Method for constructing substituted pyrimidone skeleton through reaction of gem-difluoroallene and benzamidine hydrochloride compound

Abstract

The invention provides a method for constructing a substituted pyrimidone skeleton through reaction of gem-difluoroallene and benzamidine hydrochloride compounds, and relates to the technical field of organic synthesis. The method for constructing the substituted pyrimidone skeleton through the reaction of the gem-difluoro allene and the benzamidine hydrochloride compound provided by the invention comprises the following steps: mixing the gem-difluoro allene, the benzamidine hydrochloride compound, alkali and a solvent, heating to react, and after the reaction is finished, performing post-treatment to obtain the substituted pyrimidone compound. The pyrimidone core heterocyclic ring is efficiently constructed by utilizing the special electrophilicity brought by two fluorine atoms in gem-difluoroallene molecules and through a defluorination cyclization mechanism promoted by alkali. The method has the advantages that a noble metal catalyst is not needed, raw materials are easy to obtain, operation is easy and convenient, reaction conditions are mild, one-step synthesis is achieved, functional group compatibility is good, and a new strategy is provided for green and efficient synthesis of pyrimidone compounds.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for constructing a substituted pyrimidinone skeleton by reacting gem-difluoroalkenes with benzamide hydrochloride compounds. Background Technology

[0002] Pyrimidinone compounds, as an important class of nitrogen-containing heterocyclic skeletons, are widely found in various natural alkaloids and drug molecules with significant biological activity. This structural unit is the core of many key drugs, including antibiotics, antitumor agents, anti-inflammatory drugs, and nervous system drugs, exhibiting a wide variety of pharmacological activities such as antibacterial, antiviral, antitumor, and anti-inflammatory effects. Furthermore, pyrimidinone derivatives are indispensable intermediates in the total synthesis of functional materials, pesticides, and complex natural products. Therefore, developing efficient, green, mild-conditioning methods for constructing pyrimidinone skeletons with good functional group tolerance has always been a research hotspot and a significant challenge in the fields of organic synthesis and medicinal chemistry.

[0003] Currently, traditional strategies for synthesizing polysubstituted pyrimidinones mainly rely on the condensation cyclization reaction of Michael acceptors (such as α,β-unsaturated carbonyl compounds) with urea, thiourea, or guanidine compounds. While these methods are relatively mature, they typically have some inherent limitations. For example, many methods depend on pre-functionalized substrates, resulting in lengthy synthetic steps and low atom economy. More critically, to activate the substrate or promote cyclization, many existing efficient synthetic strategies often require transition metal catalysts (such as noble metal complexes like palladium, copper, and gold). This not only increases synthetic costs and complicates the removal of metal residues in post-processing but also contradicts the principles of green and sustainable chemistry. Furthermore, some methods have stringent reaction conditions (such as anhydrous and oxygen-free environments) or use a narrow range of substrates, limiting their potential application in the later stages of complex molecule modification.

[0004] Therefore, in view of the shortcomings of existing synthesis methods, such as dependence on noble metal catalysts, insufficiently mild reaction conditions, inadequate step economy, and limited applicability of some substrates, there is an urgent need to provide a solution to improve the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide a method for constructing a substituted pyrimidinone skeleton by reacting gem-difluoroalkenes with benzamide hydrochloride compounds.

[0006] In a first aspect, the present invention provides a method for constructing a substituted pyrimidinone skeleton by reacting gemdifluoroalkenes with benzamide hydrochloride compounds, comprising the following steps: mixing gemdifluoroalkenes, benzamide hydrochloride compounds, a base and a solvent, heating and reacting the mixture, and then performing post-treatment after the reaction to obtain the substituted pyrimidinone compounds.

[0007] Optionally, the gem-difluoroalkene has the structure shown in formula (I):

[0008] ;

[0009] Among them, R 1 It is either hydrogen or methyl; R 2 It includes one of methyl, bromine, methoxy, trifluoromethyl, ester, or five-membered heteroaryl.

