Process for preparation of substituted n-(2-chloroethyl)-n´-hydroxy-3-phenoxypyridazine-3- carboxamidines and substituted 3-(3-phenoxypyridazin-4-yl)-5,6-dihydro-4h-1,2,4-oxadiazines

Abstract

The present invention relates to a new and improved process for the preparation of substituted N-(2- chloroethyl)-N´-hydroxy-3-phenoxypyridazine-3-carboxamidines, which can be converted to 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-chloro-2-fluoro-phenoxy)-N-[1-(chloromethyl)-2-(2-chloro-4-methyl- phenyl)ethyl]-N'-hydroxy-6-methyl-pyridazine-4-carboxamidine, which can be converted to 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 3-(3-chloro-2-fluoro-phenoxy)-N-[1-(chloromethyl)-2-(2-chloro-4- methyl-phenyl)ethyl]-N'-hydroxy-6-methyl-pyridazine-4-carboxamidine, which can be converted to (5S)- 3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H- 1,2,4-oxadiazine.

Description

[0001] Process for preparation of substituted N-(2-chloroethyl)-N'-hvdroxy-3-phenoxypyridazine-3- carboxamidines and substituted 3-(3-phenoxypyridazin-4-yl)-5,6-dihvdro-4H-l,2,4-oxadiazines

[0002] The present invention relates to a new and improved process for the preparation of substituted N-(2- chloroethyl)-N -hydroxy-3-phenoxypyridazine-3-carboxamidines, which can be converted to 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-chloro-2-fluoro-phenoxy)-N-[l-(chloromethyl)-2-(2-chloro-4-methyl- phenyl)ethyl]-N'-hydroxy-6-methyl-pyridazine-4-carboxamidine, which can be converted to 3-[3-(3- chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H-l,2,4- oxadiazine, more specifically to 3-(3-chloro-2-fluoro-phenoxy)-N-[(lR)-l-(chloromethyl)-2-(2-chloro-4- methyl-phenyl)ethyl]-N'-hydroxy-6-methyl-pyridazine-4-carboxamidine, which can be converted to (5S)- 3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4-methylbenzyl)-5,6-dihydro-4H- 1,2,4-oxadiazine.

[0003] Substituted N-(2-chloroethyl)-N'-hydroxy-3-phenoxypyridazine-3-carboxamidines are valuable intermediates for the production of substituted 3-(3-phenoxypyridazin-4-yl)-5,6-dihydro-4H-l,2,4- oxadiazines. 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.

[0004] WO2021 / 255071 explicitly describes the synthesis of a closely related oxadiazine derivative starting from the corresponding amide (A-l)

[0005] (A-l), which was treated with 3 equivalents PCI5 in toluene, then concentrated under reduced pressure, redissolved in acetonitrile, and reacted with 20 equivalents of hydroxylamine (aq. Solution, 50 wt%), extracted with organic solvent and purified by column chromatography to afford amidoxime (A-2)

[0006] (A-2), in only 32% yield. The amidoxime (A-2) was dissolved in THF and treated with sodium tert-butoxide (1 eq). After aqueous extraction with organic solvent and purification by column chromatography the corresponding oxadiazine (A-3)

[0007] (A-3) was obtained in 42% yield.

[0008] Drawbacks of this method is the very low overall yield (13.4%), the use of excess of hazardous phosphorous pentachloride (PCI5), large excess (20-fold) of acutely toxic and carcinogenic hydroxylamine and the requirement of solvent switch to a reactive solvent (acetonitrile is demonstrably not inert to hydroxylamine) and the use of chromatographic purification techniques.

[0009] Additionally, it was found that isolation of amidoximes of type (A-2) carries significant safety risks upon scale-up, specifically exothermic decomposition in the solid state.

[0010] 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 N-(2-chloroethyl)- T-hydroxy-3-phenoxypyridazine-3- carboxamidines, which are important intermediates for the preparation of substituted 3-(3-phenoxypyrida- zin-4-yl)-5,6-dihydro-4H-l,2,4-oxadiazines.

[0011] The object described above was achieved by a process for the preparation of a compound of formula (IV) wherein

[0012] R6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from chloro, bromo and methyl,

[0013] 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,

[0014] R8is hydrogen, halogen or Ci-Cr-alkyl, or

[0015] 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)

[0016] (a-1) (a-2) (a-3)

[0017] #’ is the attachment to the -O-Q group,

[0018] #2is the attachment to the amidoxime-group,

[0019] Q is phenyl, wherein phenyl is substituted with one or two substituents independently selected from 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 as defined above, is reacted with a chlorinating agent to form a compound of the formula (III)

[0020] (III), wherein R6, R7, R8and Q are as defined above, which in step (B) is directly treated with hydroxylamine in the presence of a suitable base.

[0021] Preferably, the present invention relates to a process for the preparation of a compound of formula (IV) wherein

[0022] R6is a group of formula wherein

[0023] §’ is the attachment to the methylene group,

[0024] R6S1is chloro, bromo or methyl,

[0025] R6S2is chloro or methyl,

[0026] 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,

[0027] R8is hydrogen, chloro, bromo, methyl or ethyl, or

[0028] 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)

[0029] (a-1) (a-2) (a-3) wherein

[0030] #> is the attachment to the -O-Q group, #2is the attachment to the amidoxine-group,

[0031] Q is a group of formula wherein

[0032] §2is the attachment to the oxygen atom,

[0033] QS1is hydrogen or fluoro,

[0034] QS2is chloro, methyl, ethyl or 1 -fluorocyclopropyl, characterized in that, in step (A), an amide of formula (II) (II), wherein R6, R7, R8and Q are as defined above, is reacted with a chlorinating agent to form a compound of the formula (III)

[0035] (HI), wherein R6, R7, R8and Q are as defined above, which in step (B) is directly treated with hydroxylamine in the presence of a suitable base. More preferably, the present invention relates to a process for the preparation of a compound of formula (IV-1)

[0036] (IV-1), characterized in that, in step (A), the amide of formula (II- 1)

[0037] (II-l), is reacted with a chlorinating agent to form the compound of the formula (III-l)

[0038] (III-l), which in step (B) is directly treated with hydroxylamine in the presence of a suitable base.

