A fluoroalkyl-substituted isochromanone compound, a preparation method thereof and an application thereof

Abstract

The present application discloses a method for preparing fluoroalkyl-substituted isochromanone compounds in the field of organic synthesis technology, which is as follows: 2-allylbenzoic acid, difluoro or perfluoroiodoalkane, silver salt and an organic solvent are mixed, and after heating reaction and subsequent separation and purification, fluoroalkyl-substituted isochromanone compounds are obtained. The starting materials of this method are cheap and easily available, the operation is simple, the use of high-dose redox reagents and additional reaction additives is avoided, and a simple and efficient preparation method for fluoroalkyl-substituted isochromanone compounds is provided. At the same time, the fluorinated isochromanone compounds provided by the present invention have certain activities against the growth of leukemia cells and can be applied to the preparation of anti-leukemia drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a fluoroalkyl-substituted isochromanone compound, a preparation method thereof, and an application thereof. Background Art

[0002] Isochromanone is a class of important heterocyclic molecules and can be widely used as active molecules or organic synthesis intermediates in the fields of medicinal chemistry and synthetic chemistry. For example, dihydroisocoumarin containing an isochromanone skeleton has anticancer activity (BioconJugChem. 2009, 20, 1737). Therefore, developing new experimental methods to achieve the efficient synthesis of novel isochromanone molecules is of great significance for expanding the sources of important isochromanone skeleton compounds in medicinal chemistry and the discovery of lead compounds. Due to the high electronegativity of fluorine, the fluoroalkyl modification strategy is widely used in the design of medicinally active molecules, aiming to improve the lipophilicity, metabolic stability, and pharmacological activity of the parent molecule. Therefore, developing a synthesis method for difluoroalkyl- and polyfluoroalkyl-modified isochromanone compounds plays an important promoting role in further exploring the medicinal activity value of related molecules.

[0003] However, although there are many strategies for the cyclization reaction of fluoroalkyl to form lactones, palladium (J.Fluo.Chem. 2005, 126, 319) and iridium metal catalysts (J.Org.Chem. 2017, 82, 9824) are often required, and the synthesis of isochromanone compounds is not involved in the prior art. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention designs a silver-catalyzed tandem cyclization reaction to synthesize fluoroalkyl-substituted isochromanone compounds.

[0005] One of the objectives of the present invention is to provide a fluoroalkyl-substituted isochromanone compound, which is characterized in that its structural formula is as follows:

[0006]

[0007] Wherein, R is independently selected from hydrogen, 8-fluoro, 8-chloro, 8-bromo, 8-iodo, 7-fluoro, 7-chloro, 7-bromo, 7-iodo, 7-trifluoromethyl, 7-methoxy, 7-methyl, 6-fluoro, 6-chloro, 6-bromo, 6-iodo, 6-trifluoromethyl, 6-methoxy, 6-methyl, 5-fluoro, 5-chloro, 5-bromo, 5-iodo, 5-methyl, 5-trifluoromethyl, 5-methoxy, 6,7-dimethoxy, 6,7-dimethyl, 6-fluoro-7-methoxy, 6-bromo-7-methoxy, 6-chloro-7-methoxy, 6-iodo-7-methoxy, 6-methoxy-7-iodo, 6-methoxy-7-bromo, 6-methoxy-7-chloro, 6-methoxy-7-fluoro, 7-bromo-8-fluoro, 6-bromo-7-fluoro, 6,7-difluoro, 6,7-dichloro, 5-methoxy-8-fluoro, 5-methoxy-8-chloro, 5-methyl-8-fluoro or 5-methyl-8-chloro;

[0008] R’ is selected from ethoxycarbonyl, methoxycarbonyl, perfluorobutyl, perfluoropropyl, perfluoroisopropyl, perfluoropentyl, perfluorohexyl, perfluoroheptyl or perfluorooctyl.

[0009] The second object of the present invention is to provide a preparation method of fluoroalkyl-substituted isochromanone compounds, specifically: mixing 2-allylbenzoic acid, difluoro or perfluoroiodoalkane, silver salt with an organic solvent, and obtaining fluoroalkyl-substituted isochromanone compounds through heating reaction and subsequent separation and purification;

[0010]

[0011] Furthermore, the silver salt is selected from silver acetate, silver oxide, silver carbonate, silver trifluoroacetate or silver chloride. Silver oxide is preferred.

[0012] Furthermore, the organic solvent is selected from acetonitrile, tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or ethyl acetate. 1,4-dioxane is preferred.

