Preparation method of 2-chloro-3-fluoro-4-alkoxy-aniline and 2-fluoro-3-chlorophenol

Abstract

The invention relates to a novel method for preparing 2-chloro-3-fluoro-4-alkoxy-aniline, and the 2-chloro-3-fluoro-4-alkoxy-aniline can be further converted into 2-fluoro-3-chlorophenol. The invention also relates to a preparation method of the 2-chloro-3-fluoro-4-alkoxy-aniline.

Description

[0001] The invention relates to a novel method for preparing 2-chloro-3-fluoro-4-alkoxy-aniline, which can be further converted into 2-fluoro-3-chlorophenol.

[0002] 2-Fluoro-3-chlorophenol is an important precursor of active fungicidal ingredients (WO2020127780). 2-Chloro-3-fluoro-4-alkoxy-aniline can be used to prepare 1,3-benzothiazole compounds with pharmaceutical activity (WO2018 / 013774A1).

[0003] A typical procedure for preparing phenol derivatives involves reacting the corresponding commercially available aniline derivative with nitrous acid to form a diazonium salt, which is then converted in situ to a hydroxyl group upon heating in the presence of water and an acid (HE Ungnade et al., Organic Synthesis 1943, 23, 11-13; EP 1138713 A2).

[0004] The inventors of the present invention have found that according to the above steps, 2-fluoro-3-chlorophenol can be synthesized in one step from 2-fluoro-3-chloroaniline. However, the main disadvantages of this method are the generation of a highly explosive byproduct 2-chloro-6-diazo-cyclohexa-2,4-diene-1-one, and a low yield (20%) of the product.

[0005] CN112142567 discloses a four-step method for preparing 2-fluoro-3-chlorophenol starting from 1,3-dichloro-2-fluoro-4-nitrobenzene, through a mixture of 2-chloro-3-fluoro-4-methoxy-aniline and 4-chloro-3-fluoro-2-methoxyaniline as intermediates. The first step is that in the presence of sodium methoxide, one of the chlorine atoms undergoes a nucleophilic substitution reaction to obtain a mixture of regional isomer compounds 3-chloro-2-fluoro-1-methoxy-4-nitrobenzene and 1-chloro-2-fluoro-3-methoxy-4-nitrobenzene. Subsequently, the nitro group in the mixture of the two regional isomers is reduced to an amino group by catalytic hydrogenation. Then, the compounds 2-chloro-3-fluoro-4-methoxy-aniline and 4-chloro-3-fluoro-2-methoxy-aniline are deaminized, followed by a demethylation reaction of the methoxy group to obtain 2-fluoro-3-chlorophenol.

[0006] Surprisingly, the inventors of the present invention observed a conversion rate of only 50% when replicating the first step of the process disclosed in patent CN 112142567. Because of the lack of reactivity of the starting materials, many unwanted by-products are formed, thus requiring tedious separation and purification.

[0007] In view of the above-mentioned prior art, the object of the present invention is to provide a cleaner process which does not have the above-mentioned disadvantages, thereby providing a selective route for the synthesis of 2-chloro-3-fluoro-4-alkoxy-aniline to obtain 2-fluoro-3-chlorophenol under mild conditions with high yield and high purity, and the product can be easily separated.

[0008] The above object is achieved by a method for preparing a compound of general formula (V):

[0009]

[0010] Where R 1 is C1-C7 alkyl or C7-C 12 Aralkyl,

[0011] It is characterized in that, in step (A), 1-chloro-2,3-difluorobenzene of formula (I)

[0012]

[0013] reacting with a nitrating agent to produce a compound of formula (II);

[0014]

[0015] Then,

[0016] In step (B), a compound of formula (II) is reacted with an alcohol of general formula (III) in the presence of a base and optionally a solvent.

[0017] R 1 OH(III)

[0018] Where R 1 As defined above,

[0019] To form a compound of formula (IV)

[0020]

[0021] Where R 1 As defined above; then

[0022] In step (C), the compound of general formula (IV) reacts with a reducing agent A and a solvent to generate a compound of general formula (V).