[0039] Most preferably, the present invention relates to a process for the preparation of the compound of formula (IV-1-1)

[0040] (IV-1-1), characterized in that, in step (A), the amide of formula (II- 1-1)

[0041] (II-l-l) is reacted with a chlorinating agent to form the compound of the formula (III- 1-1)

[0042] (III-l-l), which in step (B) is directly treated with hydroxylamine in the presence of a suitable base. In a further embodiment, the present invention relates to a process for the preparation of a compound of formula (I)

[0043] (I), wherein

[0044] R6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from chloro, bromo and methyl,

[0045] 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,

[0046] R8is hydrogen, halogen or Ci-Cr-alkyl, or

[0047] 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)

[0048] (a-1) (a-2) (a-3)

[0049] #’ is the attachment to the -O-Q group,

[0050] #2is the attachment to the amidoxime-group,

[0051] Q is phenyl, wherein phenyl is substituted with one or two substituents independently selected from 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 the process comprises after steps (A) and (B) a further step (C), wherein a compound of formula (IV) wherein R6, R7, R8and Q are as defined above, is reacted with a suitable base.

[0052] Preferably, the present invention relates to a process for the preparation of a compound of formula (I)

[0053] (I), wherein

[0054] R6is a group of formula wherein §’ is the attachment to the methylene group,

[0055] R6S1is chloro, bromo or methyl,

[0056] R6S2is chloro or methyl,

[0057] 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,

[0058] R8is hydrogen, chloro, bromo, methyl or ethyl, 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)

[0059] (a-1) (a-2) (a-3) wherein

[0060] #’ is the attachment to the -O-Q group, #2is the attachment to the amidoxine-group,

[0061] Q is a group of formula wherein

[0062] §2is the attachment to the oxygen atom, QS1is hydrogen or fluoro,

[0063] QS2is chloro, methyl, ethyl or 1 -fluorocyclopropyl, characterized in that the process comprises after steps (A) and (B) a further step (C), wherein a compound of formula (IV) wherein R6, R7, R8and Q are as defined above, is reacted with a suitable base.

[0064] More preferably, the present invention relates to a process for the preparation of a compound of formula (1-1)

[0065] (1-1), characterized in that the process comprises after steps (A) and (B) a further step (C), wherein a compound of formula (IV- 1) (IV-1), is reacted with a suitable base.

[0066] Most preferably, the present invention relates to a process for the preparation of the compound of formula (1-1-1)

[0067] (1-1-1) characterized in that the process comprises after steps (A) and (B) a further step (C), wherein a compound of formula (IV- 1-1) (IV-1-1), is reacted with a suitable base.

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

[0069] (Ill), wherein

[0070] R6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from chloro, bromo and methyl,

[0071] 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,

[0072] R8is hydrogen, halogen or Ci-Cr-alkyl, or

[0073] 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)

[0074] (a-1) (a-2) (a-3)

[0075] #’ is the attachment to the -O-Q group,

[0076] #2is the attachment to the amidoxime-group,

[0077] Q is phenyl, wherein phenyl is substituted with one or two substituents independently selected from 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.

[0078] Preferably, the present invention relates to a compound of formula (III)

[0079] (Ill), wherein

[0080] R6is a group of formula wherein

[0081] §’ is the attachment to the methylene group,

[0082] R6S1is chloro, bromo or methyl,

[0083] R6S2is chloro or 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,

[0084] R8is hydrogen, chloro, bromo, methyl or ethyl, or

[0085] 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)

[0086] (a-1) (a-2) (a-3) wherein

[0087] #’ is the attachment to the -O-Q group,

[0088] #2is the attachment to the amidoxine-group, Q is a group of formula wherein

[0089] §2is the attachment to the oxygen atom,

[0090] QS1is hydrogen or fluoro,

[0091] QS2is chloro, methyl, ethyl or 1 -fluorocyclopropyl.

[0092] More preferably, the present invention relates to the compound of formula (III- 1)

[0093] (III-l).

[0094] Most preferably, the present invention relates to the compound of formula (III- 1 - 1 )

[0095]

[0096] (III-l-l).

[0097] General definition

[0098] Unless otherwise stated, the following definitions apply for the substituents and residues used throughout this specification and claims:

[0099] 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). The compounds of formula (III) wherein R6, R7, R8and Q are as defined above, can exist in two isomeric forms, (E)-isomer and (Z)-isomer

[0100] Z-lsomer E-lsomer wherein R6, R7, R8and Q are as defined 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.

[0101] The compounds of formula (III) wherein R6, R7, R8and Q are as defined above, can exist in two isomeric forms, (E)-isomer and (Z)-isomer

[0102] Z- Isom er E-lsomer wherein R6, R7, R8and Q are as defined 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.

[0103] Depending on the nature of the substituents, the compound of formula (I), (II), (III) and (IV) may be present in the form of the free compound and / or a salt thereof, such as an agrochemically active salt.

[0104] 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.

[0105] Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.

[0106] The compounds of the invention may exist in multiple crystalline and / or amorphous forms. Crystalline forms include unsolvated crystalline forms, solvates and hydrates.

[0107] 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.

[0108] Preference is given to those compounds of formulas (I), (II), (III) and (IV) in which each of the definitions (substituents and variables) have the abovementioned preferred meanings.

[0109] Particular preference is given to those compounds of formula (I), (II), (III) and (IV) in which each of the definitions (substituents and variables) have the abovementioned more, even more and / or most preferred meanings.

[0110] Process description

[0111] The process of the present invention is illustrated in Scheme 1 below.

[0112] Scheme 1 base step (C)

[0113] Step (A):

[0114] In step (A) of the present invention a compound of formula (II) is converted to a compound of formula (III) with a chlorinating agent in a suitable solvent.

