Process for the preparation of substituted azines

Abstract

The present invention relates to a process for providing substituted azines of formula (T). Further it relates to a process for converting it to substituted azine compounds with herbicidal activity.

Description

[0001] 250053

[0002] 1

[0003] Process for the preparation of substituted azines

[0004] The present invention relates to a process for providing substituted azines. Further it relates to a process for converting it to substituted azine compounds with herbicidal activity.

[0005] WO 2022 / 161801 describes the above mentioned azine compounds, their herbicidal activity and their synthesis. These compounds are highly efficient herbicides. Therefore, there is an ongoing need for processes that easily make them available.

[0006] The present invention provides a process for the preparation of substituted azines.

[0007] The preparation of substituted azines is known from WO 2022 / 161801. However, the disclosed method has some disadvantages. One of the most relevant disadvantages is the poor yield. Furthermore, commercially not available chlorotriazines are used as raw materials together with the toxicologically problematic solvent dioxane (example 4, step 3; example 6, step 5; example 7, step 5; example 32, step 1 ; example 49, step 5). For two other examples the biguanide starting material used was similar to the newly described process of this application, but a commercially not available acid chloride together with an auxiliary base has been used for the reaction. A very complex not scaleable work up led to a yield of only 35 % (example 133, step 6; example 147, step 6).

[0008] Therefore, it was an object of the present invention to provide an industrially simple, cost-effective process for the preparation of substituted azines in good yields. In addition, the process should be environmentally friendly in order to reduce unfavorable environmental effects.

[0009] It has now surprisingly been found a highly efficient process for the synthesis of substituted azines of formula (T).

[0010] The present invention thus relates to a process for the preparation of the compound of formula (T)

[0011]

[0012] wherein

[0013] R1is selected from the group consisting of H, halogen, CN, Ci-C6-alkyl, (Ci-C6-alkoxy)-Ci-C6- alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C -alkyl, Ci-C6-alkoxy, C2-C6-alkenyloxy, C2- C6-alkynyloxy, C3-C6-cycloalkoxy, (C3-C6-cycloalkyl)-Ci-C4-alkoxy, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated;

[0014] R2is selected from the group consisting of H, halogen, CN, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci- C6-alkoxy and Ci-C6-haloalkoxy;

[0015] R3is selected from the group consisting of halogen, CN, Ci-C6-alkyl, C2-C6-alkenyl, C3-C6- alkynyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C -alkyl, C3-C6-cycloalkenyl and Ci-C6-250053

[0016] alkoxy-Ci-C6-alkyl, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated;

[0017] X is Cl or Br,

[0018] Y is H or F

[0019] comprising the following step:

[0020] (vi) reacting a compound of formula (VII) with a compound of formula (VIII)

[0021] >

[0022]

[0023] (Vll) (VIII)

[0024] in the presence of metal alkoxylate.

[0025] The present invention further relates to the process for the preparation of compound of formula (VII) as defined above comprising the following steps:

[0026] (i) preparing the compound (II) via a halogenation reaction of a compound of formula (I)

[0027]

[0028] (ii) preparing the compound of formula (III) via reaction of the compound of formula (II) with HNO3

[0029]

[0030] (iii) converting the compound of formula (III) to a compound of formula (IV)250053

[0031]

[0032] in presence of a methylation agent;

[0033] (iv) reducing the compound of formula (IV) to a compound of formula (V)

[0034]

[0035] (v) reacting the compound of formula (V) with the compound of formula (VI)

[0036]

[0037] to give the compound of formula (VII)

[0038]

[0039] Further embodiments of the invention are evident from the claims, the description and the examples. It is to be understood that the single features of the subject matter of the invention described herein can be applied not only in the combination given in each particular case but also in other combinations, without leaving the scope of the invention.

[0040] In the definitions of the variables given herein, collective terms are used which are generally representative for the substituents in question. The term “Cn-Cm” indicates the number of carbon atoms possible in each case in the substituent or substituent moiety in question. Examples of such meanings are:

[0041] halogen: fluorine, chlorine, bromine and iodine. The term “halogen” refers to fluorine, chlorine, bromine and iodine.

[0042] Ci-C4-alkyl and also the Ci-C4-alkyl moieties of Ci-C4-alkoxy, Ci-C4-alkylthio, Ci-C4-alkyl-sulfonyl, (Ci-C4-alkyl)carbonyl, (Ci-C4-alkyl)carbonyl, (Ci-C4-alkoxy)carbonyl, (Ci-C4-alkyl)car-bonyloxy, Ci-C4-alkyoxy-Ci-C4-alkyl, C3-C6-cycloalkyl-Ci-C4-alkyl, (Ci-C4-alkylamino)carbonyl,250053

[0043] 4

[0044] di(Ci-C4-alkyl)aminocarbonyl, (Ci-C4-alkylamino)sulfonyl, di(Ci-C4-alkyl)aminosulfonyl or phe-nyl-Ci-C4-alkyl: for example CH3, C2H5, n-propyl, CH(CH3)2, n-butyl, CH(CH3)-C2H5, CH2-CH(CH3)2and C(CH3)3;

[0045] Ci-C6-alkyl and also the Ci-C6-alkyl moieties of Ci-C6-alkoxy, Ci-C6-alkylthio, Ci-C6-alkyl-sulfonyl, (Ci-C6-alkyl)carbonyl, (Ci-C6-alkyl)carbonyl, (Ci-C6-alkoxy)carbonyl, (Ci-C6-alkyl)car-bonyloxy, Ci-C6-alkyoxy-Ci-C6-alkyl, C3-C6-cycloalkyl-Ci-C6-alkyl, phenyl(Ci-C6-alkyl)aminocar-bonyl, (Ci-C6-alkylamino)carbonyl, di(Ci-C6-alkyl)aminocarbonyl, (Ci-C6-alkylamino)sulfonyl, di(Ci-C6-alkyl)aminosulfonyl or phenyl-Ci-C6-alkyl: Ci-C4-alkyl as mentioned above, and also, for example, n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1 -dimethylpropyl, 1,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1 -dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dime-thylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 -ethyl- 1 -methylpropyl or 1-ethyl-2-methylpropyl, preferably methyl, ethyl, n-propyl, 1 -methylethyl, n-butyl, 1 , 1— dimethylethyl, n-pentyl or n-hexyl;

[0046] C2-C6-alkenyl and also the C2-C6-alkenyl moieties of (Ci-C6-alkoxy)-C2-C6-alkenyl: a linear or branched ethylenically unsaturated hydrocarbon group having 2 to 6 carbon atoms and a C=C-double bond in any position, such as ethenyl, 1 -propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1 -propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1 ,1-dimethyl-2-propenyl, 1 ,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1 -ethyl- 1 -propenyl, 1-ethyl-2-propenyl, 1 -hexenyl, 2-hex-enyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl- 1-pentenyl, 2-methyl- 1-pentenyl, 3-methyl-1-pentenyl, 4-methyl- 1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pen-tenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-bu-tenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-bu-tenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-bu-tenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1 -ethyl-1 -butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1 -butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1 ,1 ,2-trimethyl-2-pro-penyl, 1 -ethyl-1 -methyl-2-propenyl, 1-ethyl-2-methyl-1 -propenyl and 1-ethyl-2-methyl-2-pro-penyl;

[0047] C2-C6-alkynyl and also the C2-C6-alkynyl moieties of (Ci-C6-alkoxy)-C2-C6-alkynyl: linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing at least one C-C-triple bond, such as ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and the like;

[0048] Ci-C6-haloalkyl: Ci-C4-haloalkyl as mentioned above, and also, for example, 5-fluoropen-tyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chloro-hexyl, 6-bromohexyl, 6-iodohexyl and dodecafluorohexyl;

[0049] C3-C6-cycloalkyl: monocyclic saturated hydrocarbons having 3 to 6 ring members, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0050] Ci-C4-alkoxy: for example methoxy, ethoxy, propoxy, 1 -methylethoxy butoxy, 1-250053

[0051] 5

[0052] methylpropoxy, 2-methylpropoxy and 1,1 -dimethylethoxy;

[0053] Ci-C6-alkoxy and also the Ci-C6-alkoxy moieties of (Ci-C6-alkoxy)carbonyl, (Ci-C6-alkoxy)sulfonyl, (Ci-C6-alkoxy)-Ci-C6-alkyl, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (Ci-C6-alkoxy)-C2-C6-alkenyl, (Ci-C6-alkoxy)-C2-C6-alkynyl: Ci-C4-alkoxy as mentioned above, and also, for example, pentoxy, 1 -methylbutoxy, 2-methylbutoxy, 3-methoxylbutoxy, 1 ,1 -dimethylpropoxy, 1,2-dime-thylpropoxy, 2,2-dimethylpropoxy, 1 -ethylpropoxy, hexoxy, 1 -methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1 -dimethylbutoxy, 1 ,2-dimethylbutoxy, 1 ,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1-ethyl-1 -methylpropoxy and 1-ethyl-2-methylpropoxy;

