Process for the preparation of 5,6-dihydro-4h-1,2,4-oxadiazine derivatives

Abstract

The present invention relates to a process for the preparation of 5,6-dihydro-4H-1,2,4- oxadiazine derivatives suitable for use, e.g., as active ingredients, which have microbiocidal activity, in particular, fungicidal activity.

Description

[0001] Process for the preparation of 5,6-dihydro-4H-l,2,4-oxadiazine derivatives

[0002] The present invention relates to a process for the preparation of 5,6-dihydro-4H-l,2,4- oxadiazine derivatives suitable for use, e.g., as active ingredients, which have microbiocidal activity, in particular, fungicidal activity.

[0003] The preparation of 5,6-dihydro-4H-l,2,4-oxadiazine derivatives is described for isntnance in in WO-A- 2020 / 127780 and in WO-A-2021 / 255070. The process disclosed in these publications involves a dehydrative cyclization of N-(2-aminooxyethyl)carboxamide derivatives. This process step is disadvantageously carried out with phosphorus oxychloride, phosphorus pentoxide or triflic anhydride as dehydrating agents, requiring drastic conditions and quenching of the strongly acidic reaction mixture with a base. These conditions as well as the quenching however are leading to the formation of undesired side products, and a low yield of the desired 5,6-dihydro-4H-l,2,4-oxadiazine derivatives.

[0004] Surprisingly, it has been now found that the process of the invention can be advantageously carried out with a trialkylsilylphosphate, which allows to perform the dehydration step at much milder conditions as those required for the reagents disclosed in WO-A-2020 / 127780 and WO-A-2021 / 255070, in particular phosphorus oxychloride, phosphorus pentoxide, or triflic anhydride.

[0005] According to the present disclosure, there is provided a process for the preparation of a compound of formula (I): wherein R1represents halogen, Ci-Csa Ikyl or Cs-Cscycloalkyl, R2represents halogen and R3and R4each independently represent halogen or Ci-Csalkyl, the process comprising reacting a compound of formula (II): wherein R1, R2, R3and R4are as set out above for the compound of formula (I) herein above, with a trialkylsilylphosphate.

[0006] Preferably, the present invention relates to a process for the preparation of a compound of formula (I): wherein R1represents halogen or Cs-Cscycloalkyl, R2represents fluoro or chloro and R3and R4each independently represent halogen or methyl, the process comprising reacting a compound of formula (II): wherein R1represents halogen or Cs-Cscycloalkyl, R2represents fluoro or chloro and R3and R4each independently represent halogen or methyl, with a trialkylsilylphosphate.

[0007] More preferably, the present invention relates to a process for the preparation of a compound of formula (I): wherein R1represents chloro or cyclopropyl, R2represents fluoro and R3and R4each independently represent chloro, bromo or methyl, the process comprising reacting a compound of formula (II), wherein R1represents chloro or cyclopropyl, R2represents fluoro and R3and R4each independently represent chloro, bromo or methyl, with a trialkylsilylphosphate.

[0008] 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 such as acetonitrile, chlorinated hydrocarbons such as dichloromethane, chloroform and dichloroethane, aromatic hydrocarbons such as toluene and o-, m- and p-xylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, but also solvents such as 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 dichloromethane, chloroform or 1,2-dichloroethane, more preferably in the presence of 1,2-dichloroethane. Preferably, hence the dehrydration and ring closure reaction it carried out in in the presence of dichloromethane, chloroform or 1,2-dichloroethane, preferably in the presence of 1,2-dichloroethane.

[0009] 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. The novel 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.

[0010] 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.

[0011] 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.

[0012] Accordingly, the present invention also relates to the use of a isolated, or isolated and purified compound (I) fraction obtained according to the process, as a microbiocidally active, in particular, fungicida lly active ingredient in an agrochemical composition.

[0013] 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.

[0014] 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

[0015] (chloro), bromine (bromo) or iodine (iodo), preferably fluorine, chlorine or bromine.

[0016] As used herein, the term "Ci-Csalkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to three carbon atoms, and which is attached to the rest of the molecule by a single bond. Examples of Ci-Csa I kyl include, but are not limited to, methyl, ethyl, n-propyl and n-propyl.

