Fluorinated derivatives of methoxydibenzo[b,f]oxepine and methods for obtaining them

Abstract

The present invention provides a fluorinated derivative of methoxydibenzo[b,f]oxepin of general formula (1) and general formula (2), and a method for obtaining the same by a catalytic reaction of fluoroazobenzene and methoxydibenzo[b,f]oxepin. A suitable catalyst for the reaction is triethylamine, and the obtained compound may be useful as a molecular switch in biological systems and photopharmacology. JPEG2025516454000006.jpg70157

Description

Technical Field

[0001] The present invention provides a fluorinated derivative of methoxydibenzo[b,f]oxepine which may be useful as a molecular switch in biological systems and photopharmacology, and a method for obtaining the same by a catalytic reaction of fluoroazobenzene and methoxydibenzo[b,f]oxepine.

Background Art

[0002] Molecular photoswitches are photoreactive compounds characterized by the ability to isomerize cis-trans double bonds, such as those in azobenzene. They have been applied to remote control of biological systems [1], smart materials [2], and molecular machines [3]. One of the more remarkable biological applications is the restoration of vision. During research in blind mice, a photochemical restoration of visual response was observed by the action of an azo compound, which is a molecular switch enabling control of nerve excitation [4]. In particular, the potential of their use in photopharmacology [5] has attracted great interest in recent years. The development of new molecular photoswitches has been largely driven by addressing the challenge of enabling 'bidirectional' action using visible and red light or even near-infrared (NIR) light [6]. This is particularly relevant for medical applications, since red / NIR light can reach deep (1 cm) tissues by transmitting without the toxic effects caused by high-energy light [7].

[0003] Dibenzo[b,f]oxepines are an interesting class of compounds due to their numerous biological properties, such as anti-inflammatory effects [8], antihypertensive effects [9], or anticancer effects

[10] . On the other hand, fluoroazobenzene is a molecule that provides the characteristics of stable and bidirectional photoconversion and tissue compatibility

[11] .

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

[0005] The object of the present invention is to provide a rapid, inexpensive, and simple method for obtaining a branched dibenzo[b,f]oxepin derivative with fluoroazobenzene, which is characterized by good atom economy.

[0006] The present invention relates to general formula (1) and general formula (2):

[0007] [Chemical Formula]

[0008] [In the formula, R 1 , R 2 = H, OMe; R 3 , R 4 , R 5 = H, F] To provide a fluorinated derivative of methoxydibenzo[b,f]oxepine.

[0009] The present invention further provides a method for obtaining methoxydibenzo[b,f]oxepine derivatives of general formula (1) and general formula (2), which are preferably of the formula 3a-b of substituted methoxydibenzo[b,f]oxepine and the formula 4a-d and 5a-d and are obtained by a reaction in which the reaction with the fluoroazobenzene of is carried out in the presence of a solvent and a catalyst.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Modes for Carrying Out the Invention

[0011] In the first step, thionyl chloride is added to fluoroazobenzene 4a-d and 5a-d and then the mixture is heated. Next, the reaction mixture is evaporated to dryness and then dissolved several times in an aprotic organic solvent and evaporated to dryness again.

[0012] In the next step, methoxydibenz[b,f]oxepin is dissolved in an aprotic organic solvent, a catalyst is added, the residue from step (b) is dissolved in an aprotic organic solvent, and then the reaction mixture is stirred.

[0013] Preferably, the ratio of fluorobenzene to thionyl chloride in step (a) is 1:50 mol / mol. Preferably, the reaction in step (a) is heated at 80 °C for 30 minutes.

[0014] Preferably, the aprotic solvent in step (b) is methylene chloride. Preferably, the aprotic solvent in step (c) is ethyl acetate. Preferably, the catalyst in step (c) is triethylamine.

[0015] Preferably, the ratio of fluoroazobenzene to methoxydibenz[b,f]oxepin is 1:1 mol / mol, more preferably 1:0.85 mol / mol. Preferably, in step (c), a catalyst in a ratio of 25:1 mol / mol with respect to fluoroazobenzene is used.

[0016] Preferably, the reaction in step (d) is stirred at 25 °C for 1 to 24 hours. A rapid, inexpensive and simple method for obtaining fluorinated dibenz[b,f]oxepin derivatives of general formula 1 and general formula 2 is characterized by good atom economy. The method according to the present invention may be useful for the synthesis of dibenz[b,f]oxepin derivatives containing fluorine groups. This type of compound can be used as a photoswitch in biological systems and photopharmacology.

