WO2018202677A1

WO2018202677A1 - Process for the manufacture of carboxylic acids or carboxylic acid derivatives

Info

Publication number: WO2018202677A1
Application number: PCT/EP2018/061139
Authority: WO
Inventors: Qingyi Li; Mingchun WANG; Janis Jaunzems
Original assignee: Solvay Sa; Changzhou Keylab Biochemical Co., Ltd.
Priority date: 2017-05-02
Filing date: 2018-05-02
Publication date: 2018-11-08
Also published as: WO2018201272A1

Abstract

This invention concerns a process for the manufacture of carboxylic acids or carboxylic acid derivatives and a process for the manufacture of agrochemically and pharmaceutically active compounds comprising the process for the manufacture of carboxylic acids or their derivatives. The process for the manufacture of carboxylic acids or carboxylic acid derivatives comprises a step of catalytic oxidation in the presence of at least one catalyst and at least one oxidant, of compound number (I) to obtain a compound of formula (II).

Description

PROCESS FOR THE MANUFACTURE OF CARBOXYLIC ACIDS OR CARBOXYLIC ACID DERIVATIVES

This application claims priority to PCT application No.

PCT/CN2017/082689, the whole content of this application being incorporated herein by reference for all purposes.

This invention concerns a process for the manufacture of carboxylic acids or carboxylic acid derivatives and a process for the manufacture of

agrochemically and pharmaceutically active compounds comprising the process for the manufacture of carboxylic acids or their derivatives.

Carboxylic acid and their derivatives, in particular 3-halomethylpyrazol-4- yl carboxylic acids and esters, are valuable intermediates in the synthesis of agrochemical and pharmaceutical active ingredients. Agrochemical active ingredients which contain 3-halomethylpyrazol-4-yl building blocks are, for example, 2'-[l,l'-bicycloprop-2-yl]-3-(difluoromethyl)-l-methylpyrazole-4- carboxanilide (Sedaxane), as described, for example, in WO2006015866, 3- (difluoromethyl)- 1 -methyl-N- [2-(3 ' ,4' ,5 ' -trifluorophenyl)phenyl]pyrazole-4- carboxamide (Fluxapyroxad), as described, for example, in WO2006087343, N- (3',4'-Dichloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-l-methylpyrazole-4- carboxamide (Bixafen), as described, for example, in WO2003070705, 3- (Difluoromethyl)- 1 -methyl-N- [ 1 ,2,3,4-tetrahydro-9-( 1 -methylethyl)- 1 ,4- methanonaphthalen-5-yl]-lH-pyrazole-4-carboxamide (Isopyrazam), as described, for example, in WO2004035589, (RS)-N-[9-(Dichloromethylen)- l,2,3,4-tetrahydro-l,4-methanonaphthalin-5-yl]-3-(difluoromethyl)-l-methyl- lH-pyrazole-4-carboxamide (Benzovindiflupyr), as described, for example, in WO07048556. Generally, 3-halomethylpyrazol-4-yl carboxylic acids, often obtained by hydrolysis of their esters, are converted into the carboxamides, for example after conversion into the 3-halomethylpyrazol-4-yl carboxylic acid halide. Other conversions, wherein the carboxamide is generated directly from the ester or acid, have also been described, such as in WO2012055864 and WO 2007/031323. All foregoing cited patent applications are hereby incorporated for all purposes.

WO2016/152886 discloses oxidation of pyrazolyl ketone derivatives with hypohalite solutions. When hypohalites are used for oxidation of the keto function, a large amount, at least three equivalents, of hypohalite is necessary to convert the keto group into a carboxylate salt. This results in a large volume of salt waste per mole carboxylate produced, which is often also difficult to treat because of its organic impurities. As hypohalite solutions are often restricted in their upper concentration limit due to stability concerns, the waste volume is even higher per mole carboxylate produced.

It has been found that the process according to the present invention allows for the manufacture of a carboxylic acid or its derivative while avoiding a large amount of salt waste. The process shows good yields, lower waste and can be processed on a large scale.

