Preparation method of fluoro-azabenzene and derivatives thereof

Abstract

The invention discloses a preparation method of fluoro-azabenzene and derivatives thereof, the preparation method has the advantages of strong substrate compatibility, mild reaction conditions and excellent product yield, and shows good compatibility for substituent groups (including electron withdrawing groups and electron donating groups) with different electronic effects on azacyclo. The method is not limited by substitution sites (ortho-position or meta-position); the method can be successfully applied to later-stage fluoro modification of complex natural product molecules, and a diversified fluoro product library is provided for biological activity research.

Description

Technical Field

[0001] The present invention relates to the technical field of fluorination reactions, and particularly to a method for preparing fluorinated azabenzenes and their derivatives. Background Art

[0002] In recent years, the research and development and application of fluorine-containing compounds have shown a significant growth trend. Due to its strong electronegativity (3.98 Pauling), atomic radius close to hydrogen and unique lipophilic characteristics, the fluorine atom can significantly improve the pharmacokinetic properties of drug molecules. Statistical data shows that among the small molecule drugs approved by the FDA in the past five years, the proportion of fluorine-containing structures has exceeded 35% (reaching 37.6% in 2022), and its penetration rate in pesticide active molecules has also been continuously increasing at an annual rate of 2.3%. This trend also extends to the field of materials science: thanks to the high bond energy of the C-F bond (~485 kJ / mol) and the low surface energy characteristics of fluorocarbon chains, the market share of fluorine-containing polymers in special engineering plastics has reached 47.8% (statistical data in 2023), especially dominating in cutting-edge fields such as spacecraft thermal protection systems and military stealth materials. Currently, the application boundaries of fluorine chemistry have expanded to diverse scenarios such as drug R & D, precision agriculture, organic catalysis, high-performance materials, and the development of positron emission tomography (PET) tracers.

[0003] It is worth noting that through the structural analysis of drugs approved by the FDA in the past decade (2013 - 2023), the nitrogen-containing heterocyclic skeleton remains the core framework of drug design, accounting for 68.4%. Among them, pyridine and its derivatives are particularly prominent. In new molecular entities in cutting-edge therapeutic fields such as anti-tumor (e.g., Palbociclib) and anti-infection (e.g., Delpazolid), the occurrence frequency of the pyridine ring is as high as 41.2%, highlighting its key position as a "dominant structure" in drug discovery. Therefore, in the process of drug R & D, the pyridine structure contained in drug molecules is of great significance. Functional group modification of it can effectively improve and enhance the drug efficacy, precisely optimize the activity and affinity of the molecule, and help drug upgrading. However, the late-stage fluorination modification of the para-position of pyridine has become a thorny problem, and there is still a lack of simple and efficient strategies so far.

[0004] In the field of traditional organic synthesis, the para-fluorination reaction of pyridine has not been fully and systematically explored for a long time, and only shows a fragmented research situation. Regarding the previous fluorination reactions involving pyridine halides, diazonium salts, and fluoroborates, they are mostly scattered in the vast literature of fluorination reactions of various aromatic substrates, only appearing as sporadic and isolated cases, without forming a coherent and in-depth research context.

[0005] Until recent years, with the continuous refinement of scientific research, a series of fluorination methods with significantly improved applicability have emerged one after another, injecting new vitality into this field. In 2023, the Ritter research group made a breakthrough by targeting the para-carbon-hydrogen bond of pyridine. Relying on a sophisticated electron transfer strategy, they successfully achieved the leap from theoretical concept to practical operation of the para-fluorination reaction of pyridine (Electron-Transfer-Enabled Concerted Nucleophilic Fluorination of Azaarenes: Selective C-H Fluorination of Quinolines, Li Zhang, Jiyao Yan, Dilgam Ahmadli, Zikuan Wang, and Tobias Ritter*, J. Am. Chem. Soc. 2023, 145, 20182-20188). However, this method has inherent defects in the aspect of regioselectivity control, making it difficult to accurately direct fluorination at the para-position of pyridine during the reaction process, greatly increasing the probability of by-product formation and limiting its universality in practical application scenarios. Summary of the Invention

[0006] The object of the present invention is to provide a method for preparing fluorinated azaarenes and their derivatives in view of the technical defects existing in the prior art.

