PROCESS FOR THE PREPARATION OF SUBSTITUTED OXIRANES AND TRIAZOLES

Abstract

The present invention relates to a process for the preparation of the compounds II

##STR00001##

from the respective oxo compounds. Furthermore, the invention relates to a process for the preparation of triazole compounds from oxiranes II.

Claims

1. A process for the preparation of a triazole compound of formula I ##STR00023## comprising (iia) reacting a compound of formula II ##STR00024## with 1H-1,2,4-triazole and an inorganic base, wherein the amount of the inorganic base is less than 1 equivalent of said base per 1 equivalent of compound II, resulting in the compound of formula I, wherein R.sup.1 is selected from 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 phenylC.sub.2-C.sub.4-alkynyl; wherein the aliphatic moieties of R.sup.1 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.sub.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.1 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 R.sup.3 is independently selected from halogen, CN, NO.sub.2, OH, SH, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, 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-cycloalkyloxy, NH.sub.2, NH(C.sub.1-C.sub.4-alkyl), N(C.sub.1-C.sub.4-alkyl).sub.2, NH(C.sub.3-C.sub.6-cycloalkyl), N(C.sub.3-C.sub.6-cycloalkyl).sub.2, S(O).sub.p(C.sub.1-C.sub.4-alkyl), C(O)(C.sub.1-C.sub.4-alkyl), C(O)(OH), C(O)(OC.sub.1-C.sub.4-alkyl), C(O)(NH(C.sub.1-C.sub.4-alkyl)), C(O)(N(C.sub.1-C.sub.4-alkyl).sub.2), C(O)(NH(C.sub.3-C.sub.6-cycloalkyl)) and C(O)(N(C.sub.3-C.sub.6-cycloalkyl).sub.2); wherein p is 0, 1 or 2; and wherein each of R.sup.3 is unsubstituted or further substituted by one, two, three or four R.sup.3a; wherein R.sup.3a is independently selected from halogen, CN, NO.sub.2, OH, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-haloalkyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halocycloalkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-haloalkoxy; R.sup.4 is independently selected from the substituents as defined for R.sup.3, wherein said R.sup.4 are unsubstituted or further substituted by one, two, three or four R.sup.4a, wherein each R.sup.4a is independently selected from the substituents as defined for R.sup.3a; n is 0, 1, 2, 3 or 4; and m is 0, 1, 2, 3, 4 or 5.

2. The process of claim 1, wherein the product resulting from step (iia) is crystallized from toluene and/or an aliphatic alcohol.

3. The process of claim 1, wherein the aliphatic alcohol is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol or any mixture thereof.

4. The process of claim 1, wherein the base used in step (iia) is selected from NaOH, KOH, Na.sub.2CO.sub.3 and K.sub.2CO.sub.3.

5. The process of claim 1, wherein the base used in step (iia) is selected from NaOH and KOH.

6. The process of claim 1, wherein the amount of base used in step (iia) is equal to or less than 0.6 equivalents per 1 equivalent of compound II.

Description

EXAMPLES AND FIGURES

[0387] The following figures and examples further illustrate the present invention and do not restrict the invention in any manner.

[0388] FIG. 1 shows an X-ray powder diffraction diagram of form A of compound I.3.

[0389] FIG. 2 shows an X-ray powder diffraction diagram of form A of compound I.5.

ANALYTICS

[0390] The X-ray powder diffractogramm of forms A and B were recorded with a Panalytical X'Pert Pro diffractometer in reflection geometry in the range from 2=3-35 with a step width of 0.0167 using CuK radiation (1.54178 ) at 25 C. The recorded 2 valuese were used to calculate the d values. The intensity of the peaks (linear intensity counts) is plotted versus 2 angel (x axis in 2).

[0391] 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). Absorbtion correction was performed with SADABS software.

[0392] 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.

A) Preparation of Reagent IV

Example A1

Preparation of an Aqueous Trimethylsulfonium-Methylsulfate Solution (11.3 wt-% Water)

[0393] 304 g dimethylsulfide and 30 g water (1.67 mole) were stirred at 25 C. Then, 146 g dimethylsulfate (1.15 mole) were added over 60 min, wherein the temperature increased to up to 35 C. Then, it was stirred 2 h at 35 to 38 C. In order to achieve phase separation, it was cooled to 30 C. and not stirred. 246 g of the lower aqueous phase were obtained.

