A process for the synthesis of N-oxobutanamide and derivatives thereof

Abstract

The present application relates to the field of chemical synthesis, in particular to a synthesis method of N-oxobutane acetamide and derivatives thereof.The synthesis method comprises the following steps: reacting a phenone compound with a nitrile compound, an acid and a reaction solvent to obtain the N-oxobutane acetamide and derivatives thereof; the phenone compound is p-bromophenone, p-fluorophenone, p-chlorophenone, p-iodophenone, p-cyanophenone, 3,4-dimethylphenone or 2-naphthaldehyde; the nitrile compound is acetonitrile, 3-chloropropionitrile, dichloroacetonitrile or deuterated acetonitrile; the acid is CF3SO3H or BF3; and the reaction solvent is acetonitrile or dichloroethane.The present application directly constructs the N-oxobutane acetamide and derivatives thereof in one step with the nitrile compound as the only nitrogen source, and has the advantages of cheap and easily available raw materials, mild conditions, high yield and easy scale-up production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a synthesis method of N-oxobutanamide and its derivatives. BACKGROUND

[0002] N-oxobutanamide and its derivatives are a class of compounds with special structure and performance, which have important research significance and application value in the field of organic chemistry and material science. Its asymmetric structure and potential chiral characteristics make it an important intermediate carrier in the research fields of asymmetric synthesis, drug molecules and chiral separation and purification. However, the current industrial and laboratory preparation methods of N-oxobutanamide and its derivatives mainly have the following shortcomings:

[0003] (1) Limited source of raw materials

[0004] The classic route is to use hydroxylamine or its hydrochloride as the nitrogen source, which needs to prepare hydroxylamine in advance. The process is complicated and the cost is high. In addition, hydroxylamine is sensitive to heat and impact, which poses a safety risk. If N-alkoxylation and oxidation strategy is used, high-priced oxidants (such as m-CPBA, DMP, peroxo acid, etc.) are often needed, which produces a large amount of by-products and has poor atom economy.

[0005] (2) Harsh reaction conditions

[0006] In the prior art, the synthesis of N-oxoamide usually requires strong oxidation or high-temperature reflux conditions (100-150℃), which leads to poor functional group compatibility. The substrates containing halogen, carbonyl, heterocycle and other sensitive groups are prone to side reactions, and the yield fluctuates greatly (30%-70%), which is difficult to scale up.

[0007] (3) Narrow range of substrates

[0008] The traditional Ritter reaction uses alcohol or alkene as the substrate to generate N-substituted amide with nitrile in the presence of strong acid. In addition, the reaction lacks sufficient adaptability to aryl ketone substrates, especially the systematic evaluation of aryl ketones containing bromine and trifluoromethanesulfonate leaving groups.

[0009] (4) Lack of scale-up

[0010] Due to the large polarity and hygroscopicity of the product, purification is difficult. Most of the existing literature is for milligram-level synthesis, and there is a lack of gram-level preparation of high-purity samples.

[0011] Therefore, it is a technical problem to be solved in the current field to develop a new synthesis method of N-oxobutanamide and its derivatives with cheap and readily available raw materials, mild conditions and easy scale-up production. SUMMARY

[0012] Based on the above, the present application provides a synthesis method of N-oxobutanamide and its derivatives.

[0013] To achieve the above object, the present application provides the following solutions.

[0014] The present application provides a synthesis method of N-oxobutanamide and its derivatives, comprising the following steps:

[0015] The ketone compound is reacted with a nitrile compound, an acid and a reaction solvent to obtain the N-oxobutanamide and its derivatives;

[0016] The ketone compound is reacted with a nitrile compound, an acid and a reaction solvent to obtain the N-oxobutanamide and its derivatives;

[0017] The nitrile compound is acetonitrile, 3-chloropropionitrile, dichloroacetonitrile or deuterated acetonitrile;

[0018] The acid is CF3SO3H or BF3;

[0019] The reaction solvent is acetonitrile or dichloroethane.

[0020] In a preferred embodiment of the present application, the molar ratio of the ketone compound to the nitrile compound is 1:(2-50).

[0021] In a preferred embodiment of the present application, the molar ratio of the ketone compound to the acid is 1:(2.2-2.5).