The invention thus concerns a process for the manufacture of a compound of formula (II) comprising a step of catalytic oxidation in the presence of at least one catalyst and at least one oxidant, of compound number (I),

( I) wherein R¹, R², R³, R⁴ and R⁴ will be defined in the description. The invention further concerns a process as shown above wherein the process for the manufacture of a compound of formula (II) further comprises a step of reacting a compound of formula (III) with a compound selected from the group consisting of co

wherein Y, R⁶ and compounds (IV), (V) and (VI) are defined in the description. The invention also concerns a process for the manufacture of an agrochemical or pharmaceutical compound, preferably a carboxamide SDHI fungicide, which comprises the processes as shown above for the manufacture of compound (II). In the present invention, designations in singular are in intended to include the plural; for example, "a solvent" is intended to denote also "more than one solvent" or "a plurality of solvents".

All aspects and embodiments of the present invention are combinable. In the context of the present invention, the term "comprising" is intended to include the meaning of "consisting of.

When a double bond is depicted in a particular E/Z geometry, this is intended to also denote the other geometric form as well as mixtures thereof.

In the context of the present invention, the term "catalytic oxidation" is intended to denote an oxidation wherein the oxidation is carried out in the presence of at least one oxidant and at least one catalyst. Oxidants and catalysts will be defined as below.

In a first aspect, the invention concerns a process for the manufacture of a compound of formula (II) comprising a step of catalytic oxidation in the presence of at least one catalyst and at least one oxidant, of compound number (I),

( I I) wherein

R¹ is selected from the group consisting of Ci-C4-alkyl groups which is substituted by at least one halogen atom independently selected from the group consisting of F, CI and Br or by a CF₃ group,

R is selected from the group consisting of an optionally substituted Q-Cg alkyl group, an optionally substituted C₃-Cg cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group,

R is selected from the group consisting of H, X, COOR, OR, SR,

C(0)NR₂, wherein R is selected from the group consisting of hydrogen, a Cp Ci₂-alkyl, CN, C₂-C₆ alkenyl, aryl, C₃-Cg cycloalkyl, aralkyl or heteroaryl group, each of which is optionally substituted, with the proviso that both R in C(0)NR₂ may be the same or different, wherein X is a halogen atom and is selected from the group consisting of F, CI, Br and I, and R is independently selected from the group consisting of hydrogen or a Ci-Ci₂-alkyl, C₂-C₆ alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl,

R⁴ is selected from the group consisting of H, Ci-Ci₂-alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, aryl, heteroaryl or aralkyl group, each of which is optionally substituted,

R⁵ is a -OH group or a -O^" group, wherein, when R⁵ is a -O^" group, at least one countercation is present in (II), such as an alkali or earth alkali cation.

In the context of the present invention, the term "Ci-C4-alkyl groups" is intended to denote straight or branched alkyl groups having one to four carbon atoms. This group comprises methyl, ethyl, n-propyl, isopropyl, n-, iso-, sec- and t-butyl. "Ci-Cg alkyl group" intends to denote straight or branched alkyl groups having one to eight carbon atoms. This group comprises methyl, ethyl, n-propyl, isopropyl, n-, iso-, sec- and t-butyl, n-pentyl and its isomers, n-hexyl and its isomers, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl and its isomers and n- octyl and its isomers. Often, the Q to C₄ alkyl groups are the most preferred groups of the Q-Cg alkyl group. Similarly, the term "Ci-Ci₂-alkyl groups" is intended to denote straight or branched alkyl groups having one to twelve carbon atoms. Additionally to the groups comprised in the "Ci-Cg alkyl group", the group comprises, for example, n-nonyl and its isomers, n-decyl and its isomers, n-undecyl and its isomers and n-dodecyl and its isomers. Often, the Q to C₄ alkyl groups are the most preferred groups of the C₁-C₁₂ alkyl group.

The term "C₃-C₈ cycloalkyl group" intends to denote mono-, bi- or tricyclic hydrocarbon groups comprising 3 to 10 carbon atoms, especially 3 to 6 carbon atoms. Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Examples of bicyclic groups include bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl. Examples of tricyclic groups are adamantyl and

homoadamantyl.

The term "aryl group" intends to denote C₅-C₁₈ monocyclic and polycyclic aromatic hydrocarbons with 5 to 18 carbon atoms in the cyclic system.