[0010] Optionally, the reaction equation for the heated reaction of the gemdifluoroalkene with the benzamide hydrochloride compound is shown in equation (II) below:

[0011] ;

[0012] Among them, R 1 It is either hydrogen or methyl; R 2 With R 3 It independently includes one of methyl, bromine, methoxy, trifluoromethyl, ester or five-membered heteroaryl.

[0013] Optionally, the base is an organic base, including sodium phenolate or 1,4-diazabicyclo[2.2.2]octane.

[0014] Optionally, the solvent includes one of 1,4-dioxane or tetrahydrofuran.

[0015] Optionally, the reaction temperature of the heating reaction is 100℃-150℃.

[0016] Optionally, the reaction time of the heating reaction is 12h-48h.

[0017] Optionally, the molar ratio of the gem-difluoroalkene, the benzamide hydrochloride compound, and the base is 1:(2.0-3.0):(4.0-6.0).

[0018] Optionally, the post-processing includes: cooling the reaction solution obtained after the heating reaction is completed, and obtaining a crude product by solid-liquid separation, washing, evaporation and concentration, and then purifying the crude product by column chromatography to obtain the substituted pyrimidinone compound.

[0019] Optionally, the solid-liquid separation includes rapid separation and filtration using silica gel column chromatography.

[0020] Optionally, the washing solution used for the washing includes ethyl acetate.

[0021] Optionally, the eluent used in the column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is (1:1) to (5:1).

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) The method provided by the present invention does not require the use of any precious metal catalysts. It achieves the construction of pyrimidinone skeleton in one step through base-promoted defluorination cyclization mechanism, which effectively reduces the synthesis cost and avoids the problem of metal residue, and is in line with the concept of green chemistry.

[0024] (2) The method provided by the present invention uses uniquely structured gem-difluoroalene and commercially available benzamide hydrochloride compounds as raw materials to directly construct complex pyrimidinone heterocycles through a one-step reaction, which has the advantages of high step economy and good atom economy.

[0025] (3) The method provided by the present invention is simple to operate, the reaction can be carried out in air, no strict anhydrous and oxygen-free conditions are required, and the post-processing only requires conventional filtration and column chromatography, which is easy to implement;

[0026] (4) This invention successfully applies the amphiphilic properties of gem-difluoroalene to heterocyclic synthesis, and develops a novel and practical metal-free catalytic strategy for the synthesis of pyrimidinones, providing a new method for the green synthesis of nitrogen-containing heterocyclic compounds, especially pyrimidinone derivatives. Attached Figure Description

[0027] Figure 1 The hydrogen spectrum of the product obtained in Example 1 of this invention;

[0028] Figure 2 The carbon spectrum of the product obtained in Example 1 of this invention;

[0029] Figure 3 The hydrogen spectrum of the product obtained in Example 2 of this invention;

[0030] Figure 4 The carbon spectrum of the product obtained in Example 2 of this invention;

[0031] Figure 5 The hydrogen spectrum of the product obtained in Example 3 of this invention;

[0032] Figure 6 The carbon spectrum of the product obtained in Example 3 of this invention;

[0033] Figure 7 The hydrogen spectrum of the product obtained in Example 4 of this invention;

[0034] Figure 8 The carbon spectrum of the product obtained in Example 4 of this invention;

[0035] Figure 9 The hydrogen spectrum of the product obtained in Example 5 of this invention;

[0036] Figure 10The carbon spectrum of the product obtained in Example 5 of this invention;

[0037] Figure 11 The hydrogen spectrum of the product obtained in Example 6 of this invention;

[0038] Figure 12 The carbon spectrum of the product obtained in Example 6 of this invention;

[0039] Figure 13 The hydrogen spectrum of the product obtained in Example 7 of this invention;

[0040] Figure 14 The carbon spectrum of the product obtained in Example 7 of this invention;

[0041] Figure 15 The hydrogen spectrum of the product obtained in Example 8 of this invention;

[0042] Figure 16 The carbon spectrum of the product obtained in Example 8 of this invention;

[0043] Figure 17 The hydrogen spectrum of the product obtained in Example 9 of this invention;

