-diphenylbutyronitrile, 92 mg, is a white solid powder with a yield of 78.2% and an ee value of 79.1%.

[0046] Example 8

[0047] The difference between this embodiment and Example 1 is that the reaction temperature is changed from 60℃ to 80℃. Other steps and parameters are the same as in Example 1. The obtained product, 4-oxo-2,4-diphenylbutyronitrile, 106 mg, is a white solid powder with a yield of 90.6% and an ee value of 37.0%.

[0048] Example 9

[0049] The difference between this embodiment and Example 1 is that the solvent used is replaced with toluene instead of dichloroethane. Other steps and parameters are the same as in Example 1. The resulting product, 100 mg of 4-oxo-2,4-diphenylbutyronitrile, is a white solid powder with 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 chloroform instead of dichloroethane. Other steps and parameters are the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 98 mg, is a white solid powder with a yield of 83.3% and an ee value of 0.0%.

[0052] Example 11

[0053] The difference between this embodiment and Example 1 is that the alkali used is replaced with cesium carbonate instead of lithium aminoide. Other steps and parameters are the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 101 mg, is a white solid powder with a yield of 85.9% and an ee value of 0.0%.

[0054] Example 12

[0055] The difference between this embodiment and Example 1 is that the alkali used is replaced with potassium carbonate instead of lithium aminoide. Other steps and parameters are the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 113 mg, is a white solid powder with a yield of 96.1% and an ee value of 0.0%.

[0056] Example 13

[0057] The difference between this embodiment and Example 1 is that the alkali used is replaced with n-butyllithium instead of lithium aminoide. Other steps and parameters are the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 108 mg, is a white solid powder with a yield of 91.8% and an ee value of 0.0%.

[0058] Example 14

[0059] The difference between this embodiment and Example 1 is that the alkali used is replaced with sodium aminoide instead of lithium aminoide. Other steps and parameters are the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 91 mg, is a white solid powder with a yield of 77.4% and an ee value of 27.3%.

[0060] Example 15

[0061] The difference between this embodiment and Example 1 is that the alkali used is replaced with lithium hydride instead of lithium aminoide. Other steps and parameters are the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 75.3 mg, is a white solid powder with a yield of 64.0% and an ee value of 72.3%.

[0062] Example 16

[0063] The difference between this embodiment and Example 1 is that the alkali used is replaced with dibutylmagnesium instead of lithium aminoide. Other steps and parameters are the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 112 mg, is a white solid powder with a yield of 95.2% and an ee value of 0.0%.

[0064] Example 17

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

[0066] Example 18

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

[0068] Example 19

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

[0070] Example 20

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

[0072] Example 21

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

[0074] Example 22

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

[0076] Example 23

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

[0078] Example 24

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

[0080] Example 25

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

[0082] Example 26

[0083] The difference between this example and Example 1 is that the amount of 2-tert-butylphenol was adjusted to 30 mg (0.4 equivalents of the substrate chalcone). Other steps and parameters were the same as in Example 1. The resulting product, 4-oxo-2,4-diphenylbutyronitrile, 106 mg, was 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 embodiment and Example 1 is that the substrate is changed from chalcone to 1-(2-fluorophenyl)-3-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 4-(2-fluorophenyl)-4-oxo-2-phenylbutyronitrile, 97 mg, white solid powder, with 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), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: 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 embodiment and Example 1 is that the substrate is changed from chalcone to 3-(4-fluorophenyl)-1-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(4-fluorophenyl)-4-oxo-4-phenylbutyronitrile, 103 mg, white solid powder, with 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 with a mobile phase of n-hexane / 2-propanol = 90:10 and a flow rate of 1.0 mL / min. –1 The detection wavelength was 254nm, and the retention times were: 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 changed from chalcone to 3-(4-methoxyphenyl)-1-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(4-methoxyphenyl)-4-oxo-4-phenylbutyronitrile, 111 mg, white solid powder, with 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 column with a mobile phase of n-hexane / 2-propanol = 90:10 and a flow rate of 1.0 mL / min. –1 The detection wavelength is 254nm, and the retention times are: 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 changed from chalcone to 3-(4-methoxyphenyl)-1-(4-nitrophenyl)-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(4-methoxyphenyl)-4-(4-nitrophenyl)-4-oxobutyronitrile, 133 mg, white solid powder, with 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 mm L), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: 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 changed from chalcone to 3-(3-methoxyphenyl)-1-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(3-methoxyphenyl)-4-oxo-4-phenylbutyronitrile, 115 mg, yellow solid powder, with 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 column (4.6 mm I.D. × 250 mm L), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: 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 embodiment and Example 1 is that the substrate is changed from chalcone to 1-(3-fluorophenyl)-3-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 4-(3-fluorophenyl)-4-oxo-2-phenylbutyronitrile, 100 mg, yellow solid powder, with 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), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1The detection wavelength is 214nm, and the retention times are: 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 changed from chalcone to 3-(2-chlorophenyl)-1-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(2-chlorophenyl)-4-oxo-4-phenylbutyronitrile, 103 mg, white solid, with 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-benzobutyronitrile was determined by using a CHIRALPAK IE chiral column (4.6 mm I.D. × 250 mm L), with a mobile phase of n-hexane / 2-propanol = 70:30 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: 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 changed from chalcone to 3-(4-bromophenyl)-1-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(4-bromophenyl)-4-oxo-4-phenylbutyronitrile, 120 mg, white solid powder, with 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), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: t1(minor) = 9.0min, t2(major) = 10.3min.