[0023] Unexpectedly, the inventors of the present invention have found that using 3-chloro-1,2-difluoro-4-nitrobenzene (II) instead of 1,3-dichloro-2-fluoro-4-nitrobenzene in the methoxylation reaction can obtain a single regioisomer 3-chloro-2-fluoro-1-methoxy-4-nitrobenzene in 98% yield and can be used for further reactions without purification. In addition, 3-chloro-1,2-difluoro-4-nitrobenzene (II) can be easily obtained in one step through the nitration reaction of 1-chloro-2,3-difluorobenzene (I) with high yield and high purity. Then, 3-chloro-1,2-difluoro-4-nitrobenzene (II) can be further converted into the desired 2-chloro-3-fluoro-4-alkoxyaniline (V), which can be used to prepare 2-fluoro-3-chlorophenol (VIII).

[0024] General Definition

[0025] Unless otherwise stated, the term "alkyl", when used alone or in combination with other terms, refers to a straight or branched saturated hydrocarbon chain containing up to 8 carbon atoms, i.e. C1-C8-alkyl, preferably containing up to 7 carbon atoms, i.e. C1-C7-alkyl, particularly preferably containing up to 4 carbon atoms, i.e. C1-C4-alkyl. Examples of such alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.

[0026] Unless otherwise indicated, the term "aralkyl" refers to an alkyl group substituted with an aryl group. The definition of C7-12-aralkyl covers the broadest range of aralkyl groups defined herein having a total of 7 to 12 carbon atoms in the aromatic backbone and the alkylene chain. This definition covers, for example, the meanings of benzyl and phenethyl.

[0027] Method Description

[0028] The method of the present invention is shown in Scheme 1 below.

[0029] Solution 1

[0030]

[0031] Step A :

[0032] In step (A) of the present invention, 1-chloro-2,3-difluorobenzene (I) is converted into 3-chloro-1,2-difluoro-4-nitrobenzene (II) by a nitrating agent, preferably a nitrating acid.

[0033] Preferably, the nitrating acid is a combination of fuming nitric acid (HNO3) and concentrated sulfuric acid (H2SO4). Preferably, the molar ratio of nitric acid to sulfuric acid is 1:10 to 2:1.

[0034] Preferably, the molar ratio of H2SO4 to 1-chloro-2,3-difluorobenzene (I) is from 1:1 to 6:1, more preferably from 2:1 to 5:1, most preferably from 3:1 to 5:1.

[0035] Preferably, the molar ratio of HNO3 to 1-chloro-2,3-difluorobenzene (I) is from 1:1 to 2:1, more preferably from 1:1 to 1.8:1, most preferably from 1.1:1 to 1.5:1.

[0036] The step (A) of the present invention may be carried out at a temperature ranging from 5°C to 60°C, preferably at a temperature ranging from 20°C to 40°C.

[0037] The reaction time of the reaction in step (A) is usually in the range of 5 hours to 12 hours.

[0038] To isolate the product, the reaction mixture is diluted with water and the product is extracted with an organic solvent such as ethyl acetate, methyl tert-butyl ether (MTBE) or CH2Cl2.

[0039] 3-Chloro-1,2-difluoro-4-nitrobenzene (II) was generally obtained with a purity of 92% and a yield between 85% and 92%. The latter could be used in the next step without prior purification.

[0040] The nitration can also be carried out in the presence of a solvent, preferably dichloromethane or dichloroethane.

[0041] Step B :

[0042] In step (B), 3-chloro-1,2-difluoro-4-nitrobenzene (II) reacts with alcohol (III) in the presence of a base to produce a compound of formula (IV).

[0043] When R 1 When R is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl, the reaction is preferably carried out in the absence of a solvent other than the alcohol of formula (III), and preferably an excess of the alcohol of formula (III) is used. 1 In the case of a phenethyl group or a benzyl group, the reaction is preferably carried out in the presence of a solvent.

