Method for synthesizing nitrogen ortho-substituted aryl ether containing nitrogen heterocyclic ring

Abstract

The invention belongs to the technical field of synthesis and application of new compounds, and discloses a synthesis method of nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether, which is characterized in that under the catalysis of hexamethylphosphoramide HMPA, N, N-diisopropylethylamine DIEA is used as alkali, under the assistance of POBr3, nitrogen oxide and phenol react to realize nitrogen ortho-aryloxy substitution. The method has the advantages of excellent atom economy (3a, 96%), green solvent (ethyl acetate is used as the solvent), mild reaction conditions, short reaction time (the reaction time of most substrates is 5 minutes), wide substrate range, cheap and easily available reaction substrates and the like. The method provides a convenient, efficient, green and practical method for synthesizing 1-aryloxy isoquinoline, 2-aryloxy quinoline and 2-aryloxy pyridine compounds.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis and application of new compounds, and in particular relates to a method for synthesizing an aryl ether with a nitrogen heterocycle nitrogen ortho-substitution. Background Art

[0002] Due to their unique chemical stability and functionality, aryl ethers have extremely wide applications in the fields of natural products, agrochemistry, bioactive compounds, pharmaceutical synthesis, and optoelectronic materials, and are important structural units indispensable in modern chemistry and materials science. For example, 1-aryloxyisoquinolines are widely used in the synthesis of pharmaceutical intermediates, including 6-bromo-1-phenoxyisoquinoline, 7-bromo-1-phenoxyisoquinoline, 7-methyl-1-phenoxyisoquinoline, etc.; compounds such as 1-phenoxyisoquinoline and 2-phenoxyquinoline have certain anti-tumor activities; 1-aryloxyisoquinolines and 2-aryloxypyridines are also important intermediates in some optoelectronic materials.

[0003] One of the traditional methods for synthesizing aryl ethers with a nitrogen heterocycle nitrogen ortho-substitution is to use transition metal-catalyzed nucleophilic substitution reactions of heterocyclic halides and phenols to form 1-aryloxy substitution products, which generally require harsh reaction conditions. Another method is to use readily available nitrogen heterocycle N-oxides as raw materials and phenol for nucleophilic substitution reactions. However, this method uses excessive activators and expensive or toxic reagents, thus limiting the application of this method. Currently, there is no economical, green, and mild-condition method for synthesizing aryl ethers with a nitrogen heterocycle nitrogen ortho-substitution.

[0004]

[0005] For the above reasons, a practical, rapid, and green synthesis method for aryl ethers with a nitrogen heterocycle nitrogen ortho-substitution is needed. The present invention designs a rapid and green reaction for synthesizing aryl ethers with a nitrogen heterocycle nitrogen ortho-substitution. The synthesis method of the present invention uses nitrogen heterocycle N-oxides and phenol derivatives as reaction substrates, and under the combined action of a catalytic amount of hexamethylphosphoramide (HMPA) and phosphorus oxychloride tribromide, an active phosphonium salt intermediate is in-situ generated as an efficient activator to promote the smooth progress of the reaction. This method has the advantages of mild reaction conditions, in-situ generation of the activator, and high catalytic efficiency. Summary of the Invention

[0006] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for synthesizing an aryl ether with a nitrogen heterocycle nitrogen ortho-substitution.

[0007] The technical solution adopted by the present invention to solve its technical problems is:

[0008] A method for synthesizing an aryl ether with a nitrogen heterocycle nitrogen ortho-substituted group. In this method, under the catalysis of hexamethylphosphoric triamide (HMPA), N,N-diisopropylethylamine (DIEA) is used as a base, and with the assistance of POBr 3 , a reaction is carried out between a nitrogen oxide and a phenol to achieve nitrogen ortho-aryloxy substitution.

[0009] Furthermore, the aryl ether with a nitrogen heterocycle nitrogen ortho-substituted group is an aryl heteroaryl ether, and its synthetic route is as follows:

[0010]

[0011] Using a nitrogen heterocyclic compound nitrogen oxide 1 as a raw material, ethyl acetate (EA) as a solvent, N,N-diisopropylethylamine (DIEA) as a base, hexamethylphosphoric triamide (HMPA) as a catalyst, and POBr 3 as an adjuvant, reacting with a phenol to obtain compound 3;

[0012] Among them, R 1 is an alkyl group C1-C6, a halogen group, an ester group C1-C6, a phenyl group, or a phenylacetylene group with one or two substitutions at the 3, 4, 5, 6, 7, and 8 positions on the aromatic ring; R 2 is an alkyl group C1-C6, an alkenyl group C1-C6, a cyano group, an alkoxy group C1-C6, a halogen group, or an ester group with one or two substitutions at the ortho, meta, or para positions on phenol; including pterostilbene.

[0013] Furthermore, the aryl ether with a nitrogen heterocycle nitrogen ortho-substituted group is a compound with antitumor activity, 1-phenoxyisoquinoline, and its synthetic route is as follows:

[0014]

[0015] Using isoquinoline-N-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr 3 as an adjuvant, reacting with phenol to obtain 1-phenoxyisoquinoline.

[0016] Furthermore, the method for synthesizing a pharmaceutical intermediate, 6-bromo-1-phenoxyisoquinoline, is characterized in that its synthetic route is as follows:

[0017]

[0018] Using 6-bromoisoquinoline 2-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr 3 as an adjuvant, reacting with phenol to obtain 6-bromo-1-phenoxyisoquinoline.

[0019] Further, the aryl ether with a nitrogen-containing heterocyclic nitrogen ortho-substitution is the pharmaceutical intermediate 7-bromo-1-phenoxyisoquinoline, and its synthesis route is as follows:

[0020]

[0021] Using 7-bromoisoquinoline N-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain 7-bromo-1-phenoxyisoquinoline.

[0022] Further, the aryl ether with a nitrogen-containing heterocyclic nitrogen ortho-substitution is the intermediate 7-methyl-1-phenoxyisoquinoline of the factor Xa inhibitor, and its synthesis route is as follows:

[0023]

[0024] Using 7-methylisoquinoline 2-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain 7-methyl-1-phenoxyisoquinoline.

[0025] Further, the aryl ether with a nitrogen-containing heterocyclic nitrogen ortho-substitution is the compound 2-phenoxyquinoline with antitumor activity, and its synthesis route is as follows:

[0026]

[0027] Using quinoline-N-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain 2-phenoxyquinoline.