Example

[0017] In the following examples, the present invention is illustrated without limiting it. General procedure for the preparation of compounds 1a-1h and compounds 2a-2h 0.2 mmol of the corresponding fluoroazobenzene (4a-d / 5a-d) and a magnetic stirring element were placed in a 5 ml round-bottom flask. Next, 50 equivalents of thionyl chloride were added. The whole mixture was heated at 80 °C for about 30 minutes under a reflux condenser. The reaction mixture was evaporated to dryness on a rotary evaporator. Approximately 2 ml of DCM was added and evaporated again to remove residual SOCl 2 This operation was repeated twice. 0.85 equivalent of methoxydibenzo[b,f]oxepin ( 3a-b ) was placed in a vial together with a magnetic stirring element and dissolved in 1 ml of ethyl acetate. The contents were stirred. Next, 0.25 mmol of triethylamine was added to the solution using an automatic pipette. The dry residue after evaporation of thionyl chloride was dissolved in 1 ml of ethyl acetate, transferred to the vial and the contents were stirred. The system was sealed with a stopper and left overnight with stirring. After this time, the reaction mixture was analyzed based on the position of the spot on a TLC plate of a hexane-ethyl acetate system with a volume ratio of 7:3. The mixture was evaporated, dissolved in a small amount of DCM, and then purified on a chromatography column of the above system.

[0018] Sixteen derivatives (compounds of formula 1a-h and 2a-h ) were obtained as yellow-orange powders. Compound (1a) : Yield: 46%, mp = 215.5 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): For the dibenzo[b,f]oxepin ring: 10.57 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 1.5 Hz, H 4 ), 7.66 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.27 (1H, d, H1 ), 7.12 - 7.08 (2H, m, H 7 , H 8 ), 6.83 (1H, dd, J H8,H9 = 6.5 Hz, J H7,H9 = 3 Hz, H 9 ), 6.78 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.72 (1H, spin system AB, d, H 11 ), 3.87 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.18 (2H, d, J H2,H3 = 8.5 Hz, H 3 ), 8.02 (2H, d, H 2 ), 7.95 (2H, dd, J H2’,H3’ = 8 Hz, J H2’,H4’ = 2 Hz, H 2’ ), 7.65 - 7.61 (3H, m, H 3’ , H 4’ ).

[0019] 13 C NMR (125 MHz, DMSO - d 6 , 298K): δ(ppm): 164.75, 164.53, 156.62, 156.56, 156.26, 153.53, 153.49, 151.92, 151.48, 151.45, 144.20, 144.17, 140.85, 136.74, 132.71, 132.11, 131.48, 131.47, 129.68, 129.57, 129.25, 129.17, 129.14, 128.92, 128.77, 128.69, 128.61, 127.59, 126.09, 125.95, 125.09, 125.06, 122.79, 122.40, 120.54, 120.51, 120.02, 119.52, 116.63, 116.53, 113.25, 113.16, 113.00, 112.97, 56.16, 56.13 (overlapping signals from atropisomers).

[0020] HRMS (ESI): C 28 H 21 N 3 O 3+ , calculated m / z: 447.15774; measured m / z: 447.15778. Compound (1b) : Yield: 76%, mp = 242.5 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.57 (1H, s, NH), 7.78 (1H, d, J H2,H4 = 2.5 Hz, H 4 ), 7.66 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.27 (1H, d, H 1 ), 7.10 - 7.08 (2H, m, H 7 , H 8 ), 6.83 (1H, dd, J H8,H9 = 6.5 Hz, J H7,H9 = 2.5 Hz, H 9 ), 6.78 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.72 (1H, AB spin system, d, H 11 ), 3.87 (3H, s, OCH 3 ); azofluorobenzene ring: 8.18 (2H, d, J H2,H3 = 8.5 Hz, H 2 ), 8.03 (2H, dd, J H2’,H3’ = 8.5 Hz, J H2’,F = 5 Hz, H 2’ ), 8.01 (2H, d, H 2 ), 7.47 (2H, t, J H3’,F = 8.5 Hz, H 3’ ).

[0021] 13 C NMR (125 MHz, DMSO-d6 , 298K): δ(ppm): 165.15, 164.73, 163.15, 156.61, 156.09, 153.40, 151.47, 148.72, 148.70, 144.20, 140.84, 136.76, 131.48, 129.68, 129.25, 129.14, 128.77, 128.74, 128.70, 126.09, 125.26, 125.19, 125.09, 122.75, 122.68, 122.39, 120.54, 119.43, 116.68, 116.62, 116.54, 116.50, 115.95, 115.77, 113.24, 113.17, 113.00, 56.15 (overlapping signals from atropisomers).

