PROCESS FOR PREPARATION OF 2-CHLORO-3-FLUORO-4-ALKOXY-ANILINES AND 2-FLUORO-3-CHLOROPHENOL

Abstract

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

Claims

1. A process for preparing a compound of the general formula (V): ##STR00014## in which R.sup.1 is C.sub.1-C.sub.7-alkyl or C.sub.7-C.sub.12-arylalkyl, characterized in that, in step (A), 1-chloro-2,3-difluorobenzene of formula (I) ##STR00015## is reacted with a nitrating agent to form the compound of the formula (II) ##STR00016## and, that in step (B), the compound of the formula (II) is reacted with an alcohol of the general formula (II) ##STR00017## in which R.sup.1 is as defined above, in presence of a base and optionally a solvent to form the compound of the general formula (IV) ##STR00018## in which R.sup.1 is as defined above; and that in step (C), the compound of the general formula (IV) is reacted with a reducing agent A and a solvent to form the compound of the general formula (V).

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

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

4. The process according to claim 1, wherein in step (B), the base is selected from group consisting of 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 process according to claim 1, wherein in step (B), the molar ratio of base to compound (II) is from 1:1 to 6:1.

6. The process according to claim 1, wherein in step (C), the reducing agent A is hydrogen in combination with a hydrogenation catalyst selected from the group consisting of palladium on carbon, Raney Nickel and platinum on carbon.

7. The process according to claim 1, wherein in step (C), the hydrogenation catalyst is added in an amount of 0.1-10 mol %.

8. The process according to claim 1, 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) ##STR00019## comprising the process for preparing the compound of the formula (V) according to claim 1, and further comprising step (D) reacting the compound of the formula (V) obtained in step (C) with a diazotization reagent in presence of an aqueous acid solution together with a catalyst and a reducing agent B to form a compound of the general formula (VII) ##STR00020## in which R.sup.1 is C.sub.1-C.sub.7-alkyl or C.sub.7-C.sub.12-arylalkyl; and the latter is converted, in step (E), into 2-fluoro-3-chlorophenol (VIII) upon heating in presence of an acid, acid salt or acid anhydride.

10. The process according to claim 9, wherein R.sup.1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenethyl or benzyl.

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

12. The process according to claim 9, wherein in step (D), the reducing agent B is selected in the group consisting of sodium hypophosphite, potassium hypophosphite, hypophosphorous acid, ethanol, methanol and isopropanol.

13. The process according to claim 9, wherein in step (D), the diazotization compound is selected from sodium nitrite, potassium nitrite, nitrous acid, nitrosyl sulfuric acid, methyl nitrite and n-butyl nitrite.

14. The process according to claim 9, 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.

15. The process according to claim 9, 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.

Description

EXAMPLES

Example 1

##STR00009##

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

[0085] To the mixture of 19.4 g sulfuric acid (96% purity, d 1.96) and 4 g of nitric acid (d 1.51, purity 100%), 9.5 g of 1-chloro-2,3-difluorobenzene (I) was added within 1 h at 20-25 C. The mixture was stirred for 5 h at 30 C. and poured on ice. The product was extracted with 200 ml of CH.sub.2Cl.sub.2 washed with water and the solvent was evaporated to give 11.6 g of pale-yellow oil with purity w.w. 92%. Yield=85%, adjusted to the purity.

[0086] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.7 (ddd, 1H); 8.1 (ddd, 1H) ppm.

[0087] Mass spectra (ESI.sup.+, m/z) [M+H] 194.

Example 2

##STR00010##

Example 2a: 3-Chloro-2-fluoro-1-methoxy-4-nitrobenzene (IV-a with R.SUP.1.=Methyl)

[0088] 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 methanol were heated for 2 h at 65 C. The mixture was cooled and acidified with 20 ml of 20% hydrochloric acid. The solvent and volatile products were removed in vacuum, 100 ml of cold methyl tert-butyl ether were added and the formed solid was filtered off, washed with water and cold MTBE to yield 20 g (98%) of white solid with m.p. of 74-75 C.

[0089] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 4.0 (s, 3H); 7.4 (d, 1H); 8.1 (d, 1H) ppm.

[0090] Mass spectra (ESI.sup.+, m/z) [M+H] 206.

Example 2b: 3-Chloro-2-fluoro-1-methoxy-4-nitrobenzene (IV-a with R.SUP.1.=Methyl)

Comparative Example (CN 112142567)

[0091] 21 g of 1,3-dichloro-2-fluoro-4-nitrobenzene (prepared according to CN 112047804, were placed in 50 ml methanol and heated to 40 C. 28.3 g of 20% solution of sodium methoxide were added dropwise and the mixture was stirred for 2 h at 50 C. The mixture was cooled to 20 C. and pH was adjusted to 7 upon addition of hydrochloric acid. The mixture was filtered to remove the salt and the solvent was evaporated in vacuum. The obtained oil (21 g) was analyzed using LC/MS showing a mixture of 6-7 components with 50 area % of the starting materials. The isolation of the pure product was not possible.

