A process for the preparation of alpha-allyl-alpha,alpha-difluoro amide compounds

Abstract

The present application relates to the technical field of organic synthesis, and particularly relates to a method for preparing alpha-allyl-alpha,alpha-difluoro amide by generating difluorovinyl ketone in situ. In an inert atmosphere, an activating agent reacts with alpha,alpha-difluoro-alpha-bromoacetyl silicon to generate difluorovinyl ketone in situ, and the difluorovinyl ketone reacts with allyl tertiary amine under heating conditions, and after separation and purification, alpha-allyl-alpha,alpha-difluoro amide compound is obtained. The preparation method of the present application realizes direct and efficient synthesis of alpha-allyl-alpha,alpha-difluoro amide, and the reaction condition is simple and does not need transition metal catalysis. The reaction condition involved in the preparation method of the present application has good substrate universality and functional group tolerance, and synthesis of products with different types of allyl substituents can be realized. The cyclic tertiary amine with alpha-vinyl can obtain seven to ten membered alpha,alpha-difluoro lactam structure by using the method.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing α-allyl-α,α-difluoroamide by reacting an α,α-difluoro-α-bromoacetylsilyl compound with an allyl tertiary amine. Background Technology

[0002] Introducing difluoromethylene structural fragments into compounds can increase the lipophilicity and oxidative stability of molecules, thereby endowing drug molecules with unique pharmacological properties. Furthermore, difluoromethylene can act as lipophilic mimics of polar functional groups such as carbonyl and sulfonyl groups, and can replace single oxygen atoms in phosphates, sulfates, and aryl ethers, thus finding wide application in medicinal chemistry. However, current synthetic methods for α-allyl-α,α-difluoroamide structures are very limited, mainly relying on the dehalogenation functionalization of α,α-difluoro-α-bromoacetamide, including radical allylation reactions and transition metal-catalyzed 1,4-functionalization reactions of 1,3-dienes. For example, in 2019, Ryu reported the synthesis of α-allyl-α,α-difluoroamide structures via a reductive coupling reaction of α,α-difluoro-α-bromoacetamide with allyl sulfone compounds under visible light catalysis (J. Org. Chem. 2019, 84, 9330). In 2022, Chen reported the synthesis of α-allyl-α,α-difluoroamide structures via the 1,4-bifunctionalization of α,α-difluoro-α-bromoacetamide and carboxylic acids with 1,3-diene under visible light catalysis (Org. Lett. 2022, 24, 7589). However, these methods still have significant limitations, such as the need for expensive transition metal derivative photocatalysts and the difficulty in achieving diversity in the substitution types of allyl substituents in the structure. Therefore, there is an urgent need to develop a more universal and efficient method for synthesizing α-allyl-α,α-difluoroamide structures. This invention mainly studies a method for efficiently synthesizing diverse α-allyl-α,α-difluoroamide structures by using α,α-difluoro-α-bromoacetylsilane compounds as difluoroethylene ketone precursors and through the rearrangement reaction of in-situ generated difluoroethylene ketone with allyl tertiary amines. Summary of the Invention

[0003] The purpose of this invention is to provide a general preparation method for α-allyl-α,α-difluoroamide compounds that is simple and efficient, aiming to solve the problems of complex operation and limited applicability of raw materials in existing preparation methods.

[0004] The method adopted by the present invention to achieve the objective is as follows: under a nitrogen atmosphere, an activator, an allyl tertiary amine and α,α-difluoro-α-bromoacetylsilane are added sequentially to the reaction solvent, stirred at a suitable temperature until the reaction is complete, and the crude product is filtered, concentrated under reduced pressure and separated by silica gel column chromatography to obtain the α-allyl-α,α-difluoroamide compound.

[0005] The reaction formula of the method of the present invention can be expressed as follows:

[0006]

[0007] Compound of Formula 1 represents α,α-difluoro-α-bromoacetylsilane, compound of Formula 2 represents allyl teramine, and compound of Formula 3 represents α-allyl-α,α-difluoroamide.

