Novel process for preparation of substituted 3-(3-phenoxypyridazin-4-yl)-5,6-dihydro-4h-1,2,4- oxadiazines

Abstract

The present invention relates to a novel process for the preparation of substituted 3-(3-phenoxypyridazin- 4-yl)-5,6-dihydro-4H-1,2,4-oxadiazines. In particular, the present invention relates to the preparation of 3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H- 1,2,4-oxadiazine, more specifically to (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-1,2,4-oxadizine.

Description

[0001] Novel process for preparation of substituted 3-(3-phenoxypyridazin-4-yl)-5,6-dihvdro-4H-l,2,4- oxadiazines

[0002] The present invention relates to a novel process for the preparation of substituted 3-(3-phenoxypyridazin- 4-yl)-5,6-dihydro-4H-l,2,4-oxadiazines. In particular, the present invention relates to the preparation of 3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H- 1,2,4-oxadiazine, more specifically to (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-rnethylpyridazin-4-yl]-5- (2-chloro-4-methylbenzyl)-5 ,6-dihydro-4H- 1 ,2,4-oxadiazine.

[0003] W02020 / 127780 and WO2021 / 255071 describe different heterocyclyl-substituted pyridazines as fungicides. Specifically, (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4- methylbenzyl)-5,6-dihydro-4H-l,2,4-oxadiazine is disclosed in W02020 / 127780 as a separation of enantiomers, however the explicit synthetic route is not described. A route to 3-[3-(3-chloro-2-fluoro- phenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-l,2,4-oxadiazine is described in WO2023 / 213670.

[0004] The route disclosed in WO2023 / 213670 starts by reacting the carboxylic acid of formula (A-l)

[0005] (A-l), with the amine hydrochloride of formula (A-2) in the presence of propanephosphonic anhydride as coupling reagent to yield the corresponding amide (A-3)

[0006] (A-3), which was treated with 2 equivalents PCI5 in toluene, then concentrated under reduced pressure, redissolved in 1,4-dioxane, and reacted with 20 equivalents of hydroxylamine (aq. solution, 50 wt%), extracted with organic solvent and concentrated in vacuo to afford amidoxime (A-4)

[0007] (A-4).

[0008] The amidoxime (A-4) was dissolved in acetonitrile and water and treated with sodium tert-butoxide (1 eq). After aqueous extraction with organic solvent and purification by column chromatography the corresponding oxadiazine (A-5)

[0009] (A-5) was obtained in 42% yield. The racemic oxadiazine (A-5) was separated into the enantiomers by chiral column chromatography. Drawbacks of this method is the low overall yield (48%), the use of excess of hazardous phosphorous pentachloride (PCI5), large excess (10-fold) of acutely toxic and carcinogenic hydroxylamine, the use of non-green solvents such as dichloromethane and 1 ,4-dioxane and the repetitive use of chromatographic purification techniques.

[0010] Additionally, it was found that isolation of amidoximes of type (A-4) carries significant safety risks upon scale-up, specifically exothermic decomposition in the solid state.

[0011] Considering the prior art described above, it is an object of the present invention to provide an improved process that does not have the aforementioned disadvantages and hence gives a higher yielding, less wasteful, and safer route to substituted 3-(3-phenoxypyridazin-4-yl)-5,6-dihydro-4H-l,2,4-oxadiazines.

[0012] The object described above was achieved by a process for the preparation of a compound of formula (I)

[0013] (I), wherein

[0014] R6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from the group consisiting of chloro, bromo and methyl,

[0015] R7is chloro, methyl, ethyl, iso-propyl or ethenyl, wherein methyl, ethyl and ethenyl are optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, hydroxy, methoxy and ethoxy,

[0016] R8is hydrogen, halogen or Ci-Cr-alkyl, or

[0017] R7and R8form together with the carbon-atoms to which they are attached to and the pyridazine- ring a fused ring of formulas (a- 1) to (a-3) wherein

[0018] #’ is the attachment to the -O-Q group,

[0019] #2is the attachment to the amidoxime-group, Q is phenyl, wherein phenyl is substituted with one or two substituents independently selected from the group consisiting of fluoro, chloro, methyl, ethyl and cyclopropyl, wherein cyclopropyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro and chloro, characterized in that, in step (A), an amide of formula (II)

[0020] (II), wherein R6, R7, R8and Q are defined as above, is reacted with a suitable base to form a compound of the formula (III) (III), wherein R6, R7, R8and Q are defined as above, which in step (B) is reacted with a hydroxylamine reagent optionally in the presence of a suitable base to form a compound of formula (IV) wherein R6, R7, R8and Q are defined as above, which in step (C) is treated an acetylating agent to yield a compound of formula (V) wherein R6, R7, R8and Q are defined as above, which is in step (D) treated with methylsulfonylchloride in the presence of a suitable base to form intermediate (VI) wherein R6, R7, R8and Q are defined as above, which is treated in step (E) with a suitable base to cyclize via intermediate (VII)

[0021] (VII), wherein R6, R7, R8and Q are defined as above, to finally yield compound of formula (I) .

[0022] Process step (E) proceeds via an intramolecular acetyl-shift yielding in a compound of formula (VIII)

[0023] (VIII), wherein R6, R7, R8and Q are defined as above, which then cyclizes to intermediate (VII).

[0024] Alternatively, process step (D) is followed by a step (DI), in which the acetyl group is removed to yield in a compound of formula (IX)

[0025] (IX), wherein R6, R7, R8and Q are defined as above, which in step (E) is cyclized in the presence of a suitable base to form a compound of formula (I).

[0026] In one embodiment, in the process according to the invention step (A) is preceded by a step (Aa), in which a compound of formula (X) wherein R7, R8and Q are defined as above, is reacted with a compound of formula (XI)

[0027] (XI), wherein R6is as defined above, to give a compound of formula (XII)

[0028] (XII), wherein R6, R7, R8and Q are defined as above, which in step (Ab) is treated with a chlorinating agent to give a compound of formula (II). In one embodiment, the process according to the invention is carried out as a telescoping process, i.e. the intermediates (II), (III), (IV), (V), (VI), (VII) and (IX) respectively are not isolated but directly used in the next process step.

[0029] The process according to the invention avoids the application of toxic and hazardous phosphorous reagents like PCI5 and PCI3, and involves a siginifcantly lower amount of hazardous and carcinogenic hydroxylamine reagents. Thus, by eleminating and reducing these hazardous, toxic and carcinogenic reagents the process according to the invention provides a much safer and cleaner access to compounds of formula (I) with a substantially higher overall yield. The process according to the invention allows easier isolation of the intermediates as well as desired compounds of formula (I) by crystallisation and filtration, and thus avoiding chromatographic purification steps. In addition, the telescoping route avoids laborious solvent switches in between reaction steps.

[0030] Formula (I) provides a general definition of the substituted 3-(3-phenoxypyridazin-4-yl)-5,6-dihydro-4H- 1 ,2,4-oxadiazines obtainable by the process according to the invention. Preferred radical definitions for formula (I) shown above and below are given below. These definitions apply to the end products of formula (I) and likewise to all educts and intermediates e.g. the amides of formula (II), the oxazolines of formula (III), the amidoxime of formula (IV), the acetylated amidoxime of formula (V), the mesylated acetylated amidoxime of formula (VI), the mesylated N-acetylamidoxime of formula (VIII), the N- acetylated 5,6-dihydro-4H-l,2,4-oxadiazine of formula (VII), the mesylated amidoxime of formula (IX), the ester of formula (X), the amine of formula (XI) and the amide of formula (XII).

[0031] Preferably,

[0032] R6is a group of formula wherein

[0033] §’ is the attachment to the methylene group,

[0034] R6S1is chloro, bromo or methyl,

[0035] R6S2is chloro or methyl.

