A method for preparing a benzopyridazine compound

Abstract

The application provides a preparation method of a benzopyridazine compound, which uses an alpha-substituted-N-(arylhydrazone) compound shown in formula (I) as raw material, and obtains a benzopyridazine compound shown in formula (II) through intramolecular cyclization reaction under the joint action of an electrophilic activation reagent triflic anhydride and an auxiliary triaryl phosphine oxide. Compared with the synthesis method of the benzopyridazine compound in the prior art, the synthesis of the polysubstituted benzopyridazine compound is realized by using the electrophilic activation strategy, the synthesis method has the advantages of easy availability of raw materials, simple operation, mild reaction conditions, wide application range of reaction, and avoidance of use of high-toxicity raw materials and intermediates in the traditional process, and has the advantages of green environmental protection.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing benzopyridazine compounds. Background Technology

[0002] Benzopyridazines are an important class of organic compounds, most of which possess excellent biological and pharmaceutical activities. Benzopyridazine derivatives exhibit strong inhibitory effects on receptors such as leucine repeat kinase 2 (LRRK2), phosphatidylinositol 3-kinase (PI3K), and mammalian target of rapamycin (mTOR), making them potential candidates for the treatment of cancer, immune dysfunction, cardiovascular and cerebrovascular diseases, and neurological disorders. However, existing synthetic methods for benzopyridazines often suffer from limitations such as limited or highly toxic raw material sources, complex reaction steps requiring high reaction temperatures or metal catalysts, narrow applicability, and low yields, thus restricting their practical applications. Summary of the Invention

[0003] In view of this, the technical problem to be solved by the present invention is to provide a method for preparing benzopyridazine compounds, which has readily available raw materials, simple operation, mild reaction conditions, wide applicability, and does not require the use of metal catalysts.

[0004] This invention provides a method for preparing benzopyridazine compounds, comprising:

[0005] An electrophilic activating agent and an auxiliary agent are reacted with an α-substituted-N-(arylhydrazone) compound of formula (I) in an organic solvent to obtain a benzopyridinium compound of formula (II); the electrophilic activating agent is trifluoromethanesulfonic anhydride and the auxiliary agent is triarylphosphine oxide.

[0006]

[0007] Among them, -R 1 With -R 2 Each can be independently selected from H, -OA, -A, -Ar, or -Het;

[0008] -R 3 Choose from H, -EWG, -A, -X, -Ar, or -Het;

[0009] -R 4 With -R 5 Each can be independently selected from H, -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA, or -EWG;

[0010] The -A is selected from C1 to C30 alkyl groups, C1 to C30 substituted alkyl groups, or C3 to C7 cycloalkyl groups;

[0011] The -Ar is selected from substituted or unsubstituted aryl groups;

[0012] The -Het is selected from substituted or unsubstituted unsaturated monocyclic heterocyclic groups containing 1 to 4 heteroatoms, and substituted or unsubstituted unsaturated bicyclic heterocyclic groups containing 1 to 4 heteroatoms;

[0013] The -EWG is selected from -COA, -COAr, -COOA, -CN, -NO2, or -CF3;

[0014] X is a halogen.

[0015] Preferably, the -R 1 With -R 2 Each is independently selected from H, C1-C10 alkyl, C1-C5 alkoxy, benzyl, phenyl or substituted phenyl;

[0016] The -R 3 Selected from H, -CN, -NO2, C1-C5 alkylyl, benzoyl, substituted benzoyl or -Br;

[0017] The -R 4 With -R 5 Each is independently selected from C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylthio, C1-C5 alkylamine, phenyl, -CN, -CF3, -Cl or -NO2.

[0018] Preferably, the number of substituents in the C1-C30 substituted alkyl groups is 1-20; the substituents in the C1-C30 substituted alkyl groups are selected from -Ar and / or -Het.

[0019] Preferably, the number of substituents in the substituted unsaturated monocyclic heterocyclic group and the substituted unsaturated bicyclic heterocyclic group are each independently 1 to 3;

[0020] The substituents in the substituted unsaturated monocyclic heterocyclic group and the substituted unsaturated bicyclic heterocyclic group are each independently selected from one or more of -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA and -EWG;

[0021] The number of substituents in the substituted aryl group is 1 to 5;

[0022] The substituents in the substituted aryl group are selected from one or more of -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA, and -EWG.

