A method for synthesizing aryl ethers with ortho substitution of the nitrogen heterocycle nitrogen

Abstract

The application belongs to the technical fields of new compound synthesis and application, and discloses a synthesis method of aryl ether with nitrogen heterocyclic nitrogen ortho substitution, which uses nitroxide and phenol to react under the catalysis of hexamethylphosphorus triamide HMPA, with N,N-diisopropylethylamine DIEA as an alkali and with the assistance of POBr3, so as to realize the nitrogen ortho aryloxy substitution. The method has excellent atom economy (3a, 96%), green solvent (using ethyl acetate as a solvent), mild reaction condition, short reaction time (5 minutes for most substrates), wide substrate range, cheap and easily obtained reaction substrate and other advantages. The method provides a convenient, efficient, green and practical method for synthesizing 1-aryloxyisoquinoline, 2-aryloxyquinoline and 2-aryloxy pyridine compounds.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical fields of new compound synthesis and application, and particularly relates to a synthesis method of aryl ether with nitrogen-containing heterocyclic nitrogen ortho substitution. BACKGROUND

[0002] Aryl ether has extremely wide application in the fields of natural products, agricultural chemicals, bioactive compounds, drug synthesis and optoelectronic materials due to its unique chemical stability and functionality, and is an important structural unit indispensable in modern chemistry and material science. For example, 1-aryloxyisoquinoline is widely used in the synthesis of drug intermediates, including 6-bromo-1-phenoxyisoquinoline, 7-bromo-1-phenoxyisoquinoline and 7-methyl-1-phenoxyisoquinoline and the like; 1-phenoxyisoquinoline and 2-phenoxyquinoline and the like compounds have certain antitumor activity; 1-aryloxyisoquinoline and 2-aryloxy pyridine are also important intermediates in some optoelectronic materials.

[0003] One of the traditional synthesis methods of aryl ether with nitrogen-containing heterocyclic nitrogen ortho substitution is to use transition metal catalyze nucleophilic substitution reaction of heterocyclic halide and phenol to form 1-aryloxy substitution product, which generally needs harsh reaction conditions. Another is to use easily available nitrogen-containing heterocyclic nitrogen oxide as raw material and phenol to occur nucleophilic substitution reaction. However, this method uses excessive activator and expensive or toxic reagent, thereby limiting the application of the method, and there is no economic and green, mild method to synthesize aryl ether with nitrogen-containing heterocyclic nitrogen ortho substitution.

[0004]

[0005] Based on the above reasons, a practical, rapid and green synthesis method of aryl ether with nitrogen-containing heterocyclic nitrogen ortho substitution is needed. The application designs a rapid and green reaction for synthesizing aryl ether with nitrogen-containing heterocyclic nitrogen ortho substitution. The synthesis method of the application uses nitrogen-containing heterocyclic nitrogen oxide and phenol derivative as reaction substrates, and under the joint action of catalytic amount of hexamethylphosphorus triamide (HMPA) and phosphorus tribromide, an active phosphonium salt intermediate is generated in situ as an efficient activator, so as to promote the smooth progress of the reaction. The method has the advantages of mild reaction conditions, in-situ generation of activator and high catalytic efficiency. SUMMARY

[0006] The purpose of the application is to overcome the deficiencies in the prior art, and to provide a synthesis method of aryl ether with nitrogen-containing heterocyclic nitrogen ortho substitution.

[0007] The technical scheme adopted by the application to solve the technical problems is:

[0008] A method for synthesizing aryl ether substituted at the ortho position of the nitrogen of a nitrogen-containing heterocycle, which method uses a nitroxide and a phenol in the presence of POBr3 as an auxiliary agent, with N,N-diisopropylethylamine (DIEA) as a base and hexamethylphosphoric triamide (HMPA) as a catalyst to achieve aryl ether substitution at the ortho position of the nitrogen.

[0009] Further, the aryl ether substituted at the ortho position of the nitrogen of the nitrogen-containing heterocycle is an aryl heteroaryl ether, and the synthetic route is as follows:

[0010]

[0011] The compound 3 is obtained by reacting a nitroxide 1 of a nitrogen-containing heterocycle, ethyl acetate (EA) as a solvent, N,N-diisopropylethylamine (DIEA) as a base, hexamethylphosphoric triamide (HMPA) as a catalyst, POBr3 as an auxiliary agent, and a phenol.