[0044] Figure 18 The carbon spectrum of the product obtained in Example 9 of this invention;

[0045] Figure 19 The hydrogen spectrum of the product obtained in Example 10 of this invention;

[0046] Figure 20 This is the carbon spectrum of the product obtained in Example 10 of the present invention. Detailed Implementation

[0047] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0048] This invention provides a method for constructing a substituted pyrimidinone skeleton by reacting gem-difluoroallene with benzamide hydrochloride compounds. The method involves mixing gem-difluoroallene, benzamide hydrochloride compounds, a base, and a solvent, followed by heating and reaction. After the reaction, post-treatment yields the substituted pyrimidinone compound. Essentially, this invention utilizes the unique electrophilicity of the two fluorine atoms in the gem-difluoroallene molecule, achieving a one-step [4+2] cycloaddition reaction with benzamide hydrochloride compounds via a base-promoted defluorination cyclization mechanism, thus efficiently constructing the pyrimidinone core heterocycle. This method offers advantages such as no need for precious metal catalysts, readily available raw materials, simple operation, mild reaction conditions, one-step synthesis, and good functional group compatibility, providing a new strategy for the green and efficient synthesis of pyrimidinone compounds.

[0049] In some embodiments, the gemini difluoroalkenes used have the structure shown in formula (I):

[0050] ;

[0051] Among them, R 1 It is either hydrogen or methyl; R 2 It includes one of the following: methyl, bromine, methoxy, trifluoromethyl, ester, or five-membered heteroaryl. In fact, due to the special electrophilicity of the two fluorine atoms in the gemdifluoroalkene molecule, it can undergo addition-elimination reactions with nucleophilic benzamide hydrochloride compounds.

[0052] In some embodiments, the reaction equation for the heated reaction of the geminidin and the benzamide hydrochloride compound is shown in equation (II) below:

[0053] ;

[0054] Among them, R 1 It is either hydrogen or methyl; R 2 With R 3 Each group independently includes one of methyl, bromine, methoxy, trifluoromethyl, ester, or five-membered heteroaryl groups. In fact, a substituted pyrimidinone skeleton is constructed in one step by reacting gemdifluoroalkenes with benzamide hydrochloride compounds under basic conditions. The core mechanism is a base-promoted intramolecular cyclization reaction involving defluorination.

[0055] In some embodiments, the base used is an organic base, including sodium phenolate or 1,4-diazabicyclo[2.2.2]octane. In fact, the entire process is driven entirely by the organic base, through base-promoted nucleophilic attack, defluorination, and cyclization steps, without the involvement of any transition metals, which is the most prominent green chemistry feature of this method.

[0056] In some embodiments, the solvent used includes one of 1,4-dioxane or tetrahydrofuran.

[0057] In some embodiments, the reaction temperature of the heating reaction is 100°C-150°C.

[0058] In some embodiments, the reaction time for the heating reaction is 12h-48h.

[0059] In some embodiments, the molar ratio of gem-difluoroalkene, benzamide hydrochloride, and base used is 1:(2.0-3.0):(4.0-6.0). In practice, providing sufficient base ensures that all benzamide hydrochloride is completely converted to free benzamide and initiates the activation of the gem-difluoroalkene; providing an excess of benzamide and base relative to the gem-difluoroalkene maximizes the participation of the gem-difluoroalkene in the reaction, leading to the conversion to the target product; exceeding this ratio range may result in a low yield of the target product. Preferably, the molar ratio of gem-difluoroalkene, benzamide hydrochloride, and base is 1:2.5:5.

[0060] In some embodiments, the post-processing includes: cooling the reaction solution obtained after the heating reaction is completed, performing solid-liquid separation, washing, evaporation and concentration to obtain a crude product, and then purifying the crude product by column chromatography to obtain the substituted pyrimidinone compound.

[0061] In some embodiments, solid-liquid separation includes rapid separation and filtration using silica gel column chromatography.

[0062] In some embodiments, the washing solution used for washing includes ethyl acetate.

