Simple and convenient synthesis method of 3, 5-disubstituted pyridazine compound

Abstract

The invention discloses a novel synthesis method of a 3, 5-disubstituted pyridazine compound, which comprises the following steps: adding an N-tert-butoxy substituted acylhydrazone compound, a propiophenone compound, a catalyst, an oxidizing agent, a ligand, an acid additive and an alkali additive into an organic solvent N, N-dimethylformamide, heating to 130 DEG C under an air condition, reacting, and separating to obtain the 3, 5-disubstituted pyridazine compound. And reacting for 12 hours, and after the reaction is completed, carrying out post-treatment to obtain the corresponding 3, 5-disubstituted pyridazine compound. According to the invention, simple and easy-to-synthesize N-tert-butoxy substituted acylhydrazone and propiophenone are directly used as reaction substrates, and the construction of the 3, 5-disubstituted pyridazine compound is realized in one step through direct dehydrogenation coupling between C (sp3)-H bonds promoted by copper and subsequent cyclization reaction. The reaction has the advantages of being easy and convenient to operate, good in substrate application range and functional group compatibility, excellent in chemical selectivity and step economy and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a simple and efficient synthesis method of a 3,5-disubstituted pyridazine compound. Background Art

[0002] As an important nitrogen-containing heterocyclic skeleton, polysubstituted pyridazine compounds are the core structural fragments of many natural products, drugs, bioactive molecules and functional material molecules. For example, the drug minapine for treating psychological disorders, the antihypertensive drug hydralazine and the bioactive molecule TYK2 inhibitor all contain polysubstituted pyridazine skeletons. Therefore, the development of a simple and efficient new method for the synthesis of polysubstituted pyridazine compounds has attracted widespread attention from organic synthetic chemists.

[0003] In recent years, based on the transformation of structurally diverse hydrazone compounds, synthetic chemists have developed a strategy for the intramolecular cyclization of β,γ-unsaturated hydrazone compounds and the [4+2] cycloaddition reaction of α-halogenated hydrazones and unsaturated coupling agents, which greatly facilitates the synthesis of polysubstituted pyridazine skeletons. However, in the above transformations, lengthy synthetic steps are required to prepare pre-functionalized hydrazone derivatives, and a large amount of waste is generated during the reaction, which greatly reduces the step economy and atom economy of the reaction. Ketones are a class of widely used synthetic fragments. 3 Direct functionalization of the )-H bond provides a new idea for the synthesis of various heterocyclic compounds. Based on this, the dehydrogenation coupling between simple acylhydrazone substrates and saturated ketone substrates and the subsequent cyclization reaction will provide a simple and efficient synthetic method for the synthesis of multi-substituted pyridazine skeletons. Summary of the invention

[0004] The present invention provides a simple and efficient method for synthesizing a 3,5-disubstituted pyridazine compound. The method directly uses a simple N-tert-butoxy-substituted acylhydrazone and acetophenone as reaction substrates, and promotes the C(sp 3 )-C(sp 3 ) bond dehydrogenation coupling and cyclization reaction in one step to construct 3,5-disubstituted pyridazine compounds, which have the advantages of wide substrate applicability, functional group compatibility and excellent chemical selectivity, and show excellent step economy and atom economy.

[0005] A method for synthesizing a 3,5-disubstituted pyridazine compound comprises the following steps: adding a tert-butoxy-substituted acylhydrazone compound, a phenylacetone compound, a catalyst, an oxidant, a ligand, an acid additive and a base additive to an organic solvent, controlling the temperature at 120 to 140° C. under air conditions to react for 9 to 15 hours, and after the reaction is complete, post-treating to obtain the corresponding 3,5-disubstituted pyridazine compound;

[0006] The structure of the N-tert-butoxy substituted acylhydrazone compound is shown in formula (II):

[0007]

[0008] The structure of the phenylacetone compound is shown in formula (III):

[0009]

[0010] The structure of the 3,5-disubstituted pyridazine compound is shown in formula (I):

[0011]

[0012] In formulas (I) to (III), R 1 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, phenoxy, trifluoromethyl, or R 1 Connect with R 1 The benzene rings together form a naphthyl or benzothienyl group;

[0013] R 2 is selected from H, C1-C4 alkyl, halogen, trifluoromethyl or C1-C4 alkoxy;

[0014] In the present invention, N-tert-butoxy acylhydrazone and propiophenone, which are widely available and easy to synthesize, are directly used as reaction substrates, and C(sp 3 )-C(sp 3 ) bond dehydrogenative coupling and tandem cyclization reactions can efficiently prepare 3,5-disubstituted pyridazine compounds in one step.