[0012] wherein R1 is one or two alkyl groups C1-C6, halogen groups, ester groups C1-C6, phenyl groups, and phenylacetylene groups substituted at 3, 4, 5, 6, 7, or 8 positions of an aromatic ring; and R2 is one or two alkyl groups C1-C6, alkenyl groups C1-C6, cyano groups, alkoxy groups C1-C6, halogen groups, and ester groups substituted at ortho, meta, or para positions of a phenol; and includes pterostilbene.

[0013] Further, the aryl ether substituted at the ortho position of the nitrogen of the nitrogen-containing heterocycle is a compound 1-phenoxyisoquinoline having an anti-tumor activity, and the synthetic route is as follows:

[0014]

[0015] The 1-phenoxyisoquinoline is obtained by reacting isoquinoline-N-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr3 as an auxiliary agent with a phenol.

[0016] Further, the aryl ether substituted at the ortho position of the nitrogen of the nitrogen-containing heterocycle is a method for synthesizing a pharmaceutical intermediate 6-bromo-1-phenoxyisoquinoline, and the synthetic route is as follows:

[0017]

[0018] The 6-bromo-1-phenoxyisoquinoline is obtained by reacting 6-bromoisoquinoline 2-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr3 as an auxiliary agent with a phenol.

[0019] Further, the aryl ether substituted at the ortho position of the nitrogen of the nitrogen-containing heterocycle is a pharmaceutical intermediate 7-bromo-1-phenoxyisoquinoline, and the synthetic route is as follows:

[0020] Further, the aryl ether substituted at the ortho position of the nitrogen of the nitrogen-containing heterocycle is a pharmaceutical intermediate 7-bromo-1-phenoxyisoquinoline, and the synthetic route is as follows:

[0021] 7-bromoisoquinoline N-oxide as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and phenol to react to get 7-bromo-1-phenoxyisoquinoline.

[0022] Further, the nitrogen-containing heterocyclic ring nitrogen ortho-substituted aryl ether is an intermediate 7-methyl-1-phenoxyisoquinoline of the factor Xa inhibitor, and the synthetic route is as follows:

[0023]

[0024] 7-methylisoquinoline 2-oxide as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and phenol to react to get 7-methyl-1-phenoxyisoquinoline.

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

[0026]

[0027] Quinoline-N-oxide as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and phenol to react to get 2-phenoxyquinoline.

[0028] Further, the nitrogen-containing heterocyclic ring nitrogen ortho-substituted aryl ether is a santal derivative (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline, and the synthetic route is as follows:

[0029]

[0030] Quinoline-N-oxide as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and santal to react to get (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline.

[0031] Further, the nitrogen-containing heterocyclic ring nitrogen ortho-substituted aryl ether is an intermediate 2-phenoxy-6-phenylpyridine in photoelectric material, and the synthetic route is as follows:

[0032]

[0033] 2-phenylpyridine 1-oxide as raw material, EA as solvent, DIEA as base, HMPA as catalyst, POBr3 as auxiliary agent, and phenol to react to get 2-phenoxy-6-phenylpyridine.

[0034] Further, the nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether includes 1-aryloxyisoquinoline derivatives, 2-aryloxyquinoline derivatives, and 2-aryloxy pyridine derivatives.

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

[0036]

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

[0038]

[0039] The structure of the 2-aryloxy pyridine derivative is as follows:

[0040]

[0041] The advantages and positive effects obtained by the present application are as follows:

[0042] 1. The present application provides a synthesis method of nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether. In the present application, under the catalysis of HMPA, using DIEA as a base, with the assistance of POBr3, nitroxide and phenol are used to react, and nitrogen ortho-aryloxy substitution is realized. The method has excellent atom economy (3a, 96%), green solvent (using ethyl acetate as a solvent), mild reaction conditions, short reaction time (most of the substrates have a reaction time of 5 minutes), wide substrate range, and cheap and easily obtained reaction substrates. The method provides a convenient, efficient, green and practical method for synthesizing 1-aryloxyisoquinoline, 2-aryloxyquinoline and 2-aryloxy pyridine compounds.

[0043] 2. The present application develops a simple synthesis method of nitrogen-containing heterocyclic nitrogen ortho-substituted aryl ether, which is simple to operate, mild in conditions, cheap and easy to obtain substrates, and has important economic value.

