Chemical process for the production of pydiflumetofen

Abstract

The present invention relates to an improved process for the preparation of phenyl-substituted 3- difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-phenyl-ethyl]-amides, in particular, an improved process for the preparation of 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(RS)- 1-methyl-2-(2,4,6-trichlorophenyl)ethyl]-1H-pyrazole-4-carboxamide.

Description

[0001] 332305-FF

[0002] 1

[0003] CHEMICAL PROCESS FOR THE PRODUCTION OF PYDIFLUMETOFEN

[0004] The present invention relates to an improved process for the preparation of phenyl-substituted 3-difluoromethyl-1 -methyl- 1 H-pyrazole-4-carboxylic acid methoxy-[1 -methyl-2-phenyl-ethyl]-amides, in particular, an improved process for the preparation of 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(RS)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]-1H-pyrazole-4-carboxamide.

[0005] 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(RS)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]-1H-pyrazole- 4-carboxamide (referred to herein as a Compound (I), and also known by the common name ‘pydiflumetofen’), is known from WO 2010 / 063700.

[0006] It is known from WO 2013 / 127764 that Compound (I) can be prepared from a 2,4,6-trisubstituted aniline. However, when this preparation is employed on large scale, in particular, when the synthesis of Compound (V) from Compound (IV) is employed on large scale, the subsequent reaction steps performed to obtain Compound (I) suffer from long reaction times, low yields, and poor quality of the resultant product(s). In particular, when the synthesis outlined in WO 2013 / 127764 is employed on large scale, the formation of Compound (VIII) from Compound (VII) is not economically feasible as reagent costs and / or catalyst costs can make the process uneconomic. Specifically, operating the Pt / C catalyzed hydrogenation of Compound (VII) (oxime) to Compound (VIII) (amine) as described in WO 2013 / 127764 is uneconomic if you cannot reduce the usage and / or recycle the precious metal catalyst (5% Pt / C) in the process.

[0007] The skilled person will appreciate that when a reaction proceeds slowly, taking a longer time to reach completion, it often creates an environment conducive to the formation of undesired by-products and impurities. This extended reaction time allows for secondary reactions to occur, side products to accumulate, and potentially reversible reactions to equilibrate unfavorably. Consequently, these unwanted processes can significantly reduce the yield of the target compound. The prolonged exposure of reactants, intermediates and products to reaction conditions may also lead to degradation or further transformation of the desired product. Therefore, in many synthetic processes, chemists strive to optimize reaction rates, not only to improve productivity but also to minimize the formation of impurities and maximize yield.

[0008] The aim of the present invention is to provide a novel process for the production of 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(RS)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]-1H-pyrazole-4-carboxamide (Compound (I)) on a large scale that avoids the disadvantages of the known process and makes it possible to prepare said compound in high yield, in good quality, and in an economically advantageous manner.

[0009] Thus, according to the present invention, there is provided a process for the preparation of Compound (I): 332305-FF

[0010] 2

[0011] (I),

[0012]

[0013] comprising

[0014] a) adding Compound (II)

[0015] Cl

[0016] NH2

[0017] (II),

[0018]

[0019] Cl

[0020] in the presence of a solvent, to a mixture comprising a nitrite of Formula (III)

[0021] R1-O-N=O (III),

[0022] wherein R1is hydrogen, Ci-Cealkyl, or an inorganic cation,

[0023] Compound (IV)

[0024] CH2O

[0025] H3C

[0026] and a solvent, to provide Compound

[0027]

[0028] (V)

[0029]

[0030] b-i) distilling the resulting Compound (V); or

[0031] b-ii) crystallizing the resulting Compound (V); or

[0032] b-iii) distilling the resulting Compound (V), and then crystallizing the distilled material; 332305-FF

[0033] 3

[0034] c) reacting Compound (V) as purified in step b-i), b-ii), or b-iii), with Compound (VI) or salts thereof:

[0035] H2N-O-CH3(VI),

[0036] to form a mixture of isomers (E- and Z-) depicted as Compound (VII):

[0037] Cl

[0038]

[0039] d) reducing Compound (VII) to Compound (VIII):

[0040] (VIII), and

[0041]

[0042] e) reacting Compound (VIII) with a compound of Formula (IX):

[0043]

[0044] CH3

[0045] wherein R* is halogen, hydroxy, C₁-C₆alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, phosphoryl, or other suitable leaving group, to form Compound (I).

[0046] As used herein, the term "halogen" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).

[0047] As used herein, the term “hydroxyl” or “hydroxy” means an -OH group.

[0048] As used herein, the term " Ci-Cealkyl" 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. Ci-C4alkyl and C1-C2alkyl are to be construed accordingly. Examples of Ci-Cealkyl include, but are not limited to, methyl, ethyl, n-propyl, 1 -methylethyl (iso-propyl), n-butyl, and 1 -dimethylethyl (f-butyl). 332305-FF

[0049] 4

[0050] As used herein, the term " Ci-Cealkoxy" refers to a radical of the formula -ORawhere Rais a Ci-Cealkyl radical as generally defined above. Ci-C4alkoxy is to be construed accordingly. Examples of O-C4alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy and f-butoxy.

[0051] As used herein, the term “C1-C6alkylsulfanyl” refers to a radical of the formula -SRa, where Rais a Ci-Cealkyl radical as generally defined above. The terms “Ci-C4alkylsulfanyl” and “Ci-Csalkylsulfanyl”, are to be construed accordingly. Examples of C1-C6alkylsulfanyl include, but are not limited to methylsulfanyl.

[0052] As used herein, the term “Ci-Cealkylsulfinyl” refers to a radical of the formula -S(O)Ra, where Rais a Ci-Cealkyl radical as generally defined above. The terms “Ci-C4alkylsulfinyl” and “C1-C6alkylsulfinyl”, are to be construed accordingly. Examples of Ci-Cealkylsulfinyl include, but are not limited to methylsulfinyl.

[0053] As used herein, the term “C1-C6alkylsulfonyl” refers to a radical of the formula -S(O)2Ra, where Rais a Ci-Cealkyl radical as generally defined above. The terms “Ci-C4alkylsulfonyl” and “Ci-Csalkylsulfonyl”, are to be construed accordingly. Examples of C1-C6alkylsulfonyl include, but are not limited to methylsulfonyl.

[0054] As used herein, the term “phosphoryl” refers to a radical of the formula -PO3.

[0055] As used herein, the term "inert" is relative and depends on the specific conditions of the reaction, such as temperature, pressure, and the presence of catalysts. While the solvents listed herein are generally considered inert for many applications, they may not be inert under all conditions.

[0056] As used herein, the term “suitable leaving group” refers to an atom or group of atoms that can be displaced from a molecule during a substitution or elimination reaction. A suitable leaving group is typically a weak base that can readily depart from the parent molecule, carrying with it the bonding electrons. Suitable leaving groups are generally characterized by their ability to stabilize the negative charge that develops during the reaction process. Examples of suitable leaving groups include, but are not limited to, halides (e.g., chloride, bromide, iodide), tosylates, mesylates, triflates, acetates, phosphates, sulfonates, carboxylates, alkoxides, amides, and imidazoles.

[0057] The process of the present invention may be carried out in separate process steps, wherein the intermediate compounds can be isolated at each stage.

