A method for synthesizing tetrahydropyridazine compounds

Abstract

The present invention discloses a method for synthesizing tetrahydropyridazine compounds, belonging to the technical field of organic synthesis. CF3Br and N-allyl-N-acylhydrazone undergo a radical tandem cyclization reaction under visible light induction in an organic solvent in the presence of a photocatalyst and a basic reagent. The reaction mixture is concentrated and purified by column chromatography to obtain the tetrahydropyridazine compounds. The present invention for the first time uses trifluorobromomethane in the radical amino-fluorination reaction of olefins to construct tetrahydropyridazine compounds. CF3Br is an industrial raw material that is non-toxic, odorless, inexpensive, and easily available. Compared with other fluorination reagents, it has a low price, is easily obtained, and has high atom economy.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing tetrahydropyridazine compounds. Background Art

[0002] Tetrahydropyridazine is a hydride of azacyclopyridazine, that is, a six-membered azacycle containing only one unsaturated double bond in the ring. It has been found that such compounds often exist in natural products and compound molecules with pharmaceutical activities. For example, the following chemical structures A - C:

[0003]

[0004] Research has shown that compound A can be used as a non-steroidal progesterone receptor modulator (Steroid Biochem. Mol. Biol. 2000,

[0005] 75, 33); compound B can be used as an inhibitor of influenza neuraminidase (Bioorg. Med. Chem. Lett. 1999, 9,

[0006] 1751); compound C can be used as a potential CB1 receptor antagonist (Bioorg. Med. Chem. Lett. 2009, 19, 5675). At the same time, as a special and valuable heterocyclic skeleton containing an N - N bond, tetrahydropyridazine is also a synthetic intermediate with diverse structures in organic synthesis and a leading compound for synthesizing some bioactive and structurally complex molecules (References: Angew. Chem., Int. Ed. 2010, 49, 6139; Org. Lett. 2014, 16, 3488, etc.). This type of six-membered heterocyclic compound with two adjacent nitrogen atoms has advantages in organic synthesis due to their special structural features. First, compared with aliphatic rings, the additional two nitrogen atoms can form more interactions; second, after introducing them as bioisosteres, they can regulate or improve the pharmacokinetic properties (ADME) of drug molecules. Therefore, some literature has pointed out that such six-membered rings are advantageous structures in drug research and development (Med. Chem. Commun. 2011, 2, 935 - 941). In recent years, the application of pyridazine and its hydrides in the field of optoelectronic materials has also been reported in the literature (Acta Physico-Chimica Sinica, 2014, 30(4): 589 - 607). Thus, tetrahydropyridazine compounds have very important application values, and therefore it is very necessary to explore new synthesis methods for such compounds.

[0007] Currently, the synthesis of tetrahydropyridazine compounds is mainly achieved through the cyclization reaction of open-chain compounds such as acylhydrazones or hydrazones. Specifically, there are mainly the following methods:

[0008] (1) Cycloaddition reactions involving α-haloacylhydrazones or chlorohydrazones

[0009] The traditional synthetic method of tetrahydropyridazine compounds is to synthesize tetrahydropyridazine compounds through the inverse electron demand [4 + 2] cycloaddition reaction of 1,2-diazabuta-1,3-diene generated in situ from α-haloacylhydrazones and olefins under the action of a base. The reaction formula is:

[0010]

[0011] The greatest advantage of this method is precise synthesis with good regioselectivity (References: Org. Lett. 2015, 17, 1561 - 1564; Org. Lett. 2016, 18, 5884 - 5887; J. Org. Chem. 2021, 86, 11472 - 11481; Org. Chem. Front., 2021, 8, 4392 - 4398, etc.). However, the biggest problem with this method is that the olefins used in the reaction need to be in a large excess. For example, in the synthetic method reported by the Xiao Wenjing research group (Adv. Synth. Catal. 2013, 355, 3539), 30-fold excess of olefins is required to react with α-haloacylhydrazones to obtain tetrahydropyridazine. At the same time, the substrate scope of this method is limited: it is only applicable to electron-rich olefins.

[0012] The asymmetric [4 + 2] cyclization reaction of α-haloacylhydrazones and olefins to synthesize tetrahydropyridazine compounds containing chiral centers has also been reported (References: Angew. Chem. Int. Ed. 2014, 53, 4680–4684; Chem. Commun. 2015, 51, 15374 - 15377; J. Am. Chem. Soc. 2015, 137, 32, 10124 - 10127; Chem.-Eur. J. 2017, 23, 4995; Chem. Commun. 2018, 54, 2506 - 2509, etc.).

[0013] In addition, the cycloaddition reaction of nitrile imines generated in situ from chlorohydrazones under the action of a base and cyclopropane derivatives can also be used to synthesize tetrahydropyridazine compounds. In 2016, the Werz research group reported (Org. Lett. 2016, 18, 564 - 567) that in the presence of an organic base and under the catalysis of a Lewis acid, chlorohydrazones react with donor-acceptor cyclopropane derivatives to give tetrahydropyridazine derivatives with yields between 65% and 92%. This transformation can be regarded as a formal [3 + 3] cycloaddition of a three-membered ring and in situ generated nitrile imines. The advantages of this method are: short synthetic steps and precise synthesis, but the reaction solvent is a toxic chlorinated solvent, which does not conform to the concept of green environmental protection.