[0036] Preferably, R7is chloro, methyl, ethyl, iso-propyl or ethenyl, wherein methyl, ethyl and ethenyl are optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, hydroxy, methoxy and ethoxy. R8is hydrogen, chloro, bromo, methyl or ethyl, or

[0037] R7and R8form together with the carbon-atoms to which they are attached to and the pyridazine- ring a fused ring of formulas (a-1) to (a-3) wherein

[0038] #’ is the attachment to the -O-Q group,

[0039] #2is the attachment to the amidoxime-group.

[0040] Preferably,

[0041] Q is a group of formula wherein

[0042] §2is the attachment to the oxygen atom,

[0043] QS1is hydrogen or fluoro,

[0044] QS2is chloro, methyl, ethyl or 1 -fluorocyclopropyl. More preferably, R6is 2-chloro-4-methylphenyl.

[0045] More preferably, R7is methyl and R8is hydrogen.

[0046] More preferably, Q is 2-fluoro-3-chlorophenyl.

[0047] Most preferably, the present invention relates to a process for the preparation of a compound of formula (1-1-1)

[0048] (1-1-1), characterized in that, in step (A), the amide of formula (II- 1-1)

[0049] (II-l-l), is reacted with a suitable base to form a compound of the formula (III- 1-1)

[0050]

[0051] (III-l-l), which in step (B) is reacted with a hydroxylamine reagent optionally in the presence of a suitable base to form a compound of formula (IV-1-1)

[0052] (IV-1-1) which in step (C) is treated an acetylating agent to yield a compound of formula (V-l-1)

[0053] (V-l-1) which is in step (D) treated first with methylsulfonylchloride to form intermediate (VI- 1-1)

[0054] (VI-1-1), which is treated in step (E) with a suitable base to cyclize to intermediate (VII- 1-1)

[0055] (VII-1-1), to finally yield compound of formula (I- 1-1) .

[0056] Process step (E) proceeds via an intramolecular acetyl-shift yielding in the compound of formula (VIII- 1- 1)

[0057] (VII-1-1), which then cyclizes to intermediate (VII-1-1). Alternatively, process step (D) is followed by a step (DI), in which the acetyl group is removed to yield in a compound of formula (IX- 1-1)

[0058] (IX-1-1), wherein R6, R7, R8and Q are defined as above, which in step (E) is cyclized in the presence of a suitable base to form a compound of formula (I).

[0059] In one embodiment, in the process according to the invention step (A) is preceded by a step (Aa), in which a compound of formula (X-l-1) (X-l-1), is reacted with a compound of formula (XI- 1-1)

[0060] (XI-1-1), to give a compound of formula (XII- 1-1)

[0061]

[0062] (XII-1-1), which in step (Ab) is treated with a chlorinating agent to give a compound of formula (II- 1-1).

[0063] In a further embodiment, the present invention relates to a compound of formula (II)

[0064] (II), wherein R6, R7, R8and Q are defined as above.

[0065] In a further embodiment, the present invention relates to a compound of formula (III) wherein R6, R7, R8and Q are defined as above.

[0066] In a further embodiment, the present invention relates to a compound of formula (IV) wherein R6, R7, R8and Q are defined as above.

[0067] In a further embodiment, the present invention relates to a compound of formula (V) wherein R6, R7, R8and Q are defined as above.

[0068] In a further embodiment, the present invention relates to a compound of formula (VI)

[0069] (VI), wherein R6, R7, R8and Q are defined as above.

[0070] In a further embodiment, the present invention relates to a compound of formula (VII) wherein R6, R7, R8and Q are defined as above.

[0071] In a further embodiment, the present invention relates to a compound of formula (VIII)

[0072] (VIII), wherein R6, R7, R8and Q are defined as above.

[0073] In a further embodiment, the present invention relates to a compound of formula (IX)

[0074] (IX), wherein R6, R7, R8and Q are defined as above.

[0075] In a further embodiment, the present invention relates to a compound of formula (XII)

[0076] (XII), wherein R6, R7, R8and Q are defined as above.

[0077] General definition Unless otherwise stated, the following definitions apply for the substituents and residues used throughout this specification and claims:

[0078] The term “Ci-Cr-alkyl” as used herein refers to a saturated, branched or straight hydrocarbon chain having 1, 2, 3 or 4 carbon atoms. Examples of Ci-Cr-alkyl include but are not limited to methyl, ethyl, propyl (n-propyl), 1 -methylethyl (iso-propyl), butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methyl- propyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl).

[0079] The compounds of formula (IV)

[0080] (IV), wherein R6, R7, R8and Q are defined as above, can exist in two isomeric forms, (E)-isomer and (Z)-isomer

[0081] Z-lsomer E- Isom er wherein R6, R7, R8and Q are defined as above, as well as mixtures of (E)- and (Z)-isomer in all proportions. The present invention relates to both isomeric forms (E)-Isomer and (Z)-Isomer as well as mixtures of (E)- and (Z)-isomer in all proportions.

[0082] The compounds of formula (V)

[0083] (V), wherein R6, R7, R8and Q are defined as above, can exist in two isomeric forms, (E)-isomer and (Z)-isomer wherein R6, R7, R8and Q are defined as above, as well as mixtures of (E)- and (Z)-isomer in all proportions. The present invention relates to both isomeric forms (E)-Isomer and (Z)-Isomer as well as mixtures of (E)- and (Z)-isomer in all proportions.

[0084] The compounds of formula (VI) wherein R6, R7, R8and Q are defined as above, can exist in two isomeric forms, (E)-isomer and (Z)-isomer

[0085] Z- Isom er E-lsomer wherein R6, R7, R8and Q are defined as above, as well as mixtures of (E)- and (Z)-isomer in all proportions. The present invention relates to both isomeric forms (E)-Isomer and (Z)-Isomer as well as mixtures of (E)- and (Z)-isomer in all proportions.

[0086] The compounds of formula (IX) wherein R6, R7, R8and Q are defined as above, can exist in two isomeric forms, (E)-isomer and (Z)-isomer

[0087] Z- Isom er E-lsomer wherein R6, R7, R8and Q are defined as above, as well as mixtures of (E)- and (Z)-isomer in all proportions. The present invention relates to both isomeric forms (E)-Isomer and (Z)-Isomer as well as mixtures of (E)- and (Z)-isomer in all proportions.

[0088] Depending on the nature of the substituents, the compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) may be present in the form of the free compound and / or a salt thereof, such as an agrochemically active salt.

[0089] Agrochemically active salts include acid addition salts of inorganic and organic acids well as salts of customary bases. Examples of inorganic acids are hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulfuric acid, phosphoric acid and nitric acid, and acidic salts, such as sodium bisulfate and potassium bisulfate. Useful organic acids include, for example, formic acid, carbonic acid and alkanoic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, saturated or mono- or diunsaturated fatty acids having 6 to 20 carbon atoms, alkylsulphuric monoesters, alkylsulphonic acids (sulphonic acids having straight-chain or branched alkyl radicals having 1 to 20 carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromatic radicals, such as phenyl and naphthyl, which bear one or two sulphonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals having 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which bear one or two phosphonic acid radicals), where the alkyl and aryl radicals may bear further substituents, for example p-toluenesulphonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2- acetoxybenzoic acid, etc.

[0090] Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.

[0091] The compounds of the invention may exist in multiple crystalline and / or amorphous forms. Crystalline forms include unsolvated crystalline forms, solvates and hydrates.

[0092] The above specified definitions of R6, R7, R8and Q (broad definition as well as preferred, more preferred, even more preferred and most preferred definitions) can be combined in various manners. These combinations of definitions thus provide sub-classes of compounds according to the invention, such as for instance the ones disclosed below.

[0093] Preference is given to those compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) in which each of the definitions (substituents and variables) have the abovementioned preferred meanings.

