Amide compound as well as preparation method and application thereof

Abstract

The invention discloses an amide compound as well as a preparation method and application thereof, and the preparation method comprises the following steps: in an organic solvent, reacting a carbamoyl zinc reagent with aromatic thianthrene onium salt under the action of a catalyst to obtain the amide compound, the structural general formula of the amide compound is # imgabs0 #, R1 and R2 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, and R3 is selected from aromatic groups. The amide compound is synthesized through the reaction of the carbamoyl zinc reagent and the aromatic thianthrene onium salt, the reaction condition is mild, dangerous reagents are not needed, raw materials are easy to obtain, the yield is high, and a safer and more efficient method is provided for synthesis of the amide compound and drug molecules.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to an amide compound and a preparation method and application thereof. Background Art

[0002] Amide bonds are important structural fragments in organic molecules. As the core chemical unit that constitutes proteins and peptides, they can be synthesized into a variety of chemical products and fine chemicals through chemical reactions. Their stability and structural modifiability make them a key bridge connecting active fragments in drug molecules, and therefore they occupy an irreplaceable position in the production of medicines, pesticides, and materials.

[0003] Currently, the synthesis of amide structural fragments generally involves inserting CO into copper amide or lithium amide, or by alkali metallizing various formamides with lithium at low temperatures. Both synthetic pathways are well-established, but existing amide synthesis methods generally suffer from harsh reaction conditions and rely primarily on reagents such as phosgene or its derivative, triphosgene. These reagents present significant safety risks: phosgene, triphosgene, and their alternative, carbon monoxide, are all highly toxic, posing a serious threat to experimental operations and environmental safety. Furthermore, they also suffer from limited functional group compatibility and low atom economy.

[0004] Therefore, it is of great significance to research and develop a synthetic route for amide compounds with readily available raw materials, mild reaction conditions and high yield. Summary of the Invention

[0005] The present invention addresses the deficiencies in the prior art and provides an amide compound and a preparation method and application thereof. The amide compound is synthesized by reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt. The reaction conditions are mild, no hazardous reagents are required, the raw materials are readily available, and the yield is high. This provides a safer and more efficient alternative method for the synthesis of amide compounds.

[0006] In order to solve the above technical problems, the first aspect of the present invention provides a method for preparing an amide compound, comprising the following steps: reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt in an organic solvent under the action of a catalyst to obtain the amide compound;

[0007] The general structural formula of the amide compound is:

[0008]

[0009] Among them, R 1 、R 2 R is independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, 3 Selected from aromatic groups.

[0010] The invention synthesizes amide compounds by reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt. The reaction conditions are mild, no hazardous reagents are required, the raw materials are readily available, and the yield is high, thereby providing a safer and more efficient method for synthesizing amide compounds.

[0011] Furthermore, the general structural formula of the carbamoyl zinc reagent is:

[0012]

[0013] Among them, R 1 、R 2 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl.

[0014] Furthermore, the carbamoyl zinc reagent is synthesized by reacting a formamide compound with zinc pivalate.

[0015] Furthermore, the general structural formula of the aromatic thianthrenium salt is:

[0016]

[0017] Furthermore, the aromatic thianthrenium salt is synthesized by reacting an aromatic compound, thianthren 5-oxide, diethyl tetrafluoroborate, and trifluoroacetic anhydride.

[0018] Furthermore, the preparation method of the aromatic thianthrenium salt comprises the following steps:

[0019] (1) adding an aromatic compound and thianthrene 5-oxide to an organic solvent under air atmosphere and reacting them at low temperature;

[0020] (2) slowly adding diethyl tetrafluoroborate dropwise to the reaction solution of step (1) and mixing for reaction;

[0021] (3) slowly adding trifluoroacetic anhydride dropwise to the reaction solution of step (2), heating to room temperature and continuing the reaction to obtain the aromatic thianthrenium salt.

[0022] Furthermore, the molar ratio of the aromatic compound, thianthrene 5-oxide, diethyl tetrafluoroborate, and trifluoroacetic anhydride is 1:(1-1.2):(1-1.5):(2-3).

[0023] Furthermore, the amide compound is one of the following compounds:

[0024]

[0025]

[0026] Furthermore, the molar ratio of the aromatic thianthrenium salt, the carbamoyl zinc reagent, and the catalyst is 1:(2-3):(0.05-0.1).

[0027] Furthermore, the reaction temperature is 25-50° C. and the reaction time is 10-12 h.

[0028] Furthermore, the catalyst is a palladium catalyst.

[0029] Furthermore, the organic solvent is one or more of tetrahydrofuran, dichloromethane, and dimethyl sulfoxide.

[0030] The second aspect of the present invention provides an amide compound prepared by the preparation method described in the first aspect.

[0031] The third aspect of the present invention provides the use of the amide compounds described in the second aspect in the synthesis of drug molecules.