[0063] In some embodiments, the eluent used for column chromatography purification is a mixture of petroleum ether and ethyl acetate, with a volume ratio of petroleum ether to ethyl acetate of (1:1) to (5:1).

[0064] Example 1

[0065] Example 1 provides a method for constructing a substituted pyrimidinone skeleton by reacting (5,5-difluoro-3,4-dien-1-yl)benzene with benzylamidinium hydrochloride, comprising the following steps:

[0066] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add (5,5-difluoro-3,4-dien-1-yl)benzene (0.2 mmol, 1.0 equiv.), sodium phenolate (1.0 mmol, 5.0 equiv.), benzylamidine hydrochloride (0.5 mmol, 2.5 equiv.), and 1,4-dioxane (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 6-phenylethyl-2-phenyl-5,6-dihydropyrimidin-4(3H)-one (36 mg, 65% yield). The structural formula of the product is as follows:

[0067]

[0068] The structural characterization data of the obtained product are shown below:

[0069] 1 H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.79-7.76 (m, 2H), 7.48-7.36(m, 3H), 7.25-7.11 (m, 5H), 3.72-3.64 (m, 1H), 2.94-2.80 (m, 2H), 2.53 (dd, J= 16.4, 5.2 Hz, 1H), 2.28 (dd, J= 16.5, 11.9 Hz, 1H), 2.09-1.96 (m, 1H), 1.91-1.82 (m, 1H).

[0070] 13 C NMR (100 MHz, CDCl3) δ 171.9, 150.7, 141.8, 133.4, 131.3, 128.9,128.6, 128.5, 126.7, 126.0, 53.8, 37.4, 35.2, 32.2.

[0071] Example 2

[0072] Example 2 provides a method for constructing a substituted pyrimidinone skeleton by reacting 1-bromo-4-(5,5-difluoro-3,4-dien-1-yl)benzene with benzylamidinium hydrochloride, comprising the following steps:

[0073] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add 1-bromo-4-(5,5-difluoro-3,4-dien-1-yl)benzene (0.2 mmol, 1.0 equiv.), sodium phenolate (1.0 mmol, 5.0 equiv.), benzylamidinium hydrochloride (0.5 mmol, 2.5 equiv.), and 1,4-dioxane (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 6-(4-bromophenylethyl)-2-phenyl-5,6-dihydropyrimidin-4(3H)-one (48.5 mg, 68% yield). The structural formula of the product is as follows:

[0074]

[0075] The structural characterization data of the obtained product are shown below:

[0076] 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.55-7.38 (m, 5H), 7.13 (d, J = 7.9 Hz, 2H), 3.76-3.68 (m, 1H), 2.96-2.81 (m,2H), 2.58 (dd, J = 16.4, 5.1 Hz, 1H), 2.33 (dd, J = 16.4, 11.9 Hz, 1H), 2.08-1.99 (m, 1H), 1.96-1.84 (m, 1H).

[0077] 13 C NMR (100 MHz, CDCl3) δ 171.4, 150.6, 140.7, 133.2, 131.5, 131.4,130.3, 128.9, 126.5, 119.6, 53.7, 37.2, 35.2, 31.6.

[0078] HRMS (ESI) calculated for C 18 H 17 BrN2O [(M+H + )]: 357.0597, found: 357.0600.

[0079] Example 3

[0080] Example 3 provides a method for constructing a substituted pyrimidinone skeleton by reacting 1-(5,5-difluoro-3,4-dien-1-yl)-3-methoxybenzene with benzylamidinium hydrochloride, comprising the following steps:

[0081] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add 1-(5,5-difluoro-3,4-dien-1-yl)-3-methoxybenzene (0.2 mmol, 1.0 equiv.), sodium phenolate (1.0 mmol, 5.0 equiv.), benzylamidoamine hydrochloride (0.5 mmol, 2.5 equiv.), and 1,4-dioxane (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 6-(3-methoxyphenylethyl)-2-phenyl-5,6-dihydropyrimidin-4(3H)-one (30.2 mg, 49% yield). The structural formula of the product is as follows:

[0082]

[0083] The structural characterization data of the obtained product are shown below:

[0084] 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.87-7.75 (m, 2H), 7.54-7.41(m, 3H), 7.22 (dd, J = 9.3, 6.4 Hz, 1H), 6.89-6.70 (m, 3H), 3.83-3.68 (m,4H), 2.96-2.84 (m, 2H), 2.59 (dd, J = 16.4, 5.0 Hz, 1H), 2.39-2.28 (m, 1H), 2.11-2.03 (m, 1H), 1.99-1.86 (m, 1H).

