Preparation method of trans-S-alkenyl sulfenyl pyridazine compound

Abstract

The invention belongs to the technical field of synthetic chemistry, and particularly relates to a preparation method of trans-S-alkenyl sulfenyl pyridazine compounds. The trans-S-alkenyl sulfenyl pyridazine based on the pyridazine structure has a structural general formula shown in the specification, in the structural general formula shown in the formula I, R1 is selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl and alkyl containing functional groups, R2 is selected from any one of carboxyl, alkyl and hydrogen, R3 is selected from any one of alkyl, carboxyl and halogen, R4 is selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl and alkyl containing functional groups, and R5 is selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl and alkyl containing functional groups. And R4 is selected from any one of aryl, substituted aryl, carboxyl, ester group, halogen, furan and amino. The trans-S-alkenyl sulfenyl pyridazine has a special molecular shape and a trans-configuration, the preparation method solves the problem of quickly and efficiently constructing the trans-S-alkenyl sulfenyl pyridazine structure in the field of chemical and pharmaceutical synthesis, meanwhile, the preparation method is simple and practical to operate, and the preparation process has the characteristics of being green, economical and environment-friendly. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of synthetic chemistry, and specifically relates to a trans-S-alkenylthiopyridazine and a preparation method thereof. Background Art

[0002] Pyridazine drugs have significant biological activity and occupy an important position in pesticide research. This type of pesticide has the characteristics of high activity and environmental friendliness, and plays an important role in integrated pest control and reducing the environmental pollution of pesticides. In addition, pyridazine compounds also have antibacterial, insecticidal, weeding and antiviral activities, providing a broad development space for the development of pyridazine pesticides. However, the current synthesis method of alkenylthio pyridazines is limited (EP02251173, which is a sulfo pyridazine compound generated by the affinity substitution of bromine atoms by S atoms). The first step is to generate a sulfo pyridazine compound by affinity substitution of bromine atoms by S atoms, and the second step is to oxidize the sulfonyl group to a sulfonyl group, as a sulfonyl pyridazine ketone compound of an ischemic tissue damage therapeutic agent. WO2002087584 mentions a pharmaceutical composition and a medicine box comprising a pyridazinone compound and a cyclooxygenase-2 inhibitor, a method for treating or preventing certain complications caused by diabetes in mammals, and a method for treating or preventing ischemia of mammalian cardiac tissue.

[0003] Therefore, the research on the synthesis method of trans-S-alkenylthiopyridazine is beneficial to promoting the application development in the fields of synthesis and drug development. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing trans-S-alkenylthiopyridazine, aiming to solve the technical problem that the types and synthesis methods of existing vinylpyridazine-3-one are limited.

[0005] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention is as follows:

[0006] The present invention provides a method for preparing trans-S-alkenylthiopyridazine, comprising the following steps:

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

[0008]

[0009] Specifically, under a nitrogen atmosphere, the ruthenium catalyst and the ligand are dissolved in a solvent, stirred, and the raw materials shown in formula II and formula III are added, and the mixture is stirred at 80-120° C. for 16 to 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] Among them, in the above compounds, R 1 is selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl, alkyl containing a functional group, and ferrocene, R 2 Any one selected from carboxyl, alkyl and hydrogen, R 3 is selected from any one of alkyl, carboxyl, halogen, and hydrogen, R 4 Any one selected from aryl, substituted aryl, carboxyl, ester, halogen, furan, amino, and hydrogen.

[0011] The aryl group may be a monocyclic aryl group or a polycyclic aryl group (such as a condensed aromatic hydrocarbon group), and specifically, the aryl group is selected from at least one of phenyl and naphthyl. The heteroaryl group may be a five-membered heterocyclic group, a six-membered heterocyclic group, a condensed heterocyclic group (a benzene ring is condensed with a heterocyclic group), or a condensed heterocyclic group (several heterocyclic groups are condensed), and specifically, the heteroaryl group is selected from at least one of pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl, benzofuranyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, and purinyl. The substituents 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, heterocyclyl, heterocyclylalkyl, cycloalkyl, aryloxy, heteroaryloxy and cycloalkylalkyl, that is, the above substituents are monosubstituted or the same or different polysubstituted aryl or heteroaryl. Among them, the alkyl in the above substituents can be C1-C 20 Alkyl or C1-C 10 Alkyl; alkynyl can be C2-C 20 Alkynyl or C2-C 10 Alkyl; Alkoxy can be C1-C 20 Alkoxy or C1-C 10 Alkoxy; heterocyclic group can be C3-C 10 Heterocycloalkyl, C3-C 10 Heterocycloalkenyl or C3-C 10 Heterocycloalkynyl; Cycloalkyl can be C3-C 20 Cycloalkyl or C3-C 10 Cycloalkyl.

