Alpha-amino amide derivative and synthesis method thereof

Abstract

The invention discloses an alpha-amino amide derivative and a synthesis method thereof. The invention relates to an alpha-amino substituted amide derivative, the structural formula of which is # imgabs0 #, and in the formula, X is bromine or chlorine; r is phenyl, phenyl substituted by methyl, phenyl substituted by methoxyl, phenyl substituted by halogen, naphthyl, furyl, thienyl, cyclohexyl, tetrahydropyranyl or ester substituted by C1-C4 alkyl; ar is phenyl, phenyl substituted by C1-C4 alkyl, phenyl substituted by methoxyl, and phenyl or naphthyl substituted by halogen. The synthesis method of the alpha-aminoamide derivative comprises the following steps: taking halogenated difluoroacetate, aromatic aldehyde or alkyl aldehyde and aromatic amine as raw materials, under the catalysis of metal copper salt, taking Bronsted acid as an additive and taking an organic reagent as a solvent, and carrying out one-step reaction to obtain the alpha-aminoamide derivative. The raw materials are cheap, easy to obtain, safe and non-toxic, the reaction conditions of the synthesis method are mild, the operation is simple and safe, and the synthesized alpha-amino substituted amide derivative can be widely applied to the fields of organic synthesis and drug research and development.

Description

Technical Field

[0001] The present invention relates to a compound synthesis method, in particular to an alpha-aminoamide derivative and a synthesis method thereof. Background Art

[0002] α-Aminoamide derivatives are widely used in biomedicine, such as Nirogacestat, a drug for treating desmoid tumors developed by a US pharmaceutical company, and Lidocaine, a local anesthetic drug jointly developed by a domestic pharmaceutical company. Both of them contain α-aminoamide core fragments in their structures. The molecular structures of Nirogacestat and Lidocaine are as follows:

[0003]

[0004] Therefore, the efficient construction of α-amino-modified amide derivatives has always been one of the research hotspots in biopharmaceutical research and development.

[0005] At present, the two classic reactions named Ugi reaction and Strecker reaction are commonly used methods for constructing α-amino-modified amide derivatives. However, the former requires toxic and unstable isonitrile as raw material, and the latter requires highly toxic cyanide as raw material. Therefore, the application of the above methods in drug synthesis is obviously limited. Summary of the invention

[0006] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing alpha-aminoamide derivatives catalyzed by metal copper.

[0007] The synthetic method of the α-aminoamide derivatives of the present invention adopts cheap, readily available, non-toxic and harmless raw materials as reaction substrates, and synthesizes α-amino-modified amide derivatives in one step in a multi-component reaction mode. The synthetic method has the advantages of simple operation, mild reaction conditions, good substrate universality, etc.

[0008] The technical solution adopted by the present invention is:

[0009] The present invention provides an α-aminoamide derivative, the structural formula of which is as follows:

[0010]

[0011] In formula (4), X is bromine or chlorine, R is phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, naphthyl, furanyl, thienyl, cyclohexyl, tetrahydropyranyl or C1-C4 alkyl-substituted ester; Ar is phenyl, C1-C4 alkyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl or naphthyl.

[0012] Preferably, R is p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, m-bromophenyl, m-methoxyphenyl, 2-naphthyl, 2-furyl, 2-thienyl, cyclohexyl, tetrahydropyranyl or ethyl acetate; Ar is p-methylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-bromophenyl, p-chlorophenyl, m-methylphenyl, m-chlorophenyl, m-bromophenyl or 2-naphthyl.

[0013] The present invention also provides a method for synthesizing the α-aminoamide derivative, which uses halogenated difluoroacetate, alkyl aldehyde or aromatic aldehyde, aromatic amine as raw materials, metal copper salt as catalyst, Bronsted acid as additive, and organic reagent as solvent, and obtains the α-amino substituted amide derivative through a one-step reaction. The reaction process is as follows:

[0014]

[0015] In reaction formula (I), X is bromine or chlorine, Y is potassium or sodium; R is phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, naphthyl, furanyl, thienyl, cyclohexyl, tetrahydropyranyl or C1-C4 alkyl-substituted ester; Ar is phenyl, C1-C4 alkyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl or naphthyl.