[0015] Preferably, the R 1 is selected from H, chlorine, methyl, methoxy, phenoxy, fluorine, trifluoromethyl, or R 1 Connect with R 1 The benzene rings together form a naphthyl or benzothienyl group;

[0016] The R 2 is selected from H, methyl, ethyl, chloro, trifluoromethyl or methoxy.

[0017] Preferably, the catalyst is copper acetate.

[0018] Preferably, the oxidant is 2,2,6,6-tetramethylpiperidinyloxy compound.

[0019] Preferably, the ligand is 6,6'-dimethyl-2,2'-bipyridine.

[0020] Preferably, the acid additive is n-valeric acid.

[0021] Preferably, the alkaline additive is lithium acetate.

[0022] Preferably, the organic solvent is N,N-dimethylformamide.

[0023] Preferably, the molar ratio of the N-tert-butoxy substituted acylhydrazone compound to the propiophenone compound is 1 to 1.5:1.

[0024] Preferably, the reaction gas atmosphere is under air conditions.

[0025] Preferably, the reaction temperature is 130° C. and the reaction time is 12 hours.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] (1) The present invention utilizes easily available N-tert-butoxy-substituted acylhydrazone and propiophenone as reaction substrates, directly from inert sp 3 Starting from the carbon-hydrogen bond, through C(sp 3 )-C(sp 3 ) bond coupling and the subsequent cyclization reaction can efficiently realize the synthesis of 3,5-disubstituted pyridazine compounds in one step, with excellent step economy and green economy.

[0028] (2) The synthesis method of the present invention is simple and easy to operate, exhibits excellent chemical selectivity, has a wide substrate adaptability range, and has good functional group compatibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The hydrogen and carbon spectra of the compound obtained in Example 1;

[0030] Figure 2 The hydrogen and carbon spectra of the compound obtained in Example 2;

[0031] Figure 3 The hydrogen and carbon spectra of the compound obtained in Example 3;

[0032] Figure 4 The hydrogen and carbon spectra of the compound obtained in Example 4;

[0033] Figure 5 The hydrogen and carbon spectra of the compound obtained in Example 5;

[0034] Figure 6 The hydrogen and carbon spectra of the compound obtained in Example 6;

[0035] Figure 7 The hydrogen and carbon spectra of the compound obtained in Example 7;

[0036] Figure 8 The hydrogen and carbon spectra of the compound obtained in Example 8;

[0037] Fig. 9 The hydrogen and carbon spectra of the compound obtained in Example 9;

[0038] Fig.10 The hydrogen and carbon spectra of the compound obtained in Example 10;

[0039] Fig.11 The hydrogen and carbon spectra of the compound obtained in Example 11;

[0040] Fig.12 The hydrogen and carbon spectra of the compound obtained in Example 12;

[0041] Fig.13 The hydrogen and carbon spectra of the compound obtained in Example 13;

[0042] Fig.14 The hydrogen and carbon spectra of the compound obtained in Example 14;

[0043] Fig.15 The hydrogen and carbon spectra of the compound obtained in Example 15;

[0044] Fig.16 The hydrogen and carbon spectra of the compound obtained in Example 16;

[0045] Fig.17 The hydrogen and carbon spectra of the compound obtained in Example 17;

[0046] The hydrogen spectrum was tested on a 400MHz or 500MHz nuclear magnetic resonance instrument. The carbon spectrum was tested on a 125MHz nuclear magnetic resonance instrument. The test conditions were all room temperature, tetramethylsilane was used as an internal standard, and the samples were dissolved in deuterated chloroform. DETAILED DESCRIPTION

[0047] The present invention is further described below in conjunction with specific embodiments, and the following specific embodiments are all optimal implementation modes of the present invention.