[0022] In a preferred embodiment of the present application, the use amount ratio of the ketone compound to the reaction solvent is 0.40 mmol:(1.0-1.5) mL.

[0023] In a preferred embodiment of the present application, the reaction is carried out in an air atmosphere at a temperature of 80-85°C for 12-24 hours.

[0024] In a preferred embodiment of the present application, after the reaction is completed, the steps of sequentially cooling to room temperature, removing the reaction solvent, washing, concentrating the organic phase and then performing silica gel column chromatography are further included.

[0025] The present application discloses the following technical effects:

[0026] The present application directly constructs N-oxobutanamide and its derivatives in one step with a nitrile compound as the only nitrogen source, which has the advantages of cheap and readily available raw materials, mild conditions, high yield and easy scale-up production. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to make the technical solutions in the embodiments of the present application or the prior art clearer, the accompanying drawings needed in the embodiments will be briefly introduced below. Obviously, the accompanying drawings in the following description only need to be some embodiments of the present application, and for those skilled in the art, other drawings can also be obtained from these drawings without creative effort.

[0028] Figure 1 NMR of compound 3a (500 MHz, CDCI3, 298 K).

[0029] Figure 2 NMR of compound 3a (125 MHz, CDCI3, 298 K).

[0030] Figure 3 NMR of compound 3b (500 MHz, CDCI3, 298 K).

[0031] Figure 4 NMR of compound 3b (125 MHz, CDCI3, 298 K).

[0032] Figure 5 NMR of compound 3b (470 MHz, CDCI3, 298 K).

[0033] Figure 6 NMR of compound 3c (500 MHz, CDCI3, 298 K).

[0034] Figure 7 NMR of compound 3c (125 MHz, CDCI3, 298 K).

[0035] Figure 8 NMR of compound 3d (500 MHz, CDCI3, 298 K).

[0036] Figure 9 NMR of compound 3d (125 MHz, CDCI3, 298 K).

[0037] Figure 10 NMR of compound 3e (500 MHz, CDCI3, 298 K).

[0038] Figure 11 NMR of compound 3e (125 MHz, CDCI3, 298 K).

[0039] Figure 12NMR of compound 3f (500 MHz, CDC13, 298 K).

[0040] Figure 13 NMR of compound 3f (125 MHz, CDC13, 298 K).

[0041] Figure 14 NMR of compound 3g (500 MHz, CDC13, 298 K).

[0042] Figure 15 NMR of compound 3g (125 MHz, CDC13, 298 K).

[0043] Figure 16 NMR of compound 4a (500 MHz, CDC13, 298 K).

[0044] Figure 17 NMR of compound 4a (125 MHz, CDC13, 298 K).

[0045] Figure 18 NMR of compound 4b (500 MHz, CDC13, 298 K).

[0046] Figure 19 NMR of compound 4b (125 MHz, CDC13, 298 K).

[0047] Figure 20 NMR of compound 5 (500 MHz, CDC13, 298 K).

[0048] Figure 21 HPLC of compound 3a (2 x 10 -4 M, n-hexane / isopropanol, 9 / 1, v / v, 25°C). DETAILED DESCRIPTION

[0049] Various exemplary embodiments of the present application will now be described in detail, with reference to the figures. The detailed description is not to be regarded as limiting the application, but rather as exemplifying the application in certain aspects, features and embodiments.

[0050] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. Additionally, for a range of values of, for example, concentrations, amounts, and the like, there are multiple values between the upper and lower limits that are specifically and potentially encompassed by the range. These smaller ranges are also specifically encompassed within the present application. The upper and lower limits of these smaller ranges can independently be included or excluded in the range.

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the documents are cited. In case of conflict between the present specification and any document incorporated by reference, the present specification will control.

[0052] Various modifications and changes can be made to the specific embodiments described herein without departing from the scope or spirit of the application. Other embodiments will be apparent to those of ordinary skill in the art from the description and examples herein. The description and examples are illustrative only.

[0053] As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", or variations thereof, are intended to be open-ended terms that mean including, but not limited to.

