Green and efficient preparation method and application of beta-carbonyl nitrile

Abstract

The invention relates to a green and efficient preparation method and application of beta-carbonyl nitrile. The invention belongs to the technical field of fine chemical synthesis. The invention aims to solve the technical problems that the existing method for synthesizing beta-carbonyl nitrile needs to use a large amount of organic solvent and the catalyst is difficult to recover. According to the method, alpha, beta-unsaturated ketone is taken as a substrate, acetone cyanohydrin is taken as a cyaniding reagent, and beta-carbonyl nitrile is synthesized under the action of ionic liquid. According to the method disclosed by the invention, alpha, beta-unsaturated ketone is taken as a raw material, low-toxicity and low-price acetone cyanohydrin is taken as a cyanogen source, beta-carbonyl nitrile can be efficiently synthesized at room temperature without tedious anhydrous and anaerobic operation under the action of green, pollution-free and recyclable ionic liquid, and beta-carbonyl nitrile can be obtained by selecting the ionic liquid. And meanwhile, the ratio of the substances is reasonably controlled in a synergistic manner, so that the side reaction is inhibited to the maximum extent, the efficient synthesis of the high-purity beta-carbonyl nitrile is realized, and the industrial production process of the beta-carbonyl nitrile is promoted.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical synthesis, and specifically relates to a green and efficient preparation method and application of beta-carbonyl nitrile. Background Art

[0002] β-Carbonyl nitrile is one of the important pharmaceutical intermediates. The cyano group in its structure can participate in a variety of chemical reactions in organic synthesis to achieve the transformation of functional groups. For example, it can be hydrolyzed into carboxylic acid or amide under alkaline conditions. In addition, due to the electron-withdrawing and strong polarity of cyano itself, it is widely used in the structural modification of medicines and functional materials. The addition of cyaniding agents to unsaturated bonds is the main means of preparing nitrile. With the continuous deepening of cyanidation research, the selection of cyaniding agents is also constantly optimized. In recent years, acetone cyanohydrin has entered the sight of cyanidation reaction researchers due to its relatively low toxicity and low cost. Compared with hydrocyanic acid, acetone cyanohydrin has low toxicity, is easy to transport and store, and is easy to operate in experiments; compared with metal cyanides, acetone cyanohydrin can be miscible with organic solvents and does not require special catalysts; compared with organic cyaniding agents such as trimethylsilyl cyanide, acetone cyanohydrin is cheap and easy to obtain, has mild reaction conditions, and the only by-product after participating in the reaction is acetone, which is easy to handle.

[0003] At present, the main method for preparing β-carbonyl nitrile is to react α, β-unsaturated ketone with Michael addition reaction of cyaniding reagent under alkaline conditions. However, the conventional method for preparing β-carbonyl nitrile has the following two significant drawbacks: first, additional organic solvents need to be added. Although they can efficiently dissolve organic compounds, they pose a potential threat to human health, and most of them are highly volatile, thus polluting the atmospheric environment; second, the alkaline catalyst used faces many difficulties in the recovery process, and it itself also has adverse effects on the human body and the environment. In view of the above problems, it is necessary to develop a green and efficient reaction system to prepare β-carbonyl nitrile. Summary of the invention

[0004] In order to overcome the above-mentioned deficiencies of the prior art, the present invention provides a green and efficient preparation method and application of β-carbonyl nitrile.

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

[0006] One of the purposes of the present invention is to provide a green and efficient method for preparing β-carbonyl nitrile, which is carried out according to the following steps:

[0007] β-Carbonyl nitrile was synthesized using α,β-unsaturated ketone as substrate and acetone cyanohydrin as cyanation reagent in the presence of ionic liquid.

