Process for preparing phenolic compounds

Abstract

The present invention relates to a process for preparing a phenolic compound of formula (I) wherein the variables are as defined in the claims and the description, comprising reacting the corresponding alkyl or benzyl ether with HBr in the presence of water in certain molar ratios.

Description

[0001] BASF SE 240191W001

[0002] Process for preparing phenolic compounds

[0003] The invention relates to a process for preparing phenolic compounds of formula (I):

[0004]

[0005] comprising reacting the corresponding alkyl or benzyl ether with HBr in the presence of water in certain molar ratios.

[0006] TECHNICAL BACKGROUND

[0007] Phenolic compounds of formula (I) are valuable intermediates, for example for preparing herbi-cidally active aryl ethers of formula (III) as defined below known from WO 2017 / 202768.

[0008] WO 2017 / 202768 discloses a synthesis of similar phenolic compounds by reacting respective ethers with BBra (boron tribromide) or by catalytic hydrogenation of the respective ether.

[0009] It is also known that alcohols can be prepared from the respective ethers by reacting the same with either concentrated (48%) HBr, i.e. aqueous HBr solution wherein the molar ratio of HBr to water is ca. 1:4.86, or with anhydrous HBr (e.g. R.L. Burwell, The cleavage of ethers, Chem. Rev. 1954, 54, pages 622 to 631).

[0010] However, owing to long reaction times and / or poor conversion, the use of catalysts, complicated purification steps and / or moderate yields, the known synthesis routes are not an option for an economic industrial preparation of the phenolic compounds of formula (I).

[0011] Hence, there is still room for improvement, specifically in view of economic and ecological aspects.

[0012] It is an object of the present invention to provide an efficient process for manufacturing phenolic compounds of formula (I), which is suitable for industrial scale application.

[0013] SUMMARY OF THE INVENTION

[0014] Surprisingly it has been found that compounds of formula (II) can be converted into phenolic compounds of formula (I) with higher conversion rates and yields by using HBr in the presence of water in certain molar ratios, to be more precise in a molar ratio of HBr to water from 3:1 to 1:1.7.

[0015] M / BASFTR-4226-PCBASF SE 240191W001

[0016] Accordingly, the present invention relates to a process for manufacturing a phenolic compound of formula (I)

[0017]

[0018] wherein

[0019] R1and R2, independently of each other, are selected from the group consisting of fluorine, chlorine and bromine;

[0020] R3is halogen or methyl; and

[0021] n is 0, 1 or 2;

[0022] comprising reacting a compound of formula (II)

[0023]

[0024] wherein

[0025] R1, R2, R3and n are defined as in formula (I); and

[0026] R4is Ci-C4-alkyl or benzyl;

[0027] with HBr in the presence of water,

[0028] wherein the molar ratio of HBr to water is from 3:1 to 1:1.7.

[0029] Moreover, the present invention relates to a process for manufacturing arylethers of formula (III)

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[0031]

[0032] wherein

[0033] R1, R2, R3and n are as defined above; and

[0034] R5is hydrogen or Ci-C4-alkyl;

[0035] comprising

[0036] (i) preparing a compound (I) with the method as defined above; and

[0037] (ii) reacting the compound (I) obtained in step (i) with a compound (X)

[0038]

[0039] wherein

[0040] X is a leaving group; and

[0041] R5is as defined above for the compound of formula (III).

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] Definitions

[0044] The organic moieties mentioned in the definition of the compounds and the substituents according to the invention, especially of variables R4, R5and Rxare - like the term halogen - collective terms for individual enumerations of the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

[0045] The term halogen denotes in each case fluorine, chlorine, bromine or iodine.

