N, N-dimethyl amide compound and synthesis method thereof

Abstract

According to the method, carboxylic acid compounds and DMF are used as reaction raw materials, 0.5-1.5 equivalent weight of triphenyl phosphite, 0-1.0 equivalent weight of lithium chloride and p-xylene are used as solvents, the solvents are heated to 160 DEG C in a nitrogen atmosphere, effective reaction is carried out for 24-48 h, and the amide compounds are obtained at a high yield. The method does not need to add a metal catalyst, an oxidizing agent, strong base and the like, has the advantages of high yield, simplicity and convenience in operation, few additives, low cost, no pollution and the like, and has certain feasibility for realizing industrial production.

Description

[Technical field]

[0001] The invention belongs to the field of organic synthesis mediated by organophosphorus, and specifically relates to an N,N-dimethylamide compound and a synthesis method thereof. [Background technology]

[0002] Compounds containing formamide structures are widely present in industry, agriculture and medicine. For example, N,N-dimethylformamide can be used as a polar aprotic solvent with a high boiling point to dissolve a variety of organic and inorganic substances, such as polyurethane, polyacrylonitrile, polyvinyl chloride, etc.; N,N-dimethylacetamide can be used as a solvent with a high flash point and high thermal stability to dissolve polyacrylonitrile spinning, synthetic resins and natural resins; N,N-dimethylpropionamide can be used as a solvent for the synthesis of polyimide, polysulfoneamide and other polymer compounds, and can also be used as an adhesive for coatings, and can also be used as a reaction medium in the production of fibers and films; N,N-dimethyl aromatic amine compounds are also a very important class of biologically active organic molecules, which are widely present in marketed drugs (DR Sneada and TF Jamison, Chem. Sci., 2013, 4, 2822-2827). Therefore, how to simply and efficiently synthesize N,N-dimethylamide compounds has always been one of the hot topics for organic chemists.

[0003] Carboxylic acid compounds are a class of bulk chemicals widely found in natural products and drug molecules. Due to their richness, diversity, stability and other advantages, they are widely used in the field of organic synthesis and are also one of the most ideal starting materials for organic synthesis. However, due to the low reactivity of direct transamination of carboxylic acid with N,N-dimethylformamide, many methods have been developed to increase its reactivity and yield, such as by adding [Cu], [Ru], TBHP, DTBP, K2S2O8, SOCl2, SO3·py, P2O5, POCl3, T3P, KO t Bu and acid anhydride are used to improve the reactivity of the reaction (Y. Huang, J. Zhang. Synthesis 2022, 54, 3595-3604), but these reaction conditions are relatively harsh and require the use of metal catalysts, oxidants or strong bases, which are not environmentally friendly.

[0004] Therefore, we have developed a method for generating N,N-dimethylamide compounds by transamination reaction of carboxylic acid and N,N-dimethylformamide (DMF) mediated by phosphite, which does not require special equipment, nor does it require the addition of metal catalysts, oxidants and strong bases, etc. It is simple to operate, has few additives, high yield, wide application range, and has certain industrial application value. At present, there are no public documents and patents on the synthesis of amide compounds from carboxylic acid and N,N-dimethylformamide mediated by phosphite at home and abroad. [Summary of the invention]

[0005] The purpose of the present invention is to provide a method for efficiently synthesizing N,N-dimethylamide compounds by using phosphite as an activator and carboxylic acid compounds and N,N-dimethylformamide as raw materials. The method does not require the addition of metal catalysts, oxidants and strong bases, has the advantages of simple operation and high yield, and has certain feasibility for realizing its industrial production.

[0006] In order to achieve the above-mentioned object of the invention, the present invention proposes the following technical solutions:

[0007] An N,N-dimethylamide compound and a synthesis method thereof, wherein the general structural formula of the N,N-dimethylamide compound I is as follows:

[0008]

[0009] Wherein R includes but is not limited to phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 3,4,5-trimethoxyphenyl, 4-aminophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-thiophene, 2-naphthyl, 1-naphthyl, benzyl, and p-methylphenylene.

[0010] The structural formulas of the raw materials carboxylic acid ⅠⅠ and N,N-dimethylformamide Ⅲ are as follows:

[0011]

[0012] The synthesis method of compound I is characterized in that a carboxylic acid compound and N,N-dimethylformamide are used as raw materials, 0.5 to 1.5 equivalents of triphenyl phosphite are used as an activator, 0 to 1.0 equivalents of lithium chloride, and p-xylene is used as a solvent. The reaction is carried out at 160° C. in a nitrogen environment for 24 to 48 hours to obtain N,N-dimethylamide compound I in high yield.