[0022] HRMS (ESI): C 28 H 20 FN 3 O 3 + , calculated m / z: 465.14832; measured m / z: 465.14843. Compound (1c) : Yield: 26%, mp = 246 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.58 (1H, s, NH), 7.78 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.66 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.27 (1H, d, H 1 ), 7.09 (1H, t, J H8,H9,7 = 6.5 Hz, H 8 ), 7.08 (1H, dd, J H7,H9 = 2.5 Hz, H 7 ), 6.83 (1H, dd, H 9 ), 6.78 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10), 6.72 (1H, AB spin system, d, H 11 ), 3.87 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.18 (2H, d, J H2,H3 = 8.5 Hz, H 3 ), 8.01 (2H, d, H 2 ), 7.87 (1H, td, J H5’,H6’ = 9 Hz, J H5’,F = 6.5 Hz H 6’ ), 7.62 (1H, ddd, J H3’,F = 9 Hz, J H3’,H5’ = 3 Hz, H 3’ ), 7.32 - 7.30 (1H, m, H 5’ ).

[0023] 13 C NMR (125 MHz, DMSO-d 6 , 298K): δ (ppm): 164.69, 164.45, 156.61, 156.56, 156.10, 153.54, 151.47, 151.45, 144.19, 144.17, 140.81, 140.79, 137.16, 133.73, 131.48, 131.47, 129.68, 129.66, 129.25, 129.21, 129.19, 128.78, 128.72, 126.12, 126.01, 125.09, 125.07, 122.61, 120.54, 120.52, 119.34, 119.25, 119.09, 116.64, 116.55, 113.25, 113.18, 113.00, 112.98, 112.79, 112.60, 105.97, 105.76, 105.57, 56.15, 56.13 (overlapping signals from atropisomers).

[0024] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 +, Calculated m / z: 483.13890; Measured m / z: 483.13884. Compound (1d) : Yield: 16%, mp = 230 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): Dibenz[b,f]oxepin ring: 10.59 (1H, s, NH), 7.78 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.65 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.27 (1H, d, H 1 ), 7.08 (1H, t, J H8,H7,9 = 6 Hz, H 8 ), 7.07 (1H, dd, J H7,H9 = 3 Hz, H 7 ), 6.82 (1H, dd, H 9 ), 6.77 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.71 (1H, AB spin system, d, H 11 ), 3.86 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.19 (2H, d, J H2,H3 = 8.5 Hz, H 3 ), 7.99 (2H, d, H 2 ), 7.61 (1H, tt, J H3’,H4’ = 8.5 Hz, J H4’,F = 6 Hz, H 4’ ), 7.36 (2H, t, J H3’,F = 9.5 Hz, H 3’ ).

[0025] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 164.62, 164.39, 156.62, 156.56, 156.44, 155.96, 154.00, 153.90, 151.48, 151.45, 144.20, 144.17, 140.78, 140.76, 137.59, 134.61, 132.59, 131.48, 131.47, 130.23, 129.68, 129.66, 129.26, 129.24, 129.19, 128.87, 128.80, 128.74, 126.16, 126.05, 125.10, 125.07, 122.41, 120.54, 120.52, 118.25, 116.66, 116.56, 113.27, 113.25, 113.19, 113.09, 113.01, 112.98, 112.55, 112.37, 56.16, 56.13 (signals overlapping from atropisomers).

[0026] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 + , calculated m / z: 483.13890; measured m / z: 483.13901. Compound (1e) : Yield: 30%, mp = 168 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.55 (s, 1H, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.56 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, 6.80 (1H, d, J H6,H8 = 2.5 Hz, H 6 ), 6.77 (1H, dd, H 8), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.18 (2H, d, J H2,H2 = 8.5 Hz, H 2 ), 8.02 (2H, d, H 3 ), 7.95 (2H, dd, J H2’,H3’ = 8.5 Hz, J H2’,H4’ = 2 Hz, H 2’ ), 7.63 - 7.62 (3H, m, H 3’ , H 4’ ).

[0027] 13 C NMR (125 MHz, DMSO-d 6 , 298K): δ (ppm): 164.69, 161.18, 157.31, 156.07, 153.55, 151.92, 140.62, 136.71, 132.11, 130.20, 129.57, 129.30, 129.08, 128.55, 127.20, 126.02, 122.92, 122.79, 122.43, 116.84, 112.97, 111.22, 106.68, 55.52.

[0028] HRMS (ESI): C 28 H 21 N 3 O 3 + , calculated m / z: 447.15774; measured m / z: 447.15764. Compound (1f) : Yield: 34%, mp = 218 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): Dibenz[b,f]oxepin ring: 10.55 (1H, s, NH), 7.79 (1H, d, J H2,H4= 2 Hz, H 4 ), 7.56 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, H 9 ), 6.80 (1H, d, J H6,H8 = 2.5 Hz, H 6 ), 6.77 (1H, dd, H 8 ), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.17 (2H, d, J H2,H3 = 8.5 Hz, H 3 ), 8.02 (2H, dd, J H2’,H3’ = 9 Hz, J H2’,F = 5 Hz, H 2’ ), 8.01 (2H, d, H 2 ), 7.47 (2H, t, J H3’,F = 9 Hz, H 3’ ).