[0008] It is further defined that the α,β-unsaturated ketone is chalcone, (E)-2-(furan-2-yl)-4-(5-methylthiophen-2-yl)prop-2-en-1-one, (E)-4-(5-methylfuran-2-yl)-1-phenylprop-2-en-1-one, (E)-4-phenyl-2-(pyridin-2-yl)prop-2-en-1-one, (E)-4-(5-methylfuran-2-yl)-1-phenylprop-2-en-1-one, 5-methylthiophene-2-yl)-2-(thiophene-2-yl)prop-2-en-1-one, (E)-2-phenyl-4-(pyridin-2-yl)prop-2-en-1-one, (E)-4-(pyridin-2-yl)-2-(thiophene-2-yl)prop-2-en-1-one, (E)-2-(furan-2-yl)-4-(thiophene-2-yl)prop-2-en-1-one -ketone, (E)-2-phenyl-4-(thiophen-2-yl)prop-2-en-1-one, (E)-2-phenyl-4-(thiophen-2-yl)prop-2-en-1-one, (E)-4-(furan-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one, (E)-4-(3-oxo-3-phenylprop-1-en-1-yl)benzonitrile, (E)- )-4-(5-methylthiophen-2-yl)-2-(p-tolyl)prop-2-en-1-one, (E)-2-(furan-2-yl)-4-(pyridin-2-yl)prop-2-en-1-one, (E)-2-(furan-2-yl)-4-phenylprop-2-en-1-one or (E)-4-phenyl-2-(thiophen-2-yl)prop-2-en-1-one.

[0009] In a further embodiment, the ionic liquid is 1-butyl-3-methylimidazolium acetate, 1-ethyl-3-methylimidazolium acetate or 1-butyl-3-methylimidazolium dicyanamide.

[0010] It is further defined that the amount of acetone cyanohydrin used is 2.0-4.0 times the equivalent of the α,β-unsaturated ketone, and the amount of ionic liquid used is 1.0-4.0 times the equivalent of the α,β-unsaturated ketone.

[0011] It is further defined that the amount of acetone cyanohydrin used is 2.0-3.0 times the equivalent of the α,β-unsaturated ketone, and the amount of ionic liquid used is 2.0-3.0 times the equivalent of the α,β-unsaturated ketone.

[0012] Most preferably, the amount of acetone cyanohydrin used is 1.5 times the equivalent of the ionic liquid.

[0013] It is further defined that the reaction temperature is 25-50°C.

[0014] It is further defined that after the reaction is completed, extraction, washing, water removal and filtration are performed in sequence, and the filtrate is subjected to column chromatography.

[0015] The second object of the present invention is to provide a β-carbonyl nitrile prepared by the above method, wherein the β-carbonyl nitrile has the general structural formula:

[0016]

[0017] In the formula, R1 represents phenyl, thiophen, furan, pyridin, 4-OMe-phenyl, 4-Me-phenyl, 4-CN-phenyl or 4-NO2-phenyl; R2 represents phenyl, thiophen, furan, pyridin, 4-Me-thiophen or 4-Me-furan.

[0018] The third object of the present invention is to provide a use of the above-mentioned β-carbonyl nitrile as a pharmaceutical intermediate.

[0019] Compared with the prior art, the present invention has the following advantages:

[0020] The method of the present invention uses α, β-unsaturated ketone as a raw material and low-toxic and cheap acetone cyanohydrin as a cyanide source. Under the action of green, pollution-free and recyclable ionic liquid, β-carbonyl nitrile can be efficiently synthesized at room temperature without complicated anhydrous and oxygen-free operation. By selecting the ionic liquid and coordinating the reasonable control of the proportion of each substance, the side reaction is suppressed to the maximum extent, and the efficient synthesis of high-purity β-carbonyl nitrile is achieved, which promotes the industrial production process of β-carbonyl nitrile. Compared with the conventional β-carbonyl nitrile synthesis method, the method of the present invention has mild conditions, simple operation process, short reaction time, green and environmental protection, uses acetone cyanohydrin as a cyanide source, replaces highly toxic substances such as sodium cyanide, and has a good scope of application of the substrate. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 4-oxo-2,4-diphenylbutyronitrile prepared in Example 1 1 HNMR spectrum. DETAILED DESCRIPTION

[0022] 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.

[0023] 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.

[0024] 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.