[0054] The present application designs a new method for synthesizing N-oxobutanamide and its derivatives, and conducts in-depth research on its structure, chemical composition and functional group compatibility. First, using nitrile compound (acetonitrile) as the only nitrogen source, adding p-bromoacetophenone and trifluoromethanesulfonic acid, Ritter reaction is carried out to obtain the target molecule N-oxobutanamide, and the reaction yield is good. On the basis of this synthesis, the scope of the reaction substrate is further expanded, and the functional group compatibility of the reaction is increased. The structure and performance of the synthesized N-oxobutanamide and its derivatives are confirmed and preliminarily explored by nuclear magnetic hydrogen spectrum, carbon spectrum, high resolution mass spectrometry and other characterization methods. And the gram-scale template expansion of the template reaction and the preparation of the target molecule are successfully realized, which lays a solid material research foundation for the subsequent potential performance research of N-oxobutanamide.

[0055] The present application first takes p-bromoacetophenone (reaction raw material 1) and acetonitrile (reaction raw material 2, also as a reaction solvent) as a template reaction, mainly investigates the influence of the following factors on the reaction: 1) the type of solvent; 2) the type of atmosphere; 3) time; 4) the type of acid; the specific influence of each factor is shown in Table 1. The template reaction is as follows (note: contains *C for chiral carbon atom):

[0056]

[0057] Table 1

[0058]

[0059] In Table 1, a Reaction conditions: reaction raw material 1 (0.40 mmol, 1 equiv), reaction raw material 2 (1 mL), acid (0.88 mmol, 2.20 equiv), solvent (1.0 mL), 80°C, air atmosphere.

[0060] b Yield.

[0061] c No reaction.

[0062] d Mess: various mixtures.

[0063] e Reaction conditions: reaction raw material 1 (0.40 mmol, 1 equiv), reaction raw material 2 (1 mL), acid (0.88 mmol, 2.20 equiv), solvent (1.0 mL), 80°C, argon atmosphere, reaction 12 h.

[0064] f Reaction conditions: reaction raw material 1 (0.40 mmol, 1 equiv), reaction raw material 2 (1 mL), acid (0.88 mmol, 2.20 equiv), solvent (1.0 mL), 80°C, O2 atmosphere, reaction 12 h.

[0065] As shown in Table 1, the present application optimizes the reaction solvent of the template reaction, and it is found that when the reaction solvent is acetonitrile, the reaction yield is 93%, and when the solvent is dichloroethane (DCE), dichloromethane (DCM), dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF) and tetrahydrofuran (THF), respectively, the reaction yield is not ideal, and even no reaction (Table 1, No. 1, 6-10), so acetonitrile is selected as the reaction solvent. And on this basis, the reaction atmosphere is further optimized, and it is found that when the atmosphere is air, oxygen and argon, respectively, the reaction yield is 93%, 89% and 70% (Table 1, No. 1, 14, 15), so air is selected as the template reaction atmosphere.

[0066] On this basis, the reaction time is further optimized and screened, and it is found that when the reaction time is 4, 8, 10 and 12 h, respectively, the reaction yield is 50%, 72% and 93% (Table 1, No. 1, 11-13), so the reaction time is set to 12 h. In combination with the above reaction factors, the acid is finally optimized. It is found that when trifluoromethanesulfonic acid is used, the reaction yield is best, which can reach 93% (Table 1, No. 1); but when other acids such as trifluoroacetic acid, boron trifluoride, aluminum chloride, zinc chloride are used, the reaction yield is 65%, 86%, 76% and 70%, respectively. Therefore, considering comprehensively, trifluoromethanesulfonic acid is selected as the acid in the synthesis method of the present application.

[0067] On the basis of the template reaction, the present application expands the benzaldehyde compound and the nitrile compound, and synthesizes N-oxobutane acetamide and its derivatives.

[0068] The technical solutions described in the present application are conventional solutions in the art if not specifically stated, and the reagents or raw materials used are purchased from commercial channels or are already published if not specifically stated.

[0069] The technical solutions provided by the present application will be described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0070] The synthesis routes in Examples 1 to 7 of the present application are as follows:

[0071] .

[0072] The synthesis routes in Examples 8 to 10 of the present application are as follows:

[0073] .