[0029] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 165.16, 164.67, 164.44, 163.16, 161.18, 161.15, 157.31, 157.28, 156.11, 156.07, 156.02, 153.42, 149.66, 149.64, 148.72, 148.69, 140.61, 140.50, 136.73, 136.68, 132.77, 130.20, 130.18, 129.30, 129.23, 129.08, 128.68, 128.55, 128.47, 127.20, 126.03, 125.89, 125.27, 125.20, 122.92, 122.75, 122.68, 122.43, 119.47, 116.84, 116.74, 116.69, 116.50, 115.95, 115.77, 112.97, 112.87, 111.21, 111.18, 106.68, 106.66, 55.52, 55.50 (signals overlapping from the atropisomer).

[0030] HRMS (ESI): C 28 H 20 FN 3 O 3+ , calculated m / z: 465.14832; measured m / z: 465.14824. Compound (1g) : Yield: 23%, mp = 215 °C 1 1H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.57 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.56 (1H, dd, J H1,H2 = 8 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, H 9 ), 6.80 (1H, d, J H6,H8 = 2.5 Hz, H 6), 6.77 (1H, dd, H 8 ), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azofluorobenzene ring 8.18 (2H, d, J H2,H3 = 8.5 Hz, H 3 ), 8.01 (2H, d, H 2 ), 7.87 (1H, td, J H5’,H6’ = 8.5 Hz, J H6’,F = 6.5 Hz, H 6’ ), 7.62 (1H, ddd, J H3’,F = 9 Hz, J H3’,H5’ = 2.5 Hz, H 3’ ), 7.31 - 7.27 (1H, m, H 5’ ).

[0031] 13 C NMR (125 MHz, DMSO-d 6 , 298K): δ (ppm): 164.63, 161.19, 157.30, 157.28, 156.06, 153.58, 153.55, 140.58, 137.13, 130.20, 129.31, 129.24, 129.15, 128.67, 128.56, 127.20, 126.06, 125.94, 122.92, 122.65, 119.33, 119.25, 119.13, 116.85, 116.76, 112.99, 112.82, 112.63, 111.22, 106.68, 106.66, 105.98, 105.79, 105.57, 55.52, 55.51 (overlapping signals from atropisomers).

[0032] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 +, Calculated m / z: 483.13890; Measured m / z: 483.13864. Compound (1h) : Yield: 39%, mp = 175 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): Dibenz[b,f]oxepin ring: 10.58 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.56 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, H 9 ), 6.80 (1H, d, J H6,H8 = 2.5 Hz, H 6 ), 6.77 (1H, dd, H 8 ), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.19 (2H, d, J H2,H3 = 8.5 Hz, H 3 ), 8.00 (2H, d, H 2 ), 7.62 (1H, tt, J H3’,H4’ = 8.5 Hz, J H4’,F = 6 Hz, H 4’ ), 7.37 (2H, t, J H3’,F = 9 Hz, H 3’ ).

[0033] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 164.55, 164.31, 161.19, 161.16, 157.31, 157.28, 156.44, 156.06, 156.01, 155.95, 154.00, 153.93, 150.91, 148.93, 140.55, 137.55, 134.57, 132.58, 130.20, 130.18, 129.31, 129.24, 129.18, 128.81, 128.57, 128.51, 127.19, 126.09, 125.97, 122.91, 122.90, 122.44, 118.29, 116.87, 116.75, 113.27, 113.24, 113.11, 113.09, 113.01, 112.89, 112.39, 111.22, 111.18, 106.68, 106.66, 55.52, 55.50 (signals overlapping from the atropisomer).

[0034] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 + , calculated m / z: 483.13890; measured m / z: 483.13899. Compound (2a) : Yield: 53%, mp = 175 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.62 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.67 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.28 (1H, d, H 1 ), 7.09 (1H, t, J H8,H7,9 = 6.5 Hz, H 8 ), 7.08 (1H, dd, J H7,H9 = 2 Hz, H 7), 6.83 (1H, dd, H 9 ), 6.78 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.72 (1H, AB spin system, d, H 11 ), 3.87 (3H, s, OCH 3 ); Azo fluorobenzene ring: 8.47 (1H, t, J H2,H4,6 = 2 Hz, H 2 ), 8.15 (1H, ddd, J H5,H6 = 8 Hz, J H4,H6 = 1 Hz, H 6 ), 8.10 (1H, ddd, J H4,H5 = 8 Hz, H 4 ), 7.95 (2H, dd, J H2’,H3’ = 8.5 Hz, J H2’,H4’ = 1.5 Hz, H 2’ ), 7.77 (1H, t, H 5 ), 7.66 - 7.61 (3H, m, H 3’ ,H 4’ ).

