Preparation method for 2-amino-5-fluorophenol and intermediate thereof

Abstract

Provided is a new preparation method for preparing 2-amino-5-fluorophenol and an intermediate thereof. The method uses easily available raw materials for the reaction, involves mild conditions, is convenient to operate, has a high yield, discharges a small amount of three wastes, and is safe in terms of process and suitable for industrial production.

Description

A preparation method of 2-amino-5-fluorophenol and its intermediate Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-amino-5-fluorophenol and an intermediate thereof. Background Art

[0002] 2-amino-5-fluorophenol is an important chemical intermediate that is widely used in the preparation of medicines, pesticides and special materials. For example, 2-amino-5-fluorophenol is used to prepare drugs for treating diseases such as airway obstruction, bronchiectasis, cystic fibrosis, asthma, emphysema and chronic obstructive pulmonary disease (WO2022042591A1, CN101014564B); for preparing drugs for treating parasitic diseases (CN105164124B); for preparing drugs for treating and / or preventing cancer or chronic inflammation (CN103209980B). In addition, 2-amino-5-fluorophenol is used to prepare highly effective herbicides such as fluazifop (US4792605A), thiadiazole (DE4008691A1), and trifluoperazine (CN102459205B). Recently, 2-amino-5-fluorophenol has been used to prepare a new high-temperature resistant composite material for use in aerospace, electronic packaging and other fields (CN111393642B).

[0003] There are five main methods for preparing 2-amino-5-fluorophenol:

[0004] The first method uses 2-nitro-5-fluorophenol as raw material. The method uses palladium carbon as catalyst, ethanol as solvent, and hydrogenation catalytic reduction of nitro to prepare the target compound (CN102762552B). The method yield is greater than 99%, but uses 5-fluoro-2-nitrophenol raw material (CN101948389A) with explosion risk and no commercial supply, which is not suitable for large-scale industrial production. In addition, the raw material 5-fluoro-2-nitrophenol used in the method is usually prepared by hydrolysis reaction of 2,4-difluoronitrobenzene under strong alkaline conditions (CN106083536B), and the hydrolysis reaction has selectivity problems, which leads to a decrease in yield and an increase in three wastes.

[0005] The second method uses 6-fluorobenzoxazole as the starting material. Under alkaline conditions, this method uses platinum as a catalyst and N-bromobenzenesulfonamide as an oxidant to produce the target product through an oxidative ring-opening hydrolysis reaction (Chemical Engineering Journal 163(2010)403–412). This method achieves a 93% yield, but uses a costly palladium catalyst. Furthermore, the oxidant, bromobenzenesulfonamide, is expensive, atom-uneconomical, and produces significant amounts of waste, making it unsuitable for industrial production.

[0006] The third method uses 2,4-difluoroaniline as the raw material. This method uses potassium hydroxide as a base, reacts at 50-80°C, and then acidifies and steam distills to produce 2-amino-5-fluorophenol (CN107459495A). Although the 2,4-difluoroaniline conversion rate exceeds 99.5%, the raw material used in this method is expensive, commercially unavailable, and difficult to obtain in large quantities.

[0007] The fourth method uses 4-fluoronitrobenzene as the raw material. Using zinc powder as a reducing agent, in the presence of benzaldehyde and ammonium chloride, this method first produces an α-phenylnitrone intermediate, which is then reacted with trichloroacetyl chloride to obtain the target product, 2-amino-5-fluorophenol hydrochloride (CN106496044A). This method is cumbersome, with a two-step yield of only 5.65%. It also produces a large amount of waste, making it unsuitable for industrial production.

[0008] The fifth method uses p-fluoronitrobenzene as the starting material. This method uses nitroreductase to reduce the nitro group to p-fluorophenylhydroxylamine, which is then catalyzed by a specially prepared hydroxyaminobenzene mutase to rearrange 2-amino-5-fluorophenol (WO2014104668A1). This method has a yield of only 60%, and the hydroxyaminobenzene mutase used is difficult to obtain, making it unsuitable for industrial production.

[0009] Summary of the Invention

[0010] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing 2-amino-5-fluorophenol and an intermediate thereof, which has readily available raw materials, mild reaction and high yield.

