Process for the preparation of 2-alkyl-4-trifluoromethyl-3-alkylsulphonylbenzoic acids by chemoselective thioether oxidation

Abstract

A process for the preparation of 2-alkyl-4-trifluoromethyl-3-alkylsulfonylbenzoic acids of the formula (I) is described.

##STR00001##

Herein, the substituents are radicals such as alkyl and substituted phenyl.

Claims

1. Process for preparation of 2-alkyl-4-trifluoromethyl-3-alkylsulfonylbenzoic acid of formula (I), wherein a) in a first step a 1,3-dichloro-2-alkyl-4-trifluoromethylbenzene (II) is reacted with a thiolate (IV) to give an aryl bisthioether (III), b) in a second step the aryl bisthioether (III) is reacted with an oxidizing agent selectively to give an aryl monosulfoxide monothioether (V), c) in a third step an exchange of the sulfoxide group for a metal takes place and the organometallic compound thus obtained is converted to the benzoic acid (VII), and d) in a fourth step the remaining thio group is oxidized with an oxidizing agent, optionally in the present of an oxidation catalyst: ##STR00006## and e) in which the substituents are defined as follows: R.sup.1 and R.sup.2 are, independently of one another, C.sub.1-C.sub.4-alkyl or phenyl substituted by s radicals from the group consisting of chlorine, fluorine, methoxy and ethoxy, R.sup.3 is C.sub.1-C.sub.10 alkyl or phenyl substituted by s radicals from the group consisting of chlorine, fluorine, methoxy and ethoxy, M.sup.1 is lithium, sodium or potassium, M.sup.2 is magnesium, lithium or zinc, X is chloride, bromide or iodide, m is 0 or 1, n is 1 or 2, s is 0, 1, 2 or 3.

2. Process according to claim 1, in which NaSMe or KSMe is used as thiolate (IV).

3. Process according to claim 1, in which the thiolate (IV) is used in a molar ratio of 2:1 to 3:1, based on the compound of formula (II).

4. Process according to claim 1, in which, in the first step, dimethyl sulfoxide, dimethylacetamide, dimethylformamide or N-methyl-2-pyrrolidone is used as solvent.

5. Process according to claim 1, in which, in the second step, H.sub.2O.sub.2 is used for selective oxidation.

6. Process according to claim 1, in which, in the second step, acetic acid, propionic acid or dichloromethane is used as solvent.

7. Process according to claim 1, in which Na.sub.2WO.sub.4 in an amount of 5 to 15 mol %, and hydrogen peroxide in an amount of 3 to 8 mol equivalents, in each case based on the compound of formula (VII), are used as oxidation catalyst.

8. Process according to claim 1, in which, in the third step, ethylmagnesium bromide, butylmagnesium chloride or isopropylmagnesium chloride is used as organometallic compound.

9. Process according to claim 1, in which, in the third step, toluene, tetrahydrofuran or 2-methyltetrahydrofuran is used as solvent.

10. Compound of formula (III), ##STR00007## in which R.sup.1 and R.sup.2 are, independently of one another, C.sub.1-C.sub.4-alkyl or phenyl substituted by s radicals from the group consisting of chlorine, fluorine, methoxy and ethoxy, s is 1, 2 or 3.

11. Compound according to claim 10, in which R.sup.1 and R.sup.2 are methyl, ethyl n-propyl or isopropyl or n-butyl.

12. Compound of formula (V), ##STR00008## in which R.sup.1 and R.sup.2 are, independently of one another, C.sub.1-C.sub.4-alkyl or phenyl substituted by s radicals from the group consisting of chlorine, fluorine, methoxy and ethoxy, s is 1, 2 or 3.

13. Compound according to claim 12, in which R.sup.1 and R.sup.2, independently of one another, are methyl, ethyl, n-propyl, isopropyl or n-butyl.

