Process for the preparation of halogenated 3,4-difluoro-2-nitrophenol and 3,4,5-trifluoro-2-nitrophenol

Abstract

The present invention relates to a process for providing halogenated 3,4-difluoro-2-nitrophenol and 3,4,5-trifluoro-2-nitrophenol. Further it relates to a process for converting it to substituted azine compounds with herbicidal activity.

Description

[0001] Process for the preparation of halogenated 3,4-difluoro-2-nitrophenol and 3,4,5-trifluoro-2-nitro- phenol

[0002] The present invention relates to a process for providing halogenated 3,4-difluoro-2-nitrophenol and 3,4,5-trifluoro-2-nitrophenol. Further it relates to a process for converting it to substituted azine compounds with herbicidal activity.

[0003] 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.

[0004] The present invention provides a process for the preparation of halogenated 3,4-difluoro-2- nitrophenol and 3,4,5-trifluoro-2-nitrophenol from halogenated 3,4-difluorophenol or 3,4,5- trifluorophenol, respectively, which is then used for the synthesis of the substituted azine derivatives having herbicidal activity.

[0005] The preparation of halogenated 3,4-difluoro-2-nitrophenol is known from WO 2022 / 161801. However, the disclosed method has some disadvantages which could lead to problems by up- scaling. First of all, the reaction is not very fast. Further since the reaction is an exothermic reaction the safety aspects especially by up-scaling are of relevance.

[0006] Therefore, it was an object of the present invention to provide an industrially simple, cost-effective process for the preparation of halogenated 3,4-difluoro-2-nitrophenol and 3,4, 5-trifluoro-2- nitrophenol in good yields. In addition, the process should be environmentally friendly in order to reduce unfavorable environmental effects. A further object of the present invention was to provide an improved process for the synthesis of substituted azine compounds which would utilize the halogenated 3,4-difluoro-2-nitrophenol and 3,4,5-trifluoro-2-nitrophenol.

[0007] It has now surprisingly been found a highly efficient process for the synthesis of halogenated 3,4-difluoro-nitrophenol and 3,4,5-trifluoro-2-nitrophenol of formula (III) and thus, an efficient synthesis of substituted azine compounds of formula (T) having herbicidal activity.

[0008] The present invention thus relates to a process for the preparation of the compound of formula (HI) wherein

[0009] X is Cl or Br,

[0010] Y is H or F, comprising the following step:

[0011] (ii) reacting a compound of formula (I) with a nitrating agent, wherein the reaction is carried out in a microstructured flow reactor.

[0012] The present invention further relates to the process for the preparation of the substituted azine compounds of formula (T):

[0013] X is Cl, F or Br,

[0014] Y is H or F,

[0015] R1is selected from the group consisting of H, halogen, CN, Ci-Ce-alkyl, (Ci-C6-alkoxy)-Ci-Ce- alkyl, Cs-Ce-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C4-alkyl, Ci-Ce-alkoxy, Cs-Ce-alkenyloxy, C2- Ce-alkynyloxy, Cs-Ce-cycloalkoxy, (C3-C6-cycloalkyl)-Ci-C4-alkoxy, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated;

[0016] R2is selected from the group consisting of H, halogen, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C1- Ce-alkoxy and Ci-Ce-haloalkoxy;

[0017] R3is selected from the group consisting of halogen, CN, Ci-Ce-alkyl, Cs-Ce-alkenyl, C3-C6- alkynyl, Cs-Ce-cycloalkyl, (C3-Ce-cycloalkyl)-Ci-C4-alkyl, Cs-Ce-cycloalkenyl and Ci-Ce- alkoxy-Ci-Ce-alkyl, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated; comprising the following steps:

[0018] (i) preparing the compound (I) via a halogenation reaction of a compound of formula (II)

[0019] (ii) preparing the compound of formula (III) according to any one of claims 1 to 9;

[0020] (iii) converting the compound of formula (III) to a compound of formula (IV) in presence of a methylation agent;

[0021] (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) wherein

[0022] X is Cl or Br, Y is H or F,

[0023] (vi) reacting the compound of formula (VII) with an ester of formula (VIII) wherein

[0024] R1to R3are as defined above, in presence of NaOMe or KOMe.

[0025] 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.

[0026] 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: halogen: fluorine, chlorine, bromine and iodine. The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0027] 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, 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;

[0028] Ci-Ce-alkyl and also the Ci-Ce-alkyl moieties of Ci-Ce-alkoxy, Ci -Ce-alkylthio, Ci-Ce-alkyl- sulfonyl, (Ci-Ce-alkyl)carbonyl, (Ci-Ce-alkyl)carbonyl, (Ci-Ce-alkoxy)carbonyl, (Ci-Ce-alkyl)car- bonyloxy, Ci-Ce-alkyoxy-Ci-Ce-alkyl, Cs-Ce-cycloalkyl-Ci-Ce-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-Ce-alkyl: Ci-C4-alkyl as mentioned above, and also, for example, n-pentyl, 1 -methyl butyl, 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 -di methyl butyl, 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;

[0029] C2-Ce-alkenyl and also the C2-Ce-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;

[0030] C2-Ce-alkynyl and also the C2-Ce-alkynyl moieties of (Ci-C6-alkoxy)-C2-Ce-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;

