Preparation of propan-2-imine-substituted phenyls / oxime ethers

Abstract

Process for the preparation of propan-2-imine-substituted phenyls / oxime ethers, in particular to the preparation of 1-(2,4,6-trichlorophenyl)-propan-2-one oxime and N-methoxy-1-(2,4,6-trichlorophenyl)- propan-2-imine.

Description

[0001] NEW PROCESS

[0002] The present invention relates to a process for the preparation of propan-2-imine-substituted phenyls / oxime ethers, in particular to the preparation of 1-(2,4,6-trichlorophenyl)-propan-2-one oxime and N-methoxy-1-(2,4,6-trichlorophenyl)-propan-2-imine.

[0003] Fungicides for use in crop protection are produced on a very large scale, e.g. thousands of tons per year. Given the scale on which fungicides are produced, any improvement in the production process can represent significant cost savings.

[0004] N-methoxy-1-(2,4,6-trichlorophenyl)-propan-2-imine (Compound VII) is a valuable intermediate for the preparation of pydiflumetofen (Compound (I)), as described for example in WO 2010 / 063700. The synthesis Compound (VII) from Compound (V) is known from WO 2013 / 127764, and shown below in Scheme 1 .

[0005] Scheme 1

[0006] However, the process route above utilises the raw material, methoxyamine hydrochloride (Compound (VI)), the synthesis of which is complex, usually comprising four steps to make, and produces a large amount of aqueous waste, which can be both expensive to handle and difficult to dispose of. The synthesis of methoxyamine hydrochloride is known from CN115490611 and WO 2022 / 1267926.

[0007] Aqueous waste streams can have a serious impact on the environment as they can often contain various organic and inorganic compounds, byproducts, and residues that can be harmful to the environment if not properly treated or disposed of. These waste streams may also contain toxic substances, heavy metals, or other pollutants that can contaminate water bodies, soil, and ecosystems if released untreated. As such, the treatment of aqueous waste streams to minimize harm to the environment can be very expensive as it often requires specialized equipment, chemicals, and processes. Further to this, the generation of excessive aqueous waste raises serious sustainability concerns, as the energy consumption and greenhouse gas emissions associated with the treatment and disposal of aqueous waste can contribute to the overall environmental footprint of the manufacturing process.

[0008] As such, addressing the issues associated with large volumes of aqueous waste is crucial for maintaining environmental compliance, minimizing environmental impact, and promoting sustainable and efficient manufacturing processes in the agrochemical and chemical industries. Further to this, methoxyamine hydrochloride is known to be very toxic to aquatic life.

[0009] The aim of the present invention is therefore to provide a novel process for the production of 1 -(2,4,6- trichlorophenyl)propan-2-one oxime (Compound XI) and N-methoxy-1-(2,4,6-trichlorophenyl)propan-2- imine (Compound VII) that avoids the disadvantages of the known process, and makes it possible to prepare N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine in high yields, and good quality in an economically advantageous way, and with improved selectivity.

[0010] Thus, according to the present invention, there is provided a process for the preparation of Compound (VII): said process comprising a) reacting Compound (V): with hydroxylamine or a salt thereof, in the presence of a solvent and a base, to form Compound (XI):

[0011] (XI), and b) reacting Compound (XI) with a methylating agent, in the presence of a solvent and a base, to form Compound (VII).

[0012] There is further provided a process for the preparation of Compound (I): said process comprising a) reacting Compound (V): with hydroxylamine or a salt thereof, in the presence of a solvent and a base, to form Compound (XI):

[0013] (XI); b) reacting Compound (XI) with a methylating agent, in the presence of a solvent and a base, to form Compound (VII): c) reducing Compound (VII) to Compound (VIII): d) reacting Compound (VIII) with a compound of Formula (IX): wherein R* is halogen, hydroxy, Ci-Cealkoxy, Ci-Cealkylsulfanyl, Ci-Cealkylsulfinyl, Ci-Cealkylsulfonyl, phosphoryl, or other suitable leaving group, to form Compound (I).