[0011] The first object of the present invention is to provide a method for preparing 2-amino-5-fluorophenol (I), which comprises the following steps:

[0012] Step 1: In the presence of a base 1, the compound of formula (II) reacts with the compound of formula (III) to produce a compound of formula (IV);

[0013] Step 2: reacting the compound of formula (IV) with the compound of formula (V) to produce the compound of formula (VI);

[0014] Step 3: The compound of formula (VI) is subjected to hydrolysis reaction to generate 2-amino-5-fluorophenol (I);

[0015] The reaction formula is as follows:

[0016] in,

[0017] A and B are independently selected from one of C, S and P atoms.

[0018] When A is C, n is 1 and m is 0;

[0019] When A is S, n is 1 and m is 0 or 1;

[0020] When A is P, n is 2 and m is 0.

[0021] The L1 and L2 are independently leaving groups; the leaving group is preferably halogen, R3C(=O)O-, R3S(=O)2O-; further preferably Cl, CH3C(=O)O-, CCl3C(=O)O-, ClCH2C(=O)O-, CH3S(=O)2O-, CF3S(=O)2O-.

[0022] A plurality of R1s may be the same or different.

[0023] R1, R2, and R3 are independently any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; more preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, and unsubstituted or substituted phenyl.

[0024] The heteroaryl group is a heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms, such as pyrazolyl, thiazolyl, thienyl, pyridyl, pyrimidinyl, and the like.

[0025] In step 1, the base 1 is one or more inorganic bases or organic bases. The inorganic bases include carbonates, bicarbonates, phosphates, hydroxides, hydrides, and amides of alkali metals; carbonates, bicarbonates, phosphates, hydroxides, oxides, hydrides, and amides of alkaline earth metals. The inorganic bases are preferably carbonates, bicarbonates, and hydroxides of alkali metals, and carbonates, bicarbonates, and hydroxides of alkaline earth metals; and more preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.

[0026] The organic base includes one or more organic salts or organic amines, the organic salts include alkyl carboxylates and aryl carboxylates, alkoxy salts, metal alkyls, and metal aryls; the organic amines include alkylamines and arylamine compounds; the alkylamines are preferably tertiary amines, more preferably triethylamine; the arylamines are preferably pyridinamines, more preferably pyridine and picoline.

[0027] The compound of formula (III) in step 1 and the compound of formula (V) in step 2 are independently an acyl halide, an acid anhydride, or a chloroformate, wherein the acyl halide is an unsubstituted or substituted C1-C8 alkyl acyl halide, an unsubstituted or substituted C1-C8 alkyl sulfonyl halide, an unsubstituted or substituted C3-C10 cycloalkyl acyl halide, an unsubstituted or substituted C6-C12 aryl acyl halide, an unsubstituted or substituted C6-C12 sulfonyl halide, an alkyl phosphoryl halide, an aryl phosphoryl halide, or an unsubstituted or substituted heteroaryl acyl halide. Selected are acetyl chloride, chloroacetyl chloride, bromoacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, tribromoacetyl chloride, acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, bromoacetic anhydride, methyl chloroformate, ethyl chloroformate, 2-chloro-2,2-difluoroacetyl chloride, 2-bromo-2,2-difluoroacetyl chloride, 2-bromo-2,2-dichloroacetyl chloride, benzenesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methylsulfonyl chloride, methylsulfonic anhydride, dimethylphosphoryl chloride, and diarylphosphoryl chloride.

[0028] The reaction temperature is -20 to 40°C, preferably -15 to 25°C, more preferably -15 to 5°C.

[0029] The molar ratio of compound (II) to base 1 is 1:1-2, preferably 1:1-1.5, more preferably 1:1-1.2;

[0030] The molar ratio of compound (II) to the compound of formula (III) is 1:1-2, preferably 1:1-1.5, and more preferably 1:1-1.2.

