PROCESS FOR THE MANUFACTURE OF PYRAZOLE CARBOXYLIC DERIVATIVES AND PRECURSORS THEREOF

Abstract

The present invention concerns processes for the manufacture of pyrazole carboxylic derivatives and precursors thereof.

##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) ##STR00032## wherein Z is selected from O, S and N.sup.+R.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 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.7 and R.sup.8 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 R.sup.1 is selected from the group consisting of optionally substituted C.sub.1 to C.sub.4 alkyl groups, wherein R.sup.2 is selected from the group consisting of C(O)OR.sup.9, CN, C(O)R.sup.10 and C(O)NR.sup.11R.sup.12, wherein R.sup.9, R.sup.10, R.sup.11 and R.sup.12 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 Y is selected of OR.sup.13, NR.sup.14R.sup.15 and SR.sup.16, wherein R.sup.13, R.sup.14, R.sup.15 and R.sup.16 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.14 and R.sup.15 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 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, wherein R.sup.5 and R.sup.6 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.5 and R.sup.6 is different from H, wherein R.sup.4 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.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, aryl, cycloalkyl, aralkyl and heteroaryl, each of which is optionally substituted, and wherein X′ is a halogen atom, wherein in the reaction of the compound of formula (I) and (II), an amine salt is present.

2. The process according to claim 1, wherein the anion of the amine salt is a halide anion.

3. The process according to claim 1, wherein the amine salt is derived from a secondary or tertiary amine.

4. The process according to claim 3, wherein the amine salt is a tertiary aromatic amine salt selected from the group consisting of halide salts of 2,6-lutidine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine or pyridine.

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

6. The process according to claim 5, wherein R.sup.1 is selected from the group consisting of CF.sub.3, CHF.sub.2, CH.sub.2F, CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, CBr.sub.3, CBr.sub.2H, CBrH.sub.2, CI.sub.3, CI.sub.2H, CBr.sub.2Cl, CCl.sub.2Br, C.sub.2F.sub.5, C.sub.2Br.sub.5 and C.sub.2Cl.sub.5.

7. The process according to claim 1, wherein R.sup.2 is C(O)R.sup.10 and R.sup.10 is selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.10-cycloalkyl and aryl groups, each of which is optionally substituted.

8. The process according to claim 1, wherein Z is O or N.sup.+R.sup.7R.sup.8.

9. The process according to claim 1, wherein Y is NR.sup.14R.sup.15 wherein R.sup.14 and R.sup.15 each independently are 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.14 and R.sup.15 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.

10. The process according to claim 1, wherein R.sup.3 is selected from the group consisting of H and C.sub.1-C.sub.12-alkyl each of which is optionally substituted.

11. The process according to claim 1, wherein R.sup.4 is selected from the group consisting of H and X′.

12. A process for the manufacture of a compound of formula (IV), which comprises the process according to claim 1, and which further comprises the step of contacting the compound of formula (I) with an acid, wherein Z, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are defined as in claim 1. ##STR00033##

13. A process for the manufacture of a compound of formula (V), which comprises the process according to claim 12, ##STR00034## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined as in claim 12, and further comprises at least one of the steps of a) when R.sup.2 is C(O)R.sup.10 and R.sup.10 is selected from the group consisting of CX.sub.3, C.sub.2X.sub.5, n-C.sub.3X.sub.7 or iso-C.sub.3X.sub.7, n-, iso- or tert-C.sub.4X.sub.9, wherein in all of the foregoing groups X is the same or different, selected from the group consisting of F, Cl, Br and I, the compound of formula (IV) is contacted with an aqueous base, b) when R.sup.2 is C(O)R.sup.10 and R.sup.10 is selected from the group consisting of C.sub.1-C.sub.12-alkyl, optionally substituted C.sub.3-C.sub.10-cycloalkyl, optionally substituted aryl, optionally heteroaryl, optionally substituted aralkyl or optionally substituted aralkyl group, the compound of formula (IV) is contacted with an oxidation agent, c) when R.sup.2 is CN or C(O)OR.sup.9, the compound of formula (IV) is contacted with an acid or a base.

14. A process for the manufacture of a compound of formula (VI), which comprises the process according to claim 13, and which further comprises a first step, wherein the compound of formula (V) is reacted with a halogenating agent, an acylating agent or CDI, and a second step, wherein the product from the first step is contacted with a compound of formula (VII), NHR.sup.17Q, wherein R.sup.17 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. ##STR00035##

15. A process for the manufacture of a compound of formula (VI), which comprises the process of claim 12, and which further comprises one of the steps d) and e), wherein d) when R.sup.2 in the compound of formula (IV) is C(O)R.sup.10 and R.sup.10 is selected from the group consisting selected from the group consisting of CX.sub.3, C.sub.2X.sub.5, n-C.sub.3X.sub.7 or iso-C.sub.3X.sub.7, n-, iso- or tert-C.sub.4X.sub.9, wherein in all of the foregoing groups X is the same or different, selected from the group consisting of F, Cl, Br and I, the compound of formula (IV) is contacted with a compound of formula NHR.sup.17Q, wherein R.sup.17 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, or e) when R.sup.2 in the compound of formula (IV) is C(O)OR.sup.9, wherein R.sup.9 is defined as in claim 1, the compound of formula (IV) is contacted with a compound of formula NHR.sup.17Q, wherein R.sup.17 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 at least one compound selected of the group consisting of a Lewis acid or a base.

16. The process according to claim 3, wherein the amine salt is derived from a tertiary aromatic amine.

17. The process according to claim 4, wherein the tertiary aromatic amine salt is pyridinium hydrochloride.

18. The process according to claim 14, wherein R.sup.17 is selected from the group consisting of H and C.sub.1-C.sub.4-alkyl.