[0016] Preferably, R is p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, m-bromophenyl, m-methoxyphenyl, 2-naphthyl, 2-furyl, 2-thienyl, cyclohexyl, tetrahydropyranyl or ethyl acetate; Ar is p-methylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-bromophenyl, p-chlorophenyl, m-methylphenyl, m-chlorophenyl, m-bromophenyl or 2-naphthyl.

[0017] The specific steps of the synthesis method are as follows: dissolving aromatic amine, halogenated difluoroacetate, aromatic aldehyde or alkyl aldehyde, metal copper salt and additive in an organic solvent, and then heating the mixed solution directly in an air atmosphere or in an argon atmosphere (with ventilation treatment) to obtain the multi-functional substituted amide derivative.

[0018] In the present invention, the molar ratio of the raw materials is metal copper salt: additive: aromatic amine: halogenated difluoroacetate: aromatic or alkyl aldehyde = (0.1-0.5): (0.2-1.0): (2.0-2.5): (2.0-3.0): (1.0); preferably, it is 0.1: 0.2: 2.5: 3.0: 1.0.

[0019] In the present invention, the reaction temperature is 40°C-80°C; preferably, 50°C.

[0020] In the present invention, the reaction time is 8-12 hours; preferably, 10 hours.

[0021] In the present invention, the reaction is carried out in an air atmosphere or an argon atmosphere; preferably, the reaction is carried out in an argon atmosphere.

[0022] In the present invention, the metal copper salt is any one of cuprous chloride, cuprous bromide, cuprous iodide, and tetraacetonitrile copper hexafluorophosphate; the Bronsted acid additive is any one of p-toluenesulfonic acid, toluenesulfonic acid, adamantane acid, and acetic acid, or a mixture thereof.

[0023] Preferably, the catalyst is tetraacetonitrile copper hexafluorophosphate; and the additive is p-toluenesulfonic acid.

[0024] The present invention further comprises a separation and purification step after preparing the α-amino substituted amide derivative. The separation and purification step is to perform column chromatography using a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:(20-5).

[0025] The following formula is the chemical mechanism involved in the synthesis method of the present invention:

[0026]

[0027] First, BrCF2COOK is catalyzed by Cu(I) to obtain [Cu I ]=CF2 intermediate, which is then attacked by aromatic amine 1 to obtain active ylide intermediate I. Subsequently, species I is captured by proton-activated imine to obtain active intermediate II. With the assistance of in situ generated water molecules, active species II undergoes the first defluorination atom reaction to obtain active intermediate III. Afterwards, species III releases water molecules to form species IV, which undergoes the second defluorination atom reaction under the action of bromodifluoroacetic acid anion to obtain intermediate V. Finally, intermediate V undergoes Mumm rearrangement to produce multi-component product α-amino-modified amide derivatives.

[0028] Based on the above, the present invention proposes a new method for synthesizing α-amino-modified amide derivatives. The reaction substrate is safe and non-toxic, the synthesis reaction process has the advantages of high atom economy, high universality, high yield, etc., and the operation is simple and safe, achieving one-step efficient construction of α-amino-substituted amide derivatives.

[0029] The synthesis method of the present invention uses aromatic amine, halogenated difluoroacetate, aromatic aldehyde or alkyl aldehyde as raw materials, metal copper salt as catalyst, Bronsted acid as additive, acetonitrile as solvent, and adopts one-step multi-component reaction to prepare a series of α-amino substituted amide derivative target products in one step. Since multi-component reaction has the characteristics of high flexibility, high selectivity, high efficiency atom economy, easy operation, etc., with the increasing development of the concept of atom economy in recent years, multi-component reaction has gradually become a research hotspot. Therefore, the application of multi-component reaction in the field of drug synthesis has a very broad prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG1 shows the NMR of the α-amino substituted amide derivative of Example 1 of the present invention. 1 H NMR ( Figure 1A ), 13 CNMR( Figure 1B ), 19 F NMR spectrum ( Figure 1C ).