[0014]

[0015] (2) Intramolecular cyclization of β,γ-unsaturated acylhydrazones

[0016] This method constructs the tetrahydropyridazine ring through the intramolecular radical cyclization reaction of unsaturated acylhydrazones. In 2018, the research group of Jin-Tao Liu reported that using Seletfluor (1-fluoro-4-chloromethyl-1,4-diazabicyclo[2.2.2]heptane) as the fluorination reagent, fluorinated tetrahydropyridazine derivatives were synthesized through the intramolecular aminofluorination reaction of β,γ-unsaturated sulfonylhydrazones (Org. Chem. Front. 2018, 5, 1155), with the yield ranging from 49% to 61%. The regioselectivity of this reaction is poor. When obtaining tetrahydropyridazine, there is always a small amount of five-membered ring compounds produced. In addition, the fluorination reagent used in this reaction has a large organic leaving group, with disadvantages such as low atom utilization rate. The reaction formula is:

[0017]

[0018] In 2021, Browne, Stuart and others further developed a method for synthesizing fluorinated tetrahydropyridazine derivatives from β,γ-unsaturated hydrazones and fluoroiodine reagents under the action of Lewis acid AgBF 4 or hexafluoroisopropanol (HFIP) (Chem. Commun., 2021, 57, 7406 - 7409). This method has a relatively high yield, and the product yield is between 46% and 99%, with good regioselectivity. However, this method requires the use of stoichiometric amounts of Lewis acid and strongly acidic hexafluoroisopropanol. At the same time, the fluoroiodine reagent used also has a large leaving group, with disadvantages such as low atom utilization rate, which does not conform to the concept of green chemistry. The reaction formula is:

[0019]

[0020] In 2017, the research group of Wen-Jing Xiao (Org. Lett. 2017, 19, 3620 - 3623) used β,γ-unsaturated hydrazones and allyl sulfone as raw materials, and through the radical cascade cyclization of the oxidative deprotonation single-electron transfer strategy under visible light irradiation, tetrahydropyridazine compounds were obtained. The reaction formula is:

[0021]

[0022] Although this method uses the green and environmentally friendly reaction condition of visible light irradiation, the scope of application of the reaction is too small. Only two examples are presented in the article, and tetrahydropyridazine compounds are obtained with yields of 72% and 52% respectively.

[0023] (3)Tandem Cyclization of N-Homoallyl Acylhydrazones

[0024] In 2024, the research group of Pan Changduo (Org. Lett. 2024, 26, 122 - 126) first used N-homoallyl acylhydrazones as raw materials for the synthesis of tetrahydropyridazines. In this reaction, sulfonyl chloride was used as a sulfonyl radical precursor. Under the conditions of light irradiation and ruthenium metal photocatalyst, single electron transfer and energy transfer of sulfonyl chloride occurred to generate sulfonyl radicals. Then, these radicals underwent radical tandem cyclization reactions with C=C and C=N in the N-homoallyl acylhydrazone molecule to obtain tetrahydropyridazine derivatives with a yield of 60% - 94%. The reaction formula is as follows:

[0025]

[0026] Although this method obtained sulfonylated tetrahydropyridazine derivatives in relatively high yields, there was a regioselectivity problem. Only the product of 4-substituted sulfonylethyl was obtained, and the sulfonyl group was not directly introduced into the tetrahydropyridazine compound.

[0027] In summary, although various methods for synthesizing tetrahydropyridazine compounds have been developed, each method has its own defects and limitations. Trifluoromethyl is a common fluorine-containing group. Introducing trifluoromethyl into organic compounds can significantly change the chemical, physical, and biological properties of the parent compound, such as acidity and alkalinity, bioavailability, metabolic stability, lipophilicity, and the binding ability to proteins, etc. The results of literature research show that there is currently no report on tetrahydropyridazine compounds containing trifluoromethyl. In order to further improve and enhance the biological activity of tetrahydropyridazine compounds, it is very necessary to explore a new, efficient, and simple synthesis method to prepare tetrahydropyridazine compounds containing trifluoromethyl. Summary of the Invention

[0028] The purpose of the present invention is to provide a synthesis method of tetrahydropyridazine compounds to solve the problems existing in the above-mentioned prior art.

[0029] The technical solution provided by the present invention is as follows:

[0030] A synthesis method of tetrahydropyridazine compounds, comprising the following steps: CF 3 Br and N-allyl-N-acylhydrazone in an organic solvent, in the presence of a photocatalyst and a basic reagent, undergo a radical tandem cyclization reaction through visible light induction, concentrate the reaction mixture, and purify it by column chromatography to obtain the tetrahydropyridazine compounds.

[0031] Add N-allyl-N-acylhydrazone (1 - 3 equiv.), photocatalyst (0.5 mol% - 1.5 mol%), base reagent (2 - 6 equiv.), and 1 - 5 mL of organic solvent into a 50 mL Schlenk flask. Evacuate the Schlenk flask to vacuum and then refill it with CF 3 Br gas, repeat this process three to six times, and finally maintain the pressure in the Schlenk flask at 1.0 atm - 1.5 atm (observed from the barometer). Place the reaction mixture under a light source of 390 nm - 460 nm and stir at room temperature for 12 - 48 h. After the reaction is completed, evaporate the solvent to dryness, and perform column chromatography purification using silica gel as the stationary phase and petroleum ether and ethyl acetate as the eluent (PE∶EA = (6 - 15)∶1, volume ratio).

