PROCESS FOR THE PREPARATION OF 1-(3,5-DICHLORO-4-FLUORO-PHENYL)-2,2,2-TRIFLUORO-ETHANONE

Abstract

The invention relates to a process for the preparation of a compound of formula I comprising a) reacting a compound of formula II in the presence of magnesium or an organometallic reagent of formula III R.sub.1M.sup.2X (III), wherein R.sub.1 is C.sub.I-C.sub.4alkyl; M.sup.2 is Li or Mg and X is halogen or absent; with a compound of formula IV CF.sub.3-C(O)-R.sub.2 (IV), wherein R.sub.2 is halogen, hydroxyl, C.sub.I-C.sub.4alkoxy, (di-C.sub.I-C.sub.4alkyl)amino, OC(O)CF.sub.3, phenoxy or OM.sup.1; wherein M.sup.1 is Lithium, Magnesium, Sodium or Potassium; to a compound of formula V, and b) reacting the compound of formula V with alkali metal fluoride in the presence of catalytic amounts of a phase transfer catalyst in the presence of a polar solvent to the compound of formula I.

##STR00001##

Claims

1. A process for the preparation of the compound of formula I ##STR00011## comprising a) reacting the compound of formula II ##STR00012## in the presence of magnesium or an organometallic reagent of formula III
R.sub.1—M.sup.2X  (III), wherein R.sub.1 is C.sub.1-C.sub.4alkyl; M.sup.2 is Lithium or Magnesium and X is halogen or absent; with a compound of formula IV
CF.sub.3—C(O)—R.sub.2  (IV), wherein R.sub.2 is halogen, hydroxyl, C.sub.1-C.sub.4alkoxy, (di-C.sub.1-C.sub.4alkyl)amino, OC(O)CF.sub.3, phenoxy or 0M.sup.1; wherein M.sup.1 is Lithium, Magnesium, Sodium or Potassium; to the compound of formula V, ##STR00013## and b) reacting the compound of formula V with an alkali metal fluoride in the presence of catalytic amounts of a phase transfer catalyst in the presence of a polar solvent to the compound of formula I.

2. A process according to claim 1, comprising a) reacting the compound of formula II ##STR00014## in the presence of an organometallic reagent of formula III
R.sub.1—M.sup.2X  (III) wherein R.sub.1 is C.sub.1-C.sub.4alkyl; M.sup.2 is Lithium or Magnesium and X is halogen or absent.

3. A process according to claim 2, wherein the organometallic reagent is isopropylmagnesiumchloride complexed with LiCl.

4. A process according to claim 1, wherein the alkali metal fluoride is selected from KF, LiF and NaF.

5. A process according to claim 1, wherein the phase transfer catalyst is selected from the group consisting of phosphonium salts of general formula (R.sub.3).sub.4PX and ammonium salts of general formula (R.sub.3).sub.4NX wherein R.sub.3 is C.sub.1-C.sub.4alkyl or phenyl and X is halogen.

6. A process according to claim 1, wherein the polar solvent is selected from the group consisting of sulfolane, dimethylformamide and dimethylsulfoxide.

7. A process according to claim 1, comprising a) reacting the compound of formula II ##STR00015## in the presence of an organometallic reagent of formula III
R.sub.1—M.sup.2X  (III) wherein R.sub.1 is C.sub.1-C.sub.4alkyl; M.sup.2 is Lithium or Magnesium and X is halogen or absent; with a compound of formula IV
CF.sub.3—C(O)—R.sub.2  (IV), wherein R.sub.2 is halogen, hydroxyl, C.sub.1-C.sub.4alkoxy, (di-C.sub.1-C.sub.4alkyl)amino, OC(O)CF.sub.3, phenoxy or OM.sup.1; wherein M.sup.1 is Lithium, Magnesium, Sodium or Potassium; to the compound of formula V, ##STR00016## and b) reacting the compound of formula V with an alkali metal fluoride selected from KF, LiF and NaF in the presence of catalytic amounts of a phase transfer catalyst selected from the group consisting of phosphonium salts of general formula (R.sub.3).sub.4PX and ammonium salts of general formula (R.sub.3).sub.4NX wherein R.sub.3 is C.sub.1-C.sub.4alkyl or phenyl and X is halogen; in the presence of a polar solvent selected from the group consisting of sulfolane, dimethylformamide and dimethylsulfoxide, to the compound of formula I.

8. A process according to claim 7, wherein the organometallic reagent is isopropylmagnesiumchloride complexed with LiCl.

Description

PREPARATORY EXAMPLES

Example 1: Preparation of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone of Formula V

[0020] ##STR00009##

[0021] To a solution of 5-bromo-1,2,3-trichloro-benzene (220 g, 811 mmol) in tetrahydrofuran (1600 ml) was added 1.3 M iPrMgCl.LiCl in THF (1250 ml, 1622 mmol) slowly at 20° C. The reaction mixture was stirred for 2 hours and cooled to 0° C. Methyl 2,2,2-trifluroacetate (314.8 g, 2434 mmol) was added slowly and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was cooled to 0° C. and 2.0 M HCl (810 ml, 1622 mmol) was added dropwise during 30 min. The resulting mixture was diluted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous MgSO.sub.4 and evaporated under reduced pressure. The crude product was dissolved in a minimum amount of cyclohexane and the solution was cooled to −10° C. The formed precipitate was filtered off to afford 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone (122 g) as a yellow solid. The filtrate was diluted with cyclohexane and washed twice with acetonitrile. Cyclohexane phase was evaporated under reduced pressure and the residue was dissolved in a minimum amount of cyclohexane. The solution was cooled to −10° C. and another portion of 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone (35 g) was filtered off. .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.07-8.05 (m, 2H).

Example 2: Preparation of 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone of formula I

[0022] ##STR00010##

[0023] To a solution of 2,2,2-trifluoro-1-(3,4,5-trichlorophenypethanone (1.0 g, 3.6 mmol) in sulfolane (3 ml) was added dry potassium fluoride (0.35 g, 4.32 mmol) and tetraphenylphosphonium bromide (0.015 g, 0.036 mmol). The resulting reaction mixture was stirred at 160° C. for 5 hours. The reaction mixture was distilled under reduced pressure. Fractions containing the product were further purified with silica gel chromatography (eluting with pure heptane) to afford 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (0.571 g) as a colorless oil and a mixture of ketone and hydrate forms (ca 3:1). .sup.19F NMR (400 MHz, CDCl.sub.3) δ−71.5, −84.7, −102.4, −112.9.