[0085] 13 C NMR (100 MHz, CDCl3) δ 171.7, 159.6, 150.6, 143.4, 133.3, 131.3,129.4, 128.8, 126.6, 121.0, 114.3, 111.2, 55.1, 53.8, 37.3, 35.2, 32.2.

[0086] HRMS (ESI) calculated for C 19 H 20N2O2 [(M+H + )]: 309.1598, found: 309.1597.

[0087] Example 4

[0088] Example 4 provides a method for constructing a substituted pyrimidinone skeleton by reacting (5,5-difluoro-3,4-dien-1-yl)benzene with methyl 3-methanemidylbenzoate hydrochloride, comprising the following steps:

[0089] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add (5,5-difluoro-3,4-dien-1-yl)benzene (0.2 mmol, 1.0 equiv.), sodium phenolate (1.0 mmol, 5.0 equiv.), methyl 3-formamidinylbenzoate hydrochloride (0.5 mmol, 2.5 equiv.), and 1,4-dioxane (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product methyl 3-(6-oxo-4-phenylethyl-1,4,5,6-tetrahydropyrimidin-2-yl)benzoate (41.7 mg, 62% yield). The structural formula of the product is as follows:

[0090]

[0091] The structural characterization data of the obtained product are shown below:

[0092] 1 H NMR (400 MHz, CDCl3) δ9.05 (s, 1H), 8.53 (s, 1H), 8.21 (dd, J =30.9, 7.8 Hz, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.43 - 7.27 (m, 5H), 4.02 (s,3H), 3.91 - 3.79 (m, 1H), 3.10 - 2.92 (m, 2H), 2.69 (dd, J = 16.5, 5.1 Hz,1H), 2.44 (dd, J = 16.5, 11.9 Hz, 1H), 2.18 (dtd, J = 14.4, 8.5, 6.0 Hz, 1H),2.02 (ddt, J = 13.3, 9.1, 6.4 Hz, 1H).

[0093] 13C NMR (100 MHz, CDCl3) δ171.7, 166.4, 149.9, 141.7, 133.8, 132.3,131.4, 130.9, 129.2, 128.7, 128.6, 127.6, 126.1, 54.0, 52.5, 37.4, 35.2,32.2.

[0094] HRMS (ESI) calculated for C 16 H 16 N2OS [(M+H + )]: 337.1547, found: 337.1555.

[0095] Example 5

[0096] Example 5 provides a method for constructing a substituted pyrimidinone skeleton by reacting (5,5-difluoro-3,4-dien-1-yl)benzene with 3-methoxybenzamide hydrochloride, comprising the following steps:

[0097] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add (5,5-difluoro-3,4-dien-1-yl)benzene (0.2 mmol, 1.0 equiv.), sodium phenolate (1.0 mmol, 5.0 equiv.), 3-methoxybenzomidazine hydrochloride (0.5 mmol, 2.5 equiv.), and 1,4-dioxane (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 2-(3-methoxyphenyl)-6-phenylethyl-5,6-dihydropyrimidin-4(3H)-one (45 mg, 73% yield). The structural formula of the product is as follows:

[0098]

[0099] The structural characterization data of the obtained product are shown below:

[0100] 1H NMR (400 MHz, CDCl3) δ9.07 (s, 1H), 7.44 - 7.24 (m, 8H), 7.23 -7.18 (m, 1H), 7.04 (dt, J = 7.3, 2.4 Hz, 1H), 3.87 (s, 3H), 3.79 - 3.68 (m,1H), 3.01 - 2.84 (m, 2H), 2.58 (dd, J = 16.5, 5.2 Hz, 1H), 2.34 (dd, J =16.5, 11.9 Hz, 1H), 2.15 - 2.03 (m, 1H), 1.98 - 1.88 (m, 1H).