[0032] Preferably, the general structural formula of the N-allyl-N-acylhydrazone is as follows:

[0033] In the above formula, R 1 is Ph (phenyl), 4-Me-Ph (4-methylphenyl), 3-Me-Ph (3-methylphenyl), 2-Me-Ph (2-methylphenyl), 4- t Bu-Ph (4-tert-butylphenyl), 4-OMe-Ph (4-methoxyphenyl), 4-Br-Ph (4-bromophenyl), 4-Cl-Ph (4-chlorophenyl), 4-F-Ph (4-fluorophenyl), CF 2 H or CF 3 ; R 2 is Ac (acetyl), Bz (benzoyl), Cbz (benzyloxycarbonyl) or Tos (p-toluenesulfonyl); further, when R 2 is Bz, R 1 CF 2 H or CF 3 .

[0034] Preferably, the molar ratio of the N-allyl-N-acylhydrazone to the base reagent is 1∶(1 - 3), and more preferably, the molar ratio of the N-allyl-N-acylhydrazone to the base reagent is 1∶2.

[0035] Preferably, the organic solvent is selected from CH 3 CN (acetonitrile), N,N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, and more preferably acetonitrile.

[0036] The dosage ratio of the N-allyl-N-acylhydrazone to the organic solvent is (0.1 - 0.3) mmol∶(1 - 6) mL, and the more preferred dosage ratio is 0.2 mmol∶3 mL.

[0037] Preferably, the photocatalyst is selected from fac-Ir III(ppy) 3 Iridium(III) tris(2-phenylpyridine) or 4CzIPN (2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile), and more preferably, the photocatalyst is fac-Ir III (ppy) 3 .

[0038] Preferably, the amount of the photocatalyst used is 0.5-1.5 mol% of the total molar amount of CF 3 Br and N-allyl-N-acylhydrazone. More preferably, the amount of the photocatalyst used is 1.5 mol% of the total molar amount of CF 3 Br and N-allyl-N-acylhydrazone.

[0039] Preferably, the basic reagent is selected from KHCO 3 , Et 3 N, 2,6-lutidine (2,6-dimethylpyridine), pyridine or DIPEA (N,N-diisopropylethylamine). More preferably, the base is 2,6-lutidine (2,6-dimethylpyridine).

[0040] Preferably, the wavelength of the visible light is 390-460 nm, and the power of the visible light is 5-15 W. Preferably, the visible light is blue light with a power of 5 W, 10 W, 15 W or 20 W. Most preferably, it is 15 W blue light.

[0041] Preferably, the temperature of the radical tandem cyclization reaction is room temperature, and the time is 12-24 h. More preferably, the time is 18 h.

[0042] The general structural formula of the tetrahydropyridazine compounds obtained by the above preparation method is as follows:

[0043]

[0044] In the above formula, R 1 is phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, CF 2 H or CF 3 ; R 2 is acetyl, benzoyl, benzyloxycarbonyl or p-toluenesulfonyl.

[0045] Compared with the prior art, the present invention has the following advantages and technical effects:

[0046] The present invention uses N-allyl-N-acylhydrazone as a raw material and bromotrifluoromethane as a fluorination reagent. Under visible light induction, in the presence of a photocatalyst and a base, the trifluoromethyl radical generated from bromotrifluoromethane undergoes a radical aminofluorination reaction with an alkene to prepare a tetrahydropyridazine compound containing a trifluoromethyl group in one step.

[0047] The present invention first applies the radical tandem cyclization reaction involving N-allyl-N-acylhydrazone to the synthesis of tetrahydropyridazine compounds, providing a new raw material for the synthesis of tetrahydropyridazine compounds.

[0048] The present invention first uses bromotrifluoromethane in the radical aminofluorination reaction of an alkene to construct a tetrahydropyridazine compound. CF 3 Br is a non-toxic, odorless, and inexpensive industrial raw material that is readily available. Compared with other fluorination reagents, it is inexpensive, easily accessible, and has high atom economy.

[0049] The synthesis method provided by the present invention has a high degree of regioselectivity, that is, the obtained products are all 3-substituted-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine compounds.

[0050] The synthesis method provided by the present invention has the characteristics of short reaction steps, inexpensive and readily available raw materials, simple operation, mild reaction conditions, and high reaction yields. The present invention uses visible light irradiation to generate radicals, belonging to a green synthesis process.

[0051] The tetrahydropyridazine compounds synthesized by the present invention, through 1 H NMR, 13 C NMR, 19 F NMR, and high-resolution mass spectrometry detection, prove that the synthesized products are pure target compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required in the embodiments.