[0032] Beneficial effects of the present invention:

[0033] The invention synthesizes amide compounds by reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt. The reaction conditions are mild, no hazardous reagents are required, the raw materials are readily available, and the yield is high. This provides a safer and more efficient method for the synthesis of amide compounds and drug molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the technical solution of the present invention, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0035] Figure 1 This is the reaction route of Example 1 of the present invention;

[0036] Figure 2 is the structural formula and yield of the amide compound prepared in Example 1 of the present invention;

[0037] Figure 3 These are the structural formulas and yields of the amide compounds and drug molecules prepared in Example 2 of the present invention. DETAILED DESCRIPTION

[0038] The following will provide a clear and complete description of the technical solutions of the present invention in conjunction with specific embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0039] This embodiment provides a method for preparing an amide compound, comprising the following steps: reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt in an organic solvent under the action of a palladium catalyst at 25-50° C. for 10-12 hours to obtain the amide compound; the general structural formula of the amide compound is: Among them, R 1 、R 2 R is independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, 3 This embodiment synthesizes amide compounds by reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt. The reaction conditions are mild, no hazardous reagents are required, the raw materials are readily available, and the yield is high, providing a safer and more efficient method for the synthesis of amide compounds.

[0040] Specifically, the general structural formula of the carbamoyl zinc reagent is: Among them, R 1 、R 2 The aminoformyl zinc reagent is independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl. As a preferred embodiment, the aminoformyl zinc reagent is synthesized by reacting a formamide compound with zinc pivalate.

[0041] Specifically, the general structural formula of the aromatic thianthrenium salt is:

[0042] As a preferred embodiment, the aromatic thianthrenium salt is synthesized by reacting an aromatic compound, thianthren 5-oxide, diethyl tetrafluoroborate, and trifluoroacetic anhydride. The molar ratio of the aromatic compound, thianthren 5-oxide, diethyl tetrafluoroborate, and trifluoroacetic anhydride is 1:(1-1.2):(1-1.5):(2-3). Specifically, the preparation method of the aromatic thianthrenium salt comprises the following steps:

[0043] (1) adding an aromatic compound and thianthrene 5-oxide to an organic solvent under air atmosphere and reacting them at low temperature;

[0044] (2) slowly adding diethyl tetrafluoroborate dropwise to the reaction solution of step (1) and mixing for reaction;

[0045] (3) slowly adding trifluoroacetic anhydride dropwise to the reaction solution of step (2), heating to room temperature and continuing the reaction to obtain the aromatic thianthrenium salt.

[0046] As a preferred embodiment, the amide compound is one of the following compounds:

[0047]

[0048]

[0049] As a preferred embodiment, the molar ratio of the aromatic thianthrenium salt, the carbamoyl zinc reagent, and the catalyst is 1:(2-3):(0.05-0.1).

[0050] As a preferred embodiment, the organic solvent is one or more of tetrahydrofuran, dichloromethane, and dimethyl sulfoxide.

[0051] Another embodiment provides an amide compound prepared by the preparation method described in the above embodiment.

[0052] Another embodiment provides the use of the amide compounds described in the above embodiments in the synthesis of drug molecules.

[0053] Example 1

[0054] This embodiment relates to a method for preparing an amide compound, comprising the following steps: adding a palladium catalyst (0.02 mmol), an aromatic thianthrenium salt, and a 25 mL dry reaction tube filled with N2. (0.2mmol) and tetrahydrofuran (1mL), and carbamoyl zinc reagent was added at 25℃ (0.4 mmol), react for 12 h to obtain the amide compound; the general structural formula of the amide compound is: Among them, R 1 、R 2 Independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, R3 is selected from aromatic groups, the synthesis route is as follows Figure 1 As shown. Different structures of reaction substrates aromatic thianthrenium salts and carbamoyl zinc reagents are used to synthesize amide compounds with different structures. Among them, the structural formulas and yields of the amide compounds are shown in FIG. Figure 2 shown.

[0055] Example 2

[0056] The difference between this embodiment and embodiment 1 is that: different reaction substrates, aromatic thianthrenium salts and carbamoyl zinc reagents are used to synthesize product amide compounds with different structures, and the products are applied to the synthesis of drug molecules (reaction parameters such as Figure 3 The structural formulas and yields of the amide compounds synthesized in this embodiment, as well as the structural formulas and yields of the drug molecules synthesized are shown in FIG. Figure 3 shown.

[0057] The NMR characterization data of each amide compound and each drug molecule synthesized in Example 1 and Example 2 are as follows:

[0058] (S)-(3-Fluoro-4-methoxyphenyl)[1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]methanone(a)

[0059] 1 H-NMR(400MHz,CDCl3):δ=7.32-7.15(m,10H),7.12-6.92(m,3H),3.90(s,3H),3.71(s,1H),3.47-3.31(m,1H),3.12-2.96(m,1H),2.79(d,J=16.5Hz,1H). 13 C-NMR(100MHz,CDCl3):δ=169.0,152.0(d,J C-F =248.1Hz),149.0(d,J C-F =10.6Hz),142.4,134.9,134.1,129.1,128.9(d,J C-F =5.7Hz),128.5,127.7,127.3,126.5,123.4,115.3(d,J C-F =18.9Hz),113.2(d,J C-F =2.0Hz),56.4,55.6,41.0,29.3. 19 F-NMR(376MHz,CDCl3):δ=-134.14.HR-MS(ESI)m / z calcd for C 23 H 20 FNO2[M+H + ]362.1551,found 362.1552.

