HALOGEN SUBSTITUTED DIKETONES, PYRAZOLE COMPOUNDS AND PROCESSES FOR THE MANUFACTURE OF PYRAZOLE COMPOUNDS

Abstract

The present invention concerns new halogen substituted diketone compounds, new pyrazole compounds, processes for the manufacture of pyrazole compounds and processes for the manufacture of agrochemical or pharmaceutical compounds.

Claims

1.-5. (canceled)

6. A compound of formula (VII) ##STR00044## 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; R.sup.2 is CHal.sub.3 wherein Hal is a halogen and each Hal is selected independently; wherein, when R.sup.2 is CF.sub.3, R.sup.1 contains two, one or zero fluorine atoms or, when R.sup.2 is CCl.sub.3, R.sup.1 contains two, one or zero chlorine atoms, R.sub.3 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; R.sup.4 is selected from the group consisting of H, X, COOR, OR, SR, C(O)NR.sub.2, wherein R are selected independently in C(O)NR.sub.2 where R is hydrogen or a C.sub.1-C.sub.12-alkyl group, CN, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl, each of which is optionally substituted, and X is F, Cl, Br, or I.

7.-23. (canceled)

24. The compound according to claim 6, wherein R.sup.2 is selected from the group consisting of CCl.sub.3, CF.sub.3, CBr.sub.3, and CI.sub.3.

25. The compound according to claim 24, wherein R.sup.2 is CCl.sub.3, CF.sub.3, or CBr.sub.3.

26. The compound according to claim 6, wherein R.sup.3 is CH.sub.3.

27. The compound according to claim 6, wherein R.sup.4 is H.

28. The compound according to claim 6, wherein R.sup.1 is CHF.sub.2, CClF.sub.2, CF.sub.3, or CCl.sub.3.

Description

EXAMPLES

[0179] 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (ETFBO) is obtained by the process described in EP1644306B1, Example 2. 4-ethoxy-1,1,1-trichlorobut-3-en-2-one (ETCBO) is obtained in the same manner by exchanging trifluoroacetylchloride by trichloroacetylchloride. Difluoroacetylfluoride (DFAF) and chlorodifluoroacetylchloride (CDAC) 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)-1,1,1-trifluorobut-3-en-2-one

[0180] ##STR00029##

[0181] 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (ETFBO, 20 g, 0.12 mol) is mixed with 120 mL of 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, or can also be recrystallized from cold Et.sub.2O/hexanes (1:50).

Example 2: 3-((dimethylamino)methylene)-1,1,1,5,5-pentafluoropentane-2,4-dione

[0182] ##STR00030##

[0183] 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) is introduced over a period of 60 minutes. The mixture is stirred at 15 C. for 20 minutes, slowly warmed to room temperature and then heated to 50 C. for 24 hours. The mixture cooled to 20 C., 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: 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

[0184] ##STR00031##

[0185] Monomethylhydrazine (40% v/v in water, 1.05 eq), 15 g of the product of example 2 and 2N aqueous KOH (1.1 eq) are mixed with 80 mL acetonitrile. The mixture is stirred at room temperature for 14 hours. The mixture is then heated to 80 C. for 30 minutes, cooled to room temperature and the volatiles are removed in vacuo. The organic phase is washed twice with ethyl acetate, and the organic phase discarded. The aqueous phase is acidified with 2N HCl, the resulting suspension is filtered and the solids washed with cold water to yield the product.

Example 4: 1-chloro-3-(ethoxymethylene)-1,1,5,5,5-pentafluoropentane-2,4-dione

[0186] ##STR00032##

[0187] 20 g of ETFBO is mixed with 140 mL dichloromethane. Pyridine (1.05 eq) is added and the mixture is cooled to 15 C. Chlorodifluoroacetylchloride (CDAC, 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 then heated to 50 C. for 24 hours. The mixture cooled to 20 C., diluted with water (80 mL), mixed thoroughly, the phases are separated and the aqueous phase extracted twice with dichloromethane. The combined extracts are dried over Na.sub.2SO.sub.4 and concentrated in vacuo to remove the volatiles.

[0188] Alternatively, the reaction mixture is not submitted to an aqueous extraction step but, optionally after incomplete or complete concentration, used directly in a cyclization reaction such as example 5.