[0054] Ci-C4-haloalkoxy: a Ci-C4-alkoxy radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and / or iodine, for example, chloro-methoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy2-fluoroethoxy, 2-chloroethoxy, 2-bromoeth-xoy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroeth-oxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 1-(fluoromethyl)-2-fluoroethoxy, 4-fluorobutoxy, nonafluorobutoxy, 1, 1,2,2, -tetrafluoroethoxy and 1 -trifluoromethyl- 1 ,2,2, 2-tetrafluoroethoxy;

[0055] Ci-C6-haloalkoxy: Ci-C4-alkoxy as mentioned above: Ci-C4-haloalkoxy as mentioned above, and also, for example, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl and dodecafluorohexyl;

[0056] C2-C6-alkenyloxy: C2-C6-alkenyl as defined above, which is bound via an oxygen atom, such as ethenyloxy (vinyloxy), 1 -propenyloxy, 2-propenyloxy (allyloxy), 1-butenyloxy, 2-bu-tenyloxy, 3-butenyloxy 1-methyl-2-propenyloxy and the like;

[0057] C2-C6-alkynyloxy: C2-C6-alkynyl as defined above, which is bound via an oxygen atom, such as ethynyloxy, 1-propynyl, 2-propynyloxy (propargyloxy), 1-butynyloxy, 2-butynyloxy, 3-butynyloxy 1-methyl-2-propynyloxy and the like;

[0058] C3-C6-cyclolalkyl and also the C3-C6-cyclolalkyl moieties of (C3-C6-cyclolalkyl)-carbonyl, (C3-C6-cyclolalkyl)-Ci-C6-alkyl, (C3-C6-cycloalkyl)carbonyl and (C3-C6-cyclolalkyl)-Ci-C6-alkoxy: a cycloaliphatic radical having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0059] C3-C6-cyclolalkoxy: a cycloaliphatic radical having 3 to 6 carbon atoms and bound via an oxygen atom, such as cyclopropyloxy, cyclo butyl oxy, cyclopentyloxy and cyclohexyloxy;

[0060] (C3-C6-cyclolalkyl)-Ci-C6-alkyl: Ci-C6-alkyl, in particular Ci-C4-alkyl as defined above, such as methyl or ethyl, wherein 1 hydrogen atom is replaced by C3-C6-cyclolalkyl as defined above, examples including cyclopropylmethyl (CH2-cyclopropyl), cyclobutylmethyl, cyclopentylmethyl, cycloexylmethyl, 1 -cyclopropylethyl (CH(CH3)-cyclopropyl), 1 -cyclobutylethyl, 1 -cyclopentylethyl, 1-cycloexylethyl, 2-cyclopropylethyl (CH2CH2-cyclopropyl), 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cycloexylethyl;

[0061] (C3-C6-cyclolalkyl)-Ci-C6-alkoxy: Ci-C6-alkoxy, in particular Ci-C4-alkoxy as defined above, such as methoxy or ethoxy, wherein 1 hydrogen atom is replaced by C3-C6-cyclolalkyl as250053

[0062] 6

[0063] defined above, examples including cyclopropylmethoxy (OCH2-cyclopropyl), cyclobutylmethoxy, cyclopentylmethoxy, cycloexylmethoxy, 1 -cyclopropylethoxy (0-CH(CH3)-cyclopropyl), 1-cyclo-butylethoxy, 1 -cyclopentylethoxy, 1-cycloexylethoxy, 2-cyclopropylethoxy (OCH2CH2)-cyclopro-pyl), 2-cyclobutylethoxy, 2-cyclopentylethoxy and 2-cycloexylethoxy;

[0064] (Ci-C6-alkoxy)-Ci-C6-alkyl: Ci-C6-alkyl, in particular Ci-C4-alkyl as defined above, such as methyl, ethyl or isopropyl, wherein 1 hydrogen atom is replaced by Ci-C6-alkoxy as defined above, examples including methoxymethyl, ethoxymethyl, n-propoxymethyl, butoxymethyl, 1-methoxyethyl, 1 -ethoxyethyl, 1-(n-propoxy)ethyl, 1 -butoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-(n-propoxy)ethyl, 2-butoxyethyl, 2-methoxypropyl, 2-ethoxypropyl, 2-(n-propoxy)propyl, 2-butoxypropyl;

[0065] (Ci-C6-alkoxy)-Ci-C6-alkoxy: Ci-C6-alkoxy, in particular Ci-C4-alkoxy as defined above, such as methoxy or ethoxy, wherein 1 hydrogen atom is replaced by Ci-C6-alkoxy as defined above, examples including methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, butoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(n-propoxy)ethoxy and 2-butoxyethoxy;

[0066] (Ci-C6-alkoxy)-C2-C6-alkenyl: C2-C6-alkenyl, in particular C2-C4-alkenyl as defined above, such as ethenyl, propenyl, 1-butenyl or2-butenyl, wherein 1 hydrogen atom is replaced by Ci-C6-alkoxy as defined above;

[0067] (Ci-C6-alkoxy)-C2-C6-alkynyl: C2-C6-alkynyl, in particular C2-C4-alkynyl as defined above, such as ethynyl, propynyl or 2-butynyl, wherein 1 hydrogen atom is replaced by Ci-C6-alkoxy as defined above;

[0068] (Ci-C6-alkyl)carbonyl: Ci-C6-alkyl as mentioned above, which is bound to the remainder. It was surprisingly found that the use of metal alkoxylate in the step (vi) of the inventive process provides the desired product with a high yield.

[0069] Metal alkoxylate, also known as metal alkoxides, are according to the present invention chemical compounds that consist of a metal atom or ion bonded to one or more alkoxide groups. Alkoxides are derived from alcohols, where the hydroxyl (-OH) group of the alcohol is replaced with an alkoxide group (-O-R), where R represents an organic group, typically an alkyl group. The general formula for metal alkoxylates can be represented as M(OR)n, where M is the metal, R is the alkyl group, and n is the number of alkoxide ligands attached to the metal.

[0070] According to one embodiment of the invention the metal alkoxylate is selected from: NaOMe, KOMe, NaOEt. The most preferred is NaOMe.

[0071] According to one further embodiment of the invention 2.0 to 3.0 eq, preferably 2.0 to 2.6 eq of the metal alkoxylate is used.

[0072] This embodiment is especially preferred for compound of formula (VII) being a solid free base or as a solution in Me-THF orTHF.

[0073] According to one further embodiment of the invention the compound of formula (VII) is used in protonated form as methanesulfonic salt (CH3S(=O)2O .

[0074] In that case 3.0 to 4.0 eq, preferably 3.0 to 3.6 of the metal alkoxylate is used.250053

[0075] 7

[0076] In the case the compound of formula (VII) is used as a as methanesulfonic salt (CH3S(=O)2O a higher excess of metal alkoxylate is used for neutralization of the bound methanesulfonic acid. According to one further embodiment of the invention 2.0 - 4.0 eq, preferably 2.0 - 2.6 eq, most preferably 2.3 eq of the compound of formula (VIII) is used. The excess of the compound of formula (VI 11) is recovered with a yield of at least 60 %, preferably at least 70 %, more preferably at least 80 %, most preferably at least 90 %.

[0077] This process has the advantage that the compound of formula (VIII) used in excess, that is required in order to achieve high yields of compound of formula (T), will be recovered. It was surprisingly be found that the ester can be distilled from methanol even though its boiling point is higher than the boiling point of methanol (108 °C vs. 64°C). Further the ester and water / metha-nol are separated in the distillate.

[0078] The step (vi) of the inventive process according to one embodiment can be carried out in a solvent selected from the group consisting of: aromatic solvents, ethers, amides, alcohols, nitriles.

[0079] According to the present invention aromatic solvents are organic solvents that contain aromatic hydrocarbons as their primary structure. Aromatic hydrocarbons are compounds characterized by the presence of one or more benzene rings, which are planar, cyclic arrangements of carbon atoms with delocalized ir-electrons. This delocalization gives aromatic compounds distinctive stability and unique chemical properties. Aromatic solvents typically have a pleasant odor and are often used in industrial and laboratory settings due to their solvent capabilities. Examples are e.g. benzene, toluene, xylene, halogenated benzene etc.

[0080] According to the present invention ethers are a class of organic compounds characterized by an oxygen atom bonded to two alkyl or aryl groups, with the general formula R-O-R', where R and R' can be the same or different organic groups. Ethers are widely used as solvents in various chemical processes due to their unique properties, which make them suitable for dissolving a broad range of organic compounds. Examples are e.g. diethyl ether, THF, dioxane, etc.

[0081] According to the present invention amides are a class of organic compounds characterized by the presence of a carbonyl group (C=O) directly attached to a nitrogen atom (N). The general structure of an amide can be represented as RCONR'R", where R is a carbon-containing group, and R' and R" can be hydrogen atoms or organic groups. Amides can be classified into primary, secondary, and tertiary amides based on the number of carbon-containing groups attached to the nitrogen atom. Examples are e.g. DMF, DMA, acetamide, NMP etc.