[0023] Preferably, -A is selected from C1-C10 alkyl groups, C1-C10 substituted alkyl groups, or C3-C7 cycloalkyl groups;

[0024] The -Ar is selected from phenyl, substituted phenyl, biphenyl, substituted biphenyl, naphthyl or substituted naphthyl;

[0025] The unsaturated monocyclic heterocyclic group is selected from 4- to 7-membered unsaturated monocyclic heterocyclic groups;

[0026] The unsaturated bicyclic heterocyclic group is selected from 7- to 12-membered unsaturated bicyclic heterocyclic groups;

[0027] The heteroatoms in the unsaturated unit heterocyclic group and the unsaturated bicyclic heterocyclic group are each independently selected from one or more of N, O and S.

[0028] Preferably, the molar ratio of the electrophilic activating agent trifluoromethanesulfonic anhydride to the auxiliary agent triarylphosphine oxide compound is (0.2-6.0):1.

[0029] Preferably, the adjuvant triarylphosphine oxide compound is selected from triphenylphosphine oxide and / or tri(4-methylphenyl)phosphine oxide.

[0030] Preferably, the molar ratio of the electrophilic activating agent trifluoromethanesulfonic anhydride to the α-substituted-N-(arylhydrazone) compound shown in formula (I) is (0.5-6.0):1.

[0031] Preferably, the molar ratio of the electrophilic activating agent trifluoromethanesulfonic anhydride to the auxiliary agent triarylphosphine oxide compound is (0.5-2.0):1.

[0032] Preferably, the organic solvent is selected from one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, acetonitrile, chlorobenzene, nitrobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide;

[0033] The reaction temperature is -15℃ to 80℃; the reaction time is 0.1 to 6.0 h.

[0034] This invention provides a benzopyridazine compound having the structure shown in formula (II):

[0035]

[0036] Among them, -R 1 With -R 2 Each is independently selected from H, -OA, -NHA, -NHAr, -A, -Ar, or -Het;

[0037] -R 3 Choose from H, -EWG, -A, -X, -Ar, or -Het;

[0038] -R 4 With -R 5Each can be independently selected from H, -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA, or -EWG;

[0039] The -A is selected from C1 to C30 alkyl groups, C1 to C30 substituted alkyl groups, or C3 to C7 cycloalkyl groups;

[0040] The -Ar is selected from substituted or unsubstituted aryl groups;

[0041] The -Het is selected from substituted or unsubstituted unsaturated monocyclic heterocyclic groups containing 1 to 4 heteroatoms, and substituted or unsubstituted unsaturated bicyclic heterocyclic groups containing 1 to 4 heteroatoms;

[0042] The -EWG is selected from -COA, -COAr, -COOA, -CN, -NO2, or -CF3;

[0043] X is a halogen.

[0044] Compared with the prior art, the present invention provides a method for preparing benzopyridazine compounds, comprising: reacting an electrophilic activating agent and an auxiliary agent with an α-substituted -N-(arylhydrazone) compound of formula (I) in an organic solvent to obtain a benzopyridazine compound of formula (II); wherein, -R 1 With -R 2 Each can be independently selected from H, -OA, -A, -Ar, or -Het; -R 3 Select from H, -EWG, -A, -X, -Ar, or -Het; -R 4 Selected from H, -A, -OA, -Ar, -SA, -NHA, or -NAA; -R 5 With -R 6 Each of the following components is independently selected from H, -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA, or -EWG; -A is selected from C1-C30 alkyl groups, C1-C30 substituted alkyl groups, or C3-C7 cycloalkyl groups; -Ar is selected from substituted or unsubstituted aryl groups; -Het is selected from substituted or unsubstituted unsaturated monocyclic heterocyclic groups containing 1-4 heteroatoms, or substituted or unsubstituted unsaturated bicyclic heterocyclic groups containing 1-4 heteroatoms; -EWG is selected from -COA, -COAr, -COOA, -CN, -NO2, or -CF3; and X is a halogen. Compared with the prior art, this invention utilizes electrophilic activating reagents to promote the cyclization reaction of α-substituted -N-(arylhydrazone) compounds, realizing the synthesis of benzopyridazine compounds. This synthetic method has the advantages of readily available raw materials, simple operation, mild reaction conditions, wide applicability, and no need for metal catalysis. Attached Figure Description