[0031] The solvent used is an organic solvent or a mixture thereof with water, wherein the organic solvent is one or more of an aromatic hydrocarbon solvent, an amide solvent, a (sub)sulfone solvent, a halogenated hydrocarbon solvent, an ether solvent, and an ester solvent: an aromatic hydrocarbon solvent such as a C6-C12 aromatic hydrocarbon solvent, specifically toluene, xylene, and trimethylbenzene; an amide solvent such as a C1-C6 amide solvent, specifically dimethylformamide and dimethylacetamide; a (sub)sulfone solvent such as a C1-C6 (sub)sulfone solvent, specifically dimethyl sulfoxide and sulfolane; a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; an ether solvent such as methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran; an ester solvent such as ethyl acetate; preferably toluene, tetrahydrofuran, methyltetrahydrofuran, and ethyl acetate.

[0032] The reaction temperature in step 2 is 20-120°C, preferably 30-80°C, more preferably 40-60°C;

[0033] The molar ratio of the compound of formula (IV) to the compound of formula (V) is 1:1-2, preferably 1:1-1.5, and more preferably 1:1-1.2.

[0034] The solvent used is an organic solvent or a mixture thereof with water, wherein the organic solvent is one or more of an aromatic hydrocarbon solvent, an amide solvent, a (sub)sulfone solvent, a halogenated hydrocarbon solvent, an ether, and an ester solvent: an aromatic hydrocarbon solvent such as a C6-C12 aromatic hydrocarbon solvent, specifically such as toluene, xylene, and trimethylbenzene; an amide solvent such as a C1-C6 amide solvent, specifically such as dimethylformamide and dimethylacetamide; a (sub)sulfone solvent such as a C1-C6 (sub)sulfone solvent, specifically such as dimethyl sulfoxide and sulfolane; a halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; an ether solvent such as methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran; an ester solvent such as ethyl acetate; and preferably a halogenated alkane, an aromatic hydrocarbon, acetonitrile, and tetrahydrofuran.

[0035] Step 3 is carried out under the action of acid or base 2;

[0036] The acid is a proton acid or a Lewis acid; the proton acid is hydrofluoric acid, hydrochloric acid, sulfuric acid, or phosphoric acid; the Lewis acid is AlCl3, FeCl3, SbCl5, SnCl4, BCl3, TiCl4, or ZnCl 2、 MgCl2, alkyl aluminum, alkyl boron; preferably protonic acid, more preferably hydrochloric acid, sulfuric acid;

[0037] The base 2 can be one or more inorganic bases or organic bases; the inorganic base is an alkali metal hydroxide, carbonate, bicarbonate, or an alkaline earth metal hydroxide, oxide, carbonate, or bicarbonate; preferably an alkali metal hydroxide or an alkaline earth metal hydroxide; more preferably sodium hydroxide or potassium hydroxide; the organic base is an organic amine, preferably a primary amine or a secondary ammonium.

[0038] The reaction temperature is 20 to 120°C, preferably 50 to 120°C, and more preferably 80 to 100°C.

[0039] The molar ratio of the compound of formula (VI) to the acid is 1:1-2, preferably 1:1-1.5, more preferably 1:1-1.2;

[0040] In step 3, a solvent is selectively used. The solvent is preferably a polar solvent, such as one or more of an alcohol solvent, a (sulfoxide) solvent, an amide solvent, or water. Alcohol solvents include C1-C10 alcohol solvents, such as methanol, ethanol, n-propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, glycerol, etc.; (sulfoxide) solvents include C1-C6 (sulfoxide) solvents, such as dimethyl sulfoxide and sulfolane; and amide solvents include C1-C6 amide solvents, such as N-methylpyrrolidone, dimethylformamide, and dimethylacetamide.

[0041] 2-Amino-5-fluorophenol (I) can be prepared from the compound of formula (II) in one pot.

[0042] The second object of the present invention is to provide an intermediate compound (IV) for preparing 2-amino-5-fluorophenol (I), the structural formula of which is as follows:

[0043] in,

[0044] A and B are independently selected from one of C, S, and P atoms;

[0045] When A is C, n is 1 and m is 0;

[0046] When A is S, n is 1 and m is 0 or 1;

[0047] When A is P, n is 2 and m is 0;

[0048] Multiple R1s can be the same or different;

[0049] When A is C, R1 is unsubstituted C2-C8 alkyl, substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl, preferably halogen-substituted C1-C8 alkyl, unsubstituted or substituted C6-C12 aryl, more preferably chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, chlorodifluoromethyl, bromodifluoromethyl, or substituted phenyl;