[0014] The skilled person will appreciate that steps a), b), c) and d) outlined above could equally be represented in a single scheme, such as in Scheme 2 below:

[0015] Scheme 2

[0016] Step a)

[0017] Compound (V) is reacted with hydroxylamine or a salt thereof, in the presence of a solvent, to form Compound (XI). Hydroxylamine may be used as an aqeuous solution or as a hydroxylamine salt. Preferably, a hydroxylamine salt is used in step a). Suitable salts of hydroxylamine include, but are not limited to, hydroxylamine hydrochloride, zinc dichloride di(hydroxylamine), and hydroxylammonium hydrogen sulfate.

[0018] In a preferred embodiment, hydroxylamine hydrochloride is used in step a).

[0019] Suitable solvents for step a) are for example organic solvents such as alcohols, such as methanol, ethanol, iso-propanol, butanol, or n-propanol, ketones (for example acetone or methylethylketone) or nitriles (for example, acetonitrile), or water, or mixtures thereof. Preferred solvents include alcohol solvents or a mixture of an alcohol solvent and water.

[0020] In one embodiment, the solvent of step a) is methanol or a mixture of methanol and water.

[0021] Step a) is preferably carried out in the presence of a base. Suitbable bases include, but are not limted to, alkali metal hydroxides and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate; metal alkoxides such as sodium methoxide; basic alkaline earth salts such as calcium hydroxide, and calcium oxide; organic bases such as triethylamine, diisopropylethylamine, and di-isopropyl amine. Preferred bases include alkali metal hydroxides and metal alkoxides. Particularly preferred bases include, sodium hydroxide, potassium hydroxide and sodium methoxide.

[0022] Step b)

[0023] Compound (XI) is reacted with a methylating agent, in the presence of a solvent and a base, to form Compound (VII).

[0024] Suitbable methylating agents include, but are not limted to, dimethylsulfate, methyl chloride, dichloromethane, iodomethane, trimethylphosphate and dimethylcarbonate. In a preferred embodiment, the methylating agent is dimethylsulfate.

[0025] Suitbable solvents for step b) include, but are not limted to, alcohols, such as methanol, ethanol, isopropanol, butanol, or n-propanol; ethers, such as diethyl ether, tetrahydrofuran, and methyltetrahydrofuran; aromatic hydrocarbons, such as benzene, monochlorobenzene, toluene, and xylene; alkanes, such as hexane, heptane, and octane; cycloalkanes, such as cyclohexane; polar aprotic solvents such as dimethylformamide. Preferred solvents include, ethers, such as diethyl ether, tetrahydrofuran, and methyltetrahydrofuran, more preferably, methyltetrahydrofuran.

[0026] Suitbable bases for step b) include, but are not limted to, alkali metal hydroxides and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate; metal hydrides such as sodium hydride; metal alkoxides such as sodium methoxide; basic alkaline earth salts such as calcium hydroxide, and calcium oxide; organic bases such as triethylamine, diisopropylethylamine, and di-isopropyl amine. Preferred bases include alkali metal hydroxides and metal hydrides. Particularly preferred bases include sodium hydroxide and sodium hydride.

[0027] Step c)

[0028] As described in WO 2013 / 127764, Compound (VIII) may be obtained by reduction of Compound (VII) with number of known reducing agents, in particular by treatment with a borane reagent such as sodium cyanoborohydride, complexes of borane e.g. complexes of borane with organic amines, such as complexes of borane with triethylamine, trimethylamine, pyridine or 5-ethyl-2-methylpyridine. Preferably, the reduction of Compound (VII) to Compound (VIII) takes place in a suitable solvent such as an organic acid like acetic acid, or an organic alcohol like methanol, ethanol or isopropanol.

[0029] The reduction of Compound (VII) to Compound (VIII) optionally takes place in the presence of a strong acid, such as hydrogen chloride or sulfuric acid.

