WO2021078979A1

WO2021078979A1 - Process for the preparation of (z,2e)-5-[1-(4-chlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-n,3-dimethyl-pent-3-enamide derivatives

Info

Publication number: WO2021078979A1
Application number: PCT/EP2020/079962
Authority: WO
Inventors: Thomas James Hoffman; Clemens Lamberth; Sandeep Reddy KANDUKURI
Original assignee: Syngenta Crop Protection Ag
Priority date: 2019-10-24
Filing date: 2020-10-23
Publication date: 2021-04-29

Abstract

The present invention relates to a process for the preparation of (Z,2E)-5-[1-(4- chlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-N,3-dimethyl-pent-3-enamide derivatives suitable for use, e.g., as active ingredients, which have microbiocidal activity, in particular, fungicidal activity.

Description

Process for the preparation of (Z.2E)-5-ri-(4-chlorophenvhpyrazol-3-ylloxy-2-methoxyimino-

N.3-dimethyl-pent-3-enamide derivatives

The preparation of (Z,2E)-5-[1-(4-chlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-N,3-dimethyl- pent-3-enamide is described in WO 2016/055404 by reaction of (Z,2E)-5-chloro-2-methoxyimino-N,3- dimethyl-pent-3-enamide with a hydroxyl compound, namely 1-(4-chlorophenyl)pyrazol-3-ol. This process is disadvantageously carried out under heating in the presence of two different potassium- based reagents.

The preparation of (Z,2E)-5-[1-(2,4-dichlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-N,3- dimethyl-pent-3-enamide is described in WO 2018/153707 by reaction of the corresponding ester derivative with methylamine in a suitable solvent. One of several drawbacks of this reaction is that large amounts of organotin intermediates are required forthe preparation ofthe ester deriviative, which results in the formation of by-products, thereby lowering yields of the desired products.

According to the present invention, there is provided a process for the preparation of a compound of formula (I):

wherein R¹ is hydrogen or halogen, said process comprising reacting a compound of formula (II):

wherein R¹ is hydrogen or halogen, with a compound of formula (III):

wherein

R² is halogen or a sulfonic acid ester, and

X is -NH(CH3) or -OR³, wherein R³ is Ci-ealkyl, preferably methyl, said process being carried out in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride.

When R² in the compound of formula (III) is halogen, it is preferably chloro or bromo.

When R² in the compound of formula (III) is a sulfonic acid ester, it is preferably mesylate.

According to one embodiment, R¹ in the compounds of formulae (I) and (II) is chloro. According to this embodiment, the present invention relates to a process for the preparation of a compound of formula (l-A):

said process comprising reacting a compound of formula (ll-A): (ll-A) with a compound of formula (III):

wherein

R² is halogen or a sulfonic acid ester, and X is -NH(CH3) or -OR³, wherein R³ is Ci-ealkyl, preferably methyl, said process being carried out in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride. According to a first embodiment of the present invention, there is provided a process for the preparation of a compound of formula (I):

wherein R¹ is hydrogen or halogen, said process comprising reacting a compound of formula (II): wherein R¹ is hydrogen or halogen, with a compound of formula (lll-a):

wherein R² is halogen or a sulfonic acid ester, said process being carried out in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride.

When R² in the compound of formula (lll-a) is halogen, it is preferably chloro or bromo.

When R² in the compound of formula (lll-a) is a sulfonic acid ester, it is preferably mesylate.

According to one variant of this first embodiment of the invention, R¹ in the compounds of formulae (I) and (II) is chloro. According to this embodiment, the present invention relates to a process for the preparation of a compound of formula (l-A):

said process comprising reacting a compound of formula (ll-A):

(ll-A) with a compound of formula (lll-a):

According to a second embodiment of the present invention, there is provided a process for the preparation of a compound of formula (I):

wherein R¹ is hydrogen or halogen, said process comprising: (a) reacting a compound of formula (II): wherein R¹ is hydrogen or halogen, with a compound of formula (lll-b):

(lll-b) wherein R² is halogen or a sulfonic acid ester, and R³ is Ci-6alkyl, preferably methyl, in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride, to provide a compound of formula (IV):

wherein

R¹ is hydrogen or halogen, and R³ is Ci-6alkyl, preferably methyl, and

(b) reacting the compound of formula (IV) of step (a) with methylamine to provide the compound of formula (I).

