PROCESS FOR THE MANUFACTURE OF PYRAZOLE COMPOUNDS

Abstract

Disclosed are processes for the manufacture of pyrazole compounds of formula (I) and their application in the manufacture of pyrazole derivatives, in particular in processes for the manufacture of pharmaceutically or agrochemically active compounds, wherein in the processes, at least two steps are conducted in the presence of at least one solvent which is the same in the at least two steps, wherein the at least one same solvent is selected from the group consisting of aromatic hydrocarbons, alkanes, carboxylic acid esters, ethers, nitriles and dimethylformamide.

##STR00001##

Claims

1. A process for the manufacture of a compound of formula (I) ##STR00030## 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 is selected from the group consisting of H, X, COOR, OR, SR, C(O)NR.sub.2, wherein the groups R.sup.1 are selected independently in C(O)NR.sub.2 where R is selected from the group consisting of hydrogen, C.sub.1-C.sub.12-alkyl, CN, C.sub.2-C.sub.6 alkenyl, aryl, C.sub.3-C.sub.10-cycloalkyl, aralkyl and heteroaryl, each of which is optionally substituted, and wherein X is a halogen atom, R.sup.3 is 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 and aralkyl groups, each of which is optionally substituted, R.sup.4 is selected from the group consisting of CF.sub.3, CCl.sub.3 and CBr.sub.3, wherein the process comprises at least two of the steps a) to g) wherein a) a compound of formula (II) is contacted with an acid to obtain the compound of formula (I) ##STR00031## wherein R.sup.5 is a group NH.sub.2, NC(R.sup.6R.sup.7) or a group NHC(O)R.sup.14 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, 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 not H, wherein R.sup.14 is selected from the group consisting of OR.sup.15, NR.sup.16R.sup.17 and R.sup.18, wherein R.sup.15, R.sup.16, R.sup.17 and R.sup.18 each independently are 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 or aralkyl group, each of which is optionally substituted, or wherein R.sup.16 and R.sup.17 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, may contain a further 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S as ring members, wherein Z is selected from the group consisting of O, S and N.sup.+R.sup.8R.sup.9, wherein R.sup.8 and R.sup.9 are independently selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.10-cycloalkyl, aryl, heteroaryl and aralkyl groups, each of which is optionally substituted, or wherein R.sup.8 and R.sup.9 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, may contain a further 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S as ring members, b) a compound of formula (III) is converted to a compound of formula (II) ##STR00032## wherein Y is selected of OR.sup.10, NR.sup.11R.sup.12 and SR.sup.13, wherein R.sup.10, R.sup.11, R.sup.12 and R.sup.13 each independently are 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, or wherein R.sup.11 and R.sup.12 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, may contain a further 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S as ring members, wherein the compound of formula (III) is reacted with at least one of the compounds of the group of compounds of formula (IV), (V) and (VI) ##STR00033## wherein R.sup.6 and R.sup.7 are defined as above wherein R.sup.14 is selected from the group consisting of OR.sup.15, NR.sup.16R.sup.17 and R.sup.18, wherein R.sup.15, R.sup.16, R.sup.17 and R.sup.18 each independently 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 or aralkyl group, each of which is optionally substituted, or wherein R.sup.16 and R.sup.17 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, may contain a further 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S as ring members c) a compound of formula (III), wherein R.sup.1, R.sup.2, Y, Z and R.sup.4 are defined as above, is reacted with a compound of formula (IV), which is defined as above, to obtain a compound of formula (I) ##STR00034## d) a compound of formula (VII), wherein R.sup.1, R.sup.2 and Y are defined as before, is reacted with a compound R.sup.4C(O)X, wherein X is selected from F, Cl and Br and R.sup.4 is defined as before, or with a compound of formula (R.sup.4C(O)).sub.2O to obtain the compound of formula (III), wherein Z in (III) is O ##STR00035## e) a compound of formula (VIII), wherein R.sup.4, R.sup.2 and Y are defined as before, is reacted with a compound R.sup.1C(O)X, wherein X is selected from F, Cl and Br and R.sup.1 is defined as before, or with a compound of formula (R.sup.1C(O)).sub.2O to obtain the compound of formula (III), wherein Z in (III) is O ##STR00036## f) a compound of formula (III), wherein X, R.sup.1, R.sup.2 and R.sup.4 are defined as before, and Y is OR.sup.10, is reacted with a compound of formula HNR.sup.11R.sup.12 to obtain a of formula (III) wherein Y is NR.sup.11R.sup.12 ##STR00037## g) a compound of formula (VII), wherein Z is O, R.sup.1 and R.sup.2 are defined as before, and Y is OR.sup.10, is reacted with a compound of formula HNR.sup.11R.sup.12 to obtain a of formula (VII) wherein Y is NR.sup.11R.sup.12 or a compound of formula (VIII), wherein Z is O, R.sup.2 and R.sup.4 are defined as before, and Y is OR.sup.10, is reacted with a compound of formula HNR.sup.11R.sup.12 to obtain a of formula (VIII) wherein Y is NR.sup.11R.sup.12, wherein the at least two steps which are selected from steps a) to g) are conducted in the presence of at least one solvent which is the same in the at least two steps, wherein the at least one same solvent is selected from the group consisting of aromatic hydrocarbons, alkanes, carboxylic acid esters, ethers, nitriles and dimethylformamide.

