A method for preparing o-aminophenol derivatives by TEMPO continuous dehydrogenation cyclization reaction

Abstract

The application discloses a method for preparing o-aminophenol derivatives through TEMPO continuous dehydrogenation cyclization reaction, and belongs to the field of o-aminophenol compound preparation. The method for preparing o-aminophenol derivatives through TEMPO continuous dehydrogenation cyclization reaction comprises the following steps: under the condition of non-active gas, a mixture containing 2,2,6,6-tetramethylpiperidinooxy, a cyclohexanone compound, a primary amine and a solvent is reacted to obtain the o-aminophenol derivatives. In the case that 2,2,6,6-tetramethylpiperidinooxy (TEMPO) compounds are used as oxidants and oxygen transfer reagents, the cyclohexanone compound and the primary amine are used to form imines and enamines in situ, and through the continuous dehydrogenation cyclization reaction of TEMPO, the preparation of o-aminophenol derivatives is realized.

Description

TECHNICAL FIELD

[0001] The application relates to a method for preparing an ortho-aminophenol derivative through a TEMPO continuous dehydrogenation cyclization reaction, and belongs to the field of preparation of aminophenol compounds. BACKGROUND

[0002] Ortho-aminophenol is an important structure in organic compounds, which is widely present in a series of organic bioactive molecules such as drugs and natural products. However, the current synthesis method is very limited, and most of them need to be obtained through multi-step reactions under harsh conditions starting from compounds with narrow substrate range. Therefore, it is a great challenge for chemists to synthesize ortho-aminophenol compounds in one step under mild conditions through simple and readily available raw materials.

[0003] At present, there are mainly three strategies to synthesize ortho-aminophenol compounds.

[0004] (1) Multi-step synthesis method using simple aromatic hydrocarbon as raw material;

[0005]

[0006] By using ordinary aromatic hydrocarbon as raw material, halogenation, nitration and reduction are sequentially undergone to form a simple ortho-aminophenol compound, and the simple ortho-aminophenol is reacted with various functional group reagents to obtain a complex structure of ortho-aminophenol. However, the reaction condition is harsh, the step is long, and usually only electron-rich aromatic hydrocarbons can be used. And the halogenation and nitration in the intermediate step are often accompanied by a large amount of various meta-para isomer by-products, producing a large amount of toxic and harmful waste, and the overall reaction efficiency is very low.

[0007] (2) Substituted ring closure method using substituted phenol as raw material;

[0008]

[0009] By using phenol substituted with ortho-halogen or halogen-like as raw material, an amino group is generally substituted for a halogen atom under the joint action of a transition metal and a strong base to form an ortho-aminophenol compound. However, the ortho-halogen-substituted amido phenol usually needs to be synthesized in multiple steps, and the strong base used in the reaction will also destroy the sensitive functional groups in the reaction substrate, reducing the range of tolerable functional groups.

[0010] (3) Ortho-C-H bond functionalization method using phenol or aniline derivative as raw material;

[0011]

[0012] By using phenol or aniline derivatives and their derivatives as raw materials, the ortho carbon-hydrogen bond is activated under the catalysis of transition metal to construct new C-N or C-O bond, and then various ortho-aminophenol compounds are obtained by subsequent deprotection reaction. The strategy of this method is to directly use aniline or phenol derivatives as raw materials, and not to construct ortho-aminophenol, so the synthesis of ortho-aminophenol compounds is limited to the range of available aniline or phenol, and the substrate is relatively limited. SUMMARY

[0013] According to one aspect of the present application, a method for preparing ortho-aminophenol derivatives by TEMPO continuous dehydrogenation cyclization reaction is provided. In the case of using 2,2,6,6-tetramethylpiperidine oxide (TEMPO) compounds as oxidants and oxygen transfer reagents, imines and enamines are formed by in-situ condensation of cyclohexanone compounds and primary amines. When the substrate is an alkyl primary amine, the hydrogen bonding of water generated by in-situ condensation can inhibit the further oxidation of the ortho-aminophenol intermediate to stop at the intermediate ortho-aminophenol stage without adding molecular sieves. When the substrate is an aryl primary amine, due to the relatively low nucleophilicity of aryl amines compared to alkyl amines, additional catalysts and molecular sieves are needed to promote and accelerate the dehydration condensation of aryl amines with cyclohexanone compounds, thereby improving the overall yield of aryl ortho-aminophenol. Through the TEMPO continuous dehydrogenation cyclization reaction, we achieve the preparation of various ortho-aminophenol derivatives, solving the problems of harsh reaction conditions, long reaction steps, and low efficiency in the prior art.

