Process for the Preparation of Substituted Oxiranes and Triazoles

Abstract

The present invention relates to a process for the preparation of oxirane compounds of formula II from keto compounds III using dimethyl sulfide (CH.sub.3).sub.2S and dimethylsulfate (CH.sub.3).sub.2SO.sub.4, forming the reagent IV, trimethylsulfonium methylsulfate [(CH.sub.3).sub.3S.sup.+CH.sub.3SO.sub.4.sup.], in aqueous solution in the presence of potassium hydroxide (KOH).

Claims

1-11. (canceled)

12. A process for the preparation of the compounds of formula II ##STR00027## wherein R.sup.1 is C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.8-cycloalkyl; and R.sup.4 is F or Cl comprising the following step: (i) reacting an oxo compound of the formula III ##STR00028## with dimethyl sulfide (CH.sub.3).sub.2S and dimethylsulfate (CH.sub.3).sub.2SO.sub.4, forming the reagent IV, trimethylsulfonium methylsulfate [(CH.sub.3).sub.3S.sup.+CH.sub.3SO.sub.4.sup.], in aqueous solution in the presence of potassium hydroxide (KOH), wherein dimethyl sulfide and dimethyl sulfate are used in a molar ratio of 1:1 to 2:1, and wherein at most 10 weight-% organic solvent in relation to the amount of compound III, are added.

13. The process of claim 12, wherein essentially no organic solvent is added.

14. The process of claim 12, wherein the formation of the reagent of formula IV and the reaction of IV with compound III are carried out as a one-pot reaction.

15. The process of claim 12, wherein at least 2 equivalents of base per 1 equivalent of compound III are used.

16. The process of claim 12, further comprising the following step: (ii) reacting the oxirane of the formula II resulting from step (i) with 1H-1,2,4-triazole and a base, resulting in compounds of formula I ##STR00029## wherein the variables R.sup.1 and R.sup.4 are as defined in claim 12.

17. The process of claim 16, wherein an inorganic base is used and less than 1 equivalent of said inorganic base is used per 1 equivalent of compound II.

18. The process of claim 16, wherein the product resulting from step (ii) is crystallized from toluene and/or ortho-xylene and/or an aliphatic alcohol and/or carbonic acid ester.

19. The process of claim 18, wherein the aliphatic alcohol is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol and mixtures thereof.

20. The process of claim 18, wherein n-butyl acetate or ethyl acetate or a mixture thereof is used for crystallization.

21. A process for purification of a reaction product comprising a compound of formula I, comprising the step (ii-1) crystallizing said reaction product I from one or more carbonic acid ester(s) ##STR00030## wherein R.sup.1 is C.sub.1-C.sub.6-alkyl or C.sub.3-C.sub.8-cycloalkyl; and R.sup.4 is F or Cl.

22. The process of claim 21, wherein n-butyl acetate or ethyl acetate or a mixture thereof is used for crystallization.

Description

EXAMPLES AND FIGURES

[0209] The following figures and examples further illustrate the present invention and do not restrict the invention in any manner.

[0210] FIG. 1-1 shows an X-ray powder diffraction diagram of form A of compound IC.3.

[0211] FIG. 1-2 shows a DSC trace of form A of compound IC.3, melting point at 114 C.

[0212] FIG. 2-1 shows an X-ray powder diffraction diagram of form B of compound IC.3 [(the signals marked with * might be due to minor content of form A)].

[0213] FIG. 3-1 shows an X-ray powder diffraction diagram of form C of compound IC.3.

[0214] FIG. 4-1 shows an X-ray powder diffraction diagram of form D of compound IC.3.

[0215] FIG. 4-2 shows a DSC trace of form D of compound IC.3, melting point at around 55 C.

ANALYTICS

[0216] The X-ray powder diffractogram were recorded with a Panalytical X'Pert Pro diffractometer in reflection geometry in the range from 20=3-35 with a step width of 0.0167 using Cu-K radiation (1.54178 ) at 25 C. The recorded 20 values were used to calculate the d values. The intensity of the peaks (linear intensity counts) is plotted versus 20 angel (x axis in 20).

[0217] Single crystal X-ray diffraction data were collected at 100 K on a Bruker AXS CCD Detector, using graphite-monochromated CuK radiation (=1.54178 ). The structure was solved with direct methods, refined, and expanded by using Fourier techniques with the SHELX software package (G. M. Sheldrick, SHELX-97, University of Gttingen 1997). Absorption correction was performed with SADABS software.