Example 2c: 3-chloro-2-fluoro-1-benzyloxy-4-nitrobenzene (IV-b with R.SUP.1.=Benzyl)

[0092] A solution of 19.3 g of 3-Chloro-1,2-difluoro-4-nitrobenzene, 21.6 g of benzyl alcohol and 27.6 of potassium carbonate in 100 ml acetonitrile were heated for 12 h at 65 C. The mixture was cooled and acidified with 50 ml of 10% hydrochloric acid. The solvent and volatile products were removed in vacuum, and 100 ml of cold isopropanol were added. The formed solid was filtered off, washed with water and cold isopropanol to give 23 g (82%) of white solid with m.p. of 83 C.

[0093] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 5.4 (s, 2H); 7.3-7.5 (m, 6H); 8.1 (d, 1H) ppm

[0094] Mass spectra (ESI.sup.+, m/z) [M+H] 282.

Example 3

##STR00011##

[0095] A solution of 100 mmol of compound (IV) in 100 ml of methanol and 0.4 g of catalyst (1% platinum on activated carbon) were placed in an autoclave. The autoclave was purged with hydrogen and then a hydrogen pressure of 5 bar was applied. The mixture was stirred in the autoclave at room temperature for 5 h. Then, the reaction mixture was poured through filter paper to remove the catalyst. The solvent was removed in vacuum.

Example 3a: 2-chloro-3-fluoro-4-methoxyaniline (V-a with R.SUP.1.=Methyl)

[0096] Compound V-a was obtained as a white solid (16.6 g; 95% yield).

[0097] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 3.7 (s, 3H); 5.3 (b.s., 2H); 6.55 (m, 1H); 6.8 (m, 1H) ppm.

[0098] Mass spectra (ESI.sup.+, m/z) [M+H] 176.

Example 3b: 2-chloro-3-fluoro-4-benzyloxy-aniline (V-b with R.SUP.1.=Benzyl)

[0099] Compound V-b was obtained as an oil (95% yield).

[0100] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 5.1 (b.s, 2H); 5.35 (s, 2H); 7.1-7.6 (m, 7H) ppm.

[0101] Mass spectra (ESI.sup.+, m/z) [M+H] 252.

Example 4

##STR00012##

[0102] A mixture of 100 mmol (V) and 50 ml of 10% hydrochloric acid were stirred for 30 min at 20 C. to form a homogeneous slurry followed by addition of 0.4 g CuCl in 50 ml HCl and 60 ml of isopropanol. The mixture was stirred for 30 min and cooled to 0 C. An aqueous solution of sodium nitrite (14 ml, 40%) was slowly added at 0 C. to this mixture. The temperature was adjusted to 20 C. and the reaction mixture stirred for 10 h. 100 ml of water were added to the mixture and the oily product was extracted with methyl tert-butyl ether. The organic phase was washed with water, dried and evaporated to give the desired compound of formula (VII).

Example 4a: 1-chloro-2-fluoro-3-methoxybenzene (VII-a with R.SUP.1.=Methyl)

[0103] Compound VII-a was obtained as a pale-yellow oil (13.6 g; 85% yield).

[0104] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 3.8 (s, 3H); 7.0-7.2 (m, 3H) ppm.

[0105] .sup.19F NMR (376.4 MHz, DMSO-d.sub.6) 137.9 ppm.

[0106] Mass spectra (ESI.sup.+, m/z) [M+H] 161.

Example 4b: 1-benzyloxy-3-chloro-2-fluorobenzene (VII-b with R.SUP.1.=Benzyl)

[0107] Compound VII-b was obtained as an oil in 78% yield.

[0108] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 5.3 (s, 2H); 7.2-7.5 (m, 8H) ppm.

[0109] .sup.19F NMR (376.4 MHz, DMSO-d.sub.6) 137.7 ppm.

[0110] Mass spectra (ESI.sup.+, m/z) [M+H] 237.

Example 5

##STR00013##

2-fluoro-3-chloro-phenol (VIII)

[0111] A mixture of 50 g of 1-chloro-2-fluoro-3-methoxybenzene and 100 ml of HCl (37% water solution) were heated in a Parr Glass Autoclave at 110 C. After 7 h, the mixture was cooled, and the product extracted 3 times with 100 ml CH.sub.2Cl.sub.2. The solvent was evaporated to give 40 g of 2-fluoro-3-chloro-phenol as a pale-yellow liquid.

[0112] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 6.91-6.95 (m, 2H); 7.00 (s, 1H); 10.3 (s, 1H) ppm.

[0113] .sup.19F NMR (376.4 MHz, DMSO-d.sub.6) 139.9 ppm.

[0114] Mass spectra (ESI.sup.+, m/z) [M+H] 145.