[0053] Figure 1 It is the synthesis process diagram of the present invention;

[0054] Figure 2 It is the 1 HNMR diagram of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1;

[0055] Figure 3 It is the 13 CNMR diagram of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1;

[0056] Figure 41H NMR spectrum of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1 19 1H NMR spectrum

[0057] Figure 5 High-resolution mass spectrometry detection chart of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1

[0058] Figure 6 1H NMR spectrum of N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2 1 1H NMR spectrum

[0059] Figure 7 13C NMR spectrum of N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2 13 13C NMR spectrum

[0060] Figure 8 19F NMR spectrum of N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2 19 19F NMR spectrum

[0061] Figure 9 High-resolution mass spectrometry detection chart of N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2

[0062] Figure 10 1H NMR spectrum of N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 3 1 1H NMR spectrum

[0063] Figure 11 13C NMR spectrum of N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 3 13 13C NMR spectrum

[0064] Figure 12 19F NMR spectrum of N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 3 19 19F NMR spectrum

[0065] Figure 13 High-resolution mass spectrometry detection chart of N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 3

[0066] Figure 141H NMR spectrum of N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4 1 1H NMR spectrum;

[0067] Figure 15 13C NMR spectrum of N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4 13 13C NMR spectrum;

[0068] Figure 16 19F NMR spectrum of N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4 19 19F NMR spectrum;

[0069] Figure 17 High-resolution mass spectrometry detection spectrum of N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4;

[0070] Figure 18 1H NMR spectrum of N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5 1 1H NMR spectrum;

[0071] Figure 19 13C NMR spectrum of N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5 13 13C NMR spectrum;

[0072] Figure 20 19F NMR spectrum of N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5 19 19F NMR spectrum;

[0073] Figure 21 High-resolution mass spectrometry detection spectrum of N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5. Detailed implementation manners

[0074] Now, various exemplary implementation manners of the present invention will be described in detail. This detailed description should not be regarded as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics, and implementation schemes of the present invention.

[0075] It should be understood that the terms used in the present invention are only for describing specific embodiments and are not intended to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0076] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0077] Without departing from the scope or spirit of the present invention, various improvements and changes can be made to the specific embodiments of the present invention specification, which are obvious to those skilled in the art. Other embodiments obtained from the specification of the present invention are obvious to those skilled in the art. The specification and examples of this application are merely exemplary.

[0078] Regarding the use of "comprising", "including", "having", "containing", etc. herein, they are all open-ended terms, meaning including but not limited to.

[0079] The room temperature of the present invention refers to 25 ± 2 °C.

[0080] The embodiments of the present invention provide a method for synthesizing tetrahydropyridazine compounds, that is, using N-allyl-N-acylhydrazone as a raw material and inexpensive and easily available bromotrifluoromethane as a fluorination reagent. Under the action of visible light induction, a photocatalyst and a base, through the radical amino-fluorination reaction of olefins, a tetrahydropyridazine compound containing a trifluoromethyl group is prepared in one step. Figure 1 It is the synthesis process diagram of the present invention.

[0081] The present invention introduces a trifluoromethyl group into the tetrahydropyridazine molecule for the first time. This method has the characteristics of being green and safe, with inexpensive and easily available raw materials, high atom economy, good regioselectivity of the reaction, mild reaction conditions, wide substrate scope, high yield, and easy purification of the product, belonging to green synthesis.

[0082] Example 1 Synthesis of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a)

[0083] The synthesis route is as follows:

[0084]

[0085] The specific synthesis process is as follows:

[0086] Add N-(3-methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.97 mg, 1.5 mol%), 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN (acetonitrile) into a 50 mL Schlenk flask. Evacuate the Schlenk flask to vacuum and then refill it with CF 3 Br gas, repeat three times, and finally maintain the pressure in the Schlenk flask at 1.0 atm (observed from the barometer). Place the reaction mixture on a 15 W blue light and stir at room temperature for 18 h. After the reaction is completed, concentrate the reaction mixture and purify it by column chromatography using petroleum ether (PE) and ethyl acetate (EA) as eluents (PE∶EA = 6∶1, volume ratio) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 48.9 mg, with a yield of 82%.

[0087] Detect the N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a) synthesized in this example. Figure 2 For the 1 1H NMR spectrum of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1, the corresponding characterization data are as follows:

[0088] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.39 (dd, J = 6.0, 2.4 Hz, 3H), 7.34 (dd, J = 5.2, 1.6 Hz, 2H), 4.19–4.06 (m, 2H), 2.53–2.44 (m, 1H), 2.29 (s, 3H), 1.39 (s, 3H), 1.30 (s, 3H).

[0089] Figure 3 For the 13 13C NMR spectrum of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1, the corresponding characterization data are as follows:

[0090] 13 13C{ 1 1H} NMR (150 MHz, CDCl 3)172.3, 154.6, 137.1, 128.7, 128.4, 128.0, 126.2 (q, J C-F = 280.4 Hz), 44.8 (q, J C-F = 25.4 Hz), 36.0 (q, J C-F = 4.6 Hz), 34.6, 28.4, 23.2, 21.1。

[0091] Figure 4 1H NMR spectrum of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1, and the corresponding characterization data are: 19 1H NMR(376 MHz, CDCl

[0092] 19 )δ, -63.86, (d, J = 9.02 Hz). 3 )δ, -63.86, (d, J = 9.02 Hz).