[0046] The term "alkyl" as used herein (and in the alkyl moieties of other groups comprising an alkyl group, e.g. alkoxy or alkylsulfonyl or alkylsulfonyloxy or alkylsulfonate) denotes in each case a straight-chain or branched alkyl group having 1 to 6 carbon atoms (= Ci-Ce-alkyl) or 1 to 4 carbon atoms (= Ci-C4-alkyl). Ci-C4-Alkyl is methyl (CH3), ethyl (C2H5), n-propyl (CH2CH2CH3), isopropyl (CH(CH3)2), n-butyl (CH2CH2CH2CH3), sec-butyl (CH(CH3)-C2H5), isobutyl (CH2-CH(CH3)2) or tert-butyl (C(CH3)3). Examples for Ci-Ce-alkyl are, in addition to those mentioned for Ci-C4-alkyl, 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,

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[0049] 3-methylpentyl, 4-methylpentyl, 1,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-di-methylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpro-pyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

[0050] The term "haloalkyl" as used herein (and in the alkyl moieties of other groups comprising an alkyl group, e.g. haloalkylsulfonyl or haloalkylsulfonyloxy or haloalkylsulfonate) denotes in each case a straight-chain or branched alkyl group having 1 to 6 carbon atoms (= Ci-Ce-haloalkyl) or 1 to 4 carbon atoms (= Ci-C4-haloalkyl), as defined above, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Examples for Ci-C4-haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, bromomethyl, 1 -fluoroethyl, 2-fluoro-ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1 -chloroethyl, 2-chloroethyl, 2,2,-dichloroethyl, 2,2,2-trichloroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 1 -bromoethyl, 1 -fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1 , 1 , 1 -trifluoroprop-2-yl, 3-chloropropyl, 1-fluorobutyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, nonafluorobutyl and the like.

[0051] Aryl is a monocyclic or fused carboaromatic ring of generally 6 to 16 carbon ring atoms. Examples are phenyl, naphthyl, anthracenyl or phenanthrenyl. Aryl can be unsubstituted or substituted by one or more identical or different radicals selected from the group consisting of halogen and Ci-C4-alkyl.

[0052] The term "alkoxy" denotes a straight-chain or branched alkyl group having the indicated number of carbon atoms which is bound to the remainder of the molecule via an oxygen atom. C1-C4-Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tertbutoxy.

[0053] Ci-Ce-Alkylsulfonyloxy is a group -O-S(O)2-R, where R is a Ci-Ce-alkyl group as defined above.

[0054] Ci-Ce-Haloalkylsulfonyloxy is a group -O-S(O)2-R, where R is a Ci-Ce-haloalkyl group as defined above.

[0055] The net reaction of compound (II) to (I) can be depicted as follows:

[0056]

[0057] In the process according to the invention, the molar ratio of HBr to water is important for a fast conversion and good yield and is according to the invention from 3:1 to 1:1.7. Preferably, the molar ratio of HBr to water is from 3:1 to 1:1.5, such as 3:1 to 1:1.3; more preferably from 1.5:1

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[0060] to 1 : 1.5, in particular from 1.5: 1 to 1 : 1.3, specifically from 1 : 1 to 1 : 1.3.

[0061] Examples of preferred molar ratios of HBrto water are about 3:1, 2.9:1, 2.8:1, 2.7:1, 2.6:1, 2.5:1, 2.4:1, 2.3:1, 2.2:1, 2.1:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6 and 1:1.7. More preferred examples of molar ratios of HBr to water are about 3:1, 1.5:1, 1:1, 1:1.2 and 1:1.3.

[0062] “About” as used herein includes a range of the specified ratio, wherein the specified ratio is increased or decreased by 10%. For example, “about 1:2” includes a range of 1:1.8 to 1:2.2.

[0063] The molar ratio of HBr to water is calculated from the complete amount of HBr added to the reaction and the complete amount of water added to the reaction. Water optionally present in any solvents or compound (II), if these are not anhydrous, has to be taken into account when calculating the ratio.

[0064] The molar ratio of HBr to water can be adjusted either before the reaction starts or during the reaction.