[0048] Examples 1 to 17

[0049] According to the raw material ratio in Table 1, N-tert-butoxy substituted acylhydrazone compound (II, 0.25mmol), phenylacetone (III, 0.2mmol), acetic acid ketone (0.3mmol), TEMPO (0.4mmol), 6,6'-dimethyl-2,2'-bipyridine (0.12mmol), n-pentanoic acid (0.4mmol), lithium acetate (0.4mmol) and organic solvent N,N-dimethylformamide (2mL) were added into a 25mL sealed tube, mixed and stirred evenly, and reacted in an oil bath (130°C) under air atmosphere for 12h. After the reaction was completed according to the reaction conditions in Table 2, the reaction was cooled, the organic phase was extracted and collected, dried with sodium sulfate, mixed with silica gel, and purified by column chromatography to obtain the corresponding 3,5-disubstituted pyridazine compound (I). The reaction process is shown in the following formula:

[0050]

[0051] Table 1 Raw material ratios of Examples 1 to 17

[0052]

[0053]

[0054] a R 1 Connect with R 1 The benzene rings together form a naphthyl or benzothiophenyl group

[0055] Table 2 Reaction conditions and reaction results of Examples 1 to 17

[0056]

[0057] In Table 1 and Table 2, T is the reaction temperature, and t is the reaction time.

[0058] The structural confirmation data of the 3,5-disubstituted pyridazine compounds prepared in Examples 1 to 17 are as follows:

[0059] (6-(4-chlorophenyl)pyridazin-4-yl)(p-tolyl)methanone(I-1): yellow solid (46.9 mg, 76%). mp: 178-179°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (500MHz, CDCl3) δ9.36 (s, 1H), 8.09-8.06 (m, 3H), 7.75 (d, J = 7.6Hz, 2H), 7.51 (d, J = 9.2Hz, 2H), 7.35 (d, J = 7.6Hz, 2H), 2.47 (s, 3H).13 C NMR (125MHz, CDCl3) δ192.8,158.8,148.2,145.7,137.1,135.6,134.0,132.7,130.3,129.8,129.5,128.5,122.5,21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 18 H 14 ClN2O 309.0789,Found 309.0760.

[0060]

[0061] (6-(4-chlorophenyl)pyridazin-4-yl)(phenyl)methanone(I-2): yellow solid (35.3 mg, 60%). mp: 146-147°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (500MHz, CDCl3) δ9.38 (s, 1H), 8.14-8.08 (m, 3H), 7.86 (d, J = 8.0Hz, 2H), 7.71 (t, J = 7.5Hz, 1H), 7.57 (t, J = 7.5Hz, 2H), 7.52 (d, J = 9.0Hz, 2H). 13 C NMR(125MHz, CDCl3)δ193.2,158.9,148.1,137.1,135.2,135.2,134.4,134.0,130.1,129.5,129.1,128.5,122.5.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 17 H 12 ClN2O 295.0633,Found 295.0613.

[0062]

[0063] (6-(4-chlorophenyl)pyridazin-4-yl)(4-ethylphenyl)methanone(I-3): yellow solid (35.4 mg, 55%). mp: 156-157°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1HNMR (400MHz, CDCl3) δ9.36 (s, 1H), 8.09-8.06 (m, 3H), 7.78 (d, J = 6.0Hz, 2H), 7.51 ( d,J=6.0Hz,2H),7.38(d,J=6.4Hz,2H),2.76(q,J=6.0Hz,2H),1.30(t,J=6.0Hz,3H). 13 C NMR (125MHz, CDCl3) δ192.8,158.8,151.8,148.2,137.1,135.6,134.1,132. 9,130.4,129.5,128.6,128.5,122.5,29.1,15.1.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 19 H 16 ClN2O323.0946; Found 323.0938.

[0064]

[0065] (4-chlorophenyl)(6-(4-chlorophenyl)pyridazin-4-yl)methanone(I-4): yellow solid (41.4 mg, 63%). mp: 194-195°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 HNMR (400MHz, CDCl3) δ9.36 (s, 1H), 8.09-8.05 (m, 3H), 7.81 (d, J = 8.8Hz, 2H), 7.56-7.52 (m, 4H). 13 C NMR(125MHz, CDCl3)δ192.0,159.0,147.8,141.2,137.2,134.9,133.9,133.5,131.4,129.5,128.5,122.3.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 17 H 11 Cl2N2O 329.0243; Found 329.0238.