[0035] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 164.79, 164.52, 156.62, 156.60, 153.57, 153.32, 151.85, 151.77, 151.48, 151.45, 144.21, 144.19, 140.84, 140.72, 135.97, 135.29, 131.93, 131.48, 131.46, 130.59, 129.73, 129.69, 129.66, 129.58, 129.25, 128.95, 128.92, 128.77, 127.49, 126.39, 126.09, 126.07, 125.37, 125.09, 122.69, 122.05, 121.82, 120.55, 120.02, 119.93, 116.65, 116.54, 113.27, 113.14, 113.01, 56.16, 56.15 (signals overlapping from atropisomers).

[0036] HRMS (ESI): C 28 H 21 N 3 O 3 H + , calculated m / z: 448.16557; measured m / z: 448.16562. Compound (2b) : Yield: 23%, mp = 168.5 °C 1 1H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.62 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.66 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.27 (1H, d, H 1 ), 7.12 - 7.08 (2H, m, H 7 , H 8 ), 6.83 (1H, dd, J H8,H9 = 6 Hz, J H7,H9 = 3 Hz, H 9), 6.78 (1H, AB spin system, d, J H10,H11 = 11 Hz, H 10 ), 6.72 (1H, AB spin system, d, H 11 ), 3.87 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.46 (1H, t, J H2,H4,6 = 1.5 Hz, H 2 ), 8.16 - 8.14 (1H, m, H 6 ), 8.10 - 8.08 (1H, m, H 4 ), 8.03 (2H, dd, J H2’,H3’ = 8.5 Hz, J H2’,F = 5 Hz, H 2’ ), 7.76 (1H, t, J H5,H4,6 = 8 Hz, H 5 ), 7.47 (2H, t, J H3’,F = 8.5 Hz, H 3’ ).

[0037] 13 C NMR (125 MHz, DMSO-d 6 , 298K): δ (ppm): 165.05, 164.77, 164.51, 163.06, 156.62, 156.60, 153.45, 151.65, 151.48, 151.46, 149.50, 149.47, 148.64, 148.61, 144.21, 140.83, 140.71, 135.98, 135.42, 131.48, 131.46, 130.60, 129.73, 129.69, 129.66, 129.25, 129.07, 128.77, 126.47, 126.09, 125.39, 125.15, 125.09, 125.07, 122.76, 122.69, 121.80, 120.55, 119.92, 116.68, 116.65, 116.55, 116.49, 115.95, 115.77, 113.26, 113.16, 113.01, 56.16, 56.15 (overlapping signals from atropisomers).

[0038] HRMS (ESI): C 28 H 20 FN 3 O 3 H + , calculated m / z: 466.15615; measured m / z: 466.15591. Compound (2c) : Yield: 87%, mp = 190.5 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.63 (1H, s, NH), 7.78 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.66 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.27 (1H, d, H 1 ), 7.10 - 7.09 (2H, m, H 7 ,H 8 ), 6.83 (1H, dd, J H8,H9 = 6.5 Hz, J H7,H9 = 3 Hz, H 9 ), 6.77 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.72 (1H, AB spin system, d, H 11 ), 3.87 (3H, s, OCH 3 ); azofluorobenzene ring: 8.46 (1H, t, J H2,H4,6 = 2 Hz, H 2 ), 8.17 (1H, ddd, J H5,H6 = 8 Hz, J H4,H6 = 1 Hz, H 6 ), 8.09 (1H, ddd, J H4,H5 = 8 Hz, H 4 ), 7.88 (1H, td, J H5’,H6’ = 8.5 Hz, J H6’,F = 6.5 Hz, H 6’ ), 7.77 (1H, t, H 5), 7.62 (1H, ddd, J H3’,F = 9 Hz, J H3’,H5’ = 2.5 Hz, H 3’ ), 7.31 - 7.27 (1H, m, H 5’ ).

[0039] 13 C NMR (125 MHz, DMSO - d 6 , 298K): δ (ppm): 165.46, 164.68, 164.29, 163.45, 161.01, 158.95, 156.61, 156.59, 153.68, 151.84, 151.47, 151.45, 144.20, 144.18, 140.80, 140.66, 136.91, 136.04, 135.37, 131.48, 131.46, 131.01, 129.81, 129.68, 129.65, 129.25, 129.12, 128.78, 127.34, 126.12, 125.30, 125.09, 123.36, 122.27, 121.52, 120.54, 119.38, 116.65, 116.58, 113.27, 113.19, 113.00, 112.63, 112.10, 105.96, 105.75, 105.56, 105.19, 105.00, 104.79, 56.15 (overlapping signals from atropisomers).