When R² in the compound of formula (lll-b) is halogen, it is preferably chloro or bromo.

When R² in the compound of formula (lll-b) is a sulfonic acid ester, it is preferably mesylate.

According to one variant of this second embodiment of the invention, R¹ in the compounds of formulae (I), (II) and (IV) is chloro. According to this embodiment, the present invention relates to a process for the preparation of a compound of formula (l-A):

(l-A) said process comprising:

(a’) reacting a compound of formula (I l-A):

(I l-A) with a compound of formula (lll-b):

(lll-b) wherein

R² is halogen or a sulfonic acid ester, and R³ is Ci-6alkyl, preferably methyl, in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride, to provide a compound of formula (IV-A):

wherein R³ is Ci-ealkyl, preferably methyl, and

(b’) reacting the compound of formula (IV-A) of step (a’) with methylamine to provide the compound of formula (l-A).

The process of the invention is advantangeously carried out in the presence of one base selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride. More preferably, the process of the invention is carried out in the presence of sodium hydride.

Surprisingly, it has been now found that the process of the invention can be advantageously carried out at relatively low temperatures to produce compounds of formula (I) at high isolated yields, especially with a high stereoselectivity of at least 80% of the desired (Z,2E)-isomer of compound of formula (I) versus the sum of the corresponding (E,2E)-, (E,2Z)- and (Z,2Z)-isomers of compounds of formula (I).

According to one embodiment, the process of the invention is carried out in the presence of at least one solvent. Examples of suitable solvents include, for instance, ketones such as acetone and ethyl methyl ketone, nitriles, aromatic hydrocarbons such as toluene and o-, m- and p-xylene, ethers such as dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone. Mixtures of solvents can also be used in the process of the invention. The process of the invention is preferably carried out in the presence of toluene, dioxane, tetrahydrofuran or N,N-dimethylformamide, more preferably in the presence of N,N-dimethylformamide.

The compounds of formula (I) can be used in the agricultural sector and related fields of use, e.g., as active ingredients for controlling plant pests or on non-living materials for the control of spoilage microorganisms or organisms potentially harmful to man. These compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and can be used for protecting numerous cultivated plants. The compounds of formula (I) can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later, e.g., from phytopathogenic microorganisms.

The compounds of formula (I) have, for practical purposes, a very advantageous level of biological activity for protecting plants against diseases that are caused by fungi. Thus, the compound of formula (I) is particularly suitable for use as a fungicide. The term “fungicide” as used herein means a compound that controls, modifies, or prevents the growth of fungi. According to this particular aspect of the invention, the use may exclude methods for the treatment of the human or animal body by surgery or therapy.

The compounds of formula (I) are for example effective against fungi and fungal vectors of disease as well as phytopathogenic bacteria and viruses.

As used herein, the term "halogen" or “halo” refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.

As used herein, the term "Ci-6alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. The terms “Ci-₄alkyl” and “Ci-2alkyl” are to be construed accordingly. A “Ci-6alkylene”, Ci-₄alkylene” or “Ci-2alkylene” group refers to the corresponding definition of Ci-ealkyl, Ci-₄alkyl or Ci-2alkyl, respectively, except that such radical is attached to the rest of the molecule by two single bonds. Examples of C i-ealkyl include, but are not limited to, methyl, ethyl, iso-propyl, n-propyl and tert-butyl.

Very good results have been obtained when the process of the invention is carried out in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride in an amount of from 1.0 to 2.0 molar equivalents relative to 1 mole of compound of formula (II), preferably in an amount of from 1 .0 to 1 .5 molar equivalents relative to 1 mole of compound of formula (II). The process of the invention is advantageously carried out at a temperature of from 0°C to 50°C, preferably of from 0°C to 40°C, more preferably of from 0°C to 25°C. Very good results have been obtained when the process of the invention is carried out at a temperature of 25°C.