14. Compound of formula (VIII), ##STR00009## in which R.sup.1 and R.sup.2 are, independently of one another, C.sub.1-C.sub.4-alkyl or phenyl substituted by s radicals from the group consisting of chlorine, fluorine, methoxy and ethoxy, s is 1, 2 or 3, n is 1 or 2.

15. Compound according to claim 14, in which R.sup.1 and R.sup.2, independently of one another, are methyl, ethyl, n-propyl, isopropyl or n-butyl.

Description

[0059] The examples below illustrate the invention in more detail without limiting it thereto.

Preparation of 2-methyl-3-(methylsulfonyl)-4-(trifluoromethyl)benzoic acid

Step 1: 2-methyl-1,3-bis(methylsulfanyl)-4-(trifluoromethyl)benzene

[0060] 2,4-Dichloro-3-methyltrifluorobenzene (29.7 g, 130 mmol, 1 equiv) are initially introduced into 150 ml of DMSO and stirred for 10 min until a clear solution is formed NaSMe. (24 g, 325 mmol, 2.5 equiv) are added in portions with ice cooling. After the exothermy has subsided, the mixture is heated to 40? C. and after-stirred for 20 h. After cooling to room temperature, 3.3 g (26 mmol, 0.2 equiv) of Me.sub.2SO.sub.4 are added and the mixture is after-stirred for 30 min. With cooling, 30 ml of 20% strength NaOH are added and the mixture is after-stirred for 30 min. The mixture is diluted with 250 ml of water and extracted three times with methylcyclohexane. The combined organic phases are washed with water and saturated sodium chloride solution, dried over Na.sub.2SO.sub.4 and the solvent is removed under reduced pressure. 29.5 g of 2-methyl-1,3-bis(methylsulfanyl)-4-(trifluoromethyl)benzene (88% yield) are obtained as a colourless oil.

[0061] .sup.1H NMR (600 MHz, CDCl.sub.3) 8=7.53 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 2.65 (s, 3H), 2.50 (s, 3H), 2.26 (s, 3H). GC/MS: m/e=252 (M); 237 (M-H.sub.3C.).

Step 2: 2-methyl-3-methylsulfanyl-1-methylsulfinyl-4-(trifluoromethyl)benzene

[0062] 2-Methyl-1,3-bis(methylsulfanyl)-4-(trifluoromethyl)benzene (2 g, 7.9 mmol, 1 equiv) is initially introduced with 0.5 ml of acetic acid (8.7 mmol, 1.1 equiv). 2.05 ml of a 35% strength H.sub.2O.sub.2 solution (23.8 mmol, 3 equiv) are metered in over 1 hour and the mixture is after-stirred for 2 h at room temperature. The mixture is admixed with a bisulphite solution in order to destroy peroxides. The acetic acid is removed on a rotary evaporator. Water and dichloromethane are added and the organic phase is separated off. This is washed with water and bicarbonate solution, then the solvent is removed on a rotary evaporator. This gives 2-methyl-3-methylsulfanyl-1-methylsulfinyl-4-(trifluoromethyl)benzene as white solid in a yield of 75%. Any amounts of bis-sulfoxide present (general compound VIII where R.sup.1?R.sup.2=Me, n=1) can be separated off by recrystallization from MeOH/water or by chromatography.

[0063] .sup.1H-NMR (600 MHz, CDCl.sub.3): ? 8.10 (d, J=8.3 Hz, 1H) 7.85 (d, J=8.3 Hz, 1H), 2.71 (s, 3H), 2.64 (s, 3H), 2.29 (s, 3H). GC/MS: m/e=268.

Step 3: 2-methyl-3-methylsulfanyl-4-(trifluoromethyl)benzoic acid

[0064] All operations are carried out under protective gas. 60 ml of toluene are initially introduced and cooled to ?25? C. 2-Methyl-3-methylsulfanyl-1-methylsulfinyl-4-(trifluoromethyl)benzene (10 g, 36.4 mmol, 1 equiv) is dissolved in 40 ml of toluene. In another vessel, 15 ml of a 3.26 molar EtMgBr/2-methyltetrahydrofuran solution are initially introduced and diluted with 24.3 ml of tetrahydrofuran and 9.3 ml of 2-methyltetrahydrofuran. The titer of the resulting Grignard solution is 1.03 M.