[0031] Ci-Ce-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;

[0032] Cs-Ce-cycloalkyl: monocyclic saturated hydrocarbons having 3 to 6 ring members, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0033] Ci-C4-alkoxy: for example methoxy, ethoxy, propoxy, 1 -methylethoxy butoxy, 1- methyl propoxy, 2-methylpropoxy and 1 ,1 -dimethylethoxy;

[0034] Ci-Ce-alkoxy and also the Ci-Ce-alkoxy moieties of (Ci-Ce-alkoxy)carbonyl, (Ci-Ce- alkoxy)sulfonyl, (Ci-C6-alkoxy)-Ci-Ce-alkyl, (Ci-C6-alkoxy)-Ci-Ce-alkoxy, (Ci-C6-alkoxy)-C2-Ce- alkenyl, (Ci-C6-alkoxy)-C2-Ce-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 -di methyl butoxy, 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;

[0035] 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 -trifl uoromethyl-1 ,2,2,2-tetrafluoroethoxy;

[0036] Ci-Ce-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;

[0037] C2-Ce-alkenyloxy: C2-Ce-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;

[0038] C2-Ce-alkynyloxy: C2-Ce-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;

[0039] Cs-Ce-cyclolalkyl and also the Cs-Ce-cyclolalkyl moieties of (Cs-Ce-cyclolalkyQ-carbonyl, (C3-C6-cyclolalkyl)-Ci-C6-alkyl, (C3-C6-cycloalkyl)carbonyl and (Cs-Ce-cyclolalkyQ-Ci-Ce-alkoxy: a cycloaliphatic radical having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0040] Cs-Ce-cyclolalkoxy: a cycloaliphatic radical having 3 to 6 carbon atoms and bound via an oxygen atom, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy;

[0041] (Cs-Ce-cyclolalkyO-Ci-Ce-alkyl: Ci-Ce-alkyl, in particular Ci-C4-alkyl as defined above, such as methyl or ethyl, wherein 1 hydrogen atom is replaced by Cs-Ce-cyclolalkyl as defined above, examples including cyclopropylmethyl (CH2-cyclopropyl), cyclobutyl methyl, cyclopentyl methyl, cycloexylmethyl, 1 -cyclopropylethyl (CH(CH3)-cyclopropyl), 1 -cyclobutylethyl, 1 -cyclopentylethyl,

[0042] 1-cycloexylethyl, 2-cyclopropylethyl (CH2CH2-cyclopropyl), 2-cyclobutylethyl, 2-cyclopentylethyl or 2-cycloexylethyl;

[0043] (Cs-Ce-cyclolalkyO-Ci-Ce-alkoxy: Ci-Ce-alkoxy, in particular Ci-C4-alkoxy as defined above, such as methoxy or ethoxy, wherein 1 hydrogen atom is replaced by Cs-Ce-cyclolalkyl as defined above, examples including cyclopropylmethoxy (OCH2-cyclopropyl), cyclobutylmethoxy, cyclopentylmethoxy, cycloexylmethoxy, 1 -cyclopropylethoxy (O-CH(CH3)-cyclopropyl), 1-cyclo- butylethoxy, 1 -cyclopentylethoxy, 1-cycloexylethoxy, 2-cyclopropylethoxy (OCH2CH2)-cyclopro- pyl), 2-cyclobutylethoxy, 2-cyclopentylethoxy and 2-cycloexylethoxy;

[0044] (Ci-C6-alkoxy)-Ci-Ce-alkyl: Ci-Ce-alkyl, in particular Ci-C4-alkyl as defined above, such as methyl, ethyl or isopropyl, wherein 1 hydrogen atom is replaced by Ci-Ce-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,

[0045] 2-(n-propoxy)ethyl, 2-butoxyethyl, 2-methoxypropyl, 2-ethoxypropyl, 2-(n-propoxy)propyl, 2- butoxypropyl;

[0046] (Ci-C6-alkoxy)-Ci-Ce-alkoxy: Ci-Ce-alkoxy, in particular Ci-C4-alkoxy as defined above, such as methoxy or ethoxy, wherein 1 hydrogen atom is replaced by Ci-Ce-alkoxy as defined above, examples including methoxymethoxy, ethoxymethoxy, n-propoxymethoxy, butoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-(n-propoxy)ethoxy and 2-butoxyethoxy;

[0047] (Ci-C6-alkoxy)-C2-C6-alkenyl: C2-Ce-alkenyl, in particular C2-C4-alkenyl as defined above, such as ethenyl, propenyl, 1-butenyl or 2-butenyl, wherein 1 hydrogen atom is replaced by C Ce-alkoxy as defined above;

[0048] (Ci-C6-alkoxy)-C2-C6-alkynyl: C2-Ce-alkynyl, in particular C2-C4-alkynyl as defined above, such as ethynyl, propynyl or 2-butynyl, wherein 1 hydrogen atom is replaced by Ci-Ce-alkoxy as defined above;

[0049] (Ci-Ce-alkyl)carbonyl: Ci-Ce-alkyl as mentioned above, which is bound to the remainder.

[0050] The step (ii) of the inventive process is carried out in a microstructured flow reactor.