[0040] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 H + , calculated m / z: 484.14672; found m / z: 484.14652. Compound (2d) : Yield: 36%, mp = 179.5 °C 1 H NMR (500 MHz, DMSO - d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.64 (1H, s, NH), 7.78 (1H, d, J H2,H4= 2 Hz, H 4 ), 7.66 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.27 (1H, d, H 1 ), 7.10 - 7.08 (2H, m, H 7 ,H 8 ), 6.83 (1H, dd, J H8.H9 = 6.5 Hz, J H7,H9 = 3 Hz, H 9 ), 6.78 (1H, AB spin system, d, J H10.H11 = 11.5 Hz, H 10 ), 6.72 (1H, AB spin system, d, H 11 ), 3.87 (3H, s, OCH 3 ); Azofluorobenzene ring: 8.46 (1H, t, J H2,H4,6 = 2 Hz, H 2 ), 8.21 (1H, ddd, J H5,H6 = 8 Hz, J H4,H6 = 1.5 Hz, J H2,H6 = 1 Hz, H 6 ), 8.07 (1H, ddd, J H4,H5 = 8 Hz, J H2,H4 = 1 Hz, H 4 ), 7.79 (1H, t, H 5 ), 7.61 - 7.59 (1H, m, H 4’ ), 7.37 (2H, t, J H3’,H4’ = 9 Hz, J H3’,F = 9 Hz, H 3’ ).

[0041] 13 C NMR (125 MHz, DMSO - d 6, 298K): δ (ppm): 164.56, 164.06, 156.58, 155.94, 154.17, 153.89, 152.34, 151.48, 151.45, 150.97, 149.00, 146.02, 144.21, 144.19, 140.78, 140.70, 140.60, 136.06, 135.38, 132.34, 131.61, 131.45, 130.26, 130.19, 130.11, 129.91, 129.68, 129.65, 129.35, 129.26, 128.83, 128.80, 128.19, 126.17, 126.14, 125.10, 124.96, 122.14, 121.02, 120.55, 118.36, 116.68, 116.61, 113.30, 113.24, 113.21, 113.01, 112.51, 56.16 (overlapping signals from atropisomers).

[0042] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 H + , calculated m / z: 484.14672; found m / z: 484.14667. Compound (2e) : Yield: 80%, mp = 193.5 °C 1 1H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.61 (1H, s, NH), 7.80 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.57 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, H 9 ), 6.80 (1H, d, J H6,H8 = 2.5 Hz, H 6), 6.77 (1H, dd, H 8 ), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azo fluorobenzene ring: 8.47 (1H, t, J H2,H4,6 = 2 Hz, H 2 ), 8.15 (1H, ddd, J H5,H6 = 8 Hz, J H4,H6 = 1 Hz, H 6 ), 8.10 (1H, ddd, J H4,H5 = 8 Hz, H 4 ), 7.95 (2H, dd, J H2’,H3’ = 8.5 Hz, J H2’,H4’ = 1.5 Hz, H 2’ ), 7.77 (1H, t, H 5 ), 7.65 - 7.60 (3H, m, H 3’ , H 4’ ).

[0043] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 164.72, 164.44, 161.18, 157.31, 157.29, 156.06, 156.04, 153.59, 153.32, 151.84, 151.79, 140.62, 140.49, 135.94, 135.24, 131.94, 130.55, 130.20, 129.77, 129.58, 129.30, 129.28, 129.00, 128.93, 128.54, 127.50, 127.21, 127.17, 126.32, 126.02, 125.37, 122.93, 122.90, 122.69, 122.18, 121.77, 120.00, 119.78, 116.85, 116.72, 113.00, 112.86, 111.22, 106.68, 106.66, 55.52 (signals overlapping from atropisomers).

[0044] HRMS (ESI): C 28 H 21 N 3 O 3 + , calculated m / z: 447.15774; measured m / z: 447.15789. Compound (2f) : Yield: 62%, mp = 188.5 °C 1 1H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.61 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.57 (1H, dd, J H1,H2 = 8 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, H 9 ), 6.80 (1H, d, J H6,H8 = 2.5 Hz, H 6 ), 6.77 (1H, dd, H 8), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azo fluorobenzene ring: 8.46 (1H, t, J H2,H4,6 = 1.5 Hz, H 2 ), 8.14 (1H, ddd, J H5,H6 = 8 Hz, J H4,H6 = 1 Hz, H 6 ), 8.09 (1H, ddd, J H4,H5 = 8 Hz, H 4 ), 8.03 (2H, dd, J H2’,H3’ = 9 Hz, J H3,F = 5 Hz, H 2’ ), 7.77 (1H, t, H 5 ), 7.47 (2H, t, J H3’,F = 9 Hz, H 3’ ).