[0031] FIG. 2 shows the NMR of the α-amino substituted amide derivative of Example 2 of the present invention. 1 H NMR ( Figure 2A ), 13 CNMR( Figure 2B ), 19 F NMR spectrum ( Figure 2C ).

[0032] FIG. 3 shows the NMR of the α-amino substituted amide derivative of Example 3 of the present invention. 1 H NMR ( Figure 3A ), 13 CNMR( Figure 3B ), 19 F NMR spectrum ( Figure 3C ).

[0033] FIG. 4 shows the NMR of the α-amino substituted amide derivative of Example 4 of the present invention. 1 H NMR ( Figure 4A ), 13 CNMR( Figure 4B ), 19 F NMR spectrum ( Figure 4C ).

[0034] FIG5 shows the NMR of the α-amino substituted amide derivative of Example 5 of the present invention. 1 H NMR ( Figure 5A ), 13 CNMR( Figure 5B ), 19 F NMR spectrum ( Figure 5C ).

[0035] FIG. 6 shows the NMR of the α-amino substituted amide derivative of Example 6 of the present invention. 1 H NMR ( Fig. 6A ), 13 CNMR( Figure 6B ), 19 F NMR spectrum ( Figure 6C ).

[0036] FIG. 7 shows the NMR of the α-amino substituted amide derivative of Example 7 of the present invention. 1 H NMR ( Fig. 7A ), 13 CNMR spectrum( Figure 7B ).

[0037] FIG8 shows the NMR of the α-amino substituted amide derivative of Example 8 of the present invention. 1 H NMR ( Fig. 8A ), 13 CNMR( Figure 8B ), 19 F NMR spectrum ( Figure 8C ).

[0038] FIG9 shows the NMR of the α-amino substituted amide derivative of Example 9 of the present invention. 1 H NMR ( Fig. 9A ), 13 CNMR( Fig. 9B ), 19 F NMR spectrum ( Fig. 9C ).

[0039] FIG. 10 shows the NMR of the α-amino substituted amide derivative of Example 10 of the present invention. 1 H NMR ( Fig. 10A ), 13 C NMR ( Fig. 10B ), 19 F NMR spectrum ( Fig. 10C ).

[0040] FIG. 11 shows the NMR of the α-amino substituted amide derivative of Example 11 of the present invention. 1 H NMR ( Fig.11A ), 13 C NMR ( Fig. 11B ), 19 F NMR spectrum ( Fig. 11C ).

[0041] FIG. 12 shows the NMR of the α-amino substituted amide derivative of the practical transformation application example 12 of the present invention. 1 HNMR Fig. 12A ), 13 C NMR ( Fig. 12B ), 19 F NMR spectrum ( Fig. 12C ). DETAILED DESCRIPTION

[0042] In order to make the technical concept and advantages of the present invention more clearly understood, the technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings. It should be understood that the following embodiments are only used to explain and illustrate the preferred implementation methods of the present invention, and should not be regarded as and do not constitute a limitation on the scope of patent protection claimed by the present invention.

[0043] Example 1

[0044]

[0045] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), benzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-1). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 83%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 1:

[0046] 1 H NMR (500MHz, DMSO) δ10.55(s,1H),7.82(dd,J=8.6,2.6Hz,1H),7.60(d,J=8.6Hz,2H),7.54(dd,J=8.5,2.3Hz,1H) ,7.51(d,J=8.6Hz,2H),7.23(dd,J=8.5,2.4Hz,1H),7.21–7.11(m,5H),6.78(dd,J=8.3,2.5Hz,1H),6.15(s,1H).

[0047] 13 C NMR(150MHz,DMSO)δ167.9,158.8(t,J CF=25.8Hz),138.5,136.0,134.2,133.8,132.3,132.2,131.5,131.2,131.2,129.3,128.8,122.4,121.6,115.7,111.4(t,J CF =314.9Hz),67.1.

[0048] 19 F NMR(471MHz,DMSO)δ-50.6–-56.2(m,2F).