[0394] The water content of the solution was measure by means of Karl-Fischer-titration and was 11.3 wt-%. The content of trimethylsulfonium-methylsulfate was quantified to be 85.3 wt-%; (SMe.sub.3).sup.+: 35 wt-% (quant.-NMR in D.sub.2O, di-Na-salt of fumaric acid as internal standard). The viscosity of the solution at 25 C. was 18.3 mPa*s.

[0395] Characterization: .sup.1H-NMR (400 MHz, D.sub.2O): /ppm=2.9 (s, 9H), 3.72 (s, 3H), 4.66 (s, H.sub.2O).

Example A2

Preparation of an Aqueous Trimethylsulfonium-Methylsulfate Solution (14.9 wt-% Water)

[0396] 304 g dimethylsulfide and 41.3 g water (2.3 mole) were stirred at 25 C. Then, 146 g dimethylsulfate (1.15 mole) were added over 60 min, wherein the temperature increased to up to 35 C. Then, it was stirred 2 h at 35 to 38 C. In order to achieve phase separation, it was cooled to 30 C. and not stirred. 259 g of the lower aqueous phase were obtained.

[0397] The water content of the solution was measure by means of Karl-Fischer-titration and was 14.9 wt-%. The content of trimethylsulfonium-methylsulfate was quantified to be 83.2 wt-%; (SMe.sub.3).sup.+: 34 wt-% (quant.-NMR in D.sub.2O, di-Na-salt of fumaric acid as internal standard). The viscosity of the solution at 25 C. was 12.5 mPa*s.

Example A3

Preparation of an Aqueous Trimethylsulfonium-Methylsulfate Solution (11.2 wt-% Water)

[0398] 144 g dimethylsulfide, 30 g water (1.67 mole) and 236 g toluol were stirred at 25 C. Then, 146 g dimethylsulfate (1.15 mole) were added over 60 min, wherein the temperature increased to up to 46 C. Then, it was stirred 2 h at 30 C. In order to achieve phase separation, it was cooled to 30 C. and not stirred. 245 g of the lower aqueous phase were obtained.

[0399] The water content of the solution was measure by means of Karl-Fischer-titration and was 11.2 wt-%. The content of trimethylsulfonium-methylsulfate was quantified to be 84.5 wt-%; (SMe.sub.3).sup.+: 34.8 wt-% (quant.-NMR in D.sub.2O, di-Na-salt of fumaric acid as internal standard).

Comparative Example

Preparation of an Aqueous Trimethylsulfonium-Methylsulfate Solution (6.5 wt-% Water)

[0400] 304 g dimethylsulfide and 15.0 g water (0.83 mole) were stirred at 25 C. Then, 146 g dimethylsulfate (1.15 mole) were added over 60 min, wherein the temperature was at most 35 C. Then, it was stirred for 2 h at 35 to 38 C. In order to achieve phase separation, it was cooled to 30 C. and not stirred. 237 g of the lower aqueous phase were obtained.

[0401] The water content of the solution was measured by means of Karl-Fischer-titration and was 6.5 wt-%. The content of trimethylsulfonium-methylsulfate was quantified to be 89.6 wt-%; (SMe.sub.3).sup.+: 37.2 wt-% (quant.-NMR in D.sub.2O, di-Na-salt of fumaric acid as internal standard). The viscosity of the solution at 30 C. was 35.1 mPa*s. The solution was not stable at 25 C. Long specular crystals were formed.

B) Synthesis of Oxiranes

Example B1

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

[0402] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.87 mole) dissolved in 372 g dimethylsulfide together with 250 g aqueous trimethylsulfonium-methylsulfate (86 wt-%, prepared according to Example A1) were provided at 23 C. 15 g KOH pellets, 85 wt-% (0.265 mole), were added while stirring heavily. This led to an increase of temperature of about 5 C. Then, it was continued stirring for 10 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC). After that, 1350 g 20 wt-% NaCl solution was added at 30 C. After separation of the aqueous phase, the dimethylsulfide-solution was concentrated by means of distillation of the solvent at a temperature of up to 98 C. 324 g 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane having about 90 wt-% (quant. HPLC) were obtained; yield >99%.

Characterisation

[0403] A sample oft the raw product was dissolved at 40 C. in diisopropylether and cooled down to 5 C. The product was obtained as crystalline compound. Melting point: 60 C.

