PROCESS FOR THE MANUFACTURE OF IMINIUM COMPOUNDS AND THEIR APPLICATION IN THE MANUFACTURE OF PYRAZOLE DERIVATIVES

Abstract

Process for the manufacture of iminium compounds and their application in the manufacture of pyrazole derivatives The present invention concerns processes for the manufacture of iminium compounds and their application in the manufacture of pyrazole derivatives, in particular in processes for the manufacture of pharmaceutically or agrochemically active compounds.

##STR00001##

Claims

1. A process for manufacturing a compound according to formula (I), the process comprising reacting a compound of formula (II) and a compound of formula (III) ##STR00028## wherein R.sup.1 is selected from the group consisting of C.sub.1-4 alkyl groups which is substituted by at least one halogen atom, R.sup.2 and R.sup.3 are independently selected from the group consisting of C.sub.1-C.sub.12-alkyl C.sub.3-C.sub.10-cycloalkyl, aryl, and aralkyl groups, each of which is optionally substituted, or wherein R.sup.2 and R.sup.3 together with the nitrogen atom to which they are bound form an optionally substituted 5- to 10-membered heterocyclic radical which, in addition to the nitrogen atom to which they are attached, may contain a further 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S as ring members, R.sup.4 is selected from the group consisting of CF.sub.3, CCl.sub.3 and CBr.sub.3, R.sup.5 is selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.2-12 alkynyl, aryl, heteroaryl and aralkyl groups, each of which is optionally substituted, R.sup.6 and R.sup.7 each independently are selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.2-12 alkynyl, aryl, heteroaryl or aralkyl group, each of which is optionally substituted wherein at least one of R.sup.6 and R.sup.7 is different from H, R.sup.8 is selected from the group consisting of H, X′, COOR′, OR′, SR′, C(O)NR′.sub.2, wherein the groups R′ are selected independently in C(O)NR′.sub.2 where R′ selected from the group consisting of hydrogen, C.sub.1-C.sub.12-alkyl, CN, C.sub.2-C.sub.6 alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl, each of which is optionally substituted, and wherein X′ is a halogen atom, and wherein A.sup.− is selected from the group consisting of Cl.sup.−, BF.sub.4.sup.−, PF.sub.6.sup.−, SbF.sub.6.sup.−, AlCl.sub.3F.sup.− and AlCl.sub.4.sup.−.

2. The process according to claim 1, wherein R.sup.1 is a methyl group substituted by at least one halogen atom.

3. The process according to claim 1, wherein A.sup.− is AlCl.sub.3F.sup.−, BF.sub.4.sup.− or AlCl.sub.4.sup.−.

4. The process according to claim 1, wherein R.sup.4 is CCl.sub.3.

5. The process according to claim 1, wherein R.sup.8 is H or X′.

6. The process according to claim 1, wherein R.sup.5 is selected from the group consisting of H, CH.sub.3 and optionally substituted benzyl.

7. The process according to claim 1, wherein R.sup.6 and R.sup.7 each independently are selected from the group consisting of H, C.sub.1-C.sub.12-alkyl and aryl, each of which is optionally substituted, wherein at least one of R.sup.6 and R.sup.7 is different from H.

8. A process for the manufacture of a compound of formula (IV), which comprises the process according to claim 1, and which further comprises a step wherein the compound of formula (I) is contacted with an acid ##STR00029## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and A.sup.− are defined as in claim 1.

9. The process according to claim 8, wherein the acid is selected from the group consisting of CH.sub.3COOH, H.sub.2SO.sub.4, HNO.sub.3, H.sub.2PO.sub.4, KHSO.sub.4, NaH.sub.2PO.sub.4, HCl, CF.sub.3SO.sub.3H, CF.sub.3COOH and CH.sub.3COONa.

10. A process for the manufacture of a compound of formula (IV), which comprises the process according to claim 1, and which further comprises a step of contacting the compound of formula (I) with water in the presence of an acid or a base under reaction conditions which allow the compound of formula (V) to be formed, followed by a step wherein the compound of formula (V) is contacted with an acid to form the compound of formula (IV), wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and A.sup.− are defined as in claim 1, ##STR00030##

11. A process for the manufacture of a compound of formula (VII), which comprises the process according to claim 8, and which further comprises a step wherein the compound of formula (IV) is contacted with a base, ##STR00031## wherein R.sup.1 is selected from the group consisting of C.sub.1-4 alkyl groups which is substituted by at least one halogen atom, R.sup.4 is selected from the group consisting of CF.sub.3, CCl.sub.3 and CBr.sub.3, R.sup.5 is selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.2-12 alkynyl, aryl, heteroaryl and aralkyl groups, each of which is optionally substituted, R.sup.8 is selected from the group consisting of H, X′, COOR′, OR′, SR′, C(O)NR′.sub.2, wherein the groups R′ are selected independently in C(O)NR′.sub.2 where R′ selected from the group consisting of hydrogen, C.sub.1-C.sub.12-alkyl, CN, C.sub.2-C.sub.6 alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl, each of which is optionally substituted, and wherein X′ is a halogen atom.

