PREPARATION OF SUBSTITUTED 3-ARYL-5-TRIFLUOROMETHYL-1,2,4-OXADIAZOLES

Abstract

The present invention relates to a process for the preparation of substituted 3-aryl-5-trifluoromethyl-1,2,4-oxadiazoles of formula (I), which can be obtained through reaction of amidoxime compounds of formula (II) with a haloacetic ester in the presence of a base.

##STR00001##

Claims

1. A process for preparing an oxadiazole compound of formula I, ##STR00012## wherein A is phenyl or a 5- or 6-membered aromatic heterocycle; wherein the ring member atoms of the aromatic heterocycle include besides carbon atoms 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein A is further unsubstituted or further substituted with additional n identical or different radicals R.sup.A; wherein n is 0, 1, 2, 3, or 4; R.sup.A is independently selected from the group consisting of halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, and C.sub.1-C.sub.6-haloalkoxy; R is methyl, which is further unsubstituted or further substituted with additional 1, 2, or 3 identical or different radicals R.sup.X; wherein R.sup.X is hydrogen, halogen, oxo, or OH; the process comprising reacting an amidoxime compound of formula II, ##STR00013## wherein the variables A and R are as defined above for compounds of formula I, with a haloacetic ester of formula II.a, ##STR00014## wherein R.sup.5 is C.sub.1-C.sub.6-alkyl; in the presence of a base; wherein the process is conducted in the absence of an auxiliary solvent.

2. The process according to claim 1, wherein R.sup.5 in the haloacetic ester II.a is methyl or ethyl.

3. The process according to claim 1, wherein 1 to 6 molar equivalents of the haloacetic ester I.a are used, based on the amount of the amidoxime II.

4. The process according to claim 1, wherein the base is selected from the group consisting of alkali metal C.sub.1-C.sub.6-alkoxides, alkali and earth alkali metal carbonates, alkali and earth alkali metal hydroxides, tri-(C.sub.1-C.sub.6)-alkylamines, pyridine, N-methylimidazole or quinoline, pyridine, collidine, lutidine, 2-picoline, 3-picoline, 4-picoline, N,N-dimethyl-4-aminopyridine, 5-ethyl-2-methyl-pyridine, DBU, and TBD.

5. The process according to claim 1, wherein the base is used in an amount that ranges between 90 and 200 mol %, based on the amount of the compound of formula II.

6. The process according to claim 1, wherein the process is conducted at a temperature between 20° C. and 45° C.

7. The process according to claim 1, wherein the amidoxime compound is of formula II.b, ##STR00015## wherein n corresponds to the total number of radicals R.sup.A attached to the central aromatic ring and wherein n is 0 or 1; A.sup.1 and A.sup.2 are independently selected from nitrogen, C—H, or C—R.sup.A; and wherein no more than one of A.sup.1 and A.sup.2 is nitrogen; and wherein the meaning of R is as defined or preferably defined herein for compounds of formula I; and wherein R.sup.A is selected from the group consisting of halogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, and C.sub.1-C.sub.6-haloalkoxy; to obtain oxadiazole compounds of formula I.b, ##STR00016## wherein the variables n, R.sup.A, A.sup.1, A.sup.2, and R have the meaning as defined for compounds II.b.

8. The process according to claim 1, wherein A.sup.1 and A.sup.2 are C—H and R.sup.A is fluorine.

9. The process according to claim 1, wherein n is 0; A.sup.1 and A.sup.2 are C—H.

10. The process according to claim 1, wherein RA is fluorine; n is 0 or 1; R is methyl, chloromethyl, dichloromethyl, or trichloromethyl.

11. The process according to claim 7, wherein n is 0; A1 and A2 are C—H; and R is methyl in compounds of formula I.b and II.b; further comprising reacting the compound of formula I.b to obtain a compound of formula I.c ##STR00017##

12. The process according to claim 9, further comprising reacting the compound of formula I.c to obtain a compound of formula III ##STR00018##

13. The process according to claim 12, wherein the step of reacting the compound of formula I.c to obtain a compound of formula III is carried out in the presence of iron(III) chloride and water.