[0051] A microstructured flow reactor according to the present invention is a type of chemical reactor comprising channels or surfaces in a range of micrometer or millimeter to facilitate chemical reactions. The microstructured flow reactor is designed to provide a high surface area-to-volume ratio, which enhances the mass and heat transfer during the chemical reaction. Microstructured flow reactors are often used in continuous flow chemistry, where reactants are continuously fed into the reactor and products are continuously collected.

[0052] The microstructured flow reactor typically consists of a series and / or parallel arrangement of microchannels or microreactors that are interconnected to form a network. The microchannels are typically made of a high-performance material, such as stainless steel, hastelloy, glass, silicon carbide or the like, and are designed to have a specific geometry and size. The size and geometry of the microchannels can be tailored to optimize the reaction conditions, such as mixing efficiency, heat transfer, residence time and total hold-up of the reactor.

[0053] Microstructured flow reactors offer several advantages over traditional batch reactors: a) they provide a high surface area-to-volume ratio, which allows for efficient mixing, heat transfer, and mass transfer. This often leads to faster reaction times, higher yields, and improved selectivity, b) microstructured flow reactors are highly scalable, and can be easily adapted to handle larger volumes of reactants, c) microstructured flow reactors can be operated under high-pressure and high-temperature conditions, which enables the synthesis of complex molecules that are difficult to obtain using traditional batch methods, d) the total hold-up of a microstructured reactor is much smaller compared to traditional batch reactors giving a lower hazard potential, e) depending on the mode of operation, mixing properties can be adjusted between plug flow and back mixed conditions.

[0054] In summary, a microstructured flow reactor is a type of chemical reactor that utilizes microchannels or microstructured surfaces to facilitate chemical reactions. It provides several advantages over traditional batch reactors, including higher surface area-to-volume ratio, faster reaction times, higher yields, improved selectivity, scalability, and the ability to handle high-pressure and high-temperature conditions. Such reactors are commercially available from companies like Flu- itec mixing + reaction solutions AG, Ehrfeld Mikrotechnik GmbH, Corning S.A.S., Chemtrix BV, Khimod Alcen or Amar Equipment Pvt. Ltd.

[0055] Using of such microstructured flow reactor in the inventive process has following advantages:

[0056] First of all, a better heat transfer for an exothermic nitration can be provided. The exothermic heat of the reaction of step (ii) can be efficiently removed. This leads to the process temperature, which can be selected closer to the onset temperature than the process temperature in a semi-batch process. This increases the reaction safety. Further, better mass transfer of the biphasic liquid-liquid reaction mixture and thus faster and more selective reaction can be achieved. This decreases the formation of byproducts of such reaction. Furthermore, an increased reaction safety can be provided, since the hazard potential of the reaction is low due to low hold-up volume.

[0057] 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.

[0058] The step (ii) of the inventive step is a nitration reaction, in which a nitrating agent is used.

[0059] 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.

[0060] 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.

[0061] 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 / IT, N2O3.

[0062] 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 HNO3 in 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 HNO3 in 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 HNO3 in a concentration from 65 wt-%.

[0063] According to one preferred embodiment of the invention 1.05 - 1.6 eq of HNO3 is used, preferably 1.1 - 1.45 eq of HNO3.

[0064] 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.

[0065] 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, 1 ,2-difluorobenzene, 1 ,4-difluorobenzene, 1,2,4-trichlorobenzene.

[0066] 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.

[0067] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene. 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, more preferably from 1 :5 to 1 :0.1 , more preferably from 1 :3 to 1 :0.2.

[0068] The order of adding the reagents to the reaction mixture is variable.

[0069] According to one embodiment, the compound of formula (I) and the nitrating agent, preferably HNO3 were dosed parallel into the microstructured flow reactor.

[0070] According to one further embodiment, the nitrating agent, preferably HNO3 is partly dosed parallel with the compound of formula (I) and partly dosed to the already partly reacted mixture in the microstructured flow reactor.

[0071] The addition of the nitrating agent can be done in one portion or in several portions. According to one embodiment, the addition is made in one portion. According to another embodiment the addition is made in several portions.

[0072] According to one embodiment of the invention the addition is carried out at a temperature of the tempering fluid between 0 and 50 °C, more preferably between 20 and 40°C.

[0073] According to one embodiment of the invention the residence time of the reaction media within the reactor is between 20 min and 1 s, more preferably below 1 min.

[0074] According to one embodiment of the invention the reaction is slowed down or stopped via dilution or chemical quench reaction with an additional fluid which is introduced after the desired residence time of the reaction media. According to one embodiment of the invention this can be realized via introduction of this additional fluid within the reactor, at its outlet or by placing it in the collection vessels. According to one embodiment of the invention the temperature of this additional fluid is between 0 and 40 °C, more preferably between 0 and 10 °C. According to one preferred embodiment of the invention this fluid is water.

[0075] 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.

[0076] The so-obtained raw product can be directly used in the next process step, i.e. step (iii) 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.

[0077] 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%.

[0078] 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.

[0079] 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. 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.

[0080] According to one further embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, bromobenzene, fluorobenzene, 1 ,2- dichlorobenzene, 1 ,4-dichlorobenzene, 1 ,2-difluorobenzene, 1 ,4-difluorobenzene, 1 ,2,4- trichlorobenzene.