[0030] Compound (VIII) can also be prepared by hydrogenation of Compound (VII) in the presence of a catalyst containing a transition metal such at Pt in a suitable solvent and in the presence of at least 1 mol equivalent of a strong acid such as hydrogen chloride or sulfuric acid.

[0031] Preferably, the solvent is an organic alcohol like methanol, or acetic acid.

[0032] Preferably, the reaction is carried out at a temperature of -10 °C to 60 °C, preferably -10 °C to 30 °C. Preferably, the reaction is carried out under the pressure of hydrogen, preferably, at a hydrogen pressure of 0.5 barg to 100 barg, more preferably 1 barg to 30 barg, even more preferably, 1 barg to 10 barg, and more preferably still 2 barg to 10 barg, for example 8 barg to 9 barg.

[0033] Step d)

[0034] As described in WO 2013 / 127764, Compound (I) is prepared by reacting Compound (VIII) with a Compound of Formula (IX), wherein in a Compound of Formula (IX), R* is halogen, hydroxy, Ci- Cealkoxy, Ci-Cealkylsulfanyl, Ci-Cealkylsulfinyl, Ci-Cealkylsulfonyl, phosphoryl, or other suitable leaving group,

[0035] Preferably, R* is halogen, hydroxy or Ci-Cealkoxy. More preferably, R* is halogen, hydroxy or Ci- Csalkoxy. Even more preferably, R* is halogen, hydroxy, ethoxy or methoxy. More preferably still, R* is chloro, hydroxy, ethoxy, or methoxy. Most preferably, R* is chloro.

[0036] Preferably, the ratio of Compound (VIII) to Compound (IX) is about 1 :1 to 1 :1 .2.

[0037] The reaction is advantageously performed in an inert solvent in the presence of a base. Suitable solvents are for example dichloromethane, xylene (for example, xylene, either as a mix of isomers, or pure 1 ,2-, 1 ,3- or 1 ,4-xylene), toluene, ethylbenzene, or ethylacetate. Preferably the suitable solvent is xylene (either as a mix of isomers, or pure 1 ,2-, 1 ,3- or 1 ,4-xylene).

[0038] Suitable bases are for example sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine. Preferably, the base is selected from sodium hydroxide and triethylamine. The present invention will now be described by way of the following non-limiting examples. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

[0039] Abbreviations: AcOH = acetic acid, DMS = dimethyl sulfide, GC = gas chromatography, MeTHF = 2- methyltetrahydrofuran, TBAB = tetrabutylammonium bromide

[0040] EXAMPLES

[0041] Example 1 : Synthesis of 1-(2,4,6-trichlorophenyl)propan-2-one oxime (Compound (XI))

[0042] (V)

[0043] In a double jacket reactor, a 50%w / w solution of 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V), 66g, 1.0 equiv.) in methanol (66g) was prepared and heated to 70°C. An aqueous solution of hydroxylamine hydrochloride (30%, 73g, 1.15 equiv.) and a NaOH 25% aqueous solution (ca. 1.01 equiv., 45g) were dosed in parallel over 1 h by maintaining the temperature at 70°C and controlling the pH range between 4-5. After 30 min of post reaction, a precipitate is formed. After a 1 h post reaction at 70°C, the conversion of Compound (V) to Compound (XI) (E / Z or syn / trans) was checked by GC (Conv. > 99%). The reaction mixture was then cooled down to 25°C and the pH adjust to 8-9 by adding a NaOH 25% solution (ca. 5g). Once the pH was adjusted, the mixture was stirred over 30 min and the formed suspension filtrated. The obtained precipitate was washed with 66g of a cold solution of MeOH / H2O (1 :1) (pre-cooled at 5°C). The solid was then dried under vacuum overnight at 40°C affording 69-70g of Compound (XI) in 99.5% yield.