[0025] Embodiment 1, the green and efficient preparation method of 4-oxo-2,4-diphenylbutyronitrile is carried out according to the following steps:

[0026] Add 100 mg of chalcone to a flask equipped with a rotor, and add 0.12 mL of acetone cyanohydrin and 0.18 mL of 1-butyl-3-methylimidazole acetate to the reaction system at room temperature (25 ° C). The reaction time is 0.3 h. Monitor the reaction by TLC. When the raw material point disappears, wash with water first, then add ethyl acetate to extract, and then wash the organic phase with saturated brine and water in turn. After drying over anhydrous magnesium sulfate, concentrate to obtain a crude product. The crude product is subjected to column chromatography, and column chromatography using n-hexane and ethyl acetate (volume ratio of 10:1) as the mobile phase to obtain 4-oxo-2,3-diphenylbutyronitrile, 109.1 mg, white solid powder, with a yield of 96.5%.

[0027] 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).

[0028] Example 2

[0029] The difference between this embodiment and embodiment 1 is that the ionic liquid used is replaced by 1-ethyl-3-methylimidazolium acetate from 1-butyl-3-methylimidazolium acetate. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 203.7 mg, white solid powder, yield 90.2%.

[0030] Example 3

[0031] The difference between this embodiment and embodiment 1 is that the ionic liquid used is replaced by 1-butyl-3-methylimidazolium dicyanamide salt instead of 1-butyl-3-methylimidazolium acetate. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 199.5 mg, white solid powder, yield 88.3%.

[0032] Example 4

[0033] The difference between this embodiment and embodiment 1 is that the ionic liquid used is replaced by 1-butyl-3-methylimidazolium hexafluorophosphate instead of 1-butyl-3-methylimidazolium acetate. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 82.2 mg, white solid powder, yield 36.4%.

[0034] Example 5

[0035] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.09 mL (1.0 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, 78.9 mg, white solid powder, yield 69.8%.

[0036] Example 6

[0037] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.27 mL (3.0 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, 96.4 mg, white solid powder, yield 85.2%.

[0038] Example 7

[0039] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.36 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, 85.5 mg, white solid powder, yield 75.6%.

[0040] Example 8

[0041] The difference between this example and Example 1 is that the amount of the cyaniding reagent acetone cyanohydrin used is adjusted to 0.04 mL (1.0 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, 41.3 mg, white solid powder, yield 36.5%.

[0042] Example 9

[0043] The difference between this example and Example 1 is that the amount of the cyaniding reagent acetone cyanohydrin used is adjusted to 0.08 mL (2.0 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, 86.4 mg, white solid powder, yield 76.4%.

[0044] Example 10

[0045] The difference between this example and Example 1 is that the amount of the cyaniding reagent acetone cyanohydrin used is adjusted to 0.16 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, 86.4 mg, white solid powder, yield 58.7%.

[0046] Embodiment 11

[0047] The difference between this embodiment and embodiment 1 is that the reaction temperature is 30° C. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 202.6 mg, white solid powder, yield 89.7%.

[0048] Example 12

[0049] The difference between this embodiment and embodiment 1 is that the reaction temperature is 40° C. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 172.6 mg, white solid powder, yield 76.4%.

[0050] Embodiment 13

[0051] The difference between this embodiment and embodiment 1 is that the reaction temperature is 50° C. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-2,4-diphenylbutyronitrile, 127.2 mg, white solid powder, yield 56.3%.

[0052] Example 14, Green and efficient preparation method of 2-(furan-2-yl)-4-(5-methylthiophene-2-yl)-4-oxobutyronitrile:

[0053] The difference between this embodiment and embodiment 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.35 mL, the amount of acetone cyanohydrin used is adjusted to 0.25 mL, and the reaction substrate is replaced with 200 mg of (E)-2-(furan-2-yl)-4-(5-methylthiophen-2-yl)prop-2-en-1-one. The other steps and parameters are the same as those in embodiment 1. The obtained product 2-(furan-2-yl)-4-(5-methylthiophen-2-yl)-4-oxobutyronitrile, 215.3 mg, light yellow oily droplets, yield 95.4%.

