Process for the preparation of 2-chloro-3-fluoro-4-alkoxy-aniline and 2-fluoro-3-chlorophenol

Abstract

The present invention relates to a novel process for preparing 2-chloro-3-fluoro-4-alkoxy-aniline which can be further converted to 2-fluoro-3-chlorophenol.

Description

Technical Field

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

Background Art

[0002] 2-Fluoro-3-chlorophenol is a valuable precursor of an effective bactericidal component (International Publication No. 2020127780). 2-Chloro-3-fluoro-4-alkoxy-aniline can be used in the preparation of pharmaceutically effective 1,3-benzotriazole compounds (International Publication No. 2018 / 013774).

[0003] Typical methods for the preparation of phenol derivatives involve forming a diazonium salt by reacting the corresponding commercially available aniline derivative with nitrous acid, which salt is then converted in situ to a hydroxyl group under heating in the presence of water and acid (H. E., Ungnade et al. Organic Synthesis 1943, 23, 11-13; European Patent Application Publication No. 1138713).

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

[0005] Chinese Patent Specification No. 112142567 discloses a four-step process for the preparation of 2-fluoro-3-chlorophenol starting from 1,3-dichloro-2-fluoro-4-nitrobenzene, which proceeds via a mixture of 2-chloro-3-fluoro-4-methoxy-aniline and 4-chloro-3-fluoro-2-methoxyaniline as intermediates. The first step involves nucleophilic substitution of one of the chlorine atoms in the presence of sodium methoxide to give a mixture of positional isomer compounds 3-chloro-2-fluoro-1-methoxy-4-nitrobenzene and 1-chloro-2-fluoro-3-methoxy-4-nitrobenzene. Subsequently, the nitro groups of this mixture of the two positional isomers are reduced to amino groups via catalytic hydrogenation. Then, deamination of the compounds 2-chloro-3-fluoro-4-methoxyaniline and 4-chloro-3-fluoro-2-methoxy-aniline, followed by demethylation of the methoxy group, gives 2-fluoro-3-chlorophenol.

[0006] Surprisingly, when reproducing the first step of the process disclosed in Chinese Patent Specification No. 112142567, what was observed by the inventors of the present invention was only a 50% conversion. As a result of the loss of reactivity of the raw materials, cumbersome isolation and purification are required due to the formation of a large number of undesirable by-products.

Disclosure of the Invention

[0007] In view of the above prior art, an object of the present invention is to provide a cleaner process that gives a selective route to 2-chloro-3-fluoro-4-alkoxy-aniline and thereby further to 2-fluoro-3-chlorophenol in high yield and high purity without the above disadvantages under mild conditions, and the product can be easily isolated.

[0008] To achieve the above object, a compound of general formula (V):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0009] Surprisingly, the inventors of the present invention have found that by using 3-chloro-1,2-difluoro-4-nitrobenzene (II) instead of 1,3-dichloro-2-fluoro-4-nitrobenzene in the methoxylation reaction, 3-chloro-2-fluoro-1-methoxy-4-nitrobenzene is obtained as a single positional isomer in a yield of 98%, which can be used in further reactions without purification. Furthermore, 3-chloro-1,2-difluoro-4-nitrobenzene (II) can be easily obtained in high yield and high purity in one step by nitration of 1-chloro-2,3-difluorobenzene (I). 3-chloro-1,2-difluoro-4-nitrobenzene (II) can then be further converted to the desired 2-chloro-3-fluoro-4-alkoxyaniline (V), which can be further used to prepare 2-fluoro-3-chlorophenol (VIII).

[0010] General Definitions Unless otherwise indicated, the term "alkyl", separately or in combination with other terms, refers to a linear or branched saturated hydrocarbon chain having up to 8 carbon atoms, i.e., C1-C8-alkyl, preferably such a saturated hydrocarbon chain having up to 7 carbon atoms, i.e., C1-C7-alkyl, very preferably such a saturated hydrocarbon chain having up to 4 carbon atoms, i.e., C1-C4-alkyl. Examples of such alkyl refer to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.

[0011] Unless otherwise indicated, the term "arylalkyl" refers to an alkyl substituted by an aryl group. The definition C7-12-arylalkyl encompasses the broadest scope defined herein for arylalkyl having a total of 7 to 12 carbon atoms in the aromatic backbone and the alkylene chain. This definition encompasses, for example, the meaning of benzyl and phenylethyl.

[0012] Description of the Process The process of the present invention is shown in Scheme 1 below.

[0013] Scheme 1

Chemical formula

[0014] Step A: In step (A) of the present invention, 1-chloro-2,3-difluorobenzene (I) is converted to 3-chloro-1,2-difluoro-4-nitrobenzene (II) by a nitrating agent, preferably nitrating acid.

[0015] 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 from 1:10 to 2:1.