2. The process according to claim 1, wherein the at least one same solvent is selected from the group consisting of aromatic hydrocarbons, carboxylic acid esters and ethers.

3. The process according to claim 1, wherein R.sup.3 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

4. The process according to claim 1, wherein R.sup.1 is selected from the group consisting of C.sub.1-4 alkyl groups which are substituted by at least one fluorine atom.

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

6. The process according to claim 1, wherein R.sup.2 is selected from the group consisting of H and X.

7. The process according to claim 1, which comprises steps b) and a).

8. The process according to claim 7, which comprises step e).

9. The process according to claim 8, which comprises step g) wherein a compound of formula (VIII), wherein Z is O, R.sup.2 and R.sup.4 are defined as before, and Y is OR.sup.10, is reacted with a compound of formula HNR.sup.11R.sup.12 to obtain a of formula (VIII) wherein Y is NR.sup.11R.sup.12.

10. The process according to claim 9, wherein in each of the steps b), a), e) and/or g), the same solvent.

11. A process for the manufacture of a compound of formula (IX), which comprises the process according to claim 1, and which further comprises a step wherein, when R.sup.21 is H, the compound of formula (I) is reacted with an aqueous base, or, when R.sup.21 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, with an alcoholate comprising R.sup.21O.sup. ##STR00038##

12. A process for the manufacture of a compound of formula (X), ##STR00039## 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 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 is selected from the group consisting of hydrogen, C.sub.1-C.sub.12-alkyl, CN, C.sub.2-C.sub.6 alkenyl, aryl, C.sub.3-C.sub.10-cycloalkyl, aralkyl and heteroaryl, each of which is optionally substituted, and wherein X is a halogen atom, R.sup.4 is selected from the group consisting of CF.sub.3, CCl.sub.3 and CBr.sub.3, wherein R.sup.22 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, the process comprising the process according to claim 1.

13. The process according to claim 12, which comprises a step wherein a compound of formula (I) is reacted with a compound of formula (XI), HNR.sup.22Q.

14. The process according to claim 12, which comprises a step wherein a compound of formula (IX) is converted an activated carboxylic acid derivative, and a step of contacting the activated carboxylic acid form of formula (VII) with a compound of formula (XI), HNR.sup.22Q.

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

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

17. The process according to claim 3, wherein R.sup.3 is methyl.

18. The process according to claim 5, wherein R.sup.4 is CCl.sub.3.

19. The process according to claim 12, wherein R.sup.22 is selected from the group consisting of H and C.sub.1-C.sub.4-alkyl.