Example 5: 1-(3-(chlorodifluoromethyl)-1-methyl-1H-pyrazol-4-yl)-2,2,2-trifluoroethanone

[0189] ##STR00033##

[0190] Monomethylhydrazine (40% v/v in water, 1.05 eq) and 15 g in appr. 20 mL dichloromethane of the product of example 4 are diluted with 80 mL acetonitrile. The dichloromethane is removed in vacuo. The mixture is stirred at room temperature for 14 hours. The volatiles are removed in vacuo. The mixture is diluted with tetrahydrofurane, the THF phase is washed with brine. The organic phase is dried over NaSO.sub.4 and volatiles removed in vacuo.

Example 6: 1,1,1-trichloro-3-(ethoxymethylene)-5,5-difluoropentane-2,4-dione

[0191] ##STR00034##

[0192] 20 g of ETCBO is dissolved in 40 mL pyridine, and the mixture is cooled to 15 C. Difluoroacetylfluoride (DFAF, 2 eq) is introduced over a period of 60 minutes. The mixture is stirred at 15 C. for 20 minutes, slowly warmed to room temperature, then heated to 50 C. and stirred at 50 C. for another 24 hours. The reaction product is used, optionally after incomplete or complete concentration, as a crude product in example 7.

Example 7: 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone

[0193] ##STR00035##

[0194] Monomethylhydrazine (MMH, 40% v/v in water, 1.05 eq) is cooled to 20 C. and 15 g of the crude product of example 6 in approximately 45 mL of dichloromethane are added to the MMH. After 1 hour, the mixture is slowly warmed to room temperature and diluted with 20 mL water. The mixture is acidified with 1N HCl, the organic phase is separated, dried over Na.sub.2SO.sub.4 and the volatiles are removed in vacuo. The crude product is purified by column chromatography (dichloromethane:hexanes 2:3).

Example 8: 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

[0195] ##STR00036##

[0196] Monomethylhydrazine (40% v/v in water, 1.05 eq), 15 g of the product of example 7 and 2N aqueous KOH (1.1 eq) are mixed with 80 mL acetonitrile. The mixture is stirred at room temperature for 14 hours. The mixture is then heated to 80 C. for 30 minutes, cooled to room temperature and the volatiles are removed in vacuo. The organic phase is washed twice with ethyl acetate, and the organic phase discarded. The aqueous phase is acidified with 2N HCl, the resulting suspension is filtered and the solids washed with cold water to yield the product.

Example 9: Bixafen (N-(3,4-dichloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0197] ##STR00037##

[0198] The product of example 7 (5.0 g, 18 mmol) and 3,4-dichloro-5-fluorobiphenyl-2-amine (4.6 g, 18 mmol) are dissolved in 30 ml dry toluene. To this solution 1,1,3,3-tetramethylguanidine (TMG, 0.2 eq) is added and the mixture is stirred at room temperature for 16 hours. The volatiles of the resulting yellow suspension are evaporated and the residue is triturated with cold water to yield a gray suspension. Solids are filtered, washed with water and dried yielding crude Bixafen.

Example 10: Fluxapyroxad (3-(difluoromethyl)-1-methyl-N-(3,4,5-trifluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide)

[0199] ##STR00038##

[0200] Fluxapyroxad is obtained using the procedure of example 9, wherein 3,4,5-trifluorobiphenyl-2-amine is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.

Example 11: Sedaxane (N-(2-(bi(cyclopropan)-2-yl)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0201] ##STR00039##

[0202] Sedaxane is obtained using the procedure of example 9, wherein 2-(bi(cyclopropan)-2-yl)aniline is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.

Example 12: 1,1,1-trichloro-3-(ethoxymethylene)-5,5,5-trifluoropentane-2,4-dione

[0203] ##STR00040##

[0204] 20 g of ETCBO is mixed with 40 mL pyridine in a hastelloy reactor. The reactor is sealed and trifluoracetylchloride (TFAC, 2 eq) is introduced over a period of 60 minutes. The mixture is brought to a temperature of 50 C. and stirred for 16 hours. The reaction product is used, optionally after incomplete or complete concentration, as a crude product in example 13.