[0013] Furthermore, the temperature is 20°C to 100°C, preferably 50°C to 80°C; more preferably 70°C; the time is 2h to 40h, the time is preferably 12h to 48h; preferably 36h; the gas atmosphere is selected from air, nitrogen or argon, and argon is most preferred.

[0014] Furthermore, the molar ratio of 2-allylbenzoic acid: difluoro or perfluoroiodoalkane: silver salt is 1:1 to 5:0.1 to 2. Preferably, the molar ratio of 2-allylbenzoic acid: difluoro or perfluoroiodoalkane: silver salt is 1:3:0.5.

[0015] Furthermore, the separation and purification method is selected from silica gel column chromatography and recrystallization; silica gel column chromatography separation is preferred.

[0016] The third object of the present invention is to provide the use of fluoroalkyl-substituted isochromanones in the preparation of anti-leukemia drugs.

[0017] In view of the fact that silver salts often act as good bases, transition metals and single-electron oxidants, the present invention innovatively develops a silver-catalyzed tandem cyclization reaction for the synthesis of fluoroalkyl-substituted isochromanones. This method uses inexpensive and readily available starting materials, is easy to operate, and avoids the use of high-dose redox reagents and additional reaction additives, providing a simple and efficient preparation method for fluoroalkyl-substituted isochromanones.

[0018] Experiments have confirmed that the fluoroalkyl-substituted isochromanones described in this application have certain anti-leukemia (human promyelocytic leukemia cell line HL-60) drug activities. Therefore, this application also provides the use of isochromanones modified with fluoroalkyl groups in the treatment of leukemia drugs. Description of the Drawings

[0019] Figure 1 1H NMR spectrum of compound 2a prepared in Example 1 1 ;

[0020] Figure 2 1H NMR spectrum of compound 2a prepared in Example 1 13 13C NMR spectrum;

[0021] Figure 3 1H NMR spectrum of compound 2a prepared in Example 1 19 19F NMR spectrum;

[0022] Figure 4 1H NMR spectrum of compound 2b prepared in Example 2 1 ;

[0023] Figure 5 1H NMR spectrum of compound 2b prepared in Example 2 13 13C NMR spectrum;

[0024] Figure 6 1H NMR spectrum of compound 2b prepared in Example 2 19 19F NMR spectrum;

[0025] Figure 7 1H NMR spectrum of compound 2c prepared in Example 3 1 ;

[0026] Figure 8 1H NMR spectrum of compound 2c prepared in Example 3 13 13C NMR spectrum;

[0027] Figure 9 1H NMR spectrum of compound 2c prepared in Example 3 1919F NMR spectrum;

[0028] Figure 10 19F NMR spectrum of compound 2d prepared in Example 4 1 1H NMR spectrum;

[0029] Figure 11 1H NMR spectrum of compound 2d prepared in Example 4 13 13C NMR spectrum;

[0030] Figure 12 13C NMR spectrum of compound 2d prepared in Example 4 19 19F NMR spectrum;

[0031] Figure 13 19F NMR spectrum of compound 2e prepared in Example 5 1 1H NMR spectrum;

[0032] Figure 14 1H NMR spectrum of compound 2e prepared in Example 5 13 13C NMR spectrum;

[0033] Figure 15 13C NMR spectrum of compound 2e prepared in Example 5 19 19F NMR spectrum;

[0034] Figure 16 19F NMR spectrum of compound 2f prepared in Example 6 1 1H NMR spectrum;

[0035] Figure 17 1H NMR spectrum of compound 2f prepared in Example 6 13 13C NMR spectrum;

[0036] Figure 18 13C NMR spectrum of compound 2f prepared in Example 6 19 19F NMR spectrum;

[0037] Figure 19 19F NMR spectrum of compound 2g prepared in Example 7 1 1H NMR spectrum;

[0038] Figure 20 1H NMR spectrum of compound 2g prepared in Example 7 13 13C NMR spectrum;

[0039] Figure 21 13C NMR spectrum of compound 2g prepared in Example 7 19 19F NMR spectrum;

[0040] Figure 22 19F NMR spectrum of compound 2k prepared in Example 11 1 1H NMR spectrum;

[0041] Figure 23 1H NMR spectrum of compound 2k prepared in Example 11; 13 13C NMR spectrum;

[0042] Figure 24 1H NMR spectrum of compound 2k prepared in Example 11; 19 19F NMR spectrum;

[0043] Figure 25 1H NMR spectrum of compound 2l prepared in Example 12; 1 1H NMR spectrum;

[0044] Figure 26 13C NMR spectrum of compound 2l prepared in Example 12; 13 13C NMR spectrum;