[0074] Example 1 (template reaction under the best reaction condition)

[0075] Into a 15 mL Schlenk tube, was added reactant 1, 4-bromoacetophenone (0.40 mmol, 1.00 equiv.), reactant 2, acetonitrile (1.0 mL), CF3SO3H (TfOH, 0.88 mmol, 2.2 equiv.) and reaction solvent, acetonitrile (1.0 mL) and reacted at 80 °C for 12 h under air atmosphere. After completion of the reaction, it was cooled to room temperature. After removing acetonitrile by rotary evaporation, it was washed with dichloromethane (15 mL x 3) and distilled water (15 mL x 3). After concentrating the organic phase under vacuum, compound 3a was obtained by silica gel (200-300 mesh) column chromatography using eluent ethyl acetate and petroleum ether (1 / 6, v / v) (white solid, 81.3 mg, yield 93 %).

[0076] Structure of compound 3a: ;1H NMR as shown in Figure 1 ;13C NMR as shown in Figure 2 .

[0077] N-(2,4-Bis(4-bromophenyl)-4-oxobutan-2-yl)acetamide (3a): m.p. 136.5-137.0 °C. 1 HNMR (500 MHz, CDCl3): δ 7.71 (d, J = 7.0 Hz, 2H), 7.59 (d, J = 7.0 Hz, 2H), 7.44(d, J = 7.0 Hz, 2H), 7.24 (d, J = 7.0 Hz, 2H), 6.82 (s, 1H), 3.81 (d, J = 13.0 Hz,1H), 3.43 (d, J = 13.5 Hz, 1H), 2.01 (s, 3H), 1.85 (s, 3H); 13 C NMR (125 MHz,CDCl3): δ 198.2, 169.7, 144.4, 136.0, 132.0 131.6, 129.7, 128.9, 126.5,120.9, 57.5, 46.8, 27.4, 24.2. HRMS (ESI): calculated for C 14 H 18 Br2NO2[M + H] + 437.9699, found 437.9695.

[0078] Example 2

[0079] The only difference between Example 1 and this example is that the reaction starting material 1-bromoacetophenone is replaced with equimolar of 1-fluoroacetophenone, and the eluent is ethyl acetate and petroleum ether (1 / 4, v / v); compound 3b (pale yellow solid, 53.9 mg, yield 85 %) is obtained.

[0080] The structural formula of compound 3b: ;1H NMR is shown in Figure 3 ;13C NMR is shown in Figure 4 ;19F NMR is shown in Figure 5 .

[0081] N-(2,4-Bis(4-fluorophenyl)-4-oxobutan-2-yl)acetamide (3b): melting point 118.5-119.0 °C. 1 HNMR (500 MHz, CDCl3): δ 7.84 (t, J = 4.5 Hz, 2H), 7.31-7.29 (m, 2H), 7.10 (s,1H), 7.04 (d, J = 7.0 Hz, 2H), 6.93 (d, J = 7.0 Hz, 2H), 3.80 (d, J = 13.0 Hz, 1H),3.38 (d, J = 13.5 Hz, 1H), 1.92 (s, 3H), 1.81 (s, 3H). 13 C NMR (125 MHz, CDCl3):δ 197.6, 169.7, 166.7,165.0, 162.3, 160.7, 141.2,133.8, 130.9 (d, J = 7.5 Hz),126.5 (d, J = 6.2 Hz), 115.7 (d, J = 18.8 Hz), 115.1 (d, J = 17.5 Hz), 57.3, 47.1,27.4, 24.0. 19 F NMR (470 MHz, CDCl3): δ -116.1 (s, 1F), -104.0 (s, 1F). HRMS(ESI): calculated C 14 H 18 F2NO2[M + H] + 318.1300, found 305.1297.

[0082] Example 3

[0083] The difference between Example 1 and this example is that the reaction material 1, p-bromoacetophenone, is replaced by equimolar p-iodoacetophenone, and the eluent is ethyl acetate and petroleum ether (1 / 5, v / v); compound 3d (yellow solid, 85.3 mg, yield 80%) is obtained.