[0101] 13 C NMR (100 MHz, CDCl3) δ 172.0, 160.0, 150.7, 141.8, 134.8, 130.0,128.7, 128.5, 126.0, 118.9, 117.7, 111.8, 55.5, 53.8, 37.4, 35.2, 32.2.

[0102] HRMS (ESI) calculated for C 24 H 22 N2O [(M+H + )]: 309.1598, found: 309.1588.

[0103] Example 6

[0104] Example 6 provides a method for constructing a substituted pyrimidinone skeleton by reacting (5,5-difluoro-3-methyl-3,4-dien-1-yl)benzene with benzylamidinium hydrochloride, comprising the following steps:

[0105] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add (5,5-difluoro-3-methyl-3,4-dien-1-yl)benzene (0.2 mmol, 1.0 equiv.), DABCO (1.0 mmol, 5.0 equiv.), benzylamidinium hydrochloride (0.5 mmol, 2.5 equiv.), and tetrahydrofuran (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 6-methyl-6-phenylethyl-2-phenyl-5,6-dihydropyrimidin-4(3H)-one (30.4 mg, 52% yield). The structural formula of the product is as follows:

[0106]

[0107] The structural characterization data of the obtained product are shown below:

[0108] 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.84 (q, J = 2.9 Hz, 2H), 7.50 (ddt, J = 12.2, 7.9, 4.2 Hz, 3H), 7.34 - 7.27 (m, 2H), 7.26 - 7.18 (m, 3H), 2.82 (qd, J = 8.6, 3.5 Hz, 2H), 2.62 (dd, J = 16.4, 3.1 Hz, 1H), 2.49 (dd, J= 16.6, 3.1 Hz, 1H), 1.98 (td, J = 8.7, 3.0 Hz, 2H), 1.39 (d, J = 3.1 Hz, 3H).

[0109] 13 C NMR (100 MHz, CDCl3) δ 171.2, 148.8, 142.2, 133.7, 131.1, 128.8,128.4, 128.4, 126.53, 125.8, 56.9, 43.6, 40.6, 30.5, 25.5.

[0110] HRMS (ESI) calculated for C 19 H 20 N2O [(M+H + )]: 293.1648, found: 293.1644.

[0111] Example 7

[0112] Example 7 provides a method for constructing a substituted pyrimidinone skeleton by reacting 4-(5,5-difluoro-3-methyl-3,4-dien-1-yl)phenylpropionate with benzylamidinium hydrochloride, comprising the following steps:

[0113] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add 4-(5,5-difluoro-3-methyl-3,4-dien-1-yl)phenylpropionate (0.2 mmol, 1.0 equiv.), DABCO (1.0 mmol, 5.0 equiv.), benzylamidinium hydrochloride (0.5 mmol, 2.5 equiv.), and tetrahydrofuran (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 4-(2-(4-methyl-6-oxo-2-phenyl-1,4,5,6-tetrahydropyrimidin-4-yl)ethyl)benzoate (35.7 mg, 49% yield). The structural formula of the product is as follows:

[0114]

[0115] The structural characterization data of the obtained product are shown below:

[0116] 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.98 - 7.93 (m, 2H), 7.79 (d,J = 7.7 Hz, 2H), 7.48 (dt, J = 28.6, 7.4 Hz, 3H), 7.27 (d, J = 7.8 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 2.85 (dddd, J = 36.1, 13.6, 11.0, 5.9 Hz, 2H), 2.58 (d, J = 16.3 Hz, 1H), 2.47 (d, J = 16.4 Hz, 1H), 1.96 (dq, J = 11.1, 6.4, 5.1Hz, 2H), 1.40 - 1.33 (m, 6H).

[0117] 13 C NMR (100 MHz, CDCl3) δ 171.0, 166.8, 149.0, 147.8, 133.7, 131.4,129.9, 129.0, 128.5, 128.3, 126.6, 60.9, 57.0, 43.4, 40.7, 30.7, 25.5, 14.5.