[0045] Figure 27 19F NMR spectrum of compound 2l prepared in Example 12; 19 19F NMR spectrum;

[0046] Figure 28 1H NMR spectrum of compound 2m prepared in Example 13; 1 1H NMR spectrum;

[0047] Figure 29 13C NMR spectrum of compound 2m prepared in Example 13; 13 13C NMR spectrum;

[0048] Figure 30 19F NMR spectrum of compound 2m prepared in Example 13; 19 19F NMR spectrum;

[0049] Figure 31 1H NMR spectrum of compound 3 prepared in Example 14; 1 1H NMR spectrum;

[0050] Figure 32 13C NMR spectrum of compound 3 prepared in Example 14; 13 13C NMR spectrum;

[0051] Figure 33 19F NMR spectrum of compound 3 prepared in Example 14; 19 19F NMR spectrum. Detailed Description of the Invention

[0052] The following provides a more detailed description through specific embodiments:

[0053] Example 1

[0054] Taking the preparation of isochromanone compound 2a with the following structural formula as an example, the raw materials and preparation method are as follows:

[0055] 2-Allyl-4-bromobenzoic acid (0.2 mmol), Ag 2 O (0.1 mmol), 1,4-Dioxane (2 mL) were added into a 10 mL reaction flask, and then ethyl difluoroiodoacetate (0.6 mmol) was added. After the reaction flask was evacuated with an oil pump, argon was injected into the flask (repeated three times), and it was placed in an oil bath at 70 °C and stirred for reaction. After 36 hours, the reaction was cooled to room temperature. The reaction solution was extracted, dried, filtered, concentrated and purified by silica gel column chromatography to obtain a light yellow oily liquid compound 2a (53.2 mg, 73% yield).

[0056] The detection data of product 1a are as follows:

[0057] 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.44 (s, 1H), 4.89–4.80 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.06 (d, J = 10.8 Hz, 2H), 2.86–2.70 (m, 1H), 2.54–2.41 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H).

[0058] 13 C NMR (101 MHz, CDCl 3 ) δ 163.5, 163.4, 139.8, 132.0, 131.6, 130.7, 129.2, 123.6, 114.3 (t, J = 246.5 Hz), 72.5, 63.6, 39.8 (t, J = 23.8 Hz), 32.9, 14.0.

[0059] 19 F NMR (376 MHz, CDCl 3 ) δ -101.35– -102.26 (m, 1F), -106.64– -107.79 (m, 1F).

[0060] HRMS (ESI, Q-TOF) m / z: [M+H + Calcd for C 14 H 14 BrF 2 O 4 , 363.0038; Found: 363.0033.

[0061] Example 2

[0062] Prepare isochromanone compound 2b with the following structural formula:

[0063] Replace 2 - allyl - 4 - bromobenzoic acid in Example 1 with 2 - allyl - 5 - bromobenzoic acid, and keep other conditions the same as in Example 1. Finally, a light yellow solid compound 2b (45.5 mg, 63% yield) is obtained.

[0064] The test data of product 2b are as follows:

[0065] 1 H NMR(400MHz,CDCl 3 )δ8.20(s,1H),7.67(d,J = 10.2Hz,1H),7.15(s,1H),4.87–4.80(m,1H),4.38(q,J = 7.2Hz,2H),3.02(d,J = 7.3Hz,2H),2.83–2.72(m,1H),2.51–2.42(m,1H),1.38(t,J = 7.2Hz,3H).

[0066] 13 C NMR(101MHz,CDCl 3 )δ163.5,162.8,137.1,136.8,133.2,129.3,126.4,121.8,114.3(t,J = 252.9Hz),72.7,63.6,39.9(t,J = 23.6Hz),32.7,14.0.

[0067] 19 F NMR(376MHz,CDCl 3 )δ - 101.34– - 102.16(m,1F), - 106.82– - 107.69(m,1F).

[0068] HRMS(ESI,Q - TOF)m / z:[M + H + Calcd for C 14 H 14 BrF 2 O 4 ,363.0038; Found:363.0038.

[0069] Example 3

[0070] Prepare isochromanone compound 2c with the following structural formula:

[0071] Replace 2 - allyl - 4 - bromobenzoic acid in Example 1 with 2 - allyl - 4 - fluorobenzoic acid, and keep other conditions the same as in Example 1. Finally, a white solid compound 2c (39.8 mg, yield 66%) was obtained, with a melting point of 38.7 - 40.6 °C.

[0072] The detection data of product 2c are as follows:

[0073] Melting point: 38.7 - 40.6 °C.