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

[0045] 4. The present application has a wide range of applicable substrates, and isoquinoline, quinoline and pyridine can be successfully reacted.

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

[0047] 6. The present application uses cheap and easily obtained HMPA as a catalyst.

[0048] 7. The present application first provides a general synthesis method of 1-aryloxy reaction of isoquinoline derivatives. BRIEF DESCRIPTION OF DRAWINGS

[0049] Figure 1 A nuclear magnetic hydrogen spectrum of compound 3c in deuterated chloroform in the present application;

[0050] Figure 2 A nuclear magnetic hydrogen spectrum of compound 3g in deuterated chloroform in the present application;

[0051] Figure 3 A nuclear magnetic carbon spectrum of compound 3g in deuterated chloroform in the present application;

[0052] Figure 4 A nuclear magnetic hydrogen spectrum of compound 3s in deuterated chloroform in the present application;

[0053] Figure 5 A nuclear magnetic carbon spectrum of compound 3s in deuterated chloroform in the present application;

[0054] Figure 6 A nuclear magnetic hydrogen spectrum of compound 5a in deuterated chloroform in the present application. DETAILED DESCRIPTION

[0055] The present application is further described below in conjunction with examples, which are illustrative rather than limiting, and the scope of the present application should not be limited by the following examples.

[0056] The various experimental operations involved in the specific examples are all conventional techniques in the art, and the parts not specially noted herein can be implemented by referring to various commonly used tool books, scientific and technical literature or related instructions, manuals, etc. before the filing date of the present application.

[0057] A method for synthesizing aryl ether substituted at the ortho position of the nitrogen of a nitrogen-containing heterocycle, which uses a nitroxide and a phenol to react in the presence of a catalyst of hexamethylphosphoric triamide HMPA, an alkali of N,N-diisopropylethylamine DIEA, and an auxiliary agent of POBr3 to achieve the ortho position aryloxy substitution of the nitrogen.

[0058] More preferably, the aryl ether substituted at the ortho position of the nitrogen of the nitrogen-containing heterocycle is an aryl heteroaryl ether, and the synthesis route is as follows:

[0059]

[0060] The compound 3 is obtained by reacting a nitroxide 1 of a nitrogen-containing heterocycle, ethyl acetate EA as a solvent, N,N-diisopropylethylamine DIEA as a base, hexamethylphosphoric triamide HMPA as a catalyst, POBr3 as an auxiliary agent, and a phenol.

[0061] Wherein, R1 is alkyl C1-C6, halogen group, ester group C1-C6, phenyl and phenylacetylene group substituted at 3,4,5,6,7,8 positions of the aromatic ring; R2 is alkyl C1-C6, alkenyl C1-C6, cyano, alkoxy C1-C6, halogen group and ester group substituted at ortho, meta, para positions of the phenol; including pterostilbene.

[0062] More preferably, the aryl ether substituted at ortho position of the nitrogen of the nitrogen-containing heterocycle is compound 1-phenoxyisoquinoline with anti-tumor activity, and the synthetic route is as follows:

[0063]

[0064] The 1-phenoxyisoquinoline is obtained by reacting isoquinoline-N-oxide with phenol, with EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr3 as the auxiliary agent.

[0065] More preferably, the aryl ether substituted at ortho position of the nitrogen of the nitrogen-containing heterocycle is a synthetic method of pharmaceutical intermediate 6-bromo-1-phenoxyisoquinoline, and the synthetic route is as follows:

[0066]

[0067] The 6-bromo-1-phenoxyisoquinoline is obtained by reacting 6-bromoisoquinoline 2-oxide with phenol, with EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr3 as the auxiliary agent.

[0068] More preferably, the aryl ether substituted at ortho position of the nitrogen of the nitrogen-containing heterocycle is a pharmaceutical intermediate 7-bromo-1-phenoxyisoquinoline, and the synthetic route is as follows:

[0069]

[0070] The 7-bromo-1-phenoxyisoquinoline is obtained by reacting 7-bromoisoquinoline N-oxide with phenol, with EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr3 as the auxiliary agent.