14. The process according to claim 12, further comprising the step of reacting the compound of formula III with a compound of formula IV,
R.sup.1—NH—R.sup.2  IV wherein R.sup.1 is C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, C.sub.3-C.sub.11-cycloalkyl, C.sub.3-C.sub.8-cycloalkenyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkoxyimino-C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.6-alkenyloxyimino-C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.6-alkynyloxyimino-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkylamino, diC.sub.1-C.sub.6-alkylamino, —C(═O)—C.sub.1-C.sub.6-alkyl, —C(═O)—O—C.sub.1-C.sub.6-alkyl, phenyl-C.sub.1-C.sub.4-alkyl, phenyl-C.sub.1-C.sub.4-alkenyl, phenyl-C.sub.1-C.sub.4-alkynyl, heteroaryl-C.sub.1-C.sub.4-alkyl, phenyl, naphthyl, or a 3- to 10-membered saturated, partially unsaturated or aromatic mono- or bicyclic heterocycle, wherein the ring member atoms of said mono- or bicyclic heterocycle include besides carbon atoms further 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heteroaryl group in the group heteroaryl-C.sub.1-C.sub.4-alkyl is a 5- or 6-membered aromatic heterocycle, wherein the ring member atoms of the heterocyclic ring include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein any of the above-mentioned aliphatic or cyclic groups are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different groups R.sup.1a; or R.sup.1 and R.sup.2, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated mono- or bicyclic 3- to 10-membered heterocycle, wherein the heterocycle includes beside one nitrogen atom and one or more carbon atoms no further heteroatoms or 1, 2 or 3 further heteroatoms independently selected from N, O, and S as ring member atoms with the provision that the heterocycle cannot contain 2 contiguous atoms selected from O and S; and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or up to the maximum possible number of identical or different groups R.sup.1a; wherein R.sup.1a is halogen, oxo, cyano, NO.sub.2, OH, SH, NH.sub.2, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-haloalkylthio, C.sub.3-C.sub.8-cycloalkyl, —NHSO.sub.2—C.sub.1-C.sub.4-alkyl, (C═O)—C.sub.1-C.sub.4-alkyl, C(═O)—O—C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-alkylsulfonyl, hydroxyC.sub.1-C.sub.4-alkyl, C(═O)—NH.sub.2, C(═O)—NH(C.sub.1-C.sub.4-alkyl), C.sub.1-C.sub.4-alkylthio-C.sub.1-C.sub.4-alkyl, aminoC.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl, diC.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl, aminocarbonyl-C.sub.1-C.sub.4-alkyl, or C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl; 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.1-C.sub.6-alkoxy, C.sub.3-C.sub.11-cycloalkyl, —C(═O)H, —C(═O)—C.sub.1-C.sub.6-alkyl, —C(═O)—C.sub.3-C.sub.11-cycloalkyl, or —C(═O)—O—C.sub.1-C.sub.6-alkyl; and wherein any of the aliphatic or cyclic groups in R.sup.2 are unsubstituted or substituted with 1, 2, 3, or up to the maximum possible number of identical or different radicals selected from the group consisting of halogen, hydroxy, oxo, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, and C.sub.3-C.sub.11-cycloalkyl; to obtain a compound of formula V ##STR00019##

15. The process according to claim 14, further comprising reacting the compound of formula V to obtain a compound of formula VI ##STR00020##

16. The process according to claim 14, wherein in compounds of formula IV, V and VI R.sup.1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, cyclopropyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, or phenyl; and wherein the phenyl group is unsubstituted or substituted with 1, 2, 3 or up to the maximum possible number of identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, OH, NH.sub.2, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and cyclopropyl; and R.sup.2 is hydrogen, methyl, or ethyl.

17. The process according to claim 14, wherein in compounds of formula IV, V and VI. R.sup.1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl, or 2,4-difluorophenyl; in particular methyl or 2-fluoro-phenyl; and R.sup.2 is hydrogen.

Description

WORKING EXAMPLES

[0103] The present invention is further illustrated by means of the following working examples.

[0104] Analytical method: HPLC Agilent 1100 Series; column: Agilent Zorbax Phenyl-Hexyl 1.8 μm 50*4.6 mm, Column Flow: 1 mL/min, time: 25 min, pressure: 20000 kPa; temperature: 20° C.; wavelength 200 nm; injector volume: 2 uL; retention time of the respective products is based on reference material and given in the table below.

[0105] Eluent: A: Water with 0.1 vol % H.sub.3PO.sub.4; B: Acetonitrile

TABLE-US-00001 Time (min) % B Rate (mL/min) 0.0 14 1.0 16.0 86 1.0 20.0 86 1.0 20.1 14 1.0

Example 1) Preparation of 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[0106] A reaction vessel was charged with 40 g (259 mmol) solid N′-hydroxy-4-methyl-benzamidine and 184 g (1.30 mol) of ethyl trifluoroacetate at 22° C. 16.8 g solid sodium methylate (311 mmol) was added in 3 portions over a period of 40 minutes while maintaining a temperature below 33° C. The resulting mixture was stirred for an additional 90 min before 8.8 g hydrogen chloride (1 M in water) was added to adjust the pH to 4. The volatiles were removed under reduced pressure and the distillation sump was washed with water (80 g). After phase separation the tile compound was isolated in a yield of 94.8% and a purity of 92.7% (w/w).