[0404] .sup.1H-NMR (400 MHz, CDCl3): /ppm=1.63 (s, 3H), 2.92 (d, 1H), 3.02 (d, 1H), 6.95 (d, 2H), 7.13 (m, 1H), 7.22 (s, 1H), 7.34 (d, 2H) 7.64 (d, 1H);

[0405] .sup.13C-NMR (125 MHz, CDCl3): /ppm=24.82 (q), 55.41 (t), 57.27 (s), 115.94 (d), 120.63 (d, 2C) 121.48 (d), 123.91 (s), 128.60 (s), 129.36 (s), 130.05 (d, 2C), 131.04 (d), 134.59 (s), 154.50 (s), 156.56 (s)

Example B2

Synthesis of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane

[0406] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone (0.80 mole) dissolved in 343 g dimethylsulfide together with 263.4 g aqueous trimethylsulfonium-methylsulfate (86 wt %, prepared according to Example A1) were provided at 23 C. 212 g KOH pellets, 85 wt-% (3.21 mole), were added while stirring heavily. This led to an increase of temperature of about 5 C. to 7 C. Then, it was continued stirring for 8 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC). After that, 1236 g 20 wt-% ige NaCl solution was added at 30 C. After separation of the aqueous phase, the dimethylsulfide-solution was concentrated by means of distillation of the solvent at a temperature of up to 90 C. 332 g of 82 wt-%-product (quant. HPLC) (2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane) were obtained; yield >95%.

Characterisation

[0407] A sample oft the raw product was dissolved at 60 C. in isopropanole and cooled down to 10 C.

[0408] The product was obtained as crystalline compound. Melting point: 45 C. .sup.13C-NMR (125 MHz, CDCl3): /ppm=1.06 (t), 2.17 (t), 15.87 (d), 53.09 (t), 58.46 (s), 115.47 (d), 121.20 (d, 2C) 121.65 (d), 124.01 (s), 127.59 (s), 128.4 (s), 130.16 (d, 2C), 132.10 (d), 133.52 (s), 154.26 (s), 156.27 (s)

Example B3

Synthesis of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-isopropyl-oxirane

[0409] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-propan-1-one (0.078 mole) dissolved in 62 g dimethylsulfide together with 22.2 g aqueous trimethylsulfonium-methylsulfate (80 wt-%, prepared according to Example A1) were provided at 27 C. 15.4 g KOH pellets, 85 wt-% (0.23 mole), were added while stirring heavily. This led to an increase of temperature of about 5 C. to 7 C. Then, it was continued stirring for 3.5 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC). After that, 45 g water were added at 25 C. After separation of the aqueous phase, the dimethylsulfide-solution was diluted with a little toluol and washed again with 105 g water. Then, the organic phase was concentrated by means of distillation of the solvent at 50 C. and up to a pressure of 2 mbar. 30 g of about 81% (area-% HPLC) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-isopropyl-oxirane were obtained; yield about 88%.

[0410] Characterization:

[0411] A sample of the raw product was analyzed by means of NMR spectroscopy.

[0412] .sup.13C-NMR (125 MHz, CDCl3): /ppm=17.32 (q), 17.55 (q), 31.57 (d), 52.93 (t), 62.71 (s), 116.28 (d), 120.73 (d, 2C) 121.69 (d), 123.95 (s), 127.41 (s), 129.41 (s), 130.12 (d, 2C), 131.97 (d), 134.12 (s), 154.67 (s), 156.56 (s)

[0413] .sup.1H-NMR (400 MHz, CDCl3): /ppm=0.85-0.95 (dd, 6H), 2.22-2.35 (md, 1H), 2.78 (d, 1H), 3.20 (d, 1H), 6.98 (d, 2H), 7.10 (m, 1H), 7.23 (s, 1H), 7.35 (d, 2H) 7.55 (d, 1H)

Example B4

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

[0414] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.13 mole) dissolved in 55 g dimethylsulfide together with 45 g aqueous trimethylsulfonium-methylsulfate (80 wt-%, 17 wt-% H.sub.2O), prepared according to Example A2), were provided at 23 C. 25 g KOH pellets, 85 wt-% (0.38 mole), were added while stirring heavily. This led to an increase of temperature of about 5 C. Then, it was continued stirring for 8 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC). After that, 199 g 20 wt-% NaCl solution was added at 30 C. After separation of the aqueous phase, the dimethylsulfide-solution was concentrated by means of distillation of the solvent at a temperature of up to 90 C. 56 g of 77 wt-% (quant. HPLC) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were obtained; yield >95%.