[0014] The method for preparing ortho-aminophenol derivatives by TEMPO continuous dehydrogenation cyclization reaction described in the present application comprises: under the condition of non-active gas, a mixture containing 2,2,6,6-tetramethylpiperidine oxide, cyclohexanone compound, primary amine, and solvent is reacted to obtain the ortho-aminophenol derivative.

[0015] The ortho-aminophenol derivative has the following structure shown in formula I:

[0016]

[0017] The cyclohexanone compound has the following structure shown in formula II:

[0018]

[0019] The primary amine has the following structure shown in formula III:

[0020]

[0021] wherein, R 1 is selected from hydrogen, C1-C6 alkyl, C6-C 15 phenyl, substituted C6-C15 phenyl, C 10 -C 20 naphthyl, substituted C 10 -C 20 naphthyl, C6-C 10 heteroaromatic ring, C6-C 10 heteroaromatic ring, C5-C 10 heteroaromatic ring, C1-C 10 ester, substituted C1-C8 amine, straight or branched C1-C6 alkoxy, C3-C8 thiazole, C5-C 10 thiophene, C1-C 10 ether, any one or more of;

[0022] R 2 selected from C2-C 17 alkyl, C2-C 17 alkenyl, substituted C2-C 17 cycloalkyl, substituted C5-C 18 amine, substituted C3-C 10 ether, C6-C 18 phenyl, substituted C6-C 18 phenyl, substituted C 10 -C 15 naphthyl, C5-C 10 heteroaromatic ring, C5-C 10 heteroaromatic ring, C5-C 10 heteroaromatic ring, phosphine-substituted C2-C 17 alkyl, C2-C 17 alkoxy, C1-C 15 ester, any one or more of;

[0023] in R 2 ,

[0024] the substituents of the substituted phenyl are R 2a , R 2a is selected from any one or more of alkyl, halogen, trifluoromethyl, benzyl, trityl, ester, phenyl, pyridine, thiomethyl, thiotrifluoromethyl, trifluoromethoxy, carbonyl, amine, alkoxy, cycloalkyl, heteroatom-containing cycloalkane;

[0025] the substituents of the substituted amine are R 2b , R 2b is selected from any one or more of alkyl, carbonyl, ester, sulfonic acid;

[0026] the substituents of the substituted cycloalkyl are R 2c , R 2cone or more of alkyl, trifluoromethyl, sulfonic acid group, hydroxyl, carbonyl, ester, benzyl, amine;

[0027] When the primary amine contains a benzene ring structure, the mixture further comprises a catalyst and a molecular sieve.

[0028] Optionally, the catalyst is 3,5-diaminobenzoic acid;

[0029] The molecular sieve is a molecular sieve.

[0030] Optionally, the molar ratio of the catalyst and the primary amine is 1:(15-25); preferably, the molar ratio of the catalyst and the primary amine is 1:20.

[0031] Optionally, the mass ratio of the dehydrating agent and 2,2,6,6-tetramethylpiperidine oxide is 1:(0.1-1); preferably, the mass ratio of the dehydrating agent and 2,2,6,6-tetramethylpiperidine oxide is 1:(0.3-0.5).

[0032] Optionally, the alkyl is a linear alkyl, a branched alkyl or a cyclic alkyl;

[0033] The alkenyl is a linear alkenyl, a branched alkenyl or a cyclic alkenyl;

[0034] The amine group is a linear amine group, a branched amine group or a cyclic amine group;

[0035] The ether group is a linear ether group, a branched ether group or a cyclic ether group.

[0036] Optionally, in R 1 ,

[0037] The substituent of the substituted phenyl is R 1a , and R 1a is selected from one or more of alkyl, cycloalkyl, carbonyl, pyrrole, halogen, hydroxyl, alkoxy, fluoromethoxy, fluoromethylsulfonyl, nitro, phenyl, ester;

[0038] The substituent of the substituted amine group is R 1b , and R 1b is selected from one or more of carbonyl, alkyl, alkoxy, siloxy.

[0039] The substituent of the substituted ether group and the substituted naphthyl group in the present application is not limited.

[0040] The reaction equation involved in the present application is as follows:

[0041]

[0042] Optionally, the solvent is 1,4-dioxane.