[0118] HRMS (ESI) calculated for C 22 H 24N2O3 [(M+H + )]: 365.1860, found: 365.1871.

[0119] Example 8

[0120] Example 8 provides a method for constructing a substituted pyrimidinone skeleton by reacting 1-(5,5-difluoro-3-methyl-3,4-dien-1-yl)-4-methoxybenzene with benzylamidinium hydrochloride, comprising the following steps:

[0121] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add 1-(5,5-difluoro-3-methyl-3,4-dien-1-yl)-4-methoxybenzene (0.2 mmol, 1.0 equiv.), DABCO (1.0 mmol, 5.0 equiv.), benzylamidinium hydrochloride (0.5 mmol, 2.5 equiv.), and tetrahydrofuran (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 6-(4-methoxyphenethyl)-6-methyl-2-phenyl-5,6-dihydropyrimidin-4(3H)-one (32.8 mg, 51% yield). The structural formula of the product is as follows:

[0122]

[0123] The structural characterization data of the obtained product are shown below:

[0124] 1 H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.79 (d, J = 7.7 Hz, 2H), 7.52- 7.42 (m, 3H), 7.12 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.78 (s,3H), 2.79 - 2.65 (m, 2H), 2.58 (d, J = 16.3 Hz, 1H), 2.45 (d, J = 16.3 Hz,1H), 1.92 (t, J = 8.6 Hz, 2H), 1.35 (s, 3H).

[0125] 13C NMR (100 MHz, CDCl3) δ 157.9, 134.3, 133.8, 131.3, 129.4, 129.0, 126.6, 114.0, 57.0, 55.4, 43.9, 40.7, 29.7, 25.7.

[0126] HRMS (ESI) calculated for C 20 H 22 N2O2 [(M+H + )]: 323.1754, found: 323.1753.

[0127] Example 9

[0128] Example 9 provides a method for constructing a substituted pyrimidinone skeleton by reacting (5,5-difluoro-3-methyl-3,4-dien-1-yl)benzene with 3-methoxybenzamide hydrochloride, comprising the following steps:

[0129] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add (5,5-difluoro-3-methyl-3,4-dien-1-yl)benzene (0.2 mmol, 1.0 equiv.), DABCO (1.0 mmol, 5.0 equiv.), 3-methoxybenzomididine hydrochloride (0.5 mmol, 2.5 equiv.), and tetrahydrofuran (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 2-(3-methoxyphenyl)-6-methyl-6-phenylethyl-5,6-dihydropyrimidin-4(3H)-one (29.6 mg, 46% yield). The structural formula of the product is as follows:

[0130]

[0131] The structural characterization data of the obtained product are shown below:

[0132] 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.36 (dt, J = 8.5, 3.1 Hz,3H), 7.32 - 7.23 (m, 3H), 7.24 - 7.13 (m, 3H), 7.03 (dq, J = 7.0, 3.1 Hz,1H), 3.86 (d, J = 3.0 Hz, 3H), 2.77 (qd, J = 8.5, 3.1 Hz, 2H), 2.62 - 2.40(m, 2H), 1.94 (td, J = 8.8, 2.8 Hz, 2H), 1.35 (d, J = 3.0 Hz, 3H).

[0133] 13 C NMR (100 MHz, CDCl3) δ 171.4, 160.1, 148.8, 142.3, 135.2, 130.0,128.6, 128.5, 126.0, 118.8, 117.4, 111.9, 57.0, 55.6, 43.7, 40.7, 30.6, 25.6.

[0134] HRMS (ESI) calculated for C 22 H 26 N2O [(M+H + )]: 323.1754, found: 323.1747.

