PROCESS FOR THE MANUFACTURE OF CARBOXAMIDES

Abstract

The present invention concerns a process for the manufacture of carboxamides, in particular agrochemical or pharmaceutically active ingredients, from pyrazole ketone compounds.

Claims

1. A process for the manufacture of carboxamides, the process comprising the step of reacting a pyrazole compound of the formula (I) ##STR00026## with a compound of the formula (II) NR.sup.3H(A*)Q to obtain a compound of the formula (III) ##STR00027## wherein R.sup.1 is selected from the group consisting of H, R, X, CN, COOR, OR, SR and C(O)NR.sub.2, wherein R is selected independently from the group consisting of hydrogen, CN, C.sub.1-C.sub.12-alkyl, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, aryl, cycloalkyl, aralkyl and heteroaryl, each of which is optionally substituted, and X is selected from the group consisting of F, Cl, Br and I; wherein R.sup.2 is selected from the group consisting of optionally substituted C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, cycloalkyl, aryl, heteroaryl, and aralkyl; wherein R.sup.3 is selected from the group consisting of H, optionally substituted C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl [[or]] and C.sub.3-C.sub.8-cycloalkyl group; wherein R.sup.4 is selected from the group consisting of H, X, COOR, OR, SR, and C(O)NR.sub.2, wherein R and X are as defined above; wherein R.sup.5 is selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, cycloalkyl, aryl, heteroaryl, and aralkyl, each of which is optionally substituted; wherein A* is absent or an optionally substituted C.sub.1-C.sub.4-alkylene group; wherein Q is an optionally substituted aryl or heteroaryl group.

2. The process according to claim 1, wherein R.sup.1 is selected from the group consisting of CF.sub.2Cl, CF.sub.2H, CFCl.sub.2, CFClH, CF.sub.2Br, CCl.sub.3, CF.sub.3, CBr.sub.3, and CI.sub.3.

3. The process according to claim 1, wherein R.sup.5 is an alkyl or cycloalkyl residue, each of which is optionally substituted.

4. The process according to claim 1, wherein R.sup.5 is an optionally substituted C.sub.1-C.sub.4-alkyl group.

5. The process according to claim 1, wherein R.sup.2 is H or an optionally substituted C.sub.1-C.sub.4-alkyl group.

6.The process according to claim 1, wherein Q is selected from the group consisting of Q39, Q40, Q41, Q42, Q43 and Q44 wherein Q39, Q40,Q41, Q42, Q43 and Q44 are defined below ##STR00028## wherein R.sup.36, R.sup.35b, R.sup.35c and R.sup.35d are each, independently, selected from the group consisting of hydrogen and halogen.

7. The process according to claim 1, wherein the step of reacting (I) and (II) to obtain (III) is performed in the presence of at least one oxidation agent.

8. The process according to claim 1, wherein the step of reacting (I) and (II) to obtain (III) is performed in the presence of at least one catalyst.

9. The process according to claim 8, wherein the at least one catalyst comprises at least one metal compound, wherein the at least one metal compound is a metal salt or a metal complex.

10. The process according to claim 9, wherein the at least one metal compound comprises at least one metal ion or metal atom selected from the group consisting of transition metals.

11. The process according to claim 9, wherein the at least metal compound is selected from the group consisting of transition metal halides, transition metal cyanates and transition metal acetates.

12. The process according to claim 9, wherein the at least one metal compound is selected from the group consisting of CuBr, CuCN, CuCl.sub.2 and Pd(OAc).sub.2.

13. The process according to claim 12, wherein the at least metal compound is selected from the group consisting of transition metal complexes.

14. The process according to claim 13, wherein the transition metal complex is selected from the group consisting of palladium and ruthenium complexes.

15. A process for the manufacture of an agrochemically or pharmaceutically active compound, which comprises the process of claim 1.

16. The process according to claim 5, wherein R.sup.2 is optionally substituted methyl.

17. The process according to claim 7, wherein the at least one oxidation agent is oxygen.

18. The process according to claim 14, wherein the transition metal complex is PdCl.sub.2(dppf) or Pd.sub.2(dba).sub.3.

Description

EXAMPLES

[0094] Difluoroacetylfluoride (DFAF) can be obtained from commercial sources, or manufactured according to the publications cited in the description. 3,4-dichloro-5-fluorobiphenyl-2-amine, 3,4,5-trifluorobiphenyl-2-amine and 2-(bi(cyclopropan)-2-yl)aniline can be obtained from commercial sources.

Example 1: 4-(dimethylamino)but-3-en-2-one

[0095] ##STR00020##

[0096] 4-ethoxy-3-buten-2-one is prepared by reacting ethylvinylether and acetylchloride. The product is mixed with dichloromethane and cooled to 5 C. 40% v/v of aqueous dimethylamine (1.1 eq) is added, the mixture is stirred for 10 minutes at 5 C., warmed to room temperature by removing the ice bath and stirred for one hour at room temperature. The mixture is washed with brine, dried over NaSO.sub.4 and the volatiles are removed in vacuo. The product is used without further purification.

Example 2: 3-((dimethylamino)methylene)-1,1-difluoropentane-2,4-dione

[0097] ##STR00021##

[0098] 20 g of the product of example 1 is mixed with 140 mL dichloromethane. Pyridine (1.05 eq) is added and the mixture is cooled to 15 C. Difluoroacetylfluoride (DFAF, 1.05 eq) in dichloromethane is added over a period of 60 minutes. The mixture is stirred at 15 C. for 20 minutes, slowly warmed to room temperature and stirred at room temperature for another 60 minutes. The mixture is diluted with water (80 mL) mixed thoroughly, the phases are separated and the aqueous phase extracted twice with dichloromethane. The combined extracts are concentrated in vacuo to remove the volatiles.

Example 3: 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)lethanone

[0099] ##STR00022##

[0100] Monomethylhydrazine (40% v/v in water, 1.05 eq) and 15 g of the product of example 2 are mixed with 80 mL acetonitrile. The mixture is stirred at room temperature for 14 hours. The volatiles are removed in vacuo. The aqueous phase is extracted twice with ethyl acetate, the combined extracts are concentrated in vacuo to remove the volatiles.

Example 4: Bixafen (N-(3,4-dichloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0101] ##STR00023##

[0102] The product of example 3 (5.0g, 18 mmol) and 3,4-dichloro-5-fluorobiphenyl-2-amine (5.52 g, 21.6 mmol) are dissolved in 50 ml xylene. To this solution pyridine (5 ml, 2 eq) and 10 mol % CuBr is heated for 12 h at 130 C. The mixture is cooled to 20 Cm filtered, washed with water, dried over Na.sub.2O.sub.4 and the volatiles are evaporated. The residue is triturated with cold water to yield a gray suspension. Solids are filtered, washed with water and dried yielding crude Bixafen.

Example 5: Fluxapyroxad (3-(difluoromethyl)-1-methyl-N-(3,4,5-trifluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide)

[0103] ##STR00024##

[0104] Fluxapyroxad is obtained using the procedure of example 4, wherein 3,4,5-trifluorobiphenyl-2-amine is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.

Example 6: Sedaxane (N-(2-(bi(cyclopropan)-2-yl)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0105] ##STR00025##

[0106] Sedaxane is obtained using the procedure of example 4, wherein 2-(bi(cyclopropan)-2-yl)aniline is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.