[0028] Further, the aryl ether with a nitrogen-containing heterocyclic nitrogen ortho-substitution is the pterostilbene derivative (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline, and its synthesis route is as follows:

[0029]

[0030] Using quinoline-N-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with pterostilbene to obtain (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline.

[0031] Further, the aryl ether with a nitrogen-containing heterocyclic nitrogen ortho-substitution is the optoelectronic material intermediate 2-phenoxy-6-phenylpyridine, and its synthesis route is as follows:

[0032]

[0033] Using 2-phenylpyridine 1-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain 2-phenoxy-6-phenylpyridine.

[0034] Furthermore, the nitrogen ortho-substituted aryl ethers of the nitrogen-containing heterocycles include 1-aryloxyisoquinoline derivatives, 2-aryloxyquinoline derivatives, and 2-aryloxypyridine derivatives;

[0035] The structure of the 1-aryloxyisoquinoline derivative is shown as follows:

[0036]

[0037] The structure of the 2-aryloxyquinoline derivative is shown as follows:

[0038]

[0039] The structure of the 2-aryloxypyridine derivative is shown as follows:

[0040]

[0041] The advantages and positive effects achieved by the present invention are as follows:

[0042] 1. The present invention provides a synthetic method for synthesizing nitrogen ortho-substituted aryl ethers of nitrogen-containing heterocycles. Under the catalysis of HMPA, using DIEA as the base, and with the assistance of POBr 3 , reacting nitrogen oxides with phenol to achieve nitrogen ortho-aryloxy substitution. This method has excellent atom economy (3a, 96%), green solvent (using ethyl acetate as the solvent), mild reaction conditions, short reaction time (the reaction time of most substrates is 5 minutes), wide substrate scope, and cheap and easily available reaction substrates. This method provides a convenient, efficient, green, and practical method for synthesizing 1-aryloxyisoquinoline, 2-aryloxyquinoline, and 2-aryloxypyridine compounds.

[0043] 2. The present invention develops a concise synthetic method for nitrogen ortho-substituted aryl ethers of nitrogen-containing heterocycles, which is simple to operate, has mild conditions, and the substrates are cheap and easily available, having important economic value.

[0044] 3. The present invention has high atom economy (3a, 96%), does not require metal catalysis, recycles by-products, and has the characteristics of being green and environmentally friendly.

[0045] 4. The present invention has a wide substrate scope of application, and isoquinoline, quinoline, pyridine, etc. can all react successfully.

[0046] 5. The idea of in-situ generating the activator in the present invention is unprecedented.

[0047] 6. The present invention uses cheap and easily available HMPA as the catalyst.

[0048] 7. The present invention provides a set of general synthetic methods for the 1-aryloxylation reaction of isoquinoline derivatives for the first time. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 1H NMR spectrum of compound 3c in deuterochloroform in the present invention;

[0050] Figure 2 1H NMR spectrum of compound 3g in deuterochloroform in the present invention;

[0051] Figure 3 13C NMR spectrum of compound 3g in deuterochloroform in the present invention;

[0052] Figure 4 1H NMR spectrum of compound 3s in deuterochloroform in the present invention;

[0053] Figure 5 13C NMR spectrum of compound 3s in deuterochloroform in the present invention;

[0054] Figure 6 1H NMR spectrum of compound 5a in deuterochloroform in the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0055] The present invention will be further described below in conjunction with embodiments. The following embodiments are narrative and not restrictive, and the protection scope of the present invention cannot be limited by the following embodiments.

[0056] All kinds of experimental operations involved in the specific embodiments are conventional techniques in the art. For the parts not specifically noted in this article, those of ordinary skill in the art can refer to various commonly used reference books, scientific and technological literatures, or relevant specifications, manuals, etc. before the filing date of the present invention application for implementation.

[0057] A synthetic method of an aryl ether with a nitrogen heterocycle nitrogen ortho-substituted. The method uses N,N-diisopropylethylamine (DIEA) as the base and POBr 3 with the assistance of a nitrogen oxide and a phenol to react to achieve nitrogen ortho-aryloxy substitution.

[0058] Preferably, the aryl ether with a nitrogen heterocycle nitrogen ortho-substituted is an aryl heteroaryl ether, and its synthetic route is as follows:

[0059]

[0060] Using a nitrogen-containing heterocyclic compound N-oxide 1 as the raw material, ethyl acetate EA as the solvent, N,N-diisopropylethylamine DIEA as the base, hexamethylphosphoric triamide HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain compound 3;

[0061] Among them, R 1 is an alkyl group C1-C6, a halogen group, an ester group C1-C6, a phenyl group, or a phenylacetylene group with one or two substituents at the 3, 4, 5, 6, 7, or 8 positions on the aromatic ring; R 2 is an alkyl group C1-C6, an alkenyl group C1-C6, a cyano group, an alkoxy group C1-C6, a halogen group, or an ester group with one or two substituents at the ortho, meta, or para positions on phenol; including pterostilbene.

[0062] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle is the compound 1-phenoxyisoquinoline with antitumor activity, and its synthetic route is as follows:

[0063]

[0064] Using isoquinoline-N-oxide as the raw material, EA as the solvent, DIEA as the base, and HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain 1-phenoxyisoquinoline.

[0065] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle is a synthetic method of the pharmaceutical intermediate 6-bromo-1-phenoxyisoquinoline, and its characteristics are as follows: its synthetic route is as follows:

[0066]

[0067] Using 6-bromoisoquinoline 2-oxide as the raw material, EA as the solvent, DIEA as the base, and HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain 6-bromo-1-phenoxyisoquinoline.

[0068] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle is the pharmaceutical intermediate 7-bromo-1-phenoxyisoquinoline, and its synthetic route is as follows:

[0069]

[0070] Using 7-bromoisoquinoline N-oxide as the raw material, EA as the solvent, DIEA as the base, and HMPA as the catalyst, and POBr 3 as the adjuvant, reacting with phenol to obtain 7-bromo-1-phenoxyisoquinoline.

[0071] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle is the intermediate 7-methyl-1-phenoxyisoquinoline of the Xa factor inhibitor, and its synthesis route is as follows:

[0072]

[0073] Using 7-methylisoquinoline 2-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the auxiliary agent, reacting with phenol to obtain 7-methyl-1-phenoxyisoquinoline.

[0074] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle is the compound 2-phenoxyquinoline with antitumor activity, and its synthesis route is as follows:

[0075]

[0076] Using quinoline-N-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the auxiliary agent, reacting with phenol to obtain 2-phenoxyquinoline.