[0058] In one embodiment, there is provided a process for the preparation of Compound (I)

[0059]

[0060] comprising purifying crude Compound (V): 332305-FF

[0061] 5

[0062]

[0063] (V)

[0064] wherein Compound (V) is

[0065] b-i) distilled; or

[0066] b-ii) crystallized; or

[0067] b-iii) distilled and then crystallized;

[0068] c) reacting Compound (V) as purified by step b-i), b-ii), or b-iii), with Compound (VI) or salts thereof:

[0069] H2N-O-CH3(VI),

[0070] to form a mixture of isomers (E- and Z-) depicted as Compound (VII):

[0071] Cl

[0072]

[0073] d) reducing Compound (VII) to Compound (VIII):

[0074] (VIII), and

[0075]

[0076] e) reacting Compound (VIII) with a compound of Formula (IX):

[0077]

[0078] CH3

[0079] wherein R* is halogen, hydroxy, C₁-C₆alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, phosphoryl, or other suitable leaving group, to form the compound of Formula (I).

[0080] In a further embodiment, there is provided a purification of crude Compound (V): 332305-FF

[0081] 6

[0082]

[0083] (V) wherein Compound (V) is

[0084] b-i) distilled; or

[0085] b-ii) crystallized; or

[0086] b-iii) distilled and then crystallized.

[0087] There is further provided a process for the preparation of Compound (I)

[0088]

[0089] comprising:

[0090] a) adding Compound (II)

[0091] Cl

[0092]

[0093] in the presence of a solvent, to a mixture comprising a nitrite of Formula (III)

[0094] R1-O-N=O (III),

[0095] wherein R1is hydrogen, Ci-Cealkyl, or an inorganic cation,

[0096] Compound (IV)

[0097]

[0098] and a solvent, to provide Compound (V) 332305-FF

[0099] 7

[0100]

[0101] b-iii) distilling the resulting Compound (V), and then crystallizing the distilled material;

[0102] c) reacting the purified Compound (V) with Compound (VI) or salts thereof:

[0103] H2N-O-CH3(VI),

[0104] to form a mixture of isomers (E- and Z-) depicted as Compound (VII):

[0105] Cl

[0106]

[0107] d) reducing Compound (VII) to Compound (VIII):

[0108] (VIII), and

[0109]

[0110] e) reacting Compound (VIII) with a compound of Formula (IX):

[0111]

[0112] CH3

[0113] wherein R* is halogen, hydroxy, C₁-C₆alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, phosphoryl, or other suitable leaving group, to form Compound (I).

[0114] The skilled person would appreciate that steps a), b), c), d), and e) outlined above could equally be represented in a single scheme, such as in Scheme 1 below. 332305-FF

[0115] 8

[0116]

[0117] Pressures are reported as mbara (millibar absolute) for vacuum operations and barg (bar gauge) for hydrogenations. Temperatures are reported in °C.

[0118] Step a)

[0119] Compound (V) may be prepared in a one-pot reaction by adding Compound (II) to a mixture of Compound (IV) and a Compound of Formula (III) in the presence of a solvent.

[0120] In a Compound of Formula (III), R1is hydrogen, Ci-Cealkyl, or an inorganic cation. Preferably, R1is hydrogen, Ci-Cealkyl, or an inorganic cation selected from a cation of potassium, sodium, calcium, lithium, zinc, or magnesium. More preferably, R1is hydrogen, Ci-C4alkyl, or an inorganic cation selected from a cation of potassium, sodium, calcium, or magnesium. More preferably still, R1is tert-butyl or an inorganic cation of sodium. In one set of embodiments, R1is tert-butyl, and the compound of Formula (III) is tert-butyl nitrite. In another set of embodiments, R1is an inorganic cation of sodium, the compound of Formula (III) is sodium nitrite, and the reaction is carried out under acidic conditions. In yet another set of embodiments, R1is hydrogen, the compound of Formula (III) is nitrous acid, and the reaction is carried out under acidic conditions.

[0121] Suitable solvents for step a) are for example organic solvents such as ketones (for example acetone or methylethylketone) or nitriles (for example, acetonitrile), or water, or mixtures thereof. Preferred solvents are acetone, acetonitrile, and water, or mixtures thereof.

[0122] The mixture of Compound (IV), a Compound of Formula (III) and a solvent can additionally contain a copper compound which can be advantageous to increase yield and / or quality of the product. Preferred copper compounds are CuO, CuCl2or CuSO4. The amount of the copper compound is preferably about 1 to 20 mol% in the relation to Compound (II). Preferably, the reaction is conducted at a temperature of -10°C to 50°C. No isolation or accumulation of diazonium salt is required for this process step. 332305-FF

[0123] 9

[0124] Advantageously the same solvent is used for Compound (II) and the mixture of Compound (IV) and a Compound of Formula (III).

[0125] The reaction without the use of copper can be environmentally more advantageous since the production of copper waste can be avoided.

[0126] Compound (II), Compound (IV), as well as Compounds of Formula (III) are all commercially available. An example of the synthesis of Compound (V) may be found in WO 2013 / 127764.

[0127] Step b)

[0128] Distillation of crude 1-(2,4,6-trichlorophenyl)-propan-2-one (Compound (V)) - For example as used in Step b-i) or Step b-iii):

[0129] Compound (V) is a solid at ambient temperature and has a boiling point of around 290°C to 300°C at ambient pressure. Therefore, distillation is preferably carried out under reduced pressure to ensure that the boiling point of the compound is suitable for industrial equipment and also to ensure that distillation is carried out at a temperature at which the thermal degradation rate of the product is not too high. For this process, the pressure in the distillation apparatus should be less than about 10 mbara, and preferably, less than or equal to about 5 mbara. It may be beneficial to operate the process in a thin film evaporator, for example, but not limited to, a wiped-film evaporator, or short path distillation equipment.

[0130] The skilled person will recognise that the temperature inside a thin film evaporator is generally lower than the temperature of the oil or other service providing the heat input, and that the distillation temperature achieved by the material being distilled will be dependent on the equipment used and the pressure of operation. Variable parameters in the design include, for example, the type of thin film evaporator (for example, falling film or rising film, wiped film, short path still), evaporation surface area, material of construction of evaporating surface (for example, glass, metal or enamel coated metal), heating service material (for example, steam, oil, heat transfer agent), the temperature of the heating service material, temperature of the feed material, the flow rate of feed material, the presence of other volatile materials in the feed material as well as the pressure achieved in the evaporation equipment.

[0131] The skilled person will recognise that each distillation equipment design will be unique and optimisation will be required to optimise the performance of a system. For example, a system designed for the distillation of Compound (V) at 5 ± 2 mbara should achieve sufficient heat input to give a vapour temperature of 140°C ± 10°C. The parameters discussed above can be optimised to achieve these conditions for the particular equipment constructed.

[0132] The distillation of Compound (V) is preferably carried out at a heating service temperature of 150°C to 200°C, more preferably, at a temperature of 155 °C to 190°C. Even more preferably, at a heating service temperature of 155°C to 180°C. More preferably still, the distillation is carried out at a heating service temperature of 160°C to 185°C. 332305-FF

[0133] 10

[0134] The distillation of Compound (V) is preferably carried out at a pressure of less than 10 mbara, preferably, between a pressure of 1 mbara and 10 mbara, more preferably between 2 mbara and 8 mbara, even more preferably between 4 mbara and 6 mbara. More preferably still, the distillation of Compound (V) is carried out at a pressure of about 5 mbara.

[0135] The skilled person will understand that, when distilling a compound, which is a solid at ambient temperature, from residues which can solidify at higher temperatures than the desired product, it may be necessary to add additional materials. If it is necessary to add these materials, they may be added to:

[0136] a) keep the residues mobile and therefore flowing; and

[0137] b) act as a vapour carrier stream to drive off the desired product and also keep ‘cooler surfaces’ of the distillation system free from solid condensate (fouling) by washing the surfaces free of any solids.

[0138] These two requirements require materials with different properties.