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

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

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

[0015]

[0016] The structural formula of N, N-dimethyl dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphine-4-amine is:

[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. Preferably, the ruthenium catalyst is Ru(methallyl)2COD, the ligand is 2,4-bis(diphenylphosphino)pentane, and the solvent is toluene.

[0020] The present invention provides an organic compound of a trans-S-alkenylthiopyridazine structure, and a catalytic synthesis method for catalytically constructing a trans-S-alkenylthiopyridazine. Such trans-S-alkenylthiopyridazine has a special molecular shape, which makes it have special pharmaceutical properties and has great prospects in the development of new drugs. The preparation method overcomes the problem that the trans-S-alkenylthiopyridazine structure cannot be directly catalytically constructed in the field of chemistry and drug synthesis. At the same time, the preparation method provided by the present invention is simple and practical to operate, and the preparation process has the characteristics of green economy, environmental friendliness, and easy industrialization, 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 invention more clearly understood, the present invention is further described in detail below in conjunction with the 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.

[0022] The present invention has been tested many times, and some test results are now cited as references to further describe the invention in detail, and the following is a detailed description in conjunction with specific embodiments. The reactions of the embodiments of the present invention are as follows:

[0023] Example 1

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

[0025]

[0026] Under nitrogen atmosphere, the catalyst bis-(2-methylallyl) cyclooctane-1,5-diene ruthenium (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. It was then added to a 10 mL reaction bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 eq.) with R being H and p-bromophenylacetylene (3 mmol, 1.0 eq.) with R being p-bromophenyl. 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 (400MHz, CDCl3) δ8.25-8.22(m,1H),7.62(d,J=7.2Hz,1H),7.58-7.55(m,1H),7.47-7.44(m ,2H),7.05-7.02(m,1H),6.97(d,J=8.3Hz,1H),6.97(d,J=8.3Hz,1H),5.64(d,J=7.2Hz,1H)ppm.

[0028] 13 C NMR (100MHz, CDCl3) δ161.0,139.5,138.0,133.9,131.3,130.4,120.2,119.0,111.4,108.7ppm.

[0029] Embodiment a

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

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

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

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

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

[0035] The ruthenium catalyst in Example 1 was replaced with 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 with ruthenium iodide, and the yield of the target compound was 23%.

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

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

[0040] From the above screening, bis-(2-methylallyl)cyclooct-1,5-diene ruthenium catalyst was selected as the optimal catalyst.

[0041] Embodiment b

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

[0043] The ligand in Example 1 was replaced by a cyclohexylbisphosphine 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 with tributylphosphine, and the yield of the target compound was 31%.

[0049] The ligand in Example 1 was replaced with 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 with diadamantane n-butylphosphine ligand, and the yield of the target compound was <5%.

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

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

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

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

[0059] The ligand in Example 1 was replaced with bis(dicyclohexylphosphine) and the yield of the target compound was 39%.

[0060] The ligand in Example 1 was replaced with bis(dicyclohexylphosphine)ethane, and the yield of the target compound was 32%.

[0061] The ligand in Example 1 was replaced with bis(dicyclohexylphosphino)propane, and the yield of the target compound was 35%.

[0062] The ligand in Example 1 was replaced with bis(dicyclohexylphosphinobutane), and the yield of the target compound was 37%.

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

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

[0065] Example c

[0066] Compared with Example 1, under the conditions of bis-(2-methylallyl)cyclooct-1,5-dieneruthenium as catalyst and 2,4-bis(diphenylphosphino)pentane as ligand, other conditions were the same as Example 1 to study the effect of solvent type on the reaction.

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

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

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

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

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

[0072] When the reaction solvent is hexane, the yield of the target compound is <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 chloroform (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 is trifluorotoluene (PhCF3), the yield of the target compound is 34%.