[0077] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle is the pterostilbene derivative (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline, and its synthesis route is as follows:

[0078]

[0079] Using quinoline-N-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the auxiliary agent, reacting with pterostilbene to obtain (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline.

[0080] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle is the optoelectronic material intermediate 2-phenoxy-6-phenylpyridine, and its synthesis route is as follows:

[0081]

[0082] Using 2-phenylpyridine 1-oxide as the raw material, EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr 3 as the auxiliary agent, reacting with phenol to obtain 2-phenoxy-6-phenylpyridine.

[0083] Preferably, the nitrogen ortho-substituted aryl ether of the nitrogen-containing heterocycle includes 1-aryloxyisoquinoline derivatives, 2-aryloxyquinoline derivatives, and 2-aryloxypyridine derivatives;

[0084] The structure of the 1-aryloxyisoquinoline derivative is as follows:

[0085]

[0086] The structure of the 2-aryloxyquinoline derivative is as follows:

[0087]

[0088] The structure of the 2-aryloxypyridine derivative is as follows:

[0089]

[0090] Specifically, the related preparation and detection are as follows:

[0091] Method 1: A green synthesis method of 1-aryloxyisoquinoline, the steps are as follows:

[0092] Dissolve the isoquinoline N-oxide derivative (1.0 mmol) in EA (1.0 mL) solution, then add phenol (3.0 mmol), DIEA (2.0 mmol) and HMPA (0.4 mmol), cool the resulting solution to 0 °C, and then add POBr 3 (2.0 mmol) in EA (1.0 mL) solution dropwise. Then heat the reaction mixture to room temperature and stir for 5 minutes. Quench the reaction with saturated potassium carbonate solution and separate the organic phase. Extract the aqueous phase once with ethyl acetate. Combine the organic phases, dry with anhydrous sodium sulfate and concentrate in vacuo to obtain the crude product. Use PE / EA (200:1 - 100:1, volume ratio) as the mobile phase and silica gel column chromatography to obtain the target product.

[0093] The following is specifically illustrated by examples.

[0094] Example 1

[0095]

[0096] Dissolve isoquinoline N-oxide (100 mg, 0.69 mmol) in EA (0.7 mL) solution, then add phenol (198 mg, 2.1 mmol), DIEA (181 mg, 1.4 mmol) and HMPA (50 mg, 0.28 mmol), cool the resulting solution to 0 °C, and then add POBr 3A solution of (401 mg, 1.4 mmol) in EA (0.7 mL). Then the reaction mixture was heated to room temperature and stirred for 5 minutes. The reaction was quenched with saturated potassium carbonate solution, and the organic phase was separated. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Column chromatography on silica gel using PE / EA (200:1 - 100:1, v / v) as the mobile phase gave the target product (110 mg, 72% yield). Structural parameters: 1 HNMR(600MHz,CDCl 3 ) δ 8.35 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.71 - 7.70 (m, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.22 (d, J = 6.0 Hz, 1H), 7.18 - 7.15 (m, 3H).

[0097] Example 2

[0098] Isoquinoline N - oxide (1.0 g, 6.9 mmol) was dissolved in EA (7 mL) solution, then phenol (1.95 g, 20.7 mmol), DIEA (1.78 g, 13.8 mmol) and HMPA (0.50 g, 2.8 mmol) were added. The resulting solution was cooled to 0 °C, and then a solution of POBr 3 (3.96 g, 13.8 mmol) in EA (7 mL) was added dropwise. Then the reaction mixture was heated to room temperature and stirred for 5 minutes. The reaction was quenched with saturated potassium carbonate solution, and the organic phase was separated. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. Column chromatography on silica gel using PE / EA (200:1 - 100:1, v / v) as the mobile phase gave the target product (967 mg, 63%). Structural parameters: 1 H NMR(600MHz,CDCl 3 ) δ 8.35 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.71 - 7.70 (m, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 2H), 7.22 (d, J = 6.0 Hz, 1H), 7.18 - 7.15 (m, 3H).

[0099] Example 3

[0100]

[0101] The synthesis method of Example 3 is the same as the above general method 1.

[0102] Reaction yield: 65%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.44 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.72 - 7.69 (m, 1H), 7.62 - 7.59 (m, 1H), 7.28 (d, J = 5.4 Hz, 1H), 7.25 - 7.24 (m, 2H), 7.14 - 7.13 (m, 2H), 2.38 (s, 3H).

[0103] Example 4

[0104]

[0105] The synthesis method of Example 4 is the same as the above general method 1.

[0106] Reaction yield: 43%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.44 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.47 - 7.46 (m, 2H), 7.31 (d, J = 6.0 Hz, 1H), 7.20 - 7.19 (m, 2H), 1.36 (s, 9H). The proton nuclear magnetic resonance spectrum is as Figure 1 .

[0107] Example 5

[0108]

[0109] The synthesis method of Example 5 is the same as the above general method 1.

[0110] Reaction yield: 52%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.45 (d, J = 9.6 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.80 - 7.79 (m, 1H), 7.74 - 7.71 (m, 1H), 7.64 - 7.61 (m, 1H), 7.30 (d, J = 6.6 Hz, 1H), 7.20 - 7.18 (m, 2H), 7.00 - 6.98 (m, 2H), 3.84 (s, 3H).

[0111] Example 6

[0112]

[0113] The synthesis method of Example 6 is the same as the above general method 1.

[0114] Reaction yield: 67%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.44 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.82 - 7.81 (d, J = 7.8 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.66 - 7.63 (m, 1H), 7.33 (d, J = 5.4 Hz, 1H), 7.25 - 7.22 (m, 2H), 7.16 - 7.13 (m, 2H).

[0115] Example 7

[0116]

[0117] The synthesis method of Example 7 is the same as the above general method 1.

[0118] Reaction yield: 70%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.42 (d, J = 9.6 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.65 - 7.63 (m, 1H), 7.42 - 7.41 (m, 2H), 7.34 (d, J = 6.6 Hz, 1H), 7.22 - 7.21 (m, 2H).

[0119] Example 8

[0120]

[0121] The synthesis method of Example 8 is the same as the above general method 1.

[0122] Reaction yield: 45%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.42 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.82 - 7.81 (m, 1H), 7.76 - 7.73 (m, 1H), 7.65 - 7.63 (m, 1H), 7.57 - 7.56 (m, 2H), 7.34 (d, J = 6.6 Hz, 1H), 7.17 - 7.16 (m, 2H). The proton nuclear magnetic resonance spectrum is as Figure 2, the carbon-13 NMR spectrum is as follows Figure 3 .