[0045] Figure 1The 1H NMR spectrum of 3-acetyl-4-anilinebenzopyridazine obtained in Example 1 of this invention;

[0046] Figure 2 This is the carbon NMR spectrum of 3-acetyl-4-aniline benzopyridazine obtained in Example 1 of the present invention. Detailed Implementation

[0047] This invention provides a method for preparing benzopyridazine compounds. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and fall within the scope of this invention. The method and application of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately change and combine the method and application described herein without departing from the content, spirit, and scope of this invention to implement and apply the technology of this invention.

[0048] This invention provides a method for preparing benzopyridinium compounds, comprising: reacting an α-substituted-N-(arylhydrazone) compound of formula (I) with an electrophilic activating agent and an auxiliary agent to obtain a benzopyridinium compound of formula (II); wherein the electrophilic activating agent is trifluoromethanesulfonic anhydride and the auxiliary agent is a triarylphosphine oxide compound;

[0049]

[0050] Among them, -R 1 With -R 2 Each can be independently H, -OA, -A, -Ar, or -Het;

[0051] -R 3 For H, -EWG, -A, -X, -Ar, or -Het;

[0052] -R 4 With -R 5 Each can be independently H, -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA, or -EWG;

[0053] In this invention, -A is an alkyl group of C1 to C30, a substituted alkyl group of C1 to C30, or a cycloalkyl group of C3 to C7; preferably an alkyl group of C1 to C20, a substituted alkyl group of C1 to C20, or a cycloalkyl group of C3 to C7; more preferably an alkyl group of C1 to C15, a substituted alkyl group of C1 to C15, or a cycloalkyl group of C3 to C7; even more preferably an alkyl group of C1 to C10, a substituted alkyl group of C1 to C10, or a cycloalkyl group of C3 to C7; even more preferably an alkyl group of C1 to C5, a substituted alkyl group of C1 to C5, or a cycloalkyl group of C3 to C7; most preferably an alkyl group of C1 to C3, a substituted alkyl group of C1 to C3, or a cycloalkyl group of C3 to C7.

[0054] The number of substituents in the substituted alkyl groups of C1 to C30 is preferably 1 to 20, more preferably 1 to 15, even more preferably 1 to 10, even more preferably 1 to 5, even more preferably 1 to 3, and most preferably 1 to 2; the substituents in the substituted alkyl groups of C1 to C30 are preferably -Ar and / or -Het.

[0055] The -Ar is a substituted or unsubstituted aryl group, preferably a substituted or unsubstituted C6-C20 aryl group, more preferably a substituted or unsubstituted C6-C15 aryl group, and even more preferably a phenyl, substituted phenyl, biphenyl, substituted biphenyl, naphthyl, or substituted naphthyl group; the number of substituents in the substituted aryl group is preferably 1-5, more preferably 1-3, and even more preferably 1-2; the position of the substituents in the substituted aryl group is preferably ortho and / or para; the substituents in the substituted aryl group are preferably one or more of -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA, and -EWG; the -A is the same as described above and will not be repeated here.

[0056] The -Het is a substituted or unsubstituted unsaturated monocyclic heterocyclic group containing 1 to 4 heteroatoms, or a substituted or unsubstituted unsaturated bicyclic heterocyclic group containing 1 to 4 heteroatoms; the heteroatoms in the unsaturated monocyclic heterocyclic group and the unsaturated bicyclic heterocyclic group are each preferably one or more of N, O, and S; the unsaturated monocyclic heterocyclic group is preferably a 4-7 member unsaturated monocyclic heterocyclic group, more preferably a 5-7 member unsaturated monocyclic heterocyclic group, and even more preferably a 5-6 member unsaturated monocyclic heterocyclic group; the unsaturated bicyclic heterocyclic group is preferably a 7-12 member unsaturated bicyclic heterocyclic group. The cyclic group is more preferably an 8-12 member unsaturated bicyclic heterocyclic group, and even more preferably a 9-12 member unsaturated bicyclic heterocyclic group; the number of substituents in the substituted unsaturated monocyclic heterocyclic group and the substituted unsaturated bicyclic heterocyclic group is preferably 1-3, more preferably 1-2; the substituents in the substituted unsaturated monocyclic heterocyclic group and the substituted unsaturated bicyclic heterocyclic group are each independently one or more of -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA and -EWG; the A is the same as described above and will not be repeated here.