[0074] 1 H NMR (400 MHz, CDCl 3 ) δ 8.13–8.07 (m, 1H), 7.13–7.06 (m, 1H), 6.99–6.94 (m, 1H), 4.90–4.81 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.11–3.02 (m, 2H), 2.85–2.72 (m, 1H), 2.54–2.42 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H).

[0075] 13 C NMR (101 MHz, CDCl 3 ) δ 167.3, 164.7, 163.2, 141.2 (d, J = 9.4 Hz), 133.5 (d, J = 9.9 Hz), 121.1 (d, J = 2.7 Hz), 116.8, 115.8 (d, J = 22.1 Hz), 114.6 (t, J = 22.3 Hz), 77.1, 72.5, 63.6, 39.9 (t, J = 23.9 Hz), 33.3, 14.0.

[0076] 19 F NMR (376 MHz, CDCl 3 ) δ - 101.81– - 102.70 (m, 1F), - 103.09– - 103.64 (m, 1F), - 107.31– - 108.22 (m, 1F).

[0077] HRMS (ESI, Q - TOF) m / z: [M + H + Calcd for C 14 H 13 F 3 NaO 4 , 325.0658; Found: 325.0653.

[0078] Example 4

[0079] Prepare isochromanone compound 2d with the following structural formula:

[0080] Replace 2 - allyl - 4 - bromobenzoic acid in Example 1 with 2 - allyl - 5 - fluorobenzoic acid, and keep other conditions the same as those in Example 1. Finally, a yellow oily liquid 2d (41.0 mg, 68% yield) is obtained.

[0081] The detection data of product 2d are as follows:

[0082] 1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (d, J = 9.8 Hz, 1H), 7.25 (d, J = 6.9 Hz, 2H), 4.88–4.79 (m, 1H), 4.38 (q, J = 7.2 Hz, 2H), 3.03 (d, J = 7.1 Hz, 2H), 2.85–2.70 (m, 1H), 2.53–2.41 (m, 1H), 1.37 (t, J = 7.2 Hz, 3H).

[0083] 13 C NMR (101 MHz, CDCl 3 ) δ 163.3, 163.1, 160.8, 133.9, 129.5 (d, J = 7.4 Hz), 126.4 (d, J = 7.3 Hz), 121.5 (d, J = 21.9 Hz), 116.8 (d, J = 23.2 Hz), 113.0 (t, J = 254.4 Hz), 72.9, 63.6, 39.9 (t, J = 23.8 Hz), 32.5, 14.0.

[0084] 19 F NMR (376 MHz, CDCl 3 ) δ - 101.36– - 102.19 (m, 1F), - 106.89– - 107.84 (m, 1F), - 112.54 (s, 1F).

[0085] HRMS (ESI, Q - TOF) m / z: [M + H + Calcd for C 14 H 14 F 3 O 4 , 303.0839; Found: 303.0839.

[0086] Example 5

[0087] Prepare the isochromanone compound 2e with the following structural formula:

[0088]

[0089] Replace 2-allyl-4-bromobenzoic acid in Example 1 with 2-allyl-6-fluorobenzoic acid, and keep other conditions the same as in Example 1. Finally, a brown oily liquid compound 2e (39.9 mg, 66% yield) was obtained.

[0090] The detection data of product 2e are as follows:

[0091] 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 6.8 Hz, 2H), 4.82–4.74 (m, 1H), 4.33 (q, J = 7.2 Hz, 2H), 2.98 (d, J = 7.3 Hz, 2H), 2.78–2.65 (m, 1H), 2.47–2.37 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).

[0092] 13 C NMR (101 MHz, CDCl 3 ) δ 147.7 146.8, 138.0, 118.8 (d, J = 31.0 Hz), 118.0 (d, J = 10.3 Hz), 108.0 (t, J = 13.2 Hz), 106.4 (d, J = 33.0 Hz), 101.3 (t, J = 27.6 Hz), 84.6, 77.2, 68.4 (t, J = 23.9 Hz), 37.7, 26.3, 19.4.

[0093] 19 F NMR (376 MHz, CDCl 3 ) δ -101.31– -102.15 (m, 1F), -106.84– -107.69 (m, 1F), -112.36– -112.57 (m, 1F).

[0094] HRMS (ESI, Q-TOF) m / z: [M+H + Calcd for C14H14F3O4, 303.0839; Found: 303.0840.

[0095] Example 6

[0096] Prepare the isochromanone compound 2f with the following structural formula:

[0097]

[0098] Replace 2 - allyl - 4 - bromobenzoic acid in Example 1 with 2 - allyl - 4 - chlorobenzoic acid, and keep other conditions the same as in Example 1. Finally, a yellow oily liquid compound 2f (35.8 mg, 56% yield) is obtained.

