Method for the regioselective synthesis of 1-alky1-3-haloalkyl-pyrazole-4-carboxylic acid derivatives

1. A process for preparing a 1-alkyl-3-haloalkylpyrazole-4-carboxylic acid derivative of formula (I)

in which

R 1 is C 1-12 -alkyl, which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, —OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group and X′ is F, Cl, Br, or I;

R 2 is a C 1 -C 4 -alkyl group which is optionally substituted by one, two or three halogen atoms selected from the group consisting of F, Cl and Br or by a CF 3 group;

Y is (C═O)OR 3 , where R 3 is selected from the group consisting of C 1-12 -alkyl, C 3-8 -cycloalkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 6-8 -aryl, C 7-19 -aryl-alkyl and C 7-19 -alkylaryl, each of which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group and X′ is F, Cl, Br, or I;

comprising at least one of the reaction sequences consisting of steps (A) and (D), (B) and (D) or (C) and (D) below:

(A) reaction of a 2-acylated or 2-iminoalkylated acrylic acid derivative of formula (II),

in which

Z is selected from the group consisting of O, S and N + R 10 R 11 , where R 10 and R 11 independently of one another are selected from the group consisting of C 1-12 -alkyl, C 3-8 -cycloalkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 6-8 -aryl, C 7-19 -arylalkyl and C 7-19 -alkylaryl groups, each of which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, —OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group, X′ is F, Cl, Br, or I, and R 10 and R 11 together with the nitrogen atom to which they are attached optionally form a 5- or 6-membered ring which optionally contains one or two further heteroatoms selected from the group consisting of O, S and an SO 2 group and which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, —OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group, and X′ is F, Cl, Br, or I;

A is a leaving group NR 12 R 13 , where R 12 and R 13 independently of one another are selected from the group consisting of C 1-12 -alkyl, C 3-8 -cycloalkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 6-8 -aryl, C 7-19 -aryl-alkyl and C 7-19 -alkylaryl each of which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, —OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group, X′ is F, Cl, Br, or I, and R 12 and R 13 together with the nitrogen atom to which they are attached optionally form a 5- or 6-membered ring which optionally contains one or two further heteroatoms selected from the group consisting of O, S and an SO 2 group and which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, —OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group and X′ is F, Cl, Br, or I;

with an N-alkylhydrazone of formula (III)

in which

R 8 and R 9 independently of one another are selected from the group consisting of C 1-12 -alkyl, C 3-8 -cycloalkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 6-8 -aryl, C 7-19 -aryl alkyl and C 7-19 -alkylaryl, each of which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, —OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group, X′ is F, Cl, Br, or I, and R 8 and R 9 together with the carbon atom to which they are attached optionally form a 5- or 6-membered ring which optionally contains one or two further heteroatoms selected from the group consisting of O, S and an SO 2 group and which is optionally substituted by one or more groups selected from the group consisting of —R′, —X′, —OR′, —SR′, —NR′ 2 , —SiR′ 3 , —COOR′, —(C═O)R′, —CN and —CONR′ 2 , where R′ is hydrogen or a C 1-12 -alkyl group and X′ is F, Cl, Br, or I;

(B) acylation of an acrylic acid hydrazone of formula (VI);

with an acyl halide of formula (X), where X′ is selected from the group consisting of F, Cl, Br and I:

(C) iminoalkylation of an acrylic acid hydrazone of the formula (VI) above with an α,α-dihaloamine of formula (XI), where X′ is selected from the group consisting of F, Cl, Br and I:

(D) cyclization of an intermediate obtained in step (A), (B) or (C) to give the 3-haloalkylpyrazole-4-carboxylic acid derivative of the formula (I).

2. The process according to claim 1 , wherein the reaction sequence consists of steps (A) and (D).

3. The process according to claim 1 , wherein the reaction sequence consists of steps (B) and (D).

4. The process according to claim 1 , wherein the reaction sequence consists of steps (C) and (D).

5. The process according to claim 1 , wherein the acyl halide of the formula (X) in step (B) is selected from the group consisting of difluoroacetyl fluoride and difluoroacetyl chloride.

6. The process according to claim 1 , wherein the α,α-dihaloamine of the formula (XI) in step (C) is 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine.