[0008] Among them, R 1 R is any one of hydrogen, alkyl, or halogen; 2 Hydrogen, alkyl, halogen, phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-n-butoxyphenyl, 4-morpholinylphenyl, phenylthio, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-cyanophenyl, 4-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-nitrophenyl, 4-acetoxyphenyl, methyl 3-benzoate, 4-ethynylphenyl and other substituted phenyl, 2-furanyl, 2-thiophenyl, dimethylphosphonoyl, 1-propenyl; R 1 With R 2 They can be the same or different; R 3 It is hydrogen, cyano, methyl ester, 3-bromophenyl, 4-methylthiophenyl, 4-phenyl; R 4 It is hydrogen; R 5 It is hydrogen, phenyl, phenylacetylene (R 1 With R 5 (Can be connected to form a six-membered ring); R 6 Methyl, ethyl, allyl, 2-butynediyl, 2-methoxyethyl; R 7 Ethyl, allyl, 2-methoxyethyl, benzyl, 4-trifluoromethylbenzyl, 4-cyanobenzyl; R 6 With R 7 They can be the same or different, and they can also be connected to form a ring (morpholine ring or piperidine ring).

[0009] The activator is one of potassium fluoride, potassium tert-butoxide, cesium carbonate, and sodium acetate, preferably cesium carbonate.

[0010] The reaction solvent is acetonitrile, C 3-10 One of the following: saturated alkyl nitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and dimethyl sulfoxide, preferably acetonitrile.

[0011] The molar ratio of α,α-difluoro-α-bromoacetylsilane, allylamine, and activator is 2.0:1.0:1.0, and the concentration of allylamine in the mixed solution is between 0.2M and 2M.

[0012] The reaction is carried out at room temperature or 60 degrees Celsius.

[0013] The reaction time is 24 hours.

[0014] The present invention has the following advantages and beneficial effects:

[0015] (1) The α-allyl-α,α-difluoroamide prepared by the preparation method of the present invention has potential application value in the pharmaceutical and chemical industry, and can also be used as an intermediate to prepare α-allyl-α,α-difluorocarboxylic acid derivatives and α,α-difluoropentabutane compounds.

[0016] (2) The α,α-difluoro-α-bromoacetylsilane compound used in the preparation method of the present invention is stable and easy to prepare.

[0017] (3) Compared with the previously reported methods, the preparation method of the present invention avoids the use of transition metal catalysts and is simpler and more economical to operate.

[0018] (4) The preparation method of the present invention is applicable to various types of α-allyl-α,α-difluoroamide structures, demonstrating a wider range of applicability than previous methods. This method can also be applied to α-vinyl cyclic tertiary amines to obtain 7- to 10-membered α,α-difluorolactam structures. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0020] Example 1

[0021]

[0022] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B1 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetyltriethylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C1 (33.6 mg of pale yellow oily liquid, yield 82%). 1H NMR (400MHz, Chloroform-d) δ5.86 (ddt, J=17.3, 10.3, 7.0Hz, 1H), 5.34-5.22 (m, 2H), 3.90-3.54 (m, 8H), 2.90 (tdt, J=18.1, 7.0, 1.4Hz, 2H). 19 FNMR (376MHz, Chloroform-d) δ-98.63 (t, J=18.2Hz, 2F). 13 C NMR (101MHz, Chloroform-d) 6161.8 (t, J=29.4Hz), 128.3 (t, J=5.4Hz), 121.2, 118.5 (t, J=25 5.3Hz), 66.9, 66.8, 46.5 (t, J=6.4Hz), 43.4, 39.4 (t, J=23.6Hz). HRMS (ESI, m / z): calculated for[M+H] + :206.0993, found:206.0986.

