CN108623586A - A kind of synthetic method of imidazo nitrogen-containing hetero cyclics and application - Google Patents

Abstract

The invention relates to the field of organic synthesis. The invention discloses a synthesis method of an imidazolonitrogen-containing heterocyclic compound, which comprises the following steps: in the presence of an inert solvent, a compound of formula (I), a compound of formula (II) and a compound of formula ( Ⅲ-1) compound reacts under the effect of catalyst and oxidizing agent, obtains formula (Ⅳ-1) compound, or, in the presence of inert solvent, formula (I) compound, formula (II) compound and formula (Ⅲ-1) compound 2) The compound is reacted under the action of a catalyst and an oxidizing agent to obtain a compound of formula (IV-2). This method uses a multi-component reaction strategy to efficiently and orderly synthesize multifunctional molecules from simple substrates, which solves the technical problem of orderly and efficient synthesis in multi-component reactions that is difficult to control in the prior art. A variety of imidazoheterocyclic molecules with potential biological activity obtained through the above synthesis method, and the imidazonitrogen-containing heterocyclic compounds can be widely used in the fields of medicine and materials.

Description

A kind of synthetic method and application of imidazo nitrogen-containing heterocyclic compound

technical field

The invention relates to the technical field of organic synthesis, in particular to a synthesis method and application of an imidazolonitrogen-containing heterocyclic compound.

Background technique

Pyridimidazoles are a class of pharmaceutically active groups that are widely present in natural active molecules. As a basic active molecular fragment with important pharmacologically active molecules, imidazo[1,2-a]pyridine plays an important role in many antioxidant drugs. For example, the psychiatric drug Alpidem, whose main component is 6-chloro-2-(4-chlorophenyl)-N,N-dipropylimidazo[1,2-a]pyridine-3-acetamide, can be used For the treatment of central nervous system diseases, it is an imidazopyridine derivative. Its anxiolytic effect is better than that of the traditional drug buspirone, comparable to that of benzodiazepines, and it is better tolerated and does not cause dependence sex. Necopidem, an important class of imidazopyridine derivatives, is related to the better known drug zolpidem and opioids, and is structurally similar to other non-benzodiazepine hypnotics and thus has sedative and anti-inflammatory properties. Anxiety role; Saripidem, widely used in sedative and anxiolytic drugs, is related to zolpidem and traditional opioid sedatives, and it has pharmacological profiles similar to benzodiazepines, including sedative and Anxiolytic properties, but its chemical structure is completely different from benzodiazepines, and thalidomide, as a non-benzodiazepine, produces sedative and anxiolytic effects through modulation of GABA receptors However, unlike other traditional drug molecules, thalidomide is a highly isoform-selective drug molecule that mainly binds to the ω1 isoform.

The traditional methods for constructing imidazo[1,2-a]pyridine molecular skeletons include: 1) condensation reaction of α-halogenated carbonyl compounds; 2) cross-coupling reaction of pyridine and imine derivatives. As a means of rapidly constructing such compounds, these methods still have some shortcomings, such as the narrow range of substrates and the pre-preparation of initial substrates. Therefore, starting from simple and easy-to-obtain raw materials, a direct and universal method is developed to construct imidazoles. [1,2-a]pyridine skeletons are still highly anticipated.

In this context, in 2010, Professor Vladimir Gevorgyan developed a universal and efficient copper-catalyzed 2-aminopyridine, alkyne, and aldehyde one-pot method for the construction of pyridimidazole derivatives. This method also achieved the high efficiency of drugs such as Alpidem Synthesis; In 2011, Zhu and Zhang's research group realized the copper-catalyzed intramolecular amine oxidation reaction of alkenes, and realized carbonyl-substituted pyridimidazole heterocyclic derivatives. This method has also been proved to be efficient in the synthesis of bioactive pyridimidazole molecules ; In 2012, Lei's research group reported the oxidative cross-coupling and cyclization reaction of the final alkyne and 2-aminopyridine promoted by stoichiometric silver salts to construct pyridimidazole molecules. Although predecessors have made some progress in the rapid synthesis of pyridoimidazole derivatives, we believe that the development is catalyzed by cheap metals, oxygen is involved as a green oxidant, and multi-component reactions using cheap and readily available starting materials are used to construct imidazoles. And the synthesis method of nitrogen-containing heterocyclic compounds is still very valuable.