[0060] (S)-(3-Chloro-4-methoxyphenyl)[1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]methanone(b)

[0061] 1 H-NMR(400MHz,CDCl3):δ=7.45(s,1H),7.35-7.18(m,9H),7.14-6.89(m,3H),3.91(s,3H),3.84-3.55(m,1H),3.48-3.35(m,1H),3.15-2.96(m,1H),2.79(d,J=16.2Hz,1H). 13C-NMR(100MHz,CDCl3):δ=168.9,156.1,142.5,134.9,134.1,129.4,129.1,128.5,127.7,127.3,126.8,126.5,122.7,111.8,56.3,55.5,41.0,29.3.HR-MS(ESI)m / z calcdfor C 23 H 20 ClNO2[M+H + ]378.1255,found378.1258.

[0062] (S)-2-Methoxy-5-(1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzonitrile(c)

[0063] 1 H-NMR(400MHz,CDCl3):δ=7.67-7.60(m,2H),7.33-7.20(m,8H),7.13-6.97(m,3H),3.96(s,3H),3.68(dd,J=45.8,32.1Hz,1H),3.50-3.36(m,1H),3.14-2.96(m,1H),2.86-2.77(m,1H). 13 C-NMR(100MHz,CDCl3):δ=168.1,162.1,134.7,133.4,132.6,129.1,129.1,128.8,128.7,128.6,128.3,127.8,127.4,126.6,115.7,111.5,102.1,56.5,55.0,41.2,29.0.HR-MS(ESI)m / z calcd forC 24 H 20 N2O2[M+H + ]369.1598,found 369.1596.

[0064] (S)-2-Fluoro-6-[4-(1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenoxy]benzonitrile(d)

[0065] 1H-NMR(400MHz,CDCl3):δ=7.52-7.43(m,3H),7.37-7.20(m,8H),7.17-7.00(m,4H),6.93(t,J=8.4Hz,1H),6.68(d,J=8.5Hz,1H),3.83-3.55(m,1H),3.48-3.37(m,1H),3.15-2.97(m,1H),2.82(d,J=16.3Hz,1H). 13 C-NMR(100MHz,CDCl3):δ=169.4,164.1(d,J C-F =260.1Hz),160.3(d,J C-F =3.7Hz),155.6,142.4,135.1(d,J C-F =10.2Hz),134.7,134.1,133.7,129.1,129.0,128.5,127.7,127.3,126.5,120.2,112.6(d,J C-F =2.8Hz),111.0,110.4(d,J C-F =19.5Hz),94.2(d,J C-F =18.1Hz),55.5,41.1,29.3. 19 F-NMR(376MHz,CDCl3):δ=-104.21.HR-MS(ESI)m / z calcd for C 29 H 21 FN2O2[M+H + ]449.1660,found449.1665.

[0066] (S)-2-Methoxy-5-(1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzaldehyde(e)

[0067] 1 H-NMR(400MHz,CDCl3):δ=10.46(s,1H),7.88(s,1H),7.67(d,J=8.5Hz,1H),7.32-7.19(m,8H),7.12-6.97(m,3H),3.97(s,3H),3.69(s,1H),3.46-3.33(m,1H),3.12-3.01(m,1H),2.79(d,J=16.4Hz,1H). 13C-NMR(100MHz,CDCl3):δ=189.1,169.2,162.6,142.3,135.1,134.8,134.1,129.1,128.8,128.5,127.7,127.3,127.0,126.5,124.3,112.1,56.0,55.6,41.1,29.3.HR-MS(ESI)m / zcalcd for C 24 H 21 NO3[M+H + ]372.1594,found372.1590.

[0068] N,N-Bis{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-formyl-4-methoxybenzamide(f)

[0069] 1 H-NMR(400MHz,CDCl3):δ=10.44(s,1H),7.89(d,J=2.2Hz,1H),7.68(dd,J=8.6,2.2Hz,1H),7.00(d,J=8.6Hz,1H),3.95(s,3H),3.91-3.83(m,2H),3.70-3.60(m,4H),3.56-3.48(m,2H),0.91-0.83(m,18H),0.09--0.02(m,12H). 13 C-NMR(100MHz,CDCl3):δ=189.0,171.0,162.3,135.3,129.5,127.7,124.3,111.8,61.4,60.9,56.0,52.6,48.3,26.0,18.4,-5.3.HR-MS(ESI)m / z calcd forC 25 H 45 NO5Si2[M+H + ]496.2909,found496.2911.

[0070] N-Benzyl-N-ethyl-3-formyl-4-methoxybenzamide(g)

[0071] 1H-NMR(400MHz,CDCl3):δ=10.44(s,1H),7.92(d,J=2.2Hz,1H),7.69(d,J=8.1Hz,1H),7.40-7.22(m,5H),7.02(s,1H),4.63(s,2H),3.95(s,3H),3.36(d,J=61.6Hz,2H),1.24-1.00(m,3H). 13 C-NMR(100MHz,CDCl3):δ=189.1,170.7,162.5,137.2,134.8,129.2,128.9,128.3,127.7,127.0,124.3,112.0,56.0.HR-MS(ESI)m / z calcd forC 18 H 19 NO3[M+H + ]298.1438,found 298.1437.