[0045] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 165.05, 164.70, 164.42, 163.05, 161.64, 161.18, 159.68, 157.31, 157.29, 156.06, 156.04, 153.46, 151.66, 149.49, 149.47, 148.63, 148.60, 140.61, 140.48, 135.95, 135.37, 130.55, 130.20, 129.77, 129.29, 129.12, 128.54, 127.20, 127.17, 126.40, 126.02, 126.00, 125.38, 125.14, 125.07, 122.92, 122.90, 122.74, 122.67, 121.96, 121.76, 119.76, 116.84, 116.73, 116.67, 116.49, 115.95, 115.77, 112.99, 112.88, 111.21, 106.68, 106.66, 55.51, 54.89 (signals overlapping from atropisomers).

[0046] HRMS (ESI): C 28 H 20 FN 3 O 3 + , calculated m / z: 465.14832; measured m / z: 465.14853. Compound (2g) : Yield: 89%, mp = 169.5 °C 1 1H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.61 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.56 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, H 9 ), 6.80 (1H, d, JH6,H8 = 2.5 Hz, H 6 ), 6.77 (1H, dd, H 8 ), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azo fluorobenzene ring: 8.46 (1H, t, J H2,H4,6 = 2 Hz, H 2 ), 8.17 (1H, ddd, J H5,H6 = 8 Hz, J H4,H6 = 1 Hz, H 6 ), 8.09 (1H, ddd, J H4,H5 = 8 Hz, H 4 ), 7.87 (1H, td, J H5’,H6’ = 8.5 Hz, J H6’,F = 6 Hz, H 6’ ), 7.78 (1H, t, H 5 ), 7.62 (1H, ddd, J H3’,F = 9 Hz, J H3’,H5’ = 2.5 Hz, H 3’ ), 7.27 - 7.31 (1H, m, H 5’ ).

[0047] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 165.37, 164.62, 164.21, 163.45, 161.18, 161.01, 158.95, 157.31, 157.29, 156.06, 156.04, 153.71, 151.86, 140.57, 140.43, 136.92, 136.02, 135.33, 130.95, 130.20, 129.85, 129.30, 129.28, 129.17, 128.55, 127.26, 127.19, 127.16, 126.05, 125.31, 123.38, 122.92, 122.89, 122.22, 121.66, 119.37, 119.29, 116.86, 116.77, 113.01, 112.92, 112.62, 112.11, 111.22, 106.68, 105.96, 105.77, 105.56, 105.19, 105.00, 104.79, 55.51 (signals overlapping from atropisomers).

[0048] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 + , calculated m / z: 483.13890; measured m / z: 483.13893. Compound (2h) : Yield: 91%, mp = 167.5 °C 1 H NMR (500 MHz, DMSO-d 6 , 298K): δ (ppm): dibenzo[b,f]oxepin ring: 10.63 (1H, s, NH), 7.79 (1H, d, J H2,H4 = 2 Hz, H 4 ), 7.57 (1H, dd, J H1,H2 = 8.5 Hz, H 2 ), 7.23 (1H, d, H 1 ), 7.18 (1H, d, J H8,H9 = 8.5 Hz, H 9 ), 6.80 (1H, d, J H6,H8= 2.5 Hz, H 6 ), 6.76 (1H, dd, H 8 ), 6.64 (1H, AB spin system, d, J H10,H11 = 11.5 Hz, H 10 ), 6.59 (1H, AB spin system, d, H 11 ), 3.78 (3H, s, OCH 3 ); Azo fluorobenzene ring: 8.46 (1H, t, J H2,H4,6 = 1.5 Hz, H 2 ), 8.20 (1H, ddd, J H5,H6 = 8 Hz, J H4,H6 = 1 Hz, H 6 ), 8.07 (1H, ddd, J H4,H5 = 8 Hz, H 4 ), 7.79 (1H, t, H 5 ), 7.61 (1H, tt, J H3’,H4’ = 8.5 Hz, J H4’,F = 6 Hz, H 4’ ), 7.37 (2H, t, J H3’,F = 9 Hz, H 3’ ).

[0049] 13 C NMR (125 MHz, DMSO-d 6, 298K): δ (ppm): 164.49, 163.98, 161.18, 157.31, 157.29, 156.06, 156.03, 154.21, 153.85, 152.35, 150.91, 148.98, 140.56, 140.37, 136.03, 135.33, 132.35, 131.55, 130.19, 129.94, 129.38, 129.29, 129.28, 128.59, 128.56, 128.09, 127.19, 127.15, 126.10, 126.07, 124.96, 122.92, 122.89, 122.09, 121.13, 118.21, 116.88, 116.80, 113.23, 113.04, 112.94, 112.50, 111.23, 106.68, 55.52 (signals overlapping from atropisomers).