[0066]

[0067] (6-(4-chlorophenyl)pyridazin-4-yl)(4-(trifluoromethyl)phenyl)methanone(I-5): yellow solid (34.8 mg, 48%). mp: 180-181°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (400MHz, CDCl3) δ9.38 (s, 1H), 8.09-8.08 (m, 3H), 7.97 (d, J = 8.0Hz, 2H), 7.84 (d, J = 8.0Hz, 2H), 7.53 (d, J = 8.4Hz, 2H). 13 C NMR (125MHz, CDCl3) δ192.4,159.1,147.7,138.0,137.3,135.5(q,J C-F =32.5Hz),134.2,133.7,130.3,129.6,128.5,126.2(q,J C-F =2.5Hz),123.3(q,J C-F =271.2Hz),122.2.HRMS(ESI-TOF)m / z:[M+H] + Calcdfor C 18 H 11 ClF3N2O 363.0507,Found 363.0532.

[0068]

[0069] (6-(4-chlorophenyl)pyridazin-4-yl)(3-methoxyphenyl)methanone(I-6): yellow solid (31.8 mg, 49%). mp: 156-157°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (400MHz, CDCl3) δ9.39 (s, 1H), 8.12-8.09 (m, 3H), 7.53 (d, J = 8.0Hz, 2H) ,7.47-7.43(m,2H),7.34(d,J=7.2Hz,1H),7.28-7.24(m,1H),3.89(s,3H). 13C NMR (125MHz, CDCl3) δ193.0,160.2,158.9,148.1,137.1,136.5,135.3,134.0,1 30.0,129.5,128.5,123.0,122.5,120.9,114.0,55.6.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 18 H 14 ClN2O2325.0738,Found 325.0714.

[0070]

[0071] Phenyl(6-phenylpyridazin-4-yl)methanone(I-7): yellow solid (33.3 mg, 64%). mp: 130-131°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (500MHz, CDCl3) δ9.39 (s, 1H), 8.14-8.12 (m, 2H), 8.10 (s, 1H), 7.86 (d, J = 7.5Hz, 2H), 7.71 (t, J = 7.0Hz, 1H), 7.58-7.53 (m, 5H). 13 C NMR (125MHz, CDCl3) δ193.4,160.0,148.0,135.6,135.3,135.1,134.3,130.7,130.1,129.2,129.1,127.3,122.8.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 17 H 13 N2O 261.1022,Found 261.1033.

[0072]

[0073] (6-phenylpyridazin-4-yl)(p-tolyl)methanone(I-8): yellow solid (38.4 mg, 70%). mp: 170-171°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1H NMR (500MHz, CDCl3) δ9.38 (s, 1H), 8.14 (d, J = 8.0Hz, 2H), 8.08 (s, 1H), 7.77 (d, J = 8.0Hz, 2H), 7.57-7.54 (m, 3H), 7.36 (d, J = 8.0Hz, 2H), 2.48 (s, 3H). 13 C NMR (125MHz, CDCl3) δ193.0,159.9,148.0,145.6,135.7,135.5,132.8,130.6,130.3,129.8,129.2,127.3,122.8,21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 18 H 15 N2O 275.1179,Found 275.1186.

[0074]

[0075] p-tolyl(6-(p-tolyl)pyridazin-4-yl)methanone(I-9): yellow solid (30.0 mg, 52%). mp: 164-165°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (500MHz, CDCl3) δ9.33 (s, 1H), 8.05-8.02 (m, 3H), 7.76 (d, J = 8.5Hz, 2H), 7.36-7.34 (m, 4H), 2.47 (s, 3H), 2.44 (s, 3H). 13 C NMR (125MHz, CDCl3) δ193.0,159.8,147.7,145.5,141.0,135.4,132.9,132. 8,130.3,129.9,129.7,127.2,122.4,21.8,21.4.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 19 H 17 N2O 289.1335,Found 289.1358.

[0076]

[0077] (6-(4-methoxyphenyl)pyridazin-4-yl)(p-tolyl)methanone(I-10): yellow solid (45.6 mg, 75%). mp: 153-154°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 8.10 (d, J = 8.8Hz, 2H), 8.02 (s, 1H), 7.76 (d, J = 8 .0Hz,2H),7.35(d,J=7.6Hz,2H),7.04(d,J=8.8Hz,2H),3.88(s,3H),2.47(s,3H). 13 C NMR (125MHz, CDCl3) δ193.1,161.8,159.4,147.4,145.5,135.4,132.8,130. 3,129.7,128.7,128.0,122.0,114.6,55.5,21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 19 H 17 N2O2305.1285,Found305.1297.