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

[0082] Embodiment d

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

[0084]

[0085] Under nitrogen atmosphere, the catalyst bis-(2-methylallyl)cycloocta-1,5-dieneruthenium (Ru(methallyl)2COD) (23.9 mg, 0.075 mmol, 2.5 mol%) and the ligand 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 minutes. It was then added to a 10 mL reaction bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and p-bromophenylacetylene (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 as a yellow solid 70.2 mg with a calculated yield of 75%.

[0086] Embodiment e

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

[0088] Embodiment f

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

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

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

[0092] When the reaction temperature was 120°C, the yield was 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(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. It was then added to a 10 mL reaction bottle 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, with a calculated yield of 80%.

[0097] NMR data: 1 HNMR (400MHz, CDCl3) δ8.22 (dd, J1=4.2H Z ,J2=1.0Hz,1H),7.71-7.64(m,3H),7.34(t,J=7.9H Z 2H),7.23-7.19(m,1H),7.01-6.96(m,2H),5.70(d,J=7.2H Z ,1H)ppm.

[0098] 13 C NMR (100 MHz, CDCl3) δ 139.3, 137.3, 134.9, 128.8, 128.2, 126.6, 118.8, 111.4, 109.9 ppm Example 3:

[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(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. It was then added to a 10 mL reaction bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and p-chlorophenylacetylene (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 as a yellow solid 59.3 mg with a calculated yield of 78%.

[0102] NMR data: 1 HNMR (400MHz, CDCl3) δ8.24 (dd, J1=4.9H Z ,J2=1.4Hz,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=8.3H Z ,1H),5.66(d,J=7.2H Z ,1H)ppm.

[0103] 13 C NMR (100 MHz, CDCl3) δ 161.0, 147.2, 137.8, 133.4, 132.0, 130.1, 128.4, 119.0, 111.4 ppm Example 4:

[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(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. Then pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and m-methoxyphenylacetylene (6 mmol, 2.0 eq) were added to a 10 mL reaction bottle. 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 as a transparent liquid 51.5 mg with a calculated yield of 65%.

[0107] NMR data: 1 H NMR (400MHz, CDCl3) δ8.18-8.16(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=7.2H Z ,1H),2.29(s,3H)ppm.

[0108] 13 C NMR (100MHz, CDCl3) δ161.3,147.2,139.4,137.7,137.2,134.8,129.6,128.2,127.4,126.0,111.5,110.1ppm

[0109] Embodiment 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(diphenylphosphine)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 bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and o-chlorophenylacetylene (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 as a yellow solid 85.4 mg with a calculated yield of 72%.

[0113] NMR data: 1 H NMR (400MHz, CDCl3) δ8.16-8.14 (m, 1H), 8.04 (dd, J1 = 7.9H Z ,J2=1.6Hz,1H),7.63-7.57(m,1H),7.29(dd,J1=8.0H Z ,J2=1.3Hz,1H),7.19-7.15(m,1H),6.95-6.92(m,1H),6.84(d,J=8.3H Z ,1H),6.02(d,J=7.4H Z ,1H)ppm.

[0114] 13 C NMR (100MHz, CDCl3) δ161.0,138.6,132.6,132.64,132.60,130.6,129.3,127.6,126.4,119.0,111.4ppm

[0115] Embodiment 6:

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

[0117]

[0118] Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. Then, it was added to a 10 mL reaction bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and m-fluorophenylacetylene (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, a transparent 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] Embodiment 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(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. It was then added to a 10 mL reaction bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and 1-naphthyne (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 as a white solid 53.6 mg with a calculated yield of 70%.

[0125] NMR data: 1 H NMR (400MHz, CDCl3) δ8.29-8.27(m,1H),7.79-7.94(m,1H),7.87-7.82(m,3 H),7.74-7.70(m,2H),7.50-7.44(m,2H),7.07-7.03(m,2H),5.90(d,J=7.2H Z ,1H)ppm.

[0126] 13 C NMR (100MHz, CDCl3) δ161.2,139.4,137.7,133.5,132.5,132.2,128.0,127.7,127.6,127.5,127.1,125.9,125.6,118.9,110.0ppm

[0127] Embodiment 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(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. Then, it was added to a 10 mL reaction bottle 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 as a yellow solid 50.3 mg with a calculated yield of 80%.