[0017] As used herein, the term "Cs-Cscycloalkyl" refers to a hydrocarbon ring consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from three to five carbon atoms, and which is attached to the rest of the molecule by a single bond. Examples of Cs-Cscycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl and cyclopentyl.

[0018] Examples of suitable trialkylsilylphosphates are tris(trimethylsilyl)phosphate, tris(triethylsilyl)phosphate, tris(tert-butyldimethylsilyl)phosphate and trimethylsilyl polyphosphate. Accordingly, in the process of the invention, advantageously the trialkylsilylphosphate is selected from tris(trimethylsilyl)phosphate, tris(triethylsilyl)- phosphate, tris(tert-butyldimethylsilyl)phosphate and trimethylsilyl polyphosphate, or mixtures thereof.

[0019] The process of the invention is advantageously carried out at a temperature of from 0°C to 180°C, preferably of from 80°C to 160°C, more preferably of from 100°C to 140°C. Very good results have been obtained when the process of the invention is carried out at a temperature of 140°C. Accordingly, the present reaction is carried out at a temperature in the range of from 0°C to 180°C, more preferably at a temprater in the range of from 100°C to 140°C.

[0020] The process of the invention is usually carried out at a pressure from 1 atm to 5 atm. Atmosphere (atm) herein refers to a unit of pressure, whrerein one atmosphere (1 atm) is defined as the average atmospheric pressure at sea level, or 101,325 pascals (Pa). While any useful checmialr eactor may be applied that allows for heating and sa suseful movement of the reaction components, preferably, the process of the invention is carried out in a microwave reactor.

[0021] The process of the invention advantageously further comprises one or more steps of isolating the compound (I) from the reaction mixture. Preferably, isolating the compound (I) comprises cooling and quenching of the reaction mixture with a saturated aqueous sodium bicarbonate solution, followed by separation of an organic layer comprising the desired product from an aqueous layer, and optionally, washing, and drying of the isolated compound (I) fraction.

[0022] The process of the invention advantageously further comprises one or more purification steps, to obtain the isolated and purified compound (I) fraction. Accordingly, preferably, the process according to the invention further comprising formulating the isolated, or the isolated and purified compound (I) fraction into an agrochemical composition.

[0023] The compounds of formula (II), wherein R1, R2, R3and R4are as defined for formula (I), can be prepared by reaction of a compound of formula (III), wherein R1, R2, R3and R4are as defined for formula (I), with hydrazine hydrate or a similar phthalimide deprotection agent. This is shown in Scheme 1 below.

[0024] Scheme 1

[0025] The compounds of formula (III), wherein R1, R2, R3and R4are as defined for formula (I), can be prepared by reaction of a compound of formula (IV), wherein R1and R2are as defined for formula (I) and R5is halogen, hydroxy or Ci-Cealkyl, with a compound of formula (V), wherein R3and R4are as defined for formula (I), and a base or a peptide coupling reagent. This is shown in Scheme 2 below.

[0026] Scheme 2

[0027] The compounds of formula (V), wherein R3and R4are as defined for formula (I), can be prepared by reaction of a compound of formula (VI), wherein R3and R4are as defined for formula (I) and R6is Ci-Cea Ikyl, with trifluoroacetic acid or a similar carbamate deprotection agent. This is shown in Scheme 3 below.

[0028] Scheme 3

[0029] The compounds of formula (VI), wherein R3and R4are as defined for formula (I) and R6is Ci-Cealkyl, can be prepared by reaction of a compound of formula (VII), wherein R3and R4are as defined for formula (I) and R6is Ci-Cealkyl, with N-hydroxyphthalimide, triphenylphosphine and an azodicarboxylate under conditions of the Mitsunobu reaction. This is shown in Scheme 4 below. Scheme 4

[0030] The compounds of formula (VII), wherein R3and R4are as defined for formula (I) and R6is Ci-Cealkyl, can be prepared by reaction of a compound of formula (VIII), wherein R3and R4are as defined for formula (I) and both R6and R7are Ci-Cea I kyl, with a reducing agent, such as sodium borohydride. This is shown in Scheme 5 below.

[0031] Scheme 5

[0032] The compounds of formula (VIII), wherein R3and R4are as defined for formula (I) and both R6and R7are Ci-Cea I kyl, can be prepared by reaction of a compound of formula (IX), wherein R3and R4are as defined for formula (I) and R7is Ci-Cealkyl, with di-tert-butyl decarbonate and a base. This is shown in Scheme 6 below.