[0065] Now, the solutions of 2-methyl-3-methylsulfanyl-1-methylsulfinyl-4-(trifluoromethyl)benzene and EtMgBr are introduced dropwise in parallel into the reaction flask at ?25? C. over 30 min. The mixture is after-stirred at this temperature for 40 min, then dry CO.sub.2 is introduced. The internal temperature is kept below ?10? C. The reaction solution is allowed to reach room temperature, and is then admixed with concentrated HCl. The phases are separated and the aqueous phase is after-washed twice with toluene. The combined organic phases are rendered basic with 1N aqueous NaOH. The aqueous phase is separated off and the organic phase is after-extracted twice with 1N NaOH. The aqueous phase is adjusted to pH 0-1 with concentrated HCl and extracted three times with ethyl acetate. The combined organic phases are dried over Na.sub.2SO.sub.4, then the solvents are removed under reduced pressure. 6.2 g of 2-methyl-3-methylsulfanyl-4-(trifluoromethyl)benzoic acid (59% yield according to NMR quantification) are isolated as a slightly yellowish solid.

Step 4: 2-Methyl-3-(methylsulfonyl)-4-(trifluoromethyl)benzoic acid

[0066] 2-methyl-3-(methylsulfanyl)-4-(trifluoromethyl)benzoic acid (9.6 g, 38 mmol, 1 equiv) are dissolved in 60 ml of n-butyl acetate and 1.1 g (3.8 mmol, 0.1 equiv) of sodium tungstate dihydrate are added. The mixture is stirred intensively and heated to 55? C. By means of injection pump, 16.2 ml (190 mmol, 5 equiv) of 35% strength hydrogen peroxide solution are metered in over two hours at an internal temperature of 55-60?. The mixture is further stirred at this temperature for 8 to 10 hours. Then, the mixture is cooled and adjusted to pH=0 with dilute HCl. The reaction solution is heated to 60? C., and the phases are separated while warm. The majority of the n-butyl acetate is removed under reduced pressure. The resulting thick slurry is cooled and admixed with a small amount of toluene. The precipitate is filtered off with suction, washed with water and dried. 8.7 g of 2-methyl-3-(methylsulfonyl)-4-(trifluoromethyl)benzoic acid (81% yield) are obtained as a white solid.

Preparation of the general compounds VIII, example: 2-methyl-1,3-bis(methylsulfonyl)-4-(trifluoromethyl)benzene

[0067] 0.7 g of 2-methyl-1,3-bis(methylsulfanyl)-4-(trifluoromethyl)benzene (2.77 mmol, 1 equiv) are initially introduced into dichloromethane (50 ml). 5 g of meta-chloroperbenzoic acid (22 mmol, 8 equiv) are added at room temperature and the mixture is stirred for 20 h. The resulting suspension is filtered, and the filtrate is washed with aqueous bicarbonate and aqueous sodium chloride solution. After removing the solvent under reduced pressure, a white solid is obtained which, for the purposes of recrystallization, is heated in 50 ml of isopropanol, then cooled and filtered. Drying gives 0.76 g of 2-methyl-1,3-bis(methylsulfonyl)-4-(trifluoromethyl)benzene (86% yield) as white crystals.

[0068] .sup.1H-NMR (600 MHz, CD.sub.3CN): ? 8.48 (d, 1H, J=8.6 Hz) 8.08 (d, 1H, J=8.6 Hz), 3.35 (s, 3H), 3.26 (s, 3H), 3.11 (s, 3H). LC/MS (ESI-neg): m/e=315.0 (M-1).