Example B5

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

[0415] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.45 mole) dissolved in 280 g toluol together with 129 g aqueous trimethylsulfonium-methylsulfate (86 wt-%), prepared according to Example A1, were provided at 24 C. 89 g KOH pellets, 85 wt-% (0.38 mole) were added while stirring heavily. This led to an increase of temperature of about 4 C. Then, it was continued stirring for 21 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC). After that, 500 g 20 wt-% 20 wt-% NaCl solution was added at 30 C. After separation of the aqueous phase, the toluol solution was concentrated by means of distillation of the solvent at a temperature of up to 98 C. and a pressure of 50 mbar. 163 g of about 89 wt-% (quant. HPLC) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane were obtained; yield >95%.

Example B6

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

[0416] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]ethanone (0.128 mole) dissolved in 55.4 g dimethylsulfide were provided at 22 C. 25.4 g KOH pellets, 85 wt-% (0.385 mole) were added while stirring heavily. Then, 42.1 g aqueous trimethylsulfonium-methylsulfate (85.6 wt-%, prepared according to Example A1) were added. This led to an increase of temperature of about 2 to 3 C. Then, it was continued stirring for 8 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC). After that, 199 g 20 wt-% ige 20 wt-% NaCl solution was added at 30 C. After separation of the aqueous phase, the dimethylsulfide solution was concentrated by means of distillation of the solvent at a temperature of up to 90 C. 49.7 g of about 82 wt-% (quant. HPLC) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were obtained; yield about 97%.

Example B7

Synthesis of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane

[0417] 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone (0.122 mole) dissolved in 52 g dimethylsulfide were provided at 22 C. 32.2 g KOH pellets, 85 wt-% (0.488 mole), were added while stirring heavily. Then, 40.1 g aqueous trimethylsulfonium-methylsulfate (85.6 wt-%, prepared according to Example A1) were added. This led to an increase of temperature of about 3 to 5 C. Then, it was continued stirring for 8 h at 38 C. A sample of the reaction mixture showed full conversion of the ketone (HPLC). After that, 187 g 20 wt-% ige 20 wt-% NaCl solution was added at 30 C. After separation of the aqueous phase, the dimethylsulfide solution was concentrated by means of distillation of the solvent at a temperature of up to 90 C. 50.0 g, abou 82 wt % (quant. HPLC) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were obtained; yield about 91%.

C) Synthesis of Triazoles

Example C1: 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol (compound I.3)

[0418] 235.3 g (95.4 wt-%; 0.683 mole) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were provided in 496 g DMF and heated to 60 C. Then, one after the other, 60.6 g (99 wt-%; 0.869 mole) of triazole and 13.4 g (0.335 mole) NaOH-powder were added under stirring. The reaction mixture was heated to 125 C. and then stirred for 4 h in total at this temperature. A HPLC-sample showed almost complete conversion to the desired product (ratio triazol-1-yl/triazol-4-yl about 10:1). About 80% of the DMF was evaporated at 65 C./4 mbar. To the concentrated reaction mixture, 714 g toluol and 400 g water were added. Then, the aqueous phase was separated at 60 C. The toluol phase was washed again with 200 g water. The aqueous phase was separated and the toluol solution was concentrated at 70 C./50 mbar to a solution containing about 50% of the product. Precipitated solids were re-dissolved by heating to 80 C. The solution was cooled down from 80 C. to 0 C. with a rate of 5 K/h under stirring. The suspension of solids was easily stirrable and was separated by suction filtration and washed 2 times with 2100 g fresh and cold toluol. The solid compound was dried at 25 C./50 mbar.

[0419] Yield: 456 g (98 wt-%; triazol-4-yl-isomer: not detectable); 82% of the theory.

[0420] Melting point: 126 to 127 C.

[0421] The thus obtained crystalline material was analyzed by means of DSC and by means of X-ray powder diffractometry (XRPD). The X-ray powder diffractogram is depicted in FIG. 1. The reflections are summarized in table 1.

[0422] .sup.1H-NMR (400 MHz, CDCl.sub.3): /ppm=1.64 (s, 3H), 4.55 (s, OH), 4.44 (d, 1H), 4.62 (d, 1H), 6.92-7.61 (m, 7H), 7.87 (s, 1H), 8.02 (s, 1H) .sup.13C-NMR (125 MHz, CDCl.sub.3): /ppm=27.8 (q), 59.02 (t), 74.77 (s), 118.21 (d), 120.50 (d), 120.82 (d, 2C), 123.95 (CF3), 128.96 (s), 129.54 (s), 130.09 (d, 2C), 130.42 (d), 137.30 (s), 144.34 (d), 151.46 (d), 154.24 (s), 156.49 (s)

[0423] Single crystals of form A of compound I.3 were obtained by evaporation from a solution of the title compound in acetonitrile at ambient temperature. Single crystal X-ray diffraction data were collected as described above and the crystallographic parameters were calculated therefrom. The thus calculated crystallographic parameters are summarized in table 2.