[0057] The -EWG can be -COA, -COAr, -COOA, -CN, -NO2, or -CF3; the A and Ar are the same as described above and will not be repeated here.

[0058] X is a halogen, preferably F, Cl, Br or I.

[0059] In this invention, more preferably, the -R 1 With -R 2 Each of the following is independently H, a C1-C10 alkyl group, a C1-C5 alkoxy group, benzyl group, phenyl group, or a substituted phenyl group; more preferably, each of the following is independently H, a C1-C5 alkyl group, a C1-C5 alkoxy group, benzyl group, phenyl group, or a substituted phenyl group; even more preferably, each of the following is independently H, a C1-C3 alkyl group, a C1-C3 alkoxy group, benzyl group, phenyl group, or a substituted phenyl group; the number of substituents in the substituted phenyl group is preferably 1-5, more preferably 1-3, and even more preferably 1-2; the position of the substituents in the substituted phenyl group is preferably ortho and / or para; the substituents in the substituted phenyl group are preferably one or more of -X, -CF3, -CN, -NO2, phenyl, benzyl, C1-C30 -A, -OA, SA, -NHA, NAA, COA, and -COOA, and even more preferably -X, -CF3, -CN, -NO2, phenyl, benzyl The compound is selected from one or more of the following: C1-C20: -A, -OA, SA, -NHA, NAA, COA, and -COOA; more preferably, -X, -CF3, -CN, -NO2, phenyl, benzyl; C1-C10: -A, -OA, SA, -NHA, NAA, COA, and -COOA; more preferably, -X, -CF3, -CN, -NO2, phenyl, benzyl; C1-C5: -A, -OA, SA, -NHA, NAA, COA, and -COOA; most preferably, -X, -CF3, -CN, -NO2, phenyl, benzyl; C1-C3: -A, -OA, SA, -NHA, NAA, COA, and -COOA; the -X is preferably one of -F, -Cl, -Br, and -I; the A is the same as described above and will not be repeated here.

[0060] In this invention, more preferably, the -R 3The benzoyl group is H, -CN, -NO2, C1-C5 alkylyl, benzoyl, substituted benzoyl, or -Br; more preferably H, -CN, -NO2, C1-C3 alkylyl, benzoyl, substituted benzoyl, or -Br; the number of substituents in the substituted benzoyl group is preferably 1-5, more preferably 1-3, and even more preferably 1-2; the position of the substituents in the substituted benzoyl group is preferably ortho and / or para; the substituents in the substituted benzoyl group are preferably one or more of -X, -CF3, -CN, -NO2, phenyl, benzyl, C1-C30 -A, -OA, SA, -NHA, NAA, COA, and -COOA, and even more preferably -X, -CF3, -CN, -NO2, phenyl, benzyl, C1-C20 -A, -OA, SA, -N One or more of HA, NAA, COA and -COOA, more preferably one or more of -X, -CF3, -CN, -NO2, phenyl, benzyl, C1-C10 -A, -OA, SA, -NHA, NAA, COA and -COOA, more preferably one or more of -X, -CF3, -CN, -NO2, phenyl, benzyl, C1-C5 -A, -OA, SA, -NHA, NAA, COA and -COOA, most preferably one or more of -X, -CF3, -CN, -NO2, phenyl, benzyl, C1-C3 -A, -OA, SA, -NHA, NAA, COA and -COOA; the -X is preferably one of -F, -Cl, -Br and -I; the A is the same as above, and will not be repeated here.