[0082] According to the present invention alcohols are a class of organic compounds characterized by the presence of one or more hydroxyl (-OH) functional groups attached to a carbon atom. They can be classified based on the number of hydroxyl groups present (monohydric, dihydric, or polyhydric) and the structure of the carbon chain (primary, secondary, or tertiary). Due to their unique properties, alcohols are widely used as solvents in various chemical processes.

[0083] Examples are e.g. ethanol, isopropanol, methanol, glycerol etc.

[0084] According to the present invention nitriles are a class of organic compounds characterized by the presence of a cyano group (-CEN), where a carbon atom is triple-bonded to a nitrogen atom. They can be represented by the general formula R-CEN, where R can be an alkyl or aryl group.250053

[0085] 8

[0086] Nitriles are known fortheir polar nature and unique solvent properties, making them valuable in various chemical applications. Examples are e.g. acetonitrile, propionitrile, benzonitrile etc. According to the preferred embodiment of the invention the compounds of formula (VII) and (VIII) are diluted in a halogenated aromatic solvent. Such halogenated aromatic solvents are toxicologically less of concern. Their vapor pressure is lower and less of the solvent is lost via the offgas system of the plant.

[0087] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, bromobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, fluorobenzene, 1,2-difluorobenzene, 1,4-difluorobenzene, 1,2,4-trichlorobenzene.

[0088] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 1 ,2,4-trichlorobenzene.

[0089] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0090] According to one embodiment of the invention the reaction is carried out at a temperature from 10 to 60°C, preferably from 15 to 30°C.

[0091] After step (vi), a work-up of the reaction mixture can be carried out by procedures known in a general manner to the person skilled in the art. For example, after reaction completion the reacted mixture is added to water. The organic phase is separated, washed with water and the solvent is removed from the separated organic phase. Further, it may be appropriate to wash the organic phase with acidic or basic aqueous solution instead or in addition to washing with water. In some cases after adding of water a suspension is formed. In that case the solid compound is filtered off and washed. In order to enhance the yield the suspension can be cooled before filtration.

[0092] The so-obtained raw product can be directly used or the raw product can also be further worked up and / or purified as generally known to the skilled person. If this is deemed appropriate, the solvent is evaporated and the residue is, if appropriate, purified by recrystallization and / or chromatography.

[0093] The step (i) of the inventive process is carried out in the same way for both compounds of formula (II), having Y being H or F.

[0094] The step (i) of the inventive process according to one embodiment can be carried out without any solvent. This has the advantageous that the use of the chemical substances is minimized, and which leads to cost saving.

[0095] The step (i) of the inventive process according to a further embodiment is carried out in a halogenated aromatic solvent. The use of the above-mentioned solvents has the advantage over the use of dichloromethane as disclosed in WO 2022 / 161801. Such halogenated aromatic solvents are toxicologically less of concern. Their vapor pressure is lower and less of the solvent is lost via the offgas system of the plant. The lower vapor pressure than the chlorinating agent sulfuryl chloride leaves the option to distill off an excess of sulfuryl chloride after the reaction - this is not viable in case of the low boiling dichloromethane.250053

[0096] 9

[0097] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, bromobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, fluorobenzene, 1,2-difluorobenzene, 1,4-difluorobenzene, 1,2,4-trichlorobenzene.

[0098] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 1 ,2,4-trichlorobenzene.

[0099] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0100] The molar ratio of the compound of formula (II) to the halogenated aromatic solvent is generally in the range from from 1 : 10 to 1:0.1, more preferably from 1:1 to 1:0.2.

[0101] In order to synthesize the compound of formula (I) bearing Cl as X, the halogenation agent is selected from the group consisting of: SO2CI2, Cl2, NaOCI, N-chlorosuccinimide, HCI / H2O2, 1,3-dichloro-5,5-dimethylhydantoin.

[0102] According to one preferred embodiment of the invention the halogenation agent is S02CI2.or Cl2In order to synthesize the compound of formula (I) bearing Br as X, the halogenation agent is selected from the group consisting of: Br2, NaOBr, N-bromosuccinimide, HBr / H2O2, 1,3-di-bromo-5,5-dimethylhydantoin.

[0103] According to one preferred embodiment of the invention the halogenation agent in that case is Br2.

[0104] The step (i) of the inventive process is carried out without catalyst or in the presence of a catalyst which is selected from the group consisting of: DMF, acetonitrile, N,N-dimethylacetamide, pyridine, 2,6-lutidine, 2,4,6-collidine, 2,6-dimethylpiperidine, 2, 2,6,6-tetramethylpiperidine.

[0105] According to one preferred embodiment of the invention the catalyst used in the step (i) of the inventive process is acetonitrile or DMF.

[0106] According to one preferred embodiment of the invention the catalyst used in the step (i) of the inventive process is acetonitrile.

[0107] According to one preferred embodiment of the invention the catalyst used in the step (i) of the inventive process is DMF.

[0108] According to one preferred embodiment of the invention the catalyst used in the step (i) of the inventive process is selected from the group comprising: ethers such as diethylether, dibutylether, alcohols such as methanol, ethanol, disulfides such as diphenylsulfide, 2,2'-dipyridyldisul-phide, lewis acids such as iron chloride, aluminum chloride, zinc chloride, chloro-trimethylsilane. The order of adding the reagents to the reaction mixture is variable.

[0109] According to one embodiment, the halogenation agent is added to the mixture of the compound (II) and the catalyst optionally in the halogenated aromatic solvent. The addition of the halogenation agent can be done in one portion or gradually over several hours or in several portions. According to one embodiment, the addition is made in one portion. According to another embodiment the addition is made gradually over several hours or in several portions.250053

[0110] 10

[0111] According to one preferred embodiment of the invention herein the halogenation agent is added to the mixture of compound (II) in the halogenated aromatic solvent in the presence of the catalyst.

[0112] According to one embodiment of the invention the addition is carried out at the beginning at a temperature from 30 to 45°C and then at a temperature between 20 to 25°C.

[0113] After step (i), a work-up of the reaction mixture can be carried out by procedures known in a general manner to the person skilled in the art. For example, after completion of the reacted mixture is added to water. The organic phase is separated, washed with water and the solvent is removed from the separated organic phase. Further, it may be appropriate to wash the organic phases with acidic or basic aqueous solution instead or in addition to washing with water.

[0114] The so-obtained raw product can be directly used in the next process step, i.e. step (ii) of the inventive process. However, the raw product can also be further worked up and / or purified as generally known to the skilled person. If this is deemed appropriate, the halogenated aromatic solvent is evaporated and the residue is, if appropriate, purified by chromatography.

[0115] By means of the inventive process, the compounds of formula (I) can be prepared in surprisingly high yields. Preferably, the yields of step (i) are at least 80%, more preferably at least 85 %, even more preferred at least 90%, even more preferred at least 95%.

[0116] The compound of formula (II) used in step (i) wherein Y is H is commercially available. The compound of formula (II) wherein Y is F is commercially available.

[0117] According to the present invention, the variable Y of the compound of formula (II) used in step (i) is H or F. According to one specific embodiment, the variable Y is H. According to another specific embodiment, the variable Y is F.

[0118] According to the present invention, the variable X of the compound of formula (I) is Cl or Br. According to one specific embodiment, the variable X is Cl. According to another specific embodiment, the variable X is Br.

[0119] According to one preferred embodiment of the invention the variable X of the compound of formula (I) is Cl and the variable Y is H.

[0120] The step (ii) of the inventive process is carried out in the same way for both compounds of formula (III), having Y being H or F.

[0121] The step (ii) of the inventive process is a nitration reaction, in which a nitrating agent is used. A nitrating agent, also known as a nitrogenating agent, is according to the present invention a chemical substance that is used to introduce a nitro group (-NO2) into organic compounds through a process called nitration.

[0122] Nitrating agents are typically strong oxidizing agents or contain a source of nitro groups. They react with the organic compound under specific reaction conditions, resulting in the addition of the nitro group to the target molecule. The nitro group is composed of a nitrogen atom bonded to two oxygen atoms and imparts distinct chemical and physical properties to the modified compound.250053

[0123] 11

[0124] According to one embodiment of the invention the nitrating agent used in step (ii) of the inventive process is selected from the group consisting of: HNO3, NaNO2 / H+, alkylnitrite, alkylni-trite / H+, N2O3.

[0125] According to one preferred embodiment of the invention the nitrating agent used in step (ii) of the inventive process is HNO3. According to one preferred embodiment of the invention the nitrating agent used in step (ii) of the inventive process is HNO3in a concentration from 10 to 100 wt-%. According to one further preferred embodiment of the invention the nitrating agent used in step (ii) of the inventive process is HNO3in a concentration from 60 to 70 wt-%. According to the most preferred embodiment of the invention the nitrating agent used in step (ii) of the inventive process is HNO3in a concentration from 65 wt-%.

[0126] According to one preferred embodiment of the less than 1 eq of the nitrating agent is used. According to one further preferred embodiment of the invention between 0.95 and 0.99 eq, preferred 0.98 eq of the nitrating agent is used in the step (ii) of the inventive process.

