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 solvent and a base.

##STR00001##

Claims

1. A process for preparing an oxadiazole compound of formula I, ##STR00021## 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, chloromethyl, hydroxymethyl, trichloromethyl, ethyl, iso-propyl, OH, SH, cyano, halogen, CH.sub.2F, CHF.sub.2, 2,2,2-trifluoroethyl, cyclopropyl, —C(═O)H, —C(═NOR.sup.2)H, —C(═O)OH, —C(═O)OR.sup.1, —C(═W)NR.sup.1R.sup.2, —CR.sup.3R.sup.4NR.sup.1R.sup.2, —CR.sup.3R.sup.40R.sup.1, —CR.sup.3(═NR.sup.1), —CR.sup.3(═O), —CR.sup.3R.sup.4C(═O)OH, —CR.sup.3R.sup.4C(═O)R.sup.1, —CR.sup.3R.sup.4C(═W)NR.sup.1R.sup.2, —OCR.sup.3R.sup.4C(═O)OH, —OCR.sup.3R.sup.4C(═O)R.sup.1, —OCR.sup.3R.sup.4C(═W)NR.sup.1R.sup.2, —CR.sup.3R.sup.4—N(R.sup.2)—C(═W)R.sup.1, —CR.sup.3R.sup.4S(═O).sub.2R.sup.1, or —CR.sup.3R.sup.4—N(R.sup.2)—S(═O).sub.2R.sup.1; wherein W is O or S; 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)—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; 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-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 0 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-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.3, R.sup.4 independently of each other are selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkenyl, C.sub.1-C.sub.4-alkynyl, C.sub.1-C.sub.4-haloalkyl and C.sub.1-C.sub.4-alkoxy; or R.sup.3 and R.sup.4 together with the carbon atom to which they are bound form a cyclopropyl group; the process comprising reacting an amidoxime of formula II, ##STR00022## wherein the variables A and R are as defined above for compounds of formula I, with a haloacetic ester of formula II.a, ##STR00023## wherein R.sup.5 is C.sub.1-C.sub.6-alkyl, in the presence of a solvent and a base; whereas the base comprises a metal alkoxylate of formula IV,
[C.sub.1-C.sub.6-alkyl-O].sub.xM.sup.x+  IV wherein a metal M is an alkali metal, wherein x is 1, or M is an alkaline earth metal, wherein x is 2; and the solvent comprises an alkyl alcohol of formula III, or mixtures thereof,
C.sub.1-C.sub.6-alkyl-OH  III.

2. The process according to claim 1, wherein the metal M in the metal alkoxylate IV is sodium, potassium or magnesium.

3. The process according to claim 1, wherein the alkoxylate base of formula IV is sodium methoxide, sodium ethoxide, or a mixture thereof.

4. The process according to claim 1, wherein the solvent comprises methanol, ethanol, or a mixture thereof.

5. The process according to claim 1, wherein the solvent contains at least 1% by volume of the alkyl alcohol of formula III, or mixtures thereof, based on the total amount of solvents, whereas further solvents include auxiliary solvents, the haloacetic ester of formula II.a, or mixtures thereof.

6. The process according to claim 1, wherein the alkoxylate base of formula IV is the corresponding conjugate Bronsted base of the solvent of formula III.

7. The process according to claim 1, wherein the process is conducted at a temperature in the range of from 0° C. to 60° C.

8. The process according to claim 1, wherein the radical R.sup.5 in haloacetic esters of formula II.a is methyl or ethyl.

9. The process according to claim 1, wherein an amount of the haloacetic ester of formula II.a is between 1 to 5 equivalents based on the amount of amidoxime II.

10. The process according to claim 1, wherein the amidoxime compound is of formula II.b, ##STR00024## wherein n is 0 or 1, and the meaning of R.sup.A and R is as defined in claim 1 for compounds of formula I, to obtain oxadiazoles of formula I.b, ##STR00025## wherein the variables n, R.sup.A, and R have the meaning as defined for compounds II.b.

11. The process according to claim 10, wherein the variables have the following meaning: R.sup.A is fluorine; n is 0 or 1; R is methyl, —C(═O)OH, —C(═O)NR.sup.1R.sup.2, —CH.sub.2—N(R.sup.2)—C(═O)R.sup.1, —CH.sub.2—N(R.sup.2)—S(═O).sub.2R.sup.1, ##STR00026## R.sup.1 is C.sub.1-C.sub.6-alkly, phenyl, or cyclopropyl, wherein the phenyl ring is unsubstituted or substituted with 1, 2, 3, or 4 identical or different groups selected from halogen; R.sup.2 is hydrogen, methyl, ethyl, methoxy, ethoxy, or cyclopropyl.

12. The process according to claim 10, wherein the variables have the following meaning: n is 0; R is —C(═O)NR.sup.1R.sup.2; R.sup.1 is methyl, 2-methoxyiminoethyl, bicyclo[1.1.1]pentan-1-yl, 2-fluoro-phenyl, 4-fluoro-phenyl, or 2,4-difluorophenyl; R.sup.2 is hydrogen.