[0049] Example 2

[0050]

[0051] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), p-methoxybenzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-2). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:5) to obtain a pure product. The yield was 85%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 2:

[0052] 1 H NMR(500MHz,DMSO)δ10.49(s,1H),7.81(dd,J=8.6,2.6Hz,1H),7.63–7.54(m,3H),7.53–7.48(m,2H),7.28(dd, J=8.5,2.4Hz,1H),7.12–7.01(m,2H),6.77(dd,J=8.4,2.6Hz,1H),6.76–6.70(m,2H),6.09(s,1H),3.65(s,3H).

[0053] 13 C NMR(125MHz,DMSO)δ168.2,159.8,158.7(t,J CF=25.8Hz),138.5,136.1,134.2,133.8,132.5,132.1,131.5,131.2,124.1,122.4,121.6,115.7,114.2,111.4(t,J CF =315.0Hz),66.5,55.6. 19 F NMR(471MHz,DMSO)δ-46.8–-57.8(m,2F).

[0054] Example 3

[0055]

[0056] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), p-chlorobenzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-3). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 67%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 3:

[0057] 1 H NMR (500MHz, DMSO) δ10.57(s,1H),7.80(dd,J=8.5,2.5Hz,1H),7.61–7.54(m,3H),7.51(d,J=8.8Hz,2H),7.32 (dd,J=8.5,2.4Hz,1H),7.27(d,J=8.3Hz,2H),7.19(d,J=8.3Hz,2H),6.84(dd,J=8.3,2.5Hz,1H),6.14(s,1H).

[0058] 13 C NMR(150MHz,DMSO)δ167.61,158.78(t,J CF=25.7Hz),138.35,135.89,134.23,134.07,133.78,133.03,132.17,131.69,131.42,131.39,128.84,122.63,121.67,115.86,111.34(t,J CF =314.1Hz),66.21.

[0059] 19 F NMR(471MHz,DMSO)δ-52.24–-54.87(m,2F).

[0060] Example 4

[0061]

[0062] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), 2-naphthaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-4). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 85%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 4:

[0063] 1 H NMR (500MHz, DMSO) δ10.59(s,1H),7.92(d,J=8.7Hz,1H),7.86–7.75(m,3H),7.70(d,J=8.6Hz,1H),7.61(d,J= 8.5Hz,2H),7.57–7.42(m,5H),7.23(d,J=8.5Hz,1H),7.17–7.05(m,1H),6.81(d,J=10.0Hz,1H),6.34(s,1H).

[0064] 13 C NMR(125MHz,DMSO)δ167.9,158.9(t,J CF=26.5Hz),138.5,136.0,134.1,133.9,132.9,132.7,132.2,132.1,131.5,131.2, 129.9,128.4,128.3,128.0,127.9,127.4,127.0,122.5,121.7,115.8,111.4(t,J CF =315.0Hz),67.2.

[0065] 19 F NMR(471MHz,DMSO-d6)δ-52.8–-53.8(m,2F).

[0066] Example 5

[0067]

[0068] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), 2-furancarboxaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-5). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 40%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 5:

[0069] 1 H NMR (500MHz, DMSO) δ10.61(s,1H),7.79(dd,J=8.6,2.6Hz,1H),7.59(dq,J=9.8,2.6Hz,3H),7.52( dt,J=6.8,2.5Hz,3H),7.40(dd,J=8.5,2.4Hz,1H),6.96(dd,J=8.7,2.6Hz,1H),6.33–6.21(m,3H).

[0070] 13 C NMR(125MHz,DMSO)δ165.2,158.7(t,J CF=26.5,2.6Hz),145.2,145.0,138.3,136.1,133.5,133.0,132.2,131.7,131.5,122.8,121.7,115.9,114.1,111.5,111.1(t,J CF =315.0Hz),61.3. 19 F NMR(471MHz,DMSO)δ-53.0–-54.5(m,2F).

[0071] Example 6

[0072]

[0073] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), cyclohexylcarboxaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-5). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 73%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 6: 1 H NMR (500MHz, DMSO-d6): δ10.56(s,1H),7.68(dd,J=8.6,2.4Hz,1H),7.61(dd,J=8.6 ,2.4Hz,1H),7.56–7.51(m,2H),7.51–7.47(m,2H),7.44(dd,J=8.8,2.5Hz,1H),7.3 4(dd,J=8.7,2.7Hz,1H),4.98(d,J=10.3Hz,1H),1.95(d,J=11.1Hz,1H),1.81–1.66 (m,2H),1.65–1.53(m,2H),1.49–1.36(m,1H),1.24–1.10(m,3H),1.10–1.01(m,2H).