[0127] It was found that the use of an overstoichiometric amount of the nitrating agent leads to a low onset temperature of the reaction mixture of approx. 45°C. It is known that above of this temperature the product decomposes with notable temperature and pressure rise, which could lead to serious safety issues by up-scaling. It has now surprisingly been found that the use of an under-stoichiometric amount of the nitrating agent in the step (ii) of the inventive process does not lead to a low onset temperature of the reaction mixture and the decomposition of the desired product at temperatures as low as approx. 45°C is avoided.

[0128] The step (ii) of the inventive process according to a further embodiment is carried out in a halogenated aromatic solvent. The use of the above-mentioned solvents has the advantage over the use of dichloromethane as disclosed in WO 2022 / 161801. Such halogenated aromatic solvents are toxicologically less of concern. Their vapor pressure is lower and less of the solvent is lost via the offgas system of the plant. The lower vapor pressure than the chlorinating agent sulfuryl chloride leaves the option to distill off an excess of sulfuryl chloride after the reaction - this is not viable in case of the low boiling dichloromethane.

[0129] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, bromobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, fluorobenzene, 1,2-difluorobenzene, 1,4-difluorobenzene, 1,2,4-trichlorobenzene.

[0130] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 1 ,2,4-trichlorobenzene.

[0131] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0132] The molar ratio of the compound of formula (I) to the halogenated aromatic solvent is generally in the range from from 1 : 10 to 1:0.1, more preferably from 1 :2 to 1:0.2.

[0133] The order of adding the reagents to the reaction mixture is variable.250053

[0134] 12

[0135] According to one embodiment, the compound of formula (I) and the nitrating agent, preferably HNO3were dosed parallel into reactor.

[0136] It was found that the parallel dosage of the compound of formula (I) and the nitrating agent, preferably HNO3avoids the formation of a byproduct.

[0137] According to one further embodiment, the nitrating agent, preferably HNO3is partly dosed parallel with the compound of formula (I) and partly dosed to the already partly reacted mixture in the reactor.

[0138] The addition of the nitrating agent can be done in one portion or gradually over several hours or in several portions. According to one embodiment, the addition is made in one portion. According to another embodiment the addition is made gradually over several hours or in several portions.

[0139] According to one embodiment of the invention the addition is carried out at the temperature between 15 to 30°C.

[0140] After step (ii), a work-up of the reaction mixture can be carried out by procedures known in a general manner to the person skilled in the art. For example, after completion of the reacted mixture is added to water. The organic phase is separated, washed with water and the solvent is removed from the separated organic phase. Further, it may be appropriate to wash the organic phases with acidic or basic aqueous solution instead or in addition to washing with water.

[0141] The so-obtained raw product can be directly used in the next process step, i.e. step (ii) of the inventive process. However, the raw product can also be further worked up and / or purified as generally known to the skilled person. If this is deemed appropriate, the solvent is evaporated and the residue is, if appropriate, purified by recrystallization and / or chromatography.

[0142] By means of the inventive process, the compounds of formula (III) can be prepared in surprisingly high yields. Preferably, the yields of step (i) are at least 80%, more preferably at least 85 %, even more preferred at least 90%, even more preferred at least 95%.

[0143] The step (iii) of the inventive process is a methylation reaction of a OH group. Under the term methylation of an OH group is understood a reaction which involves the addition of a methyl group (-CH3) to the hydroxyl group (-OH) of a substrate molecule. There are different methods and reagents that can be used for the methylation of an OH group, depending on the specific reaction conditions and the nature of the substrate.

[0144] According to the present invention the methylation agent is selected from the group consisting of: dimethylsulfate (CH3O)2SO2), MeCI, MeBr, MeBr, (CH3)2CO3, trimethyl orthoformate.

[0145] According to one preferred embodiment of the invention the methylation agent is dimethylsulfate (CH3O)2SO2).

[0146] The use of the above mentioned methylation agents has a cost advantage compared to the process disclosed in WO 2022 / 161801.

[0147] Further the inventive process avoids precipitation of safety critical alkali phenolate which has a high impact on the safety of such process prepared in an industrial scale.250053

[0148] 13

[0149] The methylation rection is carried out in the presence of a base. The base used in step (iii) can be an inorganic base or an organic base.

[0150] According to one embodiment the base is an inorganic base. Suitable inorganic bases are hydroxides, carbonates, hydrocarbonates, phosphates and hydrophosphates of alkali or earth alkali metals or any mixtures thereof. Examples of the suitable inorganic bases are NaOH, KOH, LiOH, Ca(OH)2, Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, CsHCO3, Na3PO4, K3PO4, Na2HPO4, K2HPO4, NaH2PO4or KH2PO4.

[0151] According to one embodiment, the bases are selected from hydroxides such as Ca(OH)2, NaOH, KOH, or LiOH. According to one specific embodiment, the inorganic base is NaOH. According to another specific embodiment, the inorganic base is KOH.

[0152] According to another embodiment, the bases are selected from carbonates, such as Na2CO3, K2CO3, or Li2CO3. According to one specific embodiment, the inorganic base is Na2CO3. According to another specific embodiment, the inorganic base is K2CO3. According to another specific embodiment, the inorganic base is Li2CO3.

[0153] According to another embodiment, the bases are selected from hydrogen carbonates such as NaHCO3, KHCO3, LiHCO3. According to another specific embodiment, the inorganic base is Na-HCO3. According to another specific embodiment, the inorganic base is KHCO3. According to another specific embodiment, the inorganic base is LiHCO3.

[0154] The base can be used in a solid form, e.g. solid pellets, flakes, microprills or powder, or as a solution, e.g. as aqueous solution.

[0155] According to another embodiment the base is an organic base. Examples of suitable organic bases are alkoxides, acetates, tertiary amines, quaternary ammonium salts, amidines, guanidine derivatives, pyridine, substituted pyridines, bicyclic amines or any mixture thereof.

[0156] According to another specific embodiment the organic base is selected from tertiary amines. Examples of suitable tertiary amines are tri-(Ci-C6)-alkylamines such as trimethylamine, triethylamine, tributylamine and N,N-diisopropylethylamine; di-(Ci-C6)-alkyl-phenylamines such as N,N-dimethylaniline and N, N-diethylaniline; N-methyl imidazole, N,N-dimethylaminopyridine and the like.

[0157] According to another specific embodiment the organic base is selected from diisoproylethylamin (DIPEA), tri-n-butylamin, N,N-dimethylcyclohexanamin, triethylamin, tri-n-propylamin, 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,1 ,3,3-tetra-methylguanidine (TMG), 1,1,3,3-tetramethylguanidine (TMG), collidine, 2,6-lutidine (2,6-dime-thylpyridine).

[0158] According to another specific embodiment the organic base is diisoproylethylamin (DIPEA). According to another specific embodiment the organic base is tri-n-butylamin.

[0159] According to another specific embodiment the organic base is N,N-dimethylcyclohexylamin. According to another specific embodiment the organic base is triethylamin.

[0160] According to another specific embodiment the organic base is tri-n-propylamin.

[0161] According to another specific embodiment the organic base is 1 ,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD).250053

[0162] 14

[0163] According to another specific embodiment the organic base is 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0164] According to another specific embodiment the organic base is 1 ,1 ,3,3-tetramethylguani-dine (TMG).

[0165] According to another specific embodiment the organic base is collidine.

[0166] According to another specific embodiment the organic base is 2,6-lutidine (2,6-dimethylpyri-dine).

[0167] According to another preferred specific embodiment the base is DIPEA or KOH.

[0168] According to another preferred specific embodiment the base is DIPEA.

[0169] In the case the inorganic base is used as disclosed above a phase-transfer catalyst can be used. Phase-transfer catalysts are commonly used in methylation reactions to facilitate the transfer of the methyl group from the methylating agent to the substrate molecule. Transfer catalysts can increase the reaction rate, selectivity, and yield of the methylation reaction, as well as minimize the formation of unwanted byproducts.

[0170] According one embodiment of the invention the phase-transfer catalyst is selected from the group consisting of: tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogensulfate, tetrabutylammonium iodide, tetrahexylammonium bromide, tetraoctylammonium bromide, tetraheptylammonium chloride, hexaethylguanidinium chloride, butyltriphenylphosphonium chloride, 15-crown-5, polyglycol 250 DME, phosphazen-base P2-Et, benzyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide.

[0171] According to one preferred embodiment of the invention the phase-transfer catalyst is tetrabutylammonium bromide (TBAB).

[0172] If a combination of an inorganic base and a phase-transfer catalyst is used the molar ratio of the compound of formula (III) to the inorganic base is generally in the range from 1:10 to 1:1, more preferably from 1 :2 to 1:1. The phase-transfer catalyst is used from 0,01 eq to 0,1 eq, preferably 0,01 to 0,05 eq.

[0173] If an organic base is used the molar ratio of the compound of formula (III) to the organic base is generally in the range from 1 : 10 to 1:1, more preferably from 1 :2 to 1:1, most preferably 1 : 1 ,2 to 1:1.