[0115] Suitable chlorinating agent are phosgene, diphosgene, triphosgene, thionylchloride in combination with a suitable base, phosphorous pentachloride (PCI5), phosphorous pentachloride (PCI5) in combination with phosphorous oxychloride (POC13), phosphorous trichloride (PCI3) in combination with chlorine gas or phosphorous trichloride (PCI3) in combination with a suitable base.

[0116] Suitable solvents for the chlorination are aromatic hydrocarbons such as toluene, xylene (isomers of dimethylbenzene), mesitylene, benzene, anisole or chlorobenzene or other solvents such as THF, 2- methyl-tetrahydrofuran, 4-methylpyran, cyclopentyl methyl ether, tert-amyl methyl ether, methyl tertbutyl ether, dioxane, acetonitrile and butyronitrile or mixtures thereof. Preferably, the chlorination is carried out in chlorobenzene or in mixtures of chlorobenzene and acetonitrile.

[0117] Suitable bases for the chlorination are tertiary amines such as triethylamine, triisopropylamine, tri-n-butyl- amine, N,N-dimethylaniline, N,N-dicyclohexylmethylamine, N,N-diisopropylethylamine, N-methyl- piperidine, N,N-dimethylaminopyridine, N-methylimidazole, N-methylmorpholine, N,N-dimethyl- cyclohexylamine, diazabicyclooctane (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)morpholine, 4-(piperidin-l-yl)pyridine or 4-(pyrrolidin-l-yl)pyridine, other bases such as N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF) or N,N-dibutylformamide. 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-l-yl)pyridine and 4-(pyrrolidin-l-yl)pyridine.

[0118] Preferably, the molar ratio of compound of formula (II) to chlorinating agent is in the range from 1:10 to 1:1, more preferably in the range from 1:5 to 1:2.

[0119] The chlorination reaction is carried out in a temperature range from +20°C to +150°C, preferably in a temperature range from +20°C to 120°C. The reaction time is range from 1 h to 24 h.

[0120] Preferably, in case of phosgene, diphosgene or triphosgene as chlorinating agent, the base is selected from the group consisting of pyridine, 2,4,6-trimethylpyridine, 2-methylpyridine, 3-methylpyridine, N,N- dimethylpyridine-4-amine, 4-(pyridine-4-yl)morpholine, 4-(piperidin-l-yl)pyridine or 4-(pyrrolidin-l- yl)pyridine. More preferably, phosgene or triphosgene are used as chlorinating agent in combination with a suitable base, wherein the suitable base is selected from the group consisting of N,N-dimethylpyridine- 4-amine, 4-(pyridine-4-yl)morpholine, 4-(piperidin-l-yl)pyridine and 4-(pyrrolidin-l-yl)pyridine and wherein the solvent is a mixture of chlorobenzene and acetonitrile. The chlorination reaction is carried out in a temperature range from +20°C to +120°C, more preferably in a temperature range from +50°C to +80°C.

[0121] Preferably, in case of PQs as chlorinating agent, step (A) is carried out in chlorobenzene as solvent at a temperature in the range of +40°C to +60°C.

[0122] Preferably, in case of PCI5 in combination with POCI3 as chlorinating agent, step (A) is carried out without solvent.

[0123] More preferably, in case of PCI5 in combination with POCI3 as chlorinating agent, step (A) is carried out without solvent at a temperature in the range of +40°C to +60°C.

[0124] Preferably, in case of PCI3 in combination with chlorine gas as chlorinating agent, step (A) is carried out in chlorobenzene as solvent at a temperature in the range of +40°C to +70°C.

[0125] Preferably, in case of PCI3 in combination with a suitable base as chlorinating agent, the suitable base is selected from the group consisitng of tri-n-butylamine, N,N-diisopropylethylamine, N,N-dimethylamino- pyridine, N-methylimidazole, N-methylmorpholine, N,N-dimethylcyclohexylamine and diazabicyclo- octane (DABCO). More preferably, PCI3 in combination with a suitable base selected from the group consisiting of tri-n-butylamine, N,N-diisopropylethylamine, N-methylmorpholine and N,N-dimethyl- cyclohexylamine in chlorobenzene or toluene as solvent at a temperature in the range of +40°C to +70°C. Preferably, in case of SOCh in combination with a suitable base as chlorinating agent, the suitable base is selected from the group consisting of tri-n-butylamine, N,N-diisopropylethylamine, N,N-dimethylamino- pyridine, N-methylimidazole, N-methylmorpholine, N,N-dimethylcyclohexylamine and diazabicyclo- octane (DABCO).

[0126] More preferably, SOCh in combination with a suitable base as chlorinating agent, the suitable base is selected from the group consisiting of tri-n-butylamine, N,N-diisopropylethylamine, N-methylmorpholine and N,N-dimethylcyclohexylamine in chlorobenzene or toluene as solvent at a temperature in the range of +40°C to +70°C.

[0127] Step (B):

[0128] In step (B) of the present invention a compound of formula (III) is reacted with hydroxylamine to a compound of formula (IV) in the presence of a suitable base in a suitable solvent.

[0129] Suitable solvents for the reaction with hydroxylamine are aromatic hydrocarbons such as toluene, benzene, anisole or chlorobenzene or other solvents such as THF, dioxane, acetonitrile and butyronitrile. More preferably, the reaction is carried out in THF.

[0130] 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-methylmorpholine, 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, other bases such as N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF) or N,N-dibutylformamide. More preferably, the base is selected from the group consisting of triethylamine, triisopropylamine, tri-n- butylamine, N,N-diisopropylethylamine and N,N-dicyclohexylmethylamine.

[0131] Preferably, the molar ratio of compound of formula (III) to hydroxylamine is in the range from 1 :5 to 1 : 1 , more preferably in the range from 1:3 to 1:2.

[0132] The reaction with hydroxylamine is carried out in a temperature range from 0°C to +50°C, more preferably in a temperature range from +10°C to +30°C.

[0133] The reaction time is in the range from 1 h to 24 h.

