MANUFACTURE OF HYDRAZINYL COMPOUNDS USEFUL IN THE MANUFACTURE OF PYRAZOLE CARBOXYLIC ACID AND DERIVATIVES, HYDRAZINYL COMPOUNDS AND THEIR USE

Abstract

The present invention concerns the manufacture of hydrazinyl compounds useful in the manufacture of pyrazole carboxylic acid and derivatives thereof and processes for the manufacture of agrochemical or pharmaceutical compounds. The invention also concerns hydrazinyl compounds and their use.

Claims

1. A process for the manufacture of a compound according to formula (I), ##STR00017## the process comprising a step of reacting a compound of formula (II) ##STR00018## with a compound of formula (III) ##STR00019## wherein R.sup.1 is selected from C.sub.1-C.sub.4-alkyl groups which may be substituted by one, two or three halogen atoms selected from the group consisting of F, Cl and Br, or by a CF.sub.3 group R.sup.2 is selected from the group consisting of C.sub.1-C.sub.8-alkyl, aryl, C.sub.3-C.sub.8 cycloalkyl, aralkyl and heteroaryl, each of which is optionally substituted, R.sup.3 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.8 cycloalkyl, aryl, heteroaryl, aralkyl, each of which is optionally substituted; or R.sup.3 is a nitrogen protecting group R.sup.4 and R.sup.5 independently from each other are selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.8 cycloalkyl which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, aryl and heteroaryl, each of which is optionally substituted; or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a 4, 5 or 6-membered optionally substituted cycloalkyl, which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, aryl or heteroaryl group, each of which is optionally substituted, X is a halogen atom; or with a respective anhydride (Ma) of the compound of formula (III).

2. A process for the manufacture of a compound according to formula (II), ##STR00020## the process comprising a step of reacting a compound of formula (IV) and a compound of formula (V) ##STR00021## wherein R.sup.1 is selected from C.sub.1-C.sub.4-alkyl groups which may be substituted by one, two or three halogen atoms selected from the group consisting of F, Cl and Br, or by a CF.sub.3 group R.sup.2 is selected from the group consisting of C.sub.1-C.sub.8-alkyl, aryl, C.sub.3-C.sub.8 cycloalkyl, aralkyl and heteroaryl, each of which is optionally substituted R.sup.3 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.8 cycloalkyl, aryl, heteroaryl, aralkyl, each of which is optionally substituted; or R.sup.3 is a nitrogen protecting group R.sup.4 and R.sup.5 independently from each other are selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.8 cycloalkyl which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, aryl and heteroaryl, each of which is optionally substituted; or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a 4, 5 or 6-membered optionally substituted cycloalkyl, which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, aryl or heteroaryl group, each of which is optionally substituted, Y is selected from the group consisting of S, O and NR.sup.7, R.sup.7 and R.sup.6 independently are selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl or C.sub.3-C.sub.10-cycloalkyl, each of which is optionally substituted, or, when Y═NR.sup.6, R.sup.6 together with R.sup.7 and the nitrogen atom to which the two radicals are attached are 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.

3. The process of claim 1, wherein R.sup.1 is methyl or ethyl, which is substituted by at least one fluorine atom.

4. The process according to claim 1, wherein R.sup.1 is selected from the group consisting of CF.sub.2Cl, CF.sub.2H, CFCl.sub.2, CFClH, CF.sub.2Br, CF.sub.2CF.sub.3 and CF.sub.3.

5. The process according to claim 1, wherein R.sup.2 is a C.sub.1-C.sub.8-alkyl group, which is optionally substituted.

6. The process according to claim 1, wherein R.sup.4 is a hydrogen atom and R.sup.5 is selected from the group consisting of C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.8 cycloalkyl, aryl and heteroaryl, each of which is optionally substituted.

7. The process according to claim 1, wherein R.sup.3 is a methyl group.

8. A process for the manufacture of a compound of formula (VI) ##STR00022## wherein R.sup.1 and R.sup.3 have the same meaning as above, and R.sup.8 is selected from the group consisting of H, X′, COOR′, OR′, SR′, C(O)NR′.sub.2, wherein R′ is hydrogen or a C.sub.1-C.sub.12-alkyl group, CN, C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.6 alkenyl, aryl, cycloalkyl, aralkyl, heteroaryl, each of which is optionally substituted, with the proviso that in C(O)NR′.sub.2 both R′ may be the same or different; the process comprising a step of performing the process according to claim 1.