[0023] Example 2

[0024]

[0025] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B2 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetyltriethylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to give the target compound C2 (36.4 mg of pale yellow oily liquid, 69% yield). The product existed as a pair of rotational isomers in the NMR spectrum. 1 H NMR (400MHz, Chloroform-d) δ7.68-7.61(m, 2H), 7.36-7.28(m, 2H), 5.93-5.78(m, 1H), 5.35-5.17( m, 2H), 4.78 (s, 0.69H), 4.63 (s, 1.43H), 3.12 (t, J=2.2Hz, 2.0H), 3.04-2.88 (m, 2H), 2.86 (s, 1.0H). 19 F NMR (376MHz, Chloroform-d) δ -97.43 (t, J=18.2Hz, 0.5F), -99.50 (t, J=18.1Hz, 1.5F).13 C NMR (101MHz, Chloroform-d) δ163.7 (t, J=29.5Hz), 163.6 (t, J=29.2Hz), 141.7, 141.6, 132.7, 132.7, 128.5, 128.3-128.0(m), 127.8, 121.4, 121.3, 118.7, 118. 6(d, J=255.0Hz), 118.6, 118.4 (d, J=254.7Hz), 111.9, 111.8, 52.7 (t, J=6.5Hz) , 52.3, 39.4 (t, J=23.8Hz), 35.2 (t, J=7.2Hz), 34.7.HRMS (ESI, m / z): calculated for[M+H] + :265.1152, found:265.1151.

[0026] Example 3

[0027]

[0028] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B3 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetyltriethylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C3 (42.7 mg of yellow oily liquid, 80% yield). 1 H NMR (400MHz, Chloroform-d) δ7.36-7.26 (m, 5H), 6.31-6.18 (m, 1H), 5.36-5.16 (m, 2H) , 4.41-4.23 (m, 1H), 3.44-3.19 (m, J, 4H), 1.11 (t, J = 7.0Hz, 3H), 1.04 (t, J = 7.1Hz, 3H). 19 F NMR (376MHz, Chloroform-d) δ -101.78 (dd, J=267.6, 17.1Hz, 1F), -103.18 (dd, J=267.6, 15.6Hz, 1F). 13C NMR (101MHz, Chloroform-d) δ162.6 (t, J=28.6Hz), 136.0, 133.1 (t, J=4.5Hz), 129.8, 128.5, 127.8, 120.1, 118. 5(t, J=259.3Hz), 54.4 (t, J=22.5Hz), 42.2, 42.0 (t, J=6.8Hz), 14.5, 12.2.HRMS (ESI, m / z): calculated for [M+H] + :268.1513, found:268.1512.

[0029] Example 4

[0030]

[0031] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B4 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetyltriethylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C4 (28.2 mg of reddish-brown oily liquid, yield 52%). 1 H NMR (400MHz, Chloroform-d) δ7.40 (dd, J=2.0, 0.8Hz, 1H), 6.37 (dd, J=3.3, 1.8Hz, 1H), 6.29 (d, J=3.3Hz, 1H ), 6.10 (ddd, J=17.1, 10.3, 8.1Hz, 1H), 5.44-5.20 (m, 2H), 4.45 (td, J=15.4, 8.1Hz, 1H), 3.78-3.54 (m, 9H). 19 F NMR (376MHz, Chlotoform-d) δ -100.58 (dd, J=275.3, 15.3Hz, 1F), -101.78 (dd, J=274.7, 15.8Hz, 1F). 13C NMR (101MHz, Chloroform-d) δ161.4 (t, J=28.6Hz), 149.1 (t, J=3.8Hz), 142.4, 130.3 (t, J=4.1Hz), 121.1, 117.4 (t , J=260.0Hz), 110.7, 109.0, 66.8, 53.6, 48.5 (t, J=23.7Hz), 46.5 (t, J=7.0Hz), 43.6.HRMS (ESI, m / z): calculated for[M+H] + :272.1098, found:272.1097.

[0032] Example 5

[0033]

[0034] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B5 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetyltriethylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C5 (29.4 mg of pale yellow oily liquid, yield 60%). 1 H NMR (400MHz, Chloroform-d) δ5.89 (ddd, J=17.4, 10.5, 7.6Hz, 1H), 5.65 (dq, J=15.6, 6.4Hz, 1H), 5.5 8-5.43 (m, 1H), 5.29-5.16 (m, 2H), 3.81-3.59 (m, 8H), 3.55-3.45 (m, 1H), 1.71 (dd, J=6.3, 1.6Hz, 3H). 19 F NMR (376MHz, Chloroform-d) δ-101.66 (d, J=14.9Hz, 2F). 13 C NMR (101MHz, Chloroform-d) δ161.7 (t, J=29.3Hz), 132.9 (t, J=4.5Hz), 131.2, 124.5 (t, J=4.4Hz), 119.4, 118 .3 (t, J=258.0Hz), 77.4, 66.9, 52.3 (t, J=22.4Hz), 46.7 (t, J=6.8Hz), 43.4, 18.3.HRMS (ESI, m / z): calculated for[M+H]+ :246.1306, found:246.1299.