Specifically, this definition comprises, for example, the meanings

cyclopentadienyl, phenyl, cycloheptatrienyl, cyclooctatetraenyl, naphthyl and anthracenyl.

The term "heteroaryl group" intends to denote C₅-C₁₈ monoyclic and polycyclic aromatic hydrocarbons with 5 to 18 carbon atoms in the cyclic system, wherein one or more methine (-C=) and/or vinylene (-CH=CH-) groups are replaced by trivalent or divalent heteroatoms, in particular nitrogen, oxygen and/or sulphur, respectively, in such a way as to maintain the continuous π- electron system characteristic of aromatic systems. Specifically, this definition comprises, for example, the meanings 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4- imidazolyl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, l,2,4-triazol-3-yl, l,3,4-oxadiazol-2-yl, l,3,4-thiadiazol-2- yl and l,3,4-triazol-2-yl; 1-pyrrolyl, 1-pyrazolyl, 1 ,2,4-triazol- l-yl, 1-imidazolyl, 1,2,3-triazol-l-yl, 1,3,4-triazol- l-yl; 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, l,3,5-triazin-2-yl and l,2,4-triazin-3- yi-

The term "C₂-C6 alkenyl" intends to denote a group comprising a carbon chain and at least one double bond. Alkenyl group are, for example, ethenyl, propenyl, butenyl, pentenyl or hexenyl.

The term "aralkyl" intends to denote alkyl groups which are substituted by aryl groups, which have a Ci-Cg-alkylene chain and which may be substituted in the aryl skeleton or the alkylene chain by one or more heteroatoms selected from the group consisting of O, N, P and S.

Where indicated, a C1-C4 alkyl group, Q-Cg alkyl group, Ci-Ci₂ alkyl group, aryl group, heteroaryl group, Ci-Ci₂-alkyl group, C₂-C₆ alkenyl group, aryl group, aralkyl group or heteroaryl group each can be optionally substituted by one or more substituents of the following group consisting of R', -X', -OR', - SR', -NR'₂, -SiR'₃, -COOR', -(C-O)R', -CN and -CONR'₂, wherein R' is selected independently, from the group consisting of hydrogen or Ci-Ci₂-alkyl group and X' is selected from the group consisting of F, CI, Br, or I.

R¹ is a group selected from the group consisting of Ci-C₄-alkyl groups, which is substituted by at least one halogen atom independently selected from the group consisting of F, CI and Br or by a CF₃ group. Preferably, Ri is selected from the group consisting of CF₂H, CF₃, CC1F₂, CC1₂H and CC1₃, wherein CF₂H and CF₃ are most preferred.

R is selected from the group consisting of an optionally substituted Q-Cg alkyl group, an optionally substituted C₃-Cg cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group. Preferred

2 2

R are ethyl, methyl and phenyl, wherein a methyl group is most preferred as R . R³ is selected from the group consisting of H, X, COOR, OR, SR, C(0)NR₂, wherein R is selected from the group consisting of hydrogen, a Ci-Ci₂-alkyl, C₂- C alkenyl, aryl, C₃-C₈ cycloalkyl, aralkyl or heteroaryl group, each of which is optionally substituted, with the proviso that both R in C(0)NR₂ may be the same or different, wherein X is a halogen atom and is selected from the group consisting of F, CI, Br and I, and R is independently selected from the group consisting of hydrogen or a Ci-Ci₂-alkyl, C₂-C₆ alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl, each of which can be optionally substituted. In a preferred aspect, R is H or X, wherein F is a preferred X. H is the most preferred R .

R⁴ is selected from the group consisting of H, Ci-Ci₂-alkyl, C₂-C₆ alkenyl,

C₃-C₈ cycloalkyl, aryl, heteroaryl or aralkyl group, each of which is optionally substituted. R⁴ is preferably selected from the group consisting of Q to C₄ alkyl groups, H, optionally substituted phenyl and optionally substituted benzyl, wherein a methyl group is the most preferred R⁴.