[0134] Step (C):

[0135] In step of the process according to the invention, a compound of formula (IV) is converted to a compound of formula (I) in the presence of a suitable base in a suitable solvent. 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-methylformanilide, N-methylpyrrolidone or hexa- methylphosphoric triamide or water and / or mixtures thereof. Preferably, water is used in step B.

[0136] Suitable inorganic and organic bases for step (C) include, but are not limited to, alkaline earth metal or alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or cesium 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). Preferably, sodium hydroxide is used.

[0137] The base is used in amounts in the range from 1.0 to 5.0 equivalents, based on the total amount of compounds of the formula (IV) used, preferably in the range from 1.05 to 3.0 equivalents, more preferably in the range from 1 .1 to 2.5 equivalents.

[0138] 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.

[0139] More preferably, step (C) is carried out in water a solvent with sodium hydroxide as base, wherein the base is used in amounts in the range from 1.1 to 2.5 equivalents, based on the total amount of compounds of the formula (IV) used, and at a temperature in the range from +10°C to +30°C.

[0140] The reaction time is range from 1 h to 24 h.

[0141] The invention is illustrated by but not limited to the following examples:

[0142] EXAMPLES

[0143] A-l. Abbreviations

[0144] A-2. General considerations

[0145] Method 1: HPLC method: Instrument: Agilent 1220 Infinity LC; detector: Agilent 1220 series DAD; column: Zorbax Eclipse Plus C18 4.6 x50 mm 1.8 pm; injection volume: 1 pl; flow rate 2 ml / min; column temperature: 50°C; measurement wavelength: 210 nm; eluent A: 0.1% (v / v) aqueous phosphoric acid; eluent B: acetonitrile; program:

[0146] Method 2: qHPLC method: Instrument: Agilent 1260 Infinity II LC; detector: Agilent 1290 Infinity II DAD; column: Phenomenex Gemini C18 3 x 150 mm 3 pm; injection volume: 3 pl; flow rate 0.9 mL / min; column temperature: 60°C; measurement wavelength: 270 nm; eluent A: water with 1750 mg / L K2HPO4 and 200 pL / L phosphoric acid; eluent B: methanol; program: Analytes are quantitatively determined against certified reference items. Method 3:

[0147] HPLC Method: Instrument Agilent: 1100 LC-System; detector: DAD detector 190-400 nm; column: Phenomenex Prodigy 100 x 4mm ODS 3 pm; injection volume: 1 pl; flow rate 2 ml / min; column temperature: 25°C; measurement wavelength: 210 nm; eluent A: acetonitrile; eluent B: 0.025% (v / v) aqueous trifluoroacetic acid; program:

[0148] Method 4:

[0149] HPLC Method:

[0150] Instrument: Agilent 1260 HPLC (or equivalent apparatus); Detector: Agilent 1260 DAD (or equivalent apparatus); Column: Phenomenex Gemini C18; 150 x 3 mm; 3 pm; Flow rate: 0.9 mL / min; Oven: 60°C;

[0151] Wavelength: 270 nm; Injection vol.: 3 pL; Post time: 2.5 min; Mobile phase: A: Water with 1750 mg / L

[0152] KiHPOr and 200 pL / L ortho phosphoric acid; B: Methanol

[0153] Gradient elution: Quantification is performed by calibration using a certified external standard.

[0154] The yield was determined by the following equation :

[0155] Rel. area % (single peak) = area (single peak) / sum area of all peaks A-3. Synthetic preparations

[0156] A-3.1 Preparation of N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2- fluorophenoxy) -6-methylpyridazine-4-carboximidoyl chloride

[0157] A-3.1.1

[0158] 18.1 g (182 mmol) phosgene gas were added at 20°C through a dip tube into a stirred solution of 30 g (94.5%, 60.8 mmol) N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2-fluoro- phenoxy)-6-methylpyridazine-4-carboxamide and 10.8 g (73 mmol) 4-(pyrrolidin-l-yl)pyridine in 75 ml acetonitrile and 75 ml chlorobenzene. After complete addition the temperature was increased to 80°C and the mixture was stirred for 5 h. Acetonitrile and excess of phosgene were then distilled off at 100 mbar und 50°C. The distillation sump was cooled to 5°C and then filtered under argon through a glass suction filter. The filter cake was washed with 40 ml dry chlorobenzene and dried under vacuum yielding 15 g 4- (pyrrolidin-l-yl)pyridine hydrochloride (92% of theory). The filtrate was concentrated at 65 °C under reduced pressure down to 10 mbar until a dark oil remained as residue. The conversion of the starting material to the desired compound was determined by HPLC after derivatization of the sample with excess of 50% aq. hydroxylamine.

[0159] HPLC (Method 1): Rt= 3.65 min, 90 area-%

[0160] A-3.1.2

[0161] 12.3 g (124 mmol) phosgene gas were added at 20°C through a dip tube to a stirred solution of 12.3 g (82.7 mmol) 4-(pyrrolidin-l-yl)pyridine in 75 ml chlorobenzene. The resulting suspension was stirred 15 min and then excess of phosgene was distilled off under reduced pressure. Next, 23.7 g (44.1 mmol) N- [(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2-fluorophenoxy)-6-methylpyrida- zine-4-carboxamide hydrochloride (1:1) and 75 ml acetonitrile were added. The suspension was stirred 21 h at 50°C and then acetonitrile was distilled off at 65 mbar and 50°C. The distillation sump was cooled to 5 °C and then filtered under argon through a glass suction filter. The filter cake was washed with 30 ml dry chlorobenzene and dried under vacuum yielding 15.5 g 4-(pyrrolidin-l-yl)pyridine hydrochloride (95% of theory). The filtrate was concentrated at 65°C under reduced pressure down to 10 mbar until a dark oil remained as residue. The conversion of the starting material to the desired compound was determined by HPLC after derivatization of the sample with excess of 50% aq. hydroxylamine.