[0035] Example 6

[0036]

[0037] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B6 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetylsilylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C6 (27.0 mg of pale yellow oily liquid, yield 58%). 1 H NMR (400MHz, Chlotoform-d) δ6.05 (dd, J=17.5, 10.8Hz, 1H), 5.22-5.13 (m, 2H), 3.74-3.57 (m, 8H), 1.26 (s, 6H). 19 F NMR (376MHz, Chlotoform-d) δ-105.43 (s, 2F). 13 C NMR (101MHz, Chloroform-d) δ161.6 (t, J=30.3Hz), 140.6 (t, J=3.8Hz), 120.0 (t, J=260.3Hz), 115.2, 6 6.9, 66.9, 47.3 (t, J=7.9Hz), 44.1 (t, J=21.5Hz), 43.5, 21.4 (t, J=4.5Hz). HRMS (ESI, m / z): calculated for[M+H] + :233.1227, found:233.1233.

[0038] Example 7

[0039]

[0040] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B7 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetylsilylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C7 (35.8 mg of pale yellow oily liquid, yield 46%). 1 H NMR (400MHz, Chloroform-d) δ7.45-7.37 (m, 2H), 7.34-7.26 (m, 3H), 6.67 (dd, J=15.8, 4.4Hz, 1H), 6.16 (ddd, J=15.8, 10.0, 6.5Hz, 1H), 4.18-3.92 (m, 1H), 3.79 (d, J=4.0Hz, 3H), 3.76 (d, J=4.1Hz, 3H), 3.74-3.60 (m, 3H). 19 F NMR (376MHz, Chloroform-d) δ -95.70 (t, J=14.4Hz), -96.45 (t, J=14.4Hz), -96.54 (dd, J=16.2, 11.9Hz), -97.29 (dd, J=16.2, 11.9Hz). 31 P NMR (162MHz, Chloroform-d) δ22.44 (t, J=13.5Hz). 13 C NMR (101MHz, Chloroform-d) δ 160.6 (td, J=28.8, 5.2Hz), 138.2 (d, J=12.4Hz), 136. 2(d, J=3.0Hz), 128.7, 128.4, 126.8, 120.3, 117.8 (t, J=263.3Hz), 116.8, 116.7, 116 .7, 116.6, 116.6, 115.2, 66.8, 66.8, 54.1 (d, J=6.8Hz), 53.3 (d, J=6.8Hz), 48.7 (t, J =23.5Hz), 47.3 (t, J = 23.7Hz), 46.6 (d, J = 7.0Hz), 43.9.HRMS (ESI, m / z): calculated for[M+H] + :390.1282, found:390.1273.

[0041] Example 8

[0042]

[0043] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B8 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetylsilylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C8 (41.0 mg of pale yellow oily liquid, yield 85%). 1 H NMR (400MHz, Chloroform-d) δ6.21-6.05 (m, 1H), 5.88 (dt, J=17.4, 2.3Hz, 1H), 5.70 (d, J=11.0Hz, 1H), 4.06-3.29 (m, 8H). 19 F NMR (376MHz, Chloroform-d) δ-113.31 (t, J=4.6Hz), -114.05--114.75 (m). 13 C NMR (101MHz, Chloroform-d) δ158.4 (t, J=26.4Hz), 126.8 (t, J=23.8Hz), 124.5 (t, J=9.5H z), 119.06-106.83 (m), 66.8, 66.7, 46.8 (t, J=6.3Hz), 43.7.HRMS (ESI, m / z): calculated for[M+H] + :242.0804, found:242.0805.