[0013] The raw material carboxylic acid II includes but is not limited to benzoic acid, 2-methylbenzoic acid, 4-tert-butylbenzoic acid, 4-cyclohexylbenzoic acid, 4-phenoxybenzoic acid, 2'-tert-butyl-4-phenylbenzoic acid, 4-trifluoromethyl-4-phenylbenzoic acid, 3-trifluoromethylbenzoic acid, 4-carboxylic acid benzophenone, 4-nitrobenzoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid, 4-fluorobenzoic acid, 4-chlorobenzoic acid, 4-bromobenzoic acid, 4 -Iodobenzoic acid, 2-phenylaminobenzoic acid, 2-diphenylphosphinobenzoic acid, 3,4,5-trimethoxybenzoic acid, piperic acid, 1-naphthoic acid, 2-naphthoic acid, 5-methoxyindole 2-carboxylic acid, benzothiophene 3-carboxylic acid, thiophene 2-carboxylic acid, 4-methylcinnamic acid, phenylacetic acid, 9-fluorene acid, α-phenylcinnamic acid, phenylbutyric acid, diphenylacetic acid, 3-methyl-8-carboxychromone, ibuprofen, ketoprofen, indomethacin, febuxostat.

[0014] Preferably, the phosphorus activator may be: triaryl phosphite, trialkyl phosphite, diaryl phosphite, dialkyl phosphite.

[0015] Preferably, the salt can be lithium chloride, sodium chloride, potassium chloride, cesium chloride, ammonium chloride, magnesium chloride, copper chloride, aluminum chloride, lithium bromide, potassium bromide, sodium bromide, sodium iodide, potassium iodide, sodium fluoride, potassium fluoride, sodium bisulfite, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, lithium carbonate, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium acetate, lithium acetate, sodium acetate, ammonium sulfate, sodium sulfate, potassium sulfate, potassium thiosulfate, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, sodium ethoxide, etc.

[0016] Preferably, the organic solvent may be: p-xylene, 1,4-dioxane, tetrahydrofuran, toluene, cyclohexane, n-hexane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide.

[0017] The synthesis method of a class of N,N-dimethylamide compounds provided by the present invention is a class of green and efficient synthesis route, which has the advantages of: no need to add metal catalysts, oxidants and strong bases, high yield of target products, simple reaction operation, and green and pollution-free.

Brief Description of the Drawings

[0018] Attached photos Figure 1 Shown is a route diagram for preparing N,N-dimethylamide compounds provided by the present invention. [Specific implementation method]

[0019] The present invention provides a method for synthesizing N,N-dimethylamide compounds, see the attached drawings Figure 1: Using carboxylic acid compounds and N,N-dimethylformamide as raw materials, 1.5 equivalents of triphenyl phosphite as an activator, 1.0 equivalents of lithium chloride, and p-xylene as a solvent, the effective reaction is carried out at 160°C under a nitrogen environment for 24 hours. After the reaction is completed, the corresponding target product is separated and purified by column chromatography.

[0020] The present invention is further described below in conjunction with some specific preparation examples:

[0021] Preparation Example 1

[0022] 0.2 mmol of benzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 91%. 1 HNMR (400MHz, CDCl3): δ7.41-7.37(m,5H),3.03(s,6H). 13 C NMR (100MHz, CDCl3): δ171.6,136.2,129.5,128.3,127.0,35.4.

[0023] Preparation Example 2

[0024] 0.2 mmol of 4-methylbenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 75%. 1 H NMR (400MHz, CDCl3): δ7.32-7.30(m,2H),7.19-7.17(m,2H),3.03(s,6H),2.36(s,3H). 13 C NMR (100MHz, CDCl3): δ171.8,139.6,133.2,128.9,127.1,37.7,21.3.

[0025] Preparation Example 3

[0026] 0.2 mmol of 4-tert-butylbenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 80%. 1H NMR (400MHz, CDCl3): δ7.38 (dd, J=20.8, 8.4Hz, 4H) 7.41-7.34 (m, 4H), 3.05 (s, 6H), 1.31 (s, 9H). 13 C NMR (100MHz, CDCl3): δ171.8,152.7,133.2,126.9,125.2,34.7,31.2.