[0007] The technical solution adopted to achieve the object of the present invention is as follows:

[0008] A method for preparing fluorinated azaarenes and their derivatives, wherein the fluorinated azaarenes and their derivatives have the structures shown in the following formulas 1 to 3:

[0009]

[0010] R 1 independently is H, aldehyde group, carbonyl group, cyano group, 4- to 8-membered heterocyclic group, O-4- to 8-membered heterocyclic group, H, -C 1-6 alkyl group, O-C 1-6 alkyl group, O-C 1-6 alkyl group -O, -C 3-7 cycloalkyl group, O-(4- to 12-membered heteroaryl group), C 6-10 aryl group, 4- to 12-membered heteroaryl group, -C 1-6 alkyl group -C 6-10 aryl group, -C 1-6 alkyl group -4- to 12-membered heteroaryl group, -C(O)N(R 4 )(R 4 ) or -C(O)N(H)C 6-12 aryl group; wherein the alkyl group, O-C 1-6Alkyl, O-C 1-6 Alkyl-O, cycloalkyl, aryl, heteroaryl, O-(4- to 12-membered heteroaryl) or O-heterocyclic group is optionally substituted with 1 to 4 halogens and optionally substituted with one or two R 3 ; R 2 is H, halo, C 1-6 alkyl; or C 3-6 cycloalkyl, wherein the alkyl or C 3-6 cycloalkyl is optionally substituted with halo; R 3 is C 1-6 alkyl, -C 3-7 cycloalkyl, OH, O-C 1-6 alkyl or -O-C 3-7 cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 R 2 ; and R 4 are each independently H, -C 1-6 alkyl, -C 1-6 alkyl-C 3-7 cycloalkyl, -C 3-7 cycloalkyl-C 1-6 alkyl, -C 3-7 cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 halogens;

[0011] The synthetic route of the compound of Formula 1 is shown as Synthetic Route (1) below:

[0012] Synthetic Route (1):

[0013]

[0014] The synthesis steps include: mixing the compound of Formula A, an oxidizing agent and a fluoride salt, adding a solvent to carry out a reaction, and purifying after the reaction to obtain the compound of Formula 1;

[0015] The synthetic route of the compound of Formula 2 is shown as Synthetic Route (2) below,

[0016] Synthetic Route (2):

[0017]

[0018] The synthesis steps include: mixing the compound of Formula B, an oxidizing agent and a fluoride salt, adding a solvent to carry out a reaction, and purifying after the reaction to obtain the compound of Formula 2;

[0019] The synthetic route of the compound of Formula 3 is shown as Synthetic Route (3) below,

[0020] Synthetic Route (3):

[0021]

[0022] The synthesis steps include: mixing the compound of formula C, an oxidizing agent and a fluoride salt, adding a solvent, carrying out a reaction, and purifying after the reaction to obtain the compound of formula 3.

[0023] In some specific embodiments, the conditions for the reaction in the synthesis route (1) to the synthesis route (3) are to react at 60 °C to 120 °C for 12 h to 18 h, and the solvent is tetrahydrofuran, 1,4-dioxane, dimethyl carbonate or dimethylacetamide;

[0024] And / or, the synthesis steps further include mixing the compound of formula A, an oxidizing agent and a fluoride salt, adding a solvent and a trifluoromethoxy-containing compound, carrying out a reaction, and purifying after the reaction to obtain the compound of formula 1. The trifluoromethoxy-containing compound includes at least one of trifluoromethyl p-toluenesulfonate, cesium trifluoromethoxide and trifluoromethyl trifluoromethanesulfonate;

[0025] And / or, the synthesis steps further include mixing the compound of formula B, an oxidizing agent and a fluoride salt, adding a solvent and a trifluoromethoxy-containing compound, carrying out a reaction, and purifying after the reaction to obtain the compound of formula 2. The trifluoromethoxy-containing compound includes at least one of trifluoromethyl p-toluenesulfonate, cesium trifluoromethoxide and trifluoromethyl trifluoromethanesulfonate;

[0026] And / or, the synthesis steps further include mixing the compound of formula C, an oxidizing agent and a fluoride salt, adding a solvent and a trifluoromethoxy-containing compound, carrying out a reaction, and purifying after the reaction to obtain the compound of formula 3. The trifluoromethoxy-containing compound includes at least one of trifluoromethyl p-toluenesulfonate, cesium trifluoromethoxide and trifluoromethyl trifluoromethanesulfonate.