[0139] To maintain a mobile residue, an additive should preferably:

[0140] have a boiling point significantly higher than the desired product (such that it does not distil with the desired product);

[0141] be stable to the temperature and other conditions in the mixture; and

[0142] be mobile (fluid) at the residue temperature.

[0143] To act as a carrier stream, an additive should preferably have a lower boiling point than the desired distillate and more preferably should not condense with the product (to any problematic extent), and should be inert with respect to reacting with the product or other additives.

[0144] In one embodiment, the distillation of Compound (V) is carried out in the absence of an additive. In another embodiment, the distillation of Compound (V) is carried out in the presence of a high boiling additive. Such materials should have a boiling point typically above 330°C at atmospheric pressure.

[0145] More preferably, distillation of Compound (V) is carried out in the presence of a high boiling additive such as, but not limited to polyethylene glycol or esters of phthalic acid (1,2-benzene dicarboxylic acid), terephthalic acid (1,4-benzene dicarboxylic acid), or trimellitic acid (1,2,4-benzene tricarboxylic acid).

[0146] Examples of polyethylene glycols (PEGs) which may be utilized as high boiling additives in the present invention include, but are not limited to, polyethylene glycols with an average molecular weight between 600 to 6000 g / mol (i.e., PEG 600 to PEG 6000). Preferably, the polyethylene glycol used as a high boiling additive has an average molecular weight of between 1800 to 2200 g / mol (i.e., PEG 1800 to PEG 2200). In one embodiment, the polyethylene glycol used as a high boiling additive has an average molecular weight of 2000 g / mol (i.e., PEG 2000). 332305-FF

[0147] 11

[0148] Examples of terephthalic acid esters (1,4-benzenedicarboxylic acid esters) which may be utilized as high boiling additives in the present invention include, but are not limited to, C₆-C₁₀alkyl esters of terephthalic acid include, but are not limited to, bis(2-ethylhexyl)terephthalate (DEHT).

[0149] Examples of trimellitic acid esters which may be utilized as high boiling additives in the present invention are products typically based on C₆, C₈, and C₁₀ alcohols and include, but are not limited to, Palatinol® products such as Palatinol®810TM. Palatinol®810TM is a trimellitate triester product based on C₈ alcohols. Palatinol® 810TM is available from BASF.

[0150] Examples of phthalic acid esters which may be utilized as high boiling additives in the present invention include, but are not limited to, Palatinol® products such as Palatinol®10P and Palatinol®N. Palatinol® products are typically C₆-C₁₀alkyl esters of phthalic acid and are commercially available from BASF. In particular, Palatinol®10P is a C₁₀ester of phthalic acid, also known as bis(2-propylheptyl) phthalate. Palatinol®N is a C₉ester of phthalic acid also known as diisononyl phthalate.

[0151] Preferably, when the distillation of Compound (V) is conducted in the presence of a high boiling additive, that high boiling additive is polyethylene glycol or an ester of phthalic acid. More preferably, when the distillation of Compound (V) is conducted in the presence of a high boiling additive, that high boiling additive is PEG 2000 or bis(2-propylheptyl) phthalate. Even more preferably, when the distillation of Compound (V) is conducted in the presence of a high boiling additive, that high boiling additive is PEG 2000.

[0152] Preferably, the high boiling additive is present at between 5 % and 15 % by weight relative to Compound (V), more preferably, at between 7 % and 12 % by weight. In a particularly preferred embodiment, polyethylene glycol e.g. PEG 2000 is present at 10% by weight relative to Compound (V).

[0153] In a further embodiment, the distillation may be carried out in the presence of a low boiling additive. Such materials should have a boiling point in the range 150°C to 200°C at atmospheric pressure and are preferably liquids at less than about 50°C, more preferably liquid at less than 30°C, even more preferably liquid at ambient temperatures (0°C to 25°C). Examples of such compounds include, but are not limited to, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,3,5-trichlorobenzene, N, N-dimethylformamide, and N, N-dimethylacetamide.

[0154] Preferably, the distillation is carried out in the presence of 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene or 1,3,5-trichlorobenzene. Even more preferably, the distillation is carried out in the presence of 1,2-dichlorobenzene or 1,3-dichlorobenzene. More preferably still, the distillation is carried out in the presence of 1,3-dichlorobenzene. 332305-FF

[0155] 12

[0156] Preferably, when a low boiling additive is added to the distillation, it is present at between 1 % and 10 % by weight relative to Compound (V), more preferably, the low boiling additive is present at between 2 % and 6 % by weight, even more preferably, the low boiling additive is present at between 3 % and 5 % by weight relative to Compound (V).

[0157] During a chemical distillation process, two different temperatures are typically referenced: the boiling point of the liquid being distilled and the temperature of the condensing vapours. Preferably, the distillation of Compound (V) is carried out at a temperature of between 150°C to 200°C (at reduced pressure, e.g., 1 mbara to 10 mbara), and with a condenser temperature of 70°C to 100°C. More preferably, the distillation of Compound (V) is carried out at a temperature of between 155°C to 190°C (at reduced pressure, e.g., 1 mbara to 7 mbara), and with a condenser temperature of 75°C to 95°C. Even more preferably, the distillation of Compound (V) is carried out at a temperature of 180±5°C (at reduced pressure, e.g., 1 mbara to 6 mbara), and with a condenser temperature of 80±5°C.

[0158] Crystallisation of Crude 1-(2,4,6-trichlorophenyl)-propan-2-one (Compound (V)) - Step b-ii) The crystallisation of crude Compound (V) may be carried out in the absence of a solvent (i.e., as a melt crystallisation), or in at least one solvent. Preferably, the at least one solvent is an organic solvent. Preferably, the organic solvent is selected from alkanes, such as hexane, heptane, and octane; cycloalkanes, such as cyclohexane; aromatic hydrocarbons, such as benzene, toluene, and xylene; chlorinated hydrocarbons, such as monochlorobenzene, dichlorobenzene, dichloromethane and chloroform; alcohols, such as methanol, ethanol, iso-propanol, butanol, n-propanol, and glycerol; fluorinated hydrocarbons, such as perfluorohexane and perfluorodecalin; ethers, such as diethyl ether and tetrahydrofuran; esters, such as isopropyl acetate and ethyl acetate; silicone-based solvents, such as hexamethyldisiloxane and octamethylcyclotetrasiloxane; aliphatic ethers, such as ethyl tert-butyl ether; and fluorinated ethers, such as perfluorodiethyl ether.

[0159] More preferably, the organic solvent is selected from hexane and a C₁-C₄alcohol, or mixtures thereof. Even more preferably, the organic solvent is selected from hexane, methanol, ethanol, n-propanol, and iso-propanol, or mixtures thereof. More preferably still, the organic solvent is hexane or methanol. Even more preferably still, the crystallisation of crude Compound (V) is carried out in methanol.

[0160] Preferably, Compound (V) in the solvent system is heated. More preferably, Compound (V) in the solvent system is heated to a temperature of between 50 °C to 70 °C.

[0161] Crystallisation of distilled 1-(2,4,6-trichlorophenyl)-propan-2-one (Compound (V)) - Step b-iii):

[0162] The crystallisation of distilled Compound (V) is carried out as a melt (melt crystallisation) or in a solvent system comprising a least one organic solvent.