[0093] Figure 5 High-resolution mass spectrometry detection chart of N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 1, and the corresponding characterization data are:

[0094] HRMS(ESI): m / z calcd for C 15 H 18 ON 2 F 3 [M + H] + 299.1366, found 299.1364.

[0095] After 1 1H NMR, 13 13C NMR, 19 19F NMR and high-resolution mass spectrometry detection, it is proved that the N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in this example is the pure target compound.

[0096] Synthesis of Example 2 N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3b)

[0097] The synthesis route is as follows:

[0098]

[0099] The specific synthesis process is as follows:

[0100] N-(3-methylbut-2-en-1-yl)-N-acetyl-(4-methyl)phenylhydrazone (48.8 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.97 mg, 1.5 mol%), 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3 Br gas, and this was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 18 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE∶EA = 7∶1) to obtain N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3b): a colorless oily liquid, 49.9 mg, with a yield of 80%.

[0101] The N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3b) synthesized in this example was detected, Figure 6 and it was the 1 1H NMR spectrum of the N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2. The corresponding characterization data were as follows:

[0102] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.27–7.25 (m, 2H), 7.19 (d, J = 8.0 Hz, 2H), 4.16 (dd, J = 14.4, 4.4 Hz, 1H), 4.06 (dd, J = 14.0, 7.2 Hz, 1H), 2.52–2.45 (m, 1H), 2.39 (s, 3H), 2.29 (s, 3H), 1.38 (s, 3H), 1.30 (s, 3H).

[0103] Figure 7 It was the 13 13C NMR spectrum of the N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2. The corresponding characterization data were as follows:

[0104] 13 13C{ 1 1H} NMR (150 MHz, CDCl 3 ) δ 172.2, 154.6, 138.3, 134.3, 128.7, 128.4, 126.3 (q, JC-F = 280.4 Hz), 44.8 (q, J C-F = 25.5 Hz), 36.0 (q, J C-F = 4.2 Hz), 34.6, 28.3, 23.2, 21.2, 21.1。

[0105] Figure 8 19F NMR spectrum of N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2, and the corresponding characterization data are as follows: 19 19F NMR spectrum of N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2, and the corresponding characterization data are as follows:

[0106] 19 19F NMR (376 MHz, CDCl 3 ) δ -63.84, (d, J = 8.65 Hz).

[0107] Figure 9 High-resolution mass spectrometry detection chart of N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 2, and the corresponding characterization data are as follows:

[0108] HRMS (ESI): m / z calcd for C 16 H 20 ON 2 F 3 [M + H] + 313.1522, found 313.1521. By 1 1H NMR, 13 13C NMR, 19 19F NMR and high-resolution mass spectrometry detection, it is proved that the N-acetyl-3-(4-methyl)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3b) synthesized in this example is a pure target compound.

[0109] Synthesis of N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3c) in Example 3

[0110] The synthesis route is as follows:

[0111]

[0112] The specific synthesis process is as follows:

[0113] N-(3-methylbut-2-en-1-yl)-N-acetyl-(4-methoxy)phenylhydrazone (52.6 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3(1.97 mg, 1.5 mol%), 2,6 - dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN was added to a 50 mL Schlenk flask. The Schlenk flask was evacuated to vacuum and then filled with CF 3 Br gas, and this was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 18 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 8:1) to obtain N - acetyl - 3 - (4 - methoxyphenyl) - 4,4 - dimethyl - 5 - trifluoromethyltetrahydropyridazine (3c): a colorless oily liquid, 49.9 mg, with a yield of 76%.

[0114] The N - acetyl - 3 - (4 - methoxyphenyl) - 4,4 - dimethyl - 5 - trifluoromethyltetrahydropyridazine (3c) synthesized in this example was detected, Figure 10 which is the 1 1H NMR spectrum of the N - acetyl - 3 - (4 - methoxyphenyl) - 4,4 - dimethyl - 5 - trifluoromethyltetrahydropyridazine synthesized in Example 3, and the corresponding characterization data are as follows:

[0115] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.17–4.05 (m, 2H), 3.84 (s, 3H), 2.52–2.42 (m, 1H), 2.30 (s, 3H), 1.39 (s, 3H), 1.31 (s, 3H).

[0116] Figure 11 which is the 13 13C NMR spectrum of the N - acetyl - 3 - (4 - methoxyphenyl) - 4,4 - dimethyl - 5 - trifluoromethyltetrahydropyridazine synthesized in Example 3, and the corresponding characterization data are as follows:

[0117] 13 13C{ 1 1H}NMR (150 MHz, CDCl 3 ) δ 172.1, 159.6, 154.3, 129.9, 129.6, 126.2 (q, J C-F = 280.5 Hz), 113.4, 55.2, 44.9 (q, J C-F = 25.4 Hz), 36.0 (q, J C-F = 4.2 Hz), 34.6, 28.4, 23.2, 21.1.

[0118] Figure 12 For the N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 3 19 19F NMR spectrum, and the corresponding characterization data are:

[0119] 19 19F NMR (376 MHz, CDCl 3 ) δ -63.82, (d, J = 9.02 Hz).

[0120] Figure 13 High-resolution mass spectrometry detection chart of the N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 3, and the corresponding characterization data are:

[0121] HRMS (ESI): m / z calcd for C 16 H 20 O 2 N 2 F 3 [M + H] + 329.1471, found 329.1470.