[0084] The structural formula of compound 3d: ; the nuclear magnetic hydrogen spectrum is as shown in Figure 6 , and the nuclear magnetic carbon spectrum is as shown in Figure 7 .

[0085] N-(2,4-bis(4-chlorophenyl)-4-oxobut-2-yl)acetamide (3c): melting point 123.7-124.1 °C. 1 HNMR (500 MHz, CDCl3): δ 7.74 (d, J = 10.5 Hz, 2H), 7.36 (d, J = 10.5 Hz, 1H),7.27-7.24 (m, 4H), 6.86 (s, 1H), 3.77 (d, J = 20.0 Hz, 1H), 3.38 (d, J = 20.0 Hz,1H), 1.95 (s, 3H), 1.80 (s, 3H). 13 C NMR (125 MHz, CDCl3):δ 198.1, 169.9,144.0, 140.2, 135.6, 132.8, 129.7, 129.1, 128.7, 126.3, 57.4, 47.0, 27.4,24.2. HRMS (ESI): calculated C 14 H 18 Cl2NO2[M + H] + 350.0709, found 350.0700.

[0086] Example 4

[0087] The difference between Example 1 and this example is that the reaction material 1, p-bromoacetophenone, is replaced by equimolar p-iodoacetophenone, and the eluent is ethyl acetate and petroleum ether (1 / 5, v / v); compound 3d (yellow solid, 85.3 mg, yield 80%) is obtained.

[0088] The structural formula of compound 3d: ; the nuclear magnetic hydrogen spectrum is as shown in Figure 8 , and the nuclear magnetic carbon spectrum is as shown in Figure 9shown.

[0089] N-(2,4-Bis(4-iodophenyl)-4-oxobutan-2-yl)acetamide (3d): melting point 134.5-135.0 °C. 1 HNMR (500 MHz, CDCl3): δ 7.76 (d, J =10.5 Hz, 2H), 7.58 (d, J = 11.0 Hz, 2H), 7.50(d, J =10.5 Hz, 2H), 7.06 (d, J = 11.0 Hz, 2H), 6.81 (s, 1H), 3.75 (d, J = 20.0 Hz,1H), 3.37 (d, J = 20.5 Hz, 1H), 1.95 (s, 3H), 1.78 (s, 3H). 13 C NMR (125 MHz,CDCl3):δ 198.6, 169.9, 145.3, 138.1, 137.7, 136.5, 129.6, 126.9, 101.9, 92.6,57.5, 46.8, 27.4, 24.3. HRMS (ESI): calculated for C 14 H 18 I2NO2[M + H] + 533.9512, found as 533.9510.

[0090] Example 5

[0091] The only difference from Example 1 was that the p-bromoacetophenone in reaction starting material 1 was replaced by an equimolar amount of p-cyanoacetophenone, and ethyl acetate and petroleum ether (1 / 4, v / v) were used as eluents; compound 3e was obtained (white solid, 37.7 mg, yield 57%).

[0092] The structural formula of compound 3e: ; H NMR spectrum Figure 10 As shown, the NMR carbon spectrum is Figure 11 shown.

[0093] N-(2,4-Bis(4-cyanophenyl)-4-oxobutan-2-yl)acetamide (3e): melting point 170.2-170.8 °C. 1 HNMR (500 MHz, CDCl3): δ 8.13-8.06 (m, 2H), 7.83 (d, J= 9.5 Hz, 1H), 7.76-7.58(m, 3H), 7.51 (d, J = 9.5 Hz, 1H), 7.43 (t, J = 9.5 Hz, 1H), 6.60 (s, 1H), 4.01(d, J = 21.0 Hz, 1H), 3.48 (d, J = 20.5 Hz, 1H), 1.98 (s, 3H), 1.82 (s, 3H). 13 CNMR (125 MHz, CDCl3): δ 196.5, 170.1, 147.0, 137.8, 136.5, 132.1, 131.9,130.8, 129.9, 129.6, 129.3, 128.7, 118.9, 117.8, 113.5, 112.9, 57.2, 46.2,28.0, 24.1. HRMS (ESI): calculated for C 20 H 18 N3O2[M + H] + 332.1394, found as 332.1389.