R⁵ is a -OH group or a -O^" group, wherein, when R⁵ is a -O^" group, at least one countercation is present in (II), such as an alkali or earth alkali cation, wherein alkali cations such as sodium or potassium are preferred. In one aspect, the process can comprise a step in which a compound (II) in which R⁵ is -O^" is treated with an aqueous acidic solution, for example an aq. HC1 solution, such that the compound (II) is protonated and R⁵ is -OH.

In the process according to the present invention, compound (I) is submitted to a step of catalytic oxidation, wherein the at least one oxidant present often is selected from the group consisting of oxygen, a gas comprising oxygen, a peroxide, KMn0₄ and ozone. The term "a gas comprising oxygen" is intended to denote a gas mixture in which from 1 vol to 99% oxygen is present; for example, such a gas is air. Peroxides can be organic and inorganic peroxides, such as tert-Butylhydroperoxid and hydrogen peroxide, wherein the peroxides and the reaction conditions must be chosen such that they are compatible with the compound (I), in particular with the pyrazole ring system. In the process according to the present invention, oxygen and a gas comprising oxygen, in particular air, are the most preferred oxidants. Oxygen and a gas comprising oxygen can be applied at elevated pressure or ambient pressure, or can be bubbled through the reaction mixture.

In the present invention, the at least one catalyst often is selected from the group consisting of a metal salt comprising at least one metal species and a metal complex comprising at least one metal species. The term "metal species" intends to denote a metal atom with charge zero or a positive charge of one, two, three or up to seven, depending on the valency in the respective catalyst compound. In some catalyst compounds, more than one metal species can be present, but generally, the catalyst is preferred to have one metal species present. When the catalyst compound is a metal salt, the at least one metal species often is a cation with a positive charge of one, two, three, four, five, six or seven.

In one aspect, the at least one metal salt or metal complex can comprise at least one metal species selected from the group consisting from the groups 3 to 12 of the periodic system. This includes the groups of the lanthanides and actinides (atomic numbers 57 to 71 and 89 to 103). In particular, the at least one metal species is selected from Ti, Co, Y, Ce, Yb, La, Zr, V, Nb, Ta, Cr, Mo, W, Mn, Tc, Re, Fe, Ru, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd and Hg. This is in particular applicable for metal salt catalysts. Co, Y, Ce, Yb, La, Cr, Mo, Mn, Fe, Ni, Cu, Zn and Hg are preferred metal species, in particular in metal salt catalysts. Metal salt catalysts comprising Co, Y, Ce, Yb, La, Fe and Mn are more particularly preferred.

In one aspect of the present invention, the at least one metal salt can be selected from the group consisting of oxides, halide, nitrates, acetates, or hydrates of any of the foregoing. In one aspect, the at least one metal salt may be a mixed salt, wherein any of the anions oxide, hydroxide, carbonate, halide, nitrate, acetate are mixed, such that a mixed salt of two or more anions exist. Often, the at least one catalyst is selected from the group consisting of Fe(N0₃)₃ or its hydrate, Co(N0₃)₃ or its hydrate, Ni(N0₃)₃ or its hydrate, Co(N0₃)₃ or its hydrate, Mn(N0₃)₃ or its hydrate, Zn(N0₃)₃ or its hydrate, Mn(OAc₂) or its hydrate, Co(OAc₂), Cu(OAc₂), CuCl₂ or its hydrate, CuO, CuBr₂, CuCl, CuBr, Cul and Re₂0₇. Nitrates and acetates are particularly preferred metal salts.

In one aspect, two or more catalysts can be present in the process for the manufacture of a compound of formula (II). Particularly preferred are catalytic systems which comprise Mn(N0₃)₃ or its hydrate, Mn(N0₃)₃4H₂0, and one additional metal salt which preferably is a nitrate or its hydrate or an acetate or its hydrate. The additional metal salt preferably comprises as metal species Co, Y, Ce, Yb, La or Fe.

The at least one catalyst in the process of the present invention often is present in an amount of from 0.01 to 30 mol calculated on the amount of compound (I). Generally, the at least one catalyst in the process of the present invention is present in an amount of equal to or more than 0.01 mol , preferably equal to or more than 1 mol calculated on the amount of compound (I). In some systems, an amount of equal to or more than 5 mol calculated on the amount of compound (I) gives good results. Often, the at least one catalyst in the process of the present invention is present in an amount of equal to or less than 30 mol , preferably equal to or less than 20 mol calculated on the amount of compound (I). In some systems, an amount of equal to or less than 15 mol calculated on the amount of compound (I) gives good results.