[0081] 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.

[0082] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0083] 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.

[0084] In order to synthesize the compound of formula (I) bearing Cl as X, the halogenation agent is selected from the group consisting of: SO2CI2, CI2, NaOCI, N-chlorosuccinimide, HCI / H2O2, 1 ,3- dichloro-5,5-dimethylhydantoin.

[0085] According to one preferred embodiment of the invention the halogenation agent is SO2CI2 or Cl2.

[0086] According to the most preferred embodiment of the invention the halogenation agent is CI2.

[0087] In 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 / H2C>2, 1 ,3-di- bromo-5,5-dimethylhydantoin.

[0088] According to one preferred embodiment of the invention the halogenation agent in that case is Br2

[0089] The step (i) of the inventive process is carried out with or without the presence of a catalyst. If a catalyst is used, it 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.

[0090] According to one preferred embodiment of the invention the catalyst used in the step (i) of the inventive process is acetonitrile or DMF.

[0091] According to one preferred embodiment of the invention the catalyst used in the step (i) of the inventive process is acetonitrile.

[0092] According to one preferred embodiment of the invention the catalyst used in the step (i) of the inventive process is DMF. 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.

[0093] According to most preferred embodiment of the invention the halogenation agent is Ch and the step (i) of the inventive process is carried out without the presence of a catalyst.

[0094] The order of adding the reagents to the reaction mixture is variable.

[0095] 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.

[0096] According to a further preferred embodiment of the invention herein the halogenation agent is added to compound (II) in the halogenated aromatic solvent without the presence of a catalyst.

[0097] 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.

[0098] In the case Ch is used as the halogenation agent the addition is carried out at a temperature from 0 to 30°C, preferably 10 to 15°C.

[0099] 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 reaction completion vacuum and elevated temperature are applied. Or 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 phases with acidic or basic aqueous solution instead or in addition to washing with water.

[0100] 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.

[0101] 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%.

[0102] 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.

[0103] 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.

[0104] 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. 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.

[0105] 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.

[0106] According to the present invention the methylation agent is selected from the group consisting of: dimethylsulfate (CH3O)2SO2), MeCI, MeBr, (CH3)2CO3, trimethyl orthoformate.

[0107] According to one preferred embodiment of the invention the methylation agent is dimethylsulfate (CH3O)2SO2).

[0108] The use of the above mentioned methylation agents has a cost advantage compared to the process disclosed in WO 2022 / 161801.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] The base can be used in a solid form, e.g. solid pellets, flakes, micropills or powder, or as a solution, e.g. as aqueous solution.

[0116] 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.

[0117] 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.

[0118] 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).

[0119] According to another specific embodiment the organic base is diisoproylethylamin (DI PEA).

[0120] According to another specific embodiment the organic base is tri-n-butylamin.

[0121] According to another specific embodiment the organic base is N,N-dimethylcyclohexylamin.

[0122] According to another specific embodiment the organic base is triethylamin.

[0123] According to another specific embodiment the organic base is tri-n-propylamin.

[0124] According to another specific embodiment the organic base is 1,5,7-triazabicyclo(4.4.0)dec-5- ene (TBD).

[0125] According to another specific embodiment the organic base is 1,8-diazabicyclo[5.4.0]undec-7- ene (DBU).

[0126] According to another specific embodiment the organic base is 1,1,3,3-tetramethylguanidine (TMG).

[0127] According to another specific embodiment the organic base is collidine.

[0128] According to another specific embodiment the organic base is 2,6-lutidine (2,6-dimethylpyri- dine).

[0129] According to another preferred specific embodiment the base is DIPEA or KOH.

[0130] According to another preferred specific embodiment the base is DI PEA.

[0131] 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.

[0132] 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.

[0133] According to one preferred embodiment of the invention the phase-transfer catalyst is tetrabutylammonium bromide (TBAB). 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.

[0134] 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.

[0135] The step (iii) 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.

[0136] 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 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.

[0137] According to one further embodiment of the invention the halogenated aromatic solvent for step (iii) is selected from the group consisting of: chlorobenzene, bromobenzene, fluorobenzene, 1 ,2- dichlorobenzene, 1 ,4-dichlorobenzene, 1,2-difluorobenzene, 1 ,4-difluorobenzene, 1,2,4- trichlorobenzene.

[0138] 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.

[0139] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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%.

[0144] According to step (iv) of the inventive process, compounds of formula (IV) are reduced to a compound of formula (V) wherein

[0145] X is Cl or Br,

[0146] Y is H or F.

[0147] The step (iv) of the inventive process according to one embodiment is carried out in a halogenated aromatic solvent.

[0148] According to one embodiment of the invention the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, bromobenzene, fluorobenzene, 1,2- dichlorobenzene, 1 ,4-dichlorobenzene, 1,2-difluorobenzene, 1 ,4-difluorobenzene, 1,2,4- trichlorobenzene.

[0149] 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.

[0150] According to one preferred embodiment of the invention the halogenated aromatic solvent is chlorobenzene.

[0151] The step (iv) of the inventive process is a reduction reaction of the NO2 group to NH2.

[0152] As suitable reductions agents can be used all known by the skilled person.

[0153] 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.