[0122] By 1 1H NMR, 13 13C NMR, 19 19F NMR and high-resolution mass spectrometry detection, it is proved that the N-acetyl-3-(4-methoxy)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in this example is the pure target compound.

[0123] Synthesis of N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3d) in Example 4

[0124] The synthesis route is as follows:

[0125]

[0126] The specific synthesis process is as follows:

[0127] Add N-(3-methylbut-2-en-1-yl)-N-acetyl-(4-fluoro)phenylhydrazone (49.6 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.97 mg, 1.5 mol%), 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN into a 50 mL Schlenk flask. Evacuate the Schlenk flask to vacuum and then fill it with CF 3The Br gas was added and the operation was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 18 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as the eluent (PE∶EA = 8∶1) to obtain N-acetyl-3-(4-fluorophenyl)-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3d): a colorless oily liquid, 54.4 mg, with a yield of 86%.

[0128] The N-acetyl-3-(4-fluorophenyl)-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3d) synthesized in this example was detected. Figure 14 For the N-acetyl-3-(4-fluorophenyl)-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4 1 H NMR spectrum, and the corresponding characterization data are as follows:

[0129] 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 (dd, J = 8.8, 5.2 Hz, 2H), 7.08 (t, J = 8.8 Hz, 2H), 4.13 (d, J = 6.0 Hz, 2H), 2.54–2.44 (m, 1H), 2.29 (s, 3H), 1.39 (s, 3H), 1.30 (s, 3H).

[0130] Figure 15 For the N-acetyl-3-(4-fluorophenyl)-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4 13 C NMR spectrum. The corresponding characterization data are as follows:

[0131] 13 C{ 1 H}NMR (150 MHz, CDCl 3 ) δ 172.1, 162.7 (d, J C-F = 247.1 Hz), 153.5, 133.2 (d, J C-F = 3.5 Hz), 130.4 (d, J C-F = 8.1 Hz), 126.1 (q, J C-F = 280.4 Hz), 115.1 (d, J C-F = 21.3 Hz), 44.7 (q, J C-F = 25.5 Hz), 36.0 (q, J C-F = 4.2 Hz), 34.5, 28.4, 23.3, 21.0.

[0132] Figure 16For the N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4 19 19F NMR spectrum, and the corresponding characterization data are as follows:

[0133] 19 19F NMR (376 MHz, CDCl 3 ) δ -63.89, (d, J = 9.02 Hz), -118.84~-112.91 (m).

[0134] Figure 17 High-resolution mass spectrometry detection chart of the N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 4, and the corresponding characterization data are as follows:

[0135] HRMS (ESI): m / z calcd for C 15 H 17 ON 2 F 4 [M + H] + 317.1272, found 317.12723.

[0136] After 1 1H NMR, 13 13C NMR, 19 19F NMR and high-resolution mass spectrometry detection, it is proved that the N-acetyl-3-(4-fluoro)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in this example is the pure target compound.

[0137] Synthesis of N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3e) in Example 5

[0138] The synthesis route is as follows:

[0139]

[0140] The specific synthesis process is as follows:

[0141] Add N-(3-methylbut-2-en-1-yl)-N-acetyl-(4-bromo)phenylhydrazone (61.8 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.97 mg, 1.5 mol%), 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN into a 50 mL Schlenk flask. Evacuate the Schlenk flask to vacuum and then refill it with CF 3Br gas, repeat three times, and finally maintain the pressure in the Schlenk flask at 1.0 atm (observed from the manometer). Place the reaction mixture on a 15 W blue light and stir at room temperature for 18 h. After the reaction, concentrate the reaction mixture and purify it by column chromatography using petroleum ether and ethyl acetate as eluents (PE∶EA = 12∶1) to obtain N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3e): a colorless oily liquid, 62.6 mg, with a yield of 83%.

[0142] Detect N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3e) synthesized in this example, Figure 18 which is for N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5 1 1H NMR spectrum, and the corresponding characterization data are as follows:

[0143] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.53 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.12 (d, J = 5.2 Hz, 2H), 2.51–2.45 (m, 1H), 2.29 (s), 1.39 (s, 3H), 1.30 (s, 3H).

[0144] Figure 19 which is for N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5 13 13C NMR spectrum, and the corresponding characterization data are as follows:

[0145] 13 13C{ 1 1H}NMR (150 MHz, CDCl 3 ) δ 172.2, 153.3, 136.0, 131.3, 130.3, 126.1 (q, J C-F = 280.2 Hz), 122.8, 44.7 (q, J C-F = 24.9 Hz), 36.0 (q, J C-F = 4.1 Hz), 34.4, 28.4, 23.2, 21.1.

[0146] Figure 20 which is for N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5 19 19F NMR spectrum, and the corresponding characterization data are as follows:

[0147] 1919F NMR (376 MHz, CDCl 3 ) δ -63.88, (d, J = 9.4 Hz);

[0148] Figure 21 This is the high-resolution mass spectrometry detection chart of N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in Example 5, and the corresponding characterization data are as follows:

[0149] HRMS (ESI): m / z calcd for C 15 H 17 ON 2 BrF 3 [M + H] + 337.0471, found 337.0471.