[0054] Product 2-(furan-2-yl)-4-(5-methylthiophen-2-yl)-4-oxobutyronitrile: 1 HNMR(300MHz,Chloroform-d)δ7.58(d,J=3.7Hz,1H),7.40(d,J=1.6Hz,1H),6.87-6.80(m,1H),6.37( m,2H),4.66(t,J=7.0Hz,1H),3.56(dd,J=17.1,7.2Hz,1H),3.50(dd,J=17.1,6.9Hz,1H),2.56(s,3H).

[0055] Example 15, Green and efficient preparation method of 4-(5-methylfuran-2-yl)-4-oxo-2-phenylbutyronitrile:

[0056] The difference between this embodiment and embodiment 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.35 mL, the amount of acetone cyanohydrin used is adjusted to 0.25 mL, and the reaction substrate is replaced with 200 mg of (E)-4-(5-methylfuran-2-yl)-1-phenylprop-2-ene-1-one. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-(5-methylfuran-2-yl)-4-oxo-2-phenylbutyronitrile, 232.5 mg, yellow oily droplets, yield 97.2%.

[0057] Product 4-(5-methylfuran-2-yl)-4-oxo-2-phenylbutyronitrile: 1 HNMR(300MHz,Chloroform-d)δ7.43(d,J=2.1Hz,1H),7.40(q,J=2.8,2.1Hz,2H),7.37(d,J=1.0Hz,1H),7.34(m,1H),7.14(d,J=3. 6Hz,1H),6.23-6.12(m,1H),4.53(dd,J=7.9,6.5Hz,1H),3.52(dd,J=17.3,7.9Hz,1H),3.31(dd,J=17.3,6.5Hz,1H),2.37(s,3H).

[0058] Example 16, Green and efficient preparation method of 4-oxo-4-phenyl-2-(pyridin-2-yl)butyronitrile:

[0059] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.36 mL, the amount of acetone cyanohydrin used is adjusted to 0.26 mL, and the reaction substrate is replaced with 200 mg of (E)-4-phenyl-2-(pyridin-2-yl)prop-2-en-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-4-phenyl-2-(pyridin-2-yl)butyronitrile, 230.1 mg, brown solid powder, yield 97.4%.

[0060] Product 4-oxo-4-phenyl-2-(pyridin-2-yl)butyronitrile: 1 HNMR(300MHz,Chloroform-d)δ8.58(d,J=4.9Hz,1H),7.98(d,J=7.8Hz,2H),7.80(t,J=7.7Hz,1H),7.63(dd,J=16.5,7.8Hz,2H) ,7.50(t,J=7.6Hz,2H),7.32(d,J=6.0Hz,1H),4.76(t,J=6.5Hz,1H),4.05(dd,J=18.1,6.5Hz,1H),3.82(dd,J=18.1,6.7Hz,1H).

[0061] Example 17, Green and efficient preparation method of 4-(5-methylthiophene-2-yl)-4-oxo-2-(thiophene-2-yl)butyronitrile:

[0062] The difference between this embodiment and embodiment 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazole acetate used is adjusted to 0.32 mL, the amount of acetone cyanohydrin used is adjusted to 0.23 mL, and the reaction substrate is replaced with (E)-4-(5-methylthiophene-2-yl)-2-(thiophene-2-yl)prop-2-en-1-one 200 mg. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-(5-methylthiophene-2-yl)-4-oxo-2-(thiophene-2-yl)butyronitrile, 229.2 mg, yellow solid powder, yield 94.6%.

[0063] Product 4-(5-methylthiophen-2-yl)-4-oxo-2-(thiophen-2-yl)butyronitrile: 1HNMR(300MHz,Chloroform-d)δ7.56(d,J=3.8Hz,1H),7.30-7.27(m,1H),7.15(dd,J=3.4,1.3Hz,1H),7.02-6.95(m,1H) ,6.83(d,J=3.7Hz,1H),4.85(t,J=7.0Hz,1H),3.63(dd,J=17.1,7.2Hz,1H),3.50(dd,J=17.1,6.9Hz,1H),2.56(s,3H).