In one aspect of the present invention, at least one additional reagent can be present in the reaction, wherein the at least one additional reagent is a co-oxidant or an auxiliary. Co-oxidants can be, for example, TEMPO (2,2,6,6- Tetramethylpiperidinyloxyl), 4-hydroxy-TEMPO, 4-acetamido-TEMPO, 2- Azaadamantane N-Oxyl (AZADO), 9-Azabicyclo[3.3.1]nonane N-Oxyl (ABNO) and 9-Azanoradamantane N-oxyl (Nor- AZADO). Auxiliary agents can be, for example, KC1, Ν,Ν',Ν' '-trihydroxyisocyanuric acid (THICA) and N- hydroxyphthalimide (NHPI), tetra-n-butylammonium bromide or even NaCl. Particularly suitable catalytic systems employing a co-oxidant and/or auxiliary are, for example, THICA/Mn(OAc)₂, NHPI/Mn(OAc)2,

NHPI/Mn(OAc)2/Co(OAc)2, THICA/Co(OAc)₂, THICA/Mn(OAc)₂/Co(OAc)₂, TEMPO/Fe(N0₃₎3 9H₂0 or TEMPO/Fe(N0₃₎₃ 9H₂0/KC1.

The oxidation often is carried out in a suitable solvent, such as

dichloromethane, dichloroethane, methanol, ethanol, DMSO, DMF, acetonitrile or aliphatic ethers such as diethylether, or aromatic hydrocarbons such as toluene. Other very suitable solvents often are optionally substituted carboxylic acids, in particular acetic acid, trichloroacetic acid, dichloro acetic acid, propionic acid and butyric acid.

The oxidation often is carried out at temperatures of from 0°C to 120°C. A temperature of from 60°C to 110°C can be particularly preferred.

The invention also concerns a process as described for the manufacture of a compound of formula (II) which further comprises a step of reacting a compound of formula (III) with a compound selected from the group consisting of compound (IV), (V) and (VI) to obtain the compound of

( I II) ( I) wherein compound (IV), (V) and (VI) are defined as follows:

wherein R⁴ is defined as above for any compound comprising R⁴ above, wherein Y is selected from the group consisting of S, O and NR⁶, wherein O and NR⁶ are preferred,

wherein R⁶ independently is selected from the group consisting of an Cp Ci₂-alkyl, C₂-C₆ alkenyl or C₃-Cg-cycloalkyl group, each of which is optionally substituted

wherein R 7 and R 7' independently from each other are selected from the group consisting of H, Ci-Ci₂-alkyl, C₂-C₆ alkenyl, cycloalkyl, aryl, heteroaryl or aralkyl group, each of which is optionally substituted,

R⁸ is selected from the group consisting of Ci-Ci₂-alkyl, OR⁹ and NR⁹R⁹ , wherein R⁹ and R⁹ independently are selected from the group consisting of Cp Ci₂-alkyl and H.

Preferably, in such a process, Y is O and R⁶ is ethyl, or Y is NR⁶ and both R⁶ are methyl, R³ is H, R⁴ and R² are methyl, and R¹ is CF₂H or CF₃.

Often, R 7 in (V) is H, and R 7' is phenyl, benzyl or C₃ to C₆ cycloalkyl, each of which can be optionally substituted.

In one aspect, when Y = NR⁶, both R⁶ in (III) with the N to which they are attached can form a heterocyclic compound, such as piperidinyl.

Compounds of formula (III) and their preparation are described, for example, in WO2017054112. Compounds of formula (IV), (V) and (VI) and their preparation are described, for example, in WO2016/152886. The catalysts, oxidants, co-oxidants and auxiliary compounds are well known and can be purchased or made according to methods known to the person skilled in the art.