Sequential and selective assembly of target molecules enables rapid access to complex scaffolds, which can be applied in pharmaceutical and materials science. In this context, the development of multicomponent reactions (MCRs) provides a facile approach for constructing multifunctional modules as well as complex natural products in a single reaction. By rapidly increasing molecular complexity, MCRs can provide a convenient method for studying the relationship between structure and reactivity. Nevertheless, the rational design of tandem reactions that transform readily available substrates into complex structures remains a formidable challenge

The selective oxidation of organic molecules to prepare valuable molecular frameworks is a convenient strategy in both experiments and industry. Utilizing the oxidative cascade reaction of metal catalysts and oxidants enables the formation of multiple bond combinations in a single operation, while also meeting the requirements of green and sustainable chemistry. However, for the overall efficiency, the large-scale use of oxidants will cause environmental pollution, and the yield in industrial production is often unsatisfactory; while molecular oxygen is a green, abundant and sustainable oxidant, molecular oxygen as an oxidant can solve above question. Therefore, we believe that an oxidative cascade reaction combined with molecular oxygen activation to produce valuable complex-structured products is a better approach.

Contents of the invention

The technical problem solved by the present invention is to provide a synthesis method of imidazolonitrogen-containing heterocyclic compounds, which can efficiently and orderly synthesize imidazolonitrogen-containing heterocyclic compounds from simple substrates.

In view of this, the application provides a kind of synthetic method of imidazo nitrogen-containing heterocyclic compound, comprising the following steps:

In an inert solvent, the compound of formula (I), the compound of formula (II) and the compound of formula (III-1) are reacted under the action of catalyst and oxidant to obtain the compound of formula (IV-1);

Or, in an inert solvent, the compound of formula (I), the compound of formula (II) and the compound of formula (III-2) are reacted under the action of catalyst and oxidant to obtain the compound of formula (IV-2);

The catalyst is a copper salt;

Wherein, R is selected from substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl ^;

R ² is selected from unsaturated substituted or unsubstituted hydrocarbon groups;

X and Y are independently selected from N, O, S or C;

^R3 is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, substituted or unsubstituted C5-C20 heterocycle A group, a substituted or unsubstituted C6-C30 aryl group or ^R3 can form a ring with its adjacent or next-adjacent group;

n is 1 or 2.

Preferably, the catalyst is selected from copper acetate, copper trifluoromethanesulfonate, cuprous halide or copper halide.

Preferably, the oxidizing agent is selected from one or more of air, oxygen, tetramethylpiperidine nitrogen oxide and tert-butyl peroxide.

Preferably, the raw materials for the reaction further include additives, and the additives are selected from one or more of silver acetate, silver carbonate, silver nitrate, sodium acetate, lithium carbonate, potassium carbonate, cesium carbonate and potassium acetate.

Preferably, the inert solvent is selected from toluene, tetrahydrofuran, 1,4-dioxane, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, One or more of dimethylsulfoxide, acetonitrile and 1,2-dichloroethane.

Preferably, the molar ratio of the compound of the formula (I) to the compound of the formula (II) is 3:1 to 1:3, the compound of the formula (II) and the compound of the formula (III-1) or the compound of the formula (III-2) The molar ratio is 3:1～1:3.

Preferably, the catalyst is used in an amount of 1 mol% to 50 mol% of the compound of formula (I).

Preferably, the temperature of the reaction is 60-120° C., and the reaction time is 6-24 hours.

The application also provides the application of the imidazo nitrogen-containing heterocyclic compounds synthesized by the synthesis method in the preparation of medicines.

The application provides a synthetic method of imidazo and nitrogen-containing heterocyclic compounds, which reacts the compound of formula (I), the compound of formula (II) and the compound of formula (III-1) under the action of catalyst and metal compound oxidant, Obtained imidazo and nitrogen-containing heterocyclic compounds, or, in an inert solvent, the compound of formula (I), the compound of formula (II) and the compound of formula (III-2) are reacted under the effect of catalyst and oxidizing agent, obtain formula ( Ⅳ-2) compound; in the reaction process, the addition of catalyst has greatly promoted the nucleophilic substitution reaction of formula (Ⅲ-1) compound or formula (Ⅲ-2) compound and formula (Ⅱ) compound, obtained intermediate secondary amine; and the catalyst and the oxidizing agent jointly promote the addition of the compound of formula (I) and the above-mentioned intermediate secondary amine, and further oxidize the cyclization, and oxidize into a cyclization product, thus obtaining the imidazole and nitrogen-containing heterocyclic compound . The above method uses a multi-component reaction strategy to efficiently and orderly synthesize multifunctional molecules from simple substrates.