[0078]

[0079] (6-(4-phenoxyphenyl)pyridazin-4-yl)(p-tolyl)methanone(I-11): yellow solid (40.3 mg, 55%). mp: 130-131°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (500MHz, CDCl3) δ8.19 (d, J = 7.5Hz, 2H), 7.84 (s, 1H), 7.55-7.51 (m, 5H), 7.35-7.30 (m, 3H), 7.16-7.15 (m, 4H), 2.37 (s, 3H). 13 C NMR (125MHz, CDCl3) δ196.2,158.3,157.7,139.5,138.8,137.0,136.2,134.2,130.0,1 30.0,129.5,129.0,129.0,128.7,128.1,127.1,124.8,21.3.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 24 H19 N2O2 367.1441,Found367.1479.

[0080]

[0081] (6-(4-fluorophenyl)pyridazin-4-yl)(p-tolyl)methanone(I-12): yellow solid (34.5 mg, 59%). mp: 146-147°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (400MHz, CDCl3) δ9.43(s,1H),8.22-8.17(m,2H),8.12(s,1H),7.82(d,J=6.4Hz,2H),7.42(d,J=6.8Hz,2H),7.32-7.27(m,2H),2.54(s,3H). 13 C NMR(125MHz,CDCl3)δ192.9,164.5(d,J C-F =250.0Hz),148.0,145.7,135.7,132.7,131.8(d,J C-F =3.8Hz),130.3,129.8,129.3(d,J C-F =8.8Hz),122.4,116.3(d,J C-F =21.3Hz),21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 18 H 14 FN2O 293.1085,Found 293.1064.

[0082]

[0083] p-tolyl(6-(4-(trifluoromethyl)phenyl)pyridazin-4-yl)methanone(I-13): yellow solid (41.0 mg, 60%). mp: 196-197°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (400MHz, CDCl3) δ9.42 (s, 1H), 8.27 (d, J = 8.0Hz, 2H), 8.13 (s, 1H), 7.79 (q, J = 8.8Hz, 4H), 7.37 (d, J = 8.0Hz, 2H), 2.49 (s, 3H). 13C NMR (125MHz, CDCl3) δ192.6,158.6,148.6,145.8,139.0,135.7,132.6,132.4(q,J C-F =32.5Hz),130.3,129.8,127.6,126.1(q,J C-F =3.8Hz),123.9(q,J C-F =270.0Hz),123.0,21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 19 H 14 F3N2O 343.1053,Found 343.1066.

[0084]

[0085] (6-(3-fluorophenyl)pyridazin-4-yl)(p-tolyl)methanone(I-14): yellow solid (25.1 mg, 43%). mp: 124-125°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR(500MHz, CDCl3)δ9.39(s,1H),8.09(s,1H),7.95-7.90(m,2H),7.80-7. 77(m,2H),7.53(s,1H),7.42-7.36(m,2H),7.29-7.23(m,1H),2.50(s,3H). 13 C NMR(125MHz,CDCl3)δ192.7,163.4(d,J C-F =245.0Hz),158.7,148.4,145.7,137.9,135.6,132.7,130.8(d,J C-F =7.5Hz),130.3,129.8,122.8(d,J C-F =32.5Hz),117.6(d,J C-F =20.0Hz),114.3(d,J C-F =25.0Hz),21.8.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 18 H 14 FN2O 293.1085,Found 293.1081.

[0086]

[0087] (6-(3-methoxyphenyl)pyridazin-4-yl)(p-tolyl)methanone(I-15): yellow solid (25.5 mg, 42%). mp: 144-145°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (500MHz, CDCl3) δ9.36 (s, 1H), 8.06 (s, 1H), 7.78-7.75 (m, 3H), 7.62 (d, J = 7.5Hz, 1H), 7. 44(d,J=8.0Hz,1H),7.36(t,J=8.0Hz,2H),7.07(d,J=8.0Hz,1H),3.91(s,3H),2.47(s,3H). 13 C NMR (125MHz, CDCl3) δ192.9,160.4,159.6,148.1,145.6,137.0,135.5,132.8,130. 3,130.2,129.8,122.8,119.5,116.9,112.3,55.5,21.8.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 19 H 17 N2O2 305.1285,Found 305.1294.