[0027] In some specific embodiments, the molar ratio of the compound of formula A to the trifluoromethoxy-containing compound is 1:1 to 1:3, the molar ratio of the compound of formula B to the trifluoromethoxy-containing compound is 1:1 to 1:3, and the molar ratio of the compound of formula C to the trifluoromethoxy-containing compound is 1:1 to 1:3.

[0028] In some specific embodiments, the molar ratio of the compound of formula A to the oxidizing agent is 1:1 to 1:2, the molar ratio of the compound of formula B to the oxidizing agent is 1:1 to 1:2, and the molar ratio of the compound of formula C to the oxidizing agent is 1:1 to 1:2. Preferably, the oxidizing agent is persulfate N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (selectfluor·2OTf), NaIO 4 , N-fluorodibenzenesulfonamide (NFSI) or potassium peroxymonosulfate compound salt. More preferably, the oxidizing agent is potassium persulfate.

[0029] In some specific embodiments, the molar ratio of the compound of formula A to the fluoride salt is 1:0.5 to 1:3, the molar ratio of the compound of formula B to the fluoride salt is 1:0.5 to 1:3, and the molar ratio of the compound of formula C to the fluoride salt is 1:0.5 to 1:3. Preferably, the fluoride salt is CsF, KF or NaF.

[0030] In some specific embodiments, the synthetic route of the compound of formula A is as shown in synthetic route (4) below.

[0031] Synthetic route (4):

[0032]

[0033] The synthesis steps include: adding the compound of formula X to a solvent, cooling, adding trifluoromethanesulfonic anhydride for the first stirring, then adding triphenylphosphine for the second stirring, and then adding DBU to raise the temperature for reaction. After the reaction is completed, purification gives the compound of formula A.

[0034] The synthetic route of the compound of formula B is as shown in synthetic route (5) below.

[0035] Synthetic route (5):

[0036]

[0037] The synthesis steps include: adding the compound of formula Y to a solvent, cooling, adding trifluoromethanesulfonic anhydride for the first stirring, then adding triphenylphosphine for the second stirring, and then adding DBU to raise the temperature for reaction. After the reaction is completed, purification gives the compound of formula B.

[0038] The synthetic route of the compound of formula C is as shown in synthetic route (6) below.

[0039] Synthetic route (6):

[0040]

[0041] The synthesis steps include: adding the compound of formula Z to a solvent, cooling, adding trifluoromethanesulfonic anhydride for the first stirring, then adding triphenylphosphine for the second stirring, and then adding DBU to raise the temperature for reaction. After the reaction is completed, purification gives the compound of formula C.

[0042] In some specific embodiments, the synthesis steps of the compound of formula A include: mixing the compound of formula X with dichloromethane and cooling to -78°C to -70°C, then dropping trifluoromethanesulfonic anhydride, stirring for 30 minutes, adding triphenylphosphine, replacing with a protective gas, and stirring at -78°C to -70°C for 1 hour. Adding DBU and raising the temperature to room temperature for reaction for 30 minutes. After the reaction is completed, purification gives the compound of formula A.

[0043] The synthesis steps of the compound of formula B include: mixing the compound of formula Y with dichloromethane and cooling to -78°C to -70°C, then dropwise adding trifluoromethanesulfonic anhydride, stirring for 30 minutes, adding triphenylphosphine, replacing with protective gas, stirring at -78°C to -70°C for 1 hour, adding DBU, raising the temperature to room temperature and reacting for 30 minutes, and purifying after the reaction to obtain the compound of formula B;

[0044] The synthesis steps of the compound of formula C include: mixing the compound of formula Z with dichloromethane and cooling to -78°C to -70°C, then dropwise adding trifluoromethanesulfonic anhydride, stirring for 30 minutes, adding triphenylphosphine, replacing with protective gas, stirring at -78°C to -70°C for 1 hour, adding DBU, raising the temperature to room temperature and reacting for 30 minutes, and purifying after the reaction to obtain the compound of formula C.