[0154] 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. 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] As a rule, 0.5 to 3, preferably 0.75 to 2.5 moles of metal hydride, metal hemihydride, borohydride or boranate per mole of nitro compound of formula (IV) are used.

[0159] 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, ZrC>2, TiC>2, SiC>2, 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 0.01 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.

[0160] 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

[0161] In the preferred embodiment of the invention the catalyst for step (iv) is Pt / V catalyst.

[0162] The so-obtained raw product can be directly used in the next process step, i.e. step (v) 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 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.

[0163] By means of the inventive process, the compounds of formula (V) can be prepared in surprisingly high yields. Preferably, the yields of step (iv) are at least 80%, more preferably at least 85 %, even more preferred at least 90%, even more preferred at least 95%.

[0164] According to step (v) of the inventive process, compounds of formula (V) react with a compound of formula (VI) to give the compound of formula (VII) wherein

[0165] X is Cl or Br,

[0166] Y is H or F in the presence of an acid.

[0167] The reaction of guanidines of formula (VI) with halogenated amines of formula (IV) is usually carried out from 50 °C to 150 °C, preferably from 80 °C to 130 °C. Microwave-Technology can be used where applicable (e.g. C.O. Kappe, A. Stadler, Microwaves in Organic and Medicinal Chemistry, Weinheim 2012).

[0168] The reaction can be carried out at atmospheric pressure or under elevated pressure, if appropriate under an inert gas, in flow reactors or batchwise.

[0169] In one embodiment of the process according to the invention, the guanidines of formula (VI) and the halogenated amines of formula (IV) are used in equimolar amounts.

[0170] In another embodiment of the process according to the invention, the guanidines of formula (VI). are used in excess with regard to the halogenated amines of formula (IV)

[0171] The reaction of the guanidines of formula (VI) with the amines of formula (IV) is carried out in an organic solvent or without organic solvent in a melt. The term solvent as used herein also includes mixtures of two or more solvents.

[0172] Suitable in principle are all solvents which are capable of dissolving the guanidines of formula (VI) and the amines of formula (IV) at least partly and preferably fully under reaction conditions. Examples of suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane, nitromethane and mixtures of C5-C8-alkanes, aromatic hydrocarbons such as benzene, chlorobenzene, toluene, cresols, o-, m- and p-xylene, halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert.-butyl methylether (TBME), dioxane, anisole and tetra hydrofuran (THF), esters such as ethyl acetate and butyl acetate; nitriles such as acetonitrile and propionitrile, as well as dipolar aprotic solvents such as sulfolane, dimethylsulfoxide, N.Ndimethylformamide (DMF), N,N-dimethylacetamide (DMAC), 1 ,3-dimethyl-2-imidazoli- dinone (DMI), N,N'-dimethylpropylene urea (DMPLI), dimethyl sulfoxide (DMSO) and 1-methyl-2 pyrrolidinone (NMP).

[0173] Preferred solvents are ethers, nitriles and dipolar aprotic solvents as defined above.

[0174] More preferred solvents are nitriles as defined above.

[0175] The reaction of the guanidines of formula (VI) with the amines of formula (IV) is carried out in the presence of an acid.

[0176] Example of suitable acids are inorganic acids like hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid; Lewis acids like boron trifluoride, aluminium chloride, ferric-lll-chloride, tin-IV-chloride, titanium-IV-chloride and zinc-l l-chloride, as well as organic acids like formic acid, acetic acid, propionic acid, oxalic acid, methylbenzenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, trifluoroacetic acid, can be used. The acids are generally employed in excess or, if appropriate, can be used as solvent.

[0177] The guanidines of formula (VI) required for the preparation of biguanides of formula (VII) are commercially available or can be prepared in accordance with literature procedures (e.g. J.L. LaMattina et al., J. Med. Chem. 1990, 33, 543 - 552; A. Perez-Medrano et al., J. Med. Chem. 2009, 52, 3366 - 3376).

[0178] According to step (vi) of the inventive process, compounds of formula (VII) react with an ester of formula (VIII) wherein

[0179] R1to R3are as defined above, in the presence of NaOMe or KOMe to provide the azine compounds of formula (T) wherein

[0180] X is Cl, F or Br,

[0181] Y is H or F,

[0182] R1is selected from the group consisting of H, halogen, CN, Ci-Ce-alkyl, (Ci-C6-alkoxy)-Ci-Ce- alkyl, Cs-Ce-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C4-alkyl, Ci-Ce-alkoxy, C2-Ce-alkenyloxy, C2- Ce-alkynyloxy, Cs-Ce-cycloalkoxy, (C3-C6-cycloalkyl)-Ci-C4-alkoxy, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated;

[0183] R2is selected from the group consisting of H, halogen, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C1- Ce-alkoxy and Ci-Ce-haloalkoxy;

[0184] R3is selected from the group consisting of halogen, CN, Ci-Ce-alkyl, C2-Ce-alkenyl, C3-C6- alkynyl, Cs-Ce-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C4-alkyl, Cs-Ce-cycloalkenyl and Ci-Ce- alkoxy-Ci-Ce-alkyl, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated.