[0043] Optionally, the molar ratio of the cyclohexanone compound and the primary amine is (1-2):1; preferably, the molar ratio of the cyclohexanone compound and the primary amine is (1.3-1.8):1.

[0044] Optionally, the molar ratio of the cyclohexanone compound and the primary amine is independently selected from any one of 1:1, 1.3:1, 1.4:1, 1.5:1, 1.8:1, 2:1 or a range value between any two of them.

[0045] Optionally, the ratio of the added amount of the solvent and the cyclohexanone compound is (1-2)mL:1mmol; preferably, the ratio of the added amount of the solvent and the cyclohexanone compound is (1.2-1.5)mL:1mmol.

[0046] Optionally, the ratio of the added amount of the solvent and the cyclohexanone compound is independently selected from any one of 1mL:1mmol, 1.2mL:1mmol, 1.3mL:1mmol, 1.4mL:1mmol, 1.5mL:1mmol, 2mL:1mmol or a range value between any two of them.

[0047] Optionally, the molar ratio of the 2,2,6,6-tetramethylpiperidine oxide and the primary amine is (1-5):1; preferably, the molar ratio of the 2,2,6,6-tetramethylpiperidine oxide and the primary amine is (2-4):1.

[0048] Optionally, the molar ratio of the 2,2,6,6-tetramethylpiperidine oxide and the primary amine is independently selected from any one of 1:1, 2:1, 3:1, 4:1, 5:1 or a range value between any two of them.

[0049] Optionally, the temperature of the reaction is 100-140℃; preferably, the temperature of the reaction is 120℃.

[0050] Optionally, the time of the reaction is 30-50h.

[0051] Optionally, after the reaction, spin dry and refine.

[0052] Optionally, the refining condition is that a mixture of petroleum ether and ethyl acetate is used to pass through a column.

[0053] Optionally, the volume ratio of the petroleum ether and the ethyl acetate is 20:1-10:1.

[0054] The present application prepares ortho-aminophenol derivatives by continuous oxidation and dehydrogenation of imine or enamine formed by in-situ condensation of cyclohexanone and primary amine using TEMPO as oxidant. In the above reaction, TEMPO not only acts as oxidant but also as an oxygen transfer reagent.

[0055] The scope of ortho-alkyl aminophenol derivatives synthesized in the present application is as follows:

[0056]

[0057] The scope of ortho-aryl aminophenol derivatives synthesized in the present application is as follows:

[0058]

[0059] The scope of ortho-aminophenol derivatives with bioactive complex structure synthesized in the present application is as follows:

[0060]

[0061] The beneficial effects that can be produced by the present application include:

[0062] (1) The present application provides a preparation method of ortho-aminophenol derivatives. When the substrate is an alkyl primary amine, the hydrogen bond of water generated by in-situ condensation can inhibit the further oxidation of the ortho-aminophenol intermediate to stay at the intermediate ortho-aminophenol stage without adding molecular sieves. When the substrate is an aryl primary amine, additional catalyst and molecular sieves are needed to promote and accelerate the dehydration condensation of aryl amine and cyclohexanone compounds to improve the overall yield of aryl ortho-aminophenol due to the lower nucleophilicity of aryl amine compared to alkyl amine. This new systematic synthesis method of amine phenol has never been reported before, and the ortho-aminophenol product is also an important synthetic precursor of drugs, natural alkaloids and functional materials, which has very broad application prospects.

[0063] (2) The present application realizes the preparation of ortho-aminophenol derivatives by one-step reaction of cyclohexanone compounds and primary amines through the control of the selectivity of TEMPO oxidation, which provides a new way for the preparation of such compounds. This method realizes multiple continuous dehydrogenation and construction of ortho-aminophenol in one-step reaction under neutral conditions, which is simple to operate, environmentally friendly, efficient, and has the advantages of step economy, reducing the synthesis cost.

[0064] (3) The present application not only has simple reaction conditions and low cost, but also has wide application substrates. The reaction has high selectivity and less side reactions without the participation of transition metals. The substituents on the skeleton structure (i.e. R) have good reactivity, and the yield of the finished product is good. BRIEF DESCRIPTION OF DRAWINGS

[0065] Figures 1A-1B Compound A1 prepared in Example 1, successively 1 H spectrum, 13 C spectrum.

[0066] Figures 2A-2B Compound A2 prepared in Example 2, successively 1 H spectrum, 13 C spectrum.