[0094] Particular preference is given to those compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII) in which each of the definitions (substituents and variables) have the abovementioned more, even more and / or most preferred meanings. Process description

[0095] The process of the present invention is illustrated in Schemes 1 to 3 below. Scheme 3

[0096] Step (A):

[0097] In step (A) of the present invention a compound of formula (II) is converted to a compound of formula (III) with a suitable base in a suitable solvent.

[0098] Suitable inorganic and organic bases for step (A) include, but are not limited to, alkaline earth metal or alkali metal carbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or cesium carbonate, alkali metal hydrides such as sodium hydride, alkaline earth metal or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide, lithium hydroxide, organic amines such as dimethylcyclohexylamine, tri-n-butylamine, triethylamine, diisopropylamine, diisopropylethylamine, methylamine, dimethylamine, diethylamine as well as alcoholic solutions thereof such as triethylammonium methoxide, triethylammonium ethoxide, triethylammonium isopropoxide, triethylammonium propoxide, triethylammonium 2-butoxide, diisopropylammonium methoxide, diisopropylammonium ethoxide, diisopropylammonium isopropoxide, diisopropylammonium propoxide, diisopropylammonium 2-butoxide, methylammonium methoxide, methylammonium ethoxide, methylammonium isopropoxide, methylammonium propoxide, methylammonium 2-butoxide, dimethylammonium methoxide, dimethylammonium ethoxide, dimethylammonium isopropoxide, dimethylammonium propoxide, dimethylammonium 2-butoxide, diethylammonium methoxide, diethylammonium ethoxide, diethylammonium isopropoxide, diethylammonium propoxide or diethylammonium 2-butoxide, other ammonium hydroxide derivatives such as ammonia or ammonium hydroxide, or ammonium alkoxides such as ammonium methoxide, ammonium ethoxide, ammonium isopropoxide or ammonium butoxide. Preferably, sodium hydroxide is used. More preferably, an aqueous solution of sodium hydroxide is used.

[0099] Suitable solvents for step (A) are alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tertbutanol, nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamine, N-methylpyrrolidone or hexa- methylphosphoric triamide, N-ethyl-pyrrolidone, hydrocarbons such as toluene, anisole, chlorobenzene, xylene, ethylbenzene, ethers such as tetrahydrofuran, methyl-tert-butyl ether, cyclopentyl methyl ether, esters such as isopropyl acetate and isoamyl acetate or water and / or mixtures thereof. Preferably, isopropanol is used in step (A).

[0100] Optionally a phase transfer catalyst is present in step (A). Suitable phase transfer catalysts are selected from the group consisting of tetrabutylammoinium hydroxide, Adogen464 and Aliquat336.

[0101] Preferably, the molar ratio of compound of formula (II) to base is in the range from 1 : 10 to 1 : 1 , preferably in the range of 1:5 to 1:1, more preferably in the range from 1:2 to 1:1.2.

[0102] Step (A) is carried out in a temperature range from 0°C to +80°C, preferably in a temperature range from +10°C to +50°C. The reaction time is range from 1 h to 24 h.

[0103] More preferably, the compound of formula (II) is added to a solution of the suitable base.

[0104] Step (B):

[0105] In step (B) of the present invention a compound of formula (III) is reacted with a suitable hydroxylamine reagent to a compound of formula (IV) optionally in the presence of a suitable base in a suitable solvent.

[0106] Suitable hydroxylamine reagents are hydroxylamine hydrate, hydroxylamine hydrochloride or hydroxylamine dihydrogensulfate.

[0107] Suitable solvents for the reaction with hydroxylamine are aromatic hydrocarbons such as toluene, benzene, anisole or chlorobenzene, alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol or other solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF) or N,N- dibutylformamide THF, dioxane, acetonitrile and butyronitrile. More preferably, the reaction is carried out in methanol.

[0108] Suitable bases for step (B) of the present invention are tertiary amines such as triethylamine, triisopropylamine, tri-n-butylamine, N,N-dimethylaniline, N,N-dicyclohexylmethylamine, N,N-diiso- propylethylamine, N-methylpiperidine, N,N-dimethylaminopyridine, N-methylimidazole, N-methyl- morpholine, N,N-dimethylcyclohexylamine, diazabicyclooctane (DABCO), diazabicyclononene (DBN), diazabicycloundecene (DBU), aromatic bases such as pyridine, 2,4,6-trimethylpyridine, 2-methyl- pyridine, 3 -methylpyridine, 4-(piperidin-l-yl)pyridine or 4-(pyrrolidin-l-yl)pyridine, 5-Ethyl-2- methylpyridine,. More preferably, the base is selected from the group consisting of triethylamine and N,N- dicyclohexylmethylamine.

[0109] Preferably, the molar ratio of compound of formula (III) to hydroxylamine is in the range from 1:3 to 1:1.005, preferably in the range from 1:2 to 1:1.01, more preferably in the range from 1:1.5 to 1:1.01. The reaction with hydroxylamine is carried out in a temperature range from 0°C to +80°C, preferably in a temperature range from +20°C to +60°C, more preferably in a temperature range from +30°C to +50°C.

[0110] The reaction time is in the range from 0.5 h to 10 h.

[0111] More preferably, step (B) of the present invention is carried out using hydroxylamine hydrate in combination with hydroxylamine hydrochloride or a combination of hydroxylamine hydrochloride or hydroxylamine dihydrogensulfate with a base, wherein the base is selected from the group consisting of sodium hydroxide, triethylamine and N,N-dimethylcyclohexylamine.

[0112] In case hydroxylamine hydrate is used in combination with hydroxylamine hydrochloride, the ratio of hydroxylamine hydrate to hydroxylamine hydrochloride is in the range from 1:0.05 to 1:1, preferably in the range of 1:0.08 to 1:0.7, more preferably in the range of 1:0.09 to 1:0.5.

[0113] In case hydroxylamine hydrate or hydroxylamine dihydrogensulfate is used in combination with with a base wherein the base is selected from the group consisting of sodium hydroxide, triethylamine and N,N- dimethylcyclohexylamine, the ratio of hydroxylamine hydrate or hydroxylamine dihydrogensulfate to base is in the range from 1:0.1 to 1:1.2, preferably in the range of 1:0.2 to 1:1.2, more preferably in the range of 1:0.2 to 1:1.1.

[0114] Step (C):

[0115] In step of the process according to the invention, a compound of formula (IV) is treated with an acetylating reagent to a compound of formula (V) in a suitable solvent.

[0116] Suitable acetylating agent for step (C) are acetic anhydride, acetyl chloride or acetic formic anhydride. Preferably, acetic anhydride is applied in step (C).

[0117] Suitable solvents for step (C) are alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tertbutanol, nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide, N-methylpyrrolidone N-ethyl- pyrrolidone or hexamethylphosphoric triamide, hydrocarbons such as toluene, anisole, chlorobenzene, xylene, ethylbenzene, ethers such as tetrahydrofuran, methyl-tert-butyl ether, cyclopentyl methyl ether, esters such as isopropyl acetate, butyl acetate, isoamyl acetate or water and / or mixtures thereof. Preferably, iso-propanol is used in step (C).

[0118] The acetylating agent is used in the range from 1.0 to 2.0 equivalents, based on the total amount of compounds of the formula (IV) used, preferably in the range from 1.001 to 1.5 equivalents, more preferably in the range from 1.02 to 1.1 equivalents.

[0119] Step (C) is carried out in a temperature range from 0°C to +50°C, preferably in a temperature range from +10°C to +30°C. The reaction time is in the range from 5 min to 1 h.

[0120] Step (D):

[0121] In step (D) of the process according to the invention, a compound of formula (V) is treated with methanesulfonylchloride or methanesulfonic anhydride to form a compound of formula (VI) in the presence of a suitable base in a suitable solvent.