[0071] More preferably, the aryl ether substituted at ortho position of the nitrogen of the nitrogen-containing heterocycle is an intermediate 7-methyl-1-phenoxyisoquinoline of Xa factor inhibitor, and the synthetic route is as follows:

[0072]

[0073] The 7-methyl-1-phenoxyisoquinoline is obtained by reacting 7-methylisoquinoline 2-oxide with phenol, with EA as the solvent, DIEA as the base, HMPA as the catalyst, and POBr3 as the auxiliary agent.

[0074] More preferably, the aryl ether substituted ortho to the nitrogen of a nitrogen-containing heterocycle is the compound 2-phenoxyquinoline, which has anti-tumor activity, and its synthetic route is as follows:

[0075]

[0076] 2-phenoxyquinoline is obtained by reacting quinoline-N-oxide with phenol, using EA as solvent, DIEA as base, HMPA as catalyst, and POBr3 as auxiliary agent.

[0077] More preferably, the aryl ether substituted ortho to the nitrogen of a nitrogen-containing heterocycle is the santal derivative (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline, and its synthetic route is as follows:

[0078]

[0079] (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline is obtained by reacting quinoline-N-oxide with santal, using EA as solvent, DIEA as base, HMPA as catalyst, and POBr3 as auxiliary agent.

[0080] More preferably, the aryl ether substituted ortho to the nitrogen of a nitrogen-containing heterocycle is the photoelectric material intermediate 2-phenoxy-6-phenylpyridine, and its synthetic route is as follows:

[0081]

[0082] 2-phenoxy-6-phenylpyridine is obtained by reacting 2-phenylpyridine 1-oxide with phenol, using EA as solvent, DIEA as base, HMPA as catalyst, and POBr3 as auxiliary agent.

[0083] More preferably, the aryl ether substituted ortho to the nitrogen of a nitrogen-containing heterocycle includes 1-aryloxyisoquinoline derivatives, 2-aryloxyquinoline derivatives, and 2-aryloxy pyridine 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-aryloxy pyridine derivative is as follows:

[0089]

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

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

[0092] The isoquinoline N-oxide derivative (1.0 mmol) was dissolved in EA (1.0 mL) solution, then phenol (3.0 mmol), DIEA (2.0 mmol) and HMPA (0.4 mmol) were added, the resulting solution was cooled to 0 °C, then POBr3 (2.0 mmol) in EA (1.0 mL) solution 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, 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. Silica gel column chromatography with PE / EA (200:1-100:1, volume ratio) as the mobile phase to give the target product.

[0093] The following is specifically illustrated by examples.

[0094] Example 1

[0095]

[0096] The isoquinoline N-oxide (100 mg, 0.69 mmol) was dissolved in EA (0.7 mL) solution, then phenol (198 mg, 2.1 mmol), DIEA (181 mg, 1.4 mmol) and HMPA (50 mg, 0.28 mmol) were added, the resulting solution was cooled to 0 °C, then POBr3 (401 mg, 1.4 mmol) in EA (0.7 mL) solution 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, 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. Silica gel column chromatography with PE / EA (200:1-100:1, volume ratio) as the mobile phase to give the target product (110 mg, 72% yield). Structural parameters: 1 HNMR (600 MHz, CDC13) 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, then POBr3 (3.96 g, 13.8 mmol) in EA (7 mL) solution 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, 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. Silica gel column chromatography with PE / EA (200:1-100:1, volume ratio) as the mobile phase gave the target product (967 mg, 63%). Structural parameters: 1 H NMR (600 MHz, CDC13) 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, CDC13) 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).

[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: 1H NMR (600 MHz, CDC13) 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). Nuclear magnetic hydrogen spectrum 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, CDC13) 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, CDC13) 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, CDC13) 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, CDC13) 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). Figure 2 , nuclear magnetic carbon spectrum is 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, CDC13) 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).

[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, CDC13) 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] Example 11 was synthesized according to General Procedure 1.

[0134] Reaction yield: 46%; structural parameters: 1 H NMR (600 MHz, CDC13) 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] Example 12 was synthesized according to General Procedure 1.

[0138] Reaction yield: 43%; structural parameters: 1 H NMR (600 MHz, CDC13) 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] Example 13 was synthesized according to General Procedure 1.

[0142] Reaction yield: 57%; structural parameters:1 H NMR (600 MHz, CDC13) 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 of Example 14 was performed according to General Procedure 1.