[0218] DSC was performed on a Mettler Toledo DSC 823e module. The sample was placed in crimped but vented aluminium pans. Sample size was 3 mg. The thermal behaviour was analysed in the range 30-200 C. by using a heating rate of 10 C./min and a nitrogen stream of 150 mL/min. Melting point values and polymorphic transitions were confirmed by a Mettler Hot Stage in combination with a light microscope.

Examples

[0219] The following examples further illustrate the present invention and do not restrict the invention in any manner. Further compounds II and I, respectively, as described above, can be prepared in analogous manner to the following examples.

Example N1Synthesis of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

[0220] 65 g water (3.61 mole) are charged at room temperature. 346.6 g (2.72 mole) dimethyl sulfate are added under stirring. The temperature is increased to 33 C.

[0221] 180.3 g (2.87 mole) dimethylsulfide are dosed within 90 minutes at 33-39 C. (inside temperature control of the vessel). The first 50 g are dosed slower (in 30 minutes) than the rest due to the highly exothermic reaction. Poststirring period after dosage end: 15 minutes at 38 C.

[0222] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (1.77 mole) melt (approx. 60 C.) is added at 35 C. 400 g KOH pellets (85 wt-%, 6.06 mole) are added while stirring in 6 portions (30 g, 30 g, 40 g, 100 g, 100 g, 100 g) at 35 to 45 C. Then, it was continued stirring for 2 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC).

[0223] 2500 g water is added at 60 C. and the mixture stirred over 20 minutes. The lower organic product phase is separated and dissolved in DMF. The dimethylsulfide is removed by distillation. 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane was determined by quantitative HPLC chromatography in DMF solution (1.75 mole), 99.2% of theory in respect to the ketone starting material.

Example N2Synthesis of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

[0224] 4.8 g water (0.27 mole) were charged at room temperature. 25.5 g (0.2 mole) dimethyl sulfate were added under stirring. The temperature was increased to 33 C.

[0225] 13.3 g (0.21 mole) dimethylsulfide were dosed within 90 minutes at 33-39 C. (inside temperature control of the vessel). The first 5 g were dosed slower (in 30 minutes) than the rest due to the highly exothermic reaction. Poststirring period after dosage end: 15 minutes at 38 C.

[0226] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.13 mole) melt (at approx. 60 C.) was added at 35 C. 31 g KOH pellets, 85 wt-% (0.47 mole) were added while stirring in one portion at 35 to 45 C. Then, it was continued stirring for 1.5 h at 40 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC).

[0227] 220 g water was added at 41 C. and the mixture was heated to 60 C. over 10 minutes. The agitor was stopped and the lower organic product phase was separated, dissolved in DMF and the dimethylsulfide removed by distillation. 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane was determined by quantitative HPLC chromatography in 50 g DMF solution (0.122 mole), 96.9% of theory in respect to the ketone starting material.

Example N3Synthesis of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

[0228] 40 g (0.314 mole) dimethyl sulfate were charged at room temperature and 8 g (0.444 mole) water were added under stirring.

[0229] 22.5 g (0.359 mole) dimethylsulfide were dosed in at 20-44 C. within approximately 60 minutes (inside temperature control of the vessel). Poststirring period after dosage end: 1 h at 37 C. and over night at room temperature.

[0230] 43 g (0.651 mole, 85% w/w) KOH pellets were added as 25 C. (exotherm, temperature increase to 32 C.). Afterwards 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.13 mole) melt (approx. 60 C.) was dosed at 30-43 C. during 15 minutes. Then, stirring was continued for 2 h at 39 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC).

[0231] 310 g water was added at 38 C. and the mixture was heated to 60 C. over 10 minutes. The agitor was stopped and the lower organic product phase was separated and dissolved in 33.7 g DMF. 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane was determined by quantitative HPLC chromatography in solution with 96.4% (0.122 mole) in respect to the ketone starting material.

Example N4Synthesis of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane

[0232] 15 g dimethylsulfide (0.239 mole) and 5.4 g water (0.3 mole) were charged at room temperature. The temperature was increased to 35 C.

[0233] 26 g (0.204 mole) dimethyl sulfate were added under stirring at 35-39 C. over 30 minutes. Poststirring period after dosage end: 3 h at 36 C.