Description of drawings

Fig. 1 is the nuclear magnetic resonance ¹ of 3-(4-bromobenzoyl)-2-(thienyl)imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester (4a) prepared in Example 1 of the present invention H spectrum;

Fig. 2 is the NMR of 3-(4-bromobenzoyl)-2-(thienyl)imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester (4a) prepared in Example 1 of the present invention ^13C spectrum;

Figure 3 is the nuclear magnetic resonance ¹ H spectrum of (E)-phenyl(2-styrylimidazo[1,2-a]pyridine)-3-methylketone (4b) prepared in Example 2 of the present invention;

Figure 4 is the nuclear magnetic resonance ¹³ C spectrum of (E)-phenyl(2-styrylimidazo[1,2-a]pyridine)-3-methylketone (4b) prepared in Example 2 of the present invention;

Figure 5 is the nuclear magnetic resonance ¹ H spectrum of 1-(2-phenylimidazo[1,2-a]pyridyl)-3-pentanone (4c) prepared in Example 3 of the present invention;

Figure 6 is the nuclear magnetic resonance ¹³ C spectrum of 1-(2-phenylimidazo[1,2-a]pyridyl)-3-pentanone (4c) prepared in Example 3 of the present invention;

Figure 7 shows (2-(4-methoxyphenyl)benzo[d]imidazo[2,1-b]thiazol-3-yl)(phenyl)methanone (4g) prepared in Example 4 of the present invention ) nuclear magnetic resonance ¹ H spectrogram;

Figure 8 is (2-(4-methoxyphenyl)benzo[d]imidazo[2,1-b]thiazol-3-yl)(phenyl)methanone (4g) prepared in Example 4 of the present invention ) nuclear magnetic resonance ¹³ C spectrum;

Figure 9 is the NMR ¹ of (6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)(phenyl)methanone (4h) prepared in Example 5 of the present invention H spectrum;

Figure 10 is the NMR ¹³ of (6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)(phenyl)methanone (4h) prepared in Example 5 of the present invention C spectrum;

Figure 11 is (6-chloro-2-(4-methoxyphenyl)imidazo[1,2-b]pyridazin-3-yl)(phenyl)methanone (4i) prepared in Example 6 of the present invention ) nuclear magnetic resonance ¹³ C spectrum;

Figure 12 is (6-chloro-2-(4-methoxyphenyl)imidazo[1,2-b]pyridazin-3-yl)(phenyl)methanone (4i) prepared in Example 6 of the present invention ) nuclear magnetic resonance ¹³ C spectrum;

Figure 13 is (5-chloro-2-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-3-yl)(phenyl)methanone (4j) prepared in Example 7 of the present invention The nuclear magnetic resonance ¹³ C spectrogram;

Figure 14 is (5-chloro-2-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-3-yl)(phenyl)methanone (4j) prepared in Example 7 of the present invention NMR ¹³ C spectrum.

Detailed ways

In order to further understand the present invention, the preferred embodiments of the present invention are described below in conjunction with examples, but it should be understood that these descriptions are only to further illustrate the features and advantages of the present invention, rather than limiting the claims of the present invention.

Aiming at the preparation method of imidazolonitrogen-containing heterocyclic compounds in the prior art, the present invention discloses a preparation method of imidazolonitrogen-containing heterocyclic compounds. Under the action of the reaction, the imidazole and nitrogen-containing heterocyclic compounds were obtained efficiently and orderly. Specifically, the synthesis method of imidazo nitrogen-containing heterocyclic compounds described in the present application comprises the following steps:

In an inert solvent, the compound of formula (I), the compound of formula (II) and the compound of formula (III-1) are reacted under the action of catalyst and oxidant to obtain the compound of formula (IV-1);

Or, in an inert solvent, the compound of formula (I), the compound of formula (II) and the compound of formula (III-2) are reacted under the action of catalyst and oxidant to obtain the compound of formula (IV-2);

The catalyst is a copper salt;

Wherein, R is selected from substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl ^;

R ² is selected from unsaturated substituted or unsubstituted hydrocarbon groups;

X and Y are independently selected from N, O, S or C.

^R3 is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, substituted or unsubstituted C5-C20 heterocycle A group, a substituted or unsubstituted C6-C30 aryl group or ^R3 can form a ring with its adjacent or next-adjacent group;

n is 1 or 2.

In the above-mentioned process of preparing imidazolonitrogen-containing heterocyclic compounds, the raw materials involved include compounds of formula (I), compounds of formula (II) and compounds of formula (III-1) or formula (III-2), and the above-mentioned compounds are actually It corresponds to terminal alkyne, benzyl bromide and 2-aminopyridine in turn, and the structural formula of the imidazo nitrogen-containing heterocyclic compound is shown in formula (IV-1) or (IV-2).