[0099] The detection data of product 2f are as follows:

[0100] 1 H NMR (400 MHz, CDCl 3 ) δ8.00 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 4.88–4.81 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.09–3.02 (m, 2H), 2.85–2.72 (m, 1H), 2.54–2.42 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H).

[0101] 13 C NMR (101 MHz, CDCl 3 ) δ163.5, 163.3, 140.5, 139.7, 132.0, 128.7, 127.7, 123.1, 115.5 (t, J = 249.0 Hz), 72.5, 63.6, 39.9 (t, J = 23.8 Hz), 33.0, 14.0.

[0102] 19 F NMR (376 MHz, CDCl 3 ) δ - 102.46– - 103.37 (m, 1F), - 107.97– - 108.86 (m, 1F).

[0103] HRMS (ESI, Q - TOF) m / z: [M + H + Calcd for C 14 H 14 ClF 2 O 4 , 319.0543; Found: 319.0544.

[0104] Example 7

[0105] Prepare isochromanone compound 2g with the following structural formula:

[0106] Replace 2 - allyl - 4 - bromobenzoic acid in Example 1 with 2 - allyl - 5 - chlorobenzoic acid, and keep other conditions the same as in Example 1. Finally, a yellow solid compound 2g (25.9 mg, 41% yield) is obtained.

[0107] The detection data of Product 2g are as follows:

[0108] The melting point is 55.5 - 57.2 °C

[0109] 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 8.2, 2.3 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.87–4.81 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.04 (d, J = 7.3 Hz, 2H), 2.85–2.73 (m, 1H), 2.53–2.44 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H).

[0110] 13 C NMR (101 MHz, CDCl 3 ) δ 163.6 (t, J = 31.8 Hz), 162.9, 136.4, 134.2, 130.2, 129.1, 126.2, 115.5 (t, J = 248.2 Hz), 77.1, 72.7, 63.6, 39.9 (t, J = 23.8 Hz), 32.7, 14.0.

[0111] 19 F NMR (376 MHz, CDCl 3 ) δ -101.34– -102.16 (m, 1F), -106.68– -107.89 (m, 1F).

[0112] HRMS (ESI, Q-TOF) m / z: [M+H + Calcd for C 14 H 14 ClF 2 O 4 , 319.0543; Found: 319.0542.

[0113] Example 8

[0114] Prepare isochromanone compound 2h with the following structural formula:

[0115] Replace 2-allyl-4-bromobenzoic acid in Example 1 with 2-allyl-5-trifluorobenzoic acid, and keep other conditions the same as in Example 1. Finally, a white oily liquid compound 2h (29.1 mg, 41% yield) is obtained. The detection data of Product 2h are as follows:

[0116] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.35 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 4.94–4.84 (m, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.15 (d, J = 7.2 Hz, 2H), 2.89–2.74 (m, 1H), 2.57–2.46 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H).

[0117] 13 13C NMR (101 MHz, CDCl 3 ) δ 163.4 (q, J = 31.0 Hz), 162.9, 141.8, 130.9 (q, J = 33.6 Hz), 130.5 (q, J = 3.6 Hz), 128.5, 127.6 (q, J = 3.8 Hz), 125.4, 123.4 (q, J = 272.5 Hz), 114.2 (t), 72.6 (t), 63.9, 39.9 (t), 33.1, 14.0.

[0118] 19 19F NMR (376 MHz, CDCl 3 ) δ -62.95 (s, 3F), -101.37–-102.19 (m, 1F), -106.75–-107.62 (m, 1F).

[0119] HRMS (ESI, Q-TOF) m / z: [M+H + Calcd for C 15 H 14 F 5 O 4 , 353.0807; Found: 353.0809.

[0120] Example 9

[0121] Prepare isochromanone compound 2i with the following structural formula:

[0122]

[0123] Replace 2-allyl-4-bromobenzoic acid in Example 1 with 2-allylbenzoic acid, and keep other conditions the same as in Example 1. Finally, obtain white oily liquid compound 2i (31.2 mg, 55% yield).

[0124] The test data of product 2i are as follows:

[0125] 11H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.27–7.24 (m, 1H), 4.88–4.81 (m, 1H), 4.42–4.37 (m, 2H), 3.09–3.04 (m, 2H), 2.86–2.72 (m, 1H), 2.53–2.42 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H).

[0126] 13 13C NMR (101 MHz, CDCl 3 ) δ 164.1, 163.6 (t, J = 31.4 Hz), 138.2, 134.2, 130.5, 128.2, 127.6, 124.7, 114.4 (t, J = 248.2 Hz), 72.7, 63.6, 40.0 (t, J = 22.9 Hz), 33.2, 14.0.