Example C2: 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol

[0424] 12.8 g (98 wt-%; 0.182 mole) triazole and 2.86 g (0.07 mole) NaOH powder were added to 217.5 of a 22.8 wt-% DMF-solution of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-cyclopropyl-oxirane (0.14 mole) at 25 C. After heating to 125 C. the reaction mixture was stirred at this temperature for 10 h in total. A HPLC-sample showed almost complete conversion to the desired product (ratio triazol-1-yl/triazol-4-yl about 7.3:1). About 90% of the DMF was evaporated at 125 C./60 mbar. To the concentrated reaction mixture, 140 g toluole and 86 g water were added at 40 C. Then, the aqueous phase was separated at 80 C. The toluene solution was concentrated up to 86 C./40 mbar. About 133 g of destillate were obtained. The residue was cooled to 60 C. and 25 g methanol were added. After cooling to 45 C., seed crystals were added and the reaction mixture was held at 45 C. for 30 min. Then, the mixture was cooled to 0 C. within 5 h and stirred for 12 h. The suspension of solids was easily stirrable and was separated by suction filtration and washed 1 time with 21 g methanol of a temperature of 0 C. The solid compound was dried at 55 C. and 15 mbar.

[0425] Yield: 42.4 g (94.6 wt-%; about 3 wt-% MeOH; ratio triazole-1-yl/triazole-4-yl about 39:1); 68% of the theory.

[0426] Melting point: 86 to 87 C.

[0427] .sup.1H-NMR (400 MHz, CDCl.sub.3): /ppm=0.28-0.42 (m, 4H), 1.38-1.43 (m, 1H), 4.2-4.4 (s, breit, OH), 4.49 (d, 1H), 4.76 (d, 1H), 6.92-7.76 (m, 7H), 7.92 (s, 1H), 8.0 (s, 1H) .sup.13C-NMR (125 MHz, CDCl.sub.3): /ppm=0.12 (t), 1.61 (t), 18.91 (d), 58.78 (t), 75.09 (s), 118.14 (d), 120.34 (d), 120.9 (d, 2C), 123.97 (CF3), 129.20 (s), 129.53 (s), 130.08 (d, 2C), 130.92 (d), 137.06 (s), 144.18 (d), 151.84 (d), 154.24 (s), 156.44 (s)

Example C.SUB.2.a: crystallization of 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol

[0428] 206.5 g of a toluene solution of 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-1-cyclopropyl-2-(1,2,4-triazol-1-yl)ethanol (41.8 wt-%; 0.204 mol) prepared as described in example C.sub.2 were concentrated up to 60 C./10 mbar. The residue was cooled to 50 C. and dissolved in mixture of 50 g ethanole and 9 g water. After cooling to 30 C., seed crystals are added and the reaction mixture was held at 30 C. for 60 min. Then, the mixture was cooled to 0 C. with a rate of 2.5 K/min 5 h and stirred for at 0 C. for 4 days. The suspension of solids was easily stirrable and was separated by suction filtration and washed 1 time with 39 g ethanole of a temperature of 0 C. The solid compound was dried at 60 C./10 mbar.

[0429] 76.4 g (93.7 wt-%; ratio triazole-1-yl/triazole-4-yl about 44:1) colourless crystals containing ethanole in a molar ratio relative to the product of about 1/3 (detected by .sup.1H-NMR spectroscopy) were obtained; 83% crystallization yield.

[0430] Melting point: 81.5 C.

Example C3: 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol (compound I.5)

[0431] 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 evapoarted at up to 60 C./4 mbar. 413 g toluole and 205 g water were added to the concentrated reaction mixture at 80 C. Then, the aqueous phase was separated at 55 C. The toluol 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.

[0432] 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

[0433] Melting point: 114 to 115 C.