[0072] 2-Fluoro-6-[4-(piperidine-1-carbonyl)phenoxy]benzonitrile(h)

[0073] 1 H-NMR(400MHz,CDCl3):δ=7.49-7.41(m,3H),7.11(d,J=8.6Hz,2H),6.91(t,J=8.4Hz,1H),6.65(d,J=8.6Hz,1H),3.81-3.24(m,4H),1.73-1.46(m,6H). 13 C-NMR(100MHz,CDCl3):δ=169.4,164.1(d,J C-F =260.0Hz),160.4(d,J C-F =4.1Hz),155.4,135.1(d,J C-F =10.2Hz),133.8,129.2,120.2,112.5(d,J C-F =3.5Hz),111.0,110.3(d,J C-F =19.5Hz),94.1(d,J C-F =18.1Hz),49.0,43.4,26.6,25.7,24.6. 19 F-NMR(376MHz,CDCl3):δ=-104.37.HR-MS(ESI)m / z calcd forC 19 H 17 FN2O2[M+H+ ]325.1347,found 325.1343.

[0074] 2-{(1R,5S)-3-Azabicyclo[3.1.0]hexane-3-carbonyl}-9H-xanthen-9-one(i)

[0075] 1 H-NMR(400MHz,CDCl3):δ=8.38(s,1H),8.30(d,J=7.8Hz,1H),7.87(d,J=8.6Hz,1H),7.72(t,J=7.7Hz,1H),7.50(dd,J=12.3,5.5Hz,2H),7.38(t,J=6.4Hz,1H),4.18(d,J=12.0Hz,1H),3.74(d,J=9.7Hz,1H),3.51(d,J=10.2Hz,2H),1.53(d,J=25.8Hz,2H),0.69(dd,J=13.3,6.9Hz,1H),0.19(d,J=3.6Hz,1H). 13 C-NMR(100MHz,CDCl3):δ=176.8,169.1,156.8,156.1,135.3,134.3,132.8,126.8,125.6,124.4,121.8,121.1,118.6,118.2,51.8,48.3,16.1,14.5,8.7.HR-MS(ESI)m / z calcd for C 19 H 15 NO3[M+H + ]306.1125,found 306.1125.Methyl 1-[4-(azepane-1-carbonyl)phenyl]cyclopropane-1-carboxylate(j)

[0076] 1 H-NMR(400MHz,CDCl3):δ=7.32(q,J=8.1Hz,4H),3.68-3.63(m,2H),3.61(s,3H),3.39(t,J=5.4Hz,2H),1.87-1.78(m,2H),1.67-1.54(m,8H),1.17(dd,J=6.7,3.9Hz,2H). 13C-NMR(100MHz,CDCl3):δ=174.8,171.5,140.6,136.2,130.6,126.5,52.5,49.9,46.4,29.6,28.9,28.1,27.4,26.5,16.7.HR-MS(ESI)m / z calcd for C 18 H 23 NO3[M+H + ]302.1751,found 302.1750.

[0077] 1-{4-[4-(Pyrimidin-2-yl)piperazine-1-carbonyl]phenyl}ethan-1-one(k)

[0078] 1 H-NMR(400MHz,CDCl3):δ=8.32(d,J=4.7Hz,2H),8.01(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),6.54(t,J=4.6Hz,1H),4.01-3.72(m,6H),3.59-3.31(m,2H),2.62(s,3H). 13 C-NMR(100MHz,CDCl3):δ=197.4,169.6,161.6,157.9,140.1,138.1,128.7,127.4,110.8,47.5,44.1,43.7,42.2,26.8.HR-MS(ESI)m / z calcd for C 17 H 18 N4O2[M+H + ]311.1503,found 311.1500.

[0079] 4-Bromo-N,N,2,5-tetramethylbenzamide(l)

[0080] 1 H-NMR(400MHz,CDCl3):δ=7.38(s,1H),7.02(s,1H),3.10(s,3H),2.82(s,3H),2.34(s,3H),2.21(s,3H). 13 C-NMR(100MHz,CDCl3):δ=170.7,136.0,135.7,134.0,133.4,128.1,125.1,38.5,34.7,22.4,18.3.HR-MS(ESI)m / z calcd forC11 H 14 BrNO[M+H + ]256.0332,found 256.0332.

[0081] (4-Bromo-2,5-dimethylphenyl)[4-(pyrimidin-2-yl)piperazin-1-yl]methanone(m)

[0082] 1 H-NMR(400MHz,CDCl3):δ=8.32(d,J=4.7Hz,2H),7.42(s,1H),7.05(s,1H),6.54(t,J=4.7Hz,1H),3.97-3.72(m,6H),3.30(t,J=4.9Hz,2H),2.36(s,3H),2.26(s,3H). 13 C-NMR(100MHz,CDCl3):δ=169.5,161.7,157.9,135.9,135.3,134.2,133.6,128.1,125.5,110.8,46.7,44.3,43.8,41.6,22.5,18.4.HR-MS(ESI)m / z calcd for C 17 H 19 BrN4O[M+H + ]375.0815,found 375.0811.

