Process for the preparation of a class of trans-s-alkenylsulfanyl pyridazines

Abstract

The application belongs to the technical field of synthetic chemistry, and particularly relates to a preparation method of a class of trans-S-alkenylthio pyridazine compounds. The structural general formula of the trans-S-alkenylthio pyridazine based on a pyridazine structure is as follows: in the structural general formula shown in formula I, R 1 is any one selected from aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl, functional group-containing alkyl, R 2 is any one selected from carboxyl, alkyl and hydrogen, R 3 is any one selected from alkyl, carboxyl and halogen, R 4 is any one selected from aryl, substituted aryl, carboxyl, ester, halogen, furan and amino. The trans-S-alkenylthio pyridazine has a special molecular shape and a trans configuration, the preparation method solves the problem of rapidly and efficiently constructing the trans-S-alkenylthio pyridazine structure in the fields of chemistry and drug synthesis, the preparation method is simple and practical to operate, the preparation process has the characteristics of green economy and environmental friendliness.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of synthetic chemistry, and particularly relates to a kind of trans-S-alkenyl thio pyridazine and a preparation method thereof. BACKGROUND

[0002] Pyridazine drugs have significant biological activity and play an important role in pesticide research. This kind of pesticide has the characteristics of high activity and environmental friendliness, and plays an important role in integrated pest management and reducing environmental pollution caused by pesticides. In addition, pyridazine compounds also have antibacterial, insecticidal, herbicidal and antiviral activities, providing a broad development space for the development of pyridazine pesticides. However, the current synthesis method of alkenyl thio pyridazine is limited (EP02251173, the s atom is substituted for the bromine atom to generate a thio pyridazine compound), the first step is to substitute the s atom for the bromine atom to generate a thio pyridazine compound, and the second step is to oxidize the thio group to a sulfonyl group. The sulfonyl pyridazine ketone compound is an ischemic tissue damage treatment agent. WO2002087584 mentions a pharmaceutical composition and kit comprising a pyridazine ketone compound and a cyclooxygenase-2 inhibitor, a treatment method for treating or preventing certain complications caused by diabetes in mammals, and a treatment method for treating or preventing ischemia of heart tissue in mammals.

[0003] Therefore, the research on the synthesis method of trans-S-alkenyl thio pyridazine is beneficial to promote the application development in the fields of synthesis and drug development. SUMMARY

[0004] The present application aims to provide a preparation method of trans-S-alkenyl thio pyridazine, which aims to solve the technical problems of the limited types and synthesis methods of existing vinyl pyridazine-3-ketones.

[0005] To achieve the above-mentioned application purposes, the technical solutions adopted by the present application are as follows:

[0006] The present application provides a preparation method of trans-S-alkenyl thio pyridazine, comprising the following steps:

[0007] The compound shown in formula II and the compound shown in formula III are dissolved in a solvent, and a synthesis reaction is carried out under the condition of a ruthenium catalyst and a ligand to obtain the compound shown in formula I.

[0008]

[0009] Specifically, under a nitrogen atmosphere, the ruthenium catalyst and the ligand are dissolved in a solvent, and after stirring, the raw materials shown in formula II and formula III are added, and the mixture is stirred at 80-120℃ for 16-24 hours. The reaction mixture is concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the target compound of formula I.

[0010] wherein, in the above compound, R 1 is selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl, alkyl containing functional group, ferrocene, R 2 is selected from any one of carboxyl, alkyl and hydrogen, R 3 is selected from any one of alkyl, carboxyl, halogen, hydrogen, R 4 is selected from any one of aryl, substituted aryl, carboxyl, ester, halogen, furan, amino, hydrogen.