[0044] Example 9

[0045]

[0046] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B9 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetylsilylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C9 (70.9 mg of yellow oily liquid, 93% yield). The product contained a pair of Z / E double bond isomers in a 9:1 ratio. 1H NMR (400MHz, Chloroform-d) δ7.69-7.31 (m, 10H), 6.61 (dd, J=15.8, 8.2Hz, 1H), 5.91 (dd, J= 15.9, 1.2Hz, 1H), 4.46 (tdd, J=15.5, 8.2, 1.3Hz, 1H), 3.76-3.54 (m, 7H), 3.51-3.41 (m, 1H). 19 FNMR (376MHz, Chloroform-d) δMajor isomer: -99.91 (dd, J=274.6, 16.8Hz, 1F), -101.14 (dd, J=274.4, 15.3Hz, 1F).Minor isomer: -100.06 (dd, J=269.8, 15.6Hz, 1F), -102.12 (dd, J=269.8, 16.1Hz, 1F). 13 C NMR (101MHz, Chlotoform-d) δ161.5 (t, J=28.8Hz), 137.5 (t, J=4.4Hz), 135.0, 131.6, 131.5, 129.8, 129.7, 128.7, 128.6, 128.6 , 128.4, 128.3, 128.1, 128.0, 90.8, 87.3, 66.6, 66.6, 53.5 (t, J=22.5Hz), 46.5 (t, J=7.2Hz), 43.6.HRMS (ESI, m / z): calculated for[M+H]] + :382.1619, found:382.1612.

[0047] Example 10

[0048]

[0049] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B10 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetylsilylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C10 (13.7 mg of light green oily liquid, yield 28%). 1H NMR (400MHz, Chloroform-d) δ5.97-5.90(m, 1H), 5.71-5.63(m, 1H), 3.81-3.57(m , 8H), 3.21-2.97(m, 1H), 2.11-1.76(m, 4H), 1.67-1.60(m, 1H), 1.57-1.50(m, 1H). 19 F NMR (376MHz, Chloroform-d) δ-105.10 (t, J=21.0Hz, 2F). 13 C NMR (101MHz, Chloroform-d) δ161.9 (t, J=29.7Hz), 131.6, 122.3 (t, J=5.5Hz), 119.5 (t, J=256.7Hz), 66.9, 6 6.9, 46.8 (t, J=6.8Hz), 43.5, 40.4 (t, J=21.9Hz), 24.8, 21.9 (t, J=4.4Hz), 20.9. HRMS (ESI, m / z): calculated for[M+H] + :246.1306, found:246.1299.

[0050] Example 11

[0051]

[0052] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B11 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetylsilylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C11 (62.4 mg of yellow oily liquid, 92% yield). 1 H NMR (400MHz, Chloroform-d) δ7.46-7.31 (m, 5H), 6.51 (br, 1H), 6.11 (d, J=1.5Hz, 1H), 5.07 (dd, J=22.7, 14.0Hz, 1H), 3.76 (s, 3H), 3.73-3.48 (m, 8H). 19 F NMR (376MHz, Chloroform-d) δ -96.79 (dd, J=279.1, 14.1Hz, 1F), -101.74 (dd, J=279.0, 22.7Hz, 1F). 13C NMR (101MHz, Chloroform-d) δ160.7 (t, J=28.3Hz), 136.0, 132.9 (d, J=3.3Hz), 129.6, 129.1, 128.9, 119.6 (t, J=3.5Hz), 117.9 , 117.7 (t, J = 262.6Hz), 66.71 (d, J = 3.9Hz), 53.7 (t, J = 22.2Hz), 46.6 (t, J = 6.8Hz), 43.8.HRMS (ESI, m / z): calculated for [M+H] + :340.1360, found:340.1356.

[0053] Example 12

[0054]