[0127] 19 19F NMR (376 MHz, CDCl 3 ) δ -101.34–-102.25 (m, 1F), -106.86–-107.87 (m, 1F).

[0128] HRMS (ESI, Q-TOF) m / z: [M+H + Calcd for C 14 H 15 F 2 O 4 , 285.0933; Found: 285.0936.

[0129] Example 10

[0130] Prepare isochromanone compound 2J with the following structural formula:

[0131]

[0132] Replace 2-allyl-4-bromobenzoic acid in Example 1 with 2-allyl-4-methylbenzoic acid, and keep other conditions the same as in Example 1. Finally, a yellow oily liquid compound 2J (28.0 mg, 47% yield) is obtained. The detection data of product 2J are as follows:

[0133] 1 1H NMR (400 MHz, CDCl 3)δ7.94(d, J = 8.0 Hz, 1H), 7.20(d, J = 8.0 Hz, 1H), 7.05(s, 1H), 4.88–4.76(m, 1H), 4.39(q, J = 7.2 Hz, 2H), 3.06–2.95(m, 2H), 2.83–2.69(m, 1H), 2.52–2.42(m, 1H), 2.40(s, 3H), 1.37(t, J = 7.2 Hz, 3H).

[0134] 13 C NMR(101MHz, CDCl 3 )δ164.2, 163.6(t, J = 31.4 Hz), 145.2, 138.1, 130.4, 129.0, 128.1, 122.0, 114.4(t, J = 258.1 Hz), 72.5, 63.5, 40.0(t, J = 23.7 Hz), 33.2, 21.8, 14.0.

[0135] 19 F NMR(376MHz, CDCl 3 )δ - 101.34– - 102.18(m, 1F), - 106.83– - 107.77(m, 1F).

[0136] HRMS(ESI, Q - TOF) m / z: [M + H + Calcd for C 15 H 17 F 2 O 4 , 299.1089; Found: 299.1084.

[0137] Example 11

[0138] Prepare isochromanone compound 2k with the following structural formula:

[0139]

[0140] Replace 2 - allyl - 4 - bromobenzoic acid in Example 1 with 2 - allyl - 4 - methoxybenzoic acid, and keep other conditions the same as in Example 1. Finally, a yellow oily liquid compound 2k (46.2 mg, 74% yield) is obtained. The test data of product 2k are as follows:

[0141] 1 H NMR(400MHz, CDCl 3) δ 8.00 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 6.2 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 4.85–4.77 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.07–2.97 (m, 2H), 2.84–2.70 (m, 1H), 2.52–2.40 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H).

[0142] 13 C NMR (101 MHz, CDCl 3 ) δ 164.3 (t, J = 5.9 Hz), 140.5, 132.8, 132.5, 117.1, 114.0, 113.4 (t, J = 28.7 Hz), 112.3, 72.3, 63.6, 55.7, 39.9 (t, J = 23.6 Hz), 33.5, 14.0.

[0143] 19 F NMR (376 MHz, CDCl 3 ) δ -102.41– -103.65 (m, 1F), -108.00– -108.94 (m, 1F).

[0144] HRMS (ESI, Q-TOF) m / z: [M + H + Calcd for C 15 H 17 F 2 O 5 , 315.1039; Found: 315.1039.

[0145] Example 12

[0146] Prepare isochromanone compound 2l with the following structural formula:

[0147]

[0148] Replace 2-allyl-4-bromobenzoic acid in Example 1 with 2-allyl-4,5-dimethoxybenzoic acid, and keep other conditions the same as in Example 1. Finally, obtain yellow oily liquid compound 2l (47.6 mg, 69% yield). The detection data of product 2i are as follows:

[0149] 1 H NMR (400 MHz, CDCl 3)δ7.48(s,1H),6.66(s,1H),4.85–4.76(m,1H),4.37(q,J=7.1Hz,2H),3.90(d,J=13.3Hz,6H),3.02–2.92(m,2H),2.81–2.69(m,1H),2.51–2.39(m,1H),1.36(t,J=7.1Hz,3H).

[0150] 13 C NMR(101MHz,CDCl 3 )δ164.2,163.6(t,J=31.9Hz),154.0,148.8,131.8,116.8,115.6(t,J=251.4Hz),111.7,109.4,72.6(t,J=6.7Hz),63.5,56.3,56.2,39.9(t,J=23.6Hz),32.9,30.0(t,J=16.8Hz),14.0.

