Preparation method of alpha-allyl-alpha, alpha-difluoroamide compound

Abstract

The invention relates to the technical field of organic synthesis, in particular to a method for preparing alpha-allyl-alpha, alpha-difluoroamide through in-situ generation of ketene difluoride. The preparation method comprises the following steps: reacting an activator with alpha, alpha-difluoro-alpha-bromoacetyl silicon in an inert atmosphere to generate difluoroketene in situ, reacting with allyl tertiary amine under a heating condition, and separating and purifying to obtain the alpha-allyl-alpha, alpha-difluoroamide compound. According to the preparation method disclosed by the invention, direct and efficient synthesis of alpha-allyl-alpha, alpha-difluoroamide is realized, reaction conditions are simple, and transition metal catalysis is not needed. Reaction conditions involved in the preparation method have good substrate universality and functional group tolerance, and synthesis of products with different substitution types of allyl substituent groups can be realized. A seven-to ten-membered alpha, alpha-difluorolactam structure can be obtained from the cyclic tertiary amine with alpha-vinyl by using the method.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing α-allyl-α, α-difluoroamide by reacting an α, α-difluoro-α-bromoacetyl silicon compound with an allyl tertiary amine. Background Art

[0002] Introducing difluoromethylene structural fragments into compounds can increase the lipophilicity and oxidative stability of the molecules, thereby giving the drug molecules unique pharmacological properties. In addition, difluoromethylene can also act as a lipophilic mimetic of polar functional groups such as carbonyl and sulfonyl, and can replace single oxygen atoms in phosphates, sulfates and aromatic ethers, and has therefore been widely used in the field of medicinal chemistry. However, the current synthesis methods for α-allyl-α, α-difluoroamide structures are very limited, mainly relying on the dehalogenation functionalization of α, α-difluoro-α-bromoacetamide, including free 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 by the reductive coupling reaction of α, α-difluoro-α-bromoacetamide and 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 structure by 1,4-difunctionalization reaction of α,α-difluoro-α-bromoacetamide and carboxylic acid on 1,3-dienes under visible light catalysis (Org. Lett. 2022, 24, 7589). However, these methods still have obvious limitations, such as the need to use expensive transition metal derivative photocatalysts, and the difficulty in achieving the diversity of substitution types of allyl substituents in the structure. Therefore, it is urgent to develop a more general and efficient method for synthesizing α-allyl-α, ɑ-difluoroamide structure. The present invention mainly studies the use of α,α-difluoro-α-bromoacetyl silicon compounds as difluoroethylene ketone precursors, and the rearrangement reaction of in-situ generated difluoroethylene ketone with allyl tertiary amines to obtain a method for efficiently synthesizing diversified α-allyl-ɑ, ɑ-difluoroamide structures. Summary of the invention

[0003] The purpose of the present invention is to provide a general preparation method of α-allyl-α, α-difluoroamide compounds, which is simple and efficient to operate, and aims to solve the problems of complex operation and limited applicable scope of raw materials in existing preparation methods.

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

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

[0006]

[0007] The compound of formula 1 represents an α,α-difluoro-α-bromoacetyl silicon compound, the compound of formula 2 represents an allyl tertiary amine, and the compound of formula 3 represents an α-allyl-α,α-difluoroamide.

[0008] Among them, R 1 is any one of hydrogen, alkyl, and halogen; R 2 R is 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, 3-methylbenzoate, 4-ethynylphenyl and other substituted phenyl groups, 2-furyl, 2-thienyl, dimethylphosphonyl, 1-propenyl; 1 With R 2 Can be the same or different; R 3 is hydrogen, cyano, carbomethoxy, 3-bromophenyl, 4-methylthiophenyl, 4-phenyl; R 4 is hydrogen; R 5 is hydrogen, phenyl, phenylethynyl (R 1 With R 5 can be connected to form a six-membered ring); R 6 is methyl, ethyl, allyl, 2-propargyl, 2-methoxyethyl; R 7 is ethyl, allyl, 2-methoxyethyl, benzyl, 4-trifluoromethylbenzyl, 4-cyanobenzyl; R 6 With R 7 They may be the same or different, and may be linked 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 Saturated alkyl nitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, preferably acetonitrile.

[0011] The molar ratio of the α,α-difluoro-α-bromoacetyl silicon, 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 temperature is 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 industries, and can also be used as an intermediate to prepare α-allyl-α,α-difluorocarboxylic acid derivatives and α,α-difluoropentabutyrolactone compounds.