[0027] Preparation Example 4

[0028] 0.2 mmol of 4-cyclohexylbenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 75%. 1 H NMR (400MHz, CDCl3): δ7.35-7.33(m,2H),7.21(d,J=8.0Hz,2H),3.05(s,6H),2.51(t,J=10.0Hz,1H ),1.87-1.82(m,4H),1.75(d,J=12.4Hz,1H),1.43-1.37(m,4H),1.26(ddd,J=15.8,8.0,3.2Hz,1H). 13 CNMR (100MHz, CDCl3): δ171.8,149.6,133.7,127.2,126.7,44.5,34.3,26.8,26.1.

[0029] Preparation Example 5

[0030] 0.2 mmol of 4-phenylbenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 76%. 1 H NMR (400MHz, CDCl3): δ7.63-7.58(m,4H),7.50-7.48(d,J=8.0Hz,2H),7.46-7.43(m,2H),7.38-7.34(m,1H),3.08(s,6H). 13 CNMR (100MHz, CDCl3): δ171.4,142.3,140.2,134.9,128.8,127.6,127.5,127.0,126.9,39.4,35.4.

[0031] Preparation Example 6

[0032] 0.2 mmol of 4-phenoxybenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 76%. 1 H NMR (400MHz, CDCl3): δ7.43-7.39(m,2H),7.38-7.34(m,2H),7.16-7.12(m, 1H),7.03(dd,J=8.8,1.2Hz,2H),7.01-6.97(m,2H),3.06(d,J=25.2Hz,6H). 13 C NMR (100MHz, CDCl3): δ171.2,158.6,156.3,130.7,129.9,129.1,123.9,119.5,117.9,39.7,35.5.

[0033] Preparation Example 7

[0034] 0.2 mmol of 2'-tert-butyl-4-phenylbenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 85%. 1 H NMR (400MHz, CDCl3): δ7.45-7.34(m,8H),2.85(s,3H),2.39(s,3H),1.34(s,9H). 13 C NMR (100MHz, CDCl3): δ171.2,158.6,156.3,130.7,129.9,129.1,123.9,119.5,117.9,39.7,35.5.

[0035] Preparation Example 8

[0036] 0.2 mmol of 4'-trifluoromethyl-4-phenylbenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 80%. 1H NMR (400MHz, CDCl3): δ7.65 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.0Hz, 2H), 7.49-7.38 (m, 4H), 2.86 (s, 3H), 2.45 (s, 3H). 13 C NMR (100MHz, CDCl3): δ170.8, 143.5, 137.1, 135.8, 129.4 (d, J = 5.6Hz), 128.8, 128.5, 127.4, 125.3 (d, J = 3.6Hz), 38.0, 34.5.

[0037] Preparation Example 9

[0038] 0.2 mmol of 3-trifluoromethylbenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 88%. 1 H NMR (400MHz, CDCl3): δ7.67-7.64(m,2H),7.60-7.58(m,1H),7.54-7.50(m,1H),3.03(d,J=52.4Hz,6H). 13 C NMR (100MHz, CDCl3): δ169.9, 137.0, 130.8 (d, J = 32.5Hz), 130.3, 128.9, 126.2 (q, J = 3.2Hz), 124.0 (q, J = 3.7Hz), 123.6 (q, J = 270.8Hz), 39.4, 35.3.

[0039] Preparation Example 10

[0040] 0.2 mmol of 4-carboxylic acid benzophenone, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160° C. for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 50%. 1 H NMR (400MHz, CDCl3): δ7.84-7.79(m,4H),7.63-7.59(m,1H),7.54-7.48(m,4H),3.08(d,J=23.2Hz,6H). 13C NMR (100MHz, CDCl3): δ196.1,170.6,140.1,139.4,138.4,137.1,132.8,130.1,128.4,126.9,39.4,35.3.

[0041] Preparation Example 11

[0042] 0.2 mmol of 4-nitrobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 52%. 1 H NMR (400MHz, CDCl3): δ8.25 (d, J = 8.4Hz, 2H), 7.57 (d, J = 8.8Hz, 2H), 3.12 (s, 3H), 2.94 (s, 3H). 13 C NMR (100MHz, CDCl3): δ169.2,148.2,142.4,128.0,123.7,39.2,35.3.