[0065] Preferably the molar ratio of HBr to water is adjusted “initially”, i.e. before the reaction starts. Accordingly, “initial ratio” means the ratio before the reaction starts. Since the ether cleavage of compounds (II) generally needs a certain temperature, the reaction starts essentially only when a minimum temperature is reached, such as 50°C or 60°C. Adjusting the molar ratio of HBr to water can thus for example be carried out by providing a mixture of compound (II) (preferably dissolved in a solvent), HBr and water at a temperature at which the reaction does not start or at least not to a substantial extent, where the molar ratio of HBr to water is adjusted within the claimed range. Heating the mixture is started only after the molar ratio of HBr to water has been adjusted.

[0066] Thus, preferably, in the process according to the invention, the initial ratio of HBr to water is from 3:1 to 1:1.7, more preferably from 3:1 to 1:1.5, such as 3:1 to 1:1.3; even more preferably from 1.5:1 to 1:1.5, particularly preferably from 1.5:1 to 1:1.3, and specifically from 1:1 to 1:1.3.

[0067] In the present process, examples of further preferred initial ratios of HBr to water include about 3:1, 2.9:1, 2.8:1, 2.7:1, 2.6:1, 2.5:1, 2.4:1, 2.3:1, 2.2:1, 2.1:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6 and 1:1.7.

[0068] Since HBr takes place in the reaction as a reactant, the amount of HBr is depleted in the course of the reaction, whereas the amount of water remains essentially unchanged (unless this is removed partially with optionally removed R4-Br formed in the reaction; see below). It is possible, but not necessary, to replace reacted HBr as the reaction progresses, so as to stay within the indicated molar ratio. Preferably however, the depleted amount of HBr is not replaced.

[0069] The molar ratio can also be adjusted in the course of the reaction, e.g. by adding HBr and water while the reaction can already take place. For instance, if compound (II) is provided in form of a

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[0072] solution already having the temperature required for the onset of the ether cleavage or if compound (II) is provided in form of a melt, which also has a temperature at which ether cleavage can take place, HBr and water are added simultaneously to the compound (II), either as a mixture or separately, in the indicated molar ratio.

[0073] Preferably, however, the molar ratio of HBr to water is adjusted “initially” within the claimed range, i.e. before the reaction starts.

[0074] The compounds of formula (II) and HBr may be provided in substance or dissolved in a solvent.

[0075] In a preferred embodiment of the process according to the invention, the compounds of formula (II) are provided dissolved in an organic solvent.

[0076] In another preferred embodiment of the process according to the invention, the compounds of formula (II) are provided in substance.

[0077] More preferably however, the compounds of formula (II) are provided dissolved in an organic solvent.

[0078] Suitable in principle are all solvents which can dissolve the compounds of formula (II) at least partly and preferably fully.

[0079] Examples of suitable solvents are aromatic hydrocarbons, such as benzene, toluene, the cresols (o-, m- or p-cresol or any mixture of two or of all three thereof), the xylenes (o-, m- or p-xylene or any mixture of two or of all three thereof), and chlorobenzene; halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; organic acids, like formic acid, acetic acid, propionic acid and trifluoroacetic acid; and mixtures of two or more of these solvents.

[0080] Preferred solvents are the above aromatic hydrocarbons and organic acids; among these benzene, toluene, the cresols, the xylenes, chlorobenzene, formic acid, acetic acid and propionic acid being preferred.

[0081] More preferred solvents are benzene, toluene, the cresols, the xylenes, chlorobenzene and acetic acid.

[0082] Specifically, acetic acid is used.

[0083] In a preferred embodiment of the process according to the invention, HBr is provided in substance, i.e. gaseous.

[0084] In another preferred embodiment of the process according to the invention, HBr is provided dissolved in an organic solvent.

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[0087] In another preferred embodiment, HBr is provided in a combination of an organic solvent and water. Either HBr is provided in a mixture of water and an organic solvent, especially if this is miscible with water, or a part of HBr is provided in aqueous solution and the other part in an organic solvent.

[0088] Preference is however given to provide HBr dissolved in an organic solvent.

[0089] Suitable in principle are all solvents which can dissolve HBr at least partly and preferably fully.