[0064] Example 18, Green and efficient preparation method of 4-oxo-2-phenyl-4-(pyridin-2-yl)butyronitrile:

[0065] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.36 mL, the amount of acetone cyanohydrin used is adjusted to 0.26 mL, and the reaction substrate is replaced with 200 mg of (E)-2-phenyl-4-(pyridin-2-yl)prop-2-en-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-2-phenyl-4-(pyridin-2-yl)butyronitrile, 227.5 mg, brown solid powder, yield 96.3%.

[0066] Product 4-oxo-2-phenyl-4-(pyridin-2-yl)butyronitrile: 1 HNMR(300MHz,Chloroform-d)δ8.73-8.58(m,1H),8.09(m,1H),7.87(m,1H),7.56 -7.30(m,6H),4.55(dd,J=8.3,6.1Hz,1H),4.08-3.97(m,1H),3.88-3.77(m,1H).

[0067] Example 19, Green and efficient preparation method of 4-oxo-4-(pyridin-2-yl)-2-(thiophene-2-yl)butyronitrile:

[0068] The difference between this embodiment and embodiment 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.35 mL, the amount of acetone cyanohydrin used is adjusted to 0.25 mL, and the reaction substrate is replaced with 200 mg of (E)-4-(pyridin-2-yl)-2-(thiophene-2-yl)prop-2-en-1-one. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-oxo-4-(pyridin-2-yl)-2-(thiophene-2-yl)butyronitrile, 229.2 mg, light yellow solid powder, yield 94.6%.

[0069] Product 4-oxo-4-(pyridin-2-yl)-2-(thiophen-2-yl)butyronitrile:1 HNMR(300MHz,Chloroform-d)δ8.70(d,J=4.7Hz,1H),8.10(d,J=7.9Hz,1H),7.89(t,J=7.7Hz,1H),7.53(dd,J=7.5,5.0Hz,1H),7. 28(d,J=4.4Hz,2H), 6.99(dd,J=5.3,3.7Hz,1H), 4.84(t,J=7.1Hz,1H), 4.07(dd,J=18.6,7.8Hz,1H), 3.94(dd,J=18.6,6.5Hz,1H).

[0070] Example 20, Green and Efficient Preparation Method of 2-(Furan-2-yl)-4-oxo-4-(thiophen-2-yl)butyronitrile:

[0071] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.37 mL, the amount of acetone cyanohydrin used is adjusted to 0.27 mL, and the reaction substrate is replaced with 200 mg of (E)-2-(furan-2-yl)-4-(thiophen-2-yl)prop-2-en-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 2-(furan-2-yl)-4-oxo-4-(thiophen-2-yl)butyronitrile, 220.4 mg, light yellow solid powder, yield 95.3%.

[0072] Product 2-(furan-2-yl)-4-oxo-4-(thiophen-2-yl)butyronitrile: 1 HNMR(300MHz,Chloroform-d)δ7.62(m,1H),7.29(s,1H),7.27(d,J=1.1Hz,1H),7.15(m,1H),6.98(dd,J=5.0,3.6,1 .0Hz,1H),6.59(m,1H),4.84(t,J=7.1Hz,1H),3.64(dd,J=17.6,7.4,1.1Hz,1H),3.51(dd,J=17.6,6.8,1.0Hz,1H).

[0073] Example 21, Green and efficient preparation method of 4-oxo-2-phenyl-4-(thiophene-2-yl)butyronitrile:

[0074] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.35 mL, the amount of acetone cyanohydrin used is adjusted to 0.25 mL, and the reaction substrate is replaced with 200 mg of (E)-2-phenyl-4-(thiophen-2-yl)prop-2-en-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-2-phenyl-4-(thiophen-2-yl)butyronitrile, 228.8 mg, pink solid powder, yield 94.8%.