[0174] The step (iii) of the inventive process according to one embodiment can be carried out without any solvent. This has the advantage that the use of the chemical substances is minimized, and which leads to cost saving.

[0175] The step (iii) of the inventive process according to a further embodiment is carried out in a halogenated aromatic solvent. The use of the above-mentioned solvents has the advantage over the use of dichloromethane as disclosed in WO 2022 / 161801. Such halogenated aromatic solvents are toxicologically less of concern. Their vapor pressure is lower and less of the solvent is lost via the offgas system of the plant. The lower vapor pressure than the chlorinating250053

[0176] agent sulfuryl chloride leaves the option to distill off an excess of sulfuryl chloride after the reaction - this is not viable in case of the low boiling dichloromethane.

[0177] According to one further embodiment of the invention the halogenated aromatic solvent for step (iii) is selected from the group consisting of: chlorobenzene, bromobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, fluorobenzene, 1,2-difluorobenzene, 1,4-difluorobenzene, 1 ,2,4-trichlorobenzene.

[0178] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 1 ,2,4-trichlorobenzene.

[0179] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0180] The order of adding the reagents to the reaction mixture is variable. According to one preferred embodiment of the invention the base is added to the mixture of the methylation agent and the phenol.

[0181] According to one embodiment of the invention the addition is carried out a temperature between 20 to 60°C, preferably between 35 to 50°C, at most preferably at 40-45°C.

[0182] After step (iii), a work-up of the reaction mixture can be carried out by procedures known in a general manner to the person skilled in the art. For example, after completion the reacted mixture is added to water. The organic phase is separated, washed with water and the solvent is removed from the separated organic phase. Further, it may be appropriate to wash the organic phase with acidic or basic aqueous solution instead or in addition to washing with water. The so-obtained raw product can be directly used in the next process step, i.e. step (iv) of the inventive process. However, the raw product can also be further worked up and / or purified as generally known to the skilled person. If this is deemed appropriate, the solvent is evaporated and the residue is, if appropriate, purified by recrystallization, distillation and / or chromatography. By means of the inventive process, the compounds of formula (IV) can be prepared in surprisingly high yields. Preferably, the yields of step (iii) are at least 80%, more preferably at least 85 %, even more preferred at least 90%, even more preferred at least 95%.

[0183] According to step (iv) of the inventive process, compounds of formula (IV) are reduced to a compound of formula (V)

[0184]

[0185] wherein

[0186] X is Cl or Br,

[0187] Y is H or F.250053

[0188] 16

[0189] The step (iv) of the inventive process according to one embodiment is carried out in a halogenated aromatic solvent.

[0190] According to one embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, bromobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, fluorobenzene, 1,2-difluorobenzene, 1,4-difluorobenzene, 1,2,4-trichlorobenzene.

[0191] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 1 ,2,4-trichlorobenzene.

[0192] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0193] The step (iv) of the inventive process is a reduction reaction of the NO2group to NH2.

[0194] As suitable reductions agents can be used all known by the skilled person.

[0195] The reduction of compound of formula (IV) to compound of formula (V) can be achieved with nascent hydrogen, for example. In this case the nitro compound is reacted with an acid in the presence of a base metal. Base metals are naturally those that are dissolved by a Brbnsted acid with hydrogen evolution. Such metals generally have a normal potential < 0 V and in particular less than or equal to -0.1 V, e.g. in the range from -0.1 to -1.0 V (in acidic aqueous solution at 15 °C and 1 bar). Examples of suitable metals are Zn, Fe and Sn, especially Fe. Suitable acids for this purpose are both inorganic mineral acids, for example hydrochloric acid or dilute sulphuric acid, or mixtures of inorganic acid and one of the aforementioned solvents, for example gaseous HCI in an ether or an alcohol or in a mixture thereof, or organic carboxylic acids, suitably acetic acid, propionic acid or butyric acid.

[0196] The reaction conditions essentially correspond to the reaction conditions used for the reduction of aliphatic or aromatic nitro groups to aliphatic or aromatic amino groups with nascent hydrogen which are known from the state of the art.

[0197] Depending on the type of metal and acid, the reaction temperature is usually in the range from -20 to +120 °C, whereby temperatures in the range from 50 to 100 °C are preferably used when alkanoic acids such as acetic acid are used. The reaction time can range from a few minutes to several hours, e.g. about 20 minutes to 10 hours.

[0198] Preferably, the compound of formula (IV) to be reduced is placed in the reaction vessel and then the respective metal, preferably in finely divided form, in particular as a powder, is added to the reaction mixture while mixing. Preferably, the addition takes place over a period of 10 minutes to 2 hours. Of course, the metal and the acid can also be introduced and the compound of formula (IV) added, if necessary together with an inert solvent. The reaction mixture is often left to react at the reaction temperature for a certain period of time, e.g. 10 minutes to 10 hours. According to the further embodiment of the invention metal hydrides and semi-metal hydrides such as aluminium hydride and hydrides derived therefrom such as lithium aluminium hydride, diisobutyl aluminium hydride and boron hydrides such as diborane and boranates derived therefrom such as sodium borohydride or lithium boranate can also be considered as reducing agents for the step (iv) of the inventive process.250053

[0199] 17

[0200] For this purpose, the nitro compound of formula (IV) is brought into contact with the complete metal hydride in an inert solvent at 10 to 65 °C, preferably 20 to 50 °C. Preferably, the reaction time is 2 to 10 hours, preferably 3 to 6 hours.

[0201] As a rule, 0.5 to 3, preferably 0.75 to 2.5 moles of metal hydride, metal hemihydride, borohy-dride or boranate per mole of nitro compound of formula (IV) are used.

[0202] A further suitable reducing agent for the conversion of compound of formula (IV) into compound of formula (V) is hydrogen in the presence of catalytic amounts of transition metals or transition metal compounds. Preferred transition metals are, for example, nickel, palladium, platinum, ruthenium or rhodium. The transition metal can be combined with another metal like vanadium, tantalum, molybdenum, copper or cobalt in order to achieve the desired selectivity. The transition metals can be used as such or in supported form. Examples of carriers are activated carbon, aluminium oxide, Zr02, Ti02, Si02, carbonates and the like. The transition metals can also be used in the form of activated metals such as Raney nickel. The transition metals can also be used in the form of compounds. Suitable transition metal compounds are, for example, palladium oxide and platinum oxide. The catalysts are generally used in an amount of 0.001 to 10.0 mol% (calculated as metal), based on the compound of formula (IV) to be reduced. After separation of the catalyst, the reaction solution can be worked up to the product as usual. The hydrogenation can be carried out at normal hydrogen pressure or at elevated hydrogen pressure, for example at a hydrogen pressure of 0.01 to 50 bar, preferably 0.1 to 40 bar.

[0203] In the preferred embodiment of the invention the catalyst for step (iv) is selected from the group consisting of: platinum (with and without V), palladium, nickel.

[0204] In the especially preferred embodiment of the invention the catalyst for step (iv) is Pt / V catalyst. The so-obtained raw product can be directly used in the next process step, i.e. step (v). However, the raw product can also be further worked up and / or purified as generally known to the skilled person. If this is deemed appropriate, the reaction mixture is extracted with a suitable organic solvent (for example aromatic hydrocarbons such as toluene and xylenes) or with water and the residue is, if appropriate, purified by recrystallization and / or chromatography. Another option for purification is the distillation I rectification of solvent and I or product.

[0205] In step (v) the compound of formula (V) from step (iv) reacts with the compound of formula (VI)

[0206]

[0207] to give the compound of formula (VI I)

[0208]

[0209] 250053

[0210] 18

[0211] in the presence of an organic sulfonic acid. An use of the organic sulfonic acid is crucial for high conversion and for ensuring agitation of reaction mass.

[0212] Organic sulfonic acids according to the present invention are a class of compounds characterized by the presence of a sulfonic acid functional group (-SO3H) attached to an organic moiety. These acids are notable fortheir strong acidity and high solubility in water, making them useful in various chemical applications. The general structure of an organic sulfonic acid can be represented as R-SO3H, where R is an organic group that can vary widely, including aliphatic, aromatic, or cyclic structures. As example following acids can be used: benzene sulfonic acid (C6H5-SO3H), toluene sulfonic acid (C6H5-CH3-SO3H), methanesulfonic acid (CH3SO3H), sul-fanilic acid.

[0213] According to one preferred embodiment of the invention methanesulfonic acid is used in step (v).

[0214] According to one preferred embodiment of the invention methanesulfonic acid contains 1 to 15 wt-%, preferably 3 to 10 wt-%, more preferably 5 to 8 wt-%, most preferably 6 to 7 wt-% water. Also the exact amount of water leads to high conversion leading to the desired product with a very high yield.

[0215] According to one preferred embodiment of the invention 1.1 - 1.5 eq, preferably 1.2 - 1.4 eq, most preferably 1.3 eq of methanesulfonic acid is used. This small excess of the methanesulfonic acid is sufficient to provide the compound od formula (VII) in very high yield compared to the state of the art.