[0185] In a preferred embodiment of the present invention, the azine compound of formula (T) is synthesised wherein

[0186] R1is selected from the group consisting of H, halogen, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C1- Ce-alkoxy and Ci- Ce-haloalkoxy;

[0187] R2is selected from the group consisting of H, halogen, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, C1- Ce-alkoxy and Ci-Ce-haloalkoxy;

[0188] R3is selected from the group consisting of Ci-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl.

[0189] In a further preferred embodiment of the present invention, the azine compound of formula (T) is synthesised wherein

[0190] R1is Ci-Ce-alkyl,

[0191] R2is Ci-Ce-haloalkyl;

[0192] R3is Ci-C6-alkyl.

[0193] In a particularly preferred embodiment the compound of formula (T), is the compound of formula (T-1) wherein

[0194] X is Cl or Br;

[0195] Y is H or F.

[0196] In a further particularly preferred embodiment of the present invention, the compound of formula (T), is the compound of formula T-1 A:

[0197] In a further particularly preferred embodiment of the present invention, the compound of formula (T), is the compound of formula T-1 B:

[0198] In a further particularly preferred embodiment of the present invention, the compound of formula (T), is the compound of formula T-1C:

[0199] The reaction of biguanidines of formula (VII) with carbonyl compounds of formula (VIII) is usually carried out at temperatures from 50 °C to the boiling point of the reaction mixture, preferably from 50 °C to 200 °C (e.g. R. Sathunuru et al., J. Heterocycl. Chem. 2008, 45, 1673-1678).

[0200] The reaction can be carried out at atmospheric pressure or under elevated pressure, if appropriate under an inert gas, continuously or batchwise.

[0201] In one embodiment of the process according to the invention, the biguanidines of formula (VII) and the carbonyl compounds of formula (VIII) are used in equimolar amounts.

[0202] In another embodiment of the process according to the invention, the carbonyl compounds of formula (VIII) are used in excess with regard to the biguanidines of formula (VII).

[0203] Preferably the molar ratio of the carbonyl compounds of formula (VIII) to the biguanidines of formula (VII) is in the range from 2.5 : 1 to 1 :1 , preferably 1.2 : 1 to 1 :1 , especially preferred 1.2 : 1 , also especially preferred 1 : 1.

[0204] The reaction of the biguanidines of formula (VII) with the carbonyl compounds of formula (VIII) is carried out in an organic solvent.

[0205] Suitable solvents are in principle all solvents capable of dissolving the biguanidines of formula (VII) and the carbonyl compounds of formula (VIII) at least partly and preferably fully under reaction conditions.

[0206] Examples of suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane, nitromethane and mixtures of Cs-Cs-alkanes; aromatic hydrocarbons such as benzene, chlorobenzene, toluene, cresols, o-, m- and p-xylene; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert.-butyl methylether (TBME), dioxane, anisole and (methyl)tetrahydrofuran (THF), nitriles such as acetonitrile and propionitrile, as well as dipolar aprotic solvents such as sulfolane, dimethylsulfoxide, N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMAC), 1 ,3-dimethyl-2-imidazolidinone (DMI), N,N'-dimethylpropylene urea (DMPLI), dimethyl sulfoxide (DMSO) and 1-methyl-2 pyrrolidinone (NMP).

[0207] Preferred solvents are ethers and dipolar aprotic solvents as defined above. More preferred solvents are ethers as defined above.

[0208] The term solvent as used herein also includes mixtures of two or more of the above compounds.

[0209] The reaction of the biguanidines of formula (VII) with the carbonyl compounds of formula (VIII) is carried out in the presence of a base.

[0210] Examples of suitable bases include metal-containing bases and nitrogen-containing bases.

[0211] Examples of suitable metal-containing bases are inorganic compounds such as alkali metal and alkaline earth metal oxide, and other metal oxides, such as lithium oxide, sodium oxide, potassium oxide, magnesium oxide, calcium oxide and magnesium oxide, iron oxide, silver oxide; alkali metal and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal amides such as lithium amide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate, as well as alkali metal hydrogen carbonates (bicarbonates) such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; alkali metal and alkaline earth metal phosphates such as sodium phosphate, potassium phosphate and calcium phosphate; and furthermore organic bases, such as tertiary amines such as tri-Ci-C6- alkylamines, for example triethylamine, trimethylamine, N-ethyldiisopropylamine, and N-methyl- piperidine, pyridine, substituted pyridines such as collidine, lutidine, N-methylmorpholine and 4- dimethylaminopyridine (DMAP), and also bicyclic amines such as 1 ,8-diazabicyclo[5.4.0]undec- 7-ene (DBU) or 1 ,5- diazabicyclo[4.3.0]non-5-ene (DBN). Also alkali alkoxides like NaOMe Oder KOMe are examples for viable bases.

[0212] Preferred bases are tri-C1-C6-alkylamines as defined above. The term base as used herein also includes mixtures of two or more, preferably two of the above compounds. Particular preference is given to the use of one base. The bases are generally employed in excess; however, they can also be employed in equimolar amounts, or, if appropriate, can be used as solvent. Preferabl from 1 to 5 base equivalents, particularly preferred 3 base equivalents of base are used, based on the biguanidines of formula (VIII). The end of the reaction can easily be determined by the skilled worker by means of routine methods.

[0213] According to one preferred embodiment the base is an alkali alkoxide.