[0050] When A is S, n is 1, and m is 0, R1 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, and more preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, or unsubstituted or substituted phenyl;

[0051] When A is S, n is 1, and m is 1, R1 is unsubstituted C2-C8 alkyl, substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, or unsubstituted or substituted heteroaryl, preferably unsubstituted C2-C3 alkyl, substituted C1-C3 alkyl, unsubstituted or substituted C1-C3 alkoxy, or unsubstituted or substituted C6-C12 aryl, more preferably chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, or unsubstituted or substituted phenyl;

[0052] When A is P, R1 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, and more preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, and unsubstituted or substituted phenyl.

[0053] Compared with the prior art, the present invention has the following significant features and advantages:

[0054] (1) The present invention provides a new strategy and new intermediate compound for preparing 2-amino-5-fluorophenol;

[0055] (2) The raw and auxiliary materials for the reaction are easily available, and no special reaction equipment is required;

[0056] (3) Mild conditions and easy operation;

[0057] (4) The process is safe, with less waste, less waste and high yield;

[0058] (5) Suitable for industrial production.

[0059] Group Definition

[0060] The halogen mentioned herein means fluorine, chlorine, bromine and iodine.

[0061] The term "substituted" as used herein means that one or more hydrogen atoms on a carbon atom or a nitrogen atom are independently replaced by halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C9 cycloalkyl, C3-C9 halocycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkyl sulfinyl, C1-C6 haloalkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, C2-C7 alkylcarbonyl, C2-C7 haloalkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 haloalkylcarbonyloxy, C1-C6 alkylsulfonyloxy, C1-C6 haloalkylsulfonyloxy, C2-C7 alkoxycarbonyl, C2-C7 haloalkoxycarbonyl, C2-C7 alkylcarbonylamino, C2-C7 haloalkyl C2-C7 alkylamino, C2-C7 alkylcarbonylamino, C2-C7 haloalkoxycarbonylamino, C2-C7 alkylaminocarbonyl, C2-C7 haloalkylaminocarbonyl, C1-C6 alkylamino, C1-C6 haloalkylamino, C2-C6 alkenylamino, C2-C6 haloalkenylamino, C2-C6 alkynylamino, C2-C6 haloalkynylamino, C3-C9 cycloalkylamino, C3-C9 halocycloalkylamino, C3-C7 alkenylaminocarbonyl alkyl, C3-C7 haloalkenylaminocarbonyl, C3-C7 alkynylaminocarbonyl, C3-C7 haloalkynylaminocarbonyl, C4-C10 cycloalkylaminocarbonyl, C4-C10 halocycloalkylaminocarbonyl, amino, carbamoyl, sulfamoyl, cyano, nitro, hydroxy, carboxyl, phenyl which may have a substituent, heterocyclic group which may have a substituent, benzyl which may have a substituent, phenylcarbonyl which may have a substituent, and phenylamino which may have a substituent, are substituted. DETAILED DESCRIPTION

[0062] The following embodiments clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only a portion of the embodiments of the present invention, not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0063] Example 1

[0064] 18.45 g of p-fluorophenylhydroxylamine was dissolved in 40 mL of tetrahydrofuran and cooled to -15°C to -20°C. Then, 19 g of triethylamine and 17 g of chloroacetyl chloride were added, and the internal temperature was controlled at about -15°C. After the reaction was completed, conventional post-treatment was performed to obtain 29.5 g of the product 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide with a yield of 97%.

[0065] 1 H NMR (CDCl3, 500MHz, TMS) δ 10.73 (s, 1H), 6.90-6.87 (m, 2H), 6.82-6.78 (m, 2H,), 4.59 (s, 2H).

[0066] Example 2

[0067] 17 g of p-fluorophenylhydroxylamine was dissolved in 40 mL of ethyl acetate and cooled to -5 to 0°C. 16.8 g of chloroacetyl chloride and 145.6 g of a 10% aqueous sodium bicarbonate solution were then added dropwise. After the addition was complete, the mixture was kept warm until the reaction was complete. Conventional post-treatment afforded 26.2 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide in a yield of 98%.