[0151] 19 F NMR(376MHz,CDCl 3 )δ-100.66–-101.51(m,1F),-106.77–-107.72(m,1F).

[0152] HRMS(ESI,Q-TOF)m / z:[M+H + Calcd for C 16 H 19 F 2 O 6 ,345.1144;Found:345.1146.

[0153] Example 13

[0154] Prepare isochromanone compound 2m with the following structural formula:

[0155]

[0156] Replace 2-allyl-4-bromobenzoic acid in Example 1 with 2-allyl-4-methoxybenzoic acid, and replace ethyl difluoroiodoacetate with 1-iodoperfluorohexane. Other conditions are the same as in Example 1, and finally obtain yellow oily liquid compound 2m (69.2 mg, 68%).

[0157] The detection data of product 2m are as follows:

[0158] 1 H NMR(400MHz,CDCl 3)δ8.03(d,J=8.7Hz,1H),6.91(d,J=8.7Hz,1H),6.72(s,1H),4.99–4.90(m,1H),3.87(s,3H),3.13–3.02(m,2H),2.86–2.71(m,1H),2.58–2.42(m,1H).

[0159] 13 C NMR(101MHz,CDCl 3 )δ164.3(d,J=5.3Hz),140.3,132.9,119.8(t,J=32.0Hz),118.8–117.3(m),117.2,117.0–114.7(m),114.2,114.0–112.6(m),112.4,111.1(t,J=32.8Hz),108.4(t,J=33.2Hz),77.5,77.2,76.8,71.5,55.7,36.3(t,J=21.1Hz),34.2.

[0160] 19 F NMR(376MHz,CDCl 3 )δ-80.85(t,3F),-111.25–-112.07(m,1F),-112.92–-113.74(m,1F),-121.83(s,2F),-122.91(s,2F),-123.54(s,2F),-126.19(s,2F).

[0161] HRMS(ESI,Q-TOF)m / z:[M+Na + Calcd for C 17 H 11 F 13 NaO 3 ,533.0393;Found:533.0391.

[0162] Example 14

[0163] The compound 3 was derived from the fluoroalkyl-substituted isochromanone compound 2b:

[0164]

[0165] The fluoroalkyl-substituted isochromanone compound 2b (0.2 mmol), palladium acetate (0.01 mmol), phenylboronic acid (0.3 mmol), n-butyldi(1-adamantyl)phosphine (0.02 mmol), and cesium carbonate (0.4 mmol) were successively added to DCE (1,2-dichloroethane, 2 mL). After the reaction flask was evacuated with an oil pump, argon was injected into the flask (repeated three times), and it was placed in an 80 °C oil bath and stirred for reaction. After 12 hours, the reaction was cooled to room temperature. The reaction solution was subjected to extraction, drying, filtration, concentration, and silica gel column chromatography to obtain the light yellow solid compound 3 (43.3 mg, 60% yield).

[0166] The detection data of product 3 are as follows:

[0167] Melting point: 95.1 - 96.9 °C

[0168] 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 7.9 Hz, 1H), 7.65–7.57 (m, 3H), 7.51–7.39 (m, 4H), 4.95–4.84 (m, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.12 (d, J = 5.4 Hz, 2H), 2.90–2.74 (m, 1H), 2.57–2.43 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H).

[0169] 13 C NMR (101 MHz, CDCl 3 ) δ 163.8 (t, J = 48.4 Hz), 147.0, 139.5, 138.7, 131.1, 129.2, 128.7, 127.4, 126.9, 126.2, 123.4, 114.5 (t, J = 250.3 Hz), 72.7 (t, J = 6.9 Hz), 63.6, 40.1 (t, J = 23.7 Hz), 33.5, 14.0.

[0170] 19 F NMR (376 MHz, CDCl 3 ) δ -101.21--102.08 (m, 1F), -106.66--107.64 (m, 1F).

[0171] HRMS (ESI, Q-TOF) m / z: [M + H + Calcd for C 20 H 19 F 2 O 4, 361.1246; Found: 361.1243.

[0172] Verification of anti-tumor activity

[0173] Select the isochromanone compounds substituted with difluoroalkyl prepared in the examples, using human promyelocytic leukemia cell line (HL-60) as the receptor, and test their in vitro anti-tumor activity (MTS method).