[0033] Scheme 6 EXAMPLES

[0034] Preparation examples

[0035] The Examples which follow serve to illustrate the invention. The compounds of formula (I) may be prepared according to the synthetic techniques described above.

[0036] Example 1: This example illustrates the preparation of 5-[(4-bromo-2-methyl- phenyl)methyl]-3-[3-(3-chloro-2-fluoro-phenoxy)-6-methyl-pyridazin-4-yl]-5,6-dihydro-4H- 1,2,4-oxadiazine

[0037] Step 1: Preparation of N-[l-(aminooxymethyl)-2-(4-bromo-2-methyl-phenyl)ethyl]-3- (3-chloro-2-fluoro-phenoxy)-6-methyl-pyridazine-4-carboxamide

[0038] To a solution of N-[l-[(4-bromo-2-methyl-phenyl)methyl]-2-(l,3-dioxoisoindolin-2- yl)oxy-ethyl]-3-(3-chloro-2-fluoro-phenoxy)-6-methyl-pyridazine-4-carboxamide (500 mg, 0.76 mmol) in tetrahydrofuran (3.8 mL) was added hydrazine hydrate (0.05742 g, 1.15 mmol). The reaction mixture was stirred at RT for 10 min. Reaction mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL) and the combined organic layer was washed with water (2 x 10 ml), dried over sodium sulfate and concentrated in vacuo. The crude N-[l-(aminooxymethyl)-2-(4- bromo-2-methyl-phenyl)ethyl]-3-(3-chloro-2-fluoro-phenoxy)-6-methyl-pyridazine-4- carboxamide was used directly in the next step without purification.

[0039] LCMS (m / z): 523.0 (M+H+)

[0040] Step 2: Preparation of 5-[(4-bromo-2-methyl-phenyl)methyl]-3-[3-(3-chloro-2-fluoro- phenoxy)-6-methyl-pyridazin-4-yl]-5,6-dihydro-4H-l,2,4-oxadiazine

[0041] To a stirred solution of N-[l-(aminooxymethyl)-2-(4-bromo-2-methyl-phenyl)ethyl]-3-(3- chloro-2-fluoro-phenoxy)-6-methyl-pyridazine-4-carboxamide (420 mg, 0.80 mmol, 100 mass%, 420 mg) in 1,2-dichloroethane (4.2 mL) was added tris(trimethylsilyl)phosphate (4 equiv., 3.21 mmol, 98.0 mass%, 1.07 mL) at rt. The resulting reaction mixture was stirred at 140 °C for 1 h in an Anton Paar Microwave reactor. The reaction mixture was cooled and quenched with saturated aqueous sodium bicarbonate solution (5 mL). Then DCE layer was separated, and the aqueous layer extracted with EtOAc (20 ml x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by normal phase chromatography column on a neutral alumina column. 5-[(4-bromo-2-methyl-phenyl)methyl]-3-[3-(3-chloro-2-fluoro-phenoxy)-6-methyl-pyridazin- 4-yl]-5,6-dihydro-4H-l,2,4-oxadiazine was obtained as a white fluffy solid

[0042] XH NMR (400 MHz, CDCI3) 6 ppm 7.97 (s, 1H), 7.37 (t, 1H, J=7.0 Hz), 7.2-7.2 (m, 1H),

[0043] 7.1-7.1 (m, 1H), 7.03 (d, 1H, J=1.9 Hz), 6.09 (br s, 1H), 4.19 (s, 1H), 3.87 (br d, 1H, J=9.4 Hz), 2.9-3.0 (m, 1H), 2.8-2.8 (m, 1H), 2.81 (s, 1H), 2.7-2.8 (m, 1H), 2.7-2.8 (m, 1H), 2.67 (NH s, 3H), 2.30 (s, 3H).