[0044] Suitable solvents in step (B) of the present invention are, for example, aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene, xylene or decalin, and halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), methyl tert-amyl ether, dioxane, tetrahydrofuran (THF), 2- Methyltetrahydrofuran (2-Me-THF), 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole, nitriles such as acetonitrile, propionitrile, n-butyronitrile or isobutyronitrile or benzonitrile, amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl N-formanilide, N-methyl-2-pyrrolidone (NMP) or hexamethylphosphoramide, sulfoxides such as dimethyl sulfoxide (DMSO) or sulfones such as sulfolane, or mixtures of the above solvents.

[0045] Preference is given to using acetonitrile, toluene and dimethylacetamide (DMA), especially acetonitrile.

[0046] Suitable bases in step (B) of the present invention are potassium carbonate, sodium acetate, sodium alkoxides such as sodium tert-butoxide, sodium ethoxide and sodium methoxide, and potassium alkoxides such as potassium tert-butoxide, potassium ethoxide and potassium methoxide. Potassium carbonate is particularly preferred.

[0047] When alcohol (III) is methanol, a particularly preferred alcohol / base combination of formula (III) is methanol / methoxide, and when alcohol (III) is ethanol, a particularly preferred alcohol / base combination of formula (III) is ethanol / ethanoloxide.

[0048] The molar ratio of alcohol (III) to 3-chloro-1,2-difluoro-4-nitrobenzene (II) is preferably from 1:1 to 25:1, more preferably from 1:1 to 20:1, most preferably between 2:1 and 15:1.

[0049] When alcohol (III) is methanol or ethanol, higher ratios are preferably used.

[0050] The molar ratio of base to compound (II) is preferably from 1:1 to 6:1, more preferably from 1:1 to 5:1, most preferably from 1:1 to 4:1.

[0051] Step (B) of the present invention may be carried out in a typical temperature range between 30°C and 90°C, preferably in the range between 40°C and 80°C, most preferably in the range between 50°C and 70°C.

[0052] The reaction time is not critical and can be selected within the range of 2 h to 12 h depending on batch size and temperature.

[0053] The product can be isolated as a solid after acidification of the reaction mixture with HCl or H2SO4, removal of the solvent under reduced pressure and washing with water, cold MTBE (methyl tert-butyl ether) or isopropanol.

[0054] Typical yields of step (B) of the present invention are in the range of 82% to 95%.

[0055] Step C :

[0056] In step (C), the compound of formula (IV) is converted into the compound of formula (V) in the presence of a reducing agent A and a solvent.

[0057] Suitable reducing agent A includes: SnCl2 / HCl, Fe / HCl, Fe / NH4Cl, Zn / HCl, Zn / NH4Cl, H2 / Pd-C, H2 / Pt-C and H2 / Raney nickel. Preferably, reducing agent A is a combination of hydrogen and a hydrogenation catalyst selected from palladium on carbon, Raney nickel and platinum on carbon.

[0058] Suitable solvents for step (C) of the present invention are acetic acid and alcohols, including but not limited to methanol, ethanol, isopropanol, n-propanol and n-butanol. Acetic acid, methanol, ethanol and isopropanol are preferably used.

[0059] Preferably, when the reducing agent A is hydrogen, the catalyst is added in an amount of 0.1-10 mol%, more preferably 0.1-5 mol%, based on the molar amount of the compound of formula (IV) in each case. Suitable catalysts for hydrogenation reduction are palladium on carbon, Raney nickel and platinum on carbon. Most preferred are 1% platinum on carbon and Raney nickel.

[0060] Step (C) of the present invention is usually carried out at a pressure between 1 and 20 bar, preferably between 1 and 10 bar. Preferably, when the reducing agent is hydrogen, the reaction is carried out at a hydrogen pressure between 2 and 5 bar.

[0061] Step (C) of the present invention may be carried out in a typical temperature range of 10°C to 40°C, preferably at room temperature.