[0068] Example 3

[0069] 12 g of p-fluorophenylhydroxylamine was dissolved in 30 mL of methyltetrahydrofuran and cooled to -15°C to -20°C. Then, 10.5 g of triethylamine and 7.9 g of acetyl chloride were added. The internal temperature was controlled at about -15°C. The reaction was terminated by mid-control. After conventional post-treatment, 16.2 g of the product N-(4-fluorophenyl)-N-hydroxyacetamide was obtained with a yield of 96%.

[0070] Example 4

[0071] Dissolve 17g of p-fluorophenylhydroxylamine in 40mL of toluene, cool to -20 to -15°C, then dropwise add 13.6g of acetyl chloride and 17.04g of triethylamine. After the addition is complete, incubate and allow to react until the reaction is complete. Conventional post-processing yields 22g of N-(4-fluorophenyl)-N-hydroxyacetamide in a 97% yield.

[0072] 1 H NMR (CDCl3, 500MHz, TMS) δ10.47 (s, 1H), 7.68-7.60 (m, 2H), 7.25-7.16 (m, 2H), 2.18 (s, 3H).

[0073] Example 5

[0074] Dissolve 17g of p-fluorohydroxylamine in 30mL of dichloromethane, cool to -20-15°C, then dropwise add 18.8g of ethyl chloroformate and 13.3g of pyridine. After the addition is complete, incubate and allow to react until the reaction is complete. Conventional post-processing yields 26g of ethyl N-(4-fluorophenyl)-N-hydroxyformate in a 93% yield.

[0075] 1H NMR (CDCl3, 500MHz, TMS) δ7.43-7.22 (m, 2H), 7.19-7.08 (m, 2H), 4.33 (q, J = 7.0Hz, 2H,), 1.33 (t, J = 7.0Hz, 3H).

[0076] Example 6

[0077] Dissolve 17g of p-fluorohydroxylamine in 30mL of dimethyl sulfoxide, cool to -20-15°C, then dropwise add 30.6g of benzenesulfonyl chloride and 13.3g of pyridine. After the addition is complete, incubate and allow to react until the reaction is complete. Conventional post-processing yields 34g of N-(4-fluorophenyl)-N-hydroxybenzenesulfonamide (95% yield).

[0078] 1 H NMR (CDCl3, 500MHz, TMS) δ7.66-7.62(m,1H),7.56-7.54(m,2H), 7.46-7.43(m,2H),7.13-7.10(m,2H,),6.96-6.92(m,2H).

[0079] Example 7

[0080] Dissolve 17g of p-fluorophenylhydroxylamine in 30mL of sulfolane, cool to -20 to -15°C, then dropwise add 19.8g of methanesulfonyl chloride and 13.3g of pyridine. After the addition is complete, incubate and allow to react until the reaction is complete. Conventional post-processing yields 25g of N-(4-fluorophenyl)-N-hydroxymethanesulfonamide in a 96% yield.

[0081] 1 H NMR (CDCl3, 500MHz, TMS) δ7.50-7.47 (m, 2H), 7.10-7.06 (m, 2H), 2.86 (s, 3H).

[0082] Example 8

[0083] 20.3 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide prepared in Example 1 or 2 was dissolved in 50 mL of chloroform, and the air in the flask was replaced with nitrogen. The temperature was raised to 45-50° C., and 21.35 g of trichloroacetyl chloride was added. After the reaction was completed in the intermediate control, conventional post-treatment was performed to obtain 19.3 g of 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide, with a yield of 95%.

[0084] Example 9

[0085] 8.5 g of N-(4-fluorophenyl)-N-hydroxyacetamide prepared in Example 3 or 4 was dissolved in 50 mL of toluene, and the air in the flask was replaced with nitrogen. The temperature was raised to 50° C., and 17 g of trichloroacetic anhydride was added. After the reaction was completed in the intermediate control, conventional post-treatment was performed to obtain 8 g of the product, N-(4-fluoro-2-hydroxyphenyl)acetamide, in a yield of 95%.

[0086] Example 10

[0087] The target compound obtained in Example 6 was treated according to the method of Example 8 or 9 to obtain N-(4-fluoro-2-hydroxyphenyl)benzenesulfonamide with a yield of 92%.