All embodiments of the present invention are particularly preferred when (I) is l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)ethanone and (II) is 3- (difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid, and when (I) is l-(3- (trifluoromethyl)-l-methyl-lH-pyrazol-4-yl)ethanone and (II) is 3- (trifluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid. The invention also concerns a process for the manufacture of an agrochemical or pharmaceutical compound, preferably a carboxamide SDHI fungicide, which comprises the process for manufacturing a compound of formula (II) as described above. SDHI fungicides are SDH inhibitors which target succinate dehydrogenase (SDH, so-called complex II in the mitochondrial respiration chain), and generally contain a carboxamide moiety, wherein the carbonyl carbon atom is attached to a pyrazole ring identical to the pyrazole system of formula (II).

An agrochemically or pharmaceutically active compound can, for example, be obtained by converting a compound of formula (II) obtained by the process according to the present invention into a carboxylic acid halide or anhydride, and reacting the carboxylic acid halide or anhydride with a primary or secondary amine to obtain a carboxamide which is an agrochemically or pharmaceutically active compound. Such reactions are known, for example, from

WO2003070705,„Bioactive Heterocyclic Compound Classes", Ed. C. Lamberth und J. Dinges, Wiley 2012, S. 175-193 (Chapter 15, Pyrazole Carboxamide Fungicides Inhibiting Succinate Dehydrogenase) and„Modern Crop Protection Compounds", Ed. W. Kramer, U. Schirmer, P. Jeschke and M. Witschel, Wiley 2012, S. 627-639 and the literature cited in these books. In such a process for the manufacture of an agrochemical compound, for example compounds such as N- (3',4'-Dichlor-5-fluorbiphenyl-2-yl)-3-(difluormethyl)-l-methylpyrazol-4- carboxamid, 3-(difluoromethyl)-l-methyl-N-[2-(3',4',5'- trifluorophenyl)phenyl]pyrazole-4-carboxamide, N-(2-Bicyclopropyl-2- ylphenyl)-3-difluoromethyl-l-methyl-lH-pyrazol-4-carboxylic acid amide, 3- (Difluormethyl)- 1 -methyl-N- [ 1 ,2,3,4-tetrahydro-9-( 1 -methylethyl)- 1 ,4- methanonaphthalen-5-yl]-lH-pyrazol-4-carboxamid or N-[(lRS,4SR)-9- (dichloromethylidene)- 1 ,2,3,4-tetrahydro- 1 ,4-methanonaphthalen-5-yl]-3- (difluoromethyl)-l-methyl-lH-pyrazole-4-carboxamide (and isomers) are obtained.

The new process according to the present invention allows for efficient syntheses of carboxylic acids or a carboxylic acid derivatives, which are useful intermediates for, e.g., agrochemical and pharmaceutical compounds. Departing from easily accessible starting materials, such as methyl ketones, the carboxylic acids or a carboxylic acid derivatives can be obtained while avoiding a high amount of salt waste which often also is difficult to dispose of and/or recycle due to organic impurities. Should the disclosure of any patents, patent applications, and publications which are incorporated herein by reference conflict with the description of the present application to the extent that it may render a term unclear, the present description shall take precedence.

The following examples are intended to further explain the invention without limiting it.

Example 1 The catalytic reaction is performed in a 15-mL autoclave reactor with an internal Teflon insert.0.5 mmol of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)ethanone, 0.1 mmol of Cu(N0₃)₃ 3H₂0 and 2 mL of acetonitrile are added into the reactor. Then, the reactor is charged with 0.6 MPa Air and heated to 120 °C under magnetic stirring for approximately 12 hours. After cooling to room temperature, the reaction mixture is diluted with 4 mL methanol and 5 mL IN HC1 before analysis with HPLC. A suitable conversion of l-(3-(difluoromethyl)- 1 -methyl- lH-pyrazol-4-yl)ethanone into 3 - (difluoromethyl) - 1 -methyl- 1H- pyrazole-4-carboxylic acid is observed.

Example 2

0.029 mol (g g) of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)ethanone was dissolved in 80 mL acetic acid, and 0,0029 mol (0.85 g) of Co(N0₃)₃ 6H₂0 and 0,0029 mol (0.74 g) of Mn(N0₃)₃4H₂0 were added.