[0061] In this invention, more preferably, the -R 4 With -R 5 Each of the following is independently C1 to C5: alkyl, alkoxy, alkylthio, alkylamine, phenyl, -CN, -CF3, -Cl, or -NO2; more preferably, each of the following is independently C1 to C3: alkyl, alkoxy, alkoxy, alkylthio, alkylamine, phenyl, -CN, -CF3, -Cl, or -NO2.

[0062] An electrophilic activating agent and an auxiliary agent are reacted with an α-substituted-N-(arylhydrazone) compound of formula (I) in an organic solvent; the electrophilic activating agent is trifluoromethanesulfonic anhydride; the auxiliary agent is a triarylphosphine oxide compound; the auxiliary agent triarylphosphine oxide compound is preferably triphenylphosphine oxide and / or tri(4-methylphenyl)phosphine oxide; the molar ratio of the electrophilic activating agent trifluoromethanesulfonic anhydride to the auxiliary agent triarylphosphine oxide compound is preferably (0.2-6.0):1, more preferably (0.2-2.0):1; the molar ratio of the electrophilic activating agent trifluoromethanesulfonic anhydride to the α-substituted-N-(arylhydrazone) compound of formula (I) is preferably (0.5-6.0):1, more preferably (1.0-4.0):1, and even more preferably (1.0-2.5):1.

[0063] The organic solvent used in this invention is preferably one or more of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, acetonitrile, chlorobenzene, nitrobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; the concentration of the α-substituted-N-(arylhydrazone) compound represented by formula (I) in the reaction is preferably 0.02-0.5 mmol / mL, more preferably 0.04-0.4 mmol / mL, and even more preferably 0.04-0.2 mmol / mL;

[0064] The preferred temperature for the reaction described in this invention is -15℃ to 80℃, more preferably -15℃ to 40℃; the preferred reaction time is 0.1 to 6.0 h.

[0065] The preferred preparation method of the present invention is as follows:

[0066] The α-substituted-N-(arylhydrazone) compound shown in formula (I) and the electrophilic activating agent are mixed in an organic solvent, stirred, and reacted.

[0067] After the reaction was completed, the reaction solution was poured into an aqueous NaCl solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. Then, the mixture was extracted 1 to 3 times with an organic solvent. The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography to obtain a pale yellow solid product.

[0068] All reagents used in the following examples are commercially available;

[0069] The α-substituted-N-(arylhydrazone) compounds represented by formula (I) of the present invention are preferably prepared according to the synthetic method reported in the literature (Dyes and Pigments, 2016, 128, 246);

[0070] This invention utilizes electrophilic activating reagents to promote intramolecular cyclization reactions of α-substituted-N-(arylhydrazone) compounds, achieving the synthesis of benzopyridazine compounds. This method offers advantages such as readily available raw materials, simple operation, mild reaction conditions, wide applicability, and the elimination of the need for metal catalysts. Furthermore, the benzopyridazine compounds synthesized in this invention exhibit structural diversity and modifiability, undoubtedly providing ample research space for the screening of novel anticancer drugs and demonstrating promising potential for pharmaceutical applications.

[0071] This invention provides a benzopyridazine compound having the structure shown in formula (II):

[0072]

[0073] Among them, -R 1 With -R 2 Each is independently selected from H, -OA, -NHA, -NHAr, -A, -Ar, or -Het;

[0074] -R 3 Choose from H, -EWG, -A, -X, -Ar, or -Het;

[0075] -R 4 With -R 5 Each can be independently selected from H, -A, -OA, -Ar, -Het, -X, -SA, -NHA, -NAA, or -EWG;

[0076] The -A is selected from C1 to C30 alkyl groups, C1 to C30 substituted alkyl groups, or C3 to C7 cycloalkyl groups;

[0077] The -Ar is selected from substituted or unsubstituted aryl groups;

[0078] The -Het is selected from substituted or unsubstituted unsaturated monocyclic heterocyclic groups containing 1 to 4 heteroatoms, and substituted or unsubstituted unsaturated bicyclic heterocyclic groups containing 1 to 4 heteroatoms;

[0079] The -EWG is selected from -COA, -COAr, -COOA, -CN, -NO2, or -CF3;

[0080] X is a halogen.