[0043] Preparation Example 12

[0044] 0.2 mmol of 2-fluorobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 74%. 1 H NMR (400MHz, CDCl3): δ7.41-7.36(m,2H),7.20(t,J=7.6Hz,1H),7.09(t,J=9.2Hz,1H),3.13(s,3H),2.93(s,3H). 13 C NMR (100MHz, CDCl3): δ166.8, 159.4, 156.9, 131.1 (d, J = 7.9Hz), 129.1 (d, J = 3.7Hz), 124.6 (d, J = 3.5Hz), 115.8, 115.60, 38.3, 35.0.

[0045] Preparation Example 13

[0046] 0.2 mmol of 3-fluorobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 74%. 1 H NMR (400MHz, CDCl3): δ7.41-7.34(m,1H),7.20-7.07(m,3H),3.02(d,J=52.8Hz,6H). 13 C NMR (100MHz, CDCl3): δ170.1(d,J=1.8Hz),163.6,161.1,138.3(d,J=6.7Hz),1 30.1(d,J=8.0Hz),122.7(d,J=3.1Hz),116.6,116.4,114.4,114.1,39.4,35.3.

[0047] Preparation Example 14

[0048] 0.2 mmol of 4-fluorobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 83%. 1 H NMR (400MHz, CDCl3): δ7.43-7.40(m,2H),7.09-7.04(m,2H),3.03(s,6H). 13 C NMR (100MHz, CDCl3): δ170.6, 164.4, 161.9-132.2 (m), 129.3 (d, J = 8.4Hz), 115.3 (d, J = 21.7Hz), 39.6, 35.4.

[0049] Preparation Example 15

[0050] 0.2 mmol of 4-chlorobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 82%. 1 H NMR (400MHz, CDCl3): δ7.34-7.30 (m, 4H), 3.01-2.95 (d, J = 26.0Hz, 6H). 13C NMR (100MHz, CDCl3): δ170.3, 135.3, 134.4, 128.4 (d, J = 27.0Hz), 39.3, 35.2.

[0051] Preparation Example 16

[0052] 0.2 mmol of 4-bromobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 78%. 1 H NMR (400MHz, CDCl3): δ7.63 (d, J = 8.4Hz, 2H), 7.40-7.37 (m, 2H), 3.12 (d, J = 28.0Hz, 6H). 13 C NMR (100MHz, CDCl3): δ170.5,135.0,131.5,128.7,123.7,39.5,35.3.

[0053] Preparation Example 17

[0054] 0.2 mmol of 4-iodobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 79%. 1 H NMR (400MHz, CDCl3): δ7.73 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 3.02 (d, J = 17.6 Hz, 6H). 13 C NMR (100MHz, CDCl3): δ170.6,137.4,135.6,128.8,95.6,39.5,35.3.

[0055] Preparation Example 18

[0056] 0.2 mmol of 2-phenylaminobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 79%. 1H NMR (400MHz, CDCl3): δ7.31(m,J=8.4Hz,2H),7.21-7.10(m,4H),7.04-7.02(m,2H),6.88-6.84(m,1H),6.80-6.76(m,1H),3.00(s,6H). 13 C NMR (100MHz, CDCl3): δ170.9,142.1,142.0,130.2,129.2,128.2,123.4,121.3,119.3,118.7,116.8,39.7,35.0.

[0057] Preparation Example 19

[0058] 0.2 mmol of 2'-diphenylphosphinobenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 44%. 1 H NMR (400MHz, CDCl3): δ7.23(dd,J=7.6,1.2Hz,1H),7.20-7.18(m,10H),7.16-7.14(m,2H),7.01(dd,J=7.6,3.8Hz,1H),2.89(s,3H),2.50(s,3H). 13 C NMR (100MHz, CDCl3): δ170.8, 143.1 (d, J = 33.2Hz), 136.4 (d, J = 10.8Hz), 134.7 (d, J = 16.3Hz), 134.2, 133.8 (d, J = 20.0Hz), 132.4 (d, J=10.3Hz), 131.9, 129.1, 128.7 (d, J=8.1Hz), 128.4 (d, J=6.9Hz), 128.1 (d, J=12.5Hz), 126.2 (d, J=7.4Hz), 38.7 (d, J=2.7Hz), 34.5.