[0123] Example 9

[0124]

[0125] The synthesis method of Example 9 is the same as the above general method 1.

[0126] Reaction yield: 45%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.38 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.85 - 7.84 (m, 1H), 7.78 - 7.75 (m, 1H), 7.74 - 7.73 (m, 2H), 7.67 - 7.65 (m, 1H), 7.41 (d, J = 6.0 Hz, 1H), 7.39 - 7.38 (m, 2H).

[0127] Example 10

[0128]

[0129] The synthesis method of Example 10 is the same as the above general method 1.

[0130] Reaction yield: 40%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.41 (d, J = 7.8 Hz, 1H), 8.15 - 8.14 (m, 2H), 7.99 (d, J = 6.0 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.76 - 7.74 (m, 1H), 7.66 - 7.63 (m, 1H), 7.38 (d, J = 5.4 Hz, 1H), 7.34 - 7.32 (m, 2H), 3.93 (s, 3H).

[0131] Example 11

[0132]

[0133] The synthesis method of Example 11 is the same as the above general method 1.

[0134] Reaction yield: 46%; Structural parameters: 1 H NMR (600 MHz, CDCl 3)δ 8.51 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.83 - 7.82 (m, 1H), 7.77 - 7.74 (m, 1H), 7.70 - 7.66 (m, 2H), 7.44 - 7.41 (m, 1H), 7.36 - 7.34 (m, 2H), 7.18 - 7.15 (m, 1H).

[0135] Example 12

[0136]

[0137] The synthesis method of Example 12 is the same as the above general method 1.

[0138] Reaction yield: 43%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 )δ 8.51 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 5.4 Hz, 1H), 7.83 - 7.82 (m, 1H), 7.77 - 7.74 (m, 1H), 7.70 - 7.66 (m, 2H), 7.44 - 7.41 (m, 1H), 7.36 - 7.34 (m, 2H), 7.18 - 7.15 (m, 1H).

[0139] Example 13

[0140]

[0141] The synthesis method of Example 13 is the same as the above general method 1.

[0142] Reaction yield: 57%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 )δ 8.53 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 6.0 Hz, 1H), 7.83 - 7.81 (m, 1H), 7.76 - 7.74 (m, 1H), 7.67 - 7.64 (m, 1H), 7.28 (d, J = 6.6 Hz, 1H), 7.12 - 7.15 (m, 2H), 7.13 - 7.11 (m, 1H), 2.15 (s, 6H).

[0143] Example 14

[0144]

[0145] The synthesis method of Example 14 is the same as the above general method 1.

[0146] Reaction yield: 45%; Structural parameters: 1 H NMR (600 MHz, CDCl3 ) δ 8.64 (d, J = 9.6 Hz, 1H), 7.97 (d, J = 9.8 Hz, 1H), 7.93 - 7.91 (m, 2H), 7.87 - 7.85 (m, 1H), 7.80 - 7.77 (m, 2H), 7.72 - 7.69 (m, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.44 - 7.40 (m, 2H), 7.34 (d, J = 6.6 Hz, 1H).

[0147] Example 15

[0148]

[0149] The synthesis method of Example 15 is the same as the above general method 1.

[0150] Reaction yield: 76%; Structural parameters: 1 1H NMR (600 MHz, CDCl 3 ) δ 8.44 (d, J = 8.4 Hz, 1H), 8.13 - 8.10 (m, 2H), 7.85 - 7.82 (m, 1H), 7.69 - 7.67 (m, 1H), 7.46 - 7.43 (m, 2H), 7.27 - 7.23 (m, 3H).

[0151] Example 16

[0152]

[0153] The synthesis method of Example 16 is the same as the above general method 1.

[0154] Reaction yield: 43%; Structural parameters: 1 1H NMR (600 MHz, CDCl 3 ) δ 8.37 (d, J = 8.4 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.55 - 7.52 (m, 1H), 7.45 - 7.42 (m, 2H), 7.30 - 7.28 (m, 2H), 7.24 - 7.21 (m, 1H), 7.18 (s, 1H), 2.48 (s, 3H).

[0155] Example 17

[0156]

[0157] The synthesis method of Example 17 is the same as the above general method 1.

[0158] Reaction yield: 53%; Structural parameters: 1 1H NMR (600 MHz, CDCl 3)δ 8.46 (d, J = 8.4 Hz, 1H), 8.15 - 8.12 (m, 2H), 7.86 - 7.84 (m, 1H), 7.71 - 7.68 (m, 1H), 7.47 - 7.44 (m, 2H), 7.29 - 7.26 (m, 1H), 7.25 - 7.24 (m, 2H).

[0159] Example 18

[0160]

[0161] The synthesis method of Example 18 is the same as the above general method 1.

[0162] Reaction yield: 62%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 )δ 8.43 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.99 - 7.98 (m, 1H), 7.64 - 7.63 (m, 1H), 7.47 - 7.43 (m, 3H), 7.27 - 7.23 (m, 3H).

[0163] Example 19

[0164]

[0165] The synthesis method of Example 19 is the same as the above general method 1.

[0166] Reaction yield: 33%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 )δ 8.31 (d, J = 9.0 Hz, 1H), 7.99 - 7.98 (m, 2H), 7.72 - 7.70 (m, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.29 - 7.27 (m, 1H), 7.26 - 7.22 (m, 3H).

[0167] Example 20

[0168]

[0169] The synthesis method of Example 20 is the same as the above general method 1.

[0170] Reaction yield: 65%; Structural parameters: 1 H NMR (600 MHz, CDCl 3)δ8.31(d, J = 8.4 Hz, 1H), 7.93(d, J = 6.0 Hz, 1H), 7.56(s, 1H), 7.45 - 7.43(m, 3H), 7.25 - 7.21(m, 4H), 2.55(s, 3H). The 1H NMR spectrum is as shown in Figure 4 , and the 13C NMR spectrum is as shown in Figure 5 .

[0171] Example 21

[0172]

[0173] The synthesis method of Example 21 is the same as the above general method 1.

[0174] Reaction yield: 50%; Structural parameters: 1 H NMR(600 MHz, CDCl 3 )δ8.37(d, J = 9.0 Hz, 1H), 7.97(d, J = 6.0 Hz, 1H), 7.78(d, J = 1.8 Hz, 1H), 7.55(dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.47 - 7.44(m, 2H), 7.27 - 7.21(m, 4H).