Example 13: 2,2,2-trichloro-1-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)ethanone

[0205] ##STR00041##

[0206] Monomethylhydrazine (40% v/v in water, 1.05 eq) and 15 g of the product of example 12 mixed with 80 mL acetonitrile at room temperature. The mixture is stirred at room temperature for 14 hours. The volatiles are removed in vacuo to yield the crude reaction product.

Example 14: 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0207] ##STR00042##

[0208] 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid is obtained using the procedure of example 8, wherein the product of example 13 is used instead of the product of example 7.

Example 15: 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid

[0209] ##STR00043##

[0210] 0.231 mol 1,1,1-trichloro-4-(dimethylamino)-but-3-en-2-one, obtained by reaction between 1,1,1-trichloro-4-ethoxybut-3-en-2-one and dimethylamine, were reacted with 0.46 mol difluoroacetylchloride in dimethylformamide and ethylacetate in the presence of Na.sub.2CO.sub.3 to obtain, after aqueous workup, drying of combined organic phases and evaporation of volatiles, 1,1,1-trichloro-3-((dimethylamino)methylene)-5,5-difluoropentane-2,4-dione as yellow crystals. 0.178 mol (1 eq) of 1,1,1-trichloro-3-((dimethylamino)methylene)-5,5-difluoropentane-2,4-dione were suspended in ethanol and reacted with 1 eq 1-benzylidene-2-methylhydrazine in the presence of 1 eq NaHSO4 at room temperature for 8 hours. The resulting suspension was quenched in water, the resulting suspension filtered, washed with water, and dried to obtain (3-(2-benzylidene-1-methylhydrazinyl)methylene)-1,1,1-trichloro-5,5-difluoropentane-2,4-dione as light yellow solid. 0.162 mol of (3-(2-benzylidene-1-methylhydrazinyl)methylene)-1,1,1-trichloro-5,5-difluoropentane-2,4-dione was suspended in dimethoxyethane and 63 mL 2.5M aq. HCl were added. The mixture was stirred for 20 hours at room temperature, then diluted in ethylacetate. The combined organic phases were washed with water, brine, dried over Na.sub.2SO.sub.4 and evaporated to yield 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone as yellow liquid. 0.1497 (1 eq) 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone were diluted in toluene and 1.1 eq NaOH as 10% aq. solution were added. The mixture was stirred at room temperature overnight. The toluene phase was separated, aqueous phase extracted with toluene and combined organic phases discarded. The aqueous phase was cooled in ice and about 18 mL 32% HCl added under vigorous stirring to reach a pH of 1-2. The resulting suspension was filtered, washed with cold water and dried in vacuum. 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was obtained in +99% purity as solid and contained no regioisomer. The combined yield, starting from 1,1,1-trichloro-3-((dimethylamino)methylene)-5,5-difluoropentane-2,4-dione, over three steps was 77%.

Example 16: 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone

[0211] Under nitrogen, 17.73 g (49.49 mmol) of a 19% solution of BF.sub.3 in acetonitrile are cooled to 0 C. and 7.38 g (50.22 mmol) of 1,1,2,2-tetrafluoro-N,N-dimethylethanamine (TFEDMA) are added. The mixture is slowly warmed to 23 C., stirred for 2 hours at this temperature, and cooled to 0 C. A solution of 10.74 g (50 mmol) 1,1,1-trichloro-4-(dimethylamino)-but-3-en-2-one, obtained by reaction between 1,1,1-trichloro-4-ethoxybut-3-en-2-one and dimethylamine, in 10 mL anh. acetonitrile are slowly added. The mixture is slowly warmed to 23 C. and stirred for 2 hours at this temperature. The intermediary product vinamidinium salt can be used without further purification. The solution is cooled on ice, and 2.73 g (59.33 mmol) of methyl hydrazine in acetonitrile are added. The mixture is warmed to 23 C. and stirred at this temperature for 48 hours. The mixture is quenched with sat. NaHCO.sub.3 solution, phases separated and aq. phase extracted twice with ethyl acetate. Combined organic phases are washed with brine, dried over Na.sub.2SO.sub.4 and solvents removed. The product 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone is obtained as a crude product.