[0163] Preferably, the organic solvent is selected from alkanes, such as hexane, heptane, and octane; cycloalkanes, such as cyclohexane; aromatic hydrocarbons, such as benzene, toluene, and xylene; chlorinated hydrocarbons, such as monochlorobenzene, dichlorobenzene, dichloromethane and 332305-FF

[0164] 13

[0165] chloroform; alcohols, such as methanol, ethanol, iso-propanol, butanol, n-propanol, and glycerol; fluorinated hydrocarbons, such as perfluorohexane and perfluorodecalin; ethers, such as diethyl ether and tetrahydrofuran; esters, such as isopropyl acetate and ethyl acetate; silicone-based solvents, such as hexamethyldisiloxane and octamethylcyclotetrasiloxane; aliphatic ethers, such as ethyl tert-butyl ether; and fluorinated ethers, such as perfluorodiethyl ether.

[0166] Preferably, the crystallisation of Compound (V) which has been previously purified by distillation takes place in a mixture of alcohol and water.

[0167] More preferably, the crystallisation of Compound (V), which has been previously purified by distillation takes place in a mixture of methanol and water.

[0168] Even more preferably, the crystallisation of Compound (V), takes place in a mixture of methanol and water at a ratio of 5:1.

[0169] Preferably, Compound (V) in the solvent system is heated. More preferably, Compound (V) in the solvent system is heated to a temperature of between 50 °C to 80 °C. Even more preferably, Compound (V) in the solvent system is heated to a temperature of between 55 °C to 70 °C.

[0170] Alternatively, Compound (V) may be crystallised in absence of a solvent (melt crystallisation) by methods known in the art.

[0171] A further surprising aspect of the invention is that the two steps of distilling Compound (V) and then crystallising the resultant distilled product increases the recovery of crystallised Compound (V) compared with crystallisation of the crude Compound (V) alone. Without being bound by theory, it is believed that this due to the removal, in the distillation step, of impurities which, in the crystallisation of crude Compound (V), restrict the solvent choice for the crystallisation step. That the higher boiling impurities are removed allows a solvent system in which the recovery of the Compound (V) is higher.

[0172] Step c)

[0173] Compound (VII) may be prepared in a one pot reaction from Compound (V) and Compound (VI) or a salt thereof. Preferably Compound (VI) is present as the hydrochloride salt. Preferably, Compound (VI) is present as the hydrochloride salt in an aqueous solution and is added to Compound (V), which is present in inert solvent such as methanol or ethanol. The reaction of step c) is preferably carried out at a temperature of 10 °C to 90°C, preferably 40 °C to 60 °C. Compound (VII) can be furthermore purified by extraction into a suitable solvent such as hexane, methylcyclohexane or toluene.

[0174] Preferably, if a salt of Compound (VI) is used, the reaction is preferentially carried out in the presence of a base. Suitable bases include all inorganic and organic bases, except for ammonia or primary amines. Suitable inorganic bases include, but are not limited to, alkali metal hydroxides and carbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium 332305-FF

[0175] 14

[0176] carbonate; basic alkaline earth salts such as calcium hydroxide, and calcium oxide. Suitable organic bases include but are not limited to, triethylamine, di-isopropylethylamine, and di-isopropyl amine.

[0177] In a more preferable embodiment, if a salt of Compound (VI) is used, the reaction is preferentially carried out in the presence of sodium hydroxide, potassium hydroxide or triethylamine. More preferably, in the presence of sodium hydroxide.

[0178] Step d)

[0179] 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.

[0180] 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.

[0181] 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.

[0182] Compound (VIII) can also be prepared by hydrogenation of Compound (VII) in the presence of a catalyst containing a transition metal such as platinum (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.

[0183] Preferably, the solvent is an organic alcohol like methanol, or acetic acid.

[0184] 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.

[0185] It is known from WO 2013 / 127764 that the reduction of Compound (VII) to Compound (VIII) can be performed with a number of reducing agents such as sodium cyanoborohydride, triethylaminoborane or catalytic platinum on charcoal with hydrogen gas. A person of skill will recognize that stoichiometric reducing agents such as sodium cyanoborohydride or triethylaminoborane result in large quantities of byproducts as waste which then need to be treated. A person of skill will also recognize that catalytic hydrogenation provides a low waste option for reduction and also that, when using expensive precious metal catalysts such as platinum on charcoal, economic operation of the process can only be achieved with very low usage of catalyst.

[0186] Optimization of catalyst utilization can be achieved by minimizing fresh catalyst addition; when the reaction kinetics are sufficiently rapid, it becomes feasible to decrease the quantity of new catalyst introduced to a given reaction system. Alternatively, a system of internal catalyst recycling may be 332305-FF

[0187] 15

[0188] implemented, wherein catalyst that has already participated in the reaction process can be recovered and subsequently reused.

[0189] Overtime, however, catalysts can become deactivated due to fouling, poisoning, or structural changes during operation. Addition of small ‘top-up’ quantities of fresh catalyst can maintain catalyst activity for longer but eventually deactivated catalyst will need to be sent for precious metal recovery and the metal recycled as ‘fresh’ catalyst.

[0190] Extending the lifespan of a catalyst before external recovery and recycling is a goal for all users of precious metal heterogeneous catalysts. Therefore, discoveries that reduce the usage of fresh catalyst and improve the ability to recycle used catalyst (for longer) before external recovery and recycle of the metal, are highly valuable inventions.

[0191] Step e)

[0192] 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, C₁-C₆alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, phosphoryl, or other suitable leaving group,

[0193] Preferably, R* is halogen, hydroxy or C₁-C₆alkoxy. More preferably, R* is halogen, hydroxy or C₁-C₃alkoxy. 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.

[0194] Preferably, the ratio of Compound (VIII) to Compound (IX) is about 1:1 to 1:1.2.

[0195] 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 ethyl acetate. Preferably the suitable solvent is xylene (either as a mix of isomers, or pure 1,2-, 1,3- or 1,4-xylene).

[0196] Suitable bases are for example sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or pyridine. Preferably, the base is selected from sodium hydroxide and triethylamine.

[0197] EXAMPLES

[0198] The following examples further illustrate, but do not limit the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to the reactants and as to the reaction conditions and techniques.

[0199] The following abbreviations are used: s = singlet; GC = gas chromatography; LC = liquid chromatography; M = Molar; mol = mole; mmol = millimole; mbara = millibars absolute; barg = Bar gauge; MS = mass spectroscopy. 332305-FF

[0200] 16

[0201] Preparatory examples:

[0202] Example 1a: Preparation of crude 1-(2,4,6-trichlorophenyl)-propan-2-one (Compound (V))

[0203]

[0204] 2,4,6-trichloroaniline (98.2 g, 0.5 mol) was dissolved in isopropenyl acetate (128.6 g, 1.285 mol) and acetonitrile (71.6g, 1.725 mol) at slightly elevated temperature. A reaction vessel was charged with isopropenyl acetate (71.6 g, 0.715 mol) and acetonitrile (39.6 g, 0.955 mol), followed by sulfuric acid (0.1 g). Then, the 2,4,6-trichloroaniline solution mentioned above, sodium nitrite solution (94.9 g, 0.55 mol, 40% in water), and concentrated sulfuric acid (30.1 g, 0.303 mol) were simultaneously added portionwise over 4 hours, maintaining the reaction temperature at 15°C and pH between 0.1 and 1. After complete dosage of the 2,4,6-trichloroaniline solution, further aliquots of sodium nitrite (5.2 g, 0.03 mol, 40% in water) and concentrated sulfuric acid (1.7 g, 0.018 mol) were simultaneously added portionwise until nitrogen evolution ceased. The reaction was stirred for a further 15 minutes, followed by portionwise addition of sodium hydroxide solution (85.3 g, 0.64 mol, 30% in water) over 15 minutes, maintaining the temperature of the reaction mixture below 35 °C, followed by water (180g, 10 mol). Phase separation yielded 360.7 g of organic phase with a content of 27.1 % (w / w) of the desired product of value (GC analysis, quantification with internal standard). The yield, based on 2,4,6-trichloroaniline used, was 82.9%,1H NMR (400MHz, CDCl₃): δ 2.26 (s, 3H, CH₃), 4.05 (s, 2H, CH₂), 7.34 (s, 2H, Ar-H).