13. The process according to claim 12, further comprising reacting a compound of formula V.a, wherein the variables R.sup.1 and R.sup.2 are as defined for compound of formula II.b, to obtain the compound of formula II.b. ##STR00027##

14. The process according to claim 10, wherein n is 0 and R is methyl in compounds of formula I.b and II.b, and further comprising reacting the compound of formula I.b to obtain the compound of formula I.c. ##STR00028##

15. The process according to claim 10, wherein n is 0 and R is —C(═O)OH in compounds of formula I.b and II.b, and further comprising reacting the compound of formula I.b to obtain the compound of formula III.a. ##STR00029##

16. The process according to claim 14, further comprising the compound of formula I.c to obtain the compound of formula III.a. ##STR00030##

17. The process according to claim 15, further comprising reacting the compound of formula III.a with a compound of formula IV
R.sup.1—NH—R.sup.2  IV, wherein R.sup.1 and R.sup.2 in the compound of formula IV is defined as for compounds of formula I in any of the preceding claims to obtain a compound of formula V. ##STR00031##

18. The process according to claim 17, further comprising reacting the compound of formula V to obtain a compound of formula VI. ##STR00032##

19. The process according to claim 18, wherein in compounds of formulae 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

[0185] The present invention is further illustrated by means of the following working examples.

[0186] Analytical method 1: 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.

[0187] 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

[0188] Analytical method 2: HPLC Agilent 1100 Series; column: Agilent Zorbax Eclipse XDB-C18 1.8 μm 50*4.6 mm von Agilent, Column Flow: 1.3 mL/min, time: 10 min, pressure: 23000 kPa; temperature: 20° C.; wavelength 195 nm; injector volume: 1 uL; retention time of the respective products is based on reference material and given below.

[0189] Eluent: A: Water with 0,1 vol % H.sub.3PO.sub.4; B: Acetonitrile

TABLE-US-00002 Time (min) % B Rate (mL/min) 0.0 0 1.3 2.0 0 1.3 5.0 80 1.3 6.0 100 1.3 8.0 100 1.3 8.1 0 1.3

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

[0190] ##STR00019##

[0191] A vessel was charged at 22° C. with 40.0 g (256 mmol, purity 96.0%) of N′-hydroxy-4-methyl-benzamidine and 181 g (1.28 mol) of ethyl trifluoroacetate. 27.6 g sodium methanolate (151 mmol, 30% w/w in methanol) was added within 30 minutes and the reaction mixture was stirred for 1.5 hours at 30° C. Then, another portion of 13.8 g sodium methanolate (75.5 mmol, 30% w/w in methanol) was added within 10 minutes and the mixture was stirred for additional 40 minutes. A final portion of 13.8 g sodium methanolate (75.5 mmol, 30% w/w in methanol) was added within 10 minutes and the mixture was stirred for additional 30 minutes. 2.3 g hydrochloric acid (32% w/w) was added and all volatiles were removed under reduced pressure. Water (60 g) was added and the phases were separated. 57.4 g (94.8%, HPLC purity (method 1): 96.3%) of the title compound was isolated from the organic phase.

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

[0192] ##STR00020##

Example 2.1) TFAE as Reagent

[0193] A flask was charged with 500 mg (1.83 mmol) of N-(2-fluorophenyl)-4-[(Z)—N′ hydroxycarbamimidoyl]benzamide and 5 mL of N,N-dimethylformamide at room temperature. To this reaction mass 416 mg (2.93 mmol) of ethyl trifluoroacetate was added at room temperature followed by dropwise addition of 527 mg sodium methanolate (2.93 mmol, 30% w/w in methanol). Slight exotherm was observed during this addition and the reaction mass turned reddish brown. The reaction mass was stirred at room temperature for 1 further hour. HPLC analysis confirmed complete conversion. Then, water was added to the reaction mass, which caused the product to precipitate. The product was filtered and the filter cake was washed with water to remove N,N-dimethylformamide followed by drying to yield 0.53 g (84.6%, HPLC purity (method 1): 97.2%) of the title compound.

Example 2.2) TFAE as Solvent

[0194] A vessel was charged at 20° C. with 18.9 g (67.4 mmol, purity 97.5%) of N-(2-fluorophenyl)-4-[(Z)—N′-hydroxycarbamimidoyl]benzamide and 200 g (1.39 mol, purity 99%) of ethyl trifluoroacetate. 13.4 g sodium methanolate (74.4 mmol, 30% w/w in methanol) was added within 3 minutes and the reaction was stirred for 16 hours. Then, all volatiles were removed under reduced pressure, methanol (100 mL) and water (20 mL) was added and the solids were collected by filtration. The filter cake was washed with water (2×20 mL) and dried.

[0195] Dry weight of isolated title product: 20.4 g (83.4%), HPLC purity (method 1): 96.8%.