[0162] HPLC (Method 1): Rt= 3.66 min, 89 area-%

[0163] A-3.1.3

[0164] 7.9 g (79.9 mmol) phosgene gas were added at 20°C through a dip tube to a stirred solution of 4.74 g (31.9 mmol) 4-(pyrrolidin-l-yl)pyridine in 36 ml chlorobenzene and 36 ml acetonitrile. Next, 14.5 g (26.6 mmol) N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2-fluorophenoxy)-6- methylpyridazine-4-carboxamide hydrochloride (1:1) were added. The suspension was stirred 10 h at 80°C and then acetonitrile was distilled off at 65 mbar and 50°C. The distillation sump was cooled to 5°C and then filtered under argon through a glass suction filter. The filter cake was washed with 35 ml dry chlorobenzene and dried under vacuum yielding 5.86 g 4-(pyrrolidin-l-yl)pyridine hydrochloride (85% of theory). The filtrate was concentrated at 65°C under reduced pressure down to 10 mbar until a dark oil remained as residue. The conversion of the starting material to the desired compound was determined by HPLC after derivatization of the sample with excess of 50% aq. hydroxylamine.

[0165] HPLC (Method 1): Rt= 3.66 min, 90 area-%

[0166] ’H-NMR (600 MHz, CDC13) 5 7.65 (s, 1H), 7.19 - 7.10 (m, 4H), 7.06 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H), 4.70 - 4.62 (m, 1H), 3.79 (dd, J = 11.1, 4.0 Hz, 1H), 3.75 (dd, J = 11.1, 7.8 Hz, 1H), 3.27 (dd, J = 13.6, 5.2 Hz, 1H), 2.99 (dd, J = 13.5, 8.5 Hz, 1H), 2.89 (s, 3H), 2.19 (s, 3H). A-3.1.4

[0167] The preparation of N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2-fluoro- phenoxy)-6-methylpyridazine-4-carboximidoyl chloride was also conducted by analogy to A-3.1.1 and usage of following solvents, reagents, stochiometry and reaction conditions according to table 1. The conversion of the starting material and the selectivity of product formation was determined by HPLC. Table 1:

[0168] Derivatization method for samples of step 1 : In a HPLC vial 1 ml acetonitrile and 0.1 ml 50% aq. hydroxyl amine were mixed and shaked until a homogenous solution was obtained. A sample of 1-10 pl reaction solution or concentrate were added and shaked. The solution was used for HPLC measurement. A-3.1.5

[0169] A 2L jacketed reactor fitted with a mechanical stirrer, a temperature probe and a reflux condenser was initially charged under inert atmosphere with 156 g phosphorus pentachloride (737 mmol, 98 wt.% purity) and 216 g chlorobenzene (99.0 %) at 20°C. The resulting suspension was heated to 50°C internal temperature. To this suspension a solution of 307 g of N-[(2S)-l-chloro-3-(2-chloro-4-methyl- phenyl)propan-2-yl]-3-(3-chloro-2-fluorophenoxy)-6-methylpyridazine-4-carboxamide (604 mmol, 95 wt.%) in 653 g chlorobenzene at 60 °C was added in 2h using a dosing pump. Afterwards the solution was allowed to proceed for additional 0.5 h at 50°C. Subsequently, phosphorous oxychloride and chlorobenzene were distilled out at 50 °C under vacuum in about 4 to 5 hours.

[0170] In that respect, the vacuum was gradually reduced to 15 mbar. The distillation started at 50 °C internal temperature and at ca. 100 mbar vacuum. The endpoint of the distillation was at 50°C and 15 mbar. About 95 % of chlorobenzene were distilled out under these conditions before addition of 423 g THF at 40 °C. The conversion of 3-(3-chloro-2-fluoro-phenoxy)-N-[(lS)-l-(chloromethyl)-2-(2-chloro-4-methyl- phenyl)ethyl]-6-methyl-pyridazine-4-carboxamide or rather the formation of 3-(3-chloro-2-fluoro- phenoxy)-N-[(lS)-l-(chloromethyl)-2-(2-chloro-4-methyl-phenyl)ethyl]-6-methyl-pyridazine-4-carbox- imidoyl chloride was analyzed by quenching an analytical sample with hydroxylamine [50 wt.% in water] and analyzing the corresponding oxime with HPLC (Method 1). The conversion of 3-(3-chloro-2-fluoro- phenoxy)-N-[(lS)-l-(chloromethyl)-2-(2-chloro-4-methyl-phenyl)ethyl]-6-methyl-pyridazine-4- carboxamide using HPLC (Method 1) was > 94%. The resulted solution of step 1 was cooled down to 20 °C and is transferred to the next step without further treatment.

[0171] A-3.1.6

[0172] In a 100ml four-neck flask 12 g (24.09 mmol) N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2- yl]-3-(3-chloro-2-fluorophenoxy)-6-methylpyridazine-4-carboxamide was added to 79 g chlorobenzene. At 20°C 4.37 g of PCh (33.72 mmol, 1.4 eq) were added. Shortly thereafter, 2.3 g of chlorine gas (32.52 mmol, 1.35 eq) were added over 20 min while the internal temperature rose to 40°C; The reaction mixture was heated to 65°C and stirred for 2 hours. HPLC indicates >98% conversion of the starting material. Thereafter 15mbar vacuum was applied and bath heated to 45 °C (35 °C internal temperature) and distillate was collected (73.8g. 108 mmol NaOH was required for neutralization). The residue after distillation contains: 0.69% starting material, 94.02% desired product which was evidenced by quench with excess hydroxylamine (Method 3).

[0173] HPLC Yield determined to be 93,3% using Method 3 (based on quantification against authentic standard after hydrolysis to amide (II) to which proves intermediacy of of imidoyl chloride (III))

[0174] A-3.1.7

[0175] In a reaction Vial, 1 g (1.98 mmol) of N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3- chloro-2-fluorophenoxy)-6-methylpyridazine-4-carboxamide was placed in 5.2 g toluene. Thereafter, 0.62 g of PCL (2.25 mmol, 1.12 eq) were added to the reaction mixture. Then, 1 g (3.96 mmol) of N,N- Dimethylcyclohexanamine (2 eq) was added and the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture contains (solvent not considered) 3.09 % starting material, 96.52% desired product as evidenced by quench with excess hydroxylamine.