Description

EXAMPLE 1 1,1,1-TRICHLORO-4-ETHOXYBUT-3-EN-2-ONE (ATCBO)

[0090] ##STR00024##

[0091] 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, EtOH 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

[0092] ##STR00025##

[0093] 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

[0094] ##STR00026##

[0095] 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

[0096] ##STR00027##

[0097] 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

[0098] ##STR00028##

[0099] 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 3-(DIFLUOROMETHYL)-1-METHYL-1H-PYRAZOLE-4-CARBOXYLIC ACID CHLORIDE

[0100] 3-(difluoromethyl)-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 7 BIXAFEN

[0101] (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 6 are solved in 6 ml tetrahydrofuran and mixed with 2.6 mmol triethylamin. 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 8: FLUXAPYROXAD (3-(DIFLUOROMETHYL)-1-METHYL-N-(3′,4′,5′-TRI-FLUOROBIPHENYL-2-YL)-1H-PYRAZOLE-4-CARBOXAMIDE)

[0102] ##STR00029##

[0103] Fluxapyroxad is obtained using the procedure of example 7, wherein 3′,4′,5′-trifluorobiphenyl-2-amine is used instead of 3′,4′-dichloro-5-fluorobiphenyl-2-amine.

EXAMPLE 9: SEDAXANE (N-(2-(BI(CYCLOPROPAN)-2-YL)PHENYL)-3-(DIFLUOROME-THYL)-1-METHYL-1H-PYRAZOLE-4-CARBOXAMIDE)

[0104] ##STR00030##

[0105] Sedaxane is obtained using the procedure of example 7, wherein 2-(bi(cyclopropan)-2-yl)aniline is used instead of 3′,4′-dichloro-5-fluorobiphenyl-2-amine.

[0106] Additional experiments can be carried out under similar conditions with respectively hexanes, tetrahydrofuran and ethyl 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′═CF.sub.3.

EXAMPLE 10: 1,1,1-TRICHLORO-4-ETHOXYBUT-3-EN-2-ONE (ATCBO)

[0107] 1,1,1-trichloro-4-ethoxybut-3-en-2-one (ETCBO, 0.46 mol) was dissolved in in 200 mL i-propyl-acetate. To this mixture, 21.7 g (0.48 mol) of dimethylamine gas were added at room temperature. A mild exothermicity was observed. The mixture was stirred for 3 hours at room temperature. Full conversion into 1,1,1-trichloro-4-(dimethylamino)-but-3-en-2-one (ATCBO) was monitored by .sup.1H-NMR. The mixture was transferred into a 1 liter flask, and the volatiles were partially removed at 500 mbar/80° C. The remaining liquid contained toluene, EtOH and ATCBO. The mixture was used without further purification in the next step.

EXAMPLE 11 (1,1,1-TRICHLORO-3-((DIMETHYLAMINO)-METHYLENE)-5,5-DIFLUOROPENTANE-2,4-DIONE

[0108] The mixture obtained in example 10, containing 0.46 mol ATCBO, was diluted with 300 mL i-propyl-acetate. 44.3 mL pyridine were added (0.55 mol, 1.2 eq), and 65.19 g (0.55 mol) 2,2-difluoroacetyl chloride were added via syringe under the solvent level. The mixture was stirred at 50° C. for 4 hours until .sup.1H-NMR showed full conversion.

EXAMPLE 12 3-((2-(BENZYLIDENE)-1-METHYLHYDRAZINYL)METHYLENE)-1,1,1-TRICHLORO-5,5-DIFLUOROPENTANE-2,4-DIONE

[0109] 70 g of 1-benzylidene-2-methylhydrazine, obtained by reaction of benzaldehyde and methylhydrazine, were added to the mixture obtained in example 11, and the mixture was stirred for 3 hours at 50° C.

EXAMPLE 13 2,2,2-TRICHLORO-1-(3-(DIFLUOROMETHYL)-1-METHYL-1H-PYRAZOL-4-YL)ETHAN-1-ONE

[0110] ##STR00031##

[0111] To the mixture of example 12, 32 mL of conc. H.sub.2SO.sub.4 were added dropwise at 50° C. After completed addition, the mixture was stirred for another 2 hours at 50° C. until .sup.1H-NMR monitoring showed full conversion. The mixture was cooled to room temperature. 25 mL of water were added. The aqueous phase was separated, extracted twice with i-propyl-acetate, and the organic phases were combined. The combined organic phases were used in the next step.

EXAMPLE 14 3-(DIFLUOROMETHYL)-1-METHYL-1H-PYRAZOLE-4-CARBOXYLIC ACID

[0112] To the mixture from example 13, 26.2 g of NaOH in 80 mL water were added. The mixture was heated to 50° C. for 2 hours. Some crystallization occurred, whereupon 20 mL of water were added. An additional 6 g of NaOH in 15 mL water were added to drive full conversion. Full conversion was monitored by .sup.1H-NMR. The phases were separated and the aqueous phase extracted with 40 mL i-propyl-acetate. The aqueous phase was acidified with 32% aq HCl (66 mL) under vigorous stirring. The yellow thick suspension which formed was cooled under stirring to 10° C., filtered and washed with cold water (3 times 60 ml, water). The wet cake was dried under air stream for several hours at room temperature to yield 66.56 g (0.378 mol) of a beige, solid product. The yield 82.12% is the yield calculated on basis of the initial amount ETCBO in example 9 (yield over 5 steps). .sup.1H-NMR purity was +99%.