[0045] In some specific embodiments, the molar ratio of the compound of formula X to trifluoromethanesulfonic anhydride is 1:1 to 1:1.1, the molar ratio of the compound of formula Y to trifluoromethanesulfonic anhydride is 1:1 to 1:1.1, and the molar ratio of the compound of formula Z to trifluoromethanesulfonic anhydride is 1:1 to 1:1.1.

[0046] In some specific embodiments, the molar ratio of the compound of formula X to triphenylphosphine is 1:1.1 to 1:1.2, the molar ratio of the compound of formula Y to triphenylphosphine is 1:1.1 to 1:1.2, and the molar ratio of the compound of formula Z to triphenylphosphine is 1:1.1 to 1:1.2.

[0047] In some specific embodiments, the molar ratio of the compound of formula X to DBU is 1:1 to 1:1.1, the molar ratio of the compound of formula Y to DBU is 1:1 to 1:1.1, and the molar ratio of the compound of formula Z to DBU is 1:1 to 1:1.1.

[0048] Compared with the prior art, the beneficial effects of the present invention are:

[0049] 1. The preparation method of the present application has strong substrate compatibility, mild reaction conditions, excellent product yields, and shows good compatibility with substituents with different electronic effects on the nitrogen heterocycle (including electron-withdrawing groups and electron-donating groups), and is not restricted by the substitution site (ortho or meta). This method can be successfully applied to the late-stage fluorination modification of complex natural product molecules, providing a diverse library of fluorinated products for biological activity research. The preparation method of the present application provides a new technical route for the synthesis of fluorine-containing compounds and has important application value in the fields of drug research and development and materials science.

[0050] 2. Nicotinic acid and its derivatives (nicotinic acid esters, nicotinamide), as important bioactive molecules, play a key role in the life process. Using the preparation method of the present invention, p-fluoronicotinic acid can also be simply and efficiently obtained, providing a simple and efficient route for the synthesis of p-fluoronicotinic acid, nicotinic acid esters and nicotinamide compounds. The obtained structural unit of p-fluoronicotinic acid has good reactivity, facilitating subsequent chemical transformation. Detailed implementation manners

[0051] The present invention will be further described in detail below with reference to 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.

[0052] Example 1

[0053] Preparation of triphenyl(3-phenylpyridin-4-yl)phosphonium trifluoromethanesulfonate. The synthetic route is shown as follows.

[0054]

[0055] The specific preparation method is as follows: In a 250 mL dry reaction flask under an argon atmosphere, add 3-phenylpyridine (1.0 equivalent, 12 mmol, 1860 mg) and 120 mL of dichloromethane (DCM, 0.1 M), and cool down to -78 °C. At -78 °C, slowly dropwise add trifluoromethanesulfonic anhydride and stir for 30 minutes; add triphenylphosphine (PPh 3 , 1.1 equivalent, 13.2 mmol, 3458 mg), displace the gas three times with argon, and stir at -78 °C for 1 hour; add 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.0 equivalent, 12 mmol, 1824 mg), and raise the temperature to room temperature and react for 30 minutes. After the reaction is completed, quench with an equal volume of water, and extract with CH 2 Cl 2 (150 mL × 3). Combine the organic phases, add anhydrous MgSO 4 for drying, then concentrate to 20 mL, add an excess of ether, and precipitate a solid at 0 °C to obtain 6.125 g of triphenyl(3-phenylpyridin-4-yl)phosphonium trifluoromethanesulfonate with a yield of 90%.

[0056] Nuclear magnetic resonance spectrum: 1 H NMR (400 MHz, CDCl 3 ) δ 8.94–8.92 (m, 1H), 8.72–8.70 (m, 1H), 7.82–7.73 (m, 3H), 7.67–7.62 (m, 6H), 7.58–7.52 (m, 6H), 7.48–7.43 (m, 1H), 7.12–7.07 (m, 1H), 6.92–6.87 (m, 2H), 6.71–6.69 (m, 1H).