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

Description

EXAMPLE 1

1,1,1-trichloro-4-ethoxybut-3-en-2-one (ETCBO) (Step g)

[0087] ##STR00021##

[0088] 1,1,1-trichloro-4-ethoxybut-3-en-2-one (ETCBO, 0.46 mol) is dissolved in in 150 mL toluene. To this mixture, 21.7 g (0.48 mol) of dimethylamine gas are added. The mixture is stirred for 3 hours at room temperature. Full conversion into 1,1,1-trichloro-4-(dimethylamino)-but-3-en-2-one (ATCBO) is monitored by GC. The mixture is transferred into a 1 liter flask, and the volatiles are partially removed. The remaining liquid contains toluene and ATCBO. The mixture is used without further purification in the next step.

EXAMPLE 2

(1,1,1-trichloro-3-((dimethylamino)-methylene)-5,5-difluoropentane-2,4-dione (step e)

[0089] ##STR00022##

[0090] The mixture obtained in example 1, containing 0.46 mol ATCBO, is diluted with 200 mL toluene. 44.3 mL pyridine are added (0.55 mol, 1.2 eq), and 65.19 g (0.55 mol) 2,2-difluoroacetyl chloride are added via syringe under the solvent level. The mixture is stirred at 60 C. for 4 hours until .sup.1H-NMR shows full conversion.

EXAMPLE 3

3-((2-(benzylidene)-1-methylhydrazinyl)methylene)-1,1,1-trichloro-5,5-difluoropentane-2,4-dione (Step b)

[0091] ##STR00023##

[0092] 70 g of 1-benzylidene-2-methylhydrazine, obtained by reaction of benzaldehyde and methylhydrazine, are added to the mixture obtained in example 2, and the mixture is stirred for 3 hours at 60 C.

EXAMPLE 4

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

[0093] ##STR00024##

[0094] To the mixture of example 3, 32 mL of conc. H.sub.2SO.sub.4 are added dropwise at 60 C. After completed addition, the mixture is stirred for another 2 hours at 60 C. until .sup.1H-NMR monitoring shows full conversion. The mixture is cooled to room temperature. 25 mL of water are added. The aqueous phase is separated, extracted twice with toluene, and the organic phases are combined. The combined organic phases are used in the next step.

EXAMPLE 5

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

[0095] ##STR00025##

[0096] To the mixture from example 4, 26.2 g of NaOH in 80 mL water are added. The mixture is heated to 60 C. for 2 hours. Full conversion is monitored by .sup.1H-NMR. The phases are separated and the aqueous phase extracted with 40 mL toluene. The aqueous phase is acidified with 32% aq HCl (66 mL) under vigorous stirring. The suspension which forms is cooled under stirring to 0 C., filtered and washed with cold water (3 times 60 mL water). The wet cake is dried under air stream for several hours at room temperature to yield the product.

EXAMPLE 6

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

[0097] ##STR00026##

[0098] The solution of example 4, equalling 5.0 g (18 mmol) 2,2,2-trichloro-1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-ypethanone, 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 7

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

[0099] ##STR00027##

[0100] Fluxapyroxad is obtained using the procedure of example 6, wherein 3,4,5-trifluorobiphenyl-2-amine is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.

EXAMPLE 8

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

[0101] ##STR00028##

[0102] Sedaxane is obtained using the procedure of example 6, wherein 2-(bi(cyclopropan)-2-yl)aniline is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.

EXAMPLE 9

3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride

[0103] ##STR00029##

[0104] 3-(difluoro chloromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid obtained by example 5 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 10

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

[0105] (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 9 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 11

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

[0106] Fluxapyroxad is obtained using the procedure of example 10, wherein 3, 4,5-trifluorobiphenyl-2-amine is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.

EXAMPLE 12

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

[0107] Sedaxane is obtained using the procedure of example 10, wherein 2-(bi(cyclopropan)-2-yl)aniline is used instead of 3,4-dichloro-5-fluorobiphenyl-2-amine.

[0108] Additional experiments can be carried out under similar conditions with respectively hexanes, tetrahydrofuran, ethyl acetate and isopropyl acetate as solvent. Additional experiments can be carried out under similar conditions with respectively toluene, hexanes, ethyl acetate and isopropyl acetate as solvent and R.sup.1CF.sub.3.