[0016] 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, and most preferably from 3:1 to 5:1.

[0017] 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, and most preferably from 1.1:1 to 1.5:1.

[0018] Step (A) of the present invention can be carried out at a temperature in the range between 5 °C and 60 °C, preferably in the range between 20 °C and 40 °C.

[0019] The reaction time of the reaction in step (A) is typically in the range of 5 hours to 12 hours.

[0020] For isolation of 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.

[0021] 3-Chloro-1,2-difluoro-4-nitrobenzene (II) is usually obtained in a yield between 85% and 92% and with a purity of 92%. The latter can be used in the next step without prior purification.

[0022] Nitration can also be carried out in the presence of a solvent. Dichloromethane or dichloroethane is preferred.

[0023] Step B: In step (B), 3-chloro-1,2-difluoro-4-nitrobenzene (II) is reacted with alcohol (III) in the presence of a base to produce a compound of formula (IV).

[0024] R 1 When R is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or sec-butyl, the reaction is preferably carried out in the absence of a solvent other than the alcohol of formula (III), and an excess of the alcohol of formula (III) is preferably used. R 1 When R is phenethyl or benzyl, the reaction is preferably carried out in the presence of a solvent.

[0025] Solvents suitable for 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- or iso-butyronitrile or benzonitrile; amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylformanilide, N-methyl-2-pyrrolidone (NMP) or hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide (DMSO), or sulfones such as sulfolane, or mixtures of the above solvents.

[0026] Acetonitrile, toluene, and dimethylacetamide (DMA), especially acetonitrile, are preferred.

[0027] Bases suitable for step (B) of the present invention are potassium carbonate, sodium acetate, sodium tert-butoxide, sodium alkoxides such as sodium ethoxide and sodium methoxide, and potassium alkoxides such as potassium tert-butoxide, potassium ethoxide and potassium methoxide. Potassium carbonate is particularly preferred.

[0028] Particularly preferred combinations of the alcohol / base of formula (III) are methanol / methanoate when the alcohol (III) is methanol and ethanol / ethanoate when the alcohol (III) is ethanol.

[0029] The molar ratio of alcohol (III) to 3-chloro-1,2-difluoro-4-nitrobenzene (II) is preferably between 1:1 and 25:1, more preferably between 1:1 and 20:1, and most preferably between 2:1 and 15:1.

[0030] When the alcohol (III) is methanol or ethanol, a higher ratio is preferably used.

[0031] The molar ratio of the base to compound (II) is preferably between 1:1 and 6:1, more preferably between 1:1 and 5:1, and most preferably between 1:1 and 4:1.

[0032] Step (B) of the present invention can be carried out at a temperature in a typical range between 30 °C and 90 °C, preferably between 40 °C and 80 °C, and most preferably between 50 °C and 70 °C.

[0033] The reaction time is not critical and can be selected within the range between 2 hours and 12 hours depending on the batch size and temperature.

[0034] 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.

[0035] A typical yield of step (B) of the present invention is in the range of 82% - 95%.

[0036] Step C: In step (C), the compound of formula (IV) is converted to the compound of formula (V) in the presence of reducing agent A and a solvent.

[0037] Suitable reducing agent A includes SnCl2 / HCl, Fe / HCl, Fe / NH4Cl, Zn / HCl, Zn / NH4Cl, H2 / Pd-C, H2 / Pt-C, and H2 / Raney Ni. Preferably, reducing agent A is hydrogen in combination with a hydrogenation catalyst selected from the group consisting of palladium / carbon, Raney nickel, and platinum / carbon.

[0038] 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 preferred.

[0039] Preferably, when reducing agent A is hydrogen, the catalyst is added in an amount of 0.1 to 10 mol%, more preferably 0.1 to 5 mol%, based on the molar amount of the compound of formula (IV) in each case. Catalysts suitable for hydrogenation reduction are palladium / carbon, Raney nickel, and platinum / carbon. Most preferably, it is 1% platinum / carbon and Raney nickel.

[0040] Step (C) of the present invention typically proceeds between 1 and 20 bar, preferably between 1 and 10 bar. Preferably, when the reducing agent is hydrogen, the reaction is carried out under a hydrogen pressure between 2 and 5 bar.

[0041] Step (C) of the present invention can be carried out at a temperature in the typical range between 10°C and 40°C, preferably at room temperature.

[0042] The reaction time is typically in the range of 1 hour to 10 hours.

[0043] Typically, the yield of step (C) of the present invention is over 90%.

[0044] The present invention also relates to a process for preparing 2-fluoro-3-chlorophenol (VIII)

Chemical formula

[0045] Step D: In step (D), the compound of formula (V) is converted to a compound of formula (VII) in the presence of a diazotizing reagent, an aqueous acid solution, a catalyst and a reducing agent B via in-situ formation of a diazonium salt of formula (VI).