[0094] Example 6

[0095] The only difference from Example 1 was that the reaction starting material 1 (p-bromoacetophenone) was replaced with an equimolar amount of 3, 4-dimethylacetophenone, and the eluent was ethyl acetate and petroleum ether (1 / 10, v / v); compound 3f was obtained (yellow solid, 58.0 mg, 86% yield).

[0096] The structural formula of compound 3f is: ; H NMR spectrum Figure 12 As shown, the NMR carbon spectrum is Figure 13 shown.

[0097] N-(2,4-Bis(3,4-dimethylphenyl)-4-oxobutan-2-yl)acetamide (3f): melting point 140.1-140.6 °C. 1 H NMR (500 MHz, CDCl3): δ 7.62 – 7.61 (m, 2H), 7.19 (d, J = 10.5 Hz, 1H),7.15 (s, 1H), 7.12 – 7.06 (m, 2H), 7.04 (s, 1H), 3.65 (d, J = 19.5 Hz, 1H),3.48 (d,J = 20.0 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.22 (s,3H), 2.03 (s, 3H), 1.81 (s, 3H). 13 C NMR (125 MHz, CDCl3): δ 199.7, 169.5, 143.1(d, J = 12.5 Hz), 136.9, 136.5, 135.5, 135.0, 129.8 (d, J = 7.5 Hz), 129.4, 126.0(d, J =8.8 Hz), 122.0, 57.6, 47.6, 26.8, 24.4, 20.1, 20.0, 19.7, 19.3. HRMS(ESI): calculated C 22 H 28 NO2[M + H] + 338.2115, found as 338.2113.

[0098] Example 7

[0099] The only difference from Example 1 was that the reaction raw material 1 p-bromoacetophenone was replaced by an equimolar amount of 2-naphthylacetonone, and the eluent was ethyl acetate and petroleum ether (1 / 5, v / v); compound 3 g (pale yellow solid, 48.0 mg, yield 63%) was obtained.

[0100] The structural formula of compound 3g is: ; H NMR spectrum Figure 14 As shown, the NMR carbon spectrum is Figure 15 shown.

[0101] N-(2,4-Di(naphthalen-2-yl)-4-oxobutan-2-yl)acetamide (3 g): melting point 187.1-187.5 °C. 1 H NMR (500 MHz, CDCl3): δ 8.36 (s, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.88 – 7.84 (m, 5H), 7.82 – 7.78 (m, 2H), 7.82 – 7.78 (m, 3H), 7.49 – 7.43 (m, 2H), 7.12 (s, 1H), 4.03 (d, J = 13.5 Hz, 1H), 3.74 (d, J=13.0 Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H). 13 C NMR (125 MHz, CDCl3): δ 199.5, 169.8, 143.0, 135.7, 134.8, 133.3, 132.4,130.4, 129.7, 128.7, 128.5, 128.4, 128.2, 127.7, 127.4, 126.9, 126.1, 125.8,123.6, 123.4, 123.2, 58.1, 47.6, 27.2, 24.3. HRMS (ESI): calculated for C 26 H 24 NO2[M +H] + 382.1802, found as 382.1801.

[0102] Example 8

[0103] To a 15 mL Schlenk tube were added reaction starting material 1 (p-bromoacetophenone, 0.40 mmol, 1.00 equiv.), reaction starting material 2 (3-chloropropionitrile, 0.88 mmol, 2.2 equiv.), CF3SO3H(TfOH, 0.88 mmol, 2.2 equiv.), and dichloroethane (1.0 mL). The mixture was reacted under air at 80°C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature. The acetonitrile was removed by rotary evaporation, and the mixture was washed with dichloromethane (15 mL × 3) and distilled water (15 mL × 3). The organic phase was concentrated in vacuo and then purified by silica gel (200-300 mesh) column chromatography using ethyl acetate and petroleum ether (1 / 6, v / v) as eluent to obtain compound 4a (44.6 mg, 46% yield) as a yellow viscous oil.

[0104] The structural formula of compound 4a: ; H NMR spectrum Figure 16 As shown, the NMR carbon spectrum is Figure 17 shown.