[0081] The above-mentioned substituents have been clearly described in this invention, and will not be repeated here.

[0082] To further illustrate the present invention, the following describes in detail a method for preparing a benzopyridazine compound provided by the present invention, in conjunction with embodiments.

[0083] Example 1

[0084] Synthesis of 3-acetyl-4-anilinobenzopyridazine

[0085] At -10°C, trifluoromethanesulfonic anhydride (0.564 g, 2.0 mmol) and triphenylphosphine oxide (0.556 g, 2.0 mmol) were added to a 25 mL round-bottom flask containing 10 mL of dichloromethane. After stirring thoroughly, α-acetyl-α-(N-phenyl)formamido-N-(phenylhydrazone) (0.281 g, 1.0 mmol) dissolved in 5 mL of dichloromethane was added, and the reaction was carried out at 15°C for 2.0 h. After the reaction was completed, the reaction solution was poured into 50.0 mL of NaCl aqueous solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. The mixture was then extracted three times with 20.0 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.234 g of a yellow solid product with a purity greater than 98% and a yield of 89%.

[0086] The 3-acetyl-4-aniline-benzopyridinium obtained in Example 1 was analyzed using nuclear magnetic resonance spectroscopy. Its 1H and 1C NMR spectra were obtained, and the results are as follows:

[0087] 1 H NMR (300MHz, CDCl3): δ3.06 (s, 1H), 7.18 (d, J = 7.5Hz, 2H), 7.26-7.31 (m, 2H), 7.39 (t, J = 7.5Hz, 2 H),7.50(d,J=8.4Hz,1H),7.76(t,J1=6.6Hz,J2=8.4Hz,1H),8.39(d,J=8.4Hz,1H),11.65(s,1H);

[0088] 13 C NMR (75MHz, CDCl3): δ27.9,116.3,124.1,125.6,126.4,127.7,129.7,130.0,131.9,135.5,140.6,142.5,150.3,240.6.

[0089] Example 2

[0090] Synthesis of 3-acetyl-4-anilinobenzopyridazine

[0091] At room temperature, α-acetyl-α-(N-phenyl)formamido-N-(phenylhydrazone) (0.281 g, 1.0 mmol) and triphenylphosphine oxide (0.556 g, 2.0 mmol) were added to a 25 mL round-bottom flask containing 5 mL of chloroform. After stirring, trifluoromethanesulfonic anhydride (1.128 g, 4.0 mmol) was added, and the reaction was allowed to proceed at room temperature for 0.5 h. After the reaction was complete, the reaction solution was poured into 50.0 mL of NaCl aqueous solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. The mixture was then extracted three times with 15.0 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain 0.192 g of a pale yellow solid product with a purity greater than 98% and a yield of 73%.

[0092] Example 3

[0093] Synthesis of 3-Acrylonitrile-4-anilinebenzopyridazine

[0094] At -5°C, trifluoromethanesulfonic anhydride (0.846 g, 3.0 mmol) and triphenylphosphine oxide (0.695 g, 2.5 mmol) were added to a 50 mL round-bottom flask containing 15 mL of 1,2-dichloroethane. After stirring until homogeneous, α-cyano-α-(N-phenyl)formamido-N-(phenylhydrazone) (0.264 g, 1.0 mmol) dissolved in 10 mL of 1,1,2,2-tetrachloroethane was added, and the reaction was carried out at 0°C for 3.0 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of NaCl aqueous solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. Then, the mixture was extracted three times with 20.0 mL of dichloromethane each time. The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain 0.199 g of yellow solid product with a purity greater than 98% and a yield of 81%.

[0095] The 3-cyano-4-aniline-benzopyridinium obtained in Example 3 was analyzed by high-resolution mass spectrometry, and its mass spectrometry analysis data are as follows:

[0096] HRMS(ESI)calcd for C 15 H 11 N4[M+Na] + Theoretical value: 247.0978, measured value: 247.0991.