[0131] NMR data

[0132] 1 H NMR (400MHz, CDCl3) δ7.79 (dd, J1=3.7Hz, J2=1.6Hz, 1H), 7.48 (d, J=13.9Hz, 1H), 7.14 (dd, J1=9.4Hz, J2=3.8Hz, 1H), 6.9 3(dd, J1=9.4Hz, J2=1.7Hz,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 (100MHz, CDCl3) δ159.9,135.8,130.9,130.2,128.3,125.4,31.9,29.3,9.2,29.1,26.9,22.7,14.1.

[0134] Embodiment 9:

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

[0136]

[0137] Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. It was then added to a 10 mL reaction bottle of pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and the terminal alkyne of 1-thiophene (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, 51.1 mg of yellow liquid, with a calculated yield of 84%.

[0138] NMR data: 1 H NMR (400MHz, CDCl3) δ8.23-8.21(m,1H),7.72-7.68(m,1H),7.60(d,J=6.56Hz,1H),7.12-7.11(m,1H),7.04-7.00(m,3H),6.1(d,J=6.6Hz,1H)ppm.

[0139] 13 C NMR (100 MHz, CDCl3) δ 161.0, 147.1, 137.7, 135.2, 126.4, 125.4, 118.9, 111.5, 104.7 ppm. Example 10:

[0140]

[0141] Under nitrogen atmosphere, catalyst Ru(methallyl)2COD (23.9 mg, 0.075 mmol, 2.5 mol%) and 2,4-bis(diphenylphosphine)pentane ligand (CH3PPh2CHCH2CHPPh2CH3) (19.8 mg, 0.045 mmol, 1.5 mol%) were dissolved in 6 mL toluene and stirred for 5 minutes. It was then added to a 10 mL reaction bottle containing pyridazine-3(2H)-thione (3 mmol, 1.0 eq) and R being a terminal alkyne substituted with ferrocene (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 as a brown solid 52.2 mg with a calculated yield of 57%.

[0142] NMR data: 1 H NMR (400MHz, CDCl3) δ8.21 (d, J=3.6H Z,1H),7.66(t,J=7.3H Z ,1H),6.99-6.93(m,1H),5.51(d,J=6.1H Z ,1H),4.59(s,2H),4.20(s,2H),4.09(s,5H)ppm.

[0143] 13 C NMR (100MHz, CDCl3) δ161.5,135.7,118.3,111.2,108.2,78.9,69.1,69.0,68.2ppm

[0144] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a trans-S-alkenylthiopyridazine compound, characterized in that: Under a nitrogen atmosphere, the compound represented by formula II and the compound represented by formula III are dissolved in a solvent, and a synthesis reaction is carried out under the action of a ruthenium catalyst and a ligand to obtain a compound represented by formula I; R 1 is selected from any one of aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkyl, and ferrocene, R 2 Any one selected from carboxyl, alkyl and hydrogen, R 3 is selected from any one of aryl, alkyl, carboxyl, halogen or hydrogen, R 4 Any one selected from hydrogen, aryl, substituted aryl, carboxyl, ester, halogen, furan, and amino; The ruthenium catalyst is selected from one of Ru(methallyl)2COD, ruthenium iodide, and bis-(2-methylallyl)cycloocta-1,5-dieneruthenium; 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]dioxophosphine-4-amine, diphenylphosphine oxide, diphenylphosphine, tricyclohexylphosphine, bis(dicyclohexylphosphino)methane, 1,2-bis(dicyclohexylphosphino)-ethane, 1,3-bis(dicyclohexylphosphino)propane, and 1,4-bis(dicyclohexylphosphino)butane.

2. The method for preparing a trans-S-alkenylthiopyridazine compound according to claim 1, characterized in that: The solvent is one of toluene, mesitylene, benzene, xylene, nitrobenzene, chlorobenzene, fluorobenzene and trifluorotoluene.

3. The method for preparing a trans-S-alkenylthiopyridazine compound according to claim 1, characterized in that: The reaction temperature is 80-120°C and the reaction time is 16-20h.

4. The method for preparing a trans-S-alkenylthiopyridazine compound according to claim 1, wherein: The amount of the catalyst used is 2.5 mol% of the compound represented by formula III.

5. The method for preparing a trans-S-alkenylthiopyridazine compound according to claim 1, wherein: The amount of the ligand used is 1.5 mol% of the compound represented by formula III.

6. The method for preparing a trans-S-alkenylthiopyridazine compound according to claim 1, characterized in that: The ruthenium catalyst is Ru(methallyl)2COD, the ligand is 2,4-bis(diphenylphosphino)pentane, and the solvent is toluene.

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