[0122] Suitable bases for step (D) of the present invention are tertiary amines such as triethylamine, triisopropylamine, tri-n-butylamine, N,N-dimethylaniline, N,N-dicyclohexylmethylamine, N,N-diiso- propylethylamine, N-methylpiperidine, N,N-dimethylaminopyridine, N-methylimidazole, N-methyl- morpholine, N,N-dimethylcyclohexylamine, diazabicyclooctane (DABCO), diazabicyclononene (DBN), diazabicycloundecene (DBU), aromatic bases such as pyridine, 2,4,6-trimethylpyridine, 2-methyl- pyridine, 3 -methylpyridine, 4-(piperidin-l-yl)pyridine or 4-(pyrrolidin-l-yl)pyridine, 5-Ethyl-2- methylpyridine,. More preferably, the base is selected from the group consisting of triethylamine and N,N- dicyclohexylmethylamine.

[0123] Suitable solvents for step (D) are aromatic hydrocarbons such as toluene, benzene, anisole or chlorobenzene, alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol or other solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF) or N,N- dibutylformamide, isopropyl acetate, isobutyl acetate, isopentyl acetate, THF, methyl-tert-butyl ether, cyclopentyl-methyl ether, 4-methyl-tetrahydropyran, dioxane, acetonitrile and butyronitrile. Preferably, the reaction is carried out in iso-propanol.

[0124] Step (D) is carried out in a temperature range from 0°C to +50°C, preferably in a temperature range from +10°C to +30°C.

[0125] Step (DI):

[0126] In step (DI) of the process according to the invention, a compound of formula (VI) is treated with a suitable acid to form a compound of formula (IX) in a suitable solvent.

[0127] Suitable acids for step (DI) of the present invention are inorganic acids such as hydrochloric acid (HC1), sulfuric acid (H2SO4) and phosphoric acid (H3PO4) or organic acid such as acetic acid (CH3CO2H) and formic acid (HCO2H). More preferably, hydrochloric acid (HC1) is used.

[0128] Suitable solvents for step (DI) alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tertbutanol or other solvents such as THF, dioxane, methyl-tert-butyl ether, cyclopentyl-methyl ether, 4- methyl-tetrahydropyran, acetonitrile and butyronitrile, isopropyl acetate, isobutyl acetate, isopentyl acetate.Preferably, the reaction is carried out in methanol. Step (D) is carried out in a temperature range from 0°C to +50°C, preferably in a temperature range from +10°C to +30°C.

[0129] Step (E):

[0130] In step (E) of the process according to the invention, a compound of formula (VI) or (IX) is treated with a suitable base to form a compound of formula (I) in a suitable solvent.

[0131] Suitable inorganic and organic bases for step (E) include, but are not limited to, alkaline earth metal or alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or caesium carbonate), alkali metal hydrides (e.g. sodium hydride), alkaline earth metal or alkali metal hydroxides (e.g. sodium hydroxide, calcium hydroxide, potassium hydroxide or other ammonium hydroxide derivatives), or organic nucleophilic bases such as ammonia, methylamine, ethylamine, propylamine, butylamine. Preferably, sodium hydroxide is used. More preferably, an aqueous solution of sodium hydroxide is used.

[0132] Suitable solvents for step (E) are alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tertbutanol, l-methoxy-2-propanol, nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide, N- methylpyrrolidone, N-ethyl-pyrrolidone, hydrocarbons such as toluene, anisole, chlorobenzene, xylene, ethylbenzene, ethers such as tetrahydrofuran, methyl-tert-butyl ether, cyclopentyl methyl ether, esters such as isopropyl acetate and isoamyl acetate or water and / or mixtures thereof. Preferably, iso-propanol is used in step (E).

[0133] Optionally a phase transfer catalyst is present in step (E). Suitable phase transfer catalysts are selected from the group consisting of tetrabutylammonium hydroxide, Adogen464 and Aliquat336.

[0134] Step (E) is carried out in a temperature range from 0°C to +50°C, preferably in a temperature range from +10°C to +30°C.

[0135] Most preferably, the process steps (A), (B), (C), (D) and (E), optionally (DI) are carried out in a telescoping process, i.e. without isolation of the intermediates (II), (III), (IV), (V), (VI), (VII) and (IX) respectively.

[0136] Step (Aa):

[0137] In step (Aa) of the process according to the invention, a compound of formula (X) is reacted with a compound of formula (XI) to form a compound of formula (XII) in a suitable solvent.

[0138] Suitable solvents for step (Aa) are alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol, nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformamide, N-methylpyrrolidone or water and / or mixtures thereof. Preferably, methanol is used in step (Aa).

[0139] Step (Aa) is carried out in a temperature range from +20°C to +100°C, preferably in a temperature range from +40°C to +80°C.

[0140] Step (Ab):

[0141] In step (Ab) of the process according to the invention, a compound of formula (XII) is treated with a suitable chlorinating agent to form a compound of formula (II) in a suitable solvent.

[0142] Suitable chlorinating agents are thionyl chloride (SOCh), phosphorus trichloride (PCh), phosphorus pentachloride (PCI5), phosgene, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, methanesulfonyl chloride, hydrogen chloride, chlorine, oxalyl chloride, succinyl chloride, 2,4,6-trichloro[l,3,5]triazine, trichloroisocyanuric acid, N-chlorosuccinimide or 1,3-dichloro- 5,5-dimethylhydantoin. Preferably, thionyl chloride (SOCh) is used in step (Ab).

[0143] Optionally, a suitable base is present in step (Ab), wherein the suitable base is selected from the group consisting of tertiary amines such as triethylamine, triisopropylamine, tri-n-butylamine, N,N- dimethylaniline, N,N-dicyclohexylmethylamine, N,N-diisopropylethylamine, N-methylpiperidine, N,N- dimethylaminopyridine, N-methylimidazole, N-methylmorpholine, N,N-dimethylcyclohexylamine, di- azabicyclooctane (DABCO), diazabicyclononene (DBN), diazabicycloundecene (DBU), aromatic bases such as pyridine, 2,4,6-trimethylpyridine, 2-methylpyridine, 3 -methylpyridine, 4-methylpyridine, 4- methoxypyridine, 5-ethyl-2-methylpyridine, N,N-dimethylpyridine-4-amine, 4-(pyridine-4-yl)morpho- line, 4-(piperidin-l-yl)pyridine or 4-(pyrrolidin-l-yl)pyridine,. Preferably, the base is selected from the group consisting of triethylamine, triisopropylamine, tri-n-butylamine, N,N-diisopropylethylamine, N,N- dicyclohexylmethylamine, N,N-dimethylpyridine-4-amine, 4-(pyridine-4-yl)morpholine, 4-(piperidin- 1 - yl)pyridine and 4-(pyrrolidin-l-yl)pyridine.

[0144] Optionally, a chlorine source is present in step (Ab), wherein the chlorine source is selected from the group consisting of tetramethylammonium chloride, tetraethylammonium chloride and tetra-n- butylammonium chloride.

[0145] Suitable solvents for step (Ab) are aromatic hydrocarbons such as toluene, benzene, xylene, ethylbenzene, anisole or chlorobenzene, or other solvents such as N,N-dimethylacetamide (DMA), N,N-dimethylform- amide (DMF) or N,N-dibutylformamide THF, dioxane, methyl-tert-butyl ether, cyclopentyl-methyl ether, 4-methyl-tetrahydropyran, isopropyl acetate, isobutyl acetate, isopentyl acetate, acetonitrile and butyronitrile. Preferably, the reaction is carried out in toluene.