[0059] Preparation Example 20

[0060] 0.2 mmol of 3,4,5-trimethoxybenzoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 79%. 1H NMR (400MHz, CDCl3): δ6.58(s,2H),3.81(s,6H),3.79(s,6H),3.00(s,6H). 13 C NMR (100MHz, CDCl3): δ171.1,152.9,138.7,131.5,104.1,60.6,56.0,39.4,35.1.

[0061] Preparation Example 21

[0062] 0.2 mmol of piperic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 34%. 1 HNMR (400MHz, CDCl3): δ6.93-6.89 (m, 2H), 6.79 (d, J = 8.0Hz, 1H), 5.97 (s, 2H), 3.02 (s, 6H). 13 C NMR (100MHz, CDCl3): δ171.1,148.6,147.5,129.9,121.6,108.1,101.4,39.8,35.6.

[0063] Preparation Example 22

[0064] 0.2 mmol of 1-naphthoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 66%. 1 HNMR (400MHz, CDCl3): δ7.86-7.84(m,2H),7.79-7.77(m,1H),7.53-7.45(m,3H),7.41(d,J=6.8Hz,1H),3.24(s,3H),2.79(s,3H). 13 CNMR (100MHz, CDCl3): δ170.8,134.5,133.3,129.3,128.9,128.3,126.8,126.2,125.0,124.7,123.7,38.7,34.7.

[0065] Preparation Example 23

[0066] 0.2 mmol of 2-naphthoic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 80%. 1 HNMR (400MHz, CDCl3): δ7.90 (s, 1H), 7.86-7.83 (m, 3H), 7.52-7.49 (m, 3H), 3.07 (d, J = 56.8Hz, 6H). 13 C NMR (100MHz, CDCl3): δ170.8,134.5,133.3,129.3,128.9,128.3,126.8,126.2,125.0,124.7,123.7,38.7,34.7.

[0067] Preparation Example 24

[0068] 0.2 mmol of 8-methoxyindole 2-carboxylic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 41%. 1 H NMR (400MHz, CDCl3): δ9.51(s,1H),7.34(d,J=8.8Hz,1H),7.07(d,J=2.4Hz,1H ), 6.96 (dd, J = 9.2, 2.4Hz, 1H), 6.78 (d, J = 1.2Hz, 1H), 3.85 (s, 3H), 3.32 (s, 6H). 13 C NMR (100MHz, CDCl3): δ163.1,154.4,130.8,130.1,128.1,115.7,112.6,105.5,102.3,55.7,38.1.

[0069] Preparation Example 25

[0070] 0.2 mmol of benzothiophene 3-carboxylic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 60%. 1H NMR (400MHz, CDCl3): δ7.87(dd,J=7.2,1.6Hz,1H),7.82(dd,J=7.8,1.2Hz,1H),7.55(s,1H),7.43-7.35(m,2H),3.09(d,J=31.6Hz,6H). 13 C NMR (100MHz, CDCl3): δ166.7,139.7,136.9,132.0,126.5,124.9,124.8,123.2,122.5,39.1,35.2.

[0071] Preparation Example 25

[0072] 0.2 mmol of thiophene 2-carboxylic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 30%. 1 H NMR (400MHz, CDCl3): δ7.44 (d, J = 4.8Hz, 1H), 7.35 (d, J = 3.6Hz, 1H), 7.05-7.02 (m, 1H), 3.18 (s, 6H). 13 C NMR (100MHz, CDCl3): δ164.4,137.9,129.1,128.7,126.6,38.1.

[0073] Preparation Example 26

[0074] 0.2 mmol of 4-methylcinnamic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 63%. 1 H NMR (400MHz, CDCl3): δ7.66 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 15.6 Hz, 1H), 3.12 (s, 6H), 2.36 (s, 3H). 13 CNMR (100MHz, CDCl3): δ166.9,142.3,139.8,132.6,129.5,127.7,116.3,37.4,35.9,21.4.

[0075] Preparation Example 26

[0076] 0.2 mmol of α-phenylcinnamic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 75%. 1 H NMR (400MHz, CDCl3): δ7.27-7.23(m,2H),7.22-7.19(m,3H),7.10-7.08(m,3H),7.06-7.03(m,2H),6.64(s,1H),2.94(d,J=4.4Hz,6H). 13 CNMR (100MHz, CDCl3): δ171.5,137.8,135.4,135.3,129.9,128.8,128.6,128.1,127.9,127.7,38.6,35.0.