The process of the invention is usually carried out at a pressure from 1 atm to 5 atm.

Typical reaction times are usually in the range from 6 to 24 hours. Very good results have been obtained when the process of the invention is carried out at reaction times in the range from 16 to 20 hours.

A reaction mixture is generally obtained from the process of the invention.

The process of the invention typically further comprises the step of isolating the compound of formula (I) using an aqueous medium. The compound of formula (I) is advantageously isolated from the reaction mixture using an aqueous medium, typically by an extractive work-up. Further purification can be obtained, for example, by crystallization, distillation or chromatography.

The compounds of formula (I) can be made by the process of the invention as shown in the following Schemes 1 to 8, in which, unless otherwise stated, the definition of each variable is as defined above for any of compounds of formulae (I), (II) and (III).

The designations of R¹ with reference to the compounds of formula (I) apply generally to the compounds of any of formulae (II) and (IV).

The designations of R² with reference to the compounds of formula (III) apply generally to the compounds of any of formulae (lll-a) and (lll-b).

The designations of R³ with reference to the compounds of formula (lll-b) apply generally to the compounds of any of formulae (IV), (IV-A) and (V-b).

The designations of X with reference to the compounds of formula (III) apply generally to the compounds of formula (V).

The compound of formula (II) is commercially available and can be prepared in analogy to methods described in WO 97/03969.

According to one embodiment, the process of the invention may further comprise reacting a compound of formula (V), wherein X is -NH(CH3) or -OR³, wherein R³ is Ci-ealkyl, preferably methyl, with a halogenating agent, such as thionyl chloride orthionyl bromide, or a sulfonylating agent, such as methanesulfonyl chloride, to provide a compound of formula (III). Preferably, the process of the invention may further comprise reacting the (Z,2E)-isomer of the compound of formula (V) with a halogenating agent, such as thionyl chloride or thionyl bromide, or a sulfonylating agent, such as methanesulfonyl chloride, to provide the (Z,2E)-isomer of the compound of formula (III). This reaction is shown in Scheme 1.

Scheme 1

According to one embodiment of the process of the invention, the compound of formula (lll-a) can be obtained by reaction of a compound of formula (V), wherein X is -NH(CH3), hereinafter referred to as compound of formula (V-a), with a halogenating agent, such as thionyl chloride or thionyl bromide, or a sulfonylating agent, such as methanesulfonyl chloride. Preferably, the (Z,2E)-isomer of the compound of formula (V-a) is used in the process of the invention to provide the (Z,2E)-isomer of the compound of formula (lll-a). This reaction is shown in Scheme 2.

Scheme 2 According to another embodiment of the process of the invention, the compound of formula (lll-b) can be obtained by reaction of a compound of formula (V), wherein X is -OR³, wherein R³ is Ci-ealkyl, preferably methyl, hereinafter referred to as compound of formula (V-b), with a halogenating agent, such as thionyl chloride or thionyl bromide, or a sulfonylating agent, such as methanesulfonyl chloride. Preferably, the (Z,2E)-isomer of the compound of formula (V-b) is used in the process of the invention to provide the (Z,2E)-isomer of the compound of formula (lll-b). This reaction is shown in Scheme 3.

Scheme 3 The compound of formula (V-a) can be obtained by reaction of a compound of formula (VI) with methylamine. This reaction is shown in Scheme 4.

Scheme 4

According to one embodiment of the process of the invention, the (Z,2E)-isomer of the compound of formula (V-a) can be obtained by reaction of the (5E)-isomer of the compound of formula (VI) with methylamine.

The compound of formula (V-b) can be obtained by reaction of a compound of formula (VI) with an aliphatic alcohol, typically with a C1-C6 aliphatic alcohol, preferably methanol. This reaction is shown in Scheme 5.

Scheme 5

According to one embodiment of the process of the invention, the (Z,2E)-isomer of the compound of formula (V-b) can be obtained by reaction of the (5£)-isomer of the compound of formula (VI) with a Ci-Ce aliphatic alcohol, preferably methanol.