[0075] Product 4-oxo-2-phenyl-4-(thiophen-2-yl)butyronitrile: 1 HNMR(300MHz,Chloroform-d)δ7.71(d,J=4.5Hz,2H),7.48-7.31(m,5H),7.18-7.12(m, 1H), 4.58 (t, J=7.1Hz, 1H), 3.67 (dd, J=17.3, 7.6Hz, 1H), 3.46 (dd, J=17.3, 6.5Hz, 1H).

[0076] Example 22, Green and efficient preparation method of 4-(5-methylfuran-2-yl)-4-oxo-2-(thiophen-2-yl)butyronitrile:

[0077] The difference between this embodiment and embodiment 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazole acetate used is adjusted to 0.35 mL, the amount of acetone cyanohydrin used is adjusted to 0.25 mL, the reaction substrate is replaced with (E)-2-phenyl-4-(thiophen-2-yl)prop-2-en-1-one 200 mg, and the obtained product 4-(5-methylfuran-2-yl)-4-oxo-2-(thiophen-2-yl)butyronitrile, 230.3 mg, brown solid powder, yield 93.9%.

[0078] Product 4-(5-methylfuran-2-yl)-4-oxo-2-(thiophen-2-yl)butyronitrile: 1 HNMR(300MHz,Chloroform-d)δ7.30-7.25(m,1H),7.20(d,J=3.5Hz,1H),7.14(m,1H),6.98(m,1H),6.21(dd,J= 2.9,1.6Hz,1H),4.84(m,1H),3.58(dd,J=17.3,7.3,1.3Hz,1H),3.44(dd,J=17.2,6.9,1.3Hz,1H),2.41(s,3H).

[0079] Example 23, Green and efficient preparation method of 4-(furan-2-yl)-2-(4-methoxyphenyl)-4-oxobutyronitrile:

[0080] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.34 mL, the amount of acetone cyanohydrin used is adjusted to 0.24 mL, and the reaction substrate is replaced with 200 mg of (E)-4-(furan-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 4-(furan-2-yl)-2-(4-methoxyphenyl)-4-oxobutyronitrile, 241.7 mg, brown-yellow oily droplets, yield 94.7%.

[0081] Product 4-(furan-2-yl)-2-(4-methoxyphenyl)-4-oxobutyronitrile: 1 HNMR(300MHz,Chloroform-d)δ7.60(m,1H),7.34(d,J=8.6Hz,2H),7.24(dd,J=3.7,0.9Hz,1H),6.95-6.87(m ,2H),6.56(m,1H),4.50(t,J=7.2Hz,1H),3.81(s,J=0.9Hz,3H),3.55(dd,1H),3.37(dd,J=17.4,6.8Hz,1H).

[0082] Example 24, Green and efficient preparation method of 4-(1-cyano-3-oxo-3-phenylpropyl)benzonitrile:

[0083] The difference between this embodiment and embodiment 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.35 mL, the amount of acetone cyanohydrin used is adjusted to 0.25 mL, and the reaction substrate is replaced with (E)-4-(3-oxo-3-phenylprop-1-en-1-yl)benzonitrile 200 mg. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-(1-cyano-3-oxo-3-phenylpropyl)benzonitrile, 242.6 mg, yellow solid powder, yield 93.2%.

[0084] Product 4-(1-cyano-3-oxo-3-phenylpropyl)benzonitrile: 1 HNMR(300MHz,Chloroform-d)δ7.99-7.86(m,2H),7.69(dd,J=8.4,1.5Hz,2H),7.63-7.57(m,3H),7.56- 7.40(m,2H),4.66(t,J=6.8Hz,1H),3.77(dd,J=18.0,7.2,1.3Hz,1H),3.56(dd,J=18.1,6.5,1.2Hz,1H).