[0216] The step (v) of the inventive process according to one embodiment can be carried out in a polar protic or aprotic solvents.

[0217] According to the present invention protic solvents are those that contain at least one hydrogen atom that is bonded to an electronegative atom, typically oxygen or nitrogen. This bond enables the solvent to donate protons, making these solvents capable of hydrogen bonding. Common examples of protic solvents include water, alcohols, acids etc. Aprotic solvents, on the other hand, do not have hydrogen atoms that can be easily donated as protons. They lack O-H or N-H bonds, making them incapable of hydrogen bonding in the same way that protic solvents can. Common examples of aprotic solvents include dimethyl sulfoxide (DMSO), acetone, and dichloromethane.

[0218] According to one further embodiment of the invention the compound of formula (V) and (VI) are diluted in polar protic or aprotic solvent selected from the group consisting of: CH3CN, MeOH, EtOH, isopropanol, methoxy-propanol, NMP, DMF, acetone, methyl ethyl ketone, acetic acid, propionic acid, dimethoxy ethane, 1,4-dioxane, THF, Me-THF.

[0219] According to the preferred embodiment of the invention the compounds of formula (V) and (VI) are diluted in CH3CN.

[0220] According to one further embodiment of the invention 30 to 50 g, preferably 30 to 40 g, more preferably 30 to 35 g CH3CN per 1 mol of compound of formula (V) is used. It was found that the very low solvent amount in combination with exact amount of water coming from the methanesulfonic acid as well as used dosing sequence are crucial for high conversion >98%.250053

[0221] 19

[0222] According to one embodiment of the invention the reaction is carried out at a temperature from 60 to 100°C, preferably 75 to 80 °C, more preferred at 80°C.

[0223] According to one embodiment of the invention the protonated compound of formula (VII) is isolated as methanesulfonic salt (CH3S(=O)2O , wherein recycling washing solutions after solid isolation results in higher yields is carried out.

[0224] The present method provides the product in a high yield and the solid methanesulfonic salt (CH3S(=O)2O is very easy to handle.

[0225] According to one further embodiment of the invention the compound of formula (VII) is isolated as methanesulfonic salt (CH3S(=O)2O wherein recycling washing solutions after solid isolation results in higher yields is not carried out.

[0226] The present method with a simple procedure provides the product in a high yield with low amount of waste. Further, the solid methanesulfonic salt (CH3S(=O)2O is very good to handle. According to one further embodiment of the invention the compound of formula (VII) is isolated as a free base.

[0227] According to one further embodiment of the invention the compound of formula (VII) is isolated as a Me-THF or THF extract.

[0228] The present method provides the product in a high yield avoiding solid isolation.

[0229] After step (v), a work-up of the reaction mixture can be carried out by procedures known in a general manner to the person skilled in the art. For example, after completion water is added to the reacted mixture and a solid product in form of methanesulfonic salt is filtered off. Further, it may be appropriate to wash the solid with water or acidic aqueous solution. Further it may be appropriate to recycle the wash liquor in the next batch. In addition it may be appropriate to add basic aqueous solution and isolate the product in form of free base. In another example water and immiscible with water organic solvent may be added. The organic phase is separated, washed with water and the solvent is removed from the separated organic phase or the solution in organic solvent is used directly for the next step. Further, it may be appropriate to wash the organic phase with acidic or basic aqueous solution instead or in addition to washing with water. The so-obtained raw product can be directly used in the next process step, i.e. step (vi) of the inventive process. However, the raw product can also be further worked up and / or purified as generally known to the skilled person. If this is deemed appropriate, the product, if appropriate, purified by recrystallization and / or chromatography.

[0230] In a further preferred embodiment of the present invention, the azine compound of formula (T) is synthesised wherein

[0231] R1is Ci-C6-alkyl,

[0232] R2is Ci-C6-haloalkyl;

[0233] R3is Ci-C6-alkyl.

[0234] In a particularly preferred embodiment the compound of formula (T), is the compound of formula (T-1)250053

[0235] 20

[0236]

[0237] wherein

[0238] X is Cl or Br;

[0239] Y is H or F.

[0240] In a further particularly preferred embodiment of the present invention, the compound of formula (T), is the compound of formula T-1 A:

[0241]

[0242] In a further particularly preferred embodiment of the present invention, the compound of formula (T), is the compound of formula T-1 B:

[0243]

[0244] In a further particularly preferred embodiment of the present invention, the compound of formula (T), is the compound of formula T-1 C:

[0245]

[0246] The carbonyl compounds of formula (VIII) required for the preparation of azines of formula (T) are known in the literature and / or are commercially available.

[0247] Examples

[0248] The following examples further illustrate the present invention and do not restrict the invention in any manner.250053

[0249] 21

[0250] 1. Synthesis of 2-chloro-4,5-difluorophenol

[0251] Example 1.1

[0252] To the solution of 3,4-difluorobenzene 426 g (3.24 mol) in 147 ml chlorobenzene, N,N-dimethyl-formamide 7.54 g (0.103 mol) was added and the mixture was heated to 40°C. To this mixture, sulfuryl chloride 474 g (3.4 mol) was added continuously over 5 hours, first at 40°C, then after gas evolution is observed, the mixture is cooled and held at 20°C while dosing of sulfuryl chloride is continued. After completed sulfuryl chloride dosing and post stirring time of 1 hour the reaction mass was cooled down to 10°C and then added to 66.8 g 10°C cold water with the rate to not exceed 25°C. Organic and aqueous phases are separated. Yield of 2-chloro-4,5-difluoro-phenol determined by quantitative HPLC of organic phase is 97 %.

[0253] Example 1.2

[0254] To the solution of 3,4-difluorobenzene 104.5 g (0.8 mol) in 17.5 ml chlorobenzene, acetonitrile 1.05 g (0.025 mol) was added at 20°C. To this mixture, sulfuryl chloride 116.2 g (0.84 mol) was added continuously over 5 hours so that the temperature does not exceed 25°C. After completed sulfuryl chloride dosing and post stirring time overnight the reaction mass was cooled down to 10°C and then water 55 g is added with the rate to not exceed 20°C. Organic and aqueous phases are separated. Organic phase is extracted with 30 g water and phases are separated. Yield of 2-chloro-4,5-difluorophenol determined by quantitative HPLC of organic phase is 88 %.

[0255] Example 1.3

[0256] To the mixture of 3,4-difluorobenzene 90 g (0.67 mol) and acetonitrile 9.4 g at 10°C, sulfuryl chloride 105 g (0.75 mol) was added continuously over 5 hours so that the temperature does not exceed 15°C. After completed sulfuryl chloride dosing and post stirring time 15 minutes, water 100 g is added with the rate to not exceed 20°C. Organic and aqueous phases are separated. Yield of 2-chloro-4,5-difluorophenol determined by quantitative HPLC of organic phase is 97 %.

[0257] Example 1.4

[0258] To the solution of 3,4-difluorobenzene 495.3 g (3.80 mol) in 950 ml chlorobenzene at 10°C, gaseous Cl2272 g (3.83 mol) was added continuously over 6 hours so that the temperature does not exceed 15°C. After completed Cl2dosing and post stirring time 1 hour, vacuum 200 mbarais applied and the mixture is heated to 30°C and held for 1 hour under stirring. Yield of 2-chloro-4,5-difluorophenol determined by quantitative HPLC of resulting solution is 97 %.

[0259] 2. Synthesis of 6-chloro-3,4-difluoro-2-nitrophenol

[0260] Example 2.1

[0261] Chlorobenzene 30 mL was charged in the reactor. The 2-chloro-4,5-difluorophenol (0.58 mol, as 49.4 wt% solution in chlorobenzene) and nitric acid 65 wt% aqueous (0.57 mol) were added parallel at the temperature 20-25 °C over 25 minutes. After complete dosing of nitric acid and poststirring time of 1 hour the organic and aqueous phases are separated. Aqueous phase was diluted with 66g of water followed by 20 mL of chlorobenzene and organic and aqueous phases are separated. Both organic phases are combined and washed with 33g of water, then organic250053

[0262] 22

[0263] and aqueous phases are separated. Yield of compound 6-chloro-3,4-difluoro-2-nitrophenol determined by quantitative HPLC of organic phase is 96 %.

[0264] Example 2.2

[0265] Chlorobenzene 10 mL was charged in the reactor. The 2-chloro-4,5-difluorophenol (0.162 mol, as 73 wt% solution in chlorobenzene) and nitric acid 65wt% aqueous (0.158 mol) were added parallel at the temperature 20-25 °C over 60 minutes. After complete dosing of nitric acid and poststirring time of 1 hour the organic and aqueous phases are separated. Organic phase is washed with 10g of water, then organic and aqueous phases are separated. Yield of 6-chloro-3,4-difluoro-2-nitrophenol determined by quantitative HPLC of organic phase is 89 %.