[0105] N-(1,3-bis(4-bromophenyl)-5-chloro-1-oxopentan-3-yl)acetamide (4a): 1 H NMR (500 MHz, CDCl3): δ 7.86 – 7.71 (m, 2H), 7.62 – 7.56 (m, 2H), 7.44 (d, J= 9.0 Hz, 2H), 7.28 – 7.23 (m, 2H), 6.93 (s, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.56 (t, J = 7.0Hz, 2H), 3.42 (d, J = 13.5 Hz, 1H),2.05 (t, J = 5.0 Hz, 2H),1.84 (s, 3H). 13 C NMR (125 MHz, CDCl3): δ 198.1, 171.2, 144.5, 135.9, 132.0, 131.7, 129.7, 129.0, 126.5, 120.9, 57.4, 46.8, 44.4, 33.7, 27.9, 27.3. HRMS (ESI): calculated C 19 H 19 Br2ClNO2[M + H] + 485.9466, found 485.9462.

[0106] Example 9

[0107] The difference between Example 8 and this example is that the reaction material 2 is replaced by equimolar dichloroacetonitrile, and the eluent is ethyl acetate and petroleum ether (1 / 8, v / v); compound 4b (yellow solid, 87.8 mg, yield 87%) is obtained.

[0108] The structural formula of compound 4b: ;1H NMR is shown in Figure 18 , and13C NMR is shown in Figure 19 .

[0109] N-(2,4-bis(4-bromophenyl)-1,1-dichloro-4-oxobutan-2-yl)acetamide (4b): melting point 190.4-190.9 °C. 1 H NMR (500 MHz, CDCl3): δ 8.24 (s, 1H), 7.71 (d, J = 7.0 Hz, 2H), 7.59 (d, J =7.0 Hz, 2H), 7.47 (d, J = 7.0 Hz, 2H), 7.26 (d, J = 7.0 Hz, 2H), 5.85 (s, 1H),3.68 (d, J= 13.5 Hz, 1H), 3.43 (d, J = 13.5 Hz, 1H), 1.92 (s, 3H). 13 C NMR (125 MHz, CDCl3): δ 197.9, 163.2, 143.1, 135.6, 132.1, 131.9, 129.7, 129.3, 126.3,121.4, 66.9, 58.1, 47.3, 26.3. HRMS (ESI): calculated for C 18 H 16 Br2Cl2NO2[M + H] + 505.8920, found as 505.8917.

[0110] Example 10

[0111] The only difference from Example 8 was that the reaction raw material 2 was replaced by an equimolar amount of deuterated acetonitrile, and the eluent was ethyl acetate and petroleum ether (1 / 10, v / v); compound 5 was obtained (yellow solid, 75.7 mg, yield 86%).

[0112] The synthetic route of Example 10 is as follows:

[0113]

[0114] N-(2,4-Bis(4-bromophenyl)-4-oxobutan-2-yl-1,1,1-trideuterio)acetamide (5): melting point 157.3-157.9 °C. 1 H NMR (500 MHz, CDCl3): δ 7.71 (d, J = 11.0 Hz, 2H), 7.58 (d, J = 11.0Hz, 2H), 7.44 (d, J = 10.5 Hz, 2H), 7.24 (d, J = 10.5 Hz, 2H), 6.82 (s, 1H), 3.81(d, J = 20.0 Hz, 1H), 3.43 (d, J = 20.0 Hz, 2H), 1.84 (s, 3H). HRMS (ESI): calculated for C 18 H 15 D3Br2NO2[M + H] +440.9887, found 440.9885. The NMR carbon spectrum of compound 5 was not collected because it was consistent with the peaks of compound 3a. The NMR hydrogen spectrum is shown in Figure 2. Figure 20

[0115] In Example 10, the reaction raw material 2 was replaced with deuterated acetonitrile to verify the possibility of using the method of the present application as an isotopic tracer or a targeted amide drug.