The compound of formula (VI) can be obtained by reaction of a compound of formula (VII) with a halogenating agent, such as N-bromosuccinimide, in the presence of benzoyl peroxide, followed by reaction with a dehydrohalogenating agent, such as lithium carbonate. This reaction is shown in Scheme 6.

Scheme 6 According to one embodiment of the process of the invention, the (5E)-isomer of the compound of formula (VI) can be obtained by reaction of the (3E)-isomer of the compound of formula (VII) with a halogenating agent, such as N-bromosuccinimide, in the presence of benzoyl peroxide, followed by reaction with a dehydrohalogenating agent, such as lithium carbonate.

The compound of formula (VII) can be obtained by reaction of a compound of formula (VIII) with tert-butyl nitrite followed by reaction with potassium tert-butoxide. Usually, a mixture of (E)/(Z)-isomers of compounds of formula (VII) is obtained. Also, a tautomer of the compound of formula (VII), hereinafter referred to as compound of formula (Vll-a), is usually obtained by reaction of a compound of formula (VIII) with tert-butyl nitrite followed by reaction with potassium tert-butoxide. This reaction is shown in Scheme 7.

Scheme 7

According to one embodiment of the process of the invention, the (3E)-isomer of the compound of formula (VII) can be obtained by reaction of the compound of formula (Vll-a) with O- methylhydroxylamine hydrochloride. This reaction is shown in Scheme 8.

Scheme 8

The compound of formula (VIII) is commercially available and can be prepared in analogy to methods described in R. Achini et al. Helvetica Chimica Acta 1968, 51, 1702-1712. EXAMPLES

Preparation examples

The Examples which follow serve to illustrate the invention. The compounds of formula (I) may be prepared according to the synthetic techniques described above. Example 1 : This example illustrates the preparation of (Z,2E)-5-[1-(2,4-dichlorophenyl)pyrazol-3-yl]oxy- 2-methoxyimino-N,3-dimethyl-pent-3-enamide (Compound I. a).

Step 1 : Preparation of 4-methyltetrahydropyran-2-one.

To a 250 ml 3-necked reaction flask equipped with a continuous flow of nitrogen, thermometer and dropping funnel was added a stirred suspension of sodium borohydride (3.3660 g, 88.972 mmol, 1 .1400) in tetrahydrofuran (15 ml_) cooled in an ice bath. To this suspension, a solution of 4- methyltetrahydropyran-2,6-dione (A, 10 g, 78.046 mmol, 100 mass%) in tetrahydrofuran (85 ml_) was then added dropwise. Effervescence was observed. The temperature was increased to 10°C. After complete addition, the reaction mixture was stirred at room temperature for 1 hour and then monitored by thin layer chromatography (TLC). The reaction mixture was then again cooled to 0°C and ethanol (32 g, 680 mmol, 8.8, 40 ml_) was added dropwise over a period of 20 minutes (strong effervescence was observed with hydrogen gas evolution, temperature increased to 15°C). After complete addition, the mixture was stirred for 15 minutes at 15°C. Hydrochloric acid (3N aq) (120 mmol, 1 .5376, 40 ml_) was added dropwise and the reaction mixture was then stirred at room temperature for 16 hours. The organic phase was then extracted with methyl tert-butyl ether (200ml). The organic layer was then washed with water (100 ml) followed by aqueous sodium bicarbonate (2 x 50 ml). The aqueous layer was again reextracted with ethyl acetate (200ml). The organic layers were then combined and washed with a brine solution, dried over anhydrous sodium sulphate and concentrated to give the crude compound. The crude product was purified by distillation. The product was then vacuum distilled at 120°C (internal temperature) with external temperature of 170°C and vacuum measured as 15 mbar to obtain the pure product as a colourless liquid.

1 H NMR (400 MHz, CDCI₃) d ppm 4.44 (td, J=11 .28, 4.33 Hz, 1 H) 4.28 (td, J=10.97, 3.73 Hz, 1 H) 2.70 (br d, J=11 .74 Hz, 1 H) 2.06 - 2.33 (m, 2 H) 1 .86 - 2.01 (m, 1 H) 1 .55 (td, J=9.69, 4.71 Hz, 1 H) 1 .09 (d, J=5.87 Hz, 3 H).

