PROCESS FOR THE PREPARATION OF SUBSTITUTED PHENYL KETONES

Abstract

The present invention relates to a process for providing substituted phenyl ketones. Furthermore, the invention relates to the use of substituted phenoxyphenyl ketones obtained by the inventive process for the preparation of triazoles.

Claims

1-12. (canceled)

13. A process for the preparation of the ketone compounds of formula (II) ##STR00010## wherein X is F or Cl and R.sup.1 is C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.8-cycloalkyl; comprising the following step: (i) reacting a compound of the formula (III) ##STR00011## with RMg-Hal (IV) or Mg, and RC(?O)Cl (V), wherein the Grignard reagent is added as solution in a solvent selected from tetrahydrofurane (THF), 1,4-dioxane, diethylether and 2-methyl-tetrahydrofurane, wherein the temperature during the reaction with (V) is kept in the range of ?20? C. to 10? C., wherein R is C.sub.1-C.sub.4-alkyl or C.sub.3-C.sub.6-cycloalkyl and Hal is halogen.

14. The process of claim 13, wherein a Cu(I)-catalyst is added in step (i).

15. The process of claim 14, wherein the Cu(I)-catalyst ist Cu(I)Cl.

16. The process of claim 13, wherein R is iso-propyl.

17. The process of claim 13, wherein Hal is Br or Cl, in particular Br.

18. The process of claim 13, wherein X is F.

19. The process of claim 13, wherein R.sup.1 is selected from CH.sub.3, CH(CH.sub.3).sub.2 and cyclopropyl.

20. The process of claim 13, wherein the temperature during the reaction with (V) is kept in the range of ?15? C. to 5? C.

21. The process of claim 13, wherein the temperature during the reaction with (V) is kept in the range of ?10? C. to ?5? C.

22. A process for the preparation of triazole compounds of the formula (IC) ##STR00012## wherein R.sup.1 is C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.8-cycloalkyl; and R.sup.2 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-cycloalkyl-C.sub.1-C.sub.6-alkyl, phenyl, phenyl-C.sub.1-C.sub.4-alkyl, phenyl-C.sub.2-C.sub.4-alkenyl or phenyl-C.sub.2-C.sub.4-alkynyl; wherein the aliphatic moieties of R.sup.2 are not further substituted or do carry one, two, three or up to the maximum possible number of identical or different groups R.sup.12a which independently are selected from: R.sup.12a halogen, OH, CN, nitro, C.sub.1-C.sub.4-alkoxy, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl and C.sub.1-C.sub.4-halogenalkoxy; wherein the cycloalkyl and/or phenyl moieties of R.sup.2 are not further substituted or do carry one, two, three, four, five or up to the maximum number of identical or different groups R.sup.12b which independently are selected from: R.sup.12b halogen, OH, CN, nitro, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenalkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl and C.sub.1-C.sub.4-halogenalkoxy; and R.sup.4 is F or Cl comprising the following steps: (i) preparing a compound of formula (II) ##STR00013## by reacting a compound of the formula (III) ##STR00014## with RMg-Hal (IV) or Mg, and R.sup.1C(?O)Cl (V), wherein the Grignard reagent is added as solution in a solvent selected from tetrahydrofurane (THF), 1,4-dioxane, diethylether and 2-methyl-tetrahydrofurane, wherein the temperature during the reaction with (V) is kept in the range of ?20? C. to 10? C., wherein R is C.sub.1-C.sub.4-alkyl or C.sub.3-C.sub.6-cycloalkyl and Hal is halogen; (ii) reacting compound (II) as defined in step (i) with a phenol derivative of formula (VI) ##STR00015## wherein R is hydrogen or an alkali metal kation; in the presence of a base if R is hydrogen to result in a ketone of formula (IA) ##STR00016## (iii) reacting the ketone of the formula (IA) as defined in step (ii) to oxiranes (IB); ##STR00017## and (iv) reacting the oxirane (IB) as defined in step (iii) with 1H-1,2,4-triazole in the presence of a base to obtain compounds (IC), wherein R.sup.2 is hydrogen (compounds IC-1); and, for obtaining compounds wherein R.sup.2 is different from hydrogen (compounds IC-2); (v) derivatizing the compound of formula (IC-1) as defined in step (iv) under basic conditions with R.sup.2-LG, wherein LG is a nucleophilically replaceable leaving group; to result in compounds (IC-2).