[0266] Example 2.3

[0267] To the 2-chloro-4,5-difluorophenol (0.227 mol, as 62.4 wt% solution in chlorobenzene) chlorobenzene 39 mL was added. Then nitric acid 65wt% aqueous (0.225 mol) was added at the temperature 20-25 °C over 15 minutes. After complete dosing of nitric acid and poststirring time of 80 minutes the organic and aqueous phases are separated. To the aqueous phase 10 mL of chlorobenzene were added and organic and aqueous phases are separated. Both organic phases are combined. Yield of 6-chloro-3,4-difluoro-2-nitrophenol determined by quantitative HPLC of organic phase is 92 %.

[0268] Example 2.4

[0269] To the 2-chloro-4,5-difluorophenol (0.152 mol, as 62.4 wt% solution in chlorobenzene) chlorobenzene 32 mL was added. Then sulfuric acid aqueous solution (70.8 g of 50 wt% aqueous solution) was added and mixture was cooled to 10°C. NaNO2aqueous solution (109.8 g of 45.36 wt% aqueous solution) was then dosed over 30 minutes at the temperature 10-15°C. After complete dosing of NaNO2solution and poststirring time of 120 minutes the organic and aqueous phases are separated. To the aqueous phase 40 mL of chlorobenzene were added and organic and aqueous phases are separated. Both organic phases are combined. Yield of 6-chloro-3,4-difluoro-2-nitrophenol determined by quantitative HPLC of organic phase is 94 %.

[0270] 3. Synthesis of 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene

[0271] Example 3.1 - Experiment with DIPEA base

[0272] A solution of 47.54 g (227 mmol) 6-chloro-3,4-difluoro-2-nitro-phenol in 88.5 g of chlorobenzene was precharged to a 250 ml reactor at room temperature. Dimethyl sulfate (34.34 g, 1.2 equiv.) was then added and the mixture heated to 40 °C. N,N-diisopropylethylamine (39.77 g, 1.2 equiv.) was dosed under stirring over 3h at 40 °C. After a poststirring period of 5 h, the conversion of the starting material was confirmed by qualitative HPLC analysis. 120 g of water have been added for work up at room temperature under agitation. The phases were separated and the water phase postextracted with 20 g of chlorobenzene. The organic phases were combined and analyzed by quantitative HPLC: 51.5 % of the product 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene was determined, according to a yield of 99.6 %.

[0273] Example 3.2 - Experiment with butyl(triphenyl)phosphonium chloride and KOH base

[0274] 60 g of a 55.5 % solution of 6-chloro-3,4-difluoro-2-nitro-phenol in chlorobenzene (159 mmol) was precharged to a 250 ml reactor at room temperature. Dimethyl sulfate (40.09 g, 2 equiv.) and 0.575 g butyl(triphenyl)phosphonium chloride (0.01 equiv.) was then added and the mixture250053

[0275] 23

[0276] heated to 35 °C. 89.17 g of a 20 % solution of KOH in water were added over 5 h at 35 °C. After a poststirring period of 5 h, the conversion of the starting material was confirmed by qualitative HPLC analysis. The phases were separated and the water phase postextracted with 30 g MTBE. The organic phases were separately analyzed by quantitative HPLC: 35.6 % of the product 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene was determined in the chlorobenzene phase, 18.8 % in the MTBE phase. Both product contents are adding up to a total yield of 97.9 % 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene.

[0277] Example 3.3 - Experiment with tetrabutylammonium bromide and KOH base

[0278] 1144.2 g of a 39.1 % solution of 6-chloro-3,4-difluoro-2-nitro-phenol in chlorobenzene (2.133 mol) was precharged to a 4 I flask at room temperature. Dimethyl sulfate (538.1 g, 2 equiv.) and 6,875 g tetrabutylammonium bromide (0.01 equiv.) was then added and the mixture heated to 35 °C. 1196.8 g of a 20 % solution of KOH in water were added over 7 h at 35 °C. After a poststirring period of 15 h over night at 35 °C, the conversion of the starting material was confirmed by qualitative HPLC analysis. The phases were separated, the organic phase filtered through Celite 503 for removal of undissolved tar and the water phase postextracted with 100 g chlorobenzene. The organic phases were combined, washed with 1000 g water and analyzed by quantitative HPLC: 23.0 % of the product 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene was determined, according to a product yield of 97.4 % 1-chloro-4,5-difluoro-2-methoxy-3-nitro-ben-zene.

[0279] 4. Reduction of 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene

[0280] A solution of 27.61 g (123 mmol) 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene in 39.29 g of chlorobenzene was precharged to a small metallic pressure reactor. 4.14 g (0.09 mmol Pt) of a water-moist Pt / V-catalyst on charcoal was added together with 4.15 g of methanol. After inertization of the reactor by flushing with nitrogen, the reactor was pressurized with an excess of hydrogen at 4 bar and heated to 60 °C over 5 h. During this time period the hydrogen pressure was kept constant by replacing the consumed hydrogen gas. Afterwards the reactor was depressurized, flushed with nitrogen and discharged. The catalyst was removed from the product solution by filtration over a small glass filter nutsch. The filtrate with the product (77.9 g) was concentrated in a rotary evaporator under vacuum to a residue of 36.4 g. The residue was analyzed via quantitative GC: 63.1 % of the product 3-chloro-5,6-difluoro-2-methoxybenzenamine was determined, according to a yield of 96.1 %.

[0281] 5. Synthesis of 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine (N-Cyanocarbamimidoyl)ammonium (282.5g, 3.36 mol) and 5-chloro-2,3-difluoro-6-methoxy-aniline (469.3g, 2.4 mol) in acetonitrile (82g) were charged in the reactor and the mixture was heated to 80°C. Methanesulfonic acid (93-94 wt%, contains 6-7% water; 3.12 mol) was dosed into reactor at 80°C over 6 hours and then mixture was stirred for further 2 hours, following by isolation procedure.

[0282] Example 5.1 - Isolation as 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine free base250053

[0283] 24

[0284] Water is added to the reaction mixtrure and acetonitrile / water azeotrope is distilled off under vacuum. After acetonitrile is completely removed, more water is added, the mixture is heated to 60°C and slowly added to NaOH 50 wt% aqueous solution at 60°C, final pH should reach 11. Resulting suspension is stirred for 1 hour at 60°C and afterwards cooled down to 20°C. The solid is filtered off, washed with water twice and dried in vacuum giving 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine as free base with yield approx. 85%.

[0285] Example 5.2 - Isolation as 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine extract in Me-THF

[0286] Water is added to the reaction mixtrure and pH of the mixture is adjusted to 5 by aq. NaOH solution. acetonitrile / water azeotrope is distilled off under vacuum. After acetonitrile is completely removed, Me-THF is added and the mixture is heated to 60°C. NaOH 50 wt% aqueous solution is then added slowly till pH reach 11. Phases are separated, aqueous phase is extracted second time with Me-THF at 60°C. Combined Me-THF extracts are washed with water at 60°C, giving 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine extract in Me-THF with yield approx. 95%.

[0287] Example 5.3 - Isolation as 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine methanesulfonate salt with recycling

[0288] Water or recyclied 2ndaqueous phase from previous experiment is added to the reaction mixtrure and the mixture is cooled down to 0-5°C over 5 hours. Resulting suspension is filtered off, washed twice with water and dried in vacuum giving 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine methanesulfonate salt with yield approx. 90% without recycling or approx. 95% with recycling. For recycling, mother liquor and both wash liquors are combined, and acetonitrile / water azeotrope is distilled off under vacuum. After acetonitrile is completely removed, MTBE (fresh or recycled) is added followed by NaOH 25 wt% aqueous solution till pH approx. 11-12. The phases are separated. Aqueous phase is discharged. To the organic phase fresh water is added followed by methanesulfonic acid (93-94 wt%, contains 6-7% water) till pH approx. 4. The phases are separated. Aqueous phase containing 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine methanesulfonate salt is recyclied as 2ndaqueous phase. Organic phase consisting of mostly MTBE is recycled.

[0289] Example 5.4 - Isolation as 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine methanesulfonate salt

[0290] Water or recycled 2ndwash liquor from previous experiment is added to the reaction mixtrure and acetonitrile / water azeotrope is distilled off under vacuum. After acetonitrile is completely removed, the mixture is cooled down to 0-5°C over 5 hours. Resulting suspension is filtered off, washed twice with water. 2nd wash liquor can be recycled without any treatment. Solid is dried in vacuum giving 1-carbamimidoyl-3-(5-chloro-2,3-difluoro-6-hydroxy-phenyl)guanidine methanesulfonate salt with yield approx. 92% without recycling or approx. 94% with recycling.6. Synthesis of 1,3,5-triazine-2,4-diamine, A / 2-(3-chloro-5,6-difluoro-2-methoxyphenyl)-6-(1 -fluoro-1 -methylethyl)

[0291] Example 6.1 - Starting with 1-(5-chloro-2,3-difluoro-6-methoxy-phenyl)-3-carbamimidoyl-guani-dine methanesulfonic acid salt

[0292] 570 g (1.510 mol) 1-(5-chloro-2,3-difluoro-6-methoxy-phenyl)-3-carbamimidoyl-guanidine methanesulfonic acid salt (99 %) were charged together with 905.79 g chlorobenzene and 417.12 g (3.473 mol) methyl 2-fluoroisobutyrate to a 2.5 L reactor and heated to 50 °C. 897.31 g (4.982 mol) of sodium methylate solution (30 % in methanol) were added over 2 h at 50 °C under agitation. After 4 h poststirring, a sample was taken: HPLC analysis revealed full conversion of the biguanide starting material. The mixture was heated to 60 °C, and 1360 g demineralized water was added over 30 minutes at 60 °C under agitation. The mixture was cooled to 20 °C within 4 h and to 0 °C within 1 h. The solid product was filtered off with a pressure nutsch, washed twice with each 570 g of demineralized water and dried in a drying cabinet (120 °C, 30 mbar). 514.4 g 1,3,5-triazine-2,4-diamine, / \Z2-(3-chloro-5,6-difluoro-2-methoxyphenyl)-6-(1 -fluoro-1 -methylethyl) with a purity of 99.4 % were obtained, corresponding to a yield of 97.4 %.