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

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

[0018] (4) The preparation method of the present invention is applicable to various types of α-allyl-α,α-difluoroamide structures, showing a wider range of application than previous methods. The method can also be applied to α-vinyl cyclic tertiary amines to obtain seven to ten membered α,α-difluorolactam structures. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present 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 added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C1 (light yellow oily liquid 33.6 mg, 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 nitrogen atmosphere, cesium carbonate (0.2mmol, 1.0equiv.), allylamine B2 (0.2mmol, 1.0equiv.) and α,α-difluoro-α-bromoacetyltriethylsilane (0.4mmol, 2.0equiv.) were added to the reaction solvent acetonitrile (1mL) in sequence, and the resulting mixture was stirred at 60 degrees Celsius for 12 hours, and then the reaction mixture was filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C2 (light yellow oily liquid 36.4mg, yield 69%). The product exists in the form of a pair of rotational isomers in the nuclear magnetic 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 added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C3 (yellow oily liquid 42.7 mg, yield 80%). 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 added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred for reaction at 60 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C4 (reddish-brown oily liquid 28.2 mg, 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 added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred at 60 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C5 (light yellow oily liquid 29.4 mg, 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-bromoacetylsilane (0.4 mmol, 2.0 equiv.) were added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C6 (light yellow oily liquid 27.0 mg, 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-bromoacetylsilane (0.4 mmol, 2.0 equiv.) were added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred for reaction at 25 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C7 (light yellow oily liquid 35.8 mg, 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-bromoacetylsilane (0.4 mmol, 2.0 equiv.) were added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred at 60 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C8 (pale yellow oily liquid 41.0 mg, 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 nitrogen atmosphere, cesium carbonate (0.2mmol, 1.0equiv.), allylamine B9 (0.2mmol, 1.0equiv.) and α,α-difluoro-α-bromoacetylsilane (0.4mmol, 2.0equiv.) were added to the reaction solvent acetonitrile (1mL) in sequence, and the resulting mixture was stirred at 60 degrees Celsius for 12 hours, and then the reaction mixture was filtered through a filter, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C9 (yellow oily liquid 70.9mg, yield 93%). The product contains a pair of Z / E double bond isomers with a ratio of 9:1. 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-bromoacetylsilane (0.4 mmol, 2.0 equiv.) were added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred at 60 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C10 (light green oily liquid 13.7 mg, 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] Embodiment 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-bromoacetylsilane (0.4 mmol, 2.0 equiv.) were added sequentially to the reaction solvent acetonitrile (1 mL), and the resulting mixture was stirred at 60 degrees Celsius for 12 hours. The reaction mixture was then filtered through a filter, washed with ethyl acetate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography to obtain the target compound C11 (yellow oily liquid 62.4 mg, yield 92%). 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 nitrogen atmosphere, cesium carbonate (0.2mmol, 1.0equiv.), allylamine B12 (0.2mmol, 1.0equiv.) and α,α-difluoro-α-bromoacetylsilane (0.4mmol, 2.0equiv.) were added to the reaction solvent acetonitrile (1mL) in sequence, and the resulting mixture was stirred at 25 degrees Celsius for 12 hours, and then the reaction mixture was filtered through a filter, washed with ethyl acetate, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the target compound C12 (light yellow oily liquid 27.9mg, yield 50%). The product exists in the form of a pair of rotational isomers in the nuclear magnetic 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 descriptions are only some embodiments of the present invention and are 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 in the protection scope of the present invention.

Claims

1. A method for preparing α-allyl-α, α-difluoroamide, characterized in that: Under the action of an activator, an α, α-difluoro-α-bromoacetyl silicon compound reacts with an allyl tertiary amine to obtain an α-allyl-α, α-difluoroamide compound.

2. The method for preparing α-allyl-α, α-difluoroamide according to claim 1, characterized in that: The method comprises the following steps: (1) adding an activator, an allyl tertiary amine and α, α-difluoro-α-bromoacetyl silicon to a reaction solvent in sequence under a nitrogen atmosphere to obtain a mixture; (2) stirring the mixture in step (1) at a suitable temperature until the reaction is complete, filtering the crude reaction product, concentrating under reduced pressure, and separating by silica gel column chromatography to obtain α-allyl-α, α-difluoroamide compounds.

3. The method for preparing the α-allyl-α, α-difluoroamide compound according to claim 1, characterized in that: The molecular structure of the obtained α-allyl-α, α-difluoroamide is shown in the following formula (I): In formula (I), R 1 is any one of hydrogen, alkyl, and halogen; R 2 R is 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, 3-benzoyl, 4-ethynylphenyl and other substituted phenyl groups, 2-furyl, 2-thienyl, dimethylphosphonyl, 1-propenyl; 1 With R 2 Can be the same or different; R 3 is hydrogen, cyano, carbomethoxy, 3-bromophenyl, 4-methylthiophenyl, 4-phenyl; R 4 is hydrogen; R 5 is hydrogen, phenyl, phenylethynyl (R 1 With R 5 can be connected to form a six-membered ring); R 6 is methyl, ethyl, allyl, 2-propargyl, 2-methoxyethyl; R 7 is ethyl, allyl, 2-methoxyethyl, benzyl, 4-trifluoromethylbenzyl, 4-cyanobenzyl; R 6 With R 7 They may be the same or different, and may be linked to form a ring (morpholine ring or piperidine ring).

4. The method for preparing the α-allyl-α, α-difluoroamide compound according to claim 1, characterized in that: The molecular structure of the difluoroacetyl bromide silicon compound is shown in the following formula (II), wherein R 8 , R 9 , R 10 is an alkyl group or a phenyl group, and may be the same or different.

5. The method for preparing the α-allyl-α, α-difluoroamide compound according to claim 1, characterized in that: The activator is one of cesium carbonate, potassium fluoride, potassium tert-butoxide and sodium acetate.

6. The method for preparing the α-allyl-α, α-difluoroamide compound according to claim 2, characterized in that: The molar ratio of the activator, the allyl tertiary amine and the difluoroacetyl bromide silicon compound is 1.0:1.0:2.0, and the concentration of the allyl tertiary amine in the mixed solution is between 0.2M and 2M.

7. The method for preparing the α-allyl-α,α-difluoroamide compound according to claim 2, characterized in that: In step (1), the reaction solvent is acetonitrile, C 3-10 One of saturated alkyl nitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide; in step (2), the mixture is stirred at 60 degrees Celsius or room temperature for 24 hours.

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