[0062] The reaction time is usually in the range of 1 hour to 10 hours.

[0063] Typically, the yield of step (C) according to the invention exceeds 90%.

[0064] The present invention also relates to a method for preparing 2-fluoro-3-chlorophenol (VIII).

[0065]

[0066] The method for preparing the compound of formula (V) according to the present invention further comprises step (D) of reacting the compound of formula (V) obtained in step (C) with a diazotizing agent in the presence of an acid aqueous solution, a catalyst and a reducing agent B to produce a compound of formula (VII)

[0067]

[0068] Where R 1 is C1-C7-alkyl or C7-C 12 - aralkyl;

[0069] And in step (E), the latter is converted into 2-fluoro-3-chlorophenol (VIII) by heating in the presence of an acid, an acid salt or an acid anhydride.

[0070] Step D :

[0071] In step (D), the compound of formula (V) undergoes in situ formation of a diazonium salt of formula (VI) in the presence of a diazotizing agent, an aqueous acid solution, a catalyst and a reducing agent B to be converted into a compound of formula (VII).

[0072] Suitable diazotizing agents are sodium nitrite, potassium nitrite, nitrous acid, nitrosylsulfuric acid, methyl nitrite and n-butyl nitrite. The most preferred diazotizing agents are sodium nitrite and potassium nitrite.

[0073] Suitable acids for forming the diazonium salt (VI) are selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, hydrofluoric acid and hydrobromic acid. Hydrochloric acid (HCl) and sulfuric acid (H2SO4) are preferred.

[0074] Suitable catalysts are cuprous (I) chloride, cuprous (I) bromide, copper (II) sulfate, cuprous oxide (copper (I) oxide), cupric oxide (copper (II) oxide), copper nitrate, potassium trifluoroacetate, sodium trifluoroacetate, trifluoroacetic acid, cupric acetate, cupric carbonate, sodium acetate and potassium acetate. The most preferred catalysts are cuprous (I) chloride and cuprous (I) bromide.

[0075] Preferred reducing agents B include sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol and isopropanol. The most preferred reducing agents are isopropanol and sodium hypophosphite.

[0076] The molar ratio of the diazotizing agent to the compound of formula (V) is preferably from 1:1 to 2:1, more preferably from 1.1:1 to 1.5:1.

[0077] The molar ratio of acid to compound of formula (V) is preferably from 2:1 to 20:1, more preferably from 2:1 to 10:1.

[0078] The molar ratio of catalyst to compound of formula (V) is preferably from 0.01:1 to 0.1:1.

[0079] The molar ratio of reducing agent B to the compound of formula (V) is preferably from 1:1 to 15:1, more preferably from 2:1 to 10:1.

[0080] Step (D) of the present invention may be carried out at a temperature ranging from 0°C to 20°C, preferably from 0°C to 10°C, and most preferably from 0°C to 5°C.

[0081] The reaction time is usually in the range of 2 hours to 10 hours.

[0082] Typically, the yield of step (D) of the present invention is in the range of 78-90%.

[0083] Step E :

[0084] In step (E), the compound of formula (VII) is converted into 2-fluoro-3-chlorophenol (VIII) by heating in the presence of an acid, an acid salt or an acid anhydride.

[0085] Preferred acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, acetic acid, sulfuric acid and boron tribromide.

[0086] Preferred acid salts are pyridine hydrobromide and pyridine hydrochloride.

[0087] The preferred anhydride is acetic anhydride.

[0088] Particularly preferred are 50% aqueous hydrobromic acid, 37% aqueous HCl, pyridinium hydrochloride and boron tribromide.

[0089] The molar ratio of the acid or its salt to the compound of formula (VII) is preferably from 1:1 to 30:1, more preferably from 1:1 to 25:1, most preferably from 1:1 to 20:1.

[0090] The reaction temperature of step (E) of the present invention is usually in the range of 50°C to 150°C, preferably 70°C to 130°C, more preferably 90°C to 120°C.