[0205] Example 1b: Preparation of crude 1-(2,4,6-trichlorophenyl)-propan-2-one (Compound (V)) In a 1.5L sulfonation flask equipped with mechanical stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetone (240 ml), were added isopropenyl acetate (66 ml, 0.60 mol), tert-butyl nitrite (40 ml, 0.30 mol) and cupric sulfate pentahydrate (2.5 g, 0.001 mol), and the resulting light green-blue suspension was stirred for 15 minutes at ambient temperature. A solution of 2,4,6-trichloroaniline (40 g, 0.20 mol), dissolved in acetone (320 ml) was added dropwise over a period of 2 hours. During the addition, bubbling was observed, the temperature rose to 30 °C and the mixture turned green. 1 hour after the addition, an amber solution was obtained. The mixture was stirred for 6 hours. Completion of the reaction was confirmed by GC-MS. The crude mixture was concentrated under reduced pressure to remove most of the acetone and the residue was dissolved in ethyl acetate (300 ml) and washed with 1M hydrochloric acid (2x300 ml), water (2x300 ml), potassium carbonate solution (300 ml), followed by water (300 ml). Combined basic aqueous streams were re-extracted with ethyl acetate (150 ml). Combined organics were dried over sodium sulfate, and the organics were concentrated under reduced pressure to give crude 1-(2,4,6-trichlorophenyl)-propan-2-one (53 g) as a dark brown oil. The crude product was dissolved again in ethyl acetate (200 ml) and washed with 1M sodium hydroxide (300 ml), 1M hydrochloric acid (100 ml) and water (200 ml). The organic layers were dried and evaporated to give crude 1-(2,4,6-trichlorophenyl)-propan-2-one 49 g, as 332305-FF

[0206] 17

[0207] a crude dark brown oil.1H NMR (400MHz, CDCl₃): δ 2.26 (s, 3H, CH₃), 4.05 (s, 2H, CH₂), 7.34 (s, 2H, Ar-H).

[0208] Example 1c: Preparation of crude 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) 2,4,6-trichloroaniline (785.8 g, 4 mol) was dissolved in isopropenyl acetate (1029.0 g, 10.28 mol) and acetonitrile (572.2g, 13.8 mol) at slightly elevated temperature. A reaction vessel was charged with isopropenyl acetate (572.6 g, 5.72 mol), acetonitrile (317.1 g, 7.64 mol) and water (3 g, 0.164 mol). Then, the 2,4,6-trichloroaniline solution mentioned above, sodium nitrite solution (758.9 g, 4.4 mol, 40% in water), and concentrated sulfuric acid (241 g, 2.42 mol) were simultaneously added portionwise over 4 hours, maintaining the reaction temperature between 29°C and 30°C and pH between 0.1 and 1. After complete dosage of the 2,4,6-trichloroaniline solution, further aliquots of sodium nitrite (41.4 g, 0.24 mol, 40% in water) and concentrated sulfuric acid (13.6 g, 0.137 mol) were simultaneously added portionwise until nitrogen evolution ceased. The reaction was cooled to 25 °C with stirring, followed by portionwise addition of sodium hydroxide solution (682.7 g, 5.12 mol, 30% in water) over 30 minutes, maintaining the temperature of the reaction mixture below 30°C. Subsequently, 1440 g (80 mol) of organic phase yielded the desired product 27.2% (w / w) (GC analysis, quantification with internal standard). The yield, based on 2,4,6-trichloroaniline used, was 83.0%.

[0209] Solvents were evaporated off the organic phase to give crude Compound (V) as the starting material for the following examples.

[0210] Purification of crude 1-(2,4.6-trichlorophenyl)propan-2-one (Compound (V))

[0211]

[0212] Example 2a) Crystallisation of crude 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) in methanol (Step b-ii)

[0213] A 1,5L jacketed reaction vessel was charged with methanol (250.2 g) and heated to about 55°C. Once at temperature, the reaction vessel was charged with crude Compound (V) (250.2 g, 75.4% strength, as prepared by a process similar to Example 1c) and stirred to dissolve. The resulting mixture was then cooled over about 90 minutes to a temperature of 25°C to 26°C, and stirred for 1 hour. No initiation of crystallisation was observed. The reaction was then cooled at about 8°C per hour to 0°C and held at 0°C with stirring for one hour before the resulting product was filtered. The mother liquors were returned to the vessel, the contents of which was stirred and subsequently discharged to the filter. The filter cake was washed twice with methanol (60.6 g & 90.0 g respectively) to give a light brown product cake. The 332305-FF

[0214] 18

[0215] filtered material was dried at 30°C under vacuum to provide Compound (V) (145.9g; 98.6% 1 -(2,4,6-trichlorophenyl)propan-2-one content; 76.3% yield).

[0216] Example 2b) Crystallisation of crude 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) in methanol (Step b-ii)

[0217] A 1,5L jacketed reaction vessel was charged with methanol (250.7 g) and heated to about 61°C. Once at temperature, the reaction vessel was charged with crude Compound (V) (249.7 g, 75.7% strength, as prepared by a process similar to Example 1c) and stirred to dissolve. The resulting mixture was then cooled to 39°C over 15 minutes, and then cooled slowly to 20°C and stirred for 1 hour. Initiation of crystallisation was observed within 10 minutes of reaching 20°C. The reaction was then cooled to 0°C to 5°C over 3 hours, and held at this temperature with stirring for one hour before the resulting product was filtered. The mother liquors were returned to the vessel, the contents of which was stirred and subsequently discharged to the filter. The filter cake was washed twice with methanol (60.7 g & 90.1 g respectively) to give a light brown product cake. The filtered material was dried at 30°C under vacuum to provide Compound (V) (144.9g; 98.8% 1-(2,4,6-trichlorophenyl)propan-2-one content; 75.8% yield).

[0218] Example 3) Purification process of 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) by distillation (Step 1 b-i) & Step b-iii) Part One)

[0219] To crude Compound (V) (3878.6 g at 79% strength) was added 1,2-dichlorobenzene 156.2g) and Palatinol®10P (384.7g) to give a mixture of crude melt (4419.5 g of crude material at ca. 68.8% strength). 4344 g of this material was fed (at a temperature of 114°C to 116°C at a rate of about 703.3 g / hour) into a 0.075 m2LUWA wiped film evaporator with an oil temperature of 170°C to 180°C and under high vacuum (1 mbara pressure). The product distillate (512.9 g / hour) was condensed on a condenser held at about 80°C (condenser oil temperature held between 70°C and 90°C). The product melt (512.9 g / hour at 87.8% strength) had a recovery of 93.1 % of Compound (V) fed.

[0220] Example 4) Crystallisation of distilled 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) from methanol:water (5:1) (Step b-iii) Part Two)

[0221] A jacketed reaction vessel was charged with a mixture of methanol and water at a ratio of 5:1 w / w (283.4 g) and heated to 60°C. Once at temperature, the reaction vessel was charged with distilled 1-(2,4,6-trichlorophenyl)propan-2-one prepared as per Example 3 (218 g) and stirred to dissolve. The mixture was then cooled over 30 minutes to 47°C, and then slowly cooled further. Initiation of crystallisation was observed at about 41°C. The mixture was held at 41°C to 39°C for 150 minutes and then cooled to 0°C to -2°C over 180 minutes, and held at this temperature with stirring for one hour before the resulting product was filtered. The mother liquors were returned to the vessel, the contents of which was stirred and subsequently discharged to the filter. The filter cake was washed twice with methanol / water (5:1 w / w; (60.7 g & 90.1 g respectively) to give a white filter cake. The filtered material 332305-FF

[0222] 19

[0223] was dried at 30°C under vacuum to provide Compound (V) (180.1g; 98.3% 1-(2,4,6-trichlorophenyl)propan-2-one content; 91.6% yield).