[0146] Reaction yield: 45%; structural parameters: 1 H NMR (600 MHz, CDC13) 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).

[0147] Example 15

[0148]

[0149] The synthesis of Example 15 was performed according to General Procedure 1.

[0150] Reaction yield: 76%; structural parameters: 1 H NMR (600 MHz, CDC13) 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).

[0151] Example 16

[0152]

[0153] The synthesis of Example 16 was performed according to General Procedure 1.

[0154] Reaction yield: 43%; structural parameters: 1H NMR (600 MHz, CDC13) 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 of Example 17 was performed according to General Procedure 1.

[0158] Reaction yield: 53%; structural parameters: 1 H NMR (600 MHz, CDC13) 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 of Example 18 was performed according to General Procedure 1.

[0162] Reaction yield: 62%; structural parameters: 1 H NMR (600 MHz, CDC13) 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 of Example 19 was performed according to General Procedure 1.

[0166] Reaction yield: 33%; structural parameters: 1H NMR (600 MHz, CDC13) 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] Example 20 was synthesized according to General Procedure 1.

[0170] Reaction yield: 65%; structural parameters: 1 H NMR (600 MHz, CDC13) 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). Figure 4 , nuclear magnetic carbon spectrum as Figure 5 .

[0171] Example 21

[0172]

[0173] Example 21 was synthesized according to General Procedure 1.

[0174] Reaction yield: 50%; structural parameters: 1 H NMR (600 MHz, CDC13) 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).

[0175] Example 22

[0176]

[0177] Example 22 was synthesized according to General Procedure 1.

[0178] Reaction yield: 50%; structural parameters: 1HNMR (600 MHz, CDC13) δ 8.61 (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] Example 23 was synthesized according to General Procedure 1.

[0182] Reaction yield: 38%; structural parameters: 1 HNMR (600 MHz, CDC13) δ 8.61 (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).

[0183] Example 24

[0184]

[0185] Example 24 was synthesized according to General Procedure 1.

[0186] Reaction yield: 54%; structural parameters: 1 HNMR (600 MHz, CDC13) δ 8.61 (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).

[0187] Example 25

[0188]

[0189] Example 25 was synthesized according to General Procedure 1.

[0190] Reaction yield: 73%; structural parameters: 1H NMR (600 MHz, CDC13) δ 7.97 (d, J = 5.4 Hz, 1H), 7.69-7.66 (m, 2H), 7.57-7.54 (m, 1H), 7.47-7.44 (m, 2H), 7.31 (d, J = 5.4 Hz, 1H), 7.26-7.24 (m, 3H).

[0191] Example 26

[0192]

[0193] The synthesis of Example 26 was performed according to General Procedure 1.

[0194] Reaction yield: 47%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.49 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.80-7.78 (m, 1H), 7.73-7.70 (m, 1H), 7.63-7.60 (m, 1H), 7.28 (d, J = 6.0 Hz, 1H), 7.16 (d, J = 7.8 Hz, 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 = 6.6 Hz, 2H).

[0195] Example 27

[0196]

[0197] The synthesis of Example 27 was performed according to General Procedure 1.

[0198] Reaction yield: 65%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.49 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.82-7.81 (m, 1H), 7.75-7.73 (m, 1H), 7.66-7.63 (m, 1H), 7.29 (d, J = 7.2 Hz, 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 = 7.2 Hz, 6H).

[0199] Example 28

[0200]

[0201] The synthesis of example 28 was carried out according to the general procedure 1 described above.

[0202] Reaction yield: 44%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.46 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.83-7.81 (m, 1H), 7.76-7.73 (m, 1H), 7.66-7.63 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 6.0 Hz, 1H), 7.30-7.28 (m, 2H), 7.16-7.13 (m, 1H), 7.05-7.02 (m, 1H), 6.71 (d, J = 1.8 Hz, 2H), 6.43 (t, J = 2.4 Hz, 1H), 3.86 (s, 6H).

[0203] Example 29

[0204]

[0205] The synthesis of example 28 was carried out according to the general procedure 1 described above.

[0206] Reaction yield: 44%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.46 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.83-7.81 (m, 1H), 7.76-7.73 (m, 1H), 7.66-7.63 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 6.0 Hz, 1H), 7.30-7.28 (m, 2H), 7.16-7.13 (m, 1H), 7.05-7.02 (m, 1H), 6.71 (d, J = 1.8 Hz, 2H), 6.43 (t, J = 2.4 Hz, 1H), 3.86 (s, 6H).