Oxygen was bubbled into the solution at 0.1 atm above ambient pressure and the solution was heated to 100°C. The reaction was performed during 18 hours; after reaction, volatiles were distilled off until 25 g mixture remained. Precipitate formed. The precipitate was filtered, dried and 3.64 g (0.0207 mol, 71 ) solid was obtained containing 99.8% of product 3-(difluoromethyl)-l-methyl-lH- pyrazole-4-carboxylic acid as measured by HPLC. Example 3

0.1 mol (17.4 g) of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)ethanone was dissolved in 50 mL acetic acid, and the respective catalytic system was added. Air was bubbled into the solution and the solution was heated to 100°C. The reaction was performed during 18 hours; the content of product 3- (difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (DFMPA) was measured in the reaction mixture by HPLC. Amounts of catalysts are given in eq. in relation to the molar eq. l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)ethanone. Results are given in Table 1.

Table 1: Oxidation of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)ethanone using different catalytic systems

Example 4

0.1 mol (17.4 g) of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)ethanone was dissolved in 50 mL of the respective solvent, and Co(N03)3^'6H₂0 Mn(N0₃)2^'4 H₂0 (10mol% / 10mol% relative to the amount 1- (3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)ethanone) was added. Air was bubbled into the solution at 0.1 atm above ambient pressure and the solution was heated to 100°C. The reaction was performed during 18 hours; the content of product 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid (DFMPA) was measured in the reaction mixture by HPLC. Results are given in table 2.

Table 2: Oxidation of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)ethanone using different solvents and Co(N0₃)₃ 6H₂0/Mn(N0₃)24 H₂0

Example 5 Recycling of mother liquor comprising catalyst

Run 1: 10 kg of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)ethanone was mixed with 60 kg acetic acid, 0.28 kg Co(N0₃)26H₂0 and 1.03 kg of a 50 wt% aqueous solution of Mn(N03)₂ were added. The mixture was heated to 75- 80°C, and oxygen was bubbled through. After conversion was stable (GC), the mixture was cooled to room temperature, and crude 3-(difluoromethyl)-l- methyl-lH-pyrazole-4-carboxylic acid precipitated. The precipitate was filtered off, and the mother liquor was used as solvent in run 2.

For run 2, 10 kg of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)ethanone was mixed with the mother liquor of run 1, 0.084 kg Co(N0₃)₂ ^'6H₂0 and 0,309 kg of a 50 wt% aqueous solution of Mn(N03)₂ were added. The mixture was heated to 75-80°C, and oxygen was bubbled through. After conversion was stable (GC), the mixture was cooled to room temperature, and crude 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid precipitated. The precipitate was filtered off, and the mother liquor was used as solvent in run 3.

For run 3, 10 kg of l-(3-(difluoromethyl)-l-methyl-lH-pyrazol-4- yl)ethanone was mixed with the mother liquor of run 2, 0.084 kg Co(N0₃)₂ ^'6H₂0 and 0,309 kg of a 50 wt% aqueous solution of Μη(ΝΌ₃)₂ were added. The mixture was heated to 75-80°C, and oxygen was bubbled through. After conversion was stable (GC), the mixture was cooled to room temperature, and crude 3-(difluoromethyl)-l-methyl-lH-pyrazole-4-carboxylic acid precipitated. The precipitate was filtered off.

The crude combined 3-(difluoromethyl)-l-methyl- lH-pyrazole-4-carboxylic acid precipitate yielded 88.6%. The precipitate was washed with water (three times), and recrystallized from methanol (2.5 times of weight precipitate). The crystallisation yield was 95%. GC purity of the recrystallized 3-(difluoromethyl)- 1 -methyl- lH-pyrazole-4-carboxylic acid was >99.9%.

Claims

C L A I M S

1. Process for the manufacture of a compound of formula (II) comprising a step of catalytic oxidation in the presence of at least one catalyst and at least one oxidant, of compound number (I),

(I ) (I I)

wherein R¹ is selected from the group consisting of Ci-C4-alkyl groups which is substituted by at least one halogen atom independently selected from the group consisting of F, CI and Br or by a CF₃ group,

R is selected from the group consisting of an optionally substituted Q-Cg alkyl group, an optionally substituted C₃-Cg cycloalkyl group, an optionally substituted aryl group and an optionally substituted heteroaryl group, preferably