[0074] 13 C NMR(125MHz,DMSO)δ166.8,159.3(t,J CF=25.8Hz),138.1,135.4,133.9,132.5,132.4,132.0,132.0,123.2,122.1,116.0,111.3(t,J CF =316.3Hz),67.0,37.1,30.0,29.7,26.2,25.8.

[0075] 19 F NMR(471MHz,DMSO)δ-52.3(s,2F).

[0076] Example 7

[0077]

[0078] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), ethyl glyoxylate (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-7). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:5) to obtain a pure product. The yield was 50%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 7:

[0079] 1 H NMR (500MHz, DMSO) δ10.67 (s, 1H), 7.65 (d, J = 32.6Hz, 2H), 7.58–7.41 (m, 4H), 7.40–7.31(m,2H),5.61(s,1H),4.20(q,J=7.0Hz,2H),1.21(t,J=7.1Hz,3H).

[0080] 13 C NMR(125MHz,DMSO)δ165.9,161.5,158.9(t,J CF =26.5Hz),137.5,136.6,132.5,132.4,132.3,123.6,121.8,116.5,110.9(t,J CF =313.1Hz),67.5,62.6,14.3.

[0081] 19F NMR(471MHz,DMSO)δ-53.8(s,2F).

[0082] Example 8

[0083]

[0084] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), p-isopropylaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), benzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-7). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 66%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 8:

[0085] 1 H NMR (500MHz, DMSO) δ10.25(s,1H),7.79(d,J=7.8Hz,1H),7.57–7.48(m,2H),7.21–7.15(m,3H),7.12(dtd,J=10.5,5.5,3.0Hz,5H),6.83(d,J=8 .4Hz,1H),6.62(d,J=8.2Hz,1H),6.11(s,1H),2.84(p,J=6.9Hz,1H),2.76(p,J=6.9Hz,1H),1.17(d,J=6.9Hz,6H),1.07(dd,J=7.0,1.7Hz,6H).

[0086] 13 C NMR(125MHz,DMSO)δ167.5,159.0(t,J CF =25.6Hz),149.2,144.1,137.0,134.3,133.0,131.6,131.5,131.1,128.8,128.4,127.0,126.1,125.8,119.6,111.7(t,J CF =317.5Hz),67.2,33.3,24.4,24.4,24.1,24.1.

[0087] 19F NMR(471MHz,DMSO-d6)δ-48.3–-56.3(m,2F).

[0088] Example 9

[0089]

[0090] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), m-methylaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), benzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-9). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 57%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 9:

[0091] 1 H NMR (500MHz, DMSO) δ10.28(s,1H),7.79–7.63(m,1H),7.53(s,1H),7.35(d,J=8.1Hz,1H),7.21–7.15(m,6.5H),6.97 (d,J=7.5Hz,1H),6.90–6.86(m,1.5H),6.65–6.49(m,1H),6.13(s,1H),2.29(s,3H),2.27(s,1.5H),1.98(s,1.5H).

[0092] 13 C NMR(150MHz,DMSO)δ167.7(167.7),158.9(t,J CF =25.7Hz),139.2,138.6,137.6(137.3),136.5,132.9(132.8),132.5(132.2),131.3(131.2) ,129.5,129.1,128.9,128.7,128.5(128.4),128.1(127.8),124.7,120.1,116.7,111.7(t,J CF =314.1Hz),67.3,21.6,21.3(20.8).

[0093] 19F NMR(471MHz,DMSO)δ-52.1–-53.6(m,2F).

[0094] Example 10

[0095]

[0096] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), m-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), benzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-10). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 70%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 10:

[0097] 1 H NMR(500MHz, CDCl3)δ8.15(d,J=7.7Hz,0.5H),7.95–7.68(m,2.5H),7.37(d,J=8.1Hz,1H),7.31–7.13(m,7.5H) ,7.08(q,J=7.6Hz,1H),6.88(t,J=8.1Hz,0.5H),6.76(s,0.5H),6.57(d,J=8.0Hz,0.5H),6.17(d,J=9.1Hz,1H).