[0176] HPLC Yield determined to be 94.05% using Method 3 (based on quantification against authentic standard after hydrolysis to amide (II) quantitative hydrolysis to AMIDE which proves intermediacy of proving the existence of imidoyl chloride (III)).

[0177] A-3.1.8

[0178] The preparation of N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2-fluoro- phenoxy)-6-methylpyridazine-4-carboximidoyl chloride was also conducted in analogy on 1 g scale to A- 3.1.7 and using chlorobenzene (6 mL) as solvent as well as reagents, stoichiometry and reaction conditions according to table 2. The conversion of the starting material and the selectivity of product formation was determined by HPLC.

[0179] Table 2:

[0180] * toluene as solvent A-3.1.9

[0181] In a reaction round-bottom flask, 6 g (11,93 mmol) of N-[(2S)-l-chloro-3-(2-chloro-4- methylphenyl)propan-2-yl]-3-(3-chloro-2-fluorophenoxy)-6-methylpyridazine-4-carboxamide was placed in 25.95 g toluene. Thereafter, 2.17 g of SOCL (17,90 mmol, 1.5 eq) were added to the reaction mixture. Then, 2,68 g (1 1 ,93 mmol) of 1,4-Diazabicyclo[2.2.2]octane (2 eq) was added and the reaction mixture was stirred at 60°C for 11 hours. The reaction mixture contains (Method 3, solvent not considered) 4.30 % starting material, 91.53% desired product (III) as evidenced by quench with excess hydroxylamine to give amidoxime (IV).

[0182] A-3.1.10

[0183] The preparation of N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2-fluoro- phenoxy)-6-methylpyridazine-4-carboximidoyl chloride was also conducted in analogy on 1 g scale to A-3.1.9 and using toluene (6 mL) as solvent as well as reagents, stoichiometry and reaction conditions according to table 3. The conversion of the starting material and the selectivity of product formation was determined by HPLC (Area).

[0184] Table 3:

[0185] 2g scale, toluene 10 mL

[0186] A-3.1.11

[0187] A IL jacketed reactor fitted with a mechanical stirrer, a temperature probe and a reflux condenser was initially charged under inert atmosphere with 105.5 g phosphorus pentachloride (497 mmol, 98 wt.% purity) and 123.5 g phosphorus oxychloride (800 mmol, 99.0 %) at 20°C. The resulting suspension was heated to 50°C internal temperature. To this suspension a solution of 196.4 g of N-[(2S)-l-chloro-3-(2- chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2-fluorophenoxy)-6-methylpyridazine-4-carboxamide (400 mmol, 98.3 wt.%) in 433.7 g phosphorus oxychloride (2.8 mol, 99.0 %) at 60°C was added in 2.5 h using a dosing pump. Afterwards the solution was allowed to proceed for additional 19 h at 50°C. Subsequently, phosphorus oxychloride was distilled out at 38 to 46 °C internal temperature under vacuum in about 5 hours. In that respect, the vacuum was gradually reduced to 70 mbar. The distillation started at 46 °C internal temperature and at ca. 140 mbar vacuum. The endpoint of the distillation was at 42 °C and 70 mbar. About 67 % of phosphorus oxychloride was distilled out under these conditions.

[0188] The formation of 3-(3-chloro-2-fluoro-phenoxy)-N-[(lS)-l-(chloromethyl)-2-(2-chloro-4-methyl- phenyl)ethyl]-6-methyl-pyridazine-4-carboximidoyl chloride was analyzed by HPLC (Method 1). For this purpose, a sample was distilled at rotary evaporator to remove phosphorus oxychloride completely. The remained oil was dissolved in THF and analyzed by quenching an analytical sample with hydroxylamine [50 wt.% in water] and analyzing the corresponding oxime with HPLC. The conversion of 3-(3-chloro-2-fhroro-phenoxy)-N-[(lS)-l-(chloromethyl)-2-(2-chloro-4-methyl-phenyl)ethyl]-6- methyl-pyridazine-4-carboxamide using HPLC (Method 1) was > 96 %.

[0189] A-3.2 Preparation of N-[(2S)-l-chloro-3-(2-chloro-4-methylphenyl)propan-2-yl]-3-(3-chloro-2- fluorophenoxy)-N'-hydroxy-6-methylpyridazine-4-carboximidamide

[0190] A-3.2.1

[0191] The dark oil of example A-3.1.1 was dissolved in 60 ml THF, and the resulting solution was added in 1 h to a stirred solution of 10.1 g (152 mmol) 50% aq hydroxylamine and 15.4 g (152 mmol) triethylamine in 45 ml THF at 20°C. The mixture was stirred 16 h at 20°C and then 27 ml (176 mmol) hydrochloric acid were added. The phases were separated, and the reactor was rinsed with 30 ml THF. The organic phases were combined, weighed and the content of the desired intermediate of step 2 was determined by quantitative HPLC resulting a yield of 57% for step 1 and 2. qHPLC (Method 2): Rt= 9.28 min, 66.5 area-%

[0192] A-3.2.2

[0193] The dark oil of A-3.1.2 was dissolved in 30 ml THF and the resulting solution was added in 1 h to a stirred solution of 7.3 g (110 mmol) 50% aq hydroxylamine and 11.2 g (110 mmol) triethylamine in 46 ml THF at 20°C. The mixture was stirred 16 h at 20°C and then 20 ml (130 mmol) hydrochloric acid were added. The phases were separated, and the reactor was rinsed with 10 ml THF. The organic phases were combined, weighed and the content of the desired intermediate of step 2 was determined by quantitative HPLC resulting a yield of 83% for step 1 and 2. qHPLC (Method 2): Rt= 9.15 min, 88.5 area-%