[0097] Example 4

[0098] Synthesis of 3-acetyl-4-(4-methylaniline)benzopyridazine

[0099] At 20°C, trifluoromethanesulfonic anhydride (0.564 g, 2.0 mmol) and tris(4-methylphenyl)phosphine oxide (1.281 g, 4.0 mmol) were added to a 50 mL round-bottom flask containing 20 mL of acetonitrile. After stirring until homogeneous, α-acetyl-α-(N-(4-methylphenyl))formamido-N-(phenylhydrazone) (0.295 g, 1.0 mmol) dissolved in 5 mL of N,N-dimethylformamide solution were added, and the reaction was carried out at 20°C for 4.5 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of NaCl aqueous solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. Then, the mixture was extracted three times with 20.0 mL of dichloromethane each time. The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.198 g of yellow solid product with a purity greater than 98% and a yield of 76%.

[0100] The 3-acetyl-4-(4-methylaniline)benzopyridinium obtained in Example 4 was analyzed by nuclear magnetic resonance spectroscopy, and its 1H NMR spectrum was obtained. The results are as follows:

[0101] 1 H NMR (300MHz, CDCl3): δ2.05(s,1H),3.08(s,1H),7.15(d,J=7.5Hz,2H),7.25(t,J1=6.9Hz,J2=8.1Hz,1H),7.37 (d, J=7.5Hz, 2H), 7.55 (d, J=8.1Hz, 1H), 7.73 (t, J1=6.9Hz, J2=8.1Hz, 1H), 8.40 (d, J=8.1Hz, 1H), 11.69 (s, 1H).

[0102] Example 5

[0103] Synthesis of 3-acetyl-4-anilino-6-methylbenzopyridazine

[0104] At 5°C, trifluoromethanesulfonic anhydride (0.423 g, 1.5 mmol) and triphenylphosphine oxide (0.501 g, 1.8 mmol) were added to a 50 mL round-bottom flask containing 15 mL of dichloromethane. After stirring until homogeneous, α-acetyl-α-(N-phenyl)formamido-N-((4-methylphenyl)hydrazone) (0.295 g, 1.0 mmol) dissolved in 15 mL of chlorobenzene was added, and the mixture was reacted at 40°C for 1.0 hour. After the reaction was completed, the reaction solution was poured into 50.0 mL of NaCl aqueous solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. Then, the mixture was extracted twice with 25.0 mL of dichloromethane each time. The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.169 g of yellow solid product with a purity greater than 98% and a yield of 65%.

[0105] The 3-acetyl-4-anilino-6-methylbenzopyridinium obtained in Example 5 was analyzed by nuclear magnetic resonance spectroscopy, and its 1H NMR spectrum was obtained. The results are as follows:

[0106] 1 H NMR (300MHz, CDCl3): δ2.10 (s, 1H), 3.05 (s, 1H), 7.08 (d, J = 7.5Hz, 2H), 7.14 (t, J1 = 6.9Hz, J2 = 8.4Hz, 1H), 7.35(d,J=7.5Hz,2H),7.61(s,1H),7.73(t,J1=6.9Hz,J2=8.4Hz,1H),8.37(d,J=8.1Hz,1H),11.52(s,1H).

[0107] Example 6

[0108] Synthesis of 3-benzoyl-4-diethylaminobenzopyridazine

[0109] At 0 °C, trifluoromethanesulfonic anhydride (0.564 g, 2.0 mmol) and triphenylphosphine oxide (0.835 g, 3.0 mmol) were added to a 50 mL round-bottom flask containing 5 mL of dichloromethane. After stirring until homogeneous, α-benzoyl-α-(N-diethyl)formamido-N-(phenylhydrazone) (0.323 g, 1.0 mmol) dissolved in 15 mL of 1,1,2-trichloroethane was added, and the mixture was reacted at 80 °C for 1.5 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of NaCl aqueous solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. Then, the mixture was extracted three times with 20.0 mL of dichloromethane each time. The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.177 g of yellow solid product with a purity greater than 98% and a yield of 58%.

[0110] The 3-benzoyl-4-diethylaminobenzopyridinium obtained in Example 6 was analyzed by high-resolution mass spectrometry, and its mass spectrometry analysis data are as follows:

[0111] HRMS(ESI)calcd for C 19 H 20 N3O[M+Na] + Theoretical value: 306.1601, measured value: 306.1592.