[0085] Example 25, Green and efficient preparation method of 4-(5-methylthiophene-2-yl)-4-oxo-2-(p-tolyl)butyronitrile:

[0086] The difference between this embodiment and embodiment 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazole acetate used is adjusted to 0.33 mL, the amount of acetone cyanohydrin used is adjusted to 0.23 mL, and the reaction substrate is replaced with 200 mg of (E)-4-(5-methylthiophen-2-yl)-2-(p-tolyl)prop-2-ene-1-one. The other steps and parameters are the same as those in embodiment 1. The obtained product 4-(5-methylthiophen-2-yl)-4-oxo-2-(p-tolyl)butyronitrile, 259.1 mg, light yellow solid powder, yield 96.2%.

[0087] Product 4-(5-methylthiophene-2-yl)-4-oxo-2-(p-tolyl)butyronitrile: 1 HNMR(300MHz,Chloroform-d)δ7.51(d,J=3.8Hz,1H),7.34-7.29(m,2H),7.23-7.17(m,2H),6.81(m,1H),4.52 (dd,J=7.6,6.6Hz,1H),3.58(dd,J=17.1,7.7Hz,1H),3.36(dd,J=17.1,6.5Hz,1H),2.55(s,3H),2.36(s,3H).

[0088] Example 26, Green and Efficient Preparation Method of 2-(Furan-2-yl)-4-oxo-4-(pyridin-2-yl)butyronitrile:

[0089] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.37 mL, the amount of acetone cyanohydrin used is adjusted to 0.27 mL, and the reaction substrate is replaced with 200 mg of (E)-2-(furan-2-yl)-4-(pyridin-2-yl)prop-2-en-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 2-(furan-2-yl)-4-oxo-4-(pyridin-2-yl)butyronitrile, 216.5 mg, black oily droplets, yield 95.7%.

[0090] Product 2-(furan-2-yl)-4-oxo-4-(pyridin-2-yl)butanenitrile: 1HNMR(300MHz,Chloroform-d)δ8.74-8.66(m,1H),8.13-8.04(m,1H),7.88(m,1H),7.58-7. 49(m,1H),7.43-7.37(m,1H),6.45-6.32(m,2H),4.66(t,J=7.1Hz,1H),4.07-3.88(m,2H).

[0091] Example 27, Green and efficient preparation method of 2-(furan-2-yl)-4-oxo-4-phenylbutyronitrile:

[0092] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazolium acetate used is adjusted to 0.37 mL, the amount of acetone cyanohydrin used is adjusted to 0.27 mL, and the reaction substrate is replaced with 200 mg of (E)-2-(furan-2-yl)-4-phenylprop-2-en-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 2-(furan-2-yl)-4-oxo-4-phenylbutyronitrile, 213.8 mg, yellow oily droplets, yield 94.9%.

[0093] Product 2-(furan-2-yl)-4-oxo-4-phenylbutyronitrile: 1 HNMR(300MHz,Chloroform-d)δ8.04-7.93(m,2H),7.71-7.59(m,1H),7.58-7.46(m,2H), 7.41(dd,J=1.9,0.9Hz,1H),6.45-6.34(m,2H),4.70(m,1H),3.71(dd,J=7.0,0.7Hz,2H).

[0094] Example 28, Green and efficient preparation method of 4-oxo-4-phenyl-2-(thiophene-2-yl)butyronitrile:

[0095] The difference between this example and Example 1 is that the amount of the ionic liquid 1-butyl-3-methylimidazole acetate used is adjusted to 0.35 mL, the amount of acetone cyanohydrin used is adjusted to 0.25 mL, and the reaction substrate is replaced with 200 mg of (E)-4-phenyl-2-(thiophen-2-yl)prop-2-ene-1-one. The other steps and parameters are the same as those in Example 1. The obtained product 4-oxo-4-phenyl-2-(thiophen-2-yl)butyronitrile, 229.5 mg, yellow solid powder, yield 95.1%.

[0096] Product 4-oxo-4-phenyl-2-(thiophen-2-yl)butyronitrile: 1HNMR(300MHz,Chloroform-d)δ7.98-7.91(m,2H),7.66-7.58(m,1H),7.54-7.45(m,2H),7.30-7.26(m,1H),7.17( m,1H),6.98(dd,J=5.2,3.5Hz,1H),4.93-4.81(m,1H),3.77(dd,J=17.9,7.2Hz,1H),3.70-3.56(dd,J=16.9,1H).