Example 2.3) TFAE as Solvent

[0196] A vessel was charged at 20° C. with 18.9 g (67.6 mmol, purity 97.8%) of N-(2-fluorophenyl)-4-[(Z)—N′-hydroxycarbamimidoyl]benzamide and 200 g (1.39 mol, purity 99%) of ethyl trifluoroacetate. 18.3 g sodium methanolate (100 mmol, 30% w/w in methanol) was added within 5 minutes and the reaction mixture was stirred for 3 hours after which an additional portion of sodium methanolate (6.1 g, 33.3 mmol) was added. Iso-propanol (200 mL) was added, the mixture heated to 70° C. and part of the volatiles was removed. The resulting mixture was cooled to ambient temperature and stirred for 16 hours before water (200 mL) was added, which caused the product to precipitate. The title product was collected by filtration. The filter cake was washed with water (2×50 mL) and dried. Dry weight of isolated title product: 20.4 g (93.4%), HPLC purity (method 1): 98.1%.

Example 2.4) TFAE as Reagent

[0197] A flask was charged with N-(2-fluorophenyl)-4-[(Z)—N′-hydroxycarbamimidoyl]benzamide (5 g, 1 equivalent), ethanol (60 mL) and ethyl trifluoroacetate (6.5 g, 2.5 equivalents) at ambient temperature under an atmosphere of nitrogen. To this reaction mass sodium ethanolate (21% w/w in ethanol, 8.3 mL, 1.4 equivalents) was added over a period of 13 minutes at ambient temperature and then the reaction mixture was stirred for 60 minutes at ambient temperature.

[0198] After completion of the reaction water (100 mL) was added and the resulting mixture was stirred for 30 minutes at ambient temperature, which caused the product to precipitate. The title product was collected by filtration. The filter cake was washed with water (50 mL) and dried under vacuum, which yielded the title product as a colorless solid in 98% (HPLC purity (method 1): 99.9%).

Example 2.5) TFAE as Reagent

[0199] A flask was charged with N-(2-fluorophenyl)-4-[(Z)—N′-hydroxycarbamimidoyl]benzamide (5 g, 1 equivalent) and toluene (100 mL) at ambient temperature under an atmosphere of nitrogen before sodium ethanolate (21% in ethanol, 11.9 mL, 2.0 equivalents) was added. Ethyl trifluoroacetate (5.2 g, 2.0 equivalents) was added and the resulting mixture was stirred for 3 hours at ambient temperature. After completion of the reaction toluene was removed under reduced pressure, water (100 mL) was added and the resulting mixture was stirred for 30 minutes at ambient temperature. The solids were collected by filtration and washed with water (50 mL). Drying under vacuum yielded the title product as a colorless solid in 96.9% (HPLC purity (method 1): 99.4%).

Example 2.6) TFAE as Reagent

[0200] A flask was charged with N-(2-fluorophenyl)-4-[(Z)—N′-hydroxycarbamimidoyl]benzamide (27.5 g, 1 equivalent) and ethanol (224 g) under an atmosphere of nitrogen. Sodium ethanolate (21% w/w in ethanol, 41 g, 1.30 equivalents) is added over a period of 10 minutes at ambient temperature and the resulting mixture was heated to 51° C. After 15 minutes at 51° C. ethyl trifluoroacetate (99%, 35 g, 2.5 equivalents) was added over a period of 35 minutes and the reaction temperature was maintained at 51° C. for 5 hours. Water (400 g) was then added over a period of 2 hours. The mixture was slowly cooled to ambient temperature and then further cooled to 10° C. The solids were collected by filtration and washed with water (2×100 mL). Drying under vacuum yielded the desired product as a colorless solid in 96.5% (HPLC purity (method 1): 98.6%).

Example 2.7) TFAE as Reagent

[0201] A flask was charged with N-(2-fluorophenyl)-4-[(Z)—N′-hydroxycarbamimidoyl]benzamide (33.2 g (98.8% purity, 1 equivalent). A mixture of methanol (76.8 g) and ethyl trifluoroacetate (37.5 g, purity 100%, 2.2 equivalents) was added under an atmosphere of nitrogen. The reaction mixture was cooled to below 20° C. and sodium methanolate (30% w/w in methanol, 25.9 g, 1.20 equivalents) was added over a period of 8 minutes at a temperature below 25° C. The resulting mixture was agitated at 25° C. for 5 hours. Demineralized water (48 g) was then added at 25° C. under agitation. The suspended solids were collected by filtration. Drying under vacuum yielded the desired product as a colorless solid in 96.2% (HPLC purity (method 1): 93.4%).

Example 3) Preparation of 3-[4-(Trichloromethyl)Phenyl]-5-(Trifluoromethyl)-1,2,4-Oxadiazole

[0202] 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 98.7ar % product. Yield: 437 g crystalline product; 99%; melting point: 75° C.-78° C.; .sup.1H-NMR (CDCl): 8.1 ppm (m, 2H, 2xCH); 8.3 ppm (m, 2H, 2xCH).

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

[0203] 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 (method 2) showed >98 ar % product.

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

[0204] 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 (HPLC analysis (method 2): 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 6) Preparation of N-Methyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenecarbothioamide

[0205] 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, HPLC analysis (method 2): 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)