[0067] Figures 3A-3B Compound A3 prepared in Example 3, successively 1 H spectrum, 13 C spectrum.

[0068] Figures 4A-4B Compound A4 prepared in Example 4, successively 1 H spectrum, 13 C spectrum. DETAILED DESCRIPTION

[0069] The present application will be described in detail below with reference to examples, but the present application is not limited to these examples.

[0070] The raw materials in the examples of the present application are all purchased through commercial channels unless otherwise specified.

[0071] The analytical instruments and equipment used in this example: nuclear magnetic resonance spectrometer AVANCE III 400MHz and JEOLECZ400S 400MHz; high-resolution mass spectrometer Themo Fisher Scientific LTQFTICR-MS.

[0072] Example 1: Preparation of ortho-alkylamine phenolic derivative (A1)

[0073] Under nitrogen atmosphere, 4-phenylcyclohexanone (52.2 mg, 0.30 mmol), 1-methyl-3-phenylpropanamine (29.8 mg, 0.2 mmol), TEMPO (118.6 mg, 0.76 mmol), 1,4-dioxane (0.4 mL) were added successively in a 35 mL pressure tube, the pressure tube was capped with a tetrafluoroethylene stopcock and removed from the glove box, and then heated to 120°C for 36 hours of reaction. After the reaction was completed, it was filtered, spin-dried, and columned with petroleum ether: ethyl acetate = 20:1 (volume ratio) to obtain 50.1 mg of the target compound, yellow solid, yield 79%.

[0074] The structure of A1 is shown in formula (3), the structure of the product was detected, and the results are shown in the following table: Figure 1A and Figure 1B .

[0075]

[0076] 4-((4-phenyl-2-butyl)amino)-[1,1'-biphenyl]-3-phenol

[0077] 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),7.48(d,J=7.9Hz,2H),7.37(t,J=7.7Hz ,2H),7.29-7.26(m,2H),7.22-7.15(m,4H),6.99(s,1H),6.95(d,J=8.2Hz,1 H),6.48(d,J=8.7Hz,1H),4.42(d,J=8.9Hz,1H),3.46(p,J=6.5Hz,1H),2.67 (q,J=7.8Hz,2H),1.80(ddt,J=61.1,13.7,7.7Hz,2H),1.18(d,J=6.2Hz,3H).

[0078] 13 C NMR(101MHz,DMSO-d6)δ144.93,142.59,141.32,136.88,129.25,128.79,12 7.86,126.20,125.93,118.60,112.24,110.74,47.47,38.62,32.45,20.98.

[0079] HRMS(DART+):Calcd.for C 22 H 24 ON([M+H] + ):318.1852,found:318.1851.

[0080] Example 2: Preparation of o-aromatic aminophenol derivatives (A2)

[0081] Under a nitrogen atmosphere, 4-methylcyclohexanone (1.57 g, 14 mmol), aniline (0.93 g, 10 mmol), and 3,5-diaminobenzoic acid (76.0 mg, 0.5 mmol) were added sequentially to a 75 mL pressure-resistant tube. Molecular sieve (10.0 g), TEMPO (4.40 g, 28.0 mmol), and 1,4-dioxane (20.0 mL) were used. The reaction was first stirred at room temperature for 1 hour, then heated to 120 °C and reacted for 36 hours. After the reaction was complete, the mixture was filtered, evaporated to dryness, and purified by column chromatography with petroleum ether:ethyl acetate = 20:1 (v / v) to give 1.16 g of the target compound as a brown solid, in 58% yield.

[0082] The structure of A2 is shown in equation (4). The product structure was tested, and the results are shown in the appendix.Figure 2A and Figure 2B .

[0083]

[0084] 5-Methyl-2-(aniline)phenol

[0085] 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 7.13 (t, J = 7.7Hz, 2H), 7.07-7.03 (m, 2H) ,6.90(d,J=7.9Hz,2H),6.70-6.67(m,2H),6.55(d,J=8.0Hz,1H),2.20(s,3H).

[0086] 13 C NMR (101MHz, DMSO-d6) δ149.30,145.81,131.77,129.31,128.11,120.69,120.11,118.49,116.79,115.62,21.12.

[0087] HRMS(ESI+):Calcd.for C 13 H 14 ON([M+H] + ):200.1070,found:200.1072.