[0146] Step (Ab) is carried out in a temperature range from +20°C to +100°C, preferably in a temperature range from +50°C to +70°C. The invention is illustrated by but not limited to the following examples:

[0147] EXAMPLES

[0148] A-l. Abbreviations

[0149] A-2. General considerations Method 1:

[0150] HPLC method: Instrument: Waters UPLC; detector: SQD2; column: Agilent Eclipse Plus C18, 2.1 x 50mm; injection volume: 1 pl; flow rate 0.7 ml / min; column temperature: 60°C; measurement wavelength: Detection: Single Quad MS and Diode Array detector 210 - 450nm; eluent A: acetonitrile; eluent B: H2O; program:

[0151] A-3. Synthetic preparations

[0152] A-3.1. Preparation of (5S)-3-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-5-(2-chloro- 4-methylbenzyl)-5,6-dihydro-4H-l,2,4-oxadiazine (isolation of intermediates)

[0153] Step 1: (4S)-2-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-4-(2-chloro-4-methyl- benzyl)-4,5-dihydrooxazole

[0154] 3-(3-chloro-2-fluorophenoxy)-N-((S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl)-6-methyl- pyridazine-4-carboxamide (64 g, 129.26 mmol, 96% purity) was added portionwise to a solution of 2- propanol (235.50 g) and aqueous sodium hydroxide (27.01 g, 135.08 mmol, 20% wt, 1.05 eq) at 24°C. After one hour, water (120 g) was added. The resulting solid was filtered off and washed with a 1 : 1 mixture by volume of 2-propanol and water (100 mL total). The solid was then washed with water (150 g). 56.92 g of white solid were obtained (Yield of 96.7%, purity of 98% by qNMR)

[0155] 'H NMR (600 MHz, DMSO) 5 8.00 (s, 1H), 7.53 (ddd, J = 8.2, 6.6, 1.6 Hz, 1H), 7.38 (ddd, J = 8.5, 7.0, 1.7 Hz, 1H), 7.32 (td, J = 8.0, 1.8 Hz, 2H), 7.26 (dd, J= 1.8, 0.9 Hz, 1H), 7.05 (ddd, J = 7.8, 1.8, 0.8 Hz, 1H), 4.67 (dq, J = 9.5, 7.2 Hz, 1H), 4.50 (dd, J = 9.6, 8.5 Hz, 1H), 4.20 (dd, 7= 8.5, 7.6 Hz, 1H), 3.09 (dd, J = 13.9, 6.6 Hz, 1H), 2.91 (dd, J = 13.9, 7.3 Hz, 1H), 2.61 (s, 3H), 2.25 (s, 3H).

[0156] 13C NMR (151 MHz, DMSO) 5 159.32, 158.21, 158.10, 138.02, 133.01, 132.15, 131.48, 130.79, 129.48, 127.75, 127.27, 125.57, 125.53, 122.68, 116.60, 71.82, 66.50, 39.95, 39.80, 39.66, 39.52, 39.38, 39.24, 39.10, 37.71, 21.03, 20.67, 20.15.

[0157] LCMS (ESI) for C22H19CI2FN3O2+ [M+H]+ calculated: 446.08; found: 446.2;

[0158] Retention Time: 1.8 min (Method 1)

[0159] Step 2: 3-(3-chloro-2-fluorophenoxy)-N-((S)-l-(2-chloro-4-methylphenyl)-3-hydroxypropan-2-yl)- N'-hydroxy-6-methyl-pyridazine-4-carboximidamide

[0160] In a 500ml flask (4S)-2-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-4-(2-chloro-4-methyl- benzyl)-4,5-dihydrooxazole (50 g, 98% purity, 109.79 mmol, 1.0 eq) was added to 150 g of methanol at room temperature. Thereafter, hydroxylamine (7.62 g, 50% aq. solution, 115.28 mmol, 1.05 eq) was added and the resulting suspension was heated to 40°C for 10 hours. Thereafter, 75 g of the reaction mixture were removed by distillation ( below 40°C, 100 mbar), and the resulting residue was added to 1200 g of water. After crystallization, the solid was filtered off to afford the desired product as white solid (97.8% yield, 90% purity by qNMR, isolated as mixed hydrate (7% water content by KF titration).

[0161] 'H NMR (400 MHz, DMSO) 5 9.93 (s, 1H), 7.47 - 7.37 (m, 1H), 7.19 (dd, J = 7.2, 3.2 Hz, 2H), 7.06 - 6.97 (m, 2H), 6.93 (dd, J = 7.8, 1.8 Hz, 1H), 6.26 (s, 1H), 5.94 (d, J = 11.0 Hz, 1H), 4.88 (t, J = 5.3 Hz, 1H), 3.46 - 3.35 (m, 2H), 3.11 (td, 7 = 10.3, 4.8 Hz, 1H), 2.84 (dd, 7 = 13.3, 3.9 Hz, 1H), 2.54 (dd, 7 = 13.3, 9.9 Hz, 1H), 2.32 (s, 3H), 2.18 (s, 3H).

[0162] 13C NMR (151 MHz, DMSO) 5 160.41, 157.86, 151.26, 149.61, 148.65, 141.47, 141.39, 138.31, 133.81, 133.59, 132.82, 131.26, 129.57, 128.08, 127.90, 126.04, 126.01, 123.15, 121.88, 121.21, 121.11, 64.52, 55.08, 55.04, 21.11, 20.67.

[0163] LCMS (ESI) for C22H22C12FN4O3+[M+H]+calculated: 479,10; found: 479,3;

[0164] Retention Time: 1.36 min (Method 1)

[0165] The reactions listed in Table 1 were performed according to the procedure under Step 2 at 45 °C, using 500 mg of starting material as solution in Methanol (1.5 mL). Table 1:

[0166] ” 50% in H2O

[0167] Step 3: N'-acetoxy-3-(3-chloro-2-fluorophenoxy)-N-((S)-l-(2-chloro-4-methylphenyl)-3-hydroxy- propan-2-yl)-6-methyl-pyridazine-4-carboximidamide

[0168] 3-(3-chloro-2-fluorophenoxy)-N-((S)-l-(2-chloro-4-methylphenyl)-3-hydroxypropan-2-yl)-N' -hydroxy- 6-methyl-pyridazine-4-carboximidamide (30 g, 90% purity, 56.33 mmol, 1.0 eq) was dissolved in 2- propanol (60 mL) at room temperature. Then, acetic anhydride (6.01 g, 98% purity, 57.74 mmol, 1.025 eq) was added. After 10 minutes, the solvent was partially removed to afford a reaction mixture (46.7 g) which was added to 750 g of water under vigorous stirring. The resulting solid was stirred for Ih and filtered off to afford the title compound (31.52 g, 96.6% yield, 90% qNMR purity, 3.7% Water by K-F titration )

[0169] >H NMR (600 MHz, CDCI3) 57.27 - 7.22 (m, IH), 7.11 - 7.02 (m, 3H), 6.97 (q, 7= 8.1 Hz, 2H), 6.18 (s, IH), 5.95 (d, J = 10.9 Hz, IH), 4.70 (s, OH), 3.80 (s, IH), 3.73 (s, IH), 3.51 (tq, J = 10.9, 3.8 Hz, IH), 2.89 (dd, J = 13.7, 4.0 Hz, IH), 2.83 (dd, J = 13.8, 10.2 Hz, IH), 2.46 (s, 3H), 2.22 (s, 3H).

[0170] 13C NMR (151 MHz, CDCI3) 5 168.41, 159.77, 157.46, 152.87, 151.66, 150.00, 140.99, 140.91, 138.58, 132.19, 131.48, 129.89, 127.97, 127.80, 124.67, 124.63, 122.36, 122.24, 119.40, 64.92, 55.66, 21.13,

[0171] 21.12, 20.86, 19.87.