[0077] Preparation Example 26

[0078] 0.2 mmol of 2-carboxylic acid flavonoid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 40%. 1 H NMR (400MHz, CDCl3): δ8.12 (d, J = 8.0Hz, 1H), 7.66-7.63 (m, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.40-7.36 (m, 1H), 6.47 (d, J = 1.6Hz, 1H), 3.08-3.07 (m, 6H). 13 C NMR (100MHz, CDCl3): δ171.4,162.2,158.1,155.6,134.3,125.7,125.6,124.1,118.1,111.5,38.2,35.4.

[0079] Preparation Example 27

[0080] 0.2 mmol of phenylacetic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 65%. 1HNMR (400MHz, CDCl3): δ7.26-7.14(m,5H),3.64(s,2H),2.91(s,3H),2.89(s,3H). 13 C NMR (100MHz, CDCl3): δ171.0,134.9,128.6,128.5,126.6,40.9,37.6,35.5.

[0081] Preparation Example 28

[0082] 0.2 mmol of phenylbutyric acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 30%. 1 HNMR (400MHz, CDCl3): δ7.22-7.18(m,2H),7.13-7.09(m,3H),2.86(s,6H),2.62-2.59(m,2H),2.24(t,J=6.4Hz,2H),1.94-1.87(m,2H). 13 C NMR (100MHz, CDCl3): δ172.8,141.7,128.4,128.3,125.8,37.2,35.3,35.2,32.4,26.5.

[0083] Preparation Example 29

[0084] 0.2 mmol of diphenylacetic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 54%. 1 H NMR (400MHz, CDCl3): δ7.25-7.22(m,4H),7.18-7.14(m,6H),5.15(s,1H),2.94(d,J=4.0Hz,6H). 13 C NMR (100MHz, CDCl3): δ171.7,139.5,129.0,128.5,126.9,54.8,37.6,36.1.

[0085] Preparation Example 30

[0086] 0.2 mmol of 9-fluorene acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 62%. 1 HNMR (400MHz, CDCl3): δ7.80(s,1H),7.78(s,1H),7.55(s,1H),7.53(s,1H),7. 43(t,J=7.2Hz,2H),7.36-7.32(m,2H),5.12(s,1H),2.97(s,3H),2.34(s,3H). 13 CNMR (100MHz, CDCl3): δ170.8,142.2,140.9,127.8,127.6,124.4,120.4,36.7.

[0087] Preparation Example 31

[0088] 0.2 mmol of 8-methylchromone 2-carboxylic acid, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 80%. 1 H NMR (400MHz, CDCl3): δ8.28 (dd, J=8.0, 1.2Hz, 1H), 7.65-7.61 (m, 3H), 7.51 -7.49(m,3H),7.43(t,J=7.6Hz,1H),3.12(s,3H),2.85(s,3H),2.19(s,3H). 13 C NMR (100MHz, CDCl3): δ178.4,166.9,160.6,151.7,133.0,131.7,130.4,129.9,128.5,126.9,124.8,122.5,117.7,38.5,34.9,11.8.

[0089] Preparation Example 32

[0090] 0.2 mmol of Febuxostat, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160° C. for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 76%. 1HNMR (400MHz, CDCl3): δ8.11(d,J=2.0Hz,1H),8.04(dd,J=8.8,2.0Hz,1H),7.00(d,J=8.8Hz,1H ),3.88(d,J=6.4Hz,2H),3.10(s,6H),2.47(s,3H),2.24-2.14(m,1H),1.09(s,3H),1.07(s,3H). 13 C NMR (100MHz, CDCl3): δ164.9,163.6,162.1,152.8,132.3,131.8,126.1,124.8,115.5,112.6,102.9,75.6,28.1,19.0,16.5.

[0091] Preparation Example 33

[0092] 0.2 mmol of ibuprofen, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160° C. for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 80%. 1 HNMR (400MHz, CDCl3): δ7.15(d,J=8.0Hz,2H),7.07(d,J=8.0Hz,2H),3.85(dd,J=13.6,6.8Hz,1H),2. 91(s,6H),2.43(d,J=7.2Hz,2H),1.88-1.78(m,1H),1.41(d,J=6.8Hz,3H),0.89(s,3H),0.88(s,3H). 13 C NMR (100MHz, CDCl3): δ173.9,140.0,139.0,129.5,127.0,45.0,42.8,37.1,35.9,30.2,22.4,20.7.