9. The process according to claim 8, wherein the process comprises additionally at least one of the steps of (a) adding an acidic compound to the compound of formula (I) to obtain a compound of formula (VII) ##STR00023## (b) reacting a compound of formula (VII) with at least one oxidizing agent, wherein R.sup.1, R.sup.3, R.sup.8 and R.sup.2 have the same meaning as given above.

10. The process according to claim 9, wherein the at least one oxidizing agent is selected from the group consisting of halogen, oxyacids of halogen and salts thereof, a peroxide, molecular oxygen and molecular ozone.

11. The compound of formula (II) as defined in the process of claim 1.

12. Compound A compound of formula (I), ##STR00024## wherein R.sup.1 is selected from C.sub.1-C.sub.4-alkyl groups which may be substituted by one, two or three halogen atoms selected from the group consisting of F, Cl and Br, or by a CF.sub.3 group R.sup.2 is selected from the group consisting of C.sub.1-C.sub.8-alkyl, aryl, C.sub.3-C.sub.8 cycloalkyl, aralkyl and heteroaryl, each of which is optionally substituted, R.sup.3 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.8 cycloalkyl, aryl, heteroaryl, aralkyl, each of which is optionally substituted; or R.sup.3 is a nitrogen protecting group R.sup.4 and R.sup.5 independently from each other are selected from the group consisting of H, C.sub.1-C.sub.12-alkyl, C.sub.3-C.sub.8 cycloalkyl which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, aryl and heteroaryl, each of which is optionally substituted; or R.sup.4 and R.sup.5 together with the carbon atom to which they are attached form a 4, 5 or 6-membered optionally substituted cycloalkyl, which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, aryl or heteroaryl group, each of which is optionally substituted.

13. (canceled)

14. A process for the manufacture of an agrochemical or pharmaceutical compound or their intermediates, the process comprising a step of performing the process according to claim 1.

15. The process according to claim 1, wherein the compound of formula (II) is obtained by the reaction of a compound of formula (IX) with a compound of formula (IV) ##STR00025## wherein R.sup.2 to R.sup.5 and (IV) are defined as in claim 1, and wherein M is a metal ion.

16. The process of claim 3, wherein R.sup.1 is methyl, which is substituted by at least one fluorine atom.

17. The process according to claim 5, wherein R.sup.2 is a methyl group which is optionally substituted.

18. The process according to claim 9, wherein the acidic compound is selected from the group consisting of HCl, H.sub.2SO.sub.4, KHSO.sub.4 and HF.

19. The process according to claim 9, wherein the compound of formula (VII) is reacted with at least one oxidizing agent in the presence of a base.

20. The process according to claim 10, wherein the at least one oxidizing agent is selected from the group consisting of halogen and aqueous solutions of salts of hypohalogenous acids.

21. The process according to claim 20, wherein the at least one oxidizing agent is an aqueous solution of sodium hypochlorite and/or sodium hypobromite.

Description

EXAMPLES

[0062] The starting materials are commercially available or known from literature procedures.

Example 1a

Manufacture of 4-(-2-benzylidene-1-methylhydrazinyl)but-3-en-2-one

[0063] ##STR00013##

[0064] 1 eq of 2-methyl-1-phenylhydrazone and 1.05 eq of 4-(dimethylamino)-but-3-en-2-one are charged in 20 mL of toluene, and heated to 40° C. The reaction mixture is stirred at 40° C. for about 8 hours. The solvent and dimethylamine is distilled off to yield the desired enone.

[0065] The presence of a Lewis acid, for example NaHSO.sub.4 can enhance the reaction.

Example 1b

Manufacture of 4-(-2-benzylidene-1-methylhydrazinyl)but-3-en-2-one

[0066] 1 eq of 2-methyl-1-phenylhydrazone and 1.05 eq of 4-ethoxybut-3-en-2-one are charged in 20 mL of toluene. The reaction mixture is stirred at 20° C. for about 4 hours. The volatiles are evaporated to yield the crude product.

Example 2

Manufacture of 3-((-2-benzylidene-1-methylhydrazinyl)methylene)-1,1-difluoropentane-2,4-dione

[0067] 1 eq of the product of example 1b is reacted with 1.1 eq difluoroacetylfluoride in the presence of 1.2 eq triethylamine in 30 mL dichloromethane at 0° C. The reaction is continued for 2 hours at 25° C. The mixture is quenched with 50 mL of water, the aq. phase separated and extracted twice with dichloromethane. The organic phase is dried over Na2SO4, and the solvents are evaporated. Triethylamine can also be recovered from the aqueous phase after alkalising the aqueous phase and separation of the phases.