[0112] Example 7

[0113] Synthesis of 3-Acrylonitrile-4-(N-methoxyamino)-6-chlorobenzopyridazine

[0114] At 0 °C, trifluoromethanesulfonic anhydride (0.705 g, 2.2 mmol) and triphenylphosphine oxide (0.622 g, 2.2 mmol) were added to a 50 mL round-bottom flask containing 10 mL of dichloromethane. After stirring until homogeneous, α-cyano-α-(N-methoxy)formamido-N-((4-chlorophenyl)hydrazone) (0.253 g, 1.0 mmol) dissolved in 15 mL of ethyl acetate was added. The reaction was carried out at 20 °C for 1.0 h. After the reaction was completed, the reaction solution was poured into 50.0 mL of NaCl aqueous solution, and saturated NaHCO3 solution was added dropwise until the system was neutral. The mixture was then extracted three times with 20.0 mL of ethyl acetate each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the organic solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give 0.146 g of a yellow solid product with a purity greater than 98% and a yield of 62%.

[0115] The 3-cyano-4-(N-methoxyamino)-6-chlorobenzopyridinium obtained in Example 7 was analyzed by nuclear magnetic resonance spectroscopy, and its 1H NMR spectrum was obtained. The results are as follows:

[0116] 1 H NMR (300MHz, CDCl3): δ3.02 (s, 1H), 3.73 (s, 1H), 7.26 (d, J = 8.7Hz, 1H), 7.33 (d, J = 2.1Hz, 1H), 7.58 (s, 1H), 8.21 (dd, J1 = 8.7Hz, J2 = 2.1Hz, 1H).

[0117] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a benzopyridazine compound, characterized in that, include: Electrophilic activating agent, auxiliaries and α-substituted- as shown in formula (I) N -(arylhydrazone) compounds react in an organic solvent to give benzopyridinium compounds as shown in formula (II); the electrophilic activating agent is trifluoromethanesulfonic anhydride, and the auxiliary is a triarylphosphine oxide compound; Formula (I) Formula (II); Among them, -R 1 With -R 2 Each is independently selected from H, -A, -Ar; -Ar is selected from phenyl, substituted phenyl, biphenyl, substituted biphenyl, naphthyl, or substituted naphthyl; the substituents of the substituted phenyl, substituted biphenyl, or substituted naphthyl are independently selected from -A, -OA; -R 3 Selected from -EWG; -R 4 With -R 5 Each is independently selected from H, -A, and halogen; The -A is selected from C1~C10 alkyl groups and C3~C7 cycloalkyl groups; The -EWG is selected from -COA, -COAr, -COOA, -CN, -NO2, or -CF3.

2. The preparation method according to claim 1, characterized in that, The -R 3 Selected from -CN, -NO2, C1~C5 alkylyl, benzoyl, and substituted benzoyl groups; The -R 4 With -R 5 Each is independently selected from C1 to C5 alkyl groups and -Cl groups.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the electrophilic activating agent trifluoromethanesulfonic anhydride to the auxiliary agent triarylphosphine oxide compound is (0.5~6.0):

1.

4. The preparation method according to claim 3, characterized in that, The adjuvant triarylphosphine oxide compound is selected from triphenylphosphine oxide and / or tri(4-methylphenyl)phosphine oxide.

5. The preparation method according to claim 3, characterized in that, The electrophilic activating agent trifluoromethanesulfonic anhydride reacts with the α-substituted- as shown in formula (I) N The molar ratio of -(arylhydrazone) compounds is (0.5~6.0):1; The molar ratio of the electrophilic activating agent trifluoromethanesulfonic anhydride to the auxiliary agent triarylphosphine oxide compound is (0.5~2.0):

1.

6. The preparation method according to claim 1, characterized in that, The organic solvent is selected from dichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, acetonitrile, chlorobenzene, nitrobenzene, etc. N , N -Dimethylformamide, N , N -One or more of dimethylacetamide and dimethyl sulfoxide; The reaction temperature is -15℃ to 80℃; the reaction time is 0.1 to 6.0 h.

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