For R ¹ is selected from substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl; heterohydrocarbyl can contain elements such as N, O, S, hydrocarbyl or heterohydrocarbyl can be replaced by halogen, ester group, carbonyl, amino, nitro , cyano, sulfone, acyl and other groups to replace. In a specific embodiment, the hydrocarbon group may specifically be a substituted or unsubstituted C1-C20 hydrocarbon group, or a substituted or unsubstituted C1-C20 heterohydrocarbyl group.

^R2 is selected from unsaturated substituted or unsubstituted hydrocarbon groups, such as alkenyl, alkynyl, phenyl or substituted phenyl.

More specifically, the compound of formula (I) is phenylacetylene, phenylacetylene with substituents on the benzene ring, heterocyclic acetylene or long-chain aliphatic terminal alkyne.

The compound of formula (II) is in particular benzyl bromide, substituted benzyl bromide, allyl bromide, substituted allyl bromide, propargyl bromide or substituted propargyl bromide.

In the above-mentioned methods disclosed in the present application, as long as the raw materials for the reaction are similar to the above-mentioned structural formulas but have different substituents, the above-mentioned methods can be used.

In the process of preparing imidazolonitrogen-containing heterocyclic compounds, the catalyst is a transition metal salt, specifically, the catalyst is selected from lithium carbonate, copper acetate, copper trifluoromethanesulfonate, cuprous halide or halide Copper, more specifically, the catalyst is selected from lithium carbonate and copper trifluoromethanesulfonate.

The oxidant is selected from one or more of air, oxygen, tetramethylpiperidine nitroxide and tert-butyl peroxide, more specifically, the oxidant is selected from oxygen and tetramethylpiperidine nitroxide things.

In the present application, the molar ratio of the compound of the formula (I) to the compound of the formula (II) is 3:1～1:3, and the molar ratio of the compound of the formula (II) to the compound of the formula (III-1) is 3:1～1:3. 1:3, the molar ratio of the compound of formula (II) to the compound of formula (III-2) is 3:1 to 1:3; as a preferred option, the molar ratio of the compound of formula (I) to the compound of formula (II) is 1:1.2, the molar ratio of formula (II) compound and formula (III-1) compound is 1:1, the molar ratio of formula (II) compound and formula (III-2) compound is 1:1; If formula (Ⅰ ) when the relative proportion of the compound is high, the terminal alkyne of the excess compound of formula (I) competes with the catalyst for coordination, Galser coupling occurs, and the conjugated diyne by-product is mainly produced, and the reaction yield decreases. The dosage of the catalyst is 1mol%-50mol% of the compound of formula (I).

In the present application, the inert solvent is an inert solvent well known to those skilled in the art, and there is no particular limitation in this application. In a specific embodiment, the inert solvent is selected from toluene, tetrahydrofuran, 1,4-diox One of hexacyclic, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile and 1,2-dichloroethane or more.

The temperature of the reaction is 60-120° C., and the time is 6-24 hours; in a specific embodiment, the temperature of the reaction is 100° C., and the time of the reaction is 10 hours. Also comprise additive in the raw material of reaction, described additive is selected from one or more in silver acetate, silver carbonate, silver nitrate, sodium acetate, lithium carbonate, potassium carbonate, cesium carbonate and potassium acetate; , the additive is selected from lithium carbonate. The additive further promotes the reaction, and promotes the nucleophilic substitution reaction between the compound of formula (III-1) or the compound of formula (III-2) and the compound of formula (II).

According to the present invention, after the reaction is completed, the following steps are further included: cooling to room temperature after the reaction, suction filtration through diatomaceous earth, and concentration to obtain a crude product; the crude product is subjected to chromatographic separation on a silica gel plate to obtain the product.

The present application also provides the application of the imidazo nitrogen-containing heterocyclic compounds prepared above in the preparation of medicines.

The present application uses cheap metal copper salt as a catalyst, and 2-aminopyridine, terminal alkyne, benzyl bromide or allyl bromide participates in the oxidation cascade reaction to obtain multi-substituted imidazolonitrogen-containing heterocyclic compounds. Oxygen, which is the sole source of the carbonyl's oxygen atom, also participates in this catalytic reaction. This method has a wide range of substrates and good functional group compatibility; another advantage of this method is that it has good universality, that is, under the action of copper salts and oxidants, pyridoimidazole, imidazole, pyrazinoimidazole, thiazolo Molecules with potential biological activity, such as imidazole and benzothiazoloimidazole, can be constructed in one step and efficiently by this method.

In order to further understand the present invention, the preparation method of the carbazole nitrogen-containing heterocyclic compound provided by the present invention will be described below in conjunction with the examples, and the protection scope of the present invention is not limited by the following examples.