[0011] The aryl group can be monocyclic aryl or polycyclic aryl (such as fused ring aryl), specifically, the aryl group is selected from at least one of phenyl, naphthyl. The heteroaryl group can be five-membered heterocyclic group, six-membered heterocyclic group, benzofused heterocyclic group (benzene ring and heterocyclic ring are fused), fused heterocyclic group (several heterocyclic rings are fused), specifically, the heteroaryl group is selected from at least one of pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, indolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl and purinyl. The substituent groups in the substituted aryl and substituted heteroaryl are independently selected from at least one of fluorine, chlorine, bromine, cyano, alkyl, haloalkyl, alkenyl, alkynyl, nitro, thiol, alkyl ester, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclicalkyl, cycloalkyl, aryloxy, heteroaryloxy and cycloalkylalkyl, i.e. the above substituent groups are mono-substituted or poly-substituted aryl or heteroaryl which are the same or different. Among the above substituent groups, the alkyl group can be C1-C 20 alkyl or C1-C 10 alkyl; the alkenyl group can be C2-C 20 alkenyl or C2-C 10 alkenyl; the alkoxy group can be C1-C 20 alkoxy or C1-C 10 alkoxy; the heterocyclic group can be C3-C 10 heterocycloalkyl, C3-C 10 heterocycloalkenyl or C3-C 10 heterocycloalkynyl; the cycloalkyl group can be C3-C 20 cycloalkyl or C3-C 10 cycloalkyl.

[0012] wherein, the ruthenium catalyst is selected from one of bis-(2-methylallyl)cycloocta-1,5-diene ruthenium (Ru(methallyl)2COD), ruthenium iodide, bis-(2-methylallyl)cycloocta-1,5-diene ruthenium;

[0013] The ligand is selected from one of 2,4-bis(diphenylphosphino)pentane, Xantphos, Xphos, Sphos, tributylphosphine, triisopropylphosphine, N,N-dimethyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphos-4-amine, diphenylphosphine oxide, diphenylphosphine, tricyclohexylphosphine, bis(dicyclohexylphosphino)methane, 1,2-bis(dicyclohexylphosphino)-ethane, 1,3-bis(dicyclohexylphosphino)propane, 1,3-bis(dicyclohexylphosphino)propane.

[0014] 2,4-bis(diphenylphosphino)pentane is (2R,4R)-(+)-2,4-bis(diphenylphosphino)pentane, and its structural formula is as follows:

[0015]

[0016] The structural formula of N,N-dimethyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphos-4-amine is as follows:

[0017]

[0018] The solvent is one of toluene, mesitylene, benzene, xylene, nitrobenzene, chlorobenzene, fluorobenzene and trifluorotoluene.

[0019] The amount of the catalyst used is 2.5 mol% of the compound shown in formula III. The amount of the ligand used is 1.5 mol% of the compound shown in formula III. As preferred, the ruthenium catalyst is Ru(methallyl)2COD, the ligand is 2,4-bis(diphenylphosphino)pentane, and the solvent is toluene.

[0020] The present application provides an organic compound with a trans-S-alkenylthio pyridazine structure, and a catalytic synthesis method for constructing a trans-S-alkenylthio pyridazine. Such trans-S-alkenylthio pyridazine has a special molecular shape, so that it has special pharmaceutical properties and great prospects in new drug development. The preparation method overcomes the problem that the trans-S-alkenylthio pyridazine structure cannot be directly catalytically constructed in the field of chemical and pharmaceutical synthesis. The preparation method provided by the present application is simple and practical, the preparation process is green and economical, friendly to the environment, and easy to industrialize, so it has good application prospects in the fields of synthesis and drug development. DETAILED DESCRIPTION

[0021] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clear and explicit, the present application will be further described in detail below in combination with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application, and are not used to limit the present application.

[0022] The present application has undergone multiple tests, and now some test results are taken as a reference to further describe the application in detail. The following will be described in detail with specific examples. The reaction of each embodiment of the present application is as follows:

[0023] Example 1

[0024] (E)-3-((4-Bromostyryl)thio)pyridazine

[0025]

[0026] Under a nitrogen atmosphere, the catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and the ligand Sphos (0.045 mmol, 1.5 mol%) were dissolved in 6 mL of chlorobenzene and stirred for 5 minutes. Then it was added to a 10 mL reaction bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 equivalent) and p-bromophenyl acetylene (3 mmol, 1.0 equivalent). The reaction mixture was stirred at 100°C for 15 hours. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target compound with a calculated yield of 34%.

