PROCESS FOR THE PREPARATION OF ALPHA-ALKYL-2-(TRIFLUOROMETHYL)-BENZYL ALCOHOLS

Abstract

The present invention relates to a process for the preparation of preparation α-alkyl-2-(trifluoromethyl)-benzyl alcohol.

Claims

1. A process for the preparation of a compound of formula (I) ##STR00004## comprising: (i) reacting a compound of formula (A) ##STR00005## with R′—Mg-Hal.sup.2 (B1) or Mg (B2) and R.sup.1C(═O)H (C) in the presence of an ether solvent wherein the compound (A) is used in an amount of 2.4 to 20 mole per 1 mole of R′—Mg-Hal.sup.2 or Mg and wherein at least 1 mole of the whole amount of compound (A) is added during the reaction and the remaining amount of compound (A) is added either during the reaction or after the completion of the reaction; and (ii) removing the ether solvent from the reaction mixture wherein the variables are defined as follows: R.sup.1 is C.sub.1-C.sub.4-Alkyl; R′ is C.sub.1-C.sub.4-Alkyl or C.sub.3-C.sub.6-Cycloalkyl; Hal.sup.1 is Cl or Br; Hal.sup.2 is Cl or Br.

2. The process of claim 1, wherein the whole amount of compound A is added during the reaction.

3. The process of claim 1, wherein at least 1.2 mole of the whole amount of compound (A) is added during the reaction and the remaining amount of compound (A) is added after the completion of the reaction.

4. The process of claims 1, wherein the ether solvent is selected from the group consisting of tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, 2-methyl-tetrahydrofuran, and methyl-tert-butylether (MTBE).

5. The process of claim 1, wherein the ether solvent is THF.

6. The process of claim 1, wherein R.sup.1 is CH.sub.3.

7. The process of claim 1, wherein R′ is C.sub.2H.sub.5 or CH(CH.sub.3).sub.2.

8. The process of claim 1, wherein the reaction is carried out with R′—Mg-Hal.sup.2 (B1).

9. The process of claim 1, wherein two different R′—Mg-Hal.sup.2 (B1) are used.

10. The process of claim 1, wherein the reaction is carried out with Mg (B2).

11. The process of claim 1, wherein the compound (C) is acetaldehyde.

12. The process of claim 1, wherein LiCl is added to the reaction.

13. The process of claim 1, wherein compound (A) and compound (B1) or (B2) are added simultaneously.

14. The process of claim 1, wherein compound (A) and compound (C) are added simultaneously.

Description

Example 1: Preparation of α-methyl-2-(trifluoromethyl)-benzyl Alcohol

[0058] 12.2 g (0.50 mol) Mg-turnings are placed in a vessel and 4.3 g (0.10 mol) solid lithium chloride is added. 100 g THF is added. 2.0 g (15 mmol) 2-bromopropane is added to activate the magnesium. A rise of the internal temperature shows the start of the Grignard reaction. 15 min after initiation, the mixture is cooled to 30° C. A solution of 2-chlorobenzotrifluoride (CBTF) (183 g, 1.0 mol) in THF (390 g) is dosed into the suspension within 4 h. The mixture is post-stirred at 30° C. for 1 h. The mixture is cooled to 0° C. and a solution of 32.0 g (0.73 mol) acetaldehyde in 32 g THF is pumped sub-surface into the reaction mixture at a rate that allows to maintain the temperature below 10° C. The mixture is post-stirred for 15 min. THF is removed under reduced pressure while 183 g CBTF (1.0 mol) is added to dilute the mixture. Hydrochloric acid (2.0 M, 315 g, 0.60 mol) is placed in a second vessel and the hot distillation residue is transferred into the HCl, keeping the temperature <50° C. The mixture is stirred for 30 min and the aqueous phase is discarded. The CBTF-phase containing the product is washed with 200 g water.

[0059] Yield: 272 g CBTF-phase, concentration of compound (I) is 30.1 wt % by HPLC, corresponding to 0.43 mol=86% based on magnesium.

Example 2: Preparation of α-methyl-2-(trifluoromethyl)-benzyl Alcohol

[0060] 12.2 g (0.50 mol) Mg-turnings are placed in a vessel and 4.3 g (0.10 mol) solid lithium chloride is added. 100 g THF is added. 2.0 g (16 mmol) 2-bromopropane is added to activate the magnesium. A rise of the internal temperature shows the start of the Grignard reaction. 15 min after initiation, the mixture is cooled to 27° C. A solution of 2-chlorobenzotrifluoride (CBTF, 183 g, 1.0 mol) in THF (360 g) is prepared and dosing of this solution is started with a rate of 120 g/h, keeping the temperature below 38° C. by external cooling. After 90 min of dosage, 17.8 g acetaldehyde (0.40 mol) is mixed into the remaining CBTF-solution and its temperature is cooled to 10° C. to avoid acetaldehyde evaporation. The dosage is continued with 60 g/h. After 6.5 h, the remaining CBTF/acetaldehyde mixture is pumped into the reaction vessel. The mixture is post-stirred at 30° C. for 30 min. The mixture is cooled to 15° C. and a solution of 13.2 g (0.3 mol) acetaldehyde in 15 g THF is pumped into the reaction mixture at a rate that allows to maintain the temperature at maximum 23° C. The mixture is post-stirred for 15 min. THF is removed under reduced pressure while 183 g CBTF (1.0 mol) is added to dilute the mixture. Hydrochloric acid (2.0 M, 315 g, 0.60 mol) is added, keeping the temperature <50° C. The mixture is stirred for 30 min and the aqueous phase is discarded. The CBTF-phase containing the product is washed with 200 g water.

[0061] Yield: 264 g CBTF-phase, product concentration 30.0 wt % by HPLC, corresponding to 0.42 mol=83% based on magnesium.

[0062] .sup.1H-NMR: (400 MHz, CDCl.sub.3, mixture with CBTF): 7.82 (d, 1H, J=8.0 Hz), 7.57 (d, 1H, J=7.3 Hz), 7.54 (t, 1H, J=7.0 Hz), 7.28-7.35 (m, 1H, overlay with CBTF signals), 5.30 (q, 1H, J=6.5 Hz), 3.08 (br, 1H), 1.45 (d, 3H, J=6.3 Hz).