[0083] (S)-{3'-Bromo-[1,1'-biphenyl]-4-yl}[1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]methanone(n)

[0084] 1 H-NMR(400MHz,CDCl3):δ=7.72(s,1H),7.57(d,J=8.0Hz,2H),7.49(t,J=6.7Hz,4H),7.37-7.17(m,9H),7.14-6.95(m,2H),3.94-3.56(m,1H),3.48-3.32(m,1H),3.16-2.97(m,1H),2.86-2.72(m,1H). 13C-NMR(100MHz,CDCl3):δ=170.0,142.6,142.4,141.0,135.9,134.8,134.2,130.8,130.5,130.3,129.1,128.5,127.7,127.3,126.5,125.9,123.1,55.4,41.0,29.4.HR-MS(ESI)m / zcalcd for C 28 H 22 BrNO[M+H + ]468.0958,found 468.0961.

[0085] {8-Bromodibenzo[b,d]furan-2-yl}[4-(pyrimidin-2-yl)piperazin-1-yl]methanone(o)

[0086] 1 H-NMR(400MHz,CDCl3):δ=8.32(d,J=4.7Hz,2H),8.06(d,J=0.8Hz,1H),7.77(dd,J=15.0,4.8Hz,2H),7.67-7.53(m,2H),7.49(dd,J=8.2,1.5Hz,1H),6.54(t,J=4.7Hz,1H),4.06-3.57(m,8H). 13 C-NMR(100MHz,CDCl3):δ=170.5,161.7,157.9,157.0,157.0,130.9,126.9,126.7,124.0,122.9,121.9,121.1,120.4,115.6,112.0,110.7,44.0.HR-MS(ESI)m / z calcd for C 21 H 17 BrN4O2[M+H + ]437.0608,found 437.0605.

[0087] (S)-3-Chloro-6-methyl-9-(1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)dibenzo[c,f][1,2]thiazepin-11(6H)-one 5,5-dioxide(p)

[0088] 1H-NMR(400MHz,CDCl3):δ=8.34(s,1H),7.94(d,J=1.9Hz,1H),7.84(d,J=8.3Hz,1H),7.76-7.65(m,2H),7.35-7.23(m,9H),7.15-7.04(m,2H),3.72(d,J=11.7Hz,1H),3.52-3.43(m,1H),3.39(s,3H),3.19-3.06(m,1H),2.84(d,J=16.5Hz,1H). 13 C-NMR(100MHz,CDCl3):δ=189.2,168.4,142.3,138.9,138.2,134.6,134.3,134.0,133.7,133.4,133.2,130.3,129.2,128.6,127.8,127.4,126.6,125.2,124.4,55.7,41.2,38.9,29.3.HR-MS(ESI)m / z calcd for C 30 H 23 ClN2O4S[M+H + ]543.1140,found 543.1146.

[0089] [(S)-1-Phenyl-3,4-dihydroisoquinolin-2(1H)-yl]{4-{4-[2-(pyridin-2-yloxy)propoxy]phenoxy}phenyl}methanone(q)

[0090] 1 H-NMR(400MHz,CDCl3):δ=8.14(dd,J=5.0,1.3Hz,1H),7.60-7.50(m,1H),7.38-7.05(m,12H),6.98-6.90(m,6H),6.87-6.81(m,1H),6.73(d,J=8.3Hz,1H),5.65-5.54(m,1H),4.19(dd,J=9.9,5.3Hz,1H),4.07(dd,J=9.9,4.8Hz,1H),3.91-3.58(m,1H),3.45-3.28(m,1H),3.13-2.92(m,1H),2.87-2.67(m,1H),1.48(d,J=6.4Hz,3H). 13C-NMR(100MHz,CDCl3):δ=170.0,163.2,159.9,155.8,149.4,146.9,142.6,138.8,135.0,134.2,130.2,129.1,128.7,128.4,127.6,127.2,126.4,121.3,117.1,116.9,116.0,111.7,71.1,69.3,55.4,41.0,29.3,17.1.HR-MS(ESI)m / z calcd for C 36 H 32 N2O4[M+H + ]557.2435,found557.2439.