[0172] LCMS (ESI) C24H26CI2FN4CV [M+H]+calculated: 523,13; found: 523,3;

[0173] Retention Time: 1.44 min (Method 1) Step 4: (2S)-2-(N'-acetoxy-3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazine-4-carboximid- amido)-3-(2-chloro-4-methylphenyl)propyl methanesulfonate

[0174] A solution of N'-acetoxy-3-(3-chloro-2-fluorophenoxy)-N-((S)-l-(2-chloro-4-methylphenyl)-3-hydroxy- propan-2-yl)-6-methyl-pyridazine-4-carboximidamide (7.5 g, 11.27 mmol, 1.0 eq) in 2-propanol (24 g, contains 1 eq. of AcOH) was concentrated in vacuo to half its mass and toluene (26 g) was added. The reaction mixture was concentrated under reduced pressure to afford a reaction mass (20 g total) that was stirred at room temperature. Thereafter, N,N-dimethylcyclohexylamine (1.75 g, 13.52, 1.2 eq.) and methanesulfonyl chloride (1.45 g, 12.29 mmol, 1.1 eq) were added and the resulting suspension was stirred for 10 min. Water (10 g) was added followed by aq. HC1 (10 wt%) to reach pH = 6 in the aq. layer. Ethyl acetate (10 g) was added, the phases were separated, washed with brine, and concentrated under reduced pressure to a total mass of 10 g. Then, 2-propanol (30 g) was added, resulting in crystallization. The solid was filtered off to afford the title compoundt (6.23 g, 90.4% yield, 98% purity (q-NMR)).

[0175] >H NMR (600 MHz, CDCh) 5 7.31 (td, J = 6.5, 3.4 Hz, 1H), 7.15 - 7.09 (m, 2H), 7.08 (d, J = 1.2 Hz, 1H), 7.01 (d, J = 6.1 Hz, 2H), 6.29 (s, 1H), 5.91 (d, J = 11.0 Hz, 1H), 4.47 (s, 1H), 4.39 (s, 1H), 3.82 (tq, J = 10.9, 3.8 Hz, 1H), 3.06 (s, 3H), 3.09 - 3.00 (m, 1H), 2.89 (s, 1H), 2.50 (s, 3H), 2.35 (s, 3H), 2.26 (s, 3H).

[0176] 13C NMR (151 MHz, CDCh) 5 167.95, 159.66, 157.73, 157.71, 152.53, 151.73, 150.08, 140.99, 140.90, 139.23, 132.15, 132.14, 132.12, 130.13, 128.22, 128.00, 124.88, 124.85, 122.53, 122.51, 122.39, 118.69, 71.64, 71.62, 53.33, 37.70, 21.26, 20.96, 19.86.

[0177] LCMS (ESI) C25H28C12FN4O6S+[M+H]+calculated: 601,1; found: 601,1;

[0178] Retention Time: 1.50 min (Method 1)

[0179] Step 5: (5S)-3-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-5-(2-chloro-4-methyl- benzyl) -5,6-dihydro-4H- 1 ,2,4-oxadiazine

[0180] To a suspension of (2S)-2-(N'-acetoxy-3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazine-4-carboximid- amido)-3-(2-chloro-4-methylphenyl)propyl methanesulfonate (2.00 g, 3.27 mmol, 1.0 eq, 98% purity) in 2-Propanol (9.42 g) at room temperature was added aq. NaOH (35% , 934 mg, 8.17 mmol, 2.5 eq.) and the mixture was stirred at room temperature. After 1 h, additional 2-propanol (7.86 g) was added, followed by water (10 g) and precipitation occured. The solid was filtered off, washed with water (15 g) to afford the title compound (1.46 g, 94.81% yield, 98.08% (q-HPLC against reference standard)

[0181] A-3.2. Preparation of (5S)-3-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-5-(2-chloro- 4-methylbenzyl)-5,6-dihydro-4H-l,2,4-oxadiazine (telescoped route)

[0182] Step 1: (4S)-2-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-4-(2-chloro-4-methyl- benzyl)-4,5-dihydrooxazole 3-(3-chloro-2-fluorophenoxy)-N-((S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl)-6-methyl-pyri- dazine-4-carboxamide (100 g, 198.86 mmol, 96% purity) was added portion-wise to a solution of 2- propanol (400 g) and aqueous sodium hydroxide (25.07 g, 206.81 mmol, 33% wt, 1.04 eq.) at 24°C. The resulting mixture was stirred for 12 hr to yield the title compound; the reaction mixture was used directly in the next step.

[0183] Step 2: 3-(3-chloro-2-fluorophenoxy)-N-((S)-l-(2-chloro-4-methylphenyl)-3-hydroxypropan-2-yl)- N'-hydroxy-6-methyl-pyridazine-4-carboximidamide

[0184] To a suspension of the reaction mixture of step 1 in 2-propanol / water was added hydroxylamine hydrochloride (0.71 g, 9.94 mmol, 98% purity 0.05 eq.) followed by hydroxylamine (13.27 g, 50% aq. solution, 200.84 mmol, 1.01 eq.) and the reaction mixture was warmed to 40°C and stirred for 3h. Then, the reaction mixture was concentrated under reduced pressure to afford a suspension of the title compound which was directly used for the next step.

[0185] Step 3: N'-acetoxy-3-(3-chloro-2-fluorophenoxy)-N-((S)-l-(2-chloro-4-methylphenyl)-3-hydroxy- propan-2-yl)-6-methyl-pyridazine-4-carboximidamide

[0186] To a suspension of step 2 in 2-propanol / water was added isopropyl acetate (87 g). Then, acetic anhydride (21.02 g, 208.83 mmol, 99% purity, 1.025 eq.) was added to the reaction mixture over 15 minutes. After 2 hrs, the reaction mixture was diluted with isopropyl acetate (174 g) and washed with saturated aq. NaHCCh (50 mL) and brine (20 mL). The reaction mixture was concentrated under reduced pressure to a total mass of 175 g to afford a suspension of the title compound which was directly used for the next step.

[0187] Step 4: (2S)-2-(N'-acetoxy-3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazine-4-carboximid- amido)-3-(2-chloro-4-methylphenyl)propyl methanesulfonate

[0188] To a solution of the reaction mixture of step 3 in 2-propanol-acetate / 2-propanol / water was added xylene (87g) and the reaction mixture was concentrated in vacuo to remove residual water and 2-propanol. Then, xylene (185 g) was added, followed by N,N-dimethylcyclohexylamine (30.68 g, 238.64 mmol, 1.2 eq.). Then, methanesulfonyl chloride (25.55 g, 218.75 mmol, 1.1 eq.) was added dropwise whilst the temperature of the reaction mixture was kept below 35°C. Then, additional N,N-dimethylcyclohexylamine (7.67 g, 59.66 mmol, 0.3 eq.) and methanesulfonyl chloride (6.97 g, 59.66 mmol, 0.3 eq.) were added to reach complete conversion of the starting material. Water (200 g) was added, leading to formation of a precipitate. Ethyl acetate (270 g) was added to solubilize the solids. The phases were separated and the organic layer was washed with water (200 mg). Then, the reaction mixture was concentrated to 338 g to afford a suspension of the title compound in xylene, which was directly used for the next step.