[0175] Example 22

[0176]

[0177] The synthesis method of Example 22 is the same as the above general method 1.

[0178] Reaction yield: 50%; Structural parameters: 1 HNMR(600 MHz, CDCl 3 )δ8.61(s, 1H), 7.98(d, J = 6.0 Hz, 1H), 7.80 - 7.79(m, 1H), 7.68 - 7.66(m, 1H), 7.47 - 7.44(m, 2H), 7.28 - 7.27(m, 2H), 7.25 - 7.24(m, 2H).

[0179] Example 23

[0180]

[0181] The synthesis method of Example 23 is the same as the above general method 1.

[0182] Reaction yield: 38%; Structural parameters: 1 HNMR(600 MHz, CDCl 3)δ8.22(s,1H),7.91(d,J=6.0Hz,1H),7.71-7.70(m,1H),7.57-7.55(m,1H),7.46-7.44(m,2H),7.28(d,J=6.0Hz,1H),7.26-7.24(m,3H),2.58(s,3H).

[0183] Example 24

[0184]

[0185] The synthesis method of Example 24 is the same as the above general method 1.

[0186] Reaction yield: 54%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ7.97(d,J=6.0Hz,1H),7.93-7.92(m,1H),7.74-7.72(m,1H),7.47-7.44(m,3H),7.32(d,J=5.4Hz,1H),7.26-7.23(m,3H).

[0187] Example 25

[0188]

[0189] The synthesis method of Example 25 is the same as the above general method 1.

[0190] Reaction yield: 73%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ7.97(d,J=5.4Hz,1H),7.69-7.66(m,2H),7.57-7.54(m,1H),7.47-7.44(m,2H),7.31(d,J=5.4Hz,1H),7.26-7.24(m,3H).

[0191] Example 26

[0192]

[0193] The synthesis method of Example 26 is the same as the above general method 1.

[0194] Reaction yield: 47%; Structural parameters: 1 H NMR(600MHz,CDCl 3)δ8.49(d, J = 8.4Hz, 1H), 7.95(d, J = 6.0Hz, 1H), 7.80 - 7.78(m, 1H), 7.73 - 7.70(m, 1H), 7.63 - 7.60(m, 1H), 7.28(d, J = 6.0Hz, 1H), 7.16(d, J = 7.8Hz, 1H), 6.89 - 6.86(m, 2H), 6.06 - 6.00(m, 1H), 5.17 - 5.11(m, 2H), 3.73(s, 3H), 3.44(d, J = 6.6Hz, 2H).

[0195] Example 27

[0196]

[0197] The synthesis method of Example 27 is the same as the above general method 1.

[0198] Reaction yield: 65%; Structural parameters: 1 H NMR(600MHz, CDCl 3 )δ8.49(d, J = 9.0Hz, 1H), 7.97(d, J = 6.0Hz, 1H), 7.82 - 7.81(m, 1H), 7.75 - 7.73(m, 1H), 7.66 - 7.63(m, 1H), 7.29(d, J = 7.2Hz, 1H), 7.25 - 7.24(m, 1H), 7.09 - 7.08(m, 1H), 7.06 - 7.05(m, 1H), 2.97 - 2.90(m, 1H), 2.15(s, 3H), 1.28(d, J = 7.2Hz, 6H).

[0199] Example 28

[0200]

[0201] The synthesis method of Example 28 is the same as the above general method 1.

[0202] Reaction yield: 44%; Structural parameters: 1 H NMR(600MHz, CDCl 3)δ8.46(d,J=8.4Hz,1H),8.01(d,J=6.0Hz,1H),7.83-7.81(m,1H),7.76-7.73(m,1H),7.66-7.63(m,1H),7.61(d,J=8.4Hz,2H),7.34(d,J=6.0Hz,1H),7.30-7.28(m,2H),7.16-7.13(m,1H),7.05-7.02(m,1H),6.71(d,J=1.8Hz,2H),6.43(t,J=2.4Hz,1H),3.86(s,6H)。

[0203] Example 29

[0204]

[0205] The synthesis method of Example 29 is the same as the above general method 1.

[0206] Reaction yield: 40%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ8.50(d,J=8.4Hz,1H),7.94(d,J=6.0Hz,1H),7.79-7.78(m,1H),7.72-7.69(m,1H),7.63-7.60(m,1H),7.28(d,J=6.0Hz,1H),7.26-7.23(m,2H),7.06-7.03(m,2H),3.73(s,3H)。

[0207] Method 2: A green synthesis method of 2-aryloxyquinoline, the steps are as follows:

[0208] Dissolve quinoline N-oxide (1.0 mmol) in EA (1.0 mL) solution, then add phenol (1.5 mmol), DIEA (2.0 mmol) and HMPA (0.1 mmol), cool the resulting solution to 0 °C, and then add POBr 3 (1.0 mmol) in EA (1.0 mL) solution dropwise. Then heat the reaction mixture to room temperature and stir for 5 minutes. Quench the reaction with saturated potassium carbonate solution and separate the organic phase. Extract the aqueous phase once with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate and concentrate in vacuo to obtain the crude product. Use PE / EA (200:1 - 100:1, volume ratio) as the mobile phase and silica gel column chromatography to obtain the target product.

[0209] The following is specifically illustrated by examples.

[0210] Example 30

[0211]

[0212] Dissolve quinoline N - oxide (100 mg, 0.69 mmol) in EA (0.7 mL) solution, then add phenol (98 mg, 1.0 mmol), DIEA (181 mg, 1.4 mmol) and HMPA (13 mg, 0.07 mmol). Cool the resulting solution to 0 °C, and then add dropwise a solution of POBr 3 (198 mg, 0.69 mmol) in EA (0.7 mL). Then heat the reaction mixture to room temperature and stir for 5 minutes. Quench the reaction with saturated potassium carbonate solution, and separate the organic phase. Extract the aqueous phase with ethyl acetate once. Combine the organic phases, dry over anhydrous sodium sulfate and concentrate in vacuo to obtain the crude product. Use PE / EA (200:1 - 100:1, v / v) as the mobile phase and silica gel column chromatography to obtain the target product (106 mg, 69% yield). Structural parameters: 1 HNMR(600MHz,CDCl 3 ) δ 8.09 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.43 - 7.39 (m, 3H), 7.26 - 7.21 (m, 3H), 7.06 (d, J = 8.4 Hz, 1H). The proton nuclear magnetic resonance spectrum is as Figure 6 。