[0091] 2,2,2-Trifluoro-N-methyl-N-{(S)-3-{2-methyl-4-[(S)-1-phenyl-1,2,3,4-tetrahydroisoq uinoline-2-carbonyl]phenoxy}-3-phenylpropyl}acetamide(r)

[0092] 1 H-NMR(400MHz,CDCl3):δ=7.34-7.17(m,14H),7.11-6.95(m,3H),6.54(dd,J=15.3,8.4Hz,1H),5.22(d,J=4.5Hz,1H),3.85-3.46(m,3H),3.39-3.23(m,1H),3.13-2.92(m,4H),2.79-2.66(m,1H),2.39-2.14(m,5H). 13 C-NMR(100MHz,CDCl3):δ=170.4,157.0(q,J C-F =36.0Hz),156.7,156.5,135.1,134.3,129.8,129.1,129.0,128.7,128.5,128.4,128.3,128.2,127.5,127.4,127.4,127.2,126.3,125.7,125.5,116.6(q,J C-F =288.9Hz),116.1(q,J C-F =288.6Hz),112.3,112.1,55.4,54.1,47.1,46.7,41.0,39.8,37.5,35.7,35.4(q,J C-F=3.9Hz),34.8,30.4,29.8,29.5,16.6,16.5. 19 F-NMR(376MHz,CDCl3):δ=-68.91,-69.82.HR-MS(ESI)m / z calcd for C 35 H 33 F3N2O3[M+H + ]587.2516,found587.2522.Methyl

[0093] 2-{11-oxo-4-[4-(pyrimidin-2-yl)piperazine-1-carbonyl]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetate(s)

[0094] 1 H-NMR(400MHz,CDCl3):δ=8.30(d,J=4.7Hz,1.40H),8.19(d,J=2.1Hz,0.61H),7.91(d,J=7.5Hz,0.95H),7.68(d,J=7.1Hz,0.58H),7.65(d,J=7.2Hz,0.60H),7.56(d,J=6.4Hz,0.61H),7.53(d,J=5.5Hz,0.65H),7.49(d,J=7.8Hz,1.19H),7.45(d,J=2.3Hz,1.17H),7.33(d,J=7.3Hz,0.87H),6.53(t,J=4.7Hz,0.96H),5.23(dd,J=31.8,13.0Hz,2.00H),4.05-3.53(m,11.02H),3.31(dd,J=10.6,6.5Hz,2.03H). 13 C-NMR(100MHz,CDCl3):δ=190.3,171.5,166.8,161.6,157.9,156.2,140.1,135.4,134.7,134.0,133.2,132.3,132.2,132.1,129.8,129.6,129.1,128.7,128.6,128.5,128.1,126.0,110.6,74.2,52.4,46.9,44.1,43.6,41.9,40.0.HR-MS(ESI)m / z calcd for C 26 H 24 N4O5[M+H +]473.1819,found473.1820.Methyl2-{2-fluoro-4'-[(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]-[1,1'-biphenyl]-4-yl}propanoate(t)

[0095] 1 H-NMR(400MHz,CDCl3):δ=7.57(d,J=7.7Hz,2H),7.47(d,J=7.5Hz,2H),7.42-7.00(m,13H),3.83-3.71(m,2H),3.70(s,3H),3.40(t,J=11.2Hz,1H),3.19-2.99(m,1H),2.89-2.72(m,1H),1.54(d,J=7.2Hz,3H). 13 C-NMR(100MHz,CDCl3):δ=174.4,170.1,159.8(d,J C-F =248.8Hz),142.6,142.5(d,J C-F =7.5Hz),136.9,135.6,134.8,134.2,130.8(d,J C-F =3.5Hz),129.2,129.1,128.5,127.7,127.2,127.0(d,J C-F =13.5Hz),126.8,126.5,123.8(d,J C-F =2.9Hz),115.5(d,J C-F =23.4Hz),55.3,52.3,45.0,41.0,29.4,18.5. 19 F-NMR(376MHz,CDCl3):δ=-117.33.HR-MS(ESI)m / z calcd for C 32 H 28 FNO3[M+H + ]494.2126,found 494.2121.

[0096] (S)-2-Chloro-N-{4'-chloro-5-(1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-[1,1'-biphenyl]-2-yl}nicotinamide(u)

[0097] 1 H-NMR(400MHz,CDCl3):δ=8.53-8.35(m,3H),8.13(d,J=7.3Hz,1H),7.49-7.39(m,3H),7.34-7.22(m,11H),7.07(d,J=25.0Hz,2H),3.88-3.65(m,1H),3.50-3.34(m,1H),3.13-2.99(m,1H),2.85-2.77(m,1H). 13 C-NMR(100MHz,CDCl3):δ=169.4,162.8,151.6,146.8,142.5,140.3,135.7,135.4,135.0,134.8,134.1,133.1,132.5,130.9,130.9,129.6,129.1,128.5,127.7,127.3,127.1,126.5,123.0,121.9,55.6,41.1,29.4.HR-MS(ESI)m / z calcd for C 34 H 25 Cl2N3O2[M+H + ]578.1397,found 578.1402.

[0098] (R)-4-{4-[(S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl]benzyl}-3-propionyloxazolidin-2-one(v)

[0099] 1 H-NMR(400MHz,CDCl3):δ=7.37(d,J=7.6Hz,2H),7.33-7.18(m,10H),7.14-6.93(m,2H),4.66(t,J=8.6Hz,1H),4.20(t,J=8.3Hz,1H),4.13(dd,J=12.0,4.8Hz,1H),3.63(d,J=8.2Hz,1H),3.41-3.29(m,2H),3.11-2.88(m,3H),2.79(dd,J=19.9,10.3Hz,2H),1.20(t,J=7.3Hz,3H). 13C-NMR(100MHz,CDCl3):δ=174.1,169.9,153.4,142.5,137.1,135.6,134.8,134.1,129.7,129.1,128.5,127.7,127.3,126.5,66.3,55.3,55.1,40.9,37.9,29.3,29.2,8.4.HR-MS(ESI)m / z calcd for C 29 H 28 N2O4[M+Na + ]491.1941,found491.1937.