23. The process of claim 22, wherein the reaction to the oxirane (IB) is carried out with a trimethylsulf(ox)onium halide ((CH.sub.3).sub.3S.sup.+(O)Hal.sup.?) (VII), wherein Hal is halogen, or trimethylsulfonium methylsulfate of the formula (VIII) (CH.sub.3).sub.3S.sup.+CH.sub.3SO.sub.4.sup.?.

24. The process of claim 22, wherein R.sup.4 is Cl.

Description

EXAMPLES

[0137] The following examples further illustrate the present invention and do not restrict the invention in any manner.

Examples #1 to #4

[0138] Preparation of Compound (II) with X=F, R.sup.1=CH.sub.3 from Compound (III), with X=F:

[0139] A mixture of isopropylchloride (32.5 g) and isopropylbromide (232 g) is added to a stirred suspension of fresh Mg turnings (55.9 g), fresh THF (1415 g) and a small holdup from the last batch (9.7 g Mg turnings and some isopropyl Grignard) at ca. 50? C. within 1 h. The resulting suspension is stirred at ca. 60? C. for another hour. After cooling to ca. 25? C., the remaining Mg turnings were allowed to settle and most of the supernatant Grignard solution (1735 g) was transferred to a solution of compound (III) (490 g) in toluene (144 g) at ca. 20-32? C. within 45 min. The resulting solution was stirred at ca. 25? C. for another hour and then transferred to a suspension of acetylchloride (196 g) and copper(I)chloride (6.1 g) in toluene (737 g) at a temperature of approximately T.sub.acyl (see table below) within a time of t.sub.acyl min. The resulting suspension was stirred at the same temperature for another hour and then hydrolyzed cautiously by the addition of fresh water and the second and third water phase of the last batch (982 g combined) at about 0? C. While the temperature was allowed to rise during workup, it was not allowed to exceed 25? C. After phase separation, the aqueous phase was discarded and the organic phase was washed with fresh water (544 g) and aq. HCl (32%, 10 g). After phase separation, the aqueous phase was kept for the next batch and the organic phase was washed with a mixture of aq. NaOH (50%, 5 g) and water (15 g). After phase separation, the aqueous phase was again kept for the next batch and the organic phase was distilled under vacuum (750-120 mbar, sump temperature up to ca. 115? C.). The resulting crude compound (II) was weighed and analyzed according to the following table 1, wherein the amount of the observed undesired side products 4-chlorobutyl acetate, 4-bromobutyl acetate and others (not further specified) is listed. It can be seen that working under the inventive reaction conditions leads to higher purity of the reaction product, i.e. higher content of the desired product (II):

TABLE-US-00001 4- 4- chlorobutyl bromobutyl T.sub.acyl t.sub.acyl yield purity toluene acetate acetate others # [? C.] [min] [%].sup.a [%].sup.b [%].sup.b [%].sup.c [%].sup.c [%].sup.d 1 25-30 50 93.0 80.6 2.9 2.0 7.5 7.0 2 0 180 93.0 86.6 3.8 0.7 2.5 6.4 3 ?5 120 95.0 88.2 2.9 0.3 1.7 6.9 4 ?10 180 93.5 88.0 3.2 n. d..sup.e 1.8 7.0 .sup.acalculated from resulting weight and purity .sup.bw/w % from quantitative analytical method 1 (HPLC) .sup.cw/w % from quantitative analytical method 2 (GC) .sup.dcalculated from purity and content of the three known impurities shown in this table .sup.enot detected

Quantitative Analytical Method 1 (HPLC):

[0140] Agilent device with Agilent Zorbax Eclipse XDB-C18, 1.4 mL/min acetonitrile/water with 0.1 vol % phosphoric acid, UV detection at 210 nm.

Quantitative Analytical Method 2 (GC):

[0141] Agilent 6890N with Agilent CP7667, 3 mL/min H2, injection at 280? C., 8 min at 60? C., with 15? C./min to 280? C., detection (FID) at 320? C.