Step 2: Preparation of (3E)-3-methoxyimino-4-methyl-tetrahydropyran-2-one and N,4-dimethyl-2-oxo- tetrahydropyran-3-imine oxide.

In a 250 ml 3 necked round bottom flask equipped with a thermometer was added a stirred solution of 4-methyltetrahydropyran-2-one (1 g, 8.7612 mmol, 1.0000) in toluene (15 ml_). To this solutioin, tert- butyl nitrite (B, 2.3047 g, 21.903 mmol, 2.5000, 2.7 ml_) was added. The reaction mixture was then heated to 35°C and potassium tert-butoxide (1.5523 g, 13.142 mmol, 1.5000) was added carefully at 35°C in small portions over 15 minutes under stirring. The reaction mixture was then stirred for 2 hours at 35°C. The temperature was then increased to 40°C and iodomethane (3.8067 g, 26.284 mmol, 3.0000, 1 .67 ml_) was added dropwise. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was then quenched with 20 ml of cold 10% aqueous NaH₂PC>₄ solution and 0.014 ml of concentrated HCI, and then extracted with ethyl acetate (50 ml). The extracts were washed with 10% aqueous NaH₂PC>₄ solution (20ml) and then dried over sodium sulphate and concentrated to give the crude compound. The compound was then purified by Combiflash using 0-30% ethyl acetate in cyclohexane to give the pure product. A mixture containing N,4-dimethyl-2-oxo- tetrahydropyran-3-imine oxide, (3E)-3-methoxyimino-4-methyl-tetrahydropyran-2-one and (3Z)-3- methoxyimino-4-methyl-tetrahydropyran-2-one was obtained.

(3E)-3-methoxyimino-4-methyl-tetrahydropyran-2-one:

1 H-NMR (400 MHz, CDCb) d ppm 4.37 - 4.52 (m, 1 H) 4.18 - 4.32 (m, 1 H) 4.10 (s, 3 H) 3.23 - 3.38 (m, 1 H) 2.07 - 2.27 (m, 1 H) 1 .62 - 1 .80 (m, 1 H) 1 .23 (d, J=6.97 Hz, 3 H).

N,4-dimethyl-2-oxo-tetrahydropyran-3-imine oxide:

1 H-NMR (400 MHz, CDCIs) d ppm 4.31 - 4.51 (m, 1 H) 4.20 (s, 3 H) 3.28 - 3.46 (m, 1 H) 2.16 - 2.28 (m,

2 H) 1.64 - 1.92 (m, 1 H) 1.16 - 1.38 (m, 3 H).

Step 3: Preparation of (3E)-3-methoxyimino-4-methyl-tetrahydropyran-2-one.

To a stirred solution of N,4-dimethyl-2-oxo-tetrahydropyran-3-imine oxide (0.5 g, 3.1813 mmol, 1.0000) in N,N-dimethylformamide (4 ml_) was added O-methylhydroxylamine hydrochloride (0.5314 g, 6.3625 mmol, 2.0000) at room temperature. The reaction mixture was heated to 60°C for 3 hours. The reaction mixture was then cooled to room temperature and quenched with 10 ml of 10% aqueous NaH₂PC>₄ solution. The contents were transferred into a separating funnel and the organic layer was extracted using ethyl acetate (3 x 20ml). The combined organic layers were washed with a brine solution, dried over sodium sulphate, filtered and evaporated to give the crude product in quantitative yield. The crude compound was analysed and taken as such for the next step.

Step 4: Preparation of (5E)-5-methoxyimino-4-methyl-2H-pyran-6-one.