[0093] Preparation Example 34

[0094] 0.2 mmol of ketoprofen, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added to a 10 mL tubular reactor, and heated to 160° C. for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 50%. 1HNMR (400MHz, CDCl3): δ7.78(d,J=8.0Hz,2H),7.70(d,J=1.2Hz,1H),7.63(dd,J=7.6,1.2Hz,1H),7.60-7.5 3(m,2H),7.45-7.40(m,3H),3.97(q,J=6.8Hz,1H),2.94(dd,J=7.6,1.2Hz,6H),1.47(dd,J=6.8,1.2Hz,3H). 13 CNMR (100MHz, CDCl3): δ196.5,173.1,142.1,137.9,137.4,132.5,131.2,130.0,129.0,128.7,128.6,128.2,42.8,37.2,35.9,20.5.

[0095] Preparation Example 35

[0096] In a 10 mL tubular reactor, 0.2 mmol of indomethacin, 2.0 equivalents of N,N-dimethylformamide, 1.5 equivalents of triphenyl phosphite, 1.0 equivalents of lithium chloride, and 1 mL of p-xylene were added, and heated to 160°C for 24 hours under a nitrogen atmosphere. After the reaction, the product was separated and purified by column chromatography, and the separation yield was 55%. 1 HNMR (400MHz, CDCl3): δ7.68-7.66(m,2H),7.47(dd,J=8.4,1.6Hz,2H),7.01(d,J=2.4Hz,1H),6.82(d,J=8.8H z,1H),6.64(dd,J=8.8,2.4Hz,1H),3.82(d,J=1.2Hz,3H),3.71(s,2H),3.08(s,3H),2.99(s,3H),2.38(s,3H). 13 C NMR (100MHz, CDCl3): δ170.1,168.3,156.0,139.1,135.2,133.9,131.1,130 .9,130.8,129.1,114.8,113.4,111.5,101.6,55.7,37.6,35.8,30.3,13.4.

[0097] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be based on the attached claims.

Claims

1. An N,N-dimethylamide compound and a synthesis method thereof, wherein the general structural formula of the N,N-dimethylamide compound I is as follows: Wherein R includes but is not limited to phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 3,4,5-trimethoxyphenyl, 4-aminophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2-thiophene, 2-naphthyl, 1-naphthyl, benzyl, and p-methylphenylene. The synthesis method of compound I is characterized by: Using carboxylic acid compounds and N,N-dimethylformamide as raw materials, 0.5-1.5 equivalents of triphenyl phosphite as an additive, 0-1.0 equivalents of lithium chloride, and p-xylene as a solvent, the reaction is effectively carried out at 160° C. in a nitrogen environment for 24-48 hours to obtain N,N-dimethylamide compound I in high yield.

2. The synthesis method according to claim 1, characterized in that The structural formulas of the raw material carboxylic acid compound II and N,N-dimethylformamide III are as follows: The raw material carboxylic acid II includes but is not limited to benzoic acid, 2-methylbenzoic acid, 4-tert-butylbenzoic acid, 4-cyclohexylbenzoic acid, 4-phenoxybenzoic acid, 2'-tert-butyl-4-phenylbenzoic acid, 4-trifluoromethyl-4-phenylbenzoic acid, 3-trifluoromethylbenzoic acid, 4-carboxylic acid benzophenone, 4-nitrobenzoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid, 4-fluorobenzoic acid, 4-chlorobenzoic acid, 4-bromobenzoic acid, 4 -Iodobenzoic acid, 2-phenylaminobenzoic acid, 2-diphenylphosphinobenzoic acid, 3,4,5-trimethoxybenzoic acid, piperic acid, 1-naphthoic acid, 2-naphthoic acid, 5-methoxyindole 2-carboxylic acid, benzothiophene 3-carboxylic acid, thiophene 2-carboxylic acid, 4-methylcinnamic acid, phenylacetic acid, 9-fluorene acid, α-phenylcinnamic acid, phenylbutyric acid, diphenylacetic acid, 3-methyl-8-carboxychromone, ibuprofen, ketoprofen, indomethacin, febuxostat.

3. The synthesis method according to claim 1, characterized in that In a nitrogen atmosphere, the additive is 0.5 to 1.5 equivalents of triphenyl phosphite, and p-xylene is the solvent; the reaction time is 24 to 48 hours, and the reaction temperature is 160°C.

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