[0088] Example 3: Preparation of o-aromatic aminophenol derivatives (A3)

[0089] Under a nitrogen atmosphere, cyclohexanone (1.37 g, 14 mmol), 4-methylaniline (1.07 g, 10 mmol), and 3,5-diaminobenzoic acid (76.0 mg, 0.5 mmol) were added sequentially to a 75 mL pressure-resistant tube. Molecular sieve (10.0 g), TEMPO (4.40 g, 28.0 mmol), and 1,4-dioxane (20.0 mL) were used. The reaction was first stirred at room temperature for 1 hour, then heated to 120 °C and reacted for 36 hours. After the reaction was complete, the mixture was filtered, evaporated to dryness, and purified by column chromatography with petroleum ether:ethyl acetate = 20:1 (v / v) to give 1.72 g of the target compound as a brown solid, in 86% yield.

[0090] The structure of A3 is shown in equation (5), and the product structure is tested.

[0091]

[0092] 2-(p-Toluidine)phenol

[0093] 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 7.12-7.10 (m, 1H), 7.02-6.94 (m, 5H), 6.85-6.83 (m, 1H), 6.71-6.69 (m, 2H), 2.21 (s, 3H).

[0094] 13 C NMR (101 MHz, DMSO-d6) δ 147.77, 142.01, 132.02, 129.85, 128.33, 120.96, 119.68, 117.44, 117.31, 115.68, 20.77.

[0095] HRMS (ESI+): Calcd. for C 13 H 14 ON ([M+H] + ): 200.1070, found: 200.1073.

[0096] Example 4: Preparation of ortho-arylamino phenolic derivative (A4)

[0097] Into a 75 mL pressure tube was added n-octyl p-cyclohexanone carboxylate (3.56 g, 14 mmol), aniline (0.93 g, 10 mmol), 3,5-diaminobenzoic acid (76.0 mg, 0.5 mmol), 4- methoxyphenylboronic acid (1.20 g, 10 mmol), potassium carbonate (2.70 g, 20 mmol), Pd(PPh3)4(0.40 g, 0.5 mmol) under nitrogen atmosphere, and the mixture was stirred at 120 °C for 36 h. After the reaction was completed, the mixture was filtered and dried, and the residue was purified by column chromatography using petroleum ether: ethyl acetate = 20: 1 (volume ratio) to give the target compound 2.20 g, white solid, yield 65%.

[0098] 3-hydroxy-4-(phenylamino)benzoic acid n-octyl ester

[0099]

[0100] 1 ​H NMR (400 MHz, CDC13) δ 7.84 (d, J = 1.9 Hz, 1H), 7.55 (dd, J = 8.5, 1.9 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.25 - 7.17 (m, 3H), 7.04 (t, J = 7.4 Hz, 1H), 4.30 (t, J = 6.6 Hz, 2H), 1.78 - 1.71 (m, 2H), 1.46 - 1.39 (m, 2H), 1.36 - 1.27 (m, 8H), 0.89 - 0.86 (m, 3H).

[0101] 13 C NMR (101 MHz, CDC13) δ 167.67, 144.03, 141.04, 137.27, 129.40, 123.40, 122.64, 120.55, 120.08, 116.15, 112.65, 65.21, 31.78, 29.25, 29.19, 28.70, 26.03, 22.63, 14.08.

[0102] HRMS (ESI+): Calcd. for C 21 H 28 O3N ([M+H] + ): 342.2064, found: 342.2066.

[0103] The above is only a few embodiments of the present application, not any form of the application is limited, although the application is disclosed as above, however, not to limit the application, any skilled in the art, without departing from the scope of the technical solutions of the present application, using the above disclosed technical content to make some changes or modifications are equivalent to equivalent embodiments, all within the scope of the technical solutions.