Example 1 3-(4-Bromobenzoyl)-2-(thienyl)imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester (4a)

Under an atmosphere of oxygen at atmospheric pressure, (4-bromophenyl)acetylene 1a (72.4mg, 0.40mmol), 2-bromomethylthiophene 2a (35.4mg, 0.20mmol), 6-amino Ethyl pyridine-2-carboxylate 3a (33.23mg, 0.20mmol), copper trifluoromethanesulfonate (28.9mg, 0.08mmol), lithium carbonate (4.4mg, 0.06mmol), 2,2,6,6-tetra Methyl piperidine oxide (6.3mg, 0.04mmol), toluene (toluene, 1.5mL), reacted at a temperature of 80°C for 16 hours; after the reaction was completed, cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain crude Product, the crude product is separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent is a volume ratio of petroleum ether to ethyl acetate of 5:1 to obtain the product 3-(4-bromobenzoyl)- Ethyl 2-(thienyl)imidazo[1,2-a]pyridine-5-carboxylate (4a): Brown-yellow solid, yield 54% (97.8 mg). Above-mentioned reaction process is specifically:

3-(4-Bromobenzoyl)-2-(thienyl)imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester (4a) was determined by ¹ H NMR (400MHz ,CDCl ₃ )δ9.00(s,1H),8.09-8.07(m,2H),7.89-7.86(m,1H),7.72(d,J＝9.2Hz,1H),7.63-7.59(m,3H ), 7.44-7.43 (m, 1H), 7.27-7.24 (m, 1H), 4.41 (dd, J=6.8Hz, 2H), 1.40 (t, J=7.2Hz, 3H). As shown in Figure 1.

3-(4-Bromobenzoyl)-2-(thienyl)imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester (4a) was determined by carbon nuclear magnetic resonance spectrum: ¹³ C NMR (100MHz , CDCl ₃ ) δ188.2, 164.3, 144.6, 142.2, 136.0, 132.2, 131.4, 130.7, 129.1, 128.7, 128.2, 127.7, 126.7, 126.1, 123.0, 118.6, 118.3, 61.8, 14.2. as shown in picture 2.

This embodiment is well compatible with functional groups that are convenient for conversion, such as ester groups, bromine, etc.; at the same time, the reaction can also be performed efficiently for heterocyclic rings such as thiophene. convenience.

Example 2 (E)-phenyl (2-styryl imidazo [1,2-a] pyridine) -3-methyl ketone (4b)

Under an atmosphere of oxygen at atmospheric pressure, phenylacetylene 1b (22 μL, 0.20 mmol), cinnamyl bromide 2b (36.9 μL, 0.25 mmol), 2-aminopyridine 3b (28.2 mg, 0.30 mmol) were sequentially added to a 15 mL Schlenk reaction tube, Copper trifluoromethanesulfonate (18.1mg, 0.05mmol), lithium carbonate (3.0mg, 0.04mmol), 2,2,6,6-tetramethylpiperidine oxide (4.7mg, 0.03mmol), toluene (toluene , 1.5mL), reacted at a temperature of 90°C for 14 hours. After the reaction, cool to room temperature, filter through diatomaceous earth, and concentrate to obtain the crude product; the crude product is chromatographically separated on a prepared silica gel plate, and the selected developer or eluent is the volume of petroleum ether and ethyl acetate. Ratio 5:1, the product (E)-phenyl(2-styrylimidazo[1,2-a]pyridine)-3-methylketone (4b): light yellow solid, yield 67% (43.5 mg). The above reactions are specifically:

(E)-Phenyl(2-styrylimidazo[1,2-a]pyridine)-3-methylketone (4b) has the following H NMR spectrum measurement results: ¹ H NMR (400MHz, CDCl ₃ ) δ8.52(d, J=7.2Hz, 1H), 8.16(d, J=8.4Hz, 2H), 7.78-7.70(m, 3H), 7.63(d, J=8.4Hz, 2H), 7.59(d , J=7.2Hz, 2H), 7.42-7.36(m, 3H), 7.34-7.29(m, 2H), 6.98(t, J=6.8Hz, 1H). As shown in Figure 3.

(E)-Phenyl(2-styrylimidazo[1,2-a]pyridine)-3-methylketone (4b) has the following ^C13 C NMR (100MHz, CDCl ₃ ) δ189.6, 144.4, 140.3, 137.0, 136.7, 134.3, 132.8, 132.4, 131.4, 128.8, 126.8, 126.1, 125.9, 125.1, 119.6, 118.9, 116.3, 115.1, 114.2, 113.1. As shown in Figure 4.

The embodiment of the present invention can efficiently obtain pyridoimidazole derivatives with both carbonyl and alkene functional groups, which also provides opportunities for the rapid transformation of molecules with good biological activity; it also illustrates the chemoselectivity of the reaction, that is, unsaturated carbon-carbon Double bonds can be better compatible under this oxidation system.