[0098] 13 C NMR(150MHz,DMSO)δ168.2(168.0),158.8(t,J CF =25.7Hz)(158.7(t,J CF =25.7Hz)),140.7(140.6),138.0(137.9),135.1,134.4,132.2(132.1),132.1,131.4(131.4),131.2(131.2),130.8, 130.1(130.0),129.3,128.8(128.7),126.8(126.7),122.2,122.0(122.0),120.7(120.5),118.5(118.4),111.4(t,J CF=314.8Hz)(111.3(t,J CF =314.8Hz)),67.1.

[0099] 19 F NMR(471MHz,DMSO)δ-49.9–-56.3(m,2F).

[0100] Embodiment 11

[0101]

[0102] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), m-bromoaniline (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), benzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), and the reaction system was heated and stirred at 50°C under an argon atmosphere for 10 hours. The solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-11). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 65%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 11:

[0103] 1 H NMR(500MHz,CD3OD)δ11.46(d,J=21.1Hz,1H),9.45–9.18(m,1.6H),8.90–8.77(m,1H),8.68 (dt,J=21.6,7.3Hz,4H),8.62–8.58(m,0.5H),8.45(d,J=8.2Hz,0.5H),8.40(dd,J=8.8,2.1 Hz,1H),8.38–8.27(m,3.6H),8.24(q,J=7.4,6.0Hz,1.5H),8.13–8.01(m,2H),7.88(dd,J=8 .2,4.6Hz,2.5H),7.82(d,J=7.3Hz,0.5H),7.72(d,J=8.7Hz,0.5H),7.13(d,J=25.0Hz,1H);

[0104] 13 C NMR(125MHz,DMSO)δ168.2(168.1),159.2(t,J CF =25.8Hz)(159.2(t,J CF=25.8Hz)),136.8(136.8),134.3(134.0),133.9,132.8(132.6),132.6(132.5),132.3(132.2),131.4,131.2(131.0),130.4,129.4(1 29.1),129.0,128.7(128.5),128.6,128.3,128.0,127.9,127.9,127.6,127.5,127.0,126.9,125.3,120.2,115.9(115.9),111.6(t,J CF =315.0Hz)(111.54(t,J CF =315.0Hz)),67.8(67.2);

[0105] 19 F NMR(471MHz,DMSO-d6)δ-48.9–-58.3(m,2F).

[0106] Example 12

[0107]

[0108] Tetraacetonitrile copper hexafluorophosphate (0.02mmol, 10.0mol%), p-toluenesulfonic acid (0.04mmol, 20.0mol%), Prezista API (0.5mmol, 2.5equiv), potassium bromodifluoroacetate (0.6mmol, 3.0equiv), benzaldehyde (0.2mmol, 1.0equiv) were dissolved in acetonitrile (2.0mL), the reaction system was heated and stirred at 50°C under an argon atmosphere, reacted for 10 hours, and the solvent was removed under reduced pressure to obtain a crude product, the structure of which is shown in formula (4-10). The crude product was subjected to column chromatography (ethyl acetate: petroleum ether = 1:20 to 1:10) to obtain a pure product. The yield was 55%. Nuclear magnetic resonance 1 H NMR, 13 C NMR, 19 The F NMR spectrum is shown in Figure 12: 1H NMR(600MHz,CDCl3)δ8.63(s,1H),8.19(s,1H),7.87–7.58(m,5H),7.41(t,J=10.6Hz,1H),7.28(q,J=9.2Hz,4H),7.23–7.13(m,7H),7.08(dd,J=17.3,7.5Hz,2H),6.73(s,1H),6.26(d,J=8.3Hz,1H),5.63(dd,J=11.5,5.6Hz,2H),5.28(q,J=8.6,6.4Hz,2H),5.09–4.79(m,2H),4.03–3.79(m,8H),3.78–3.48(m,6H),3.09(d,J=13.2Hz,6H),2.93–2.65(m,8H),2.20–1.77(m,4H),1.62(h,J=10.9Hz,2H),1.44–1.28(m,2H),0.90(d,J=6.9Hz,6H),0.84(t,J=9.1Hz,6H).