[0057] 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 153.70 (d, J = 7.8 Hz), 150.05 (d, J = 10.3 Hz), 141.78 (d, J = 7.1 Hz), 135.52 (d, J = 3.0 Hz), 134.48 (d, J = 4.1 Hz), 134.26 (d, J = 10.2 Hz), 130.68 (d, J = 13.0 Hz), 129.28, 128.98, 128.38, 128.29, 126.46 (d, J = 83.2 Hz), 120.90 (q, J = 321.2 Hz), 116.95 (d, J = 89.0 Hz).

[0058] 19 F{ 1 H} NMR (376 MHz, CDCl 3 ) δ -77.37 (3F).

[0059] 31 P{ 1 H} NMR (162 MHz, CDCl 3 ) δ 21.44.

[0060] HRMS (ESI) m / z: [M - OTf] + Calcd for C 29 H 23 NP + 416.1563; Found 416.1558.

[0061] The preparation of 4 - fluoro - 3 - phenylpyridine is as follows in the synthetic route

[0062]

[0063] The specific preparation method is as follows: In the glove box, triphenyl(3 - phenylpyridin - 4 - yl)phosphonium trifluoromethanesulfonate (1.0 equiv, 0.5 mmol, 283 mg) and K 2 S 2 O 8(1.0 equiv, 0.5 mmol, 135 mg), CsF (2.0 equiv, 1.0 mmol, 150 mg), and then the solvent 1,4-dioxane (0.1 M, 5 mL) and trifluoromethanesulfonate of p-toluenesulfonic acid (TFMS) (1.0 equiv, 0.5 mmol, 90 μL) were added. After taking out of the glove box, the reaction system was stirred at 80 °C for 18 h. After the reaction was completed, the reaction solution was directly concentrated, and 4-fluoro-3-phenylpyridine as a pale yellow oil was obtained by column chromatography. The column chromatography conditions were PE / EA = 15 / 1 (v / v) to 8 / 1 (v / v), R f = 0.5 (SiO 2 , PE / EA = 4:1 (v / v)).

[0064] 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, J = 10.3 Hz, 1H), 8.55 (dd, J = 7.6, 5.6 Hz, 1H), 7.62–7.35 (m, 5H), 7.13 (dd, J = 10.1, 5.6 Hz, 1H).

[0065] 13 C{ 1 H}NMR (101 MHz, CDCl 3 ) δ 165.51 (d, 1 J C-F = 264.1 Hz), 152.21 (d, 3 J C-F = 3.1 Hz), 150.90 (d, 3 J C-F = 7.4 Hz), 132.10, 129.02 (d, 3 J C-F = 2.8 Hz), 128.81, 128.56, 125.62 (d, 2 J C-F = 9.7 Hz), 111.80 (d, 2 J C-F = 17.6 Hz).

[0066] 19 F{ 1 H}NMR (376 MHz, CDCl 3 ) δ -110.78 (s, 1F).

[0067] HRMS (ESI) m / z: [M+H] + Calcd for C 11 H 9 FN +174.0714; Found 174.0717.

[0068] Examples 2 - 4

[0069] Examples 2 - 4 are different from Example 1 in that TMFS is not added and DMAc is used as the solvent. See Table 1 and the following formula for details.

[0070]

[0071] Table 1 Influence of the type of fluoride salt on the reaction yield when TFMS is not added and DMAc is used as the solvent

[0072]

[0073] Examples 5 - 54

[0074] Examples 5 - 54 are different from Example 1 only in that the raw material azobenzene and its derivatives, as well as the prepared fluoroazobenzene and its derivatives, are different. See Table 2 for details.

[0075] Table 2 Results table of preparing different products by the method of this application

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] Among them, the fluorinated products in Examples 5-26 are all derivatives of functional groups in natural products and are all potential active pharmaceutical molecules.

[0095] Examples 55-57

[0096] The difference between Examples 55-57 and Example 1 is only the reaction solvent. For details, see Table 3.

[0097] Comparative Examples 1-7

[0098] The difference between Comparative Examples 1-7 and Example 1 is only the reaction solvent. For details, see Table 3.