[0207] Method two: a green synthesis of 2-aryloxy quinolines, the procedure is as follows:

[0208] Quinoline N-oxide (1.0 mmol) was dissolved in EA (1.0 mL) solution, then phenol (1.5 mmol), DIEA (2.0 mmol) and HMPA (0.1 mmol) were added, the resulting solution was cooled to 0°C, then POBr3 (1.0 mmol) in EA (1.0 mL) solution 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, 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. Silica gel column chromatography with PE / EA (200:1-100:1, volume ratio) as the mobile phase to give the target product.

[0209] The following will be specifically illustrated by examples.

[0210] Example 30

[0211]

[0212] Quinoline N-oxide (100 mg, 0.69 mmol) was dissolved in EA (0.7 mL) solution, then phenol (98 mg, 1.0 mmol), DIEA (181 mg, 1.4 mmol) and HMPA (13 mg, 0.07 mmol) were added, the resulting solution was cooled to 0 °C, then POBr3 (198 mg, 0.69 mmol) in EA (0.7 mL) solution 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, 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 vacuum to get the crude product. Silica gel column chromatography with PE / EA (200:1-100:1, volume ratio) as mobile phase gave the target product (106 mg, 69% yield). Structural parameters: 1 HNMR (600 MHz, CDC13) 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). Nuclear magnetic resonance hydrogen spectrum as Figure 6 .

[0213] Example 31

[0214] Quinoline N-oxide (1.0 g, 6.9 mmol) was dissolved in EA (7 mL) solution, then phenol (0.98 g, 10.4 mmol), DIEA (1.78 g, 13.8 mmol) and HMPA (0.12 g, 0.69 mmol) were added, the resulting solution was cooled to 0 °C, then POBr3 (1.98 g, 6.9 mmol) in EA (7 mL) solution 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, 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 vacuum to get the crude product. Silica gel column chromatography with PE / EA (200:1-100:1) as mobile phase gave the target product (950 mg, 62%). Structural parameters: 1HNMR (600 MHz, CDC13) 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). Nuclear magnetic hydrogen spectrum 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, CDC13) δ 8.10 (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, CDC13) δ 8.09 (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 (600 MHz, CDC13) δ 8.13 (d, J = 9.0 Hz, 1H), 7.79-7.76 (m, 2H), 7.64-7.61 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.40-7.38 (m, 2H), 7.23-7.21 (m, 2H), 7.09 (d, J = 9.0 Hz, 1H).

[0227] Example 35

[0228]

[0229] The synthesis of Example 35 was performed according to the General Procedure 2 described above.

[0230] Reaction yield: 55%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.13 (d, J = 9.0 Hz, 1H), 7.79-7.76 (m, 2H), 7.64-7.61 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.40-7.38 (m, 2H), 7.23-7.21 (m, 2H), 7.09 (d, J = 9.0 Hz, 1H).

[0231] Example 36

[0232]

[0233] The synthesis of Example 36 was performed according to the General Procedure 2 described above.

[0234] Reaction yield: 52%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.13 (d, J = 9.0 Hz, 1H), 7.79-7.76 (m, 2H), 7.64-7.61 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.40-7.38 (m, 2H), 7.23-7.21 (m, 2H), 7.09 (d, J = 9.0 Hz, 1H).

[0235] Example 37

[0236]

[0237] The synthesis of Example 37 was performed according to the General Procedure 2 described above.

[0238] Reaction yield: 68%; structural parameters: 1H NMR (600 MHz, CDC13) 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] Example 38 was synthesized according to the above General Procedure 2.

[0242] Reaction yield: 41%; structural parameters: 1 H NMR (600 MHz, CDC13) 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] Example 39 was synthesized according to the above General Procedure 2.

[0246] Reaction yield: 54%; structural parameters: 1 H NMR (600 MHz, CDC13) 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] Example 40 was synthesized according to the above General Procedure 2.

[0250] Reaction yield: 63%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.10 (d, J = 9.6 Hz, 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 Two.

[0254] Reaction yield: 54%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.29 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.26-7.22 (m, 4H), 7.08 (d, J = 9.0 Hz, 1H), 2.66 (s, 3H).