[0088]

[0089] (6-(naphthalen-2-yl)pyridazin-4-yl)(p-tolyl)methanone(I-16): yellow solid (31.8 mg, 49%). mp: 189-190°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR (500MHz, CDCl3) δ9.40(s,1H),8.61(s,1H),8.29(d,J=8.5Hz,1H),8.23(s,1H),8.01(d,J=9.0Hz,1H),7.97(d, J=8.0Hz,1H),7.91(d,J=7.0Hz,1H),7.80(d,J=8.0Hz,2H),7.57-7.55(m,2H),7.37(d,J=8.0Hz,2H),2.49(s,3H). 13C NMR (125MHz, CDCl3) δ193.0,159.9,148.0,145.6,135.6,134.4,133.4,132.9,132.8,130.3,1 29.8,129.1,128.9,127.8,127.5,127.4,126.8,124.1,122.9,21.8.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 22 H 17 N2O325.1335,Found 325.1302.

[0090]

[0091] (6-(benzo[b]thiophen-2-yl)pyridazin-4-yl)(p-tolyl)methanone(I-17): yellow solid (13.9 mg, 21%). mp: 178-179°C. Purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 12 / 1). 1 H NMR(400MHz, CDCl3)δ9.32(s,1H),8.14(s,1H),7.99(s,1H),7.93-7.90(m,1H), 7.86-7.83(m,1H),7.79-7.77(d,J=8.0Hz,2H),7.42-7.37(m,4H),2.49(s,3H). 13 C NMR (125MHz, CDCl3) δ192.6,148.2,145.7,141.5,140.0,139.8,135.3,132.7,130. 3,129.8,126.2,124.9,124.6,124.0,122.8,121.7,21.9.HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 20 H 15 N2OS331.0900, Found 331.0929.

Claims

1. A simple method for synthesizing a 3,5-disubstituted pyridazine compound, characterized in that: The method comprises the following steps: adding an N-tert-butoxy-substituted acylhydrazone compound, a phenylacetone compound, a catalyst, an oxidant, a ligand, an acid additive and a base additive into an organic solvent, controlling the temperature at 120 to 140° C. under air conditions to react for 9 to 15 hours, and after the reaction is complete, post-treating to obtain a corresponding 3,5-disubstituted pyridazine compound; The structure of the N-tert-butoxy substituted acylhydrazone compound is shown in formula (II): The structure of the phenylacetone compound is shown in formula (III): The structure of the 3,5-disubstituted pyridazine compound is shown in formula (I): In formulas (I) to (III), R 1 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, phenoxy, trifluoromethyl, or R 1 Connect with R 1 The benzene rings together form a naphthyl or benzothienyl group; R 2 Selected from H, C1-C4 alkyl, halogen, trifluoromethyl or C1-C4 alkoxy.

2. The synthesis method according to claim 1, characterized in that The R 1 is selected from H, chlorine, methyl, methoxy, phenoxy, fluorine, trifluoromethyl, or R 1 Connect with R 1 The benzene rings of 2 is selected from H, methyl, ethyl, chloro, trifluoromethyl or methoxy.

3. The synthesis method according to claim 1, characterized in that The organic solvent is N,N-dimethylformamide (DMF).

4. The synthesis method according to claim 1, characterized in that The catalyst is acetic acid ketone.

5. The synthesis method according to claim 1, characterized in that The oxidant is 2,2,6,6-tetramethylpiperidinyloxy (TEMPO).

6. The synthesis method according to claim 1, characterized in that The ligand is 6,6'-dimethyl-2,2'-bipyridine.

7. The synthesis method according to claim 1, characterized in that The acid additive is n-valeric acid.

8. The synthesis method according to claim 1, characterized in that The alkaline additive is lithium acetate.

9. The synthesis method according to claim 1, characterized in that The molar ratio of the N-tert-butoxy substituted acylhydrazone compound to propiophenone is 1.5-1:

1.

10. The synthesis method according to claim 1, characterized in that The 3,5-disubstituted pyridazine compound is one of the following compounds:

Images