[0100] (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(2-(acetoxymethyl)-4-(4-phenoxypiperidine-1-carbonyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate(w)

[0101] 1 H-NMR(400MHz,CDCl3):δ=7.44(s,1H),7.37(d,J=8.4Hz,1H),7.29(t,J=7.5Hz,2H),7.10(d,J=8.4Hz,1H),6.94(dd,J=19.6,7.6Hz,3H),5.36-5.25(m,2H),5.22-5.00(m,4H),4.59(s,1H),4.36-4.13(m,2H),4.02-3.33(m,5H),2.12-1.80(m,19H). 13 C-NMR(100MHz,CDCl3):δ=170.7,170.6,170.3,169.7,169.5,169.4,157.1,155.4,131.2,129.8,128.5,126.6,121.4,116.2,115.5,99.2,72.6,72.3,71.5,71.0,68.3,62.0,60.7,21.1,20.8,20.7.HR-MS(ESI)m / z calcd forC 35 H 41 NO 14 [M+Na + ]722.2419,found 700.2410.

[0102] Azocan-1-yl(3,4,5-trimethoxyphenyl)methanone(Trocimine,1)

[0103] 1 H-NMR(400MHz,CDCl3):δ=6.57(s,2H),3.85(s,6H),3.83(s,3H),3.60(t,J=5.9Hz,2H),3.34(s,2H),1.89-1.81(m,2H),1.64-1.58(m,8H). 13 C-NMR(100MHz,CDCl3):δ=171.1,153.4,138.6,133.1,103.8,61.0,56.3,51.3,46.8,27.0,26.6,26.5,25.7,24.2.HR-MS(ESI)m / z calcd for C 17 H 25 NO4[M+H + ]308.1856,found 308.1853.

[0104] Morpholino(3,4,5-trimethoxyphenyl)methanone(Trimetozine,2)

[0105] 1 H-NMR(400MHz,CDCl3):δ=6.61(s,2H),3.85(s,6H),3.83(s,3H),3.77-3.52(m,8H). 13 C-NMR(100MHz,CDCl3):δ=170.3,153.5,139.4,130.7,104.5,67.0,61.0,56.4.HR-MS(ESI)m / z calcd for C 14 H 19 NO5[M+H + ]282.1336,found282.1337.

[0106] {4'-(3-Chloropropoxy)-[1,1'-biphenyl]-4-yl}(morpholino)methanone(3)

[0107] 1H-NMR(400MHz,CDCl3):δ=7.58(d,J=8.2Hz,2H),7.52(d,J=8.7Hz,2H),7.46(d,J=8.2Hz,2H),6.99(d,J=8.7Hz,2H),4.16(t,J=5.8Hz,2H),3.84-3.43(m,10H),2.26(p,J=6.1Hz,2H). 13 C-NMR(100MHz,CDCl3):δ=170.5,158.8,142.5,133.5,132.9,128.3,127.9,126.8,115.0,67.0,64.5,41.6,32.3.HR-MS(ESI)m / z calcd for C 20 H 22 ClNO3[M+H + ]360.1361,found 360.1365.

[0108] (2-Chlorophenyl){6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl}methanone(4)

[0109] 1 H-NMR(400MHz,CDCl3):δ=7.43(dd,J=11.7,5.2Hz,2H),7.37-7.30(m,6H),7.17(d,J=5.1Hz,1H),7.11(d,J=5.1Hz,1H),6.87(d,J=5.1Hz,1H),6.62(d,J=5.2Hz,1H),4.98(d,J=16.8Hz,1H),4.77(d,J=16.8Hz,1H),4.39-4.27(m,2H),3.93(dt,J=12.7,6.2Hz,1H),3.64-3.46(m,3H),3.00(t,J=5.6Hz,2H),2.90(d,J=15.8Hz,1H),2.79(dd,J=14.0,7.6Hz,1H). 13C-NMR(100MHz,CDCl3):δ=167.8,167.6,136.2,136.1,134.0,132.4,131.8,131.2,130.6,130.5,130.4,129.9,129.8,128.0,127.8,127.4,125.3,124.5,123.8,123.7,46.9,44.8,42.6,40.1,25.7,24.9.HR-MS(ESI)m / z calcd for C 14 H 12 ClNOS[M+Na + ]300.0220,found300.0216.