[0189] Step 5: (5S)-3-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-5-(2-chloro-4-methyl- benzyl) -5,6-dihydro-4H- 1 ,2,4-oxadiazine To a suspension of the reaction mixture of step 4 in xylene was added sodium hydroxide (10% in water, 38.60 g, 596.57 eq, 3 eq) followed by 2-propanol (157 g). The biphasic reaction mixture was stirred at 35 °C for 4 h, and then the layers were separated. The organic layer was concentrated to a total mass of 275 g, and isoamyl acetate (88 g) was added. The mixture was cooled to 5°C and filtered to afford a filter cake which was washed with isoamyl acetate (44g), water (250 g), and dried to yield the title compound (75.01 g, 80.95% yield over 5 steps, 99.00% purity by qHPLC against reference standard). The mother liquor was concentrated to a mass of 24.5 g, and isoamyl acetate (25 g) was added. A solid crystallized, which was filtered off, washed with isoamyl acetate (35 g) and dried to afford the title compound (2nd crop, 5.19 g, 5.45% yield over 5 steps, 96.30% purity by qHPLC against reference standard. The mother liquor (77.25 g) contained 5.79% of the title compound as judged by qHPLC. This corresponded to 4.88% yield. Overall, the chemical yield of this described telescoped sequence was 91.28%.

[0190] A-3.3. Preparation of (5S)-3-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-5-(2-chloro- 4-methylbenzyl)-5,6-dihydro-4H-l,2,4-oxadiazine (hydrolysis route)

[0191] Step 1: [(2S)-2-[[C-[6-(3-chloro-2-fluoro-phenoxy)-3-methyl-l,6-dihydropyridazin-5-yl]-N- hydroxy-carbonimidoyl]amino]-3-(2-chloro-4-methyl-phenyl)propyl] methanesulfonate

[0192] To a suspension of N'-acetoxy-3-(3-chloro-2-fluorophenoxy)-N-((S)-l-(2-chloro-4-methylphenyl)-3- hydroxypropan-2-yl)-6-methyl-pyridazine-4-carboximidamide (2.00 g, 3.27 mmol, 1.0 eq., 98% purity) in Methanol (7,90 g) at room temperature was added hydrochloric acid (37% in water, 200 mg, 2.03 mmol, 0.63 eq.) and the mixture was stirred at room temperature for 24 h. Then, it was poured onto water (80 g) and stirred for Ih. The solid was filtered off, washed with water (25 g) to afford the title compound (1.82 g, 93.38% yield, 94% purity (q-HPLC against reference standard).

[0193] >H NMR (600 MHz, CDCL) 5 7.29 (td, J = 7.3, 2.4 Hz, IH), 7.17 - 7.04 (m, 4H), 7.01 (dd, J = 7.7, 1.8 Hz, IH), 6.51 - 6.35 (m, IH), 5.77 (d, J = 11.3 Hz, IH), 4.32 (d, J = 4.1 Hz, 2H), 3.77 (td, J = 10.2, 4.5 Hz, IH), 3.04 (dd, J = 13.8, 4.3 Hz, IH), 3.02 (s, 3H), 2.81 (dd, J = 13.8, 9.7 Hz, IH), 2.52 (s, 3H), 2.33 (s, 3H).

[0194] 13C NMR (151 MHz, CDCL) 5 159.94, 157.73, 151.71, 150.06, 149.69, 141.21, 141.12, 139.00, 134.58, 132.24, 131.21, 131.10, 129.98, 128.10, 127.87, 124.76, 124.73, 122.52, 122.41, 119.63, 71.84, 52.59, 37.51, 37.40, 21.28, 20.94.

[0195] LCMS (ESI) : C23H24C12FN4O5S+[M+H]+calculated: 557.1; found: 557.5;

[0196] Retention Time: 1.42 min (Method 1) Step 2: (5S)-3-(3-(3-chloro-2-fluorophenoxy)-6-methyl-pyridazin-4-yl)-5-(2-chloro-4-methyl- benzyl) -5,6-dihydro-4H- 1 ,2,4-oxadiazine

[0197] To a suspension of [(2S)-2-[[C-[6-(3-chloro-2-fluoro-phenoxy)-3-methyl-l,6-dihydropyridazin-5-yl]-N- hydroxy-carbonimidoyl]amino]-3-(2-chloro-4-methyl-phenyl)propyl] methanesulfonate (2.0 g, 3.37 mmol, 94% purity) in 2-propanol (7.42 g) was added sodium hydroxide (35% in water, 3.29 g, 8.17 mmol, 1.1 eq.) and the mixture was stirred at room temperature. The solid was filtered off, washed with water (20 g) to afford the title compound (1.34 g, 86.2% yield, 99% purity (q-HPLC against reference standard).

[0198] A-3.4. Synthesis of N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2- fluorophenoxy)-6-methylpyridazine-4-carboxamide

[0199] Step 1: 3-(3-chloro-2-fluorophenoxy)-N-[(2S)-l-(2-chloro-4-methylphenyl)-3-hydroxypro- pan-2-yl]-6-methylpyridazine-4-carboxamide

[0200] Methyl 3-(3-chloro-2-fhrorophenoxy)-6-methylpyridazine-4-carboxylate (177.94 g, 591.96 mmol, 98.7% purity) and (2S)-2-amino-3-(2-chloro-4-methylphenyl)propan-l-ol (120.00 g, 591.96 mmol, 98.5% purity, 1.00 eq.) were added to methanol (427.14 g, 13330.83 mmol, 99.0% purity, 540 mL) in a IL jacketed reactor equipped with a mechanical stirrer, a temperature probe, and a reflux condenser. The resulting suspension was heated to 64°C over 30 minutes to form a brown solution, which was stirred at this temperature for 2 hours. Seed crystals (20 mg) of the product were added to initiate product crystallization. After 5 minutes, a white solid began to precipitate. The reaction mixture was stirred at an internal temperature of 64°C for 24 hours. Analysis of the reaction mixture showed no further progress in conversion. The reaction was then cooled to 15 °C and stirred for 1 hour at this temperature and filtered. The resulting filter cake was washed twice with methanol (160 g each) and further dried by applying vacuum for 45 min. 252.15 g of the tilte compound were obtained as a colorless solid (96.9% purity by qNMR, yield of 88.9%).

[0201] In an additional step, the mother liquor and the wash liquor were combined, and the solvent was removed by rotary evaporation (40°C bath temperature and 20 mbar) to afford 27.30 g of residue containing a mixture of starting materials, minor unidentified side components. This residue (27.30 g) was added to methanol (540 mL) in a IL jacketed reactor equipped with a mechanical stirrer, a temperature probe, and a reflux condenser. The reactor was then charged with methyl 3-(3-chloro-2-fluorophenoxy)-6- methylpyridazine-4-carboxylate (177.94 g) and (2S)-2-amino-3-(2-chloro-4-methylphenyl)propan-l-ol (120.00 g). The reaction was performed in the same manner as outlined in the procedure for the first reaction batch.

[0202] Overall, this reaction was performed in sequence four times (three of which recycled the mother liquor stemming from the respective previous reaction); Average yield is 94.3%, with an average purity of 96.3%. Table 2:

[0203] 'H NMR (600 MHz, CDCh) 5 8.07 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.24 - 7.15 (m, 2H), 7.14 (d, J = 7.7 Hz, 1H), 7.10 - 7.02 (m, 1H), 6.88 (ddd, J = 1.1, 1.8, 0.8 Hz, 1H), 4.73 - 4.35 (m, 1H), 3.92 - 3.72 (m, 2H), 3.26 - 2.97 (m, 2H), 2.70 (s, 3H), 2.49 (t, J = 5.6 Hz, 1H), 2.24 (s, 3H).

[0204] 13C NMR (151 MHz, CDCh) 5 161.93, 159.40, 159.14, 151.71, 150.05, 140.85, 140.77, 138.71, 134.08, 131.88, 131.63, 131.18, 130.27, 128.23, 128.06, 124.56, 124.53, 122.74, 122.68, 120.70, 64.57, 53.48, 34.01, 21.51, 20.86, 0.15.