R is a methyl group

R is selected from the group consisting of H, X, COOR, OR, SR,

C(0)NR₂, wherein R is selected from the group consisting of hydrogen, a Cp Ci₂-alkyl, CN, C₂-C₆ alkenyl, aryl, C₃-Cg cycloalkyl, aralkyl or heteroaryl group, each of which is optionally substituted, with the proviso that both R in C(0)NR₂ may be the same or different, wherein X is selected from the group consisting of F, CI, Br and I, and R is independently selected from the group consisting of hydrogen or a Ci-Ci₂-alkyl group, Ci-Ci₂-alkyl, C₂-C₆ alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl, R⁴ is selected from the group consisting of H, Ci-Ci₂-alkyl, C₂-C₆ alkenyl,

C₃-Cg cycloalkyl, aryl, heteroaryl or aralkyl group, each of which is optionally substituted,

2. Process according to claim 1, wherein R is selected from the group consisting of CF₂H, CF₃, CC1F₂, CC1₂H and CC1₃, wherein CF₂H and CF₃ are preferred.

3. Process according to claim 1 or 2, wherein R⁴ is a C1-C4 alkyl group which is optionally substituted, preferably a methyl group.

4. Process according to anyone of claims 1 to 3, wherein R is H or X, wherein X is selected from the group consisting of F, CI, Br and I, preferably R is H.

5. Process according to anyone of claims 1 to 4, wherein the at least one oxidant is selected from the group consisting of oxygen, a gas comprising oxygen, a peroxide, KMn0₄ and ozone.

6. Process to anyone of claims 1 to 5, wherein the at least one catalyst is selected from the group consisting of a metal salt comprising at least one metal species and a metal complex comprising at least one metal species.

7. Process according to claim 6, wherein the metal salt or metal complex comprises at least one metal species selected from the group consisting from the groups 3 to 12 of the periodic system.

8. Process according to claim 7, wherein the metal salt or metal complex comprises at least one metal species selected from the group consisting of Ti, Co, Y, Ce, Yb, La, Zr, V, Nb, Ta, Cr, Mo, W, Mn, Tc, Re, Fe, Ru, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd and Hg.

9. Process according to anyone of claims 6 to 8, wherein the metal salt is selected from the group consisting of oxides, hydroxides, carbonates, nitrates, acetates, halides, or hydrates of any of the foregoing.

10. Process according to claim 9, wherein the at least one catalyst is selected from the group consisting of Fe(N0₃)₃ or its hydrate, Co(N0₃)₃ or its hydrate, Ni(N0₃)₃ or its hydrate, Co(N0₃)₃ or its hydrate, Mn(N0₃)₃ or its hydrate, Zn(N0₃)₃ or its hydrate, Mn(OAc₂) or its hydrate, Co(OAc₂), Cu(OAc₂), CuCl₂ or its hydrate, CuO, CuBr₂, CuCl, CuBr, Cul and Re₂0₇.

11. Process according anyone of claims 1 to 10, wherein the at least one catalyst is present in an amount of from 0.01 to 30 mol calculated on the amount of compound (I).

12. Process according anyone of claims 1 to 11, wherein at least one additional reagent is present in the reaction, wherein the at least one additional reagent is a co-oxidant or an auxiliary.

13. Process according anyone of claims 1 to 12, wherein the process for the manufacture of a compound of formula (II) further comprises a step of reacting a compound of formula (III) with a compound selected from the group consisting of compound (IV), (V) and (VI) to obtain the compound of formula (I)

wherein compound (IV), (V) and (VI) are defined as follows:

wherein Y is selected from the group consisting of S, O and NR⁶, wherein O and NR⁶ are preferred,

wherein R⁶ independently is selected from the group consisting of a CrC₁₂- alkyl, C₂-C6 alkenyl or C3-Cg-cycloalkyl group, each of which is optionally substituted

14. Process according to claim 13, wherein Y is O and R⁶ is ethyl, or Y is NR⁶ and both R⁶ are methyl, R³ is H,

IT 4 and IT 2 are methyl,

and R s CFaH or CFa.

15. Process for the manufacture of an agrochemical or pharmaceutical compound, preferably a carboxamide SDHI fungicide, which comprises the process according to anyone of claims 1 to 14.