[0091] Step (E) of the present invention is usually carried out under standard pressure. However, it can also be carried out under pressure in an autoclave.

[0092] The compound 2-fluoro-3-chlorophenol (VIII) obtained in step (E) of the present invention can be directly extracted from the reaction mixture using an organic solvent.

[0093] The reaction time is usually in the range of 3 hours to 8 hours.

[0094] Typically, the yield of step (E) of the present invention is in the range of 70-90%.

[0095] More preferred is the process according to the invention, wherein the radical R in formula (IV) to (VII) 1 The definition is as follows:

[0096] R 1 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenethyl or benzyl.

[0097] Most preferred is the process according to the invention, wherein the radical R in formula (IV) to (VII) 1 The definition is as follows:

[0098] R 1 is methyl, ethyl, isopropyl or benzyl.

[0099] The present invention is illustrated by the following examples: Example

[0100] Example 1

[0101]

[0102] 3-Chloro-1,2-difluoro-4-nitrobenzene(II)

[0103] 9.5 g of 1-chloro-2,3-difluorobenzene (I) were added to a mixture of 19.4 g of sulfuric acid (purity 96%, density 1.96) and 4 g of nitric acid (density 1.51, purity 100%) at 20-25° C. over 1 h. The mixture was stirred at 30° C. for 5 h and then poured onto ice. The product was extracted with 200 ml of CH2Cl2, washed with water, and then the solvent was evaporated to give 11.6 g of a pale yellow oil with a purity of 92% (WW). Yield = 85%, adjusted for purity.

[0104] 1 H NMR (400MHz, DMSO-d6) δ7,7(ddd,1H); 8,1(ddd,1H)ppm.

[0105] Mass spectrometry (ESI + ,m / z)[M+H]194.

[0106] Example 2

[0107]

[0108] Example 2a : 3-chloro-2-fluoro-1-methoxy-4-nitrobenzene (IV-a, R 1 = methyl)

[0109] A solution of 19.3 g of 3-chloro-1,2-difluoro-4-nitrobenzene (II) and 10.8 g of sodium methoxide in 150 ml of methanol is heated at 65° C. for 2 h. The mixture is cooled and acidified with 20 ml of 20% hydrochloric acid. The solvent and volatile products are removed in vacuo, 100 ml of cold methyl tert-butyl ether are then added, the solid formed is filtered off, washed with water and cold MTBE, and 20 g (98%) of a white solid is obtained with a melting point of 74-75° C.

[0110] 1 H NMR (400MHz, DMSO-d6) δ4,0(s,3H); 7,4(d,1H); 8,1(d,1H)ppm.

[0111] Mass spectrometry (ESI + ,m / z)[M+H]206.

[0112] Example 2b : 3-chloro-2-fluoro-1-methoxy-4-nitrobenzene (IV-a, R 1 = methyl)

[0113] Comparative Example (CN 112142567):

[0114] 21 g of 1,3-dichloro-2-fluoro-4-nitrobenzene prepared according to CN 112047804 was added to 50 ml of methanol and heated to 40° C. 28.3 g of a 20% sodium methoxide solution was added dropwise and the mixture was stirred at 50° C. for 2 h. The mixture was cooled to 20° C. and the pH value was adjusted to 7 by adding hydrochloric acid. The mixture was filtered to remove the salts and the solvent was evaporated in vacuo. The resulting oil (21 g) was analyzed by LC / MS and showed a mixture of 6-7 components, of which the starting material accounted for 50 area%.

[0115] Isolation of pure products is not possible.

[0116] Example 2 c: 3-Chloro-2-fluoro-1-benzyloxy-4-nitrobenzene (IV-b, R 1 =benzyl)

[0117] A solution of 19.3 g of 3-chloro-1,2-difluoro-4-nitrobenzene, 21.6 g of benzyl alcohol and 27.6 g of potassium carbonate in 100 ml of acetonitrile was heated at 65° C. for 12 h. The mixture was cooled and acidified with 50 ml of 10% hydrochloric acid. The solvent and volatile products were removed in vacuo, and 100 ml of cold isopropanol were then added. The solid formed was filtered off and washed with water and cold isopropanol to give 23 g (82%) of a white solid with a melting point of 83° C.