12. A process for the manufacture of a pharmaceutically or agrochemically active compound, which comprises the process according to claim 11.

13. The process according to claim 12, wherein the agrochemically or pharmaceutically active compound is a compound of formula (VIII) ##STR00032## wherein R.sup.9 is selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl or C.sub.3-C.sub.8-cycloalkyl group, and wherein Q is an optionally substituted aryl or heteroaryl group, and wherein R.sup.1, R.sup.8 and R.sup.9 are as defined.

14. The process according to claim 13, which comprises contacting the compound of formula (IV) with a compound of formula (IX), NHR.sup.9Q, or which comprises converting the compound of formula (VII) into an activated carboxylic acid, and contacting the activated carboxylic acid form of formula (VII) with a compound of formula (IX), NHR.sup.9Q.

15. The process according to claim 12, wherein the agrochemically active compound is selected from the group consisting of Sedaxane, Fluopyram, Benzovindiflupyr, Bixafen, Fluxapyroxad, Isopyrazam, Penflufen and Penthiopyrad.

16. The process according to claim 2, wherein R.sup.1 is CHF.sub.2 or CF.sub.3.

17. A process for the manufacture of a compound of formula (VII), which comprises the process according to claim 10, and which further comprises a step wherein the compound of formula (IV) is contacted with a base, ##STR00033## wherein R.sup.1 is selected from the group consisting of C.sub.1-4 alkyl groups which is substituted by at least one halogen atom, R.sup.4 is selected from the group consisting of CF.sub.3, CCl.sub.3 and CBr.sub.3, R.sup.5 is selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.10-cycloalkyl, C.sub.2-12 alkynyl, aryl, heteroaryl and aralkyl groups, each of which is optionally substituted, R.sup.8 is selected from the group consisting of H, X′, COOR′, OR′, SR′, C(O)NR′.sub.2, wherein the groups R′ are selected independently in C(O)NR′.sub.2 where R′ selected from the group consisting of hydrogen, C.sub.1-C.sub.12-alkyl, CN, C.sub.2-C.sub.6 alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl, each of which is optionally substituted, and wherein X′ is a halogen atom.

18. The process according to claim 13, wherein R.sup.9 is selected from the group consisting of H and C.sub.1-C.sub.4-alkyl.

19. The process according to claim 14, wherein the activated carboxylic acid is a carboxylic acid halide.

Description

EXAMPLE 1

4-(2-benzylidene)-1-methylhydrazinyl)-1,1,1-trichlorobut-3-en-2-one

[0058] ##STR00017##

[0059] 217.5 g (1 mol) 1,1,1-trichloro-4-ethoxybut-3-en-2-one (ETCBO) is dissolved in in 150 mL ethyl acetate. 141 g (1.05 mol) 1-benzylidene-2-methylhydrazine, obtained by reaction of benzaldehyde and methylhydrazine, in 150 mL ethyl acetate are added while the reaction is cooled with a water bath. After completed reaction, the reaction mixture is stirred at room temperature for 2 hours. The suspension is cooled to 0° C., filtered, the solid washed with cold ethyl acetate, and the solid is dried in vacuum.

EXAMPLE 2

Vinamidinium Salt (a), Starting from 4-(2-benzylidene)-1-methylhydrazinyl)-1,1,1-trichlorobut-3-en-2-one

[0060] ##STR00018##

[0061] 2 g AlCl.sub.3 (68.7 mmol) are placed into a Teflon flask under nitrogen. 50 mL of anh. dichloromethane were added. The mixture was cooled to 0° C. 10.2 g 1,1,2,2-tetrafluoro-N,N-dimethylethanamine (TFEDMA) were carefully added over 10 minutes. After 1 hour at 0° C., 20 g 4-(2-benzylidene)-1-methylhydrazinyl)-1,1,1-trichlorobut-3-en-2-one from example 1 were added in portions at 0° C. under nitrogen flux and stirring. After completed addition, the mixture was allowed to warm to room temperature, and then heated under nitrogen at 50° C. for 5 hours. The mixture was cooled to room temperature. A control by .sup.1H-NMR in CD.sub.3CN showed 92% conversion.

EXAMPLE 3

2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one

[0062] ##STR00019##

[0063] To the mixture of example 2, 3, 21 g H.sub.2SO.sub.4 (d=1.84, 0.5 eq) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was quenched on ice, the layers were separated and the aqueous layer extracted with dichloromethane. The layers were combined. The GC-MS showed the presence of 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one.

EXAMPLE 4

3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid

[0064] ##STR00020##

[0065] The organic phase of example 3, containing 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one, was treated with 15% aq. NaOH (1.2 eq) for 1 hour at 50° C. The mixture was cooled to room temperature. The layers were separated, the aqueous layer was washed with dichloromethane, and the aqueous layer was acidified at 0° C. with 7.1 mL HCl (37% in water). After 15 minutes at 0° C., the mixture was filtered, the solid was rinsed with cold water and dried overnight in vacuum. The overall yield, starting from example 2, was 72.4%.