[0116] Example 11 (preparation in gram scale)

[0117] Based on the reaction conditions in Example 1, the template reaction was scaled up in gram scale, and the specific operation is as follows: 50 mL of a single port flask was added with reaction raw material 1 p-bromoacetophenone (6 mmol, 1.00 equiv.), reaction raw material 2 acetonitrile (15.0 mL), CF3SO3H (13.2 mmol, 2.2 equiv.) and reaction solvent acetonitrile (15.0 mL), and the reaction was carried out under air atmosphere at 80°C for 24 hours. After the reaction was completed, it was cooled to room temperature. After removing acetonitrile by rotary evaporation, it was washed with dichloromethane (100 mL x 3) and distilled water (100 mL x 3). After vacuum concentration of the organic phase, silica gel (200-300 mesh) column chromatography was carried out with eluent ethyl acetate and petroleum ether (1 / 5, v / v) to obtain 3a (white solid, 1.05 g, yield 80 %).

[0118] In order to verify the chirality of the target molecule 3a, i.e. the existence of different enantiomers, high performance liquid chromatography analysis was carried out on the pure compound 3a synthesized in Example 1 (high performance liquid chromatography instrument model Shimadzu SCL-20AVP). It was found that when using chiral column OD-H or OJ-H, two chiral liquid chromatography signals with nearly equal areas appeared Figure 21 ). This proves that the pure compound 3a exists in a pair of chiral enantiomers, and the separation degrees are 1.9 and 1.6 respectively. This verifies the chirality of the target molecule, and since the separation degrees have reached more than 1.5, there is a possibility of separating two single chiral isomers, which also provides feasibility for subsequent chiral recognition and other potential chiral performance research.

[0119] The N-oxobutanamide and its derivatives of the present application can be developed into single chiral drug molecules, isotopic targeting tracers, targeted chiral recognition drugs and chiral functional fluorescent probes. And based on the synthesized oxobutanamide which is a small molecule nitrogen-containing skeleton and has significant chiral characteristics, it can have high selective host-guest recognition interaction with chiral carbon-rich macrocyclic molecules, and thus develop chiral host-guest composite materials.

[0120] ​The excellent synthesis strategy of the present application is used to synthesize N-oxobutanamide derivatives and introduce different functional groups or substituents in the molecular structure to regulate the specific functions and performances. The acetylamide molecules synthesized by the method of the present application exist chirality and can be applied to the recognition and preparation of new host-guest functional materials, which provides more research possibilities for the application of materials and medical fields.

[0121] The above-described embodiments are only used to describe the preferred modes of the present application, and do not limit the scope of the present application. Without departing from the design spirit of the present application, various modifications and improvements of the technical solutions of the present application made by those skilled in the art shall fall within the protection scope determined by the claims of the present application.

Claims

1. A method for synthesizing N-oxybutaneacetamide and its derivatives, characterized in that: The following steps are involved: reacting an acetophenone compound with a nitrile compound, an acid, and a reaction solvent to obtain the N-oxybutaneacetamide and its derivatives; The acetophenone compound is p-bromoacetophenone, p-fluoroacetophenone, p-chloroacetophenone, p-iodoacetophenone, p-cyanoacetophenone, 3,4-dimethylacetophenone or 2-acetophenone; The nitrile compound is acetonitrile, 3-chloropropionitrile, dichloroacetonitrile or deuterated acetonitrile; The acid is CF3SO3H or BF3; The reaction solvent is acetonitrile or dichloroethane.

2. The method for synthesizing N-oxybutaneacetamide and its derivatives according to claim 1, characterized in that: The molar ratio of the acetophenone compound to the nitrile compound is 1:(2-50).

3. The method for synthesizing N-oxybutaneacetamide and its derivatives according to claim 1, characterized in that: The molar ratio of the acetophenone compound to the acid is 1:(2.2-2.5).

4. The method for synthesizing N-oxybutaneacetamide and its derivatives according to claim 1, characterized in that: The usage ratio of the acetophenone compound to the reaction solvent is 0.40 mmol: (1.0-1.5) mL.

5. The method for synthesizing N-oxybutaneacetamide and its derivatives according to claim 1, characterized in that: The reaction is carried out in an air atmosphere at a temperature of 80-85° C. for 12-24 hours.

6. The method for synthesizing N-oxybutaneacetamide and its derivatives according to claim 1, characterized in that: After the reaction is completed, the steps of cooling to room temperature, removing the reaction solvent, washing, concentrating the organic phase and then performing silica gel column chromatography are further included.

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