[0088] 1 H NMR (500MHz, DMSO) δ10.02(s,1H),9.32(s,1H),7.70(d,J=7.5Hz,2H),7.60(t,J= 7.3Hz, 1H), 7.52 (t, J = 7.6Hz, 2H), 7.09 (dd, J = 8.6, 6.5Hz, 1H), 6.60–6.47 (m, 2H).

[0089] Example 11

[0090] The target compound obtained in Example 7 was treated according to the method of Example 8 or 9 to obtain N-(4-fluoro-2-hydroxyphenyl)methanesulfonamide with a yield of 90%.

[0091] 1 H NMR (500MHz, DMSO) δ10.36 (s, 1H), 8.77 (s, 1H), 7.17 (dd, J = 8.6, 6.5Hz, 1H), 6.72–6.56 (m, 2H), 2.91 (s, 3H).

[0092] Example 12

[0093] 19.3 g of the target compound obtained in Example 8 was added to 40 g of 10% hydrochloric acid solution, heated to 80° C., and stirred. After the intermediate control reaction was complete, conventional post-treatment was performed to obtain 11.8 g of 2-amino-5-fluorophenol with a yield of 98%.

[0094] Example 13

[0095] 8 g of the target compound obtained in Example 9 was added to 20 g of a 10% sulfuric acid solution, heated to 100° C., and stirred. After the intermediate control reaction was complete, conventional post-treatment was performed to obtain 6.1 g of 2-amino-5-fluorophenol with a yield of 96%.

[0096] Example 14

[0097] 20.3 g of 2-chloro-N-(4-fluorophenyl)-N-hydroxyacetamide prepared according to the method of Example 1 was dissolved in 50 mL of ethyl acetate. Under nitrogen protection, the temperature was raised to 45-55 degrees Celsius, and trichloroacetyl chloride was added. After the reaction was completed, 40 g of 10% hydrochloric acid was added, and the temperature was raised to reflux until the reaction was complete. After conventional post-treatment, 10.5 g of 2-amino-5-fluorophenol was obtained with a yield of 82%.

[0098] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 2-amino-5-fluorophenol (I), comprising the steps of: Step 1: In the presence of a base 1, the compound of formula (II) reacts with the compound of formula (III) to produce a compound of formula (IV); Step 2: reacting the compound of formula (IV) with the compound of formula (V) to produce the compound of formula (VI); Step 3: The compound of formula (VI) undergoes hydrolysis reaction to generate 2-amino-5-fluorophenol (I); The reaction formula is as follows: in, A and B are independently selected from one of C, S, and P atoms; When A is C, n is 1 and m is 0; When A is S, n is 1 and m is 0 or 1; When A is P, n is 2 and m is 0; The L1 and L2 are independently leaving groups; the leaving groups are preferably halogen, R3C(=O)O-, R3S(=O)2O-; Multiple R1s can be the same or different; R1, R2, and R3 are independently any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl.

2. The method according to claim 1, characterized in that R1, R2, and R3 are preferably unsubstituted or substituted C1-C3 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C3 alkoxy, unsubstituted or substituted C6-C12 aryl, or unsubstituted or substituted heteroaryl.

3. The method according to claim 2, characterized in that R1, R2, and R3 are preferably methyl, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, chlorodifluoromethyl, bromodifluoromethyl, bromodichloromethyl, unsubstituted or substituted phenyl, pyrazolyl, thiazolyl, thienyl, pyridyl, or pyrimidinyl.

4. The method according to claim 1, wherein The base 1 in step 1 is one or more inorganic bases or organic bases; and step 3 is carried out under the action of acid or base 2.

5. The method according to claim 4, characterized in that The inorganic base described in step 1 includes carbonates, bicarbonates, phosphates, hydroxides, hydrides, and amides of alkali metals; carbonates, bicarbonates, phosphates, hydroxides, hydrides, and amides of alkaline earth metals; the organic base described in step 1 includes one or more organic salts or organic amines; the acid described in step 3 is a protonic acid or a Lewis acid; and the base 2 is one or more inorganic bases or organic bases.