[0194] A-3.2.3

[0195] A 2L jacketed reactor fitted with a mechanical stirrer, a temperature probe and a reflux condenser was charged under inert atmosphere with 80 g hydroxylamine [50 wt.% in water] (1217 mmol, 50 wt.% purity in water) and 152 g triethylamine (1500 mmol, 99.9 %) at 20°C. To the resulting 2-phase mixture the THF-solution of A-3.1.5 was added ober 2h using a dosing pump at 20°C. Afterwards the solution was stirred for additional 4 h at 20°C. Subsequently, 180 g HC1 [20 wt.%] were added at 20-30°C until the pH was adjusted to < 3. After phase separation at 20°C 425 g water phase were discharged to water waste treatment and 865 g THF phase (ca. 25 wt.%) of 3-(3-chloro-2-fluoro-phenoxy)-N-[(lS)-l- (chloromethyl)-2-(2-chloro-4-methyl-phenyl)-ethyl]-N’-hydroxy-6-methyl-pyridazine-4-carboxamidine were isolated. The yield of the desired 3-(3-chloro-2-fluoro-phenoxy)-N-[(lS)-l-(chloromethyl)-2-(2- chloro-4-methyl-phenyl)ethyl]-N’-hydroxy-6-methyl-pyridazine-4-carboxamidine in THF using HPLC standard method was > 90%.

[0196] A-3.3 Preparation of (5S)-3-[3-(3-chloro-2-fluorophenoxy)-6-methylpyridazin-4-yl]-5-(2-chloro-4- methylbenzyl)-5,6-dihydro-4H-l,2,4-oxadiazine

[0197] A-3.3.1

[0198] A solution of 6.89 g (77.4 mmol) 45% aq. sodium hydroxide and 5.4 g water was added in 2 h at 20°C to the vigorously stirred solution of A-3.2.1 and then resulting mixture was stirred 16 h. Then, the phases were separated, and the organic phase was distilled at 170 mbar and 50°C while 75 ml isoamyl acetate were added by a dropping funnel. The distillation was continued under reduced pressure until THF, chlorobenzene and water residues were distilled off. The distillation sump was cooled to 10°C and a few seed crystals of the desired product were added. The resulting suspension was stirred at 10°C for 3 days, then 3 ml water were added, and the mixture was filtered through a glass suction filter. The filter cake was washed with 15 ml isoamyl acetate and dried at 60°C under vacuum. 9.2 g of the desired product were obtained as a light brown solid with a content of 72.5% (qHPLC) and a yield of 23.8% over 3 steps. qHPLC (Method 2): Rt= 9.14 min, 95.9 area-%, content 72.5 %

[0199] 'H-NMR (600 MHz, DMSO) 5 7.78 (s, 1H), 7.57-7.53 (m, 1H), 7.43 (d, 1H), 7.41 - 7.30 (m, 2H), 7.25 - 7.20 (m, 2H), 6.92 (d, 1H), 3.85 - 3.72 (m, 3H), 3.03 - 2.85 (m, 2H), 2.58 (s, 3H), 2.22 (s, 3H).

[0200] A-3.3.2

[0201] A solution of 7.55 g (84.9 mmol) 45% aq. sodium hydroxide and 3.56 g water was added in 2 h at 20°C to the vigorously stirred solution of A-3.2.2 and then resulting mixture was stirred 16 h. Then, the phases were separated, and the organic phase was distilled at 170 mbar and 50°C while 50 ml isoamyl acetate were added by a dropping funnel. The distillation was continued under reduced pressure until THF, chlorobenzene and water residues were distilled off. The distillation sump was cooled to 10°C and a few seed crystals of the desired product were added. The resulting suspension was stirred at 10°C for 3 days, then 50 ml water were added, and the mixture was filtered through a glass suction filter. The filter cake was washed with 20 ml water and isoamyl acetate each and dried at 70°C under vacuum. 12.6 g of the desired product were obtained as a light brown solid with a content of 96.3% (qHPLC) and a yield of 59.8% over 3 steps. qHPLC (Method 2): Rt= 9.22 min, 96.5 area-%, content 96.3 %

[0202] 'H-NMR (600 MHz, DMSO) 5 7.78 (s, 1H), 7.57-7.53 (m, 1H), 7.43 (d, 1H), 7.41 - 7.30 (m, 2H), 7.25 - 7.20 (m, 2H), 6.92 (d, 1H), 3.85 - 3.72 (m, 3H), 3.03 - 2.85 (m, 2H), 2.58 (s, 3H), 2.22 (s, 3H). A-3.3.3

[0203] 55 g water were added to the THF solution of A-3.2.3 (865 g) at 20°C followed by addition of 180 g caustic soda (32 wt.%) over 2 hours keeping the internal temperature at 20 to 25°C. After complete addition of caustic soda the resulting biphasic solution was allowed to proceed for additional four hours at 20°C. The pH value of the water phase was higher than 11. After phase separation at 20°C the aqueous phase (330 g) was discharged to waste treatment and the upper organic phase (810 g) was separated. THF was distilled out from the organic phase at 45-50°C under vacuum. 660 g Isoamyl acetate mixture (OXIPURITY 2170) was added to the remaining distillation sump followed by an azeotropic distillation at 45 to 80°C under vacuum to remove remaining THF and chlorobenzene. The solution was cooled down to 10°C over 2 to 5 hours. Crystallization started at approximately at 50°C. Finally, the product was separated by filtration and the wet cake was washed with 160 g pre-cooled Isoamylacetate (replacement wash) at 10°C and the wet cake was dried under vacuum at 60°C. 199 g (5S)-3-[3-(3-chloro-2-fluoro- phenoxy)-6-methyl-pyridazin-4-yl]-5-(2-chloro-4-methyl-phenyl)methyl]-5,6-dihydro-4H-l,2,4-oxadia- zine (94 wt.%) with 67% chemical yield over 3 steps was obtained. qHPLC (Method 4): Rt= 9.22 min, 96.5 area-%, content 96.3 %

Claims

CLAIMS:

1. A process for the preparation of a compound of the general formula (IV)whereinR6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from 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)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 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 as defined before, is reacted with a chlorinating agent to form a compound of the formula (III)(III), wherein R6, R7, R8and Q are as defined before, which in step (B) is directly treated with hydroxylamine in the presence of a suitable base.