[0055] Under a nitrogen atmosphere, cesium carbonate (0.2 mmol, 1.0 equiv.), allylamine B12 (0.2 mmol, 1.0 equiv.), and α,α-difluoro-α-bromoacetylsilylsilane (0.4 mmol, 2.0 equiv.) were sequentially added to the reaction solvent acetonitrile (1 mL). The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was then filtered, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C12 (27.9 mg of pale yellow oily liquid, 50% yield). The product was observed to exist as a pair of rotational isomers in the NMR spectrum. 1 H NMR (400MHz, Chloroform-d) δ7.40-7.25 (m, 3H), 7.23-7.19 (m, 2H), 6.02-5.90 (m, 0.4H), 5.72-5.60 (m, 0.5H), 5.60-5.44 (m, 1.6H), 5.39 (d, J=14.6Hz , 0.4H), 4.27-4.14(m, 0.6H), 3.83(d, J=14.9Hz, 1.4H), 3.10-2.67(m, 3H), 2.44-2.31(m, 1H), 2.17-1.84(m, 2H), 1.81-1.40(m, 2H), 1.35-1.05(m, 2H). 19 F NMR (376MHz, Chloroform-d) δ-86.02 (dd, J=240.8, 6.6Hz), -87.34 (d, J=236.5, 6.5Hz), -97.70--98.78(m), -100.69--100.96(m). 13C NMR (101MHz, Chloroform-d) δ165.9 (t, J=27.9Hz), 164.7 (t, J=26.8Hz), 140.9, 138.8, 136.2 , 128.8, 128.3, 128.0, 127.7, 127.7, 120.7 (dd, J=252.6, 258.5Hz), 120.1 (d, J=12.0Hz), 119. 4(d, J=12.0Hz), 48.1, 46.5, 45.6 (d, J=17.2Hz), 42.5 (d, J=14.9Hz), 38.5 (dd, J=26.8, 21.7Hz ), 37.8 (dd, J=27.7, 22.1Hz), 33.8, 32.9, 27.8, 27.2, 25.0, 22.4.HRMS (ESI, m / z): calculated for[M+H] + :280.1513, found:280.1505.

[0056] The above description is only a partial embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of an α-allyl-α,α-difluoro amide compound, characterized in that, Under the action of an activator, α,α-difluoro-α-bromoacetylsilane compounds react with allyl tertiary amines to give α-allyl-α,α-difluoroamide compounds. The structure of the α-allyl-α,α-difluoroamide compound is shown in formula (I) below. The structure of allyl tertiary amine is shown below in Formula 2: In equations (I) and (2), R 1 R is any one of hydrogen, alkyl, or halogen; 2 For example, hydrogen, alkyl, halogen, phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-n-butoxyphenyl, 4-morpholinylphenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-cyanophenyl, 4-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-nitrophenyl, 4-acetoxyphenyl, methyl 3-benzoate, 4-ethynylphenyl, 2-furanyl, 2-thiopheneyl; R 1 With R 2 Same or different; R 3 It is hydrogen, cyano, methyl ester, 3-bromophenyl, 4-methylthiophenyl, 4-phenyl; R 4 It is hydrogen; R 5 It is hydrogen, phenyl, phenylacetylene; R 6 Methyl, ethyl, allyl, 2-butynediyl, 2-methoxyethyl; R 7 Ethyl, allyl, 2-methoxyethyl, benzyl, 4-trifluoromethylbenzyl, 4-cyanobenzyl; R 6 With R 7 They may be the same or different, or they may be connected to form a morpholine ring; The molecular structure of the α,α-difluoro-α-bromoacetylsilane compound is shown in formula (II) below, where R 8 R 9 R 10 It is an alkyl group; The activator is cesium carbonate.

2. The method for preparing α-allyl-α,α-difluoroamide compounds according to claim 1, characterized in that, The method includes the following steps: (1) Under a nitrogen atmosphere, the activator, allyl tertiary amine and α,α-difluoro-α-bromoacetylsilane compound were added sequentially to the reaction solvent to obtain a mixture; The molar ratio of the activator, allyl tertiary amine, to α,α-difluoro-α-bromoacetylsilane compound is 1.0:1.0:2.0, and the concentration of allyl tertiary amine in the mixed solution is between 0.2M and 2M. (2) Stir the mixture described in step (1) at a suitable temperature until the reaction is complete. Filter the crude product, concentrate it under reduced pressure, and then separate it by silica gel column chromatography to obtain α-allyl-α,α-difluoroamide compounds. The mixture is stirred and reacted at 60 degrees Celsius for 24 hours.

3. The method for preparing an α-allyl-α,α-difluoroamide compound according to claim 2, characterized in that, In step (1), the reaction solvent is acetonitrile.

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