Example 3 1-(2-phenylimidazo[1,2-a]pyridyl)-3-pentanone (4c)

Under an atmosphere of oxygen at atmospheric pressure, 1-hexyne 1c (28.7 μL, 0.25 mmol), benzyl bromide 2c (29.7 μL, 0.25 mmol), 2-aminopyridine 3b (37.6 mg, 0.40 mmol), copper trifluoromethanesulfonate (14.5mg, 0.04mmol), lithium carbonate (3.0mg, 0.04mmol), 2,2,6,6-tetramethylpiperidine oxide (4.7mg, 0.03mmol), Toluene (1 mL) was reacted at 100°C for 12 hours. After the reaction, cool to room temperature, filter through diatomaceous earth, and concentrate to obtain the crude product; the crude product is chromatographically separated on a prepared silica gel plate, and the selected developer or eluent is the volume of petroleum ether and ethyl acetate. The ratio was 5:1, and the product 1-(2-phenylimidazo[1,2-a]pyridyl)-3-pentanone (4c) was obtained: pale yellow solid, yield 33% (23.0mg). The above reactions are specifically:

1-(2-Phenylimidazo[1,2-a]pyridyl)-3-pentanone (4c) was determined by H NMR spectrum: ¹ H NMR (400MHz, CDCl ₃ ) δ9.78(d, J＝8.8Hz, 1H), 7.74(d, J＝9.2Hz, 1H), 7.59-7.57(m, 2H), 7.53-7.48(m, 4H), 7.10-7.06(m, 1H), 2.46(q ,J=7.6Hz,2H),1.53(dd,J=8.4Hz,15.2Hz,2H),1.10(dd,J=7.6Hz,14.8Hz,2H),0.73(q,J=7.2Hz,14.4Hz ,3H). As shown in Figure 5.

1-(2-Phenylimidazo[1,2-a]pyridyl)-3-pentanone (4c) was determined by C13C NMR: ¹³ C NMR (101MHz, CDCl ₃ ) δ192.8, 130.5, 129.7, 129.19, 129, 14, 129.07, 128.7, 128.4, 117.3, 114.8, 40.8, 27.3, 22.3, 13.6. As shown in Figure 6.

The embodiment of the present invention can be compatible with aliphatic alkyne in similar transformations in the past, thereby increasing the diversity of products.

Example 4 (2-(4-methoxyphenyl)benzo[d]imidazo[2,1-b]thiazol-3-yl)(phenyl)methanone (4g)

Under an atmospheric oxygen atmosphere, phenylacetylene 1b (32.9 μL, 0.3 mmol), 4-methoxybenzyl bromide 2 g (43.7 μL, 0.3 mmol), 2-aminobenzothiazole 5 g ( 60.8mg, 0.40mmol), copper trifluoromethanesulfonate (10.86mg, 0.03mmol), lithium carbonate (4.0mg, 0.06mmol), 2,2,6,6-tetramethylpiperidine oxide (4.7mg, 0.03mmol), toluene (toluene, 1mL), reacted at a temperature of 100°C for 10 hours; after the reaction was completed, cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain a crude product; the crude product was layered with a prepared silica gel plate Analysis and chromatographic separation, the selected developer or eluent is a volume ratio of petroleum ether and ethyl acetate of 5:1, to obtain (2-(4-methoxyphenyl)benzo[d]imidazo[2,1 -b] Thiazol-3-yl)(phenyl)methanone (4 g): Pale yellow solid, yield 80% (92.2 mg). The above reactions are specifically:

(2-(4-methoxyphenyl) benzo [d] imidazo [2,1-b] thiazol-3-yl) (phenyl) ketone (4g) H NMR spectrum measurement results are: ¹ H NMR (400MHz, CDCl ₃ ) δ8.16-8.14 (m, 1H), 7.77 (dd, J = 2.0Hz, 2.0Hz, 2H), 7.74-7.71 (m, 1H), 7.44-7.35 (m, 4H), 7.16-7.15(m, 3H), 7.71-7.67(m, 2H), 3.76(s, 3H). As shown in Figure 7.

(2-(4-methoxyphenyl) benzo [d] imidazo [2,1-b] thiazol-3-yl) (phenyl) ketone (4g) carbon nuclear magnetic resonance spectrum measurement results are: ¹³ C NMR (101 MHz, CDCl ₃ ) δ 185.4, 163.7, 133.6, 133.3, 130.3, 130.2, 129.4, 128.1, 128.0, 126.4, 125.3, 123.9, 116.5, 113.5, 55.4. As shown in Figure 8.