[0109] 13 C NMR(150MHz,CDCl3):δ167.2(167.2),159.5(t,J CF =26.4Hz)(159.5(t,J CF =26.4Hz)),155.7(155.6),155.6(155.6),141.8,140.2(140.1),139.1,138.8,137.8,137.7,133.2(133.1),132.7,132.1,130.9,130.7,129.8,129.4(129.3),129.1(129.0),128.6(128.5),127.5,127.0,126.7(126.6),126.6,119.7(119.6),110.8(t,J CF =315.6Hz),109.4(109.3),73.5,73.5(73.4),72.7,72.7(72.6),71.1(71.0),70.9(70.9),69.7,69.6,67.6,58.6(58.5),58.1,57.8,55.4,53.5(53.5),53.0(52.8),45.6(45.5),35.8,35.7(35.4),29.3,27.2,27.1(27.1),26.9,25.9(25.8),25.9,20.1(20.1),20.0(19.9); 19F NMR (471MHz, CDCl3): δ-50.4–-55.3(m,2F).

[0110] Example 13

[0111]

[0112] The experimental method of this example is basically the same as that of Example 1. The aldehyde used in this example is p-methylbenzaldehyde, and the obtained product is shown in the structural formula (4-13). The yield is 80%.

[0113] Embodiment 14

[0114]

[0115] The experimental method of this example is basically the same as that of Example 1. The aldehyde used in this example is m-bromobenzaldehyde, and the obtained product is shown in the structural formula (4-14). The yield is 78%.

[0116] Embodiment 15

[0117]

[0118] The experimental method of this example is basically the same as that of Example 1. The aldehyde used in this example is m-methylbenzaldehyde, and the obtained product is shown in the structural formula (4-15). The yield is 70%.

[0119] Example 16

[0120]

[0121] The experimental method of this example is basically the same as that of Example 1. The aldehyde used in this example is 2-thiophenecarboxaldehyde, and the obtained product is shown in the structural formula (4-16). The yield is 42%.

[0122] Embodiment 17

[0123]

[0124] The experimental method of this example is basically the same as that of Example 1. The aldehyde used in this example is 4-tetrahydropyranaldehyde, and the obtained product is shown in the structural formula (4-17). The yield is 89%.

[0125] Embodiment 18

[0126]

[0127] The experimental method of this example is the same as that of Example 8. The aromatic amine used in this example is p-methylaniline, and the obtained product is shown in the structural formula (4-18). The yield is 70%.

[0128] Embodiment 19

[0129]

[0130] The experimental method of this example is the same as that of Example 8. The aromatic amine used in this example is p-tert-butylaniline, and the obtained product is shown in the structural formula (4-19). The yield is 68%.

[0131] Embodiment 20

[0132]

[0133] The experimental method of this example is the same as that of Example 8. The aromatic amine used in this example is p-methoxyaniline, and the obtained product is shown in the structural formula (4-20). The yield is 68%.

[0134] Embodiment 21

[0135]

[0136] The experimental method of this example is the same as that of Example 8. The aromatic amine used in this example is p-bromoaniline, and the obtained product is shown in the structural formula (4-21). The yield is 83%.

[0137] Embodiment 22

[0138]

[0139] The experimental method of this example is the same as that of Example 8. The aromatic amine used in this example is p-chloroaniline, and the obtained product is shown in the structural formula (4-22). The yield is 78%.

[0140] Embodiment 23

[0141]

[0142] The experimental method of this example is the same as that of Example 8. The aromatic amine used in this example is reduced-rate aniline, and the obtained product is shown in the structural formula (4-23). ​​The yield is 70%.

[0143] In Example 12, the marketed drug Prezista was used as a reaction substrate, and the α-aminoamide derivative modified with the double Prezista drug molecule was synthesized by the synthesis method of the present invention, which reflects the practical application value of the present invention.

[0144] As shown in the following reaction formula, the marketed drug Prezista is used as a substitute for aromatic amines in the present synthesis method to successfully obtain the reaction process of the α-aminoamide derivative modified with the double Prezista drug molecule.