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,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, 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 -O-Q group,#2is the attachment to the amidoxine-group,Q is a group of formulawherein§2is the attachment to the oxygen atom,QS1is hydrogen or fluoro,QS2is chloro, methyl, ethyl or 1 -fluorocyclopropyl.

3. The process for the preparation of the compound of formula (IV- 1)(IV-1) according to claim 1 or 2, characterized in that, in step (A), the amide of formula (II-l)(II-l), is reacted with a chlorinating agent to form the compound of the formula (III- 1)(III-l), which in step (B) is directly treated with hydroxylamine in the presence of a suitable base.

4. The process for the prepation of the compound of formula (IV- 1-1)(IV-1-1) according to any of claims 1 to 3, characterized in that, in step (A), the amide of formula (II- 1 - 1)(II-l-l) is reacted with a chlorinating agent to form the compound of the formula (III- 1-1)(III-l-l), which in step (B) is directly treated with hydroxylamine in the presence of a suitable base.

5. The process according to any of claims 1 to 4, wherein in step (A) the chlorinating agent is selected from the group consisting of phosgene, diphosgene, triphosgene, thionylchloride in combination with a suitable base, phosphorous pentachloride (PCI5), phosphorous pentachloride (PCI5) in combination with phosphorous oxychloride (POC13), phosphorous trichloride (PCI3) in combination with chlorine gas or phosphorous trichloride (PCI3) in combination with a suitable base.

6. The process according to any of claims 1 to 5, wherein in step (A) the chlorinating agent is phosphorous pentachloride (PCI5) or phosphorous trichloride (PCI3) in combination with chlorine gas or phosphorous trichloride (PCI3) in combination with a suitable base, wherein the suitable base is selected from the group consisitng of tri-n-butylamine, N,N-diisopropylethylamine, N,N- dimethylaminopyridine, N-methylimidazole, N-methylmorpholine, N,N-dimethylcyclohexyl- amine and diazabicyclooctane (DABCO).

7. The process according to any of claims 1 to 5, wherein in step (A) the chlorinating agent is phosgene or triphosgene in combination with a suitable base, wherein the suitable base is selected from the group consisting of N,N-dimethylpyridine-4-amine, 4-(pyridine-4-yl)morpholine, 4- (piperidin-l-yl)pyridine and 4-(pyrrolidin-l-yl)pyridine and wherein the solvent is a mixture of chlorobenzene and acetonitrile.

8. The process according to any of claims 1 to 5, wherein in step (A) the chlorinating agent is SOCh in combination with a suitable base, wherein the suitable base is selected from the group consisting of tri-n-butylamine, N,N-diisopropylethylamine, N,N-dimethylaminopyridine, N-methylimidazole, N-methylmorpholine, N,N-dimethylcyclohexylamine and diazabicyclooctane (DABCO).

9. The process according to any of claims 1 to 5, wherein in step (A) the chlorinating agent is PCI5 in combination with POCI3 and wherein step (A) is carried out without solvent.

10. The process according to any of claims 1 to 8, wherein in step (B) the suitable base is selected from the group consisting of tertiary amines such as triethylamine, triisopropylamine, tri-n-butyl- amine, N,N-dimethylaniline, N,N-dicyclohexylmethylamine, N,N-diisopropylethylamine, N-methylpiperidine, N,N-dimethylaminopyridine, N-methylimidazole, N-methylmorpholine, N,N-dimethylcyclohexylamine, diazabicyclooctane (DABCO), diazabicyclononene (DBN), diazabicycloundecene (DBU), aromatic bases such as pyridine, 2,4,6-trimethylpyridine, 2- methylpyridine, 3-methylpyridine, 4-(piperidin-l-yl)pyridine or 4-(pyrrolidin-l-yl)pyridine, other bases such as N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF) or N,N- dibutylformamide .

11. The process according to any of claims 1 to 10, wherein in step (B) the molar ratio of compound of formula (III) to hydroxylamine is in the range from 1:5 to 1:1.

12. The process according to any claims 1 to 11, wherein in step (B) the solvent is selected from the group consisting of aromatic hydrocarbons such as toluene, benzene, anisole or chlorobenzene or other solvents such as THF, dioxane, acetonitrile and butyronitrile.

13. A process for the preparation of a compound of formula (I)(I), whereinR6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from 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,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)#’ 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 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 the process comprises after steps (A) and (B) a further step (C), wherein a compound of formula (IV)wherein R6, R7, R8and Q are as defined before, is reacted with a suitable base.

14. The process according to claim 13, whereinis a group of formulawherein§’ is the attachment to the methylene group,R6S1is chloro, bromo or methyl,R6S2is chloro or methyl, is 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 -O-Q group,#2is the attachment to the amidoxine-group,Q is a group of formulawherein§2is the attachment to the oxygen atom,QS1is hydrogen or fluoro,QS2is chloro, methyl, ethyl or 1 -fluorocyclopropyl.

15. The process for the preparation of the compound of formula (1-1)(1-1) according to any of claims 13 or 14, wherein a compound of formula (IV- 1)(IV-1), is reacted with a suitable base.

16. The process for the preparation of the compound of formula (1-1-1)(1-1-1) according to any of claims 13 to 15, characterized in that the process comprises after steps (A) and (B) a further step (C), wherein a compound of formula (IV-1-1)(IV-1-1), is reacted with a suitable base.

17. The process according to any of claims 13 to 16, wherein step (C) is carried out in water as solvent with sodium hydroxide as base, wherein the base is used in amounts in the range from 1.1 to 2.5 equivalents based on the total amount of compounds of the formula (IV) used, and at a temperature in the range from +10°C to +30°C.

18. Compound of formula (III)whereinR6is phenyl, wherein phenyl is substituted with 2 substituents independently selected from 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, 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)#2is the attachment to the amidoxime-group,Q is phenyl, wherein phenyl is substituted with one or two substituents independently selected from 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.

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