[0224] Combining Example 3 and Example 4 (equivalent to Step b-iii) gave an overall yield from starting crude Compound (V) of 85.3% (93.1% x 91.6%) of initial Compound (V) present; this is an approximately 12% increase in yield of purified Compound (V) over Example 2a / 2b.

[0225] Example 5) Purification of 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) by distillation (Step b-i) & Step b-iii) Part One)

[0226] To crude Compound (V) (4002.1 g at 75.9% strength) was added 1,2-dichlorobenzene (160.2 g) and Palatinol® 10-P (400.4 g) to give a mixture of crude melt (4562 g of crude material at 68.8% measured strength). 4199 g of this material was fed (at 114°C to 116°C at a rate of about 641.1 g / hour) into a 0.075 m2LUWA wiped film evaporator with an oil temperature of 180°C to 190°C and under high vacuum (1.4 mbara pressure). The product distillate (478.5 g / hour) was condensed on a condenser held at about 80°C (condenser oil temperature held between 70°C and 90°C). The product melt (478.5 g / hour at 86.8% strength) had a recovery of 94.1 % of Compound (V) fed.

[0227] Example 6) Crystallisation of distilled 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) from methanol: water (5:1) (Step b-iii) Part Two)

[0228] A jacketed reaction vessel was charged with a mixture of methanol and water at a ratio of 5:1 w / w (283.5 g) and heated to 55°C. Once at temperature the reaction vessel was charged with distilled Compound (V) prepared as per Example 5 (217.1 g) and stirred to dissolve. The mixture was then cooled over 30 minutes to 45°C, and then slowly cooled further. Initiation of crystallisation was observed at about 40°C. The reaction was held at 41°C to 39°C for 60 minutes and then cooled to 0°C to 3°C over 180 minutes, and held at this temperature with stirring for one hour before the resulting product was filtered. The mother liquors were returned to the vessel, the contents of which was stirred and subsequently discharged to the filter. The filter cake was washed twice with methanol / water (5:1 w / w; (70.1 g & 70.4 g respectively) to give a white filter cake. The filtered material was dried at 30°C under vacuum to provide Compound (V) (180.0 g; 98.30% 1-(2,4,6-trichlorophenyl)propan-2-one content; 93% yield).

[0229] Overall yield from starting crude Compound (V) was 87.5% (94.1% x 93.0%) of initial 1 Compound (V) present; an approximately 15% increase in yield of pure Compound (V) compared with Examples 2a and 2b.

[0230] Example 7) Distillation of mother liquors and washes to recover 1-(2,4,6-trichlorophenyl) propan-2-one (Compound (V)) from filtrates 332305-FF

[0231] 20

[0232] The filtrates and washes obtained from processes similar to those described in Examples 1 and 2 were combined to give 1280.2 g at 9.2% Compound (V) content. To this were added 1,3-dichlorobenzene (25.6 g (2 weight% of filtrates) and PEG 2000 (64 g, 5% weight% of filtrates).

[0233] Distillation 1: The methanol solvent was removed at 80°C and about 300 mbara pressure leaving a residue.

[0234] Distillation 2: The residues (361.4 g @ 32.7% strength w / w, 118 g @ 100% strength) were then fed at 50°C onto a wiped film evaporator (oil temperature 135°C, pressure 5 mbara) to remove residual lighter boiling components (and some Compound (V) (7.3% of initial content) leaving a residue containing Compound (V) at 35% strength. This residue was subsequently fed at 90°C onto a wiped film evaporator with oil temperature of 165°C and at a pressure of 5 mbara. The distillate from this operation contained Compound (V) at 79.5% strength (82.5% of available 1-(2,4,6-trichlorophenyl)propan-2-one recovered). With a further 7.3% in the second distillation condensate trap and only 3.4% lost in the residues.

[0235] Example 8) Recycling of recovered 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V)) from Example 7 plus further mother liquors from the crystallisation process

[0236] To fresh methanol (388.7 g) was added mother liquors of Compound (V) (130 g at 10.2% strength crude Compound (V) and 74% methanol) from a process similar to Examples 1 and 2, recovered Compound (V) from Example 7 (50.3 g at 79.5% strength) and crude Compound (V) (349.6 g at 77.7% strength), giving a total charge of 325.1 g of ‘pure’ Compound (V), plus impurities in 485 g of methanol. The mixture was heated to 50°C before cooling to about 22°C over about 80 minutes. The mixture was held at about 22°C for about 60 minutes, cooled to 0°C to 5°C over about 180 minutes, and held at this temperature with stirring for one hour. The resulting slurry was then filtered by vacuum and washed twice with cold methanol (74.2 g and 111.5 g respectively), and filtered and dried to dryness overnight under vacuum at 30°C to give the product (257.5 g @ 97.0 % strength, 249.7 g, 76.8% recovery from total available crude Compound (V)).

[0237] Compared with the amount of crude Compound (V) present without the recovered material (285.1 g from crude 1 Compound (V) plus mother liquors), this represents a recovery of 87.6% of available crude Compound (V). Or if the amount of purified Compound (V) is compared with the amount of Compound (V) present in the crude charge, the recovery is approximately 92%.

[0238] The mother liquors from the process (486 g @ 10.2%, 15.2% of the initial total available Compound (V)) and the combined washes 241 g @ 9.4%, 7.0% of charge)) are available for further recovery as described above. A person of skill in the art will recognise that it may be necessary to have a purge of a portion of the recovered materials to control impurity levels.

[0239] A person of skill will recognise from these results that distillation of Compound (V) either before (Step b-iii)) or distilling the filtrates and washes after crystallisation increases the recovery of purified 332305-FF

[0240] 21

[0241] Compound (V) from the crude Compound (V) starting material when compare with just by crystallisation of crude material alone.

[0242] A person of skill will also recognise that, as filtrates and wash liquors become more pure, there is potential to recycle a portion of these into a crystallisation stage to reclaim the desired product without the need for distillation of solvents. A person of skill will further recognise that any filtrates and washes not directly recycled into the crystallisation process could be recycled by distillation of the solvents and then distillation of the Compound (V) (as per Example 8) and partially purified Compound (V) recycled a further crystallisation step.

[0243] Use of crude and purified Compound (V) in downstream processes

[0244] Example 9) Formation of 1-(2,4,6-trichlorophenyl)-propan-2-one O-methyl-oxime (Compound (VII) from 1-(2,4,6-trichlorophenyl)propan-2-one (Compound (V))

[0245] CH3

[0246]

[0247] An inerted reactor was charged with Compound (V), about 169 g as pure compound (0.71 mol), for actual weights see line 3 of Table 1 below) and 173 g of methanol. The reactor was heated to about 65°C and methoxyamine hydrochloride solution (ca. 1.14 equivalents; 30% solution in water) was added over 1 hour whilst maintaining a pH in the range 2 to 5 through addition of NaOH (30%), and maintaining the temperature in the range 65°C to 70°C. The reaction was stirred for one hour or until Compound (V) level was less than 1% (see line 5, Table 1). The pH was adjusted to between pH 7 to 9 with NaOH and the phases allowed to settle. The lower organic phase (see line 6, Table 1) was separated off to another vessel and charged with acetic acid ca. 355 g. The temperature of the separated off lower organic phase was maintained at about 64°C, vacuum applied (140 mbara), and the mixture distilled until the pressure reached about 100 mbara and the distillate was about 190 g to 200 g to provide 1 -(2,4,6-trichlorophenyl)-propan-2-one O-methyl-oxime (Compound (VII).