[0099] Table 3 Influence of Different Solvents on Reaction Yield

[0100] Solvent <]]> Example 1 1,4 - dioxane 99％ Example 55 DMC 94％ Example 56 DMAc 85％ Example 57 Tetrahydrofuran 99％ Comparative Example 1 Acetone Not detected Comparative Example 2 Toluene Not detected Comparative Example 3 DMF Not detected Comparative Example 4 Acetonitrile Not detected Comparative Example 5 DCE 12％ Comparative Example 6 Ethyl acetate 16％ Comparative Example 7 PhOMe Not detected

[0101] Examples 58-63

[0102] The difference between Examples 58-63 and Example 1 is only the type or equivalent of the oxidant. For details, see Table 4.

[0103] Comparative Examples 8-11

[0104] The difference between Comparative Examples 8-11 and Example 1 is only the choice and equivalent of the oxidant. For details, see Table 4.

[0105] Table 4 Influence of Different Oxidants and Different Equivalents on Reaction Yield

[0106]

[0107] Example 64

[0108] The difference between Example 64 and Example 1 is only the equivalent of TFMS. For details, see Table 5.

[0109] Comparative Examples 12-13

[0110] The difference between Comparative Examples 12-13 and Example 1 is only the equivalent of TFMS. For details, see Table 5.

[0111] Table 5 Influence of Different Equivalents of TFMS on Reaction Yield

[0112]

[0113] Examples 65 - 69

[0114] Examples 65 - 69 differ from Example 1 only in the type and equivalent amount of the fluoride salt. See Table 6 for details.

[0115] Comparative Examples 14 - 15

[0116] Comparative Examples 14 - 15 differ from Example 1 only in the type and equivalent amount of the fluoride salt. See Table 6 for details.

[0117] Table 6 Influence of the type and equivalent amount of different fluoride salts on the reaction yield

[0118] Fluoride salt (equivalent) <]]> Example 1 CsF (2.0 equivalents) 99 Example 65 CsF (3.0 equivalents) 99 Example 66 CsF (1.5 equivalents) 81 Example 67 CsF (1.0 equivalent) 77 Example 68 CsF (0.5 equivalent) 39 Example 69 KF (2.0 equivalents) 30 Comparative Example 14 LiF (2.0 equivalents) Not detected Comparative Example 15 None Not detected

[0119] Example 70

[0120] Example 70 differs from Example 1 only in the reaction temperature. See Table 7 for details.

[0121] Comparative Example 16

[0122] Comparative Example 16 differs from Example 1 only in the reaction temperature. See Table 7 for details.

[0123] Table 7 Influence of different reaction temperatures on the reaction yield

[0124] Temperature <]]> Example 1 80℃ 99 Example 70 60℃ 87 Comparative Example 16 40℃ 26

[0125] Examples 71 - 82

[0126] Examples 71 - 82 differ from Example 1 in that the solvent is tetrahydrofuran, and the trifluoromethoxy compound, oxidant and their dosages are different. See Table 8 and the following formula for details.

[0127] Comparative Example 17

[0128] Comparative Example 17 differs from Example 1 in that the solvent is tetrahydrofuran, and the trifluoromethoxy compound, oxidant and their dosages are different. See Table 8 and the following formula for details.

[0129]

[0130] Table 8 The trifluoromethoxy compound is cesium trifluoromethyloxide

[0131]

[0132]

[0133] Example 83

[0134] The main difference between Example 83 and Example 1 is that the trifluoromethoxy compound uses TFMT, as specifically shown in the following formula. The yield of 4-fluoro-3-phenylpyridine is 56%( 19 F NMR).

[0135]

[0136] Example 84

[0137] Using the product of Example 10 as the raw material to prepare p-fluoronicotinic acid, the synthetic route is as follows:

[0138]

[0139] Using the product of Example 10 as the raw material can prepare p-fluoronicotinic acid in a relatively high yield, enriching the synthetic strategies of nicotinic acid compounds and providing an important synthetic platform for the research of fluorine-containing bioactive molecules.