[0214] According to one more preferred embodiment the base is KOMe or NaoMe.

[0215] The reaction mixtures are worked up in a customary manner, for example by mixing with water, separation of the phases and, if appropriate, chromatographic purification of the crude product. Some of the intermediates and end products are obtained in the form of viscous oils, which can be purified or freed from volatile components under reduced pressure and at moderately elevated temperature.

[0216] If the intermediates and the end products are obtained as solid, purification can also be carried out by recrystallisation or digestion.

[0217] 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.

[0218] Examples

[0219] The following examples further illustrate the present invention and do not restrict the invention in any manner.

[0220] 1. Synthesis of 2-chloro-4,5-difluorophenol

[0221] Example 1.1

[0222] To the solution of 3,4-difluorophenol 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 %.

[0223] Example 1.2

[0224] To the solution of 3,4-difluorophenol 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 %.

[0225] Example 1.3

[0226] To the mixture of 3,4-difluorophenol 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 %. Example 1.4

[0227] A solution of 3,4-difluorophenol (3.025 kg, 23.2 mol) in chlorobenzene (6.68 kg) was cooled to 10°C. To this solution CI2 gas (1 eq, 23.2 mol, 1.646 kg) was added via dip pipe with the rate that inner temperature doesn't exceed 15°C. After dosage was complete, the reaction mass was post-stirred overnight. Vacuum 200 mbar was applied and temperature increased to 30°C to remove HCI. Yield of 2-chloro-4,5-difluorophenol determined by quantitative GC is 95.1 %.

[0228] 2. Continuous synthesis of 6-chloro-3,4-difluoro-2-nitrophenol in a microstructured reactor

[0229] In all experiments 18 equivalents of water, based on the nitration agent, were used as an in-line quench. Additionally, 10 mL of water were placed in the sample vials. During operation of the microreactor, the feed streams were controlled using scales and / or mass flow meters. After volume flow rates have remained constant for at least 5 residence times, a sample of 1 mL (organic) is withdrawn.

[0230] Example set 2.1 - Corning Low Flow reactor, HNO3, low CDFP concentration

[0231] A Corning Low Flow reactor with a total holdup of approximately 2 mL was investigated whereas the quench water was introduced in the last reaction plate at a temperature below 5 °C. The concentration of 2-chloro-4,5-difluorophenol in monochlorobenzene was set to 34.5 wt% and 65 wt% nitric acid as nitration agent was used. At a constant temperature of the tempering fluid of 30 °C and at a constant residence time of 12 seconds the equivalents of the nitration agent were varied from 1.4 to 1.5 and to 1.6 resulting in a conversion of approximately 90 %, 95 % and 99 %, respectively. Increasing the set point of the tempering fluid from 30 °C to 35 °C whereas the other parameter were kept constant (1.4 HNO3 equivalents, 12 s residence time), the conversion increased from approximately 90 % to approximately 99 %. For the latter condition an isolated yield was 97.4 % was measured.

[0232] Example set 2.2 - Corning Low Flow reactor, HNO3, high CDFP concentration

[0233] The reactor from example 1.1 and 65 wt% nitric acid as nitration agent was used. In contrast, the concentration of 2-chloro-4,5-difluorophenol in monochlorobenzene was set to 80.8 wt%. At a constant temperature of the tempering fluid of 10 °C and 1.05 equivalents of the nitration agent, an increase in the residence time from 12.6 s to 20 s and to 30 s resulted in an increase in the conversion from 81 % to 82 % and to 84 %, respectively. Increasing the equivalents of the nitration agent from 1.05 to 1.2 and to 1.4 at a constant temperature of the tempering fluid of 10 °C and a constant residence time of 12.6 s resulted in an increase in conversion from 81 % to 82 % and to 92 %, respectively. The influence of the HNO3 equivalents at an elevated temperature of 30 °C of the tempering fluid on the conversion of the starting material was also investigated whereas the residence time was kept constant at 12.6 seconds. Increasing the equivalents from 1.05 to 1.1 resulted in an increase in conversion from 97 % to 98 %. For the conditions of the temperature of tempering fluid of 30 °C and a HNO3 equivalent of 1.05, an isolated yield of 79 % was analyzed for a residence time of 40 s. Example set 2.3 - Corning Low Flow reactor, NaNCh / FLSCL

[0234] As nitration agent 40 wt% NaNCh together with 50 wt% H2SO4 was used. Based on NaNCh a fixed concentration of H2SO4 of 2 equivalents was applied. NaNCh and H2SO4 streams were mixed in a T-piece before they were fed into the reactor similar to example set 1.1. The concentration of 2-chloro-4,5-difluorophenol in monochlorobenzene was set to 34.5 wt%. Due to gas formation, the actual residence time was lower than the theoretical value. For a constant theoretical residence time of 42 s and a constant temperature of the tempering fluid of 40 °C, an increase of the equivalents of NaNCh from 1.05 to 2.0 to 3.0 to 4.0 resulted in an increase of conversion from 52 % to 70 % to 74 % to 75 % to 79 %.