Claims

1. A method for preparing ortho-aminophenol derivatives by TEMPO continuous dehydrogenative cyclization reaction, characterized in that, The application relates to a preparation method of an ortho-aminophenol derivative. The mixture containing 2,2,6,6-tetramethylpiperidine oxide, a cyclohexanone compound, a primary amine and a solvent is reacted under a non-active gas condition to obtain the ortho-aminophenol derivative. The ortho-aminophenol derivative has the following structure shown in formula I. Formula I; The cyclohexanone compound has the following structure shown in formula II. Formula II; The primary amine has the following structure shown in formula III. Formula III; Among them, R 1 Selected from hydrogen, C1-C6 alkyl, C6-C 15 Phenyl, substituted C6-C 15 Phenyl, C 10 -C 20 Naphthyl, substituted C 10 -C 20 Naphthyl group, C6-C containing nitrogen atoms 10 Aromatic heterocycles, cyclohexanone glycol ketal, C5-C containing sulfur atoms 10 Aromatic heterocycles, trifluoromethyl, C1-C 10 Ester group, substituted C1-C8 amino group, straight-chain or branched C1-C6 alkoxy group, C3-C8 thiazole group, C5-C 10 Thiophene, C1-C 10 Any one or more of the ether groups; In R 1 , the substituents of the substituted phenyl are R 1a , R 1a is selected from any one or more of alkyl, cycloalkyl, carbonyl, pyrrole, halogen, hydroxy, alkoxy, fluoromethoxy, fluoromethylsulfonyl, nitro, phenyl, ester. The substituent of the substituted amine group is R 1b , the R 1b is selected from any one or more of a carbonyl group, an alkyl group, an alkoxy group, a siloxy group; R 2 selected from C2-C 17 alkyl, substituted C2-C 17 cycloalkyl, substituted C5-C 18 amine, substituted C3-C 10 ether, C6-C 18 phenyl, substituted C6-C 18 phenyl, substituted C 10 -C 15 naphthyl, nitrogen-containing C5-C 10 aromatic heterocycle, oxygen-containing C5-C 10 aromatic heterocycle, C2-C 17 alkoxy, C1-C 15 ester; In R 2 , The substituents of the substituted phenyl are R 2a , the R 2a are selected from any one or more of alkyl, halogen, trifluoromethyl, benzyl, trityl, ester, phenyl, pyridine, thiomethyl, trifluoromethylthio, trifluoromethoxy, carbonyl, amine, alkoxy, cycloalkyl, heteroatom-containing cycloalkane. The substituents of the substituted amine group are R 2b , which is selected from any one or more of alkyl, carbonyl, ester, sulfonic acid 2b ; The substituents of the substituted cycloalkyl are R 2c , the R 2c is selected from one or more of alkyl, trifluoromethyl, sulfonic acid group, hydroxyl, carbonyl, ester, benzyl, amine. When the primary amine is directly connected with the benzene ring structure, the mixture further comprises a catalyst and a molecular sieve. The catalyst is 3,5-diaminobenzoic acid. The molecular sieve is 4A molecular sieve.

2. The process for the preparation of ortho-aminophenolic derivatives by TEMPO continuous dehydrocyclization reaction according to claim 1, characterized in that, The molar ratio of the catalyst to the primary amine is 1: (15-25).

3. The process for the preparation of ortho-aminophenolic derivatives by TEMPO continuous dehydrocyclization reaction according to claim 1, characterized in that, The mass ratio of the molecular sieve to the 2,2,6,6-tetramethylpiperidine oxide is 1: (0.1-1).

4. The process for the preparation of ortho-aminophenolic derivatives by TEMPO continuous dehydrocyclization reaction according to claim 1, characterized in that, The alkyl group is a linear alkyl group, a branched alkyl group or a cyclic alkyl group. The amine group is a linear amine group, a branched amine group or a cyclic amine group. The ether group is a linear ether group, a branched ether group or a cyclic ether group.

5. The process for the preparation of ortho-aminophenolic derivatives by TEMPO continuous dehydrocyclization reaction according to claim 1, characterized in that, The molar ratio of the cyclohexanone compound to the primary amine is (1-2):

1. The adding amount ratio of the solvent to the cyclohexanone compound is (1-2) mL: 1 mmol. The molar ratio of the 2,2,6,6-tetramethylpiperidine oxide to the primary amine is (1-5):

1.

6. The process for the preparation of ortho-aminophenolic derivatives by TEMPO continuous dehydrocyclization reaction according to claim 1, characterized in that, The reaction temperature is 100-140 DEG C. The reaction time is 30-50 h.

7. The process for the preparation of ortho-aminophenolic derivatives by TEMPO continuous dehydrocyclization reaction according to claim 1, characterized in that, After the reaction is completed, the product is spin-dried and refined. The refining condition is that a mixture of petroleum ether and ethyl acetate is used to pass through a column.

8. The process for the preparation of ortho-aminophenolic derivatives by TEMPO continuous dehydrocyclization reaction according to claim 7, characterized in that, The volume ratio of the petroleum ether to the ethyl acetate is 20:1-10:1.

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