[0293] Example 6.2 - Starting with 1-(5-chloro-2,3-difluoro-6-methoxy-phenyl)-3-carbamimidoyl-guani-dine (free base)

[0294] 15 g (0.053 mol) 1-(5-chloro-2,3-difluoro-6-methoxy-phenyl)-3-carbamimidoyl-guanidine (97.5 %) were charged together with 115.9 g chlorobenzene and 14.7 g (0.121 mol) methyl 2-fluoroisobutyrate (99 %) to a 250 ml reactor and heated to 50 °C. 21.8 g (0.121 mol) of sodium methylate solution (30 % in methanol) were added over 110 min at 50 °C under agitation. After 1 h poststirring, no biguanide starting material could be detected by HPLC. The reaction mixture was cooled down to 20 °C and 37.1 g demineralized water were added at 20-22 °C over 60 min. The precipitated solid was isolated by suction filtration and washed twice with 20 g water each. Drying was performed in a drying cabinet (65 °C, 35 mbar). 18.1 g 1,3,5-triazine-2,4-dia-mine, / \Z2-(3-chloro-5,6-difluoro-2-methoxyphenyl)-6-(1 -fluoro-1 -methylethyl) with a purity of 98.5 % were obtained, corresponding to a yield of 97.3 %.

[0295] Example 6.3 - Starting with 1-(5-chloro-2,3-difluoro-6-methoxy-phenyl)-3-carbamimidoyl-guani-dine in Me-THF

[0296] 94.5 g (0.068 mol) of a 20 % solution of 1-(5-chloro-2,3-difluoro-6-methoxy-phenyl)-3-car-bamimidoyl-guanidine in 2-methyltetrahydrofuran and 19.0 g (0.157 mol) methyl 2-fluoroisobu-tyrate (99 %) were precharged to a 250 ml reaction vessel and heated to 50 °C under agitation.

[0297] 28.2 g (0.157 mol) sodium methylate solution (30 % in methanol) were added over a period of 90 minutes at 50 °C and the mixture afterwards agitated over 4 h at the same temperature for complete conversion of the biguanide starting material. For work up, methanol and 2-methyltet-rahydrofuran were distilled off partly (45-49 °C, 500-450 mbar). 85 g demineralized water were added at 55-65 °C within 45 minutes and the remaining organic solvents distilled off (59-61 °C, 600-170 mbar) by keeping the vessel volume constant through further water addition. After 1 h poststirring, the vessel content was slowly cooled down within 4 h to 20 °C. The precipitated solid was filtered off and washed twice with each 30 g demin. water. Drying of the product hasbeen performed at 105 °C / 30 mbar in a drying cabinet. 23.2 g 1,3,5-triazine-2,4-diamine, lP-(3-chloro-5,6-difluoro-2-methoxyphenyl)-6-(1 -fluoro- 1 -methylethyl) with a purity of 98.1 % were obtained, corresponding to a yield of 96.3 %.

[0298] Example 6.4: FIB-Ester recovery - Preparation of methyl 2-fluoroisobutyrate

[0299]

[0300] FIB-Acid FIB-Ester

[0301] Protocol without distillation column for technical process :

[0302] Batch size cyclization reaction (see example 6.1): 0.0385 mol 1-(5-chloro-2,3-difluoro-6-meth-oxy-phenyl)-3-carbamimidoyl-guanidine methanesulfonic acid salt.

[0303] Phases of mother liquor from reaction to 1 ,3,5-triazine-2,4-diamine, / \ / 2-(3-chloro-5,6-difluoro-2-methoxyphenyl)-6-(1-fluoro-1 -methylethyl) were separated into organic and aqueous phase. The aqueous phase containing 0.05 mol of sodium 2-fluoroisobutyrate and 0.0385 mol sodium methansulfonate was evaporated to dryness at a rotary evaporator (50-70 °C bath temperature, 180-50 mbar) so that 13.2 g solid were obtained. 63.4 g of the organic phase of mother liquor (mainly chlorobenzene) and 8 g (0.25 mol) of methanol were added under agitation in a 100 ml reactor. 30 g (0.3 mol) sulfuric acid (98 %) was added within 5 min and the mixture heated to 50 °C for 1 h. Vacuum of 140 mbar was applied and the mixture came to reflux. All light boilers were distilled off until an inside temperature of 100 °C in the reactor was reached. The distillate contained 2 liquid phases. The lower organic phase of 66.3 g was analyzed with 8.24 % of methyl 2-fluoroisobutyrate, 89.47 % of chlorobenzene and 0.08 % of water. The content of methyl 2-fluoroisobutyrate, determined by quantitative gas chromatography, represents 91 % yield in respect to the used sodium 2-fluoroisobutyrate. A small upper phase of the distillate was also obtained with 1.3 g, consisting of approximately 68 % water, 31 % methanol, 0.2 % chlorobenzene and 0.56 % of methyl 2-fluoroisobutyrate. The phase can be recycled to the water removal step of next batch or disposed.

Claims

27Claims1. A process for the preparation of the compound of formula (T)whereinR1is selected from the group consisting of H, halogen, CN, Ci-C6-alkyl, (Ci-C6- alkoxy)-Ci-C6-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C4-alkyl, Ci-C6-alkoxy, C2-C6-alkenyloxy, C2-C6-alkynyloxy, C3-C6-cycloalkoxy, (C3-C6-cycloalkyl)-Ci-C4- alkoxy, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated;R2is selected from the group consisting of H, halogen, CN, Ci-C6-alkyl, Ci-C6- haloalkyl, Ci-C6-alkoxy and Ci-C6-haloalkoxy;R3is selected from the group consisting of halogen, CN, Ci-C6-alkyl, C2-C6-alkenyl, C3-C6-alkynyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C4-alkyl, C3-C6-cycloalkenyl and Ci-C6-alkoxy-Ci-C6-alkyl, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated;X is Cl or Br,Y is H or Fcomprising the following step:(vi) reacting a compound of formula (VII) with a compound of formula (VIII)in the presence of metal alkoxylate.

2. The process of claim 1 , wherein the compound (VII) is used as a methanesulfonic salt (CH3S(=O)2O).250053283. The process of claim 1 or 2, wherein 2.0 - 4.0 eq, preferably 2.0 - 2.6 eq, most preferably 2.3 eq of the compound of formula (VIII) is used.

4. The process of any of claims 1 to 3, wherein the excess of the compound of formula (VIII) is recovered with a yield of at least 60 %, preferably at least 70 %, more preferably at least 80 %, most preferably at least 90 %.

5. The process of any of claims 1 to 4, wherein the metal alkoxylate is selected from: NaOMe, KOMe, NaOEt.

6. The process of any of claims 1 , 3 to 5, wherein 2.0 to 3.0 eq, preferably 2.0 to 2.6 of the metal alkoxylate is used.

7. The process of any of claims 2 to 5, wherein if the compound (VII) is used as a as methanesulfonic salt (CH3S(=O)2O 3.0 to 4.0 eq, preferably 3.0 to 3.6 of the metal alkoxylate is used.

8. The process of any of claims 1 to 7, wherein the compounds of formula (VI I) and (VIII) are diluted in solvent selected from the group consisting of: aromatic solvents, ethers, amides, alcohols, nitriles.

9. The process of claim 8, wherein the solvent is chlorobenzene.

10. The process of any of claims 1 to 10, wherein the reaction is carried out at a temperature from 10 to 60°C, preferably at 15 to 30°C.

11. A process for the preparation of compound of formula (VII) as defined above comprising the following steps:(i) preparing the compound (II) via a halogenation reaction of a compound of formula (I)(ii) preparing the compound of formula (III) via reaction of the compound of formula (II) with HNO3converting the compound of formula (III) to a compound of formula (IV)250053in presence of a methylation agent;(iv) reducing the compound of formula (IV) to a compound of formula (V)(v) reacting the compound of formula (V) with a compound of formula (VI)to give the compound of formula (VII)

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