[0235] Example set 2.4 - Ehrfeld Miprowa Lab, HNO3, 20 °C, capillary

[0236] An Ehrfeld Miprowa Lab reactor with a total holdup of approximately 28 mL was used whereas the nitration agent was introduced via a capillary after the first reaction channel and the water for quenching was introduced before the last reaction channel. The concentration of 2-chloro- 4,5-difluorophenol in monochlorobenzene was set to 34.5 wt% and 65 wt% nitric acid as nitration agent with a constant amount of 1.4 equivalent was used. The tempering fluid was set to a temperature of 20 °C. Increasing the residence time from 12.6 s to 42 s to 60 s the conversion increased from 54 % to 66 % to 65 %.

[0237] Example 2.5 - Ehrfeld Miprowa Lab, HNO3, 20 °C, cascade

[0238] The reactor of example set 2.5, same concentrations of the educts as well as temperature and equivalents were used, however, the starting material and the nitration agent was mixed in a cascade mixer before there were fed into the microreactor. Compared to the corresponding condition of example set 1.4 the conversion increased from 66 % to 73 % at a constant residence time of 42 s when the cascade mixer was applied.

[0239] Example set 2.6 - Ehrfeld Miprowa Lab, HNO3, 30 °C, cascade

[0240] The reactor of example 2.6 as well as the same concentrations of the educt materials was used. The temperature of the tempering fluid was set to 30 °C and a constant residence time of 42 s was investigated. The equivalent of the nitration agent was varied from 1.05 to 1.2 to 1.4. As the result, the conversion of the starting material increased from 66 % to 72 % to 80 %.

[0241] 3. Synthesis of 1-chloro-4,5-difluoro-2-methoxy-3-nitro-benzene

[0242] Example 3.1 - Experiment with DIPEA base

[0243] 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-meth- oxy-3-nitro-benzene was determined, according to a yield of 99.6 %.

[0244] Example 3.2 - Experiment with butyl(triphenyl)phosphonium chloride and KOH base 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 mixture 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.

[0245] Example 3.3 - Experiment with tetrabutylammonium chloride and KOH base

[0246] 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.

Claims

Claims1. A process for the preparation of the compound of formula (III)whereinX is Cl or Br,Y is H or F, comprising the following step:(ii) reacting a compound of formula (I)with a nitrating agent, wherein the reaction is carried out in a microstructured flow reactor.

2. The process of claim 1 , wherein X is Cl and Y is H.

3. The process of any of claims 1 to 2, wherein the nitrating agent is selected from the group consisting of: HNO3, NaNO2 / H+, alkylnitrite, alkylnitrite / H+, N2O3.

4. The process of claim 3, wherein the nitrating agent is HNO3.

5. The process of any of claims 1 to 4, wherein the compound of formula (II) is diluted in a halogenated aromatic solvent.

6. The process of claim 5, wherein the halogenated aromatic solvent is selected from the group consisting of: chlorobenzene, bromobenzene, fluorobenzene, 1 ,2-dichlorobenzene, 1,4-dichlorobenzene, 1 ,2-difluorobenzene, 1,4-difluorobenzene, 1,2,4-trichlorobenzene.

7. The process of claim 6, wherein the aromatic solvent is chlorobenzene.

8. The process of any of claims 1 to 7, wherein 1.05 - 1.6 eq of HNO3 is used, preferably 1.1- 1.45 eq of HNO3.

9. The process of any of claims 1 to 8, wherein the compound of formula (I) and HNO3 were dosed parallel into the microstructured flow reactor.

10. The process of any of claims 1 to 9, wherein the HNO3 is partly dosed parallel with the compound of formula (I) and partly dosed to the already partly reacted mixture in the microstructured flow reactor.

11. The process of any of claims 1 to 10, wherein the reaction is carried out at a temperature from 20 to 40°C.

12. A process for the preparation of azine compounds of formula (T)X is Cl or Br,Y is H or F,R1is selected from the group consisting of H, halogen, CN, Ci-Ce-alkyl, (Ci-Ce- alkoxy)-Ci-Ce-alkyl, Cs-Ce-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C4-alkyl, Ci-Ce-alkoxy, C2-Ce-alkenyloxy, C2-Ce-alkynyloxy, Cs-Ce-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-Ce-alkyl, Ci-Ce- haloalkyl, Ci-Ce-alkoxy and Ci-Ce-haloalkoxy;R3is selected from the group consisting of halogen, CN, Ci-Ce-alkyl, C2-Ce-alkenyl, Cs-Ce-alkynyl, Cs-Ce-cycloalkyl, (C3-C6-cycloalkyl)-Ci-C4-alkyl, Cs-Ce-cycloalkenyl and Ci-Ce-alkoxy-Ci-Ce-alkyl, where the aliphatic and cycloaliphatic parts of the radicals are unsubstituted, partly or completely halogenated; comprising the following steps:(i) preparing the compound (I)via a halogenation reaction of a compound of formula (II)preparing the compound of formula (III) according to any one of claims 1 to 11 ; formula (IV)in 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)whereinX is Cl or Br,Y is H or F,(vi) reacting the compound of formula (VII) with an ester of formula (VIII)whereinR1to R3are as defined above, in presence of NaOMe or KOMe.

13. The process of claim 12, wherein the azine compound has a formula (T-1):whereinX is Cl or Br, Y is H or F.

14. The process of any of claims 12 or 13, wherein the azine compound has a formula (T-1):whereinX is Cl, Y is H.

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