[0213] Example 31

[0214] Dissolve quinoline N - oxide (1.0 g, 6.9 mmol) in EA (7 mL) solution, then add phenol (0.98 g, 10.4 mmol), DIEA (1.78 g, 13.8 mmol) and HMPA (0.12 g, 0.69 mmol). Cool the resulting solution to 0 °C, and then add dropwise a solution of POBr 3 (1.98 g, 6.9 mmol) in EA (7 mL). Then heat the reaction mixture to room temperature and stir for 5 minutes. Quench the reaction with saturated potassium carbonate solution, and separate the organic phase. Extract the aqueous phase with ethyl acetate once. Combine the organic phases, dry over anhydrous sodium sulfate and concentrate in vacuo to obtain the crude product. Use PE / EA (200:1 - 100:1) as the mobile phase and silica gel column chromatography to obtain the target product (950 mg, 62%). Structural parameters: 1 HNMR(600MHz,CDCl 3)δ8.09(d, J = 8.4 Hz, 1H), 7.80(d, J = 8.4 Hz, 1H), 7.74(d, J = 7.8 Hz, 1H), 7.60(t, J = 7.8 Hz, 1H), 7.43 - 7.39(m, 3H), 7.26 - 7.21(m, 3H), 7.06(d, J = 8.4 Hz, 1H). The 1H NMR spectrum is as Figure 6 .

[0215] Example 32

[0216]

[0217] The synthesis method of Example 32 is the same as the above General Method 2.

[0218] Reaction yield: 87%; Structural parameters: 1 H NMR(600 MHz, CDCl 3 )δ8.10(d, J = 9.0 Hz, 1H), 7.82(d, J = 8.4 Hz, 1H), 7.75(d, J = 8.4 Hz, 1H), 7.63 - 7.60(m, 1H), 7.42(t, J = 7.2 Hz, 1H), 7.24 - 7.23(m, 2H), 7.16 - 7.15(m, 2H), 7.07(d, J = 9.0 Hz, 1H), 2.40(s, 3H).

[0219] Example 33

[0220]

[0221] The synthesis method of Example 33 is the same as the above General Method 2.

[0222] Reaction yield: 79%; Structural parameters: 1 H NMR(600 MHz, CDCl 3 )δ8.09(d, J = 9.0 Hz, 1H), 7.80(d, J = 8.4 Hz, 1H), 7.75(d, J = 7.8 Hz, 1H), 7.61(t, J = 7.2 Hz, 1H), 7.41(t, J = 7.2 Hz, 1H), 7.20 - 7.18(m, 2H), 7.05(d, J = 9.0 Hz, 1H), 6.97 - 6.95(m, 2H), 3.84(s, 3H).

[0223] Example 34

[0224]

[0225] The synthesis method of Example 34 is the same as the above General Method 2.

[0226] Reaction yield: 63%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ8.13(d,J = 9.0Hz,1H),7.79 - 7.76(m,2H),7.64 - 7.61(m,1H),7.44(t,J = 7.8Hz,1H),7.40 - 7.38(m,2H),7.23 - 7.21(m,2H),7.09(d,J = 9.0Hz,1H).

[0227] Example 35

[0228]

[0229] The synthesis method of Example 35 is the same as the above general method two.

[0230] Reaction yield: 55%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ8.14(d,J = 9.0Hz,1H),7.78(t,J = 9.0Hz,2H),7.64 - 7.61(m,1H),7.55 - 7.52(m,2H),7.44(t,J = 7.2Hz,1H),7.18 - 7.15(m,2H),7.09(d,J = 9.0Hz,1H).

[0231] Example 36

[0232]

[0233] The synthesis method of Example 36 is the same as the above general method two.

[0234] Reaction yield: 52%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ8.16(d,J = 9.0Hz,1H),8.12 - 8.11(m,2H),7.79(t,J = 7.8Hz,2H),7.64(t,J = 8.4Hz,1H),7.46(t,J = 7.2Hz,1H),7.33 - 7.32(m,2H),7.13(d,J = 9.0Hz,1H),3.93(s,3H).

[0235] Example 37

[0236]

[0237] The synthesis method of Example 37 is the same as the above general method two.

[0238] Reaction yield: 68%; Structural parameters:1 1H NMR (600 MHz, CDCl 3 ) δ 8.13 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 8.4 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H), 7.43 (t, J = 7.2 Hz, 1H), 7.26 - 7.25 (m, 2H), 7.13 - 7.09 (m, 2H), 7.03 - 7.00 (m, 1H), 6.68 (d, J = 2.4 Hz, 2H), 6.41 - 6.40 (m, 1H), 3.84 (s, 6H).

[0239] Example 38

[0240]

[0241] The synthesis method of Example 38 is the same as the above general method two.

[0242] Reaction yield: 41%; Structure parameters: 1 1HNMR (600 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.70 (dd, J = 16.2 Hz, 8.4 Hz, 2H), 7.52 - 7.50 (m, 1H), 7.43 - 7.41 (m, 2H), 7.38 - 7.36 (m, 1H), 7.26 - 7.25 (m, 2H), 7.23 - 7.20 (m, 1H), 2.50 (s, 3H).

[0243] Example 39

[0244]

[0245] The synthesis method of Example 39 is the same as the above general method two.

[0246] Reaction yield: 54%; Structure parameters: 1 1H NMR (600 MHz, CDCl 3 ) δ 7.90 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.61 - 7.59 (m, 1H), 7.44 - 7.40 (m, 3H), 7.24 - 7.23 (m, 2H), 7.22 - 7.20 (m, 1H), 6.91 (s, 1H), 2.66 (s, 3H).

[0247] Example 40

[0248]

[0249] The synthesis method of Example 40 is the same as the above General Method 2.

[0250] Reaction yield: 63%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ8.10(d,J=9.6Hz,1H),7.78-7.77(m,1H),7.65-7.63(m,1H),7.51-7.48(m,1H),7.44-7.42(m,2H),7.40(s,1H),7.25-7.23(m,3H).

[0251] Example 41

[0252]

[0253] The synthesis method of Example 41 is the same as the above General Method 2.

[0254] Reaction yield: 54%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ8.29(d,J=9.0Hz,1H),7.66(d,J=8.4Hz,1H),7.50(t,J=7.2Hz,1H),7.42(t,J=7.8Hz,2H),7.26-7.22(m,4H),7.08(d,J=9.0Hz,1H),2.66(s,3H).