[0027] NMR data: 1 HNMR (400 MHz, CDCl3) δ 8.25-8.22 (m, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.58-7.55 (m, 1H), 7.47-7.44 (m, 2H), 7.05-7.02 (m, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 5.64 (d, J = 7.2 Hz, 1H) ppm.

[0028] 13 C NMR (100 MHz, CDCl3) δ 161.0, 139.5, 138.0, 133.9, 131.3, 130.4, 120.2, 119.0, 111.4, 108.7 ppm.

[0029] Example a

[0030] On the basis of Example 1, the effect of the type of ruthenium catalyst was studied. Except for the ruthenium catalyst, the other conditions were the same as in Example 1.

[0031] The ruthenium catalyst in Example 1 was replaced with ruthenium trichloride, and the yield of the target compound was <5%.

[0032] The ruthenium catalyst in Example 1 was replaced by ruthenium trichloride hydrate, and the yield of the target compound was <5%.

[0033] The ruthenium catalyst in Example 1 was replaced by (1,5-cyclooctadiene) ruthenium chloride polymer, and the yield of the target compound was 21%.

[0034] The ruthenium catalyst in Example 1 was replaced by bis(tricyclohexylphosphine) benzylidene ruthenium dichloride, and the yield of the target compound was <5%.

[0035] The ruthenium catalyst in Example 1 was replaced by tris(2,2-bipyridyl) ruthenium chloride hexahydrate, and the yield of the target compound was <5%.

[0036] The ruthenium catalyst in Example 1 was replaced by dichloro (pentamethylcyclopentadienyl) ruthenium (III) polymer, and the yield of the target compound was <5%.

[0037] The ruthenium catalyst in Example 1 was replaced by ruthenium iodide, and the yield of the target compound was 23%.

[0038] The ruthenium catalyst in Example 1 was replaced by ruthenium acetate, and the yield of the target compound was <5%.

[0039] The ruthenium catalyst in Example 1 was replaced by triphenylphosphine ruthenium chloride, and the yield of the target compound was <5%.

[0040] From the above screening, bis-(2-methylallyl) cycloocta-1,5-diene ruthenium catalyst was the best catalyst.

[0041] Example b

[0042] On the basis of Example 1, the influence of the type of ligand was studied, and other conditions were the same as in Example 1 except for the ligand.

[0043] The ligand in Example 1 was replaced by cyclohexyl bisphosphine ligand, and the yield of the target compound was <5%.

[0044] The ligand in Example 1 was replaced by Xantphos, and the yield of the target compound was 27%.

[0045] The ligand in Example 1 was replaced by Xphos, and the yield of the target compound was 25%.

[0046] The ligand in Example 1 was replaced by bipyridine, and the yield of the target compound was <5%.

[0047] The ligand in Example 1 was replaced by triphenylphosphine ligand, and the yield of the target compound was <5%.

[0048] The ligand in Example 1 was replaced by tributylphosphine, and the yield of the target compound was 31%.

[0049] The ligand in Example 1 was replaced by triisopropylphosphine, and the yield of the target compound was 32%.

[0050] The ligand in Example 1 was replaced by Binap, and the yield of the target compound was <5%.

[0051] The ligand in Example 1 was replaced by dppf, and the yield of the target compound was <5%.

[0052] The ligand in Example 1 was replaced by dppa, and the yield of the target compound was <5%.

[0053] The ligand in Example 1 was replaced by dppb, and the yield of the target compound was <5%.

[0054] The ligand in Example 1 was replaced by diadamantyl-n-butylphosphine ligand, and the yield of the target compound was <5%.

[0055] The ligand in Example 1 was replaced by N,N-dimethyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphos-4-amine, and the yield of the target compound was 24%.

[0056] The ligand in Example 1 was replaced by diphenylphosphine oxide, and the yield of the target compound was 25%.

[0057] The ligand in Example 1 was replaced by diphenylphosphine, and the yield of the target compound was 38%.