[0097] Table 1 Example results

[0098]

[0099]

[0100] From Examples 1 and 14-28, it can be seen that the method of the present invention starts from readily available α,β-unsaturated ketones, uses cheap and low-toxic acetone cyanohydrin as a cyanide source, and the ionic liquid is most preferably 1-butyl-3-methylimidazolium acetate, which efficiently realizes the Michael reaction of α,β-unsaturated ketones to generate β-carbonyl nitrile. The method has good compatibility with functional groups on aromatic rings and is a new type of green general synthesis method.

[0101] 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. A green and efficient preparation method of β-carbonyl nitrile, characterized in that: The method: β-Carbonyl nitrile was synthesized using α,β-unsaturated ketone as substrate and acetone cyanohydrin as cyanation reagent in the presence of ionic liquid.

2. The method according to claim 1, characterized in that The α,β-unsaturated ketones are chalcone, (E)-2-(furan-2-yl)-4-(5-methylthiophen-2-yl)prop-2-en-1-one, (E)-4-(5-methylfuran-2-yl)-1-phenylprop-2-en-1-one, (E)-4-phenyl-2-(pyridin-2-yl)prop-2-en-1-one, (E)-4-(5-methylthiophen-2-yl)-1-phenylprop-2-en-1-one, (E)-2-phenyl-4-(pyridin-2-yl)prop-2-en-1-one, (E)-4-(pyridin-2-yl)-2-(thiophen-2-yl)prop-2-en-1-one, (E)-2-(furan-2-yl)-4-(thiophen-2-yl)prop-2-en-1-one, (E)-2-phenyl-4-(thiophen-2-yl)prop-2-en-1-one, (E)-2-phenyl-4-(thiophen-2-yl)prop-2-en-1-one, (E)-4-(furan-2-yl)-2-(4-methoxyphenyl)prop-2-en-1-one, (E)-4-(3-oxo-3-phenylprop-1-en-1-yl)benzonitrile, (E)-4-(5-methylthiophen-2-yl)-2-(p-tolyl)prop-2-en-1-one, (E)-2-(furan-2-yl)-4-(pyridin-2-yl)prop-2-en-1-one, (E)-2-(furan-2-yl)-4-phenylprop-2-en-1-one or (E)-4-phenyl-2-(thiophen-2-yl)prop-2-en-1-one.

3. The method according to claim 1, characterized in that The ionic liquid is 1-butyl-3-methylimidazolium acetate, 1-ethyl-3-methylimidazolium acetate or 1-butyl-3-methylimidazolium dicyanamide.

4. The method according to claim 1, characterized in that The amount of acetone cyanohydrin used is 2.0-4.0 times the equivalent of the substrate, and the amount of ionic liquid used is 1.0-4.0 times the equivalent of the substrate.

5. The method according to claim 4, characterized in that The amount of acetone cyanohydrin used is 2.0-3.0 times the equivalent of the substrate, and the amount of ionic liquid used is 2.0-3.0 times the equivalent of the substrate.

6. The method according to claim 5, characterized in that The amount of acetone cyanohydrin used is 1.5 times the equivalent of the ionic liquid.

7. The method according to claim 1, characterized in that The reaction temperature is 25-50°C.

8. The method according to claim 1, characterized in that After the reaction is completed, extraction, washing, dehydration and filtration are carried out in sequence, and the filtrate is subjected to column chromatography.

9. β-Carbonyl nitrile prepared by the method according to any one of claims 1 to 8, characterized in that The general structural formula is: In the formula, R1 represents phenyl, thiophen, furan, pyridin, 4-OMe-phenyl, 4-Me-phenyl, 4-CN-phenyl or 4-NO2-phenyl; R2 represents phenyl, thiophen, furan, pyridin, 4-Me-thiophen or 4-Me-furan.

10. Use of the β-carbonyl nitrile according to claim 9 as a pharmaceutical intermediate.

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