6. The method according to claim 5, characterized in that The inorganic base in step 1 is preferably a carbonate, bicarbonate, hydroxide of an alkali metal, a carbonate, bicarbonate, hydroxide, oxide of an alkaline earth metal; the organic salt includes an alkyl carboxylate and an aryl carboxylate, an alkoxy salt, a metal alkyl, and a metal aryl; the organic amine includes an alkylamine and an arylamine compound; the protonic acid in step 3 is hydrofluoric acid, hydrochloric acid, sulfuric acid, and phosphoric acid; the Lewis acid is AlCl3, FeCl3, SbCl5, SnCl4, BCl3, TiCl4, and ZnCl 2、 MgCl2, alkyl aluminum, alkyl boron; the inorganic base is alkali metal hydroxide, carbonate, bicarbonate, alkaline earth metal hydroxide, carbonate, bicarbonate; the organic base is organic amine.

7. The method according to claim 6, characterized in that The inorganic base described in step 1 is preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; the alkylamine is a tertiary amine, preferably triethylamine; the arylamine is a pyridylamine, preferably pyridine or picoline; the acid described in step 3 is preferably a protonic acid, more preferably hydrochloric acid or sulfuric acid; the organic base is preferably a primary amine or a secondary ammonium base.

8. The method according to claim 1, characterized in that 2-Amino-5-fluorophenol (I) can be prepared from the compound of formula (II) in one pot.

9. The compound represented by formula (IV) has the following structural formula: in, A and B are independently selected from one of C, S, and P atoms; When A is C, n is 1 and m is 0; When A is S, n is 1 and m is 0 or 1; When A is P, n is 2, and m is 0; multiple R1s may be the same or different; When A is P, R1 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; When A is C, R1 is an unsubstituted C2-C8 alkyl group, a substituted C1-C8 alkyl group, an unsubstituted or substituted C3-C10 cycloalkyl group, an unsubstituted or substituted C1-C8 alkoxy group, an unsubstituted or substituted C6-C12 aryl group, or an unsubstituted or substituted heteroaryl group; When A is S, n is 1, and m is 0, R1 is any one of hydrogen, unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C1-C8 alkoxy, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl; When A is S, n is 1, and m is 1, R1 is an unsubstituted C2-C8 alkyl group, a substituted C1-C8 alkyl group, an unsubstituted or substituted C1-C8 alkoxy group, an unsubstituted or substituted C6-C12 aryl group, or an unsubstituted or substituted heteroaryl group.

10. The compound according to claim 9, characterized in that When A is P, R1 is preferably an unsubstituted or substituted C1-C3 alkyl group, an unsubstituted or substituted C1-C3 alkoxy group, or an unsubstituted or substituted C6-C12 aryl group; When A is C, R1 is preferably a halogen-substituted C1-C8 alkyl group, an unsubstituted or substituted C6-C12 aryl group, and more preferably a chloromethyl group, a bromomethyl group, a dichloromethyl group, a trichloromethyl group, a tribromomethyl group, a methoxy group, an ethoxy group, a chlorodifluoromethyl group, a bromodifluoromethyl group, a bromodichloromethyl group, or a substituted phenyl group; When A is S, n is 1, and m is 0, R1 is preferably an unsubstituted or substituted C1-C3 alkyl group, an unsubstituted or substituted C1-C3 alkoxy group, or an unsubstituted or substituted C6-C12 aryl group, and more preferably a methyl group, a chloromethyl group, a bromomethyl group, a dichloromethyl group, a trichloromethyl group, a tribromomethyl group, a methoxy group, an ethoxy group, a chlorodifluoromethyl group, a bromodifluoromethyl group, a bromodichloromethyl group, or an unsubstituted or substituted phenyl group; When A is S, n is 1, and m is 1, R1 is preferably an unsubstituted C2-C3 alkyl group, a substituted C1-C3 alkyl group, an unsubstituted or substituted C1-C3 alkoxy group, an unsubstituted or substituted C6-C12 aryl group, and more preferably a chloromethyl group, a bromomethyl group, a dichloromethyl group, a trichloromethyl group, a tribromomethyl group, a methoxy group, an ethoxy group, a chlorodifluoromethyl group, a bromodifluoromethyl group, a bromodichloromethyl group, or an unsubstituted or substituted phenyl group.