[0118] 1H NMR(400MHz,DMSO-d6)δ5,4(s,2H);7,3-7,5(m,6H);8,1(d,1H)ppm

[0119] Mass spectrometry (ESI + ,m / z)[M+H]282.

[0120] Example 3

[0121]

[0122] A solution of 100 mmol compound (IV) in 100 ml methanol and 0.4 g catalyst (1% platinum supported on activated carbon) are added to an autoclave. The autoclave is purged with hydrogen and then 5 bar of hydrogen pressure is applied. At room temperature, the mixture is stirred in the autoclave for 5 h. Then, the reaction mixture is poured through filter paper to remove the catalyst. The solvent is removed in a vacuum.

[0123] Example 3a :2-chloro-3-fluoro-4-methoxyaniline (Va, R 1 = methyl)

[0124] The obtained compound Va was a white solid (16.6 g; yield 95%).

[0125] 1 H NMR (400MHz, DMSO-d6) δ3,7(s,3H); 5,3(bs,2H); 6,55(m,1H); 6,8(m,1H)ppm.

[0126] Mass spectrometry (ESI + ,m / z)[M+H]176.

[0127] Example 3b :2-chloro-3-fluoro-4-benzyloxyaniline (Vb, R 1 =benzyl)

[0128] Compound Vb was obtained as an oil (yield 95%).

[0129] 1 H NMR (400MHz, DMSO-d6) δ5,1(bs,2H); 5,35(s,2H); 7,1-7,6(m,7H)ppm.

[0130] Mass spectrometry (ESI + ,m / z)[M+H]252.

[0131] Example 4

[0132]

[0133] A mixture of 100 mmol (V) and 50 ml 10% hydrochloric acid was stirred at 20 ° C for 30 min to form a uniform slurry, and then 0.4 g CuCl and 60 ml isopropanol in 50 ml HCl were added. After the mixture was stirred for 30 min, it was cooled to 0 ° C. At 0 ° C, sodium nitrite aqueous solution (14 ml, 40%) was slowly added to the mixture. The temperature was adjusted to 20 ° C and the reaction mixture was stirred for 10 h. 100 ml of water was added to the mixture, and the oily product was then extracted with methyl tert-butyl ether. The organic phase was washed with water, dried and evaporated to obtain the desired compound of formula (VII).

[0134] Example 4a :1-chloro-2-fluoro-3-methoxybenzene (VII-a, R 1 = methyl).

[0135] The obtained compound VII-a was a light yellow oil (13.6 g; yield 85%).

[0136] 1 H NMR(400MHz,DMSO-d6)δ3,8(s,3H);7,0-7,2(m,3H)ppm.

[0137] 19 F NMR(376,4MHz,DMSO-d6)δ-137,9ppm.

[0138] Mass spectrometry (ESI + ,m / z)[M+H]161.

[0139] Example 4b :1-Benzyloxy-3-chloro-2-fluorobenzene (VII-b, R 1 =benzyl).

[0140] The obtained compound VII-b was an oily substance with a yield of 78%.

[0141] 1 H NMR(400MHz,DMSO-d6)δ5,3(s,2H);7,2-7,5(m,8H)ppm.

[0142] 19 F NMR(376,4MHz,DMSO-d6)δ-137,7ppm.

[0143] Mass spectrometry (ESI + ,m / z)[M+H]237.

[0144] Example 5

[0145]

[0146] 2-Fluoro-3-chloro-phenol (VIII)

[0147] A mixture of 50 g of 1-chloro-2-fluoro-3-methoxybenzene and 100 ml of HCl (37% aqueous solution) was heated in a Parr glass autoclave at 110° C. After 7 h, the mixture was cooled and the product was extracted three times with 100 ml of CH2Cl2. The solvent was evaporated to give 40 g of 2-fluoro-3-chlorophenol as a pale yellow liquid.