[0205] LCMS (ESI) for C22H21CI2FN3CV [M+H]+ calculated: 464,09; found: 446,4; Retention Time: 1,48 min (Method 1)

[0206] Step 2: N-r(2S)-l-chloro-3-(2-chloro-4-methvlphenvl)propan-2-vl1-3-(3-chloro-2-fluorophenoxy)- 6-methylpyridazine-4-carboxamide

[0207] 3-(3-chloro-2-fluorophenoxy)-N-[(2S)-l-(2-chloro-4-methylphenyl)-3-hydroxypropan-2-yl]-6-methyl- pyridazine-4-carboxamide (180.00 g, 372.55 mmol, 96.1% purity) was added to toluene (674.70 g, 7322.53 mmol, 99.9% purity, 740 mL) in a IL jacketed reactor equipped with a mechanical stirrer, a temperature probe, a distillation adapter and a reflux condenser. The resulting suspension was heated to 56°C over 20 minutes. Thionyl chloride (47.38 g, 390.36 mmol, 98.0% purity, 29.05 mL) was then added over the course of 1 hour using a syringe pump. The suspension was stirred for an additional 2 hours. HPLC analysis indicated advanced conversion with less than 3% of starting material remaining. Then, water (250g, 13885.68 mmol, 99.9% purity, 250 g) was added to the reaction mixture at 56°C in one minute. After stirring for 15 minutes, the solid dissolved. Stirring was stopped to allow the layers to settle for 10 minutes, after which the aqueous phase was removed, yielding the first aqueous phase (253 g). An additional portion of water (50 g, 2788.22 mmol, 99.9% purity, 50 g) was added to the reactor, and the mixture was stirred for 15 minutes. After allowing the phases to settle for 10 minutes, the aqueous phase was removed, yielding the second aqueous phase (51.9 g). The reactor jacket was set to 70°C and a vacuum was applied (300 mbar, reaction medium temperature 54°C) to begin distillation. The vacuum was gradually lowered to 150 mbar over 45 minutes while maintaining the reaction medium temperature constant (54°C). A total of 177.2 mL of cloudy colorless distillate wass collected, after which the collection flask was changed, and the pressure was lowered to 125 mbar. After 1 hour and 40 minutes, 359 g of colorless monophasic distillate were collected. The reactor was returned to normal pressure by backfilling with nitrogen, resulting in a light brown solution. Crystallization was initiated by adding product seeding crystals (20 mg), which led to precipitate formation. After 15 minutes of stirring, heptane (123.12 g, 1228.70 mmol, 99.9% purity, 180 mL) was added over 10 minutes while maintaining an internal temperature of 54°C. The reactor jacket temperature was set to 5 °C, and the reaction mixture was cooled to 6°C over 30 minutes, resulting in a stirrable, beige suspension. After 90 minutes of stirring at 5.1 °C, the product was harvested by filtration. The filter cake was washed with heptane (68.31 g, 681.76 mmol, 99.9% purity, 100 mL) and vacuum was applied for 30 minutes to remove solvent residues, affording 182.20 g of N-[(2S)-l-chloro-3-(2-chloro-4- methylphenyl)propan-2-yl]-3-(3-chloro-2-fluorophenoxy)-6-methylpyridazine-4-carboxamide as a light tan solid (Yield of 97.4%, 96.0% purity by qNMR). Analytical Data matched the previously reported values.

Claims

CLAIMS:

1. A process for the preparation of a compound of formula (I)(I), whereinR6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from the group consisting of chloro, bromo and methyl,R7is chloro, methyl, ethyl, iso-propyl or ethenyl, wherein methyl, ethyl and ethenyl are optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, hydroxy, methoxy and ethoxy,R8is hydrogen, halogen or Ci-Cr-alkyl, or R7and R8form together with the carbon-atoms to which they are attached to and the pyridazine-ring a fused ring of formulas (a-1) to (a-3)wherein is the attachment to the -O-Q group,#2is the attachment to the amidoxime-group,Q is phenyl, wherein phenyl is substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, methyl, ethyl and cyclopropyl, wherein cyclopropyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro and chloro, characterized in that, in step (A), an amide of formula (II)wherein R6, R7, R8and Q are defined as before, is reacted with a suitable base to form a compound of the formula (III)wherein R6, R7, R8and Q are defined as before, which in step (B) is reacted with a hydroxylamine reagent optionally in the presence of a suitable base to form a compound of formula (IV)(IV), wherein R6, R7, R8and Q are defined as before, which in step (C) is treated an acetylating agent to yield a compound of formula (V)wherein R6, R7, R8and Q are defined as before, which is in step (D) treated with methylsulfonylchloride in the presence of a suitable base to form intermediate (VI)(VI), wherein R6, R7, R8and Q are defined as before, which is treated in step (E) with a suitable base to cyclize via intermediate (VII)(VII),wherein R6, R7, R8and Q are defined as before, to finally yield compound of formula (I) .

2. The process according to claim 1 , whereinR6is a group of formulawherein§’ is the attachment to the methylene group,R6S1is chloro, bromo or methyl,R6S2is chloro or methyl.

3. The process according to claim 1 or 2, whereinR7is chloro, methyl, ethyl, iso-propyl or ethenyl, wherein methyl, ethyl and ethenyl are optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, hydroxy, methoxy and ethoxy, R8is hydrogen, chloro, bromo, methyl or ethyl, orR7and R8form together with the carbon-atoms to which they are attached to and the pyridazine-ring a fused ring of formulas (a-1) to (a-3)wherein#’ is the attachment to the -0-Q group,#2is the attachment to the amidoxime-group.

4. The process according to any of claims 1 to 3, whereinQ is a group of formulawherein§2is the attachment to the oxygen atom,QS1is hydrogen or fluoro,QS2is chloro, methyl, ethyl or 1 -fluorocyclopropyl.

5. The process according to any of claims 1 to 4, whereinR6is 2-chloro-4-methylphenyl,R7is methyl,R8is hydrogen,Q is 2-fluoro-3-chlorophenyl.

6. The process according to any of claims 1 to 5, wherein in step (A) the suitable base is selected from the group consisting of alkaline earth metal or alkali metal carbonates such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or cesium carbonate, alkali metal hydrides such as sodium hydride, alkaline earth metal or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide or other ammonium hydroxide derivatives.

7. The process according to any of claims 1 to 6, wherein step (B) is carried out using hydroxylamine hydrate in combination with hydroxylamine hydrochloride or a combination of hydroxylamine hydrochloride or hydroxylamine dihydrogensulfate with a base.

8. The process according to any of claims 1 to 7, wherein step (C) is carried out using acetic anhydride as acetylating agent and iso-propanol as solvent.

9. The process according to any of claims 1 to 8, wherein process step (D) is followed by a step (DI), in which the acetyl group is removed to yield in a compound of formula (IX)wherein R6, R7, R8and Q are defined as in any one of claims 1 to 5, which in step (E) is cyclized in the presence of a suitable base to form a compound of formula (I).

10. The process according to any of claims 1 to 9, wherein step (A) is preceded by a step (Aa), in which a compound of formula (X)(X), wherein R7, R8and Q are defined as in any one of claims 1 to 5, is reacted with a compound of formula (XI)wherein R6is as defined in any one of claims 1 to 5,to give a compound of formula (XII)(XII), wherein R6, R7, R8and Q are defined as in any one of claims 1 to 5, which in step (Ab) is treated with a chlorinating agent to give a compound of formula (II).

11. The process according to any of claims 1 to 8, wherein the process is carried out as a telescoping process.

12. Compound of formula (III)wherein R6, R7, R8and Q are defined as in any one of claims 1 to 5.

13. Compound of formula (IV)wherein R6, R7, R8and Q are defined as in any one of claims 1 to 5.

14. Compound of formula (V)wherein R6, R7, R8and Q are defined as in any one of claims 1 to 5.

15. Compound of formula (VI)(VI), wherein R6, R7, R8and Q are defined as in any one of claims 1 to 5.

16. Compound of formula (XII-1-1)(XII-1-1).

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