[0434] .sup.1H-NMR (400 MHz, CDCl.sub.3): /ppm=0.87 (d, 3H), 1.2 (d, 3H), 2.38 (m, 1H), 4.3-4.65 (s, breit, OH), 4.58 (d, 1H), 4.75 (d, 1H), 6.85-7.54 (m, 7H), 7.7 (s, 1H), 7.8 (s, 1H)

[0435] .sup.13C-NMR (125 MHz, CDCl.sub.3): /ppm=16.83 (q), 17.44 (q), 37.00 (d), 57.70 (t), 80.43 (s), 117.98 (d), 120.13 (d), 120.87 (d, 2C), 123.75 (CF3), 129.54 (s), 130.10 (d, 2C), 130.20 (d), 130.82 (s), 136.65 (s), 143.83 (d), 151.69 (d), 154.20 (s), 156.06 (s)

Example C4: 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol (compound I.5)

[0436] Preparation of compound I.5 was performed as described for experiment C.3, except that no seed crystals were added at 45 C. during cooling of the solution of compound I.5 in methanol. The thus obtained crystalline material was analyzed by means of DSC and by means of X-ray powder diffractometry (XRPD). The X-ray powder diffractogram is depicted in FIG. 2. The reflections are summarized in table 3.

[0437] Single crystals of form A of compound I.5 were obtained by dissolving thus obtained compound I.5 in 3-propanol and allowing heptane to diffuse into this solution at ambient temperature. Single crystal X-ray diffraction data were collected as described above and the crystallographic parameters were calculated therefrom. The thus calculated crystallographic parameters are summarized in table 4.

D) Comparison Examples for the Amount of Base Used

[0438] The base and the triazole in the amounts detailed in the table D below were added to a 20-25% solution of the respective oxirane II in DMF. At 125 C., the product of formula I was obtained. After evaporation of the major amount of DMF, the residue was partioned between toluole and water. The yield was determined after azeotropic drying and concentration by means of quantitative HPLC from the toluol solution.

TABLE-US-00013 TABLE D example 1 eq oxirane II eq triazole eq base temp./duration yield of 1-triazolyl D1 R.sup.1 = cylopropyl 1.3 NaOH/0.5 125 C./10 h 82% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl D2 R.sup.1 = CH.sub.3 1.3 NaOH/1.3 125 C./6 h 86% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl D3 R.sup.1 = cylopropyl 1.3 NaOH/1.3 125 C./12 h 75% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl D4 R.sup.1 = CH.sub.3 1.3 KOH/0.3 125 C./5.5 h 93% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl D5 R.sup.1 = CH.sub.3 1.3 NaOH/0.3 125 C./5 h 91% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl D6 R.sup.1 = CH.sub.3 1.3 KOH/1.3 125 C./6 h 89% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl D7 R.sup.1 = cylopropyl 1.3 KOH/1.3 125 C./16 h 56% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl D8 R.sup.1 = cylopropyl 1.3 KOH/0.3 125 C./12 h 76% (R.sup.3).sub.n = 2-CF.sub.3 (R.sup.4).sub.m = 4-Cl

E1) Comparative Example

[0439] To 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone (0.13 mol) dissolved in 55 g dimethylsulfide together with 42 g aqueous trimethylsulfonium-methylsulfate (86 wt-%, prepared according top Example A1) at 22 C., 15.7 g NaOH pellets (98 wt-%) (0.385 mol) were added under vigorous stirring. This led to an increase in temperature of about 5 to 6 C. Then, stirring was continued for 20 h at 38 C. A sample of the reaction solution showed incomplete conversion of the keton (detection by means of HPLC). Then, 199 g 20 wt-% NaCl solution were added at 30 C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by means of distillation of the solvent at a temperature of up to 90 C. 59.7 g (about 47 wt-% product, determined with quantitative HPLC) 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were obtained; Yield: 66%

E2) Comparative Example

[0440] Use of 50% ig aqueous KOH leads to incomplete conversion of reagents

[0441] To 1-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]cyclopropyl-methanone (0.13 mol), dissolved in 55 g dimethylsulfide together with 42 g aqueous trimethylsulfonium-methylsulfate (86 wt-%, prepared according to Example A1) at 22 C., 15.743 g 50% aqueous KOH (0.385 mol) were added under vigorous stirring. This led to an increase in temperature of about 5 to 6 C. Then, stirring was continued for 32 h at 38 C. A sample of the reaction solution showed incomplete conversion of the keton (detection by means of HPLC). Then, 199 g 20 wt-% NaCl solution were added at 30 C. After separation of the aqueous phase, the dimethyl sulfide solution was concentrated by means of distillation of the solvent at a temperature of up to 90 C. 53.5 g (about 34.5 wt-% product, determined with quantitative HPLC) of 2-[4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl]-2-methyl-oxirane were obtained. Yield: 44%.