[0148] 1 H NMR (400MHz, DMSO-d6) δ6,91-6,95(m,2H); 7,00(s,1H); 10,3(s,1H)ppm.

[0149] 19 F NMR(376,4MHz,DMSO-d6)δ-139,9ppm.

[0150] Mass spectrometry (ESI + ,m / z)[M+H]145.

Claims

1. A method for preparing a compound of general formula (V): Where R 1 is C1-C7 alkyl or C7-C 12 Aralkyl, It is characterized in that In step (A), 1-chloro-2,3-difluorobenzene of formula (I) reacting with a nitrating agent to produce a compound of formula (II); Then, In step (B), a compound of formula (II) is reacted with an alcohol of general formula (III) in the presence of a base and optionally a solvent. R 1 OH(III) Where R 1 As defined above, Forming a compound of formula (IV) Where R 1 As defined above; then In step (C), the compound of general formula (IV) reacts with a reducing agent A and a solvent to generate a compound of general formula (V).

2. The method according to claim 1, wherein R 1 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenethyl or benzyl.

3. The method according to claim 1 or 2, wherein in step (A), the nitrating agent is a combination of fuming nitric acid and concentrated sulfuric acid, and the molar ratio of nitric acid to sulfuric acid is 1:10 to 2:

1.

4. The process according to any one of claims 1 to 3, wherein in step (B), the base is selected from potassium carbonate, sodium acetate, sodium alkoxides such as sodium tert-butoxide, sodium ethoxide and sodium methoxide, and potassium alkoxides such as potassium tert-butoxide, potassium ethoxide and potassium methoxide.

5. The method according to any one of claims 1 to 4, wherein in step (B), the molar ratio of the base to the compound (II) is 1:1 to 6:

1.

6. The process according to any one of claims 1 to 5, wherein in step (C), the reducing agent A is a combination of hydrogen gas and a hydrogenation catalyst selected from palladium supported on carbon, Raney nickel and platinum supported on carbon.

7. The method according to any one of claims 1 to 6, wherein in step (C), the amount of hydrogenation catalyst added is 0.1-10 mol%.

8. The process according to any one of claims 1 to 7, wherein in step (C), the solvent used is selected from acetic acid, methanol, ethanol and isopropanol.

9. A method for preparing 2-fluoro-3-chlorophenol (VIII) A method for preparing a compound of formula (V) according to any one of claims 1 to 8, further comprising step (D) reacting the compound of formula (V) obtained in step (C) with a diazotizing agent in the presence of an acid aqueous solution, a catalyst and a reducing agent B to produce a compound of general formula (VII) Where R 1 is C1-C7-alkyl or C7-C 12 - aralkyl; And in step (E), the latter is converted into 2-fluoro-3-chlorophenol (VIII) by heating in the presence of an acid, an acid salt or an acid anhydride.

10. The method according to claim 9, wherein R 1 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenethyl or benzyl.

11. The method according to claim 9 or 10, wherein in step (D), the catalyst is cuprous chloride (I) or cuprous bromide (I).

12. The method according to any one of claims 9 to 11, wherein in step (D), the reducing agent B is selected from sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol and isopropanol.

13. The method according to any one of claims 9 to 12, wherein in step (D), the diazotized compound is selected from sodium nitrite, potassium nitrite, nitrous acid, nitrosylsulfuric acid, methyl nitrite and n-butyl nitrite.

14. The process according to any one of claims 9 to 13, wherein in step (D), the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, hydrofluoric acid and hydrobromic acid.

15. The method according to any one of claims 9 to 14, wherein in step (E), the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, acetic acid, sulfuric acid and boron tribromide; the acid salt is selected from pyridine hydrobromide and pyridine hydrochloride; and the acid anhydride is acetic anhydride.

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