7. The process according to claim 1 , wherein the 2-acylated or 2-iminoalkylated acrylic acid derivative of the formula (II) is selected from the group consisting of N-1-(trifluoromethyl)-3-(dimethylamino)-2-(ethoxycarbonyl)prop-2-en-1-ylidene]-N-methyl-methanaminium chloride, N-1-(difluoromethyl)-3-(dimethylamino)-2-(ethoxy-carbonyl)prop-2-en-1-ylidene]-N-methylmethanaminium tetrafluoroborate and N-[3-(dimethylamino)-2-(ethoxycarbonyl)-1-(1,1,2,2-tetrafluoroethyl)prop-2-en-1-ylidene]-N-methylmethanaminium chloride.

8. The process according to claim 1 , wherein the N-alkylhydrazone of the formula (III) is selected from the group consisting of 1-methyl-2-(1-methylethylidene)hydrazine, 1-methyl-2-(1phenyl ethylidene)hydrazine, 1-methyl-2-(1,2,2-trimethylpropylidene)hydrazine, 1-methyl-2-(1-methylpropylidene)hydrazine, 1-cyclohexylidene-2-methylhydrazine, 1-methyl-2-(phenylmethylidene)hydrazine, 1-(diphenylmethyl-idene)-2-methylhydrazine, and ethyl 2-[(dimethylamino)methylidene]-4,4,4-tri-fluoro-3-oxobutanoate.

9. The process according to claim 1 , wherein the acrylic acid hydrazone of the formula (VI) in steps (B) and (C) is selected from the group consisting of ethyl (2E)-3-[1-methyl-2-(propan-2-ylidene)hydrazinyl]prop-2-enoate, ethyl (2Z)-3-[1-methyl-2-(propan-2-ylidene)hydrazinyl]prop-2-enoate, methyl 3-[1-methyl-2-(propan-2-ylidene)hydrazinyl]prop-2-enoate, propyl 3-[1-methyl-2-(propan-2-ylidene)hydrazinyl]prop-2-enoate, ethyl (2E)-3-[1-methyl-2-(3,3-dimethylbutan-2-ylidene)hydrazinyl]prop-2-enoate, methyl 3-[1-methyl-2-(3,3-dimethylbutan-2-ylidene)hydrazinyl]prop-2-enoate, methyl 3-[1-methyl-2-(phenylmethylidene)-hydrazinyl]prop-2-enoate, (2E)-3-[1-methyl-2-(phenylmethyl idene)hydrazinyl]-prop-2-enenitrile and methyl 3-[1-ethyl-2-(propan-2-ylidene)hydrazinyl]prop-2-enoate.

10. A process for preparing a 1-alkyl-3-haloalkylpyrazole-4-carboxylic acid derivative of formula (I)

in which

R 1 is C 1-4 -alkyl;

R 2 is a C 1 -C 4 -alkyl group which is optionally substituted by one, two or three halogen atoms selected from the group consisting of F, Cl and Br or by a CF 3 group;

is (C═O)OR 3 , where R 3 is selected from the group consisting of C 1-12 -alkyl, C 3-8 -cycloalkyl, C 6-8 -aryl, C 7-19 -arylalkyl and C 7-19 -alkylaryl groups; comprising;

(a) reaction of a 2-acylated or 2-iminoalkylated acrylic acid derivative of formula (II),

in which

Z is selected from the group consisting of O, S and N + R 10 R 11 , where R 10 and R 11 independently of one another are selected from the group consisting of C 1-12 -alkyl or R 10 and R 11 together with the nitrogen atom to which they are attached optionally form a 5- or 6-membered ring;

A is a leaving group NR 12 R 13 , where R 12 and R 13 independently of one another are selected from C 1-12 -alkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached optionally form a 5- or 6-membered ring;

with an N-alkylhydrazone of formula (III)

in which

R 8 and R 9 independently of one another are selected from the group consisting of hydrogen, C 1-12 -alkyl, C 3-8 -cycloalkyl, C 6-18 -aryl, C 7-19 -arylalkyl and C 7-19 -alkylaryl groups, or R 8 and R 9 together with the carbon atom to which they are attached optionally form a 5- or 6-membered ring;

to form an intermediate; and

(b) cyclization of the intermediate obtained in step (a) to give the 3-haloalkylpyrazole-4-carboxylic acid derivative of the formula (I).

11. The process according to claim 10 , wherein:

R′ is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, or tert-butyl;

R 8 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, phenyl, tolyl, and cyclohexyl;

R 9 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, phenyl, tolyl, and cyclohexyl,

wherein R 8 and R 9 , together with the C-atom to which they are bound, optionally form a 5- or 6-membered ring.