Example 3

Manufacture of 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone

[0068] 1 eq of 3-((-2-benzylidene-1-methylhydrazinyl)methylene)-1,1-difluoropentane-2,4-dione from example 2 is charged in 30 mL acetonitrile, and 0.5 eq of 10% HCl is added. The mixture is stirred at 20° C. for 1 hour. The solvent is removed, the mixture extracted with dichloromethane and dried over Na2SO4. Evaporation gives the crude product.

Example 4

Manufacture of (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid

[0069] 1 eq of 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone is added to 3.3 eq NaOH and 3.3 eq of an 8% sodium hypochlorite solution at 10° C. After addition, the reaction mixture is stirred for 3 hours at 20° C. Dichloromethane, about 20 mL, is added to the mixture and the organic phase discarded. The pH of the aq. phase is brought to 1-2 by addition of 10% HCl. The mixture is stirred for 30 minutes at 0° C., the precipitate filtered and dried to obtain (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid.

Example 5

Manufacture of 4-(2-benzylidene)hydrazinyl)but-3-en-2-one

[0070] ##STR00014##

[0071] To a four necked flask 482 ml of toluene was charged and 48 ml of anhydrous methanol were added. 58.38 g (1.08 mol) of NaOMe was charged in one portion. A mixture of 72.72 g (1.2 mol) of methyl formate and 58.08 g (1 mol) of acetone was added dropwise in 2 hours, keeping reaction temperature at 35-40° C., then stirring was continued at 40° C. for 2 h. The mixture was cooled to 35° C. and 170.68 g (1 mol) of 1-benzylidene-2-methylhydrazine HCl salt (BzH*HCl) salt was added in one portion. The mixture was stirred at room temperature overnight. The salt was filtered of and the solution partly evaporated whereupon product 4-(2-benzylidene)hydrazinyl)but-3-en-2-one crystallized out. 4-(2-benzylidene)hydrazinyl)but-3-en-2-one was filtered off and dried yielding 183 g pale yellow crystals.

[0072] BzH*HCl was obtained by reaction of 1-benzylidene-2-methylhydrazine in ethyl acetate with HCl/dimethylether. During the addition, a white-yellow solid was formed. After 30 minutes at 0° C., the suspension was filtered and dried in vacuum to yield BzH*HCl. The synthesis of 1-benzylidene-2-methylhydrazine is described, for example, in A. Dubrovskiy et al J. Org. Chem., 2012, 77 (24), pp 11232-11256, and literature cited therein.

Example 6

Manufacture of 3-((2-benzylidene)hydrazinyl)methylene)-1,1-difluoropentane-2,4-dione

[0073] ##STR00015##

[0074] To a reaction flask was charged with 183 g 4-(2-benzylidene)hydrazinyl)but-3-en-2-one (0.9 mol) obtained in example 5. 1000 ml DCM was added following by 200 g Et.sub.3N. Gaseous diflouroacetyl flouride (1 mol) was added to the mixture keeping internal temperature below 20° C. The mixture was stirred for 3 h whereupon GC showed full 4-(2-benzylidene)hydrazinyl)but-3-en-2-one consumption. The mixture was washed with water to remove the NEt.sub.3 salt. The resulting solution was used directly in example 7.

Example 7

Manufacture of 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one

[0075] ##STR00016##

[0076] To the crude 3-((2-benzylidene)hydrazinyl)methylene)-1,1-difluoropentane-2,4-dione solution from example 6 was added conc. H.sub.2SO.sub.4 (25 g) and the mixture was stirred for 2 h at room temperature. The solution was washed with water to remove acid; the solvent was evaporated. Crude 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one containing benzaldehyde was separated by distilling benzaldehyde away under reduced pressure to yield crude 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one.

Example 8

Manufacture of (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid

[0077] 1 eq of 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethanone of crude 1-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)ethan-1-one obtained by example 7 is added to 3.3 eq NaOH and 3.3 eq of an 8% sodium hypochlorite solution at 10° C. After addition, the reaction mixture is stirred for 3 hours at 20° C. Dichloromethane, about 20 mL, is added to the mixture and the organic phase discarded. The pH of the aq. phase is brought to 1-2 by addition of 10% HCl. The mixture is stirred for 30 minutes at 0° C., the precipitate filtered and dried to obtain (3-(difluoromethyl)-1-methyl-1H-pyrazol-4-carboxylic acid.