[0044] Example 2: Synthesis of N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine (Compound (VII))

[0045] In a double jacket reactor, a solution of 22%w / w of 1-(2,4,6-trichlorophenyl)propan-2-one oxime (Compound (XI), 70g, 1.0 equiv.) in 2-methyltetrahydrofuran (MeTHF, 238g) and 1g of tetrabutylammonium bromide (TBAB, 50% aq. solution, 0.006 equiv.) was prepared. To this solution was added a solution of NaOH 50%w / w (3.0 equiv.). The mixture was heated to 70°C. A solution of dimethylsulfate in MeTHF (50%w / w, 105g, 1 .5 equiv) was added to the solution in 2h. Then, a solution of NaOH 10% (174g) was added to dissolve the salts and quench the reaction. The mixture was settled, and the lower aqueous phase removed. The resulting organic layer was washed with an additional aliquot of a 10% NaOH solution. The upper organic phase was recovered and concentrated under vacuum afford a dark-orange oil (75.77g, 93.2 %, 0.42% Compound (V) I 91.80% Compound (VII) I 2.11 % Compound (XI)). Acetic acid was added affording a 43% w / w solution of Compound (VII) in AcOH, 92% yield.

[0046] Table 1 : Comparison of aqueous waste produced during the synthesis of Compound (VII) from

[0047] Compound (V) via Compound (VI) or Compound X):

[0048] *MAH = methoxyamine hydrochloride

[0049] As shown above in Table 1 , the route of the present invention which provides for the syntheis of Compound (VII) without the use of methoxyamine hydrochloride, creates less aqueous waste than routes known to use methoxyamine hydrochloride.

Claims

CLAIMS:1 . A process for the preparation of Compound (VII):said process comprising b) reacting Compound (V):with hydroxylamine or a salt thereof, in the presence of a solvent and a base, to form Compound (XI):(XI), and c) reacting Compound (XI) with a methylating agent, in the presence of a solvent and a base, to form Compound (VII).

2. The process according to claim 1 , wherein step a) utilises a hydroxylamine salt.

3. The process according to claim 1 or claim 2, wherein step a) utilises hydroxylamine hydrochloride.

4. The process according to any one of claims 1 to 3, wherein the solvent used in step a) is an alcohol solvent or a mixture of an alcohol solvent and water.

5. The process according to any one of claims 1 to 4, wherein the base used in step a) is an alkali metal hydroxide or metal alkoxide.- IQ -6. The process according to any one of claims 1 to 5, wherein the base used in step a) is sodium hydroxide, potassium hydroxide or sodium methoxide7. The process according to any one of claims 1 to 6, wherein the methylating agent of step b) is selected from dimethylsulfate, methyl chloride, dichloromethane, iodomethane, trimethylphosphate and dimethylcarbonate.

8. The process according to any one of claims 1 to 7, wherein the solvent used in step b) is selected from an alcohol, such as methanol, ethanol, iso-propanol, butanol, or n-propanol; an ether, such as diethyl ether, tetrahydrofuran, and methyltetrahydrofuran; an aromatic hydrocarbon, such as benzene, monochlorobenzene, toluene, and xylene; an alkane, such as hexane, heptane, and octane; a cycloalkane, such as cyclohexane; and a polar aprotic solvent such as dimethylformamide.

9. The process according to any one of claims 1 to 8, wherein the solvent used in step b) is an ether solvent.

10. The process according to any one of claims 1 to 9, wherein the base used in step b) is an alkali metal hydroxide or metal hydride.11 . A process process for the preparation of Compound (I):said process comprising d) reacting Compound (V):with hydroxylamine or a salt thereof, in the presence of a solvent and a base, to form Compound (XI):e) reacting Compound (XI) with a methylating agent, in the presence of a solvent and a base, to form Compound (VII):f) reducing Compound (VII) to Compound (VIII):d) reacting Compound (VIII) with a compound of Formula (IX):wherein R* is halogen, hydroxy, Ci-Cealkoxy, Ci-Cealkylsulfanyl, Ci-Cealkylsulfinyl, Ci-Cealkylsulfonyl, phosphoryl, or other suitable leaving group, to form Compound (I).

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