[0058] The ligand in Example 1 was replaced by tricyclohexylphosphine, and the yield of the target compound was 41%.

[0059] The ligand in Example 1 was replaced by bisdicyclohexylphosphine methane, and the yield of the target compound was 39%.

[0060] The ligand in Example 1 was replaced by bisdicyclohexylphosphine ethane, and the yield of the target compound was 32%.

[0061] The ligand in Example 1 was replaced by bisdicyclohexylphosphine propane, and the yield of the target compound was 35%.

[0062] The ligand in Example 1 was replaced by bisdicyclohexylphosphine butane, and the yield of the target compound was 37%.

[0063] The ligand in Example 1 was replaced by 2,4-bis(diphenylphosphino)pentane ligand, and the yield of the target compound was 53%.

[0064] From the above, the 2,4-bis(diphenylphosphino)pentane ligand was screened as the optimal ligand.

[0065] Example c

[0066] Compared with Example 1, the influence of the type of solvent on the reaction was studied under the condition that bis-(2-methylallyl)cycloocta-1,5-diene ruthenium was the catalyst, 2,4-bis(diphenylphosphino)pentane was the ligand, and other conditions were the same as in Example 1.

[0067] When the reaction solvent was toluene, the yield of the target compound was 62%;

[0068] When the reaction solvent was mesitylene, the yield of the target compound was 52%;

[0069] When the reaction solvent was benzene (Ph), the yield of the target compound was 40%;

[0070] When the reaction solvent was xylene, the yield of the target compound was 53%;

[0071] When the reaction solvent was nitrobenzene (PhNO2), the yield of the target compound was 23%;

[0072] When the reaction solvent was n-hexane, the yield of the target compound was <5%;

[0073] When the reaction solvent was tetrahydrofuran (THF), the yield of the target compound was <5%;

[0074] When the reaction solvent was 1,2-dichloroethane (DCE), the yield of the target compound was <5%;

[0075] When the reaction solvent was dichloromethane (DCM), the yield of the target compound was <5%;

[0076] When the reaction solvent was trichloromethane (CHCl3), the yield of the target compound was <5%;

[0077] When the reaction solvent was tetrachloromethane (CCl4), the yield of the target compound was <5%;

[0078] When the reaction solvent was chlorobenzene (PhCl), the yield of the target compound was 53%;

[0079] When the reaction solvent was fluorobenzene (PhF), the yield of the target compound was 50%;

[0080] When the reaction solvent was trifluoromethylbenzene (PhCF3), the yield of the target compound was 34%.

[0081] From the above screening, toluene was the optimal solvent.

[0082] Example d

[0083] (E)-3-((4-Bromostyryl)thio)pyridazine

[0084]

[0085] Under nitrogen atmosphere, catalyst bis-(2-methylallyl)cyclooct-1,5-diene ruthenium (Ru(methallyl)2COD) (23.9 mg, 0.075 mmol, 2.5 mol%) and ligand 2,4-bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 minutes. Then it was added to a 10 mL reaction vial of pyridazine-3(2H)-thione (3 mmol, 1.0 equivalent) and p-bromostyrene (6 mmol, 2.0 equivalent). The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target compound, yellow solid 70.2 mg, calculated yield 75%.

[0086] Example e

[0087] Compared with Example d, the difference is that the equivalent ratio of the ruthenium catalyst, ligand, pyridazine-3(2H)-thione and p-bromostyrene used in the reaction is different, when the equivalent ratio is (0.025:0.015:1:1), the yield is 62%; when the equivalent ratio of the ruthenium catalyst, bisphosphine ligand, pyridazine-3(2H)-thione and p-bromostyrene is 0.025:0.015:1:1.5, the yield is 68%.

[0088] Example f

[0089] Compared with Example d, the difference is that the reaction temperature is different, and the other operation conditions are the same as those of Example d.

[0090] When the reaction temperature is 80 °C, the yield is 40%.

[0091] When the reaction temperature is 90 °C, the yield is 65%.