[0046] Suitable diazotizing reagents are sodium nitrite, potassium nitrite, nitrous acid, nitrosyl sulfuric acid, methyl nitrite and n-butyl nitrite. Most preferably, the diazotizing reagent is sodium nitrite and potassium nitrite.

[0047] Acids suitable for the formation of 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.

[0048] Suitable catalysts are copper(I) chloride, copper(I) bromide, copper(II) sulfate, cuprous oxide (copper(I) oxide), copper oxide (copper(II) oxide), copper nitrate, potassium trifluoroacetate, sodium trifluoroacetate, trifluoroacetic acid, copper acetate, copper carbonate, sodium acetate, and potassium acetate. The most preferred catalysts are copper(I) chloride and copper(I) bromide.

[0049] Preferred reducing agent B includes sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol, and isopropanol. The most preferred reducing agents are isopropanol and sodium hypophosphite.

[0050] The molar ratio of the diazotizing reagent to the compound of formula (V) is preferably 1:1 to 2:1, more preferably 1.1:1 to 1.5:1.

[0051] The molar ratio of the acid to the compound of formula (V) is preferably 2:1 to 20:1, more preferably 2:1 to 10:1.

[0052] The molar ratio of the catalyst to the compound of formula (V) is preferably 0.01:1 to 0.1:1.

[0053] The molar ratio of reducing agent B to the compound of formula (V) is preferably 1:1 to 15:1, more preferably 2:1 to 10:1.

[0054] Step (D) of the present invention can be carried out at a temperature in the range between 0 °C and 20 °C, preferably in the range between 0 °C and 10 °C, and most preferably in the range between 0 °C and 5 °C.

[0055] The reaction time is typically in the range of 2 hours to 10 hours.

[0056] Typically, the yield of step (D) of the present invention is in the range of 78 - 90%.

[0057] Step E: In step (E), the compound of formula (VII) is converted to 2-fluoro-3-chlorophenol (VIII) by heating in the presence of an acid, acid salt, or acid anhydride.

[0058] Preferred acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, acetic acid, sulfuric acid, and boron tribromide.

[0059] Preferred acid salts are pyridine hydrobromide and pyridine hydrochloride.

[0060] A preferred acid anhydride is acetic anhydride.

[0061] Particularly preferred are hydrobromic acid as a 50% aqueous solution, HCl as a 37% aqueous solution, pyridine hydrochloride, and boron tribromide.

[0062] 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, and most preferably from 1:1 to 20:1.

[0063] The reaction temperature of step (E) of the present invention is typically in the temperature range of 50°C to 150°C, preferably a temperature of 70°C to 130°C, and more preferably 90°C to 120°C.

[0064] Step (E) of the present invention is generally carried out under standard pressure. Alternatively, however, it can also operate under pressure in an autoclave.

[0065] The compound 2-fluoro-3-chlorophenol (VIII) from step (E) of the present invention can be directly extracted from the reaction mixture with an organic solvent.

[0066] The reaction time is typically in the range of 3 hours to 8 hours.

[0067] Typically, the yield of step (E) of the present invention is in the range of 70 to 90%.

[0068] The radical R in formulas (IV) to (VII) 1 is defined as follows, and the process according to the present invention is most preferred: R 1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenethyl or benzyl.

[0069] The radical R in formulas (IV) to (VII)1 The process according to the invention, as defined below, is most preferred: R1 is methyl, ethyl, iso-propyl or benzyl.

[0070] The invention will be illustrated by the following examples.

Examples

[0071] Example 1

Chemical formula

[0072] Example 2

Chemical formula

[0073] Example 2b: 3-chloro-2-fluoro-1-methoxy-4-nitrobenzene (R 1 = IV-a with methyl) Comparative Example (CN112142567): 21 g of 1,3-dichloro-2-fluoro-4-nitrobenzene (prepared according to CN112047804) was placed in 50 ml of methanol and heated to 40 °C. A 20% solution of 28.3 g of sodium methoxide was added dropwise and the mixture was stirred at 50 °C for 2 hours. The mixture was cooled to 20 °C and the pH was adjusted to 7 with the addition of hydrochloric acid. The mixture was filtered to remove the salts and the solvent was evaporated in vacuo. The resulting oil (21 g) was analyzed using LC / MS and showed a mixture of 6-7 components and 50 area% of the starting material. Isolation of the pure product was not possible.

[0074] Example 2c: 3-chloro-2-fluoro-1-benzyloxy-4-nitrobenzene (R 1 = IV-b with benzyl) 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 stirred at 65 °C for 12 hours. 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 was added. The solid formed was filtered off and washed with water and cold isopropanol to give 23 g (82%) of a white solid having a melting point of 83 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 5.4 (s, 2H); 7.3 - 7.5 (m, 6H); 8.1 (d, 1H) ppm Mass spectrum (ESI + , m / z) [M+H] 282.