[0140] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing fluoroazabenzene and its derivatives, characterized in that: The fluoroazabenzene and its derivatives have structures shown in the following formulas 1 to 3: R1 is independently H, aldehyde, carbonyl, cyano, 4- to 8-membered heterocyclic group, O-4- to 8-membered heterocyclic group, H, -C 1-6 Alkyl, OC 1-6 Alkyl, OC 1-6 Alkyl-O, -C 3-7 Cycloalkyl, O-(4- to 12-membered heteroaryl), C 6-10 Aryl, 4- to 12-membered heteroaryl, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 alkyl-4- to 12-membered heteroaryl, -C(O)N(R4)(R4) or -C(O)N(H)C 6-12 Aryl; wherein the alkyl, OC 1-6 Alkyl, OC 1-6 Alkyl-O, cycloalkyl, aryl, heteroaryl, O-(4- to 12-membered heteroaryl) or O-heterocyclyl is optionally substituted with 1 to 4 halogens and optionally substituted with one or two R3; R2 is H, halo, -C 1-6 Alkyl; or C 3-6 Cycloalkyl, wherein the alkyl or C 3-6 Cycloalkyl is optionally substituted with halo; R3 is C 1-6 Alkyl, -C 3-7 Cycloalkyl, OH, OC 1-6 Alkyl or -OC 3-7 Cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 R2; and R4 is each independently H, -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-7 Cycloalkyl, -C 3-7 Cycloalkyl-C 1-6 Alkyl, -C 3-7 Cycloalkyl, wherein the alkyl, cycloalkyl, O-alkyl or -O-cycloalkyl is optionally substituted with 1 to 4 halogens; The synthetic route of the compound of formula 1 is shown in the following synthetic route (1): Synthetic route (1): The synthesis steps include: mixing a compound of formula A, an oxidant and a fluoride salt, adding a solvent to react, and purifying after the reaction to obtain a compound of formula 1; The synthetic route of the compound of formula 2 is shown in the following synthetic route (2): Synthetic route (2): The synthesis steps include: mixing a compound of formula B, an oxidant and a fluoride salt, adding a solvent to react, and purifying after the reaction to obtain a compound of formula 2; The synthetic route of the compound of formula 3 is shown in the following synthetic route (3): Synthetic route (3): The synthesis steps include: mixing a compound of formula C, an oxidant and a fluoride salt, adding a solvent, reacting, and purifying after the reaction to obtain a compound of formula 3.

2. The preparation method according to claim 1, characterized in that The reaction conditions in the synthetic routes (1) to (3) are 60° C. to 120° C. for 12 h to 18 h, and the solvent is tetrahydrofuran, 1,4-dioxane, dimethyl carbonate or dimethylacetamide; And / or, the synthesis step further comprises mixing the compound of formula A, an oxidant and a fluoride salt, adding a solvent and a trifluoromethoxy compound, reacting, and purifying after the reaction to obtain a compound of formula 1, wherein the trifluoromethoxy compound comprises at least one of trifluoromethyl p-toluenesulfonate, cesium trifluoromethyl oxide and trifluoromethyl trifluoromethanesulfonate; And / or, the synthesis step further comprises mixing the compound of formula B, an oxidant and a fluoride salt, adding a solvent and a trifluoromethoxy compound, reacting, and purifying after the reaction to obtain a compound of formula 2, wherein the trifluoromethoxy compound comprises at least one of trifluoromethyl p-toluenesulfonate, cesium trifluoromethyl oxide and trifluoromethyl trifluoromethanesulfonate; And or, the synthesis step further comprises mixing the compound of formula C, an oxidant and a fluoride salt, adding a solvent and a trifluoromethoxy compound to react, and purifying after the reaction to obtain a compound of formula 3, wherein the trifluoromethoxy compound comprises at least one of trifluoromethyl p-toluenesulfonate, cesium trifluoromethyl oxide and trifluoromethyl trifluoromethanesulfonate.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound of formula A to the trifluoromethoxy-containing compound is 1:1 to 1:3, the molar ratio of the compound of formula B to the trifluoromethoxy-containing compound is 1:1 to 1:3, and the molar ratio of the compound of formula C to the trifluoromethoxy-containing compound is 1:1 to 1:

3.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula A to the oxidant is 1:1 to 1:2, the molar ratio of the compound of formula B to the oxidant is 1:1 to 1:2, and the molar ratio of the compound of formula C to the oxidant is 1:1 to 1:

2. Preferably, the oxidant is peroxodisulfate, N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate), NaIO4, N-fluorobisbenzenesulfonamide or potassium persulfate complex salt. More preferably, the oxidant is potassium peroxodisulfate.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula A to the fluoride salt is 1:0.5 to 1:3, the molar ratio of the compound of formula B to the fluoride salt is 1:0.5 to 1:3, and the molar ratio of the compound of formula C to the fluoride salt is 1:0.5 to 1:

3. Preferably, the fluoride salt is CsF, KF or NaF.

6. The preparation method according to claim 1, characterized in that: The synthesis route of the compound of formula A is shown in the following synthesis route (4): Synthetic route (4): The synthesis steps include: adding a compound of formula X to a solvent and then cooling, adding trifluoromethanesulfonic anhydride for a first stirring, then adding triphenylphosphine for a second stirring, then adding DBU and heating to react, and purifying after the reaction to obtain a compound of formula A; The synthesis route of the compound of formula B is shown in the following synthesis route (5): Synthetic route (5): The synthesis steps include: adding a compound of formula Y to a solvent and then cooling, adding trifluoromethanesulfonic anhydride for a first stirring, then adding triphenylphosphine for a second stirring, then adding DBU and heating for reaction, and purifying after the reaction to obtain a compound of formula B; The synthesis route of the compound of formula C is shown in the following synthesis route (6): Synthetic route (6): The synthesis steps include: adding a compound of formula Z to a solvent and then cooling, adding trifluoromethanesulfonic anhydride for a first stirring, then adding triphenylphosphine for a second stirring, then adding DBU and heating for reaction, and purifying after the reaction to obtain a compound of formula C.

7. The preparation method according to claim 6, characterized in that: The synthesis steps of the compound of formula A include: mixing the compound of formula X with dichloromethane, cooling to -78 to -70°C, then dropping trifluoromethanesulfonic anhydride, stirring for 30 minutes, adding triphenylphosphine as protective gas, stirring at -78 to -70°C for 1 hour, adding DBU, heating to room temperature and reacting for 30 minutes, and purifying after the reaction to obtain the compound of formula A; The synthesis steps of the compound of formula B include: mixing the compound of formula Y with dichloromethane, cooling to -78 to -70°C, then dropping trifluoromethanesulfonic anhydride, stirring for 30 minutes, adding triphenylphosphine protective gas for replacement, stirring at -78 to -70°C for 1 hour, adding DBU, heating to room temperature for reaction for 30 minutes, and purifying after the reaction to obtain the compound of formula B; The synthesis steps of the compound of formula C include: mixing the compound of formula Z with dichloromethane and cooling to -78 to -70°C, then dropping trifluoromethanesulfonic anhydride, stirring for 30 minutes, then adding triphenylphosphine protective gas for replacement and stirring at -78 to -70°C for 1 hour, adding DBU and heating to room temperature to react for 30 minutes, and purifying after the reaction to obtain the compound of formula C.

8. The preparation method according to claim 6, characterized in that: The molar ratio of the compound of formula X to trifluoromethanesulfonic anhydride is 1:1 to 1:1.1, the molar ratio of the compound of formula Y to trifluoromethanesulfonic anhydride is 1:1 to 1:1.1, and the molar ratio of the compound of formula Z to trifluoromethanesulfonic anhydride is 1:1 to 1:1.

1.

9. The preparation method according to claim 6, characterized in that: The molar ratio of the compound of formula X to triphenylphosphine is 1:1.1 to 1:1.2, the molar ratio of the compound of formula Y to triphenylphosphine is 1:1.1 to 1:1.2, and the molar ratio of the compound of formula Z to triphenylphosphine is 1:1.1 to 1:1.

2.

10. The preparation method according to claim 6, characterized in that: The molar ratio of the compound of formula X to DBU is 1:1 to 1:1.1, the molar ratio of the compound of formula Y to DBU is 1:1 to 1:1.1, and the molar ratio of the compound of formula Z to DBU is 1:1 to 1:1.1.

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