[0255] Example 42

[0256]

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

[0258] Reaction yield: 57%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.04 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.46 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.43-7.41 (m, 2H), 7.26-7.21 (m, 3H), 7.04 (d, J = 9.0 Hz, 1H), 2.50 (s, 3H).

[0259] Example 43

[0260]

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

[0262] Reaction yield: 71%; structural parameters: 1H NMR (600 MHz, CDC13) 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).

[0263] Example 44

[0264]

[0265] Example 44 was synthesized according to the General Procedure 2 described above.

[0266] Reaction yield: 58%; structural parameters: 1 H NMR (600 MHz, CDC13) 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] Example 45 was synthesized according to the General Procedure 2 described above.

[0270] Reaction yield: 62%; structural parameters: 1 H NMR (600 MHz, CDC13) 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).

[0271] Example 46

[0272]

[0273] Example 46 was synthesized according to the General Procedure 2 described above.

[0274] Reaction yield: 42%; structural parameters: 1H NMR (600 MHz, CDC13) 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 of Example 47 was performed according to the General Procedure 2 described above.

[0278] Reaction yield: 40%; structural parameters: 1 H NMR (600 MHz, CDC13) 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).

[0279] Example 48

[0280]

[0281] The synthesis of Example 48 was performed according to the General Procedure 2 described above.

[0282] Reaction yield: 30%; structural parameters: 1 H NMR (600 MHz, CDC13) 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).

[0283] Method 3: A green synthesis of 2-aryloxy pyridines, following the procedure:

[0284] Pyridine N-oxide (1.0 mmol) was dissolved in EA (1.0 mL) solution, then phenol (2.0 mmol), DIEA (2.0 mmol) and HMPA (0.2 mmol) were added, the resulting solution was cooled to 0 °C, then POBr3 (2.0 mmol) in EA (1.0 mL) solution 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, 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. Silica gel column chromatography with PE / EA (200:1-100:1, volume ratio) as the mobile phase gave the target product.

[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, then POBr3 (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, 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. Silica gel column chromatography with PE / EA (200:1-100:1, volume ratio) as the mobile phase gave the target product (104 mg, 58% yield). Structural parameters: 1 H NMR (600 MHz, CDC13) 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 synthesis method of Example 50 is the same as the above general method three.

[0292] Reaction yield: 47%; Structural parameters: 1H NMR (600 MHz, CDC13) δ 8.19-8.18 (m, 1H), 7.67-7.64 (m, 1H), 7.08-7.07 (m, 2H), 6.96-6.92 (m, 3H), 6.86 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H).

[0293] Example 51

[0294]

[0295] Example 51 was synthesized according to General Procedure 3.

[0296] Reaction yield: 42%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 7.61 (t, J = 7.8 Hz, 1H), 7.42-7.39 (m, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.15-7.14 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H).

[0297] Example 52

[0298]

[0299] Example 52 was synthesized according to General Procedure 3.

[0300] Reaction yield: 63%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 7.79-7.78 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.27-7.23 (m, 4H), 7.21-7.18 (m, 1H), 7.09-7.04 (m, 3H), 6.61 (d, J = 7.8 Hz, 1H).

[0301] Example 53

[0302] Example 53 was synthesized according to General Procedure 3, to give two isomers:

[0303]

[0304] 7e-1: Reaction yield: 39%; structural parameters: 1H NMR (600 MHz, CDC13) 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 (600 MHz, CDC13) 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] Example 54 was synthesized according to General Procedure 3.

[0310] Reaction yield: 44%; structural parameters: 1 H NMR (600 MHz, CDC13) 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] Example 55 was synthesized according to General Procedure 3.

[0314] Reaction yield: 42%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.17-8.15 (m, 1H), 7.59 (t, J = 6.6 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.91-6.89 (m, 1H), 6.84 (d, J = 8.3 Hz, 1H), 2.32 (s, 3H).

[0315] Example 56

[0316]

[0317] Example 56 was synthesized according to the general procedure 3 described above.

[0318] Reaction yield: 44%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.19-8.18 (m, 1H), 7.67-7.64 (m, 1H), 7.14-7.09 (m, 3H), 6.95-6.93 (m, 1H), 6.84 (d, J = 8.3 Hz, 1H), 2.16 (s, 6H).