[0092] When the reaction temperature is 120 °C, the yield is 70%.

[0093] Example 2

[0094] (E)-3-(Styrylthio)pyridazine

[0095]

[0096] Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 minutes. Then it was added to a 10 mL reaction vial of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and phenylacetylene (6 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target compound, 46.1 mg of brown liquid, calculated yield 80%.

[0097] NMR data: 1 HNMR (400 MHz, CDC13) δ 8.22 (dd, Ji = 4.2 Hz, J2= 1.0 Hz, 1H), 7.71 - 7.64 (m, 3H), 7.34 (t, J = 7.9 Hz, 2H), 7.23 - 7.19 (m, 1H), 7.01 - 6.96 (m, 2H), 5.70 (d, J = 7.2 Hz, 1H) ppm. Z Z 2H), 7.23 - 7.19 (m, 1H), 7.01 - 6.96 (m, 2H), 5.70 (d, J = 7.2 Hz, 1H) ppm. Z

[0098] 13 C NMR (100 MHz, CDC13) δ 139.3, 137.3, 134.9, 128.8, 128.2, 126.6, 118.8, 111.4, 109.9 ppm

[0099] (E)-3-((4-Chlorostyryl)thio)pyridazine

[0100]

[0101] ​​Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 minutes. Then it was added to a 10 mL reaction vial of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and p-chlorostyrene (6 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target compound, yellow solid 59.3 mg, calculated yield 78%.

[0102] NMR data: 1 HNMR (400 MHz, CDC13) δ 8.24 (dd, Ji = 4.9 Hz, J2= 1.4 Hz, 1H), 7.72 - 7.68 (m, 1H), 7.65 - 7.59 (m, 3H), 7.32 - 7.29 (m, 1H), 7.05 - 7.02 (m, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.66 (d, J = 7.2 Hz, 1H) ppm. Z Z Z

[0103] 13 C NMR (100 MHz, CDC13) δ 161.0, 147.2, 137.8, 133.4, 132.0, 130.1, 128.4, 119.0, 111.4 ppm

[0104] (E)-3-((3-Methylstyryl)thio)pyridazine

[0105]

[0106] ​​​Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 minutes. Then pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and 3- methoxyphenylacetylene (6 mmol, 2.0 eq) were added into a 10 mL reaction vial. The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target compound, 51.5 mg of clear liquid, calculated yield 65%.

[0107] NMR data: 1 H NMR (400 MHz, CDC13) δ 8.18 - 8.16 (m, 1H), 7.50 - 7.47 (m, 1H), 7.41 (s, 1H), 7.19 - 7.15 (m, 1H), 6.98 - 6.95 (m, 1H), 6.94 - 6.91 (m, 1H), 5.61 (d, J = 7.2 Hz, 1H), 2.29 (s, 3H) ppm. Z

[0108] 13 C NMR (100 MHz, CDC13) δ 161.3, 147.2, 139.4, 137.7, 137.2, 134.8, 129.6, 128.2, 127.4, 126.0, 111.5, 110.1 ppm

[0109] Example 5:

[0110] (E)-3-((2-Chlorostyryl)thio)pyridazine

[0111]

[0112] ​Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 minutes. Then it was added to a 10 mL reaction vial of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and o-chlorostyrene (6 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target compound, yellow solid 85.4 mg, calculated yield 72%.

[0113] NMR data: 1 H NMR (400 MHz, CDC13) δ 8.16 - 8.14 (m, 1H), 8.04 (dd, Ji = 7.9 Hz, J2= 1.6 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.29 (dd, Ji = 8.0 Hz, J2= 1.3 Hz, 1H), 7.19 - 7.15 (m, 1H), 6.95 - 6.92 (m, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.02 (d, J = 7.4 Hz, 1H) ppm. Z Z Z Z

[0114] 13 C NMR (100 MHz, CDC13) δ 161.0, 138.6, 132.6, 132.64, 132.60, 130.6, 129.3, 127.6, 126.4, 119.0, 111.4 ppm

[0115] Example 6:

[0116] (E)-3-((3-Fluorostyryl)thio)pyridazine

[0117]

[0118] ​​​​Under a nitrogen atmosphere, the catalyst Ru(methallyl)₂COD (23.9 mg, 0.075 mmol, 2.5 mol%) and the 2,4-bis(diphenylphosphine)pentane ligand (CH₃PPh₂CHCH₂CHPPh₂CH₃) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 min. This solution was then added to a 10 mL reaction flask containing pyridazine-3(2H)-thione (3 mmol, 1.0 equivalent) and m-fluorophenylacetylene (6 mmol, 2.0 equivalent). The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target compound as a clear liquid, 54 mg, with a calculated yield of 75%.

[0119] NMR data: 1 H NMR (400MHz, CDCl3) δ8.25-8.25 (m, 1H), 7.74 (d, J = 7.2H Z ,1H),7.55-7.51(m,1H),7.38-7.34(m,1H),7.32-7.28(m,1H),7.12-7.00(m,1H),6.94-6.89(m,2H),5.68(d,J=7.2H Z ,1H)ppm.

[0120] 13 C NMR (100MHz, CDCl3) δ164.0,161.6,161.0,137.1,137.0,129.6,129.5,124.59,124.57,119.1,115.5,115.3,113.5,111.5,108.81,108.78ppm

[0121] Example 7:

[0122] (E)-3-((2-(Naphthalen-2-yl)vinyl)thio)pyridazine

[0123]

[0124] Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 minutes. Then it was added to a 10 mL reaction vial of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and 1-naphthylacetylene (6 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target compound, white solid 53.6 mg, calculated yield 70%.

[0125] NMR data: 1 H NMR (400 MHz, CDC13) δ 8.29 - 8.27 (m, 1H), 7.79 - 7.94 (m, 1H), 7.87 - 7.82 (m, 3H), 7.74 - 7.70 (m, 2H), 7.50 - 7.44 (m, 2H), 7.07 - 7.03 (m, 2H), 5.90 (d, J = 7.2 Hz, 1H) ppm. Z

[0126] 13 C NMR (100 MHz, CDC13) δ 161.2, 139.4, 137.7, 133.5, 132.5, 132.2, 128.0, 127.7, 127.6, 127.5, 127.1, 125.9, 125.6, 118.9, 110.0 ppm

[0127] Example 8:

[0128] (E)-3-(Dec-1-en-1-ylthio)pyridazine

[0129]

[0130] ​Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene and stirred for 5 minutes. Then it was added to a 10 mL reaction vial of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and 1-decyne (6 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 15 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target compound, yellow solid 50.3 mg, calculated yield 80%.

[0131] NMR data

[0132] 1 H NMR (400 MHz, CDC13) δ 7.79 (dd, J1= 3.7 Hz, J2= 1.6 Hz, 1H), 7.48 (d, J = 13.9 Hz, 1H), 7.14 (dd, J1= 9.4 Hz, J2= 3.8 Hz, 1H), 6.93 (dd, J1= 9.4 Hz, J2= 1.7 Hz, 1H), 6.34 (m, 1H), 2.20 (m, 2H), 1.48 - 1.42 (m, 2H), 1.34 - 1.20 (m, 10H), 0.88 - 0.85 (m, 3H) ppm.

[0133] 13 C NMR (100 MHz, CDC13) δ 159.9, 135.8, 130.9, 130.2, 128.3, 125.4, 31.9, 29.3, 9.2, 29.1, 26.9, 22.7, 14.1.

[0134] Example 9:

[0135] (E)-3-((2-(thiophen-2-yl)vinyl)thio)pyridazine

[0136]

[0137] The catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4- bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene under nitrogen atmosphere and stirred for 5 min. Then it was added to a 10 mL reaction vial of pyridazin-3(2H)-thione (3 mmol, 1.0 eq) and 1-thiophene terminal alkyne (6 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target compound as yellow liquid 51.1 mg, calculated yield 84%.