[0145]

[0146] The present invention adopts cheap, readily available, non-toxic and harmless raw materials as reaction substrates, and synthesizes α-amino-modified amide derivatives in one step in a multi-component reaction mode, which is significantly different from the traditional Ugi reaction and Strecker reaction, increases the universality and economy of the target product, and has good social value.

Claims

1. An α-amino-substituted amide derivative, characterized in that: Its structural formula is: Wherein, X is bromine or chlorine; R is phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, naphthyl, furyl, thienyl, cyclohexyl, tetrahydropyranyl or C1-C4 alkyl-substituted ester group; Ar is phenyl, C1-C4 alkyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl or naphthyl.

2. The α-amino substituted amide derivative according to claim 1, characterized in that: The R is p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, m-bromophenyl, m-methoxyphenyl, 2-naphthyl, 2-furyl, 2-thienyl, tetrahydropyranyl or ethyl acetate; Ar is p-methylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-bromophenyl, p-chlorophenyl, m-methylphenyl, m-chlorophenyl, m-bromophenyl or 2-naphthyl.

3. A method for synthesizing the α-aminoamide derivative according to claim 1, characterized in that: Using halogenated difluoroacetate, aromatic aldehyde or alkyl aldehyde, aromatic amine as raw materials; Using a metal copper salt as a catalyst, a Bronsted acid as an additive, and an organic reagent as a solvent, a one-step reaction is performed to obtain the α-amino-substituted amide derivative. The reaction process is shown in reaction formula (I): （I）； Wherein, X is bromine or chlorine, and Y is potassium or sodium; R is phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, naphthyl, furyl, thienyl, cyclohexyl, tetrahydropyranyl or C1-C4 alkyl-substituted ester group; Ar is phenyl, C1-C4 alkyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl or naphthyl.

4. The method for synthesizing an α-aminoamide derivative according to claim 3, characterized in that: The R is p-methylphenyl, p-methoxyphenyl, p-chlorophenyl, m-bromophenyl, m-methoxyphenyl, 2-naphthyl, 2-furyl, 2-thienyl, tetrahydropyranyl or ethyl acetate; Ar is p-methylphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-bromophenyl, p-chlorophenyl, m-methylphenyl, m-chlorophenyl, m-bromophenyl or 2-naphthyl.

5. The method for synthesizing an α-aminoamide derivative according to claim 3 or 4, characterized in that: The specific steps of the synthesis reaction are: dissolving aromatic amine, halogenated difluoroacetate, aromatic aldehyde or alkyl aldehyde, metal copper salt and additives in an organic solvent, and then heating the mixed solution in air or argon atmosphere to react to obtain the multi-functional substituted α-aminoamide derivative.

6. The method for synthesizing an α-aminoamide derivative according to claim 5, characterized in that: The molar ratio of the raw materials is metal copper salt: additive: aromatic amine: halogenated difluoroacetate: aromatic aldehyde or alkyl aldehyde = (0.1-0.5): (0.2-1.0): (2.0-2.5): (2.0-3.0): (1.0).

7. The method for synthesizing an α-aminoamide derivative according to claim 5, characterized in that: The organic solvent is acetonitrile, the reaction temperature is 40° C.-80° C., and the reaction time is 8-12 hours.

8. The method for synthesizing an α-aminoamide derivative according to claim 3, 4, 6 or 7, characterized in that: The metal copper salt is any one of cuprous chloride, cuprous bromide, cuprous iodide and tetraacetonitrile copper hexafluorophosphate; the additive Bronsted acid is any one of p-toluenesulfonic acid, toluenesulfonic acid, adamantane acid and acetic acid or a mixture thereof.

9. The method for synthesizing an α-aminoamide derivative according to claim 3, 4, 6 or 7, characterized in that: The method further comprises the step of separation and purification: after the α-amino-substituted amide derivative is obtained by reaction, column chromatography is performed using a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:(20-5) to separate and purify the final product.

10. The method for synthesizing an α-aminoamide derivative according to claim 3, 4, 6 or 7, characterized in that: The aromatic amine is Prezista, a marketed drug of HIV-1 protease inhibitor.

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