[0135] Example 10

[0136] Example 10 provides a method for constructing a substituted pyrimidinone skeleton by reacting (5,5-difluoro-3-methyl-3,4-dien-1-yl)benzene with 4-phenylbenzamide hydrochloride, comprising the following steps:

[0137] Prepare a dry 10 mL reaction tube equipped with a magnetic magnet. In air, add (5,5-difluoro-3-methyl-3,4-dien-1-yl)benzene (0.2 mmol, 1.0 equiv.), DABCO (1.0 mmol, 5.0 equiv.), 4-phenylbenzamide hydrochloride (0.5 mmol, 2.5 equiv.), and tetrahydrofuran (1 mL) sequentially. React at 120 °C for 24 h. After cooling to room temperature, filter rapidly using a homemade silica gel column. Collect the filtrate, remove the solvent under vacuum, and purify the residue by column chromatography using an eluent to obtain the product 2-([1,1'-biphenyl]-4-yl)-6-methyl-6-phenylethyl-5,6-dihydropyrimidin-4(3H)-one (33.9 mg, 46% yield). The structural formula of the product is as follows:

[0138]

[0139] The structural characterization data of the obtained product are shown below:

[0140] 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.69(d, J = 8.1 Hz, 2H), 7.62 (d, J = 6.9 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.40(t, J = 7.4 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.24 - 7.16 (m, 3H), 2.81 (dt,J = 17.4, 9.0 Hz, 2H), 2.61 (d, J = 16.3 Hz, 1H), 2.49 (d, J = 16.3 Hz, 1H), 2.01 - 1.93 (m, 2H), 1.38 (s, 3H).

[0141] 13 C NMR (100 MHz, CDCl3) δ 171.0, 148.5, 144.2, 142.4, 140.1, 132.5,129.1, 128.6, 128.5, 128.2, 127.7, 127.3, 127.0, 126.0, 57.2, 43.8, 40.8,30.7, 25.7.

[0142] HRMS (ESI) calculated for C 23 H22 N2O [(M+H + )]: 391.1781, found: 391.1789.

[0143] While embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations fall within the scope and spirit of the invention as set forth in the claims. Furthermore, the invention described herein may have other embodiments and can be implemented or carried out in various ways.

Claims

1. A method for constructing a substituted pyrimidinone skeleton by reacting a gem-difluoro allene with a formamidine hydrochloride compound, characterized in that, The method comprises the following steps: The substituted pyrimidinone compound is obtained by mixing the gem-difluoro allene, the benzamidine hydrochloride compound, the base and the solvent, heating the mixture, and post-treating the reaction product.

2. The method of claim 1, wherein, The gem-difluoro allene has the following structure shown in formula (I): ； wherein R 1 is one of hydrogen or methyl; R 2 includes one of methyl, bromo, methoxy, trifluoromethyl, ester, or a five-membered heteroaryl group.

3. The method of claim 1, wherein, The reaction equation of the heating reaction of the gem-difluoro allene and the benzamidine hydrochloride compound is shown in formula (II): ； Among them, R 1 It is either hydrogen or methyl; R 2 With R 3 It independently includes one of methyl, bromine, methoxy, trifluoromethyl, ester or five-membered heteroaryl.

4. The method of claim 1, wherein, The base is an organic base, and the organic base includes one of sodium phenolate and 1,4-diazabicyclo[2.2.2]octane.

5. The method of claim 1, wherein, The solvent includes one of 1,4-dioxane and tetrahydrofuran.

6. The method of claim 1, wherein, The reaction temperature of the heating reaction is 100-150 DEG C, and / or the reaction time of the heating reaction is 12-48 hours.

7. The method of claim 1, wherein, The molar feeding ratio of the gem-difluoro allene, the benzamidine hydrochloride compound and the base is 1:(2.0-3.0):(4.0-6.0).

8. The method of claim 1, wherein, The post-treatment includes cooling the reaction liquid obtained after the heating reaction, performing solid-liquid separation, washing, evaporating and concentrating to obtain a crude product, and purifying the crude product by column chromatography to obtain the substituted pyrimidinone compound.

9. The method of claim 8, wherein, The solid-liquid separation includes rapid separation and filtration by using a silica gel column; and / or the washing liquid used in the washing includes ethyl acetate; and / or the eluent used in the column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (1:1)-(5:1).

Images