[0255] Example 42

[0256]

[0257] The synthesis method of Example 42 is the same as the above General Method 2.

[0258] Reaction yield: 57%; Structural parameters: 1 H NMR(600MHz,CDCl 3 )δ8.04(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.53(s,1H),7.46(dd,J=9.0Hz,2.4Hz,1H),7.43-7.41(m,2H),7.26-7.21(m,3H),7.04(d,J=9.0Hz,1H),2.50(s,3H).

[0259] Example 43

[0260]

[0261] The synthesis method of Example 43 is the same as the above General Method 2.

[0262] Reaction yield: 71%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.03 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.44 (t, J = 8.4 Hz, 2H), 7.27 - 7.24 (m, 3H), 7.11 (d, J = 9.0 Hz, 1H).

[0263] Example 44

[0264]

[0265] The synthesis method of Example 44 is the same as the above general method two.

[0266] Reaction yield: 58%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.03 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.41 (t, J = 8.4 Hz, 2H), 7.29 (dd, J = 3.0 Hz, 9.6 Hz, 1H), 7.24 - 7.20 (m, 3H), 7.08 (d, J = 3.0 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 3.91 (s, 3H).

[0267] Example 45

[0268]

[0269] The synthesis method of Example 45 is the same as the above general method two.

[0270] Reaction yield: 62%; Structural parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.51 (d, J = 1.8 Hz, 1H), 8.21 - 8.19 (m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.27 - 7.26 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H).

[0271] Example 46

[0272]

[0273] The synthesis method of Example 46 is the same as the above general method two.

[0274] Reaction yield: 42%; Structural parameters:1 H NMR (600 MHz, CDCl 3 ) δ 8.10 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.78 - 7.73 (m, 2H), 7.59 - 7.56 (m, 2H), 7.46 (t, J = 7.8 Hz, 2H), 7.40 - 7.36 (m, 3H), 7.29 - 7.27 (m, 3H), 7.12 (d, J = 9.0 Hz, 1H).

[0275] Example 47

[0276]

[0277] The synthesis method of Example 47 is the same as the above general method two.

[0278] Reaction yield: 40%; Structure parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.07 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.44 - 7.41 (m, 2H), 7.27 - 7.22 (m, 4H), 7.01 (d, J = 9.0 Hz, 1H), 2.49 (s, 3H).

[0279] Example 48

[0280]

[0281] The synthesis method of Example 48 is the same as the above general method two.

[0282] Reaction yield: 30%; Structure parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.09 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 6.6 Hz, 1H), 7.44 - 7.41 (m, 2H), 7.33 - 7.31 (m, 3H), 7.23 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H). 2.55 (s, 3H).

[0283] Method three: A green synthesis method of 2 - aryloxypyridine is as follows:

[0284] Dissolve pyridine N - oxide (1.0 mmol) in EA (1.0 mL) solution, then add phenol (2.0 mmol), DIEA (2.0 mmol) and HMPA (0.2 mmol), cool the resulting solution to 0 °C, and then add POBr dropwise3 A solution of EA (1.0 mL, 2.0 mmol) was used. Then the reaction mixture was heated to room temperature and stirred for 5 minutes. The reaction was quenched with saturated potassium carbonate solution, and the organic phase was separated. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The target product was obtained by silica gel column chromatography using PE / EA (200:1 - 100:1, v / v) as the mobile phase.

[0285] The following is specifically illustrated by examples.

[0286] Example 49

[0287]

[0288] Pyridine N - oxide (100 mg, 1.05 mmol) was dissolved in EA (1.1 mL) solution, then phenol (198 mg, 2.1 mmol), DIEA (271 mg, 2.1 mmol) and HMPA (38 mg, 0.21 mmol) were added. The resulting solution was cooled to 0 °C, and then POBr 3 (602 mg, 2.1 mmol) in EA (1.1 mL) solution was added dropwise. Then the reaction mixture was heated to room temperature and stirred for 5 hours. The reaction was quenched with saturated potassium carbonate solution, and the organic phase was separated. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product. The target product (104 mg, 58% yield) was obtained by silica gel column chromatography using PE / EA (200:1 - 100:1, v / v) as the mobile phase. Structure parameters: 1 H NMR (600 MHz, CDCl 3 ) δ 8.22 - 8.21 (m, 1H), 7.69 - 7.67 (m, 1H), 7.44 - 7.39 (m, 2H), 7.22 - 7.19 (m, 1H), 7.16 - 7.14 (m, 2H), 7.00 - 6.98 (m, 1H), 6.91 (d, J = 8.4 Hz, 1H).

[0289] Example 50

[0290]

[0291] The synthetic method of Example 50 was the same as the above general method three.

[0292] Reaction yield: 47%; Structure parameters: 1 H NMR (600 MHz, CDCl 3)δ8.19 - 8.18(m, 1H), 7.67 - 7.64(m, 1H), 7.08 - 7.07(m, 2H), 6.96 - 6.92(m, 3H), 6.86(d, J=8.4Hz, 1H), 3.81(s, 3H).

[0293] Example 51

[0294]

[0295] The synthesis method of Example 51 is the same as the above general method three.

[0296] Reaction yield: 42%; Structure parameters: 1 HNMR(600MHz, CDCl 3 )δ7.61(t, J=7.8Hz, 1H), 7.42 - 7.39(m, 2H), 7.22(t, J=7.2Hz, 1H), 7.15 - 7.14(m, 2H), 7.03(d, J=7.8Hz, 1H), 6.74(d, J=7.8Hz, 1H).

[0297] Example 52

[0298]

[0299] The synthesis method of Example 52 is the same as the above general method three.

[0300] Reaction yield: 63%; Structure parameters: 1 HNMR(600MHz, CDCl 3 )δ7.79 - 7.78(m, 2H), 7.52(t, J=7.8Hz, 1H), 7.29(dJ=7.8Hz, 1H), 7.27 - 7.23(m, 4H), 7.21 - 7.18(m, 1H), 7.09 - 7.04(m, 3H), 6.61(d, J=7.8Hz, 1H).

[0301] Example 53

[0302] The synthesis method of Example 53 is the same as the above general method three, and two isomers are obtained:

[0303]

[0304] 7e - 1: Reaction yield: 39%; Structure parameters: 1 H NMR(600MHz, CDCl 3)δ 8.47 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.46 - 7.44 (m, 2H), 7.30 - 7.28 (m, 1H), 7.15 - 7.14 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H).