In a 3-necked reaction flask, to a solution of (3£)-3-methoxyimino-4-methyl-tetrahydropyran-2-one (220 mg, 1.3998 mmol) in ethyl acetate (7.7 ml_) was added N-bromosuccinimide (1.1 equiv., 1.5397 mmol), followed by addition of benzoyl peroxide (0.1 equiv., 0.13998 mmol) . The reaction mixture was heated to 65 °C for 1.5 hours. Reaction was monitored by liquid chromatography/mass spectrometry (LC/MS) and TLC. The reaction mixture was cooled to room temperature and N,N-dimethylformamide (5.5 ml_) was added followed by lithium carbonate (0.6268 g, 8.3985 mmol). The reaction mixture was heated to 65°C for 2 hours. The reaction mixture was maintained at 65°C overnight. The mixture was cooled down to room temperature, it was filtered and washed with ethyl acetate (25 ml). The organic layer was washed with 30% solution of lithium chloride in water (3 x 10 ml). The lithium chloride phase was extracted again with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulphate and concentrated to give the crude product. The crude product was taken as such for the next step. Step 5: Preparation of (Z,2E)-5-hydroxy-2-methoxyimino-N,3-dimethyl-pent-3-enamide.

A solution of (5E)-5-methoxyimino-4-methyl-2H-pyran-6-one (250 mg, 1 .6113 mmol) in tetrahydrofuran (2.2 g, 30 mmol) was treated with methylamine (40% aqueous) (1 .0009 g, 12.891 mmol, 8.0000, 1 .0009 ml_) and the reaction mixture was stirred at room temperature for 16 hours. The solvents were then evaporated on the rotavapor inside fumehood and then the compound was purified by Combiflash using 15-60% ethyl acetate in cyclohexane to obtain pure (Z,2E)-5-hydroxy-2-methoxyimino-N,3-dimethyl- pent-3-enamide as a pale yellow oil.

1 H NMR (400 MHz, CDCb) d ppm 8.02 (s, 1 H) 6.82 (br s, 1 H) 5.92 (br d, J=1.47 Hz, 1 H) 3.98 (s, 3 H) 3.80 (d, J=7.70 Hz, 2 H) 2.97 (s, 3 H) 1 .86 - 1 .89 (m, 3 H).

Step 6: Preparation of (Z,2E)-5-chloro-2-methoxyimino-N,3-dimethyl-pent-3-enamide.

(Z,2E)-5-hydroxy-2-methoxyimino-N,3-dimethyl-pent-3-enamide (50 mg, 0.26851 mmol) was dissolved in dichloromethane (1 ml_). Triethylamine (0.0410 g, 0.40277 mmol, 1.5000, 0.0564 ml_) was then added followed by thionyl chloride (0.0771 g, 0.64443 mmol, 0.0472 ml_) dissolved in (0.5 ml) of dichloromethane at 0°C, and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated on rotavapor. The residue was then diluted with ethyl acetate (10 ml) and then carefully quenched with saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (2 x 10 ml). The organic layers were combined and washed with saturated sodium bicarbonate solution (10 ml) and water followed by brine and then dried over sodium sulphate and then concentrated to give the desired product (Z,2E)-5- chloro-2-methoxyimino-N,3-dimethyl-pent-3-enamide as a brown oil.

1 H NMR (400 MHz, CDCIs) d ppm 6.69 (br s, 1 H) 5.77 - 5.83 (m, 1 H) 3.99 (s, 3 H) 3.83 (d, J=7.70 Hz, 2 H) 2.91 (d, J=5.14 Hz, 3 H) 1 .90 - 1 .94 (m, 3 H).

Step 7: Preparation of (Z,2£)-5-[1-(2,4-dichlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-N,3-dimethyl- pent-3-enamide (Compound I. a).

In a 25 ml 2 neck round bottom flask, sodium hydride (60 mass% in oil) (0.0073337 g, 0.18336 mmol) was added to a solution of 2-(2,4-dichlorophenyl)-1 H-pyrazol-5-one (0.028 g, 0.12224 mmol) in N,N- dimethylformamide (0.30 mL) at 0°C. The resulting reaction mixture was stirred for 45 mins at room temperature. A solution of (Z,2£)-5-chloro-2-methoxyimino-N,3-dimethyl-pent-3-enamide (0.030 g, 0.14669 mmol) dissolved in N,N-dimethylformamide (0.3 mL) was then added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with aqueous ammonium chloride (3 ml) and extracted with ethyl acetate (3 X 10mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum. The compound was purified by Combiflash using 0-30% ethyl acetate in cyclohexane to obtain (Z,2£)-5-[1-(2,4-dichlorophenyl)pyrazol- 3-yl]oxy-2-methoxyimino-N,3-dimethyl-pent-3-enamide (Compound I. a).