[0234] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.13 mole) C. was added as melt. 31 g KOH pellets (85 wt.-%, 0.47 mole) were dosed slowly starting at 20 C. Due to the exothermic reaction, temperature increased to 35 C. Then, it was continued stirring for 2 h at 37 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC).

[0235] 205 g water was added at 37 C. and the mixture stirred over 10 minutes. The lower aqueous phase was separated at 30 C. The organic product phase was concentrated by distillation for removal of the dimethylsulfide. The residue was dissolved in 50 g DMF and the product amount of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane was determined by quantitative HPLC chromatography in DMF solution with 98.4% in respect to the ketone starting material (0.128 mole).

Example M1(Preparation 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol

[0236] 109 g (51.3 wt-% in DMF; 0.1701 mole) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were diluted with 105.6 g DMF at room temperature. 15.6 g (98 wt-%; 0.221 mole) of 1,2,4-triazole and 3.47 g (0.085 mole) NaOH flakes were added under stirring. The reaction mixture was heated to 125-126 C. and then stirred for 5 h in total at this temperature. A HPLC-sample showed complete conversion to the desired product (ratio triazol-1-yl/triazol-4-yl about 10:1). About 93% of the DMF was evaporated at 125 C./300-60 mbar. To the concentrated reaction mixture, 150 g butyl acetate and 92.3 g water were added and the mixture stirred over 10 minutes. Then, the aqueous phase was separated at 80 C.

[0237] The organic phase was concentrated at 85 C./400-130 mbar by 50% (distillate of 117.6 g butyl acetate). The solution was cooled to 60 C. and seeded with product and stirred at this temperature over 30 minutes so that the product crystallized slowly. Further cooling to 0 C. with a rate of 7.5 K/h followed by suction filtration of the product, washing with 42.8 g n-butyl acetate at 0 C. and drying in a drying cabinet at 55 C./15 mbar led to 52.1 g of product (78.1% of the theory, with a purity of 98.9% determined by quantitative HPLC analytics. Triazol-4-yl-Isomer: 0.74%).

Example M2Preparation 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol

[0238] 50 g (83 wt-%, 0.1263 mole) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were dissolved in 102.9 g DMF at room temperature. 11.6 g (98 wt-%; 0.164 mole) of 1,2,4-triazole and 11.68 g (0.095 mole) 4-dimethylaminopyridine were added under stirring. The reaction mixture was heated to 129 C. over 22 h. A HPLC-sample showed complete conversion to the desired product. The crude yield was determined by quantitative HPLC of the final reaction mixture (172.4 g with a content of 24.9%) with 85.6%.

[0239] 165 g of the reaction mixture were distilled without using a column (13 mbar, end temperature 150 C.). The first fractions contained the major part of the DMAP. Recycling of this base using a column should therefore be feasible. The residue of the distillation contained the desired product with a purity of 83.6%. Crystallization from an organic solvent like toluene or n-butyl acetate is expected to improve the purity significantly according to the experience with the compound.

Example M3: 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol

[0240] 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-isopropyl-oxirane (92.9 g, 76.9 wt-%, 0.217 mole) were dissolved in 180.6 g DMF. To this solution, 27.4 g (98 wt-%; 0.391 mole) triazole and 4.7 g (0.117 mole) NaOH powder were added at 25 C. After heating to 125 C. the reaction mixture was stirred at this temperature for 22.5 h in total. A HPLC-sample showed still remaining oxirane and a ratio of the triazole products of 10.3:1 (triazole-1-yl/triazole-4-yl). The addition of additional 0.3 eq triazole and stirring for another 2 h at 125 C. did not improve the conversion. About 79% of the DMF were evaporated at up to 60 C./4 mbar. 413 g toluene and 205 g water were added to the concentrated reaction mixture at 80 C. Then, the aqueous phase was separated at 55 C. The toluene solution was concentrated at up to 90 C./40 mbar until a residue of 108 g remained. 111 g methanol were added to the residue at 60 C. The solution obtained was cooled down to 1 C. with a rate of 5 C./h. Seed crystals were added at 45 C. The suspension of solids was easily stirrable and was separated by suction filtration and washed 1 time with 25 g of fresh and cold (0 C.) methanol. The solid compound was dried at 55 C. and 50 mbar. Yield: 64.8 g (96.9 wt-%; ratio triazole-1-yl/triazole-4-yl about 100:1); 73% of the theory. The crystals contained residual methanol as detected be .sup.1H-NMR; Melting point: 114 to 115 C.