[0075] Example 3

Chemical formula

[0076] Example 3a: 2-chloro-3-fluoro-4-methoxyaniline (R 1 = V-a with methyl) Compound V-a was obtained as a white solid (16.6 g; 95% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 3.7 (s, 3H); 5.3 (b.s, 2H); 6.55 (m, 1H); 6.8 (m, 1H) ppm. Mass spectrum (ESI + , m / z) [M+H] 176.

[0077] Example 3b: 2-Chloro-3-fluoro-4-benzyloxy-aniline (R 1 = V-b with benzyl) Compound V-b was obtained as an oil (95% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 5.1 (b.s, 2H); 5.35 (s, 2H); 7.1 - 7.6 (m, 7H) ppm. Mass spectrum (ESI + , m / z) [M+H] 252.

[0078] Example 4

Chemical formula

[0079] Example 4a: 1-Chloro-2-fluoro-3-methoxybenzene (R 1 = VII-a with methyl). Compound VII-a was obtained as a pale-yellow oil (13.6 g; 85% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 3.8 (s, 3H); 7.0 - 7.2 (m, 3H) ppm. 19 19F NMR (376.4 MHz, DMSO-d6) δ -137.9 ppm. Mass spectrum (ESI + , m / z) [M+H] 161.

[0080] Example 4b: 1-Benzyloxy-3-chloro-2-fluorobenzene (R 1 = VII-b) with benzyl. Compound VII-b was obtained as an oil in 78% yield. 1 1H NMR (400 MHz, DMSO-d6) δ 5.3 (s, 2H); 7.2 - 7.5 (m, 8H) ppm. 19 19F NMR (376.4 MHz, DMSO-d6) δ -137.7 ppm. Mass spectrum (ESI + , m / z) [M+H] 237.

[0081] Example 5

Chemical formula

Claims

1. A process for preparing a compound of general formula (V): 【Chemical 1】 In the formula, R １ is C １ -C ７－ alkyl or C ７ -C １２ -arylalkyl; comprising: in step (A), 1-chloro-2,3-difluorobenzene of formula (I) [Chemical 2] reacts with a nitrating agent to form a compound of formula (II) 【Chemical Formula 3】 ; in step (B), the compound of formula (II) reacts with an alcohol of general formula (III) R １ OH (III) wherein, R １ is as defined above; in the presence of a base and optionally a solvent to form a compound of general formula (IV) 【Chemical Formula 4】 wherein, R １ is as defined above; ; and in step (C), the compound of general formula (IV) reacts with a reducing agent A and a solvent to form the compound of general formula (V).

2. R １ The process according to claim 1, wherein R is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenethyl or benzyl.

3. The process according to claim 1 or 2, wherein in step (A), the nitrating agent is a combination of fuming nitric acid and concentrated sulfuric acid with a molar ratio of nitric acid to sulfuric acid of 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 the group consisting of sodium alkoxides such as potassium carbonate, sodium acetate, sodium tert-butoxide, sodium ethoxide and sodium methoxide, and potassium alkoxides such as potassium tert-butoxide, potassium ethoxide and potassium methoxide.

5. The process according to any one of claims 1 to 4, wherein in step (B), the molar ratio of the base to 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 hydrogen combined with a hydrogenation catalyst selected from the group consisting of palladium / carbon, Raney nickel and platinum / carbon.

7. The process according to any one of claims 1 to 6, wherein in step (C), the hydrogenation catalyst is added in an amount of 0.1 to 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 process for preparing 2-fluoro-3-chlorophenol (VIII) comprising 【Chemical Formula 5】 the process for preparing a compound of formula (V) according to any one of claims 1 to 8, and in step (C), reacting the compound of formula (V) obtained with a diazotizing reagent in the presence of an aqueous acid solution together with a catalyst and a reducing agent B to form a compound of general formula (VII) ​ wherein, R １ is C １ -C ７ -alkyl or C ７ -C １２ -arylalkyl; further comprising a step (D) of forming a compound, wherein the latter is converted to 2-fluoro-3-chlorophenol (VIII) under heating in the presence of an acid, an acid salt or an acid anhydride in step (E), said process. **Claim 10** R １ The process according to claim 9, wherein R is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenethyl or benzyl. **Claim 11** The process according to claim 9 or 10, wherein in step (D), the catalyst is copper(I) chloride or copper(I) bromide. **Claim 12** The process according to any one of claims 9 to 11, wherein in step (D), reducing agent B is selected from the group consisting of sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol and isopropanol. **Claim 13** The process 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, nitrosyl sulfuric acid, methyl nitrite and n-butyl nitrite. **Claim 14** The process according to any one of claims 9 to 13, wherein in step (D), the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, hydrofluoric acid, and hydrobromic acid. **Claim 15** The process 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.

Images