[0107] Retention time: 11.2 min.

Example 2) Preparation of 3-[4-(trichloromethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole

[0108] 300 g (1.31 mol) 3-(p-tolyl)-5-(trifluoromethyl)-1,2,4-oxadiazole was placed in a 500 mL quartz glass round bottom flask. 427 g chlorine (6.0 mol) was passed into the reactor, heated to 125° C., and irradiated with a Heraeus TQ 150 Watt (mercury medium pressure emitter) UV-lamp over 8 hours. After completion of the reaction the reaction mass was stripped with nitrogen to remove remaining chlorine and hydrogen chloride gas. GC analysis showed 98.7 ar % product. Yield: 437 g crystalline product; 99%; melting point: 75-78° C.; .sup.1H-NMR (CDCl.sub.3): 8.1 ppm (m, 2H, 2×CH); 8.3 ppm (m, 2H, 2×CH).

Example 3) Preparation of N-(2-fluorophenyl)-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide

[0109] 150 g (0.446 mol) solid 3-[4-(trichloromethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole and 3.75 g (0.023 mol) iron(III)-chloride was filled in a 0.75 L reactor equipped with an overhead stirrer, reflux condenser and off-gas scrubber. The reactor was heated to 120° C. and 7.6 g (0.422 mol) water was dosed into the reaction mixture within 3 hours and stirred for another 30 minutes. Then the reaction mixture was cooled to 25° C. and 300 g (4.156 mol) tetrahydrofuran was added and the reaction mixture cooled to 10° C. Then a solution of 56 g 2-fluoro-aniline (0.489 mol), 50 g triethylamine (0.489 mol) and 200 g tetrahydrofuran (2.771 mol) was added in about 40 minutes, whereas the temperature of the reaction mixture was kept between 10° C. and 25° C. and the lines were flushed with 100 g (1.4 mol) tetrahydrofuran. After stirring overnight, the mixture was cooled to 5° C. and 450 mL water was added. The solid was filtered off and washed twice with 100 g cold water. A solid material was obtained, which was dried (80° C., 2 kPa) to yield 130 g (0.363 mol) of the title product. HPLC analysis showed >98 ar % product.

Example 4) Preparation of N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide

[0110] 5 g (0.015 mol) solid 3-[4-(trichloromethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole and 0.12 g (0.74 mmol) iron(III)-chloride was filled in a 0.75 L reactor equipped with an overhead stirrer, reflux condenser and off-gas scrubber. The reactor was heated to 85° C. and 0.26 g (0.014 mol) water were dosed into the reaction mixture within 1 hour and stirred for another 40 minutes. Then the temperature was cooled to 25° C. and 14.6 g (0.222 mol) tetrahydrofuran was added and the reaction mixture cooled to 0° C. Then 27 mL (5M, 0.074 mmol) of a methylamine solution in tetrahydrofuran was added and stirred overnight at room temperature. Water and ethyl acetate were added and the phases separated. The organic phase was washed with water and dried over magnesium sulfate/activated carbon. Filtration and removal of the volatiles yielded 2.9 g (88 ar %, 0.091 mol, retention time=0.93 min, M+=271) N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide.

Example 5) Preparation of N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenecarbothioamide

[0111] 15 g (54.8 mmol) N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzamide and 3.8 g (16.9 mmmol) phosphorus(V) sulfide was dissolved in 87 g toluene and heated to 112° C. for 1 hour. The reaction mixture was treated below 100° C. with 100 g water and 100 g toluene. After phase separation at 75° C. the organic phase was separated and washed with 100 g water. The volatiles were removed in vacuo (80° C., 200 to 5 mbar) to yield 15.8 g of crude product, which was suspended in 50 mL diisopropylether and heated to 60° C. for 1 hour. After cooling to room temperature, the precipitate was filtered off and washed with 20 mL diisopropylether. After drying at 80° C. and at reduced pressure, 13.5 g (44.2 mmol, 94 ar %) N-methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenecarbothioamide was obtained. .sup.1H-NMR (δ/ppm, CDCl.sub.3, 400 MHz): 3.4 ppm, s, 3H; 7.8, s, br 1H; 7.9, d, 2H; 8.1, d, 2H).