[0248] Table 1: Comparative Table for reaction of Compound (V) to Compound (VII) as conducted by the process described in Example 9

[0249] Example 9A* 9B 9C Purification State of Distilled &

[0250] 1 Crude Distilled

[0251] Compound (V) Crystallised 2 Step a) Step b-i) Step b-ii)

[0252] Weight 230.8 g 179.2 g 169.7

[0253] 3 Compound (V) Strength 73.5% 94.5% 99.3 %

[0254] Mol 0.714 mol 0.713 mol 0.709 mol

[0255]

[0256] 332305-FF

[0257] 22

[0258] Methoxyamine

[0259] 4 227g 226g 215g hydrochloride

[0260] 5 Post addition hold 1 hr 24 min 1 hr 13 min 25 min

[0261] 6 Organic Phase Weight 235 g 196.7 g 192.3 g Organic phase 184.7 g

[0262] 7 176.8 g (75.2%) 178.2 g (92.7%) returned (purity) (93.9%)

[0263] After Distillation

[0264] 8 341.7 g (39.9%) 363.8 (45.8%) 340.3 (49.9%) (Product (VII) purity)

[0265] 9 Mols in product 0.511 mol 0.625 mol 0.637 mol Yield of Compound

[0266] (VII) adjusted for

[0267] 10 95.2% 93.4% 97.0%

[0268] Organic phase

[0269] removal

[0270]

[0271] Comparative example

[0272] Table 1 shows that although the chemical yield of Examples 9A, 9B, and 9C is roughly the same, that the conversion of Compound (V) to Compound (VII) occurs more quickly (see post addition hold shown in line 5 of Table 1 above) forthe purer starting materials (see line 3, Table 1 above), thus demonstrating a clear rate benefit at constant stoichiometry and conditions. Further to the above, the product quality of the purified materials is significantly higher than that provided by crude starting material (see line 8, Table 1 above).

[0273] The purity of Compound (V) does not have a particular effect on the yield of the process set out in Example 9 (reaction of Compound (V) to Compound (VII)) perse, but it has a particularly unexpected and beneficial impact on downstream processes (e.g. synthesis of Compound (VIII)), as shown below.

[0274] Example 10) Preparation of O-Methyl-N-methyl-2-(2,4,6-trichlorophenyl)ethyl-hydroxylamine (Compound (VIII)) from A) Crude, B) Distilled and C) Distilled and Crystallised 1 -(2,4,6-trichlorophenyl)-propan-2-one O-methyl-oxime (Compound (VII)) - Comparison of hydrogenation rate between the three different qualities of Compound (VII) generated

[0275] Pt / C

[0276]

[0277] To an autoclave purged with nitrogen, mix fresh 5% Pt / C (0.50 mmol, water wet, assay ca. 2.5% Pt) 0.1 mol% Pt versus the moles of oxime starting material) and acetic acid (207 g) and charge to the autoclave. Purge the autoclave with nitrogen (x3) and hydrogen (x4), and then set pressure to 8.5 barg. Maintaining the temperature at 25 °C and the hydrogen pressure at 8.5 barg, add sulfuric acid (96%, 0.55 moles) and a solution of Compound (VII) (0.50 mol of a ca. 50% solution in acetic acid from 332305-FF

[0278] 23

[0279] Example 9 above) over about 3 hours. Stir the reaction for 3.5 hours and sample for analysis. Residual Compound (VII) (sum of isomers) was as shown in Table 2 below (lines 7 to 13). The mixture was filtered to remove Pt / C, the solid residue washed with acetic acid (15 g) and the solution available for downstream processing, for example, as described in WO 2013 / 127764 example P6c and examples P7. A comparison of the rate of reaction for Examples 10A, 10B, and 10C is shown below in Table 2.

[0280] Table 2: Comparison of rate of reaction of the hydrogenation of Compound (VII) to Compound (VIII) as described in Example 10 above

[0281] Pt / C

[0282]

[0283] Purification State of Compound (V)

[0284] Crude Distilled Distilled & Crystallised (Compound (VII) From Example

[0285] (9A) (9B) (9C) No.)

[0286] Compound (VII) Example No. 10A 10B 10C Weight 255 g 290 g 270 g Compound (VII) in

[0287] Strength 39.9 % 45.8 % 49.9 % acetic acid

[0288] Mol 0.380 mol 0.498 mol 0.506 mol Catalyst (2.275% Pt in wet catalyst 3.297 g 4.286 g 4.29 g = 0.1mol% Pt of Compound (VII)) (0.0383 mmol) (0.0498 mmol) (0.0498 mmol) Acetic Acid 158.7 g 206.3 g 207.4 g Sulfuric acid @ 95-97% 43.3 g 56.6 g 56.8 g Residual Compound (VII) 3.5 hr 69.3% 17.32% 1.25%** Residual Compound (VII) 5.0 hr - 5.42% - Residual Compound (VII) 7.25 hr - 0.71%** - 0 Residual Compound (VII) 8.25 hr 40.5% - - 1 Residual Compound (VII) 12.5 hr 27.2% - - 2 Residual Compound (VII) 17.5 hr 14.4% - - 3 Residual Compound (VII) 20.5 hr 10.74%** - -

[0289]

[0290] ** Reaction considered complete.

[0291] The data in Table 2 demonstrates that purification of Compound (V), whether that be distillation alone (as per Example 9B), or indeed distillation and subsequent crystallization (as per Example 9C), prior to the synthesis of Compound (VII) vastly improves the rate of the proceeding hydrogenation of Compound (VII) to Compound (VIII). As shown in line 13 of Table 2, although the reaction was considered complete, residual starting material (Compound (VII)) was still observed even after 20.5 hours when crude Compound (V) was used to synthesise Compound (VII). 332305-FF

[0292] 24

[0293] Example 11: Preparation of O-Methyl-N-methyl-2-(2,4,6-trichlorophenyl)ethyl-hydroxylamine (Compound (VIII)) from 1 -(2,4,6-trichlorophenyl)-propan-2-one O-methyl-oxime (Compound (VII))

[0294] 3 Pt / C

[0295]

[0296] Example 11 A used Compound (V) prepared by methods as described in Example 2a and converted to Compound (VII) by a process as described in Example 9. Example 11B used Compound (V) prepared by a process similar to that described in Examples 3, 4 and 9C.

[0297] A solution of Compound (VII) (55.4 g, 0.21 mols) in acetic acid (59.6 g) was transferred to the 300 mL pressure reactor. A solution of sulphuric acid (22.4 g, 0.23 mols) in acetic acid (85.7 g) was added followed by the catalyst 5% Pt / C (1.63 g, 0.21 mmol, water wet; assay 2.5% Pt). The reactor was sealed and purged with nitrogen (4x8.5 barg) followed by hydrogen (4x8.5 barg). The reactor was pressurised with hydrogen to 8.5 barg, heated to 25°C, and stirred at 800 rpm for 6 hours. Samples were regularly taken and analysed by LC. By LC Quantitative analysis, the level of Compound (VII) and Compound (VIII) were monitored and recorded in Table 3 below.

[0298] Table 3: Comparison of hydrogenation results from Examples 10 and 11

[0299] Examples 11A and 11 B were conducted as batch hydrogenations whereas Examples 10A, 10B, and 10C were conducted as semi-batch hydrogenations with Compound (VII) added over 180 minutes.