[0150] After 1 1H NMR, 13 13C NMR, 19 19F NMR and high-resolution mass spectrometry detection, it is proved that the N-acetyl-3-(4-bromo)phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine synthesized in this example is the pure target compound.

[0151] Example 6

[0152] Same as Example 1, except that the organic solvent CH 3 CN was replaced with N,N-dimethylformamide to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 23.8 mg, with a yield of 40%.

[0153] Example 7

[0154] Same as Example 1, except that the organic solvent CH 3 CN was replaced with dimethyl sulfoxide to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 20.9 mg, with a yield of 35%.

[0155] Example 8

[0156] Same as Example 1, except that the organic solvent CH 3 CN was replaced with tetrahydrofuran to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 10.7 mg, with a yield of 18%.

[0157] Example 9

[0158] Same as Example 1, except that the basic reagent 2,6-lutidine was replaced with Et 3 N (40.4 mg, 0.4 mmol, 2.0 equiv), to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 8.9 mg, with a yield of 15%.

[0159] Example 10

[0160] Same as Example 1, except that the basic reagent 2,6-lutidine was replaced with KHCO 3 (40 mg, 0.4 mmol, 2.0 equiv), to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 27.0 mg, with a yield of 46%.

[0161] Example 11

[0162] Same as Example 1, except that the basic reagent 2,6-lutidine was replaced with pyridine (31.6 mg, 0.4 mmol, 2.0 equiv), to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 26.8 mg, with a yield of 45%.

[0163] Example 12

[0164] Same as Example 1, except that the basic reagent 2,6-lutidine was replaced with N,N-diethylpropyethylamine (51.6 mg, 0.4 mmol, 2.0 equiv), to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 23.8 mg, with a yield of 40%.

[0165] Example 13

[0166] Same as Example 1, except that the photocatalyst fac-Ir(ppy) 3 was replaced with 4CzIPN (2.4 mg, 1.5 mol%), to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 6.0 mg, with a yield of 10%.

[0167] Example 14

[0168] Same as Example 1, except that the power of visible light was 5 W, to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 31 mg, with a yield of 52%.

[0169] Example 15

[0170] Same as Example 1, except that the power of visible light is 10 W, and N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a) is obtained: colorless oily liquid, 38.7 mg, with a yield of 65%.

[0171] Example 16

[0172] Same as Example 1, except that the power of visible light is 20 W, and N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a) is obtained: colorless oily liquid, 35.8 mg, with a yield of 60%.

[0173] Example 17

[0174] N-(3-Methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%)、2,6-dimethylpyridine (42.8 mg, 0.2 mmol, 2.0 equiv)、3 mL CH 3 CN was added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3 Br gas, and this was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether (PE) and ethyl acetate (EA) as the eluent (PE∶EA = 6∶1, volume ratio) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 40.5 mg, with a yield of 68%.

[0175] Example 18

[0176] N-(3-Methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.97 mg, 1.5 mol%)、2,6-dimethylpyridine (42.8 mg, 0.2 mmol, 2.0 equiv)、3 mL CH 3 CN was added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3Br gas was added, and the operation was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography. Using petroleum ether (PE) and ethyl acetate (EA) as eluents (PE∶EA = 6∶1, volume ratio), N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a) was obtained: a colorless oily liquid, 45.3 mg, with a yield of 76%.

[0177] Comparative Example 1

[0178] N-(3-methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), K 2 CO 3 (55.4 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3 Br gas, and the operation was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography. Using petroleum ether and ethyl acetate as eluents (PE∶EA = 6∶1), N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a) was obtained: a colorless oily liquid, 11.6 mg, with a yield of 27%.

[0179] Comparative Example 2

[0180] N-(3-methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), NaOAc (32.8 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3Br gas was added, and the process was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 6:1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 23.8 mg, with a yield of 40%.

[0181] Comparative Example 3

[0182] N-(3-Methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), K 3 PO 4 ·3H 2 O (92 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3 Br gas, and the process was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 6:1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 17.3 mg, with a yield of 29%.

[0183] Comparative Example 4

[0184] N-(3-Methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), K 2 HPO 4 (70 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3Br gas, repeat three times, and finally maintain the pressure in the Schlenk flask at 1.0 atm (observed from the barometer). Place the reaction mixture on a 15 W blue light and stir at room temperature for 24 h. After the reaction is completed, concentrate the reaction mixture and purify it by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 6:1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 7.9 mg, with a yield of 30%.

[0185] Comparative Example 5

[0186] Add N-(3-methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), Li 2 CO 3 (30 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN into a 50 mL Schlenk flask. Evacuate the Schlenk flask and then refill it with CF 3 Br gas, repeat three times, and finally maintain the pressure in the Schlenk flask at 1.0 atm (observed from the barometer). Place the reaction mixture on a 15 W blue light and stir at room temperature for 24 h. After the reaction is completed, concentrate the reaction mixture and purify it by column chromatography using petroleum ether and ethyl acetate as eluents (PE∶EA = 6∶1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 21.5 mg, with a yield of 36%.