[0050] HRMS (ESI): C 28 H 19 F 2 N 3 O 3 H + , calculated m / z: 484.14672; found m / z: 484.14640. Literature: 1. W. A. Velema, W. Szymanski, B. L. Feringa, Journal of the American Chemical Society, 2014, 136(6), 2178 - 2191. 2. Z. Li, J. Liang, W. Xue, G. Liu, S. H. Liu, J. Yin, Supramolecular Chemistry, 2013, 26(1), 54 - 65. 3. J. V. De Julian - Ortiz, B. Verdejo, V. Polo, E. Besalu, E. G. Espana, International Journal of Molecular Sciences, 2016, 17(7), 1131. doi.org / 10.3390 / ijms17071131. 4. M. Banghart, A. Mourot, D. Fortin, J. Yao, R. Kramer, D. Trauner, Angewandte Chemie, International Edition, 2009, 48(48), 9097 - 9101. 5. M. M. Lerch, M. J. Hansen, G. M. van Dam, W. Szymanski, B. L. Feringa, Angewandte Chemie, International Edition, 2016, 55(37), 10978 - 10999. 6. I. M. Welleman, M. W. H. Hoorens, B. L. Feringa, H. H. Boersma, W. Szymanski, Chemical Science, 2020, 11, 11672 - 11691. 7. G. Alachouzos, A. M. Schulte, A. Mondal, W. Szymanski, B. L. Feringa, Angewandte Chemie, International Edition, 2022, e202201308 (1 of 8). 8. Y. Nagai, A. Irie, H. Nakamura, K. Hino, H. Uno, H. Nishimura, J. Med. Chem., 1982, 25, 1065. 9. R. Kiyama, T. Honma, K. Hayashi, M. Ogawa, M. Hara, M. Fujimoto, T. Fujishita, J. Med. Chem., 1995, 38, 2728. 10. Y. Bharath, B. Thirupathi, G. Ranjit, D. K. Mohapatra, Asian J. Org. Chem, 2013, 2(10), 848. 11. L. Agnetta, M. Bermudez, F. Riefolo, C. Matera, E. Claro, R. Messerer, T. Littmann, G. Wolber, U. Holzgrabe, M. Decker, J. Med. Chem. 2019, 62, 3009.

Claims

1. General formula (1) and general formula (2): 【Chemical 1】 [wherein, R １ , R ２ = H, OMe; R ３ , R ４ , R ５ = H, F] A fluorine derivative of methoxydibenzo[b,f]oxepine.

2. A method for obtaining the derivative defined in Claim 1, comprising General formula (3): [Chemical 2] [wherein, R １ , R ２ = H, OMe] Methoxydibenzo[b,f]oxepine and General formula (4) or (5): 【Chemical Formula 3】 [wherein, R ３ , R ４ , R ５ = H, F] Characterized by including a reaction in a solvent in the presence of a catalyst with a fluoroazobenzene selected from the group of compounds of, the following steps: a. Thionyl chloride is added to the fluoroazobenzene, and then the mixture is heated; b. The reaction mixture is evaporated to dryness, then dissolved several times in an aprotic organic solvent and evaporated to dryness; c. Methoxydibenzo[b,f]oxepine is dissolved in an aprotic organic solvent, a catalyst is added, and the residue from step (b) is dissolved in an aprotic organic solvent; d. Stirring the reaction mixture A method comprising the steps.

3. The method according to Claim 2, characterized in that the ratio of fluoroazobenzene to thionyl chloride in step (a) is 1:50 mol / mol.

4. The method according to Claim 2, characterized in that the reaction in step (a) is heated to 80°C for 30 minutes.

5. The method according to Claim 2, characterized in that the aprotic solvent in step (b) is methylene chloride.

6. The method according to Claim 2, characterized in that the aprotic solvent in step (c) is ethyl acetate.

7. The method according to Claim 2, characterized in that the catalyst in step (c) is triethylamine.

8. The method according to Claim 2, characterized in that the ratio of fluoroazobenzene to methoxydibenzo[b,f]oxepine is 1:1 mol / mol, preferably 1:0.85 mol / mol.

9. The method according to Claim 7, characterized in that the catalyst in step (c) is used in a ratio of 25:1 mol / mol with respect to fluoroazobenzene.

10. The method according to Claim 2, characterized in that the reaction in step (d) is stirred at 25°C for 1 to 24 hours.

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