The embodiment of the present invention can efficiently obtain multifunctional benzothiazoloimidazole derivatives that have good application prospects in the fields of biomedicine and materials.

Example 5 (6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)(phenyl)methanone (4h)

Under an atmospheric pressure oxygen or air atmosphere, phenylacetylene 1b (22 μL, 0.20 mmol), 4-methoxybenzyl bromide 2 g (43.7 μL, 0.30 mmol), 2-aminothiazole 3 h (40.0 mg, 0.40mmol), copper trifluoromethanesulfonate (14.3mg, 0.04mmol), lithium carbonate (1.5mg, 0.02mmol), 2,2,6,6-tetramethylpiperidine oxide (6.3mg, 0.04 mmol), toluene (toluene, 1mL), reacted at a temperature of 120°C for 8 hours; cooled to room temperature after the reaction, filtered through diatomaceous earth, and concentrated to obtain a crude product; the crude product was chromatographed on a prepared silica gel plate Chromatographic separation, the selected developer or eluent is the volume ratio of petroleum ether to ethyl acetate 5:1, to obtain the product (6-(4-methoxyphenyl)imidazo[2,1-b]thiazole- 5-yl)(phenyl)methanone (4h): white solid, yield 82% (54.8mg). The above reactions are specifically:

(6-(4-Methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)(phenyl)methanone (4h) has the following H NMR spectrum measurement results: ¹ H NMR (400MHz , CDCl ₃ ) δ8.18(d, J=8.8Hz, 2H), 7.59(d, J=7.6Hz, 2H), 7.48-7.47(m, 2H), 7.45-7.41(m, 2H), 6.97( d, J=4.8Hz, 1H), 6.92(d, J=8.8Hz, 2H), 3.86(s, 3H). As shown in Figure 9.

(6-(4-Methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)(phenyl)methanone (4h) was determined by C13 NMR: ¹³ C NMR (101MHz , CDCl ₃ ) δ187.7, 163.1, 132.9, 130.8, 129.4, 129.0, 128.7, 117.5, 115.3, 113.3, 55.4. As shown in Figure 10.

The embodiment of the present invention can efficiently generate thiazoloimidazole derivatives with potential biological activity.

Example 6 (6-chloro-2-(4-methoxyphenyl)imidazo[1,2-b]pyridazin-3-yl)(phenyl)methanone (4i)

Under an atmospheric pressure oxygen or air atmosphere, add phenylacetylene 1b (22μL, 0.20mmol), 4-methoxybenzyl bromide 2g (87.2μL, 0.40mmol), 6-chloropyridazine-3 - Amine 3i (77.7mg, 0.60mmol), copper trifluoromethanesulfonate (21.5mg, 0.06mmol), lithium carbonate (3.2mg, 0.04mmol), 2,2,6,6-tetramethylpiperidine oxide (9.5mg, 0.06mmol), toluene (toluene, 1mL), reacted at a temperature of 80°C for 16 hours; after the reaction was completed, cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain a crude product; the crude product was prepared with Silica gel plate for chromatographic separation, the selected developer or eluent is the volume ratio of petroleum ether and ethyl acetate 5:1, to obtain the product (6-chloro-2-(4-methoxyphenyl) imidazo [1,2-b]pyridazin-3-yl)(phenyl)methanone (4i): yellow solid, yield 79% (57.5 mg). The above reaction is specifically as follows:

(6-Chloro-2-(4-methoxyphenyl)imidazo[1,2-b]pyridazin-3-yl)(phenyl)methanone (4i) The proton nuclear magnetic resonance spectrum measurement result is: ¹ H NMR (400MHz, CDCl ₃ ) δ8.05-8.03(m, 2H), 7.80(d, J=15.6Hz, 1H), 7.65-7.62(m, 2H), 7.54(d, J=15.6Hz, 1H), 7.42-7.40(m, 3H), 7.00-6.97(m, 2H), 3.87(s, 3H). As shown in Figure 11.

(6-Chloro-2-(4-methoxyphenyl)imidazo[1,2-b]pyridazin-3-yl)(phenyl)methanone (4i) has a carbon nuclear magnetic resonance spectrum measurement result: ¹³ C NMR (101MHz, CDCl ₃ ) δ188.6, 163.4, 143.9, 135.0, 131.0, 130.8, 130.3, 128.9, 128.3, 121.8, 113.8, 55.4 are shown in Figure 12 .

The embodiments of the present invention can efficiently obtain pyridazinoimidazole skeletons with potential biological activity, and the reaction is compatible with halogen functional groups, which provides convenience for subsequent transformations, such as various coupling reactions, so as to obtain more functionalized derivatives.