[0138] NMR data: 1 H NMR (400 MHz, CDC13) δ 8.23-8.21 (m, 1H), 7.72-7.68 (m, 1H), 7.60 (d, J = 6.56 Hz, 1H), 7.12-7.11 (m, 1H), 7.04-7.00 (m, 3H), 6.1 (d, J = 6.6 Hz, 1H) ppm.

[0139] 13 C NMR (100 MHz, CDC13) δ 161.0, 147.1, 137.7, 135.2, 126.4, 125.4, 118.9, 111.5, 104.7 ppm.

[0140]

[0141] The catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4- bis(diphenylphosphino)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL of toluene under nitrogen atmosphere and stirred for 5 min. Then it was added to a 10 mL reaction vial of pyridazin-3(2H)-thione (3 mmol, 1.0 eq) and 1-thiophene terminal alkyne (6 mmol, 2.0 eq). The reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give the target compound as yellow liquid 51.1 mg, calculated yield 84%.

[0142] NMR data: 1 H NMR (400 MHz, CDC13) δ 8.23-8.21 (m, 1H), 7.72-7.68 (m, 1H), 7.60 (d, J = 6.56 Hz, 1H), 7.12-7.11 (m, 1H), 7.04-7.00 (m, 3H), 6.1 (d, J = 6.6 Hz, 1H) ppm. Z, 1H), 7.66 (t, J = 7.3 Hz Z , 1H), 6.99 - 6.93 (m, 1H), 5.51 (d, J = 6.1 Hz Z , 1H), 4.59 (s, 2H), 4.20 (s, 2H), 4.09 (s, 5H) ppm.

[0143] 13 C NMR (100 MHz, CDC13) δ 161.5, 135.7, 118.3, 111.2, 108.2, 78.9, 69.1, 69.0, 68.2 ppm

[0144] The above description is only the preferred embodiment of the present application, and is not intended to limit the present application. Any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a class of trans-S-enylthiopyridazine compounds, characterized in that, The compound shown in formula II and the compound shown in formula III are dissolved in a solvent under a nitrogen atmosphere, and a synthesis reaction is carried out under the action of a ruthenium catalyst and a ligand, so as to obtain the compound shown in formula I. ; Formula II Formula III Formula I R 1 selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl, ferrocene, the substituents in substituted aryl and substituted heteroaryl are independently selected from at least one of fluorine, chlorine, bromine, alkyl; R 2 , R 3 , R 4 is selected from hydrogen; The ruthenium catalyst is selected from one of iodine ruthenium, bis-(2-methylallyl) cycloocta-1,5-diene ruthenium; The ligand is selected from one of 2,4-bis(diphenylphosphino)pentane, Xantphos, Xphos, Sphos, tributylphosphine, triisopropylphosphine, N,N-dimethyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphos-4-amine, diphenylphosphine oxide, diphenylphosphine, tricyclohexylphosphine, bis(dicyclohexylphosphino)methane, 1,2-bis(dicyclohexylphosphino)ethane, 1,3-bis(dicyclohexylphosphino)propane, 1,4-bis(dicyclohexylphosphino)butane; The solvent is one of toluene, mesitylene, benzene, xylene, nitrobenzene, chlorobenzene, fluorobenzene.

2. The method of preparing a trans-S-alkenylsulfanyl pyridazine compound according to claim 1, wherein: The reaction temperature is 80-120 DEG C, and the reaction time is 16-20 h.

3. The method for preparing the trans-S-alkenylthiopyridazine compound as described in claim 1, characterized in that: The amount of the catalyst used is 2.5 mol% of the compound shown in formula III.

4. The method for preparing the trans-S-enylthiopyridazine compound as described in claim 1, characterized in that: The amount of the ligand used is 1.5 mol% of the compound shown in formula III.

5. The method for preparing the trans-S-alkenylthiopyridazine compound as described in claim 1, characterized in that: The ruthenium catalyst is bis-(2-methylallyl) cycloocta-1,5-diene ruthenium, the ligand is 2,4-bis(diphenylphosphino)pentane, and the solvent is toluene.

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