[0305]

[0306] 7e - 2: Reaction yield: 26%; Structural parameters: 1 H NMR(600MHz, CDCl 3 )δ 8.31 (dd, J = 5.4 Hz, 2.4 Hz, 1H), 8.01 (dd, J = 7.2 Hz, 1.8 Hz, 1H), 7.46 - 7.43 (m, 2H), 7.29 - 7.27 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.10 - 7.08 (m, 1H).

[0307] Example 54

[0308]

[0309] The synthesis method of Example 54 is the same as the above general method three.

[0310] Reaction yield: 44%; Structural parameters: 1 H NMR(600MHz, CDCl 3 )δ 8.10 (d, J = 5.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.19 (t, J = 7.8 Hz, 1H), 7.15 - 7.14 (m, 2H), 7.01 (dd, J = 5.4 Hz, 1.2 Hz, 1H), 6.93 (t, J = 1.8 Hz, 1H), 1.32 (s, 9H).

[0311] Example 55

[0312]

[0313] The synthesis method of Example 55 is the same as the above general method three.

[0314] Reaction yield: 42%; Structural parameters: 1 H NMR(600MHz, CDCl 3)δ8.17 - 8.15(m, 1H), 7.59(t, J=6.6Hz, 1H), 7.16(d, J=8.1Hz, 2H), 7.01(d, J=8.5Hz, 2H), 6.91 - 6.89(m, 1H), 6.84(d, J=8.3Hz, 1H), 2.32(s, 3H).

[0315] Example 56

[0316]

[0317] The synthesis method of Example 56 is the same as the above general method three.

[0318] Reaction yield: 44%; Structure parameters: 1 H NMR(600MHz, CDCl 3 )δ8.19 - 8.18(m, 1H), 7.67 - 7.64(m, 1H), 7.14 - 7.09(m, 3H), 6.95 - 6.93(m, 1H), 6.84(d, J=8.3Hz, 1H), 2.16(s, 6H).

[0319] Example 57

[0320]

[0321] The synthesis method of Example 57 is the same as the above general method three.

[0322] Reaction yield: 34%; Structure parameters: 1 H NMR(600MHz, CDCl 3 )δ8.16(d, J=4.9Hz, 1H), 7.73 - 7.70(m, 1H), 7.65(dd, J=8.0, 1.5Hz, 1H), 7.38 - 7.35(m, 1H), 7.21 - 7.20(m, 1H), 7.10 - 7.13(m, 1H), 7.01 - 6.97(m, 2H).

[0323] Although the embodiments of the present invention are disclosed for illustrative purposes, those skilled in the art can understand that: without departing from the spirit and scope of the present invention and the appended claims, various substitutions, changes, and modifications are possible. Therefore, the scope of the present invention is not limited to the content disclosed in the embodiments.

Claims

1. A method for synthesizing a nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether, characterized in that: The method uses N,N-diisopropylethylamine (DIEA) as a base under the catalysis of hexamethylphosphoric acid triamide (HMPA), and with the assistance of POBr3, uses nitrogen oxides and phenol to react to achieve nitrogen ortho-aryloxy substitution.

2. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether is an aryl heteroaryl ether, and its synthesis route is as follows: Using nitrogen-containing heterocyclic compound nitrogen oxide 1 as raw material, ethyl acetate EA as solvent, N,N-diisopropylethylamine DIEA as base, hexamethylphosphoric triamide HMPA as catalyst, POBr3 as auxiliary agent, and phenol to react to obtain compound 3; Among them, R1 is an alkyl C1-C6, halogen group, ester C1-C6, phenyl and phenylacetylene group with one or two substitutions at the 3, 4, 5, 6, 7, 8 positions on the aromatic ring; R2 is an alkyl C1-C6, alkenyl C1-C6, cyano, alkoxy C1-C6, halogen group and ester group with one or two substitutions at the ortho, meta or para positions on phenol; including pterostilbene.

3. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether is a compound 1-phenoxyisoquinoline having anti-tumor activity, and its synthesis route is as follows: Isoquinoline-N-oxide is used as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and reacts with phenol to obtain 1-phenoxyisoquinoline.

4. The synthesis method according to claim 1, characterized in that: The method for synthesizing the nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether as a drug intermediate 6-bromo-1-phenoxyisoquinoline is characterized in that the synthesis route is as follows: 6-Bromoisoquinoline 2-oxide is used as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and reacts with phenol to obtain 6-bromo-1-phenoxyisoquinoline.

5. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether is a pharmaceutical intermediate 7-bromo-1-phenoxyisoquinoline, and its synthesis route is as follows: 7-Bromoisoquinoline nitrogen oxide is used as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and reacted with phenol to obtain 7-bromo-1-phenoxyisoquinoline.

6. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether is an intermediate of the factor Xa inhibitor, 7-methyl-1-phenoxyisoquinoline, and its synthesis route is as follows: 7-Methylisoquinoline 2-oxide is used as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and reacts with phenol to obtain 7-methyl-1-phenoxyisoquinoline.

7. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether is a compound 2-phenoxyquinoline having anti-tumor activity, and its synthesis route is as follows: Quinoline-N-oxide is used as raw material, EA is used as solvent, DIEA is used as base, HMPA is used as catalyst, POBr3 is used as auxiliary agent, and phenol is reacted to obtain 2-phenoxyquinoline.

8. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether is a pterostilbene derivative (E)-2-(4-(3,5-dimethoxyphenylvinyl)phenoxy)quinoline, and its synthesis route is as follows: Quinoline-N-oxide is used as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and reacts with pterostilbene to obtain (E)-2-(4-(3,5-dimethoxyphenylvinyl)phenoxy)quinoline.

9. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether is an optoelectronic material intermediate 2-phenoxy-6-phenylpyridine, and its synthesis route is as follows: 2-Phenylpyridine 1-oxide is used as raw material, EA is used as solvent, DIEA is used as base, HMPA is used as catalyst, POBr3 is used as auxiliary agent, and phenol is reacted to obtain 2-phenoxy-6-phenylpyridine.

10. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ethers include 1-aryloxyisoquinoline derivatives, 2-aryloxyquinoline derivatives and 2-aryloxypyridine derivatives; The structure of the 1-aryloxyisoquinoline derivative is shown below: The structure of the 2-aryloxyquinoline derivative is shown below: The structure of the 2-aryloxypyridine derivative is shown below:

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