[0300] Comparative

[0301] Examples According to the Invention Examples

[0302] Purification

[0303] State of Distilled & Distilled &

[0304] Unpurified Crude Distilled Crystallised Compound Crystallised Crystallised (V)

[0305] Example

[0306] Compound

[0307] P6c from Example Example Example Example Example (V) Example

[0308] WO2013 / 10A 10B 10C 11A 11 B No.

[0309] 127764

[0310] Process Batch Semi-Batch Semi-Batch Semi-Batch Batch Batch Catalyst

[0311] 0.35 mol% 0.1 mol% 0.1 mol% 0.1 mol% 0.1 mol% 0.1 mol% Loading

[0312] Time to 50%

[0313] Reduction in

[0314] - 380 min N / A <210 min- 120 min 90 min Compound

[0315] (VII)

[0316] Time to 90%

[0317] - 1230 min 260 min <210 min- 270 min 200 min

[0318]

[0319] Reduction in 332305-FF

[0320] 25

[0321] Compound

[0322] (VII)

[0323] Time to 99%

[0324] Reduction in Not

[0325] 300 min 435 min 210 min 330 min 270 min Compound Achieved

[0326] (VII)

[0327] Time to 50%

[0328] Production of

[0329] - 480 min <210 min - 120 min 90 min Compound

[0330] (VIII)

[0331] Time to 90% >1230 min

[0332] Production of (Did not

[0333] - 300 min - 270 min 200 min Compound achieve

[0334] (VIII) 90%)

[0335] Time to

[0336] Reaction

[0337] Completion

[0338] 300 min >1230 min 435 min 210 min 330 min 270 min (Formation of

[0339] Compound

[0340]

[0341] (VIII))

[0342] As mentioned above, the skilled person will appreciate that the longer a reaction takes to reach completion, the greater the risk of production of by-products and impurities. The data shown in Table 3 demonstrates that as the quality of Compound (V) is improved, the rate of reaction of the hydrogenation of Compound (VII) to Compound (VIII) increases, and thus the time to reaction completion decreases.

[0343] Higher levels of catalyst, for example 0.35 mol% as described in WO 2013 / 127764 (and as demonstrated above in Table 3), would be expected to complete the hydrogenation of Compound (VII) to Compound (VIII) much more quickly than low levels of platinum catalyst, but at much higher catalyst usage.

[0344] For most chemical reactions, the rate of reaction decreases over time because the concentration of reactants decreases as the reaction progresses. The skilled person will therefore appreciate that if the overall rate of a reaction remains faster for longer, it may in fact be economically beneficial to a) further reduce catalyst loading, thus minimizing costs whilst still achieving commercially acceptable reaction rates, or b) implement catalyst recycling with minimal additions of fresh catalyst as required. As the deactivation rate of the catalyst reduces, the quantity of fresh catalyst required to 'top-up' the catalyst loading diminishes and thus the length of time between complete catalyst removal for external recycling can be extended.

[0345] Faster overall reaction rates reduce the time catalysts spend under deactivating conditions, thereby lowering deactivation rates and improving effective turnover numbers and cost efficiency. By contrast, slow reactions associated with crude inputs increase impurity formation risk and extend time under conditions that degrade product quality and catalyst performance. 332305-FF

[0346] 26

[0347] These improvements lead to an increase in the catalyst's effective utilization, as reflected by a higher turnover number. This optimization not only enhances process efficiency but also contributes to cost reduction and improved sustainability in catalytic processes.

[0348] The above-mentioned benefits accrue without sacrificing the oximation yield in step c), but they directly address the economic bottleneck of the hydrogenation step by decreasing cycle times, mitigating impurity formation, and enabling lower catalyst intensity and extended catalyst lifetimes. They also deliver higher throughput from existing assets by shortening critical path operations and increasing the availability of Compound (V) via higher recovery and recyclable filtrate work-flows.

Claims

332305-FF27CLAIMS:

1. A process for the preparation of Compound (I)comprisinga) adding Compound (II)Clin the presence of a solvent, to a mixture comprising a nitrite of Formula (III)R1-O-N=O (III),wherein R1is hydrogen, C1-C6alkyl, or an inorganic cation, Compound (IV)and a solvent, to provide Compound (V)b-i) distilling the resulting Compound (V); or332305-FF28b-ii) crystallizing the resulting Compound (V); orb-iii) distilling the resulting Compound (V), and then crystallizing the distilled material;c) reacting Compound (V) as purified in step b-i), b-ii), or b-iii), with Compound (VI) or salts thereof:H2N-O-CH3(VI),to form a mixture of isomers (E- and Z-) depicted as Compound (VII):Cld) reducing Compound (VII) to Compound (VIII):(VIII), ande) reacting Compound (VIII) with a compound of Formula (IX):CH3wherein R* is halogen, hydroxy, C₁-C₆alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, phosphoryl, or other suitable leaving group, to form Compound (I).

2. The process according to claim 1, wherein in a compound of Formula (III), R1is tert-butyl or an inorganic cation of sodium.

3. The process according to claim 1 or claim 2, wherein in a compound of Formula (IX), R* is chloro, hydroxy, ethoxy, or methoxy.332305-FF294. The process according to any one of claims 1 to 3, wherein the distillation of Compound (V) in step b-i) or b-iii) is carried out in the presence of a high boiling additive.

5. The process according to claim 4, wherein the distillation of Compound (V) in step b-i) or b-iii) is carried out in the presence of polyethylene glycol or an ester of phthalic acid.

6. The process according to claims 4 or 5, wherein the distillation of Compound (V) in step b-i) or b-iii) is further carried out in the presence of a low boiling additive.

7. The process according to claim 6, wherein the distillation of Compound (V) in step b-i) or b-iii) is carried out in the presence of 1,2-dichlorobenzene or 1,3-dichlorobenzene.

8. The process according to any one of claims 1 to 7, wherein the distillation of Compound (V) in step b-i) or b-iii) is carried out at a temperature of between 150°C to 200°C (boiling point temperature).

9. The process according to any one of claims 1 to 8, wherein the distillation of Compound (V) in step b-i) or b-iii) is carried out with a condenser temperature of 70°C to 100°C.

10. The process according to any one of claims 1 to 9, wherein the distillation of Compound (V) in step b-i) or b-iii) is carried out a pressure of less than 10 mbara.

11. The process according to any one of claims 1 to 3, wherein the crystallisation of Compound (V) in step b-ii) or b-iii) is carried out in at least one solvent.

12. The process according to claim 11, wherein the crystallisation of Compound (V) is carried out in an organic solvent selected from hexane and a Ci-C4alcohol, or mixtures thereof.

13. The process according to claim 12, wherein the organic solvent is hexane or methanol.

14. The process according any one of claims 11 to 13, wherein the crystallisation of Compound (V) is further carried out in the presence of water.

15. The process according to claim 1, comprising:a) adding Compound (II)Clin the presence of a solvent, to a mixture comprising a nitrite of Formula (III)R1-O-N=O (III),332305-FF30wherein R1is hydrogen, Ci-Cealkyl, or an inorganic cation,Compound (IV)and a solvent, to provide Compound (V)O (V), andb-iii) distilling the resulting Compound (V), and then crystallizing the distilled material; c) reacting the purified Compound (V) with Compound (VI) or salts thereof:H2N-O-CH3(VI),to form a mixture of isomers (E- and Z-) depicted as Compound (VII):NCH3d) reducing Compound (VII) to Compound (VIII):HN(VIII), and CH3e) reacting Compound (VIII) with a compound of Formula (IX):332305-FF31CH3wherein R* is halogen, hydroxy, C1-C6alkoxy, C1-C6alkylsulfanyl, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, phosphoryl, or other suitable leaving group, to form Compound (I).

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