EXAMPLE 5

Vinamidinium Salt (Ib), Starting from 4-(2-benzylidene)-1-methylhydrazinyl)-1,1,1-trichlorobut-3-en-2-one

[0066] ##STR00021##

[0067] In a Teflon flask, 7.36 g BF.sub.3.Et.sub.2O (1.06 eq, d=1.15, 51.9 mmol) are mixed with a solution of 7.69 g (1.06 eq, 51.9 mmol) of 1,1,2,2-tetrafluoro-N,N-dimethylethanamine (TFEDMA) in 50 mL anh. dichloromethane under nitrogen at room temperature. After 1 hour at room temperature, 15 g (1.0 eq, 49.1 mmol) 4-(2-benzylidene)-1-methylhydrazinyl)-1,1,1-trichlorobut-3-en-2-one from example 1 were added in portions at room temperature under nitrogen flux and stirring. After completed addition, the mixture was allowed to warm to room temperature, and then heated under nitrogen at 50° C. for 1.15 hours. The mixture was cooled to room temperature. A control by .sup.1H-NMR in CD.sub.3CN showed full conversion.

EXAMPLE 6

2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one

[0068] ##STR00022##

[0069] To the mixture of example 5, 7.8 mL H.sub.2SO.sub.4 (d=1.84, 3 eq) was added together with 2.7 mL H.sub.2O, and the mixture was stirred at 70° C. for 30 minutes. Another 1 eq H.sub.2SO.sub.4 was added, and the mixture stirred for 1 hour at 70° C., then for 1 hour at room temperature. A .sup.1H-NMR in CD.sub.3CN showed full cyclization of (Ib). The mixture was quenched on ice, the layers were separated and the aqueous layer extracted with dichloromethane. The layers were combined. The GC-MS showed the presence of 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one.

EXAMPLE 7

3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid

[0070] ##STR00023##

[0071] The organic phase of example 6, containing 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one, was treated with 15% aq. NaOH (15.7 mL, 1.2 eq) for 1 hour at 50° C. The mixture was cooled to room temperature. The layers were separated, the aqueous layer was washed with dichloromethane, and the aqueous layer was acidified at 0° C. with 5.3 mL HCl (37% in water). After 15 minutes at 0° C., the mixture was filtered, the solid was rinsed with cold water and dried overnight in vacuum. The overall yield, starting from example 5, was 67%.

EXAMPLE 8

Bixafen(N-(3′,4′-dichloro-5-fluorobiphenyl-2-yl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0072] ##STR00024##

[0073] 5.0 g (18 mmol) 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone, and 3′,4′-dichloro-5-fluorobiphenyl-2-amine (4.6 g, 18 mmol) are mixed and diluted with 10 ml 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. Solids are filtered, washed with water and dried yielding crude Bixafen.

EXAMPLE 9

Fluxapyroxad(3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro-biphenyl-2-yl)-1H-pyrazole-4-carboxamide)

[0074] ##STR00025##

[0075] Fluxapyroxad is obtained using the procedure of example 8, wherein 3′,4′,5′-trifluorobiphenyl-2-amine is used instead of 3′,4′-dichloro-5-fluorobiphenyl-2-amine.

EXAMPLE 10

Sedaxane(N-(2-(bi(cyclopropan)-2-yl)phenyl)-3-(difluorome-thyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0076] ##STR00026##

[0077] Sedaxane is obtained using the procedure of example 8, wherein 2-(bi(cyclopropan)-2-yl)aniline is used instead of 3′,4′-dichloro-5-fluorobiphenyl-2-amine.

EXAMPLE 11

3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonylchloride

[0078] ##STR00027##

[0079] 3-(difluorochloromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid obtained by example 7 or 4 is treated with oxalyl chloride (1.25 eq) in toluene, and a few drops of dimethylformamide are added. The mixture is concentrated under reduced pressure to yield the carboxyl chloride.

EXAMPLE 12

Bixafen (N-(3′,4′-dichloro-5-fluorobiphenyl-2-yl)-3-(difluorome-thyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0080] (1.3 mmol) 3′,4′-dichloro-5-fluoro-1,1′-biphenyl-2-amine and (1.56 mmol) 3-(difluorochloromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid chloride obtained by Example 11 are solved in 6 ml tetrahydrofuran and mixed with 2.6 mmol triethylamine. The mixture is stirred for 16 h at 60° C. The mixture is concentrated and chromatographed on silica using cyclohexane/acetic acid ethyl ester to yield Bixafen.

EXAMPLE 13

Fluxapyroxad (3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-tri-fluorobiphenyl-2-yl)-1H-pyrazole-4-carboxamide)

[0081] Fluxapyroxad is obtained using the procedure of example 12, wherein 3′,4′,5′-trifluorobiphenyl-2-amine is used instead of 3′,4′-dichloro-5-fluorobiphenyl-2-amine.

EXAMPLE 14

Sedaxane (N-(2-(bi(cyclopropan)-2-yl)phenyl)-3-(difluorome-thyl)-1-methyl-1H-pyrazole-4-carboxamide)

[0082] Sedaxane is obtained using the procedure of example 12, wherein 2-(bi(cyclopropan)-2-yl)aniline is used instead of 3′,4′-dichloro-5-fluorobiphenyl-2-amine.