Example 7 (5-chloro-2-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-3-yl)(phenyl)methanone (4j)

Under an atmosphere of oxygen at atmospheric pressure, add phenylacetylene 1b (44μL, 0.40mmol), 4-methoxybenzyl bromide 2g (43.7μL, 0.30mmol), 2-chloropyrimidin-4-amine 3j to a 15mL Schlenk reaction tube in sequence (51.8mg, 0.40mmol), copper trifluoromethanesulfonate (28.9mg, 0.08mmol), lithium carbonate (3.1mg, 0.04mmol), 2,2,6,6-tetramethylpiperidine oxide (12.7mg ,0.08mmol), toluene (toluene, 1mL), reacted at a temperature of 120°C for 8 hours; after the reaction was completed, cooled to room temperature, filtered through diatomaceous earth, and concentrated to obtain the crude product; the crude product was carried out on the prepared silica gel plate Chromatographic separation, the selected developer or eluent is a volume ratio of petroleum ether to ethyl acetate of 5:1 to obtain the product (5-chloro-2-(4-methoxyphenyl)imidazo[1, 2-c]pyrimidin-3-yl)(phenyl)methanone (4j): white solid, yield 76% (110.6 mg). The above reaction is specifically as follows:

(5-Chloro-2-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-3-yl)(phenyl)methanone (4j) H NMR determination results are: ¹ H NMR (400MHz, CDCl ₃ ) δ8.04(dd, J=2.0Hz, 2.0Hz, 2H), 7.79(d, J=16.0Hz, 1H), 7.65-7.62(m, 2H), 7.54(d, J=15.6Hz, 1H), 7.43-7.40(m, 3H), 7.00-6.96(m, 2H), 3.87(s, 3H). As shown in Figure 13.

(5-Chloro-2-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-3-yl)(phenyl)methanone (4j) was determined by carbon NMR spectrum: ¹³ C NMR (101 MHz, CDCl ₃ ) δ 188.6, 163.4, 143.9, 135.0, 131.0, 130.7, 130.2, 128.8, 128.3, 121.8, 113.8, 55.4. As shown in Figure 14.

The descriptions of the above embodiments are only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

The above description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the present invention will not be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (9)

1. a synthetic method of imidazo nitrogen-containing heterocyclic compounds, comprising the following steps: In an inert solvent, the compound of formula (I), the compound of formula (II) and the compound of formula (III-1) are reacted under the action of catalyst and oxidant to obtain the compound of formula (IV-1); Or, in an inert solvent, the compound of formula (I), the compound of formula (II) and the compound of formula (III-2) are reacted under the action of catalyst and oxidant to obtain the compound of formula (IV-2); The catalyst is a copper salt; Wherein, R is selected from substituted or unsubstituted hydrocarbyl, substituted or unsubstituted heterohydrocarbyl ^; R ² is selected from unsaturated substituted or unsubstituted hydrocarbon groups; X and Y are independently selected from N, O, S or C; ^R3 is selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 heteroalkyl, substituted or unsubstituted C5-C20 heterocycle A group, a substituted or unsubstituted C6-C30 aryl group or ^R3 can form a ring with its adjacent or next-adjacent group; n is 1 or 2. 2. The synthetic method according to claim 1, wherein the catalyst is selected from copper acetate, copper trifluoromethanesulfonate, cuprous halide or copper halide. 3. synthetic method according to claim 1, is characterized in that, described oxygenant is selected from one or more in air, oxygen, tetramethylpiperidine nitrogen oxide and tert-butyl peroxide. 4. synthetic method according to claim 1, is characterized in that, the raw material of described reaction also comprises additive, and described additive is selected from silver acetate, silver carbonate, silver nitrate, sodium acetate, lithium carbonate, salt of wormwood, cesium carbonate and one or more of potassium acetate. 5. The synthetic method according to claim 1, wherein the inert solvent is selected from toluene, THF, 1,4-dioxane, N,N'-dimethylformamide, N,N' - one or more of dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile and 1,2-dichloroethane. 6. The synthetic method according to claim 1, characterized in that, the molar ratio of the compound of formula (I) to the compound of formula (II) is 3:1～1:3, the compound of formula (II) and the compound of formula (III -1) The compound or the compound of formula (III-2) has a molar ratio of 3:1 to 1:3. 7. The synthesis method according to claim 1, characterized in that, the amount of the catalyst is 1mol% to 50mol% of the compound of formula (I). 8. The synthesis method according to claim 1, characterized in that the temperature of the reaction is 60-120° C., and the time is 6-24 hours. 9. The application of the imidazolonitrogen-containing heterocyclic compounds synthesized by the synthesis method described in any one of claims 1 to 8 in the preparation of medicines.