1 H NMR (400 MHz, CDCb) d ppm 7.71 (d, J=2.69 Hz, 1 H) 7.46 - 7.57 (m, 2 H) 7.27 - 7.38 (m, 1 H) 6.71-6.72 (m, 1 H) 5.94 (m, 1 H) 5.90 (s, 1 H) 4.55 (dd, J=6.48, 1.10 Hz, 2 H) 3.96 (s, 3 H) 2.85 (d, J=5.01 Hz, 3 H) 1 .95 (d, J=1 .22 Hz, 3 H).

Claims

CLAIMS:

1 . A process for the preparation of a compound of formula (I):

(I wherein R¹ is hydrogen or halogen, said process comprising reacting a compound of formula (II):

wherein R¹ is hydrogen or halogen, with a compound of formula (III):

wherein

R² is halogen or a sulfonic acid ester, and X is -NH(CH3) or -OR³, wherein R³ is Ci-ealkyl, said process being carried out in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride.

2. The process according to claim 1 , said process comprising reacting a compound of formula (II):

wherein R¹ is hydrogen or halogen, with a compound of formula (lll-a):

3. The process according to claim 1 , said process comprising:

(a) reacting a compound of formula (II):

wherein R¹ is hydrogen or halogen, with a compound of formula (lll-b): wherein

R² is halogen or a sulfonic acid ester, and

R³ is Ci-6alkyl, in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride, to provide a compound of formula (IV):

wherein

R¹ is hydrogen or halogen, and

R³ is Ci-6alkyl, and

4. The process according to any one of claims 1 to 3, wherein R¹ in the compound of formula (II) is halogen, preferably chloro.

5. The process according to any one of claims 1 to 4, wherein the (Z,2E)-isomer of the compound of formula (III) is used.

6. The process according to any one of claims 1 to 5, said process being carried out in in the presence of one or more bases selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydride, preferably in an amount of from 1 .0 to 2.0 molar equivalents relative to 1 mole of compound of formula (II).

7. The process according to any one of claims 1 to 6, said process being carried out in the presence of at least one solvent; optionally at least one solvent selected from ketones such as acetone and ethyl methyl ketone, nitriles, aromatic hydrocarbons such as toluene and o-, m- and p-xylene, ethers such as dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone; preferably at least one solvent selected from toluene, dioxane, tetrahydrofuran and N,N-dimethylformamide; more preferably N,N- dimethylformamide.

8. The process according to claim 1 , said process further comprising reacting a compound of formula (V), wherein X is -NH(CH3) or -OR³, wherein R³ is Ci-ealkyl, with a halogenating agent or a sulfonylating agent to provide a compound of formula (III):

9. The process according to claim 8, said process comprising reacting the (Z,2E)-isomer of the compound of formula (V) to provide the (Z,2E)-isomer of the compound of formula (III).

10. The process according to claim 8 or claim 9, wherein X in the compound of formula (V) is -NH(CH3).

11 . The process according to claim 10, wherein a compound of formula (VI) is reacted with methylamine to provide a compound of formula (V-a):

12. The process according to claim 8 or claim 9, wherein X in the compound of formula (V) is -OR³, wherein R³ is Ci-ealkyl.

13. The process according to claim 12, wherein a compound of formula (VI) is reacted with a C1-C6 aliphatic alcohol to provide a compound of formula (V-b):

14. The process according to any one of claims 8 to 13, said process further comprising reacting a compound of formula (VII) with a halogenating agent, in the presence of benzoyl peroxide, followed by reaction with a dehydrohalogenating agent to provide the compound of formula (VI):

15. The process according to claim 14, said process comprising reacting the (3E)-isomer of the compound of formula (VII) to provide the (5E)-isomer of the compound of formula (VI).