[0110] 2-(2-Chlorophenyl)-2-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl}acetonitrile(5)

[0111] 1 H-NMR(400MHz,CDCl3):δ=7.75-7.66(m,1H),7.50-7.42(m,1H),7.42-7.33(m,2H),7.08(d,J=5.1Hz,1H),6.71(d,J=5.1Hz,1H),5.33(s,1H),3.80(d,J=13.8Hz,1H),3.66(d,J=13.7Hz,1H),3.03-2.81(m,4H). 13 C-NMR(100MHz,CDCl3):δ=134.8,133.1,132.6,131.0,130.7,130.7,130.2,127.0,125.2,123.3,115.4,59.4,49.6,47.9,25.7.HR-MS(ESI)m / z calcd for C 15 H 13 ClN2S[M+H + ]289.0561,found 289.0563.

[0112] 2-(2-Chlorophenyl)-2-{6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl}acetamide(6)

[0113] 1H-NMR(400MHz,DMSO-d6):δ=7.74(dd,J=7.5,1.5Hz,1H),7.66(s,1H),7.50-7.42(m,1H),7.39-7.22(m,4H),6.76(d,J=5.1Hz,1H),4.56(s,1H),3.51(q,J=14.4Hz,2H),2.86-2.67(m,4H). 13 C-NMR(100MHz,DMSO-d6):δ=172.4,135.9,134.6,134.6,133.8,131.3,130.3,130.2,128.1,126.5,124.0,69.8,51.3,49.3,26.0.HR-MS(ESI)m / z calcdfor C 15 H 15 ClN2OS[M+H + ]307.0666,found307.0664.

[0114] (4-Chlorophenyl)[4-(3-methylbenzyl)piperazin-1-yl]methanone(7)

[0115] 1 H-NMR(400MHz,CDCl3):δ=7.36(q,J=8.5Hz,4H),7.21(t,J=7.5Hz,1H),7.10(dd,J=14.3,6.3Hz,3H),3.85-3.59(m,2H),3.50(s,2H),3.48-3.30(m,2H),2.57-2.36(m,4H),2.34(s,3H). 13 C-NMR(100MHz,CDCl3):δ=169.3,138.1,137.4,135.8,134.3,130.0,128.8,128.7,128.3,128.2,126.3,63.0,53.3,52.8,47.9,42.4,21.5.HR-MS(ESI)m / zcalcd for C 19 H 21 ClN2O[M+H + ]329.1415,found329.1420.

[0116] 1-[(4-Chlorophenyl)(phenyl)methyl]-4-(3-methylbenzyl)piperazine(Mecilizine,8)

[0117] 1 H-NMR (400MHz, CDCl3): δ = 7.36-7.30 (m, 4H), 7.23 (dd, J = 15.7, 8.3Hz, 4H), 7.16 (t, J = 6 .5Hz,2H),7.11-7.01(m,3H),4.20(s,1H),3.46(s,2H),2.55-2.33(m,8H),2.31(s,3H). 13 C-NMR (100MHz, CDCl3): δ=142.4,141.6,138.0,137.9,132.6,130.1,129.4,128.7,128. 7,128.2,128.0,127.9,127.2,126.5,75.6,63.2,53.5,51.9,21.5.HR-MS(ESI)m / zcalcd for C 25 H 27 ClN2[M+H + ]391.1936,found391.1932.

[0118] In summary, the present invention synthesizes amide compounds by reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt. The reaction conditions are mild, no hazardous reagents are required, the raw materials are readily available, and the yield is high. This provides a safer and more efficient method for the synthesis of amide compounds and drug molecules.

[0119] The present invention has been described in detail above with reference to specific embodiments and exemplary examples. However, these descriptions should not be construed as limiting the present invention. Those skilled in the art will appreciate that various equivalent substitutions, modifications, or improvements may be made to the technical solutions and implementations of the present invention without departing from the spirit and scope of the present invention, all of which fall within the scope of the present invention. The scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for preparing an amide compound, characterized in that: The method comprises the following steps: reacting a carbamoyl zinc reagent with an aromatic thianthrenium salt in an organic solvent under the action of a catalyst to obtain the amide compound; The general structural formula of the amide compound is: Among them, R 1 、R 2 R is independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl, 3 Selected from aromatic groups.

2. The method for preparing an amide compound according to claim 1, wherein The general structural formula of the carbamoyl zinc reagent is: Among them, R 1 、R 2 are independently selected from chain alkyl, cyclic alkyl, substituted alkyl, aryl or benzyl.

3. The method for preparing an amide compound according to claim 1, wherein The general structural formula of the aromatic thianthrenium salt is:

4. The method for preparing an amide compound according to claim 1, wherein The amide compound is selected from one of the following compounds:

5. The method for preparing an amide compound according to claim 1, wherein The molar ratio of the aromatic thianthrenium salt, the carbamoyl zinc reagent and the catalyst is 1:(2-3):(0.05-0.1).

6. The method for preparing an amide compound according to claim 1, wherein The reaction temperature is 25-50° C. and the reaction time is 10-12 h.

7. The method for preparing an amide compound according to claim 1, wherein The catalyst is a palladium catalyst.

8. The method for preparing an amide compound according to claim 1, wherein The organic solvent is one or more of tetrahydrofuran, dichloromethane and dimethyl sulfoxide.

9. An amide compound prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the amide compound according to claim 9 in the synthesis of drug molecules.

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