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

[0117] The difference between this embodiment and Example 1 is that the substrate is changed from chalcone to 1-phenyl-3-(p-tolyl)-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 4-oxo-4-phenyl-2-(p-tolyl)butadiene nitrile, 113 mg, white solid powder, with a yield of 90.7% and an ee value of 69.5%.

[0118] Product 4-oxo-4-phenyl-2-(p-tolyl)butadiene nitrile: 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), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: 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 embodiment and Example 1 is that the substrate is changed from chalcone to 3-(3-fluorophenyl)1-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(3-fluorophenyl)-4-oxo-4-phenylbutyronitrile, 95 mg, white solid powder, with 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), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: 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 Example 1 is that the substrate is changed from chalcone to 1-(2-fluorophenyl)-3-(4-fluorophenyl)-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 4-(2-fluorophenyl)-2-(4-fluorophenyl)-4-oxobutyronitrile, 118 mg, a yellow oily liquid, with 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), with a mobile phase of n-hexane / 2-propanol = 60:40 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: 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 embodiment and Example 1 is that the substrate is changed from chalcone to 3-(2-fluorophenyll)-1-phenyl-2-propen-1-one. The other steps and parameters are the same as in Example 1. The product obtained is 2-(2-fluorophenyl)-4-oxo-4-phenylbutyronitrile, 102 mg, white solid powder, with 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), with a mobile phase of n-hexane / 2-propanol = 80:20 and a flow rate of 1.0 mL·min. –1 The detection wavelength is 214nm, and the retention times are: t1(minor) = 20.2min, t2(major) = 20.8min.

[0132]

[0133]

[0134] As shown in Examples 1 and 27-38, the method of the present invention starts from readily available α,β-unsaturated ketones, uses acetone cyanohydrin as the cyanide source, preferably 9-aminoquinin-6'-ol as the cinchona alkaloid derivative, preferably lithium aminoalkane as the base, preferably dichloroethane as the solvent, and preferably 2-tert-butylphenol as the additive. Heating to 60°C under a nitrogen atmosphere and reacting for 4 hours efficiently achieves the Michael addition reaction of α,β-unsaturated carbonyl compounds to prepare optically pure β-cyanoketones. This method has good compatibility with functional groups on the aromatic ring and is a novel, green, and universal method for preparing optically pure β-cyanoketones.

[0135] The above description is merely a preferred embodiment of the present invention. These specific embodiments are different implementations based on the overall concept of the present invention, and the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A highly efficient method for preparing optically pure β-cyanoketone, characterized in that, The method described: Optically pure β-cyanoketones were prepared by reacting α,β-unsaturated carbonyl compounds with acetone cyanohydrin in the presence of cinchona alkaloid derivatives, bases, and additives. The α,β-unsaturated carbonyl compounds included chalcone, 1-(2-fluorophenyl)-3-phenyl-2-propen-1-one, 3-(4-fluorophenyl)-1-phenyl-2-propen-1-one, 3-(4-methoxyphenyl)-1-phenyl-2-propen-1-one, 3-(4-methoxyphenyl)-1-(4-nitrophenyl)-2-propen-1-one, and 3-(3-methoxyphenyl)-1-phenyl-2-propen-1-one. Ketones, 1-(3-fluorophenyl)-3-phenyl-2-propen-1-one, 3-(2-chlorophenyl)-1-phenyl-2-propen-1-one, 3-(4-bromophenyl)-1-phenyl-2-propen-1-one, 1-phenyl-3-(p-tolyl)-2-propen-1-one, 3-(3-fluorophenyl)-1-phenyl-2-propen-1-one, 1-(2-fluorophenyl)-3-(4-fluorophenyl)-2-propen-1-one, 3-(2-fluorophenyll)-1-phenyl-2-propen-1-one; cinchona alkaloid derivatives are 9-aminoquinine-6'-ol, with the structure shown in Formula I. The base is sodium aminoide, lithium hydride, or lithium aminoide; the additives are 2-tert-butylphenol, 2,6-di-tert-butylphenol, and 1-naphthol.

2. 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.

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

2.

4. The method according to claim 1, characterized in that, The reaction temperature is 25-80℃.

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

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