[0174] Experimental method:

[0175] (1) Cell seeding: Prepare a single cell suspension with a culture medium (RMPI1640) containing 10% fetal bovine serum, seed 15,000 cells per well into a 96-well plate, with a volume of 100 μl per well, and seed and culture the cells 12 - 24 hours in advance. (2) Add the test compound solution: Dissolve the compound in DMSO, and the specific screening concentrations (μM) of the compound are 0.16, 0.8, 4, 20, 100 in sequence, with a final volume of 200 μl per well, and set 3 replicates for each treatment. (3) Color development: After culturing at 37 °C for 48 hours, discard 100 μl of the culture supernatant of the suspended cells, add 20 μl of MTS solution to each well; discard 100 μl of the culture supernatant of the suspended cells, add 20 μl of MTS solution to each well; set 3 blank replicates (a mixture of 20 μl of MTS solution and 100 μl of culture medium), continue to incubate for 2 - 4 hours, and measure the light absorption value after the reaction proceeds fully. (4) Colorimetric analysis: Select a wavelength of 492 nm, use a multi-functional microplate reader (MULTISKAN FC) to read the light absorption values of each well, record the results, and after data processing, plot a cell growth curve with the concentration as the abscissa and the cell survival rate as the ordinate, and calculate the IC50 value of the compound using the two-point method (Reed and Muench method). (5) Positive control compound: Cisplatin (DDP) is set as the positive compound in the experiment, plot a cell growth curve with the concentration as the abscissa and the cell survival rate as the ordinate, and calculate the IC50 value of the compound using the two-point method (Reed and Muench method).

[0176] Table 1 shows the inhibitory effects of some compounds in the examples on the proliferation of human promyelocytic leukemia cell line (HL-60).

[0177]

[0178]

[0179] Thus, it can be seen that the fluorine-containing isochromanone compounds provided by the present invention have certain activities of inhibiting the proliferation of leukemia cells.

[0180] The above are only embodiments of the present invention, and common knowledge such as specific structures and characteristics known in the art are not described in detail herein. It should be noted that for those skilled in the art, without departing from the structure of the present invention, several modifications and improvements can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the implementation effect of the present invention and the practicability of the patent. The protection scope required by this application shall be subject to the content of its claims, and the specific implementation manners described in the specification can be used to interpret the content of the claims.

Claims

1. A fluoroalkyl-substituted isochromanone compound, characterized in that: Its structural formula is as follows: wherein R is independently selected from 8-fluoro, 8-chloro, 8-bromo, 8-iodo, 7-fluoro, 7-chloro, 7-bromo, 7-iodo, 7-trifluoromethyl, 7-methoxy, 7-methyl, 6-fluoro, 6-chloro, 6-bromo, 6-iodo, 6-trifluoromethyl, 6-methoxy, 6-methyl, 5-fluoro, 5-chloro, 5-bromo, 5-iodo, 5-methyl, 5-trifluoromethyl, 5-methoxy, 6,7-dimethoxy, 6,7-dimethyl, 6- fluoro-7-methoxy, 6-bromo-7-methoxy, 6-chloro-7-methoxy, 6-iodo-7-methoxy, 6-methoxy-7-iodo, 6-methoxy-7-bromo, 6-methoxy-7-chloro, 6-methoxy-7-fluoro, 7-bromo-8-fluoro, 6-bromo-7-fluoro, 6,7-difluoro, 6,7-dichloro, 5-methoxy-8-fluoro, 5-methoxy-8-chloro, 5-methyl-8-fluoro or 5-methyl-8-chloro; R' is selected from ethoxycarbonyl or methoxycarbonyl.

2. The method for preparing isochromanone compounds according to claim 1, characterized in that: 2-allylarylcarboxylic acid, R'CF2I, silver salt and an organic solvent are mixed, heated to a certain temperature under a certain time and gas atmosphere to react, and then separated and purified to obtain a fluoroalkyl-substituted isochromanone compound; ， The definitions of R and R' refer to claim 1.

3. The preparation method according to claim 2, characterized in that: The silver salt is selected from silver acetate, silver oxide, silver carbonate, silver trifluoroacetate or silver chloride.

4. The preparation method according to claim 3, characterized in that: The organic solvent is selected from acetonitrile, tetrahydrofuran, 1,2-dichloroethane, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or ethyl acetate.

5. The preparation method according to claim 3 or 4, characterized in that: The temperature is 20°C to 100°C; the time is 2 h to 40 h; and the gas atmosphere is selected from air, nitrogen or argon.

6. The preparation method according to claim 5, characterized in that: The molar ratio of 2-allylcarboxylic acid: R'CF2I: silver salt is 1: 1-5: 0.1-2.

7. The preparation method according to claim 6, characterized in that: The separation and purification method is selected from silica gel column chromatography and recrystallization.

8. Use of the isochromanone compounds according to claim 1 in the preparation of anti-leukemia drugs.

Images