[0319] Example 57

[0320]

[0321] Example 57 was synthesized according to the general procedure 3 described above.

[0322] Reaction yield: 34%; structural parameters: 1 H NMR (600 MHz, CDC13) δ 8.16 (d, J = 4.9 Hz, 1H), 7.73-7.70 (m, 1H), 7.65 (dd, J = 8.0, 1.5 Hz, 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 application are disclosed for illustrative purposes, those skilled in the art can understand that various substitutions, changes and modifications are possible without departing from the spirit and scope of the present application and the appended claims, and therefore the scope of the present application 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 involves the reaction of nitrogen oxides and phenols under the catalysis of hexamethylphosphoric triamine (HMPA), using N,N-diisopropylethylamine (DIEA) as a base, and with the assistance of POBr3, to achieve nitrogen ortho-aryloxy substitution. The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is an aryl heteroaryl ether, and its synthetic route is as follows: Using nitrogen-containing heterocyclic compound nitrogen oxide 1 as a raw material, ethyl acetate (EA) as a solvent, N,N-diisopropylethylamine (DIEA) as a base, hexamethylphosphoric triamine (HMPA) as a catalyst, and POBr3 as an auxiliary agent, compound 3 was obtained by reacting it with phenol. Wherein, R1 is a C1-C6 alkyl, halogen group, C1-C6 ester group, phenyl or benzoynyl group; R2 is a C1-C6 alkyl, C1-C6 alkenyl, cyano, C1-C6 alkoxy or halogen group.

2. A method for synthesizing a nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether, characterized in that: The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is compound 1-phenoxyisoquinoline, and its synthetic route is as follows: 1-Phenoxyisoquinoline was obtained by reacting isoquinoline-N-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr3 as an auxiliary agent with phenol.

3. A method for synthesizing a nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether, characterized in that: The method for synthesizing the nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether as a pharmaceutical intermediate 6-bromo-1-phenoxyisoquinoline is characterized by the following synthetic route: Using 6-bromoisoquinoline 2-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr3 as an auxiliary agent, 6-bromo-1-phenoxyisoquinoline was obtained by reacting it with phenol.

4. A method for synthesizing a nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether, characterized in that: The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is the pharmaceutical intermediate 7-bromo-1-phenoxyisoquinoline, and its synthetic route is as follows: 7-bromoisoquinoline nitrogen oxides were reacted with phenol to obtain 7-bromo-1-phenoxyisoquinoline, using EA as solvent, DIEA as base, HMPA as catalyst, and POBr3 as auxiliary agent.

5. A method for synthesizing a nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether, characterized in that: The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is an intermediate for the Xa factor inhibitor, 7-methyl-1-phenoxyisoquinoline, and its synthetic route is as follows: 7-methyl-1-phenoxyisoquinoline was obtained by reacting 7-methylisoquinoline 2-oxide with phenol, using EA as solvent, DIEA as base, HMPA as catalyst, and POBr3 as auxiliary agent.

6. A method for synthesizing a nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether, characterized in that: The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is compound 2-phenoxyquinoline, and its synthetic route is as follows: Using quinoline-N-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr3 as an auxiliary agent, 2-phenoxyquinoline was obtained by reacting it with phenol.

7. A method for synthesizing a nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether, characterized in that: The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is a pterostilbene derivative (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline, and its synthetic route is as follows: Using quinoline-N-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr3 as an auxiliary agent, (E)-2-(4-(3,5-dimethoxystyryl)phenoxy)quinoline was obtained by reacting it with pterostilbene.

8. A method for synthesizing a nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether, characterized in that: The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is the optoelectronic material intermediate 2-phenoxy-6-phenylpyridine, and its synthetic route is as follows: Using 2-phenylpyridine 1-oxide as a raw material, EA as a solvent, DIEA as a base, HMPA as a catalyst, and POBr3 as an auxiliary agent, 2-phenoxy-6-phenylpyridine was obtained by reacting it with phenol.

9. The synthesis method according to claim 1, characterized in that: The nitrogen-containing heterocyclic nitrogen-ortho-substituted aryl ether is a 1-aryloxyisoquinoline derivative, a 2-aryloxyquinoline derivative, or a 2-aryloxypyridine derivative. 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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