[0044] Example 2: This example illustrates the preparation of 3-[3-(3-cyclopropyl-2-fluoro- phenoxy)-6-methyl-pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H-l,2,4- oxadiazine

[0045] To a stirred solution of N-[l-(aminooxymethyl)-2-(2,4-dimethylphenyl)ethyl]-3-(3- cyclopropyl-2-fluoro-phenoxy)-6-methyl-pyridazine-4-carboxamide (310 mg, 0.67 mmol) in

[0046] 1.2-dichloroethane (3.1 mL) was added tris(tri methylsi lyl) phosphate (0.89 mL, 2.67 mmol) at rt. The resulting reaction mixture was stirred at 140 °C for 1 h in an Anton Paar Microwave reactor. The reaction mixture was cooled and quenched with saturated aqueous sodium bicarbonate solution (5 mL). Then DCE layer was separated and the aqueous layer extracted with EtOAc (20 ml x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by normal phase chromatography column on a neutral alumina column. 3-[3-(3-cyclopropyl-2- fluoro-phenoxy)-6-methyl-pyridazin-4-yl]-5-[(2,4-dimethylphenyl)methyl]-5,6-dihydro-4H- 1,2,4-oxadiazine was obtained as a yellow gummy mass.

[0047] TH NMR (400 MHz, CDCI3) 6 ppm 7.9-8.0 (m, 1H), 7.0-7.1 (m, 1H), 6.9-7.0 (m, 2H),

[0048] 6.9-6.9 (m, 1H), 6.8-6.8 (m, 1H), 6.6-6.7 (m, 1H), 6.2-6.3 (m, 1H), 4.2-43 (m, 1H), 3.83.9 (m, 1H), 2.9-3.0 (m, 1H), 2.7-2.8 (m, 1H), 2.6-2.7 (m, 3H), 2.3-23 (m, 3H), 2.1-2.2 (m, 3H), 2.0-2.1 (m, 1H), 1.0-1.1 (m, 2H), 0.7-0.8 (m, 2H).

Claims

CLAIMS1. A process for the preparation of a compound of formula (I):wherein R1represents halogen, Ci-Csa Ikyl or Cs-Cscycloalkyl, R2represents halogen and R3and R4independently from each other represent halogen or Ci-Csa I kyl. comprising reacting a compound of formula (II):wherein R1to R4are as set out above for formula (I), with a trialkylsilylphosphate.

2. The process according to claim 1, wherein a compound of formula(II):wherein R1represents halogen or Cs-Cscycloalkyl, R2represents fluoro or chloro, and R3and R4each independently represent halogen or methyl, is reacted with a trialkylsilylphosphate.

3. The process according to claim 1, wherein a compound of formula(II):wherein R1is chloro or cyclopropyl, R2is fluoro and R3and R4each independently represent chloro, bromo or methyl, is reacted with a trialkylsilylphosphate.

4. The process according to any one of claims 1 to 3, further comprising isolating the compound (I) from the reaction mixture.

5. The process according to any one of claims 1 to 4 , wherein isolating the compound (I) comprises cooling and quenching of the reaction mixture with a saturated aqueous sodium bicarbonate solution, followed by separation of an organic layer comprising the desired product from an aqueous layer, and optionally, washing, and drying of the isolated compound (I) fraction.

6. The process according to claim 5, further comprising and a purification step, to obtain the isolated and purified compound (I) fraction.

7. The process according to any one of claims 1 to 6, wherein the trialkylsilylphosphate is selected from tris(trimethylsilyl)phosphate, tris(triethylsilyl)phosphate, tris(tert- butyldimethylsilyl)phosphate and trimethylsilyl polyphosphate, or mixtures thereof.

8. The process according to any one of claims 1 to 7, wherein the reaction is carried out at a temperature in the range of from 0°C to 180°C.

9. The process according to claim 8, wherein the reaction is carried out at a temperature in the range of from 100°C to 140°C.

10. The process according to any one of the previous claims, wherein the reaction is carried out at a pressure in the range of from 1 atm to 5 atm.

11. The process according to any one of the previous claims, wherein the reaction it carried out in in the presence of dichloromethane, chloroform or 1,2-dichloroethane, preferably in the presence of 1,2-dichloroethane.

12. The process according to any one of the previous claims, wherein the reaction is carried out in a microwave reactor.

13. The process according to any one of the previous claims, further comprising formulating the isolated, or the isolated and purified compound (I) fraction into a agrochemical composition.

14. Use of a isolated and purified compound (I) fraction obtained according to the process of any one of claims 1 to 12, or a composition obtained according to the process of claim 13, as an as a microbiocidally active, in particular, fungicidally active ingredient in an agrochemical composition.

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