[0187] Comparative Example 6

[0188] Add N-(3-methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), Cs 2 CO 3 (130 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN into a 50 mL Schlenk flask. Evacuate the Schlenk flask and then refill it with CF 3Br gas, repeat three times, and finally maintain the pressure in the Schlenk flask at 1.0 atm (observed from the manometer). Place the reaction mixture on a 15 W blue light and stir at room temperature for 24 h. After the reaction is completed, concentrate the reaction mixture and purify it by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 6:1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 16.7 mg, with a yield of 28%.

[0189] Comparative Example 7

[0190] Add N-(3-methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), NaHCO 3 (84 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN into a 50 mL Schlenk flask. Evacuate the Schlenk flask and then refill it with CF 3 Br gas, repeat three times, and finally maintain the pressure in the Schlenk flask at 1.0 atm (observed from the manometer). Place the reaction mixture on a 15 W blue light and stir at room temperature for 24 h. After the reaction is completed, concentrate the reaction mixture and purify it by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 6:1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 25 mg, with a yield of 42%.

[0191] Comparative Example 8

[0192] Add N-(3-methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL CH 3 CN into a 50 mL Schlenk flask. Evacuate the Schlenk flask and then refill it with CF 3 Br gas, repeat three times, and finally maintain the pressure in the Schlenk flask at 1.0 atm (observed from the manometer). Place the reaction mixture on a 15 W blue light and stir at room temperature for 24 h. After the reaction is completed, concentrate the reaction mixture and purify it by column chromatography using petroleum ether and ethyl acetate as eluents (PE∶EA = 6∶1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): colorless oily liquid, 40.5 mg, with a yield of 68%.

[0193] Comparative Example 9

[0194] N-(3-Methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL of 1,4-dioxane were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3 Br gas, and this was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the manometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 6:1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 13.7 mg, with a yield of 23%.

[0195] Comparative Example 10

[0196] N-(3-Methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3 (1.31 mg, 1 mol%), 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv), 3 mL of acetone were added to a 50 mL Schlenk flask. The Schlenk flask was evacuated and then filled with CF 3 Br gas, and this was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the manometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE:EA = 6:1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 31 mg, with a yield of 52%.

[0197] Comparative Example 11

[0198] N-(3-Methylbut-2-en-1-yl)-N-acetylphenylhydrazone (46 mg, 0.2 mmol, 1.0 equiv), fac-Ir(ppy) 3(1.31 mg, 1 mol%) and 2,6-dimethylpyridine (42.8 mg, 0.4 mmol, 2.0 equiv) were added to a 50 mL Schlenk flask, followed by 3 mL of DCE (dichloroethane). The Schlenk flask was evacuated and then filled with CF 3 Br gas, and this evacuation and filling process was repeated three times. Finally, the pressure in the Schlenk flask was maintained at 1.0 atm (observed from the barometer). The reaction mixture was placed on a 15 W blue light and stirred at room temperature for 24 h. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography using petroleum ether and ethyl acetate as eluents (PE∶EA = 8∶1) to obtain N-acetyl-3-phenyl-4,4-dimethyl-5-trifluoromethyltetrahydropyridazine (3a): a colorless oily liquid, 25 mg, with a yield of 42%.

[0199] The above-described embodiments are only descriptions of the preferred embodiments of the present invention and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for synthesizing a tetrahydropyridazine compound, characterized in that: The following steps are involved: CF3Br and N-allyl-N-acylhydrazone are subjected to a free radical tandem cyclization reaction induced by visible light in an organic solvent in the presence of a photocatalyst and an alkaline reagent, and the reaction mixture is concentrated and purified by column chromatography to obtain the tetrahydropyridazine compound; The general structural formula of the N-allyl-N-acylhydrazone is: In the above formula, R 1 is phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, CF2H or CF3; R 2 is acetyl, benzoyl, benzyloxycarbonyl or p-toluenesulfonyl; The photocatalyst is selected from fac-Ir III (ppy)3 (tris(2-phenylpyridine)iridium) and 4CzIPN (2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile); The wavelength of the visible light is 390-460nm, and the power of the visible light is 5-15W; The general structural formula of the tetrahydropyridazine compound is: In the above formula, R 1 is phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, CF2H or CF3; R 2 It is acetyl, benzoyl, benzyloxycarbonyl or p-toluenesulfonyl.

2. The method for synthesizing tetrahydropyridazine compounds according to claim 1, characterized in that: The molar ratio of the N-allyl-N-acylhydrazone to the alkaline reagent is 1:(1-3).

3. The method for synthesizing tetrahydropyridazine compounds according to claim 1, characterized in that: The organic solvent is selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran.

4. The method for synthesizing tetrahydropyridazine compounds according to claim 1, characterized in that: The amount of the photocatalyst used is 0.5-1.5 mol% of the total molar amount of CF3Br and N-allyl-N-acylhydrazone.

5. The method for synthesizing tetrahydropyridazine compounds according to claim 1, characterized in that: The alkaline agent is selected from KHCO3, Et3N, 2,6-lutidine, pyridine or N,N-diethylpropylethylamine.

6. The method for synthesizing tetrahydropyridazine compounds according to claim 1, characterized in that: The temperature of the free radical tandem cyclization reaction is room temperature and the time is 12-24 hours.

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