[0090] Examples of suitable solvents are aromatic hydrocarbons, such as benzene, toluene, the cresols (o-, m- or p-cresol or any mixture of two or of all three thereof), the xylenes (o-, m- or p-xylene, or any mixture of two or of all three thereof) and chlorobenzene; halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; organic acids like formic acid, acetic acid, propionic acid and trifluoroacetic acid; and mixtures of two or more of these solvents.

[0091] Preferred solvents are the above aromatic hydrocarbons and organic acids; among these benzene, toluene, the cresols, the xylenes, chlorobenzene, formic acid, acetic acid and propionic acid being preferred.

[0092] More preferred solvents are benzene, toluene, the cresols, the xylenes, chlorobenzene and acetic acid.

[0093] Specifically, acetic acid is used.

[0094] The reaction of the compounds of formula (II) with HBr may in principle be carried out in solution or in melt.

[0095] However, preference is given to react the compounds of formula (II) with HBr in an organic solvent.

[0096] Suitable in principle are all solvents which can dissolve the compounds of formula (II) and HBr at least partly and preferably fully under reaction conditions.

[0097] Examples of suitable solvents are aromatic hydrocarbons, such as benzene, chlorobenzene, toluene, the cresols, the xylenes, and chlorobenzene; halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; organic acids like formic acid, acetic acid, propionic acid and trifluoroacetic acid; and mixtures of two or more of these solvents.

[0098] Preferred solvents are the above aromatic hydrocarbons and organic acids; among these benzene, toluene, the cresols, the xylenes, chlorobenzene, formic acid, acetic acid and propionic acid being preferred.

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[0101] More preferred solvents are benzene, toluene, the cresols, the xylenes, chlorobenzene and acetic acid.

[0102] Specifically, acetic acid is used.

[0103] In case the solvents contain water, this should be considered for the ratio of HBr to water, which is from 3:1 to 1:1.7.

[0104] Preferably however, the solvents are used in anhydrous form, i.e. they contain less than 2% by weight of water, preferably less than 1% by weight of water, based on the total weight of the solvent. If acetic acid is for example to be used as solvent and in anhydrous form, this is expediently used in form of glacial acetic acid.

[0105] The reaction of the compounds of formula (II) with HBr is preferably carried out at a temperature of from 50°C to the boiling point of the reaction mixture, more preferably from 60°C to the boiling point of the reaction mixture, even more preferably from 70°C to 120°C, in particular from 70°C to 110°C, and particularly preferably from 80°C to 110°C.

[0106] The reaction can be carried out at atmospheric pressure (i.e. 1013 mbar + / - 200 mbar) or under elevated pressure, e.g. from atmospheric pressure to 5 bar (0.5 MPa) or to 2 bar (0.2 MPa).

[0107] If desired, the reaction can be carried out under an inert gas, such as nitrogen or argon.

[0108] The reaction can be carried out continuously or batchwise.

[0109] The molar ratio in which HBr and the compound (II) are used is not very critical. HBr and the compound (II) can be used in approximately equimolar amounts, or one of them can be used in excess. Preferably however, HBr and the compound (II) are used in approximately equimolar amounts, or HBr is used in excess. “Approximately” means to include small deviations from the 1:1 ratio due to weighing errors and the like, where the deviation does not exceed 10%.

[0110] Preferably the molar ratio of the compounds of formula (II) to HBr is in the range of from 1:1 to 1:5, preferably from 1:1 to 1:4, more preferably from 1:1 to 1:3.5, e.g. from 1:1 to 1:3.

[0111] More preference is however given to using HBr in excess over the compounds of formula (II). The molar ratio of the compounds of formula (II) to HBr is thus more preferably from 1:1.5 to 1 :5, even more preferably from 1 :2 to 1 :4, and in particular from 1 :2 to 1 :3.5, e.g. from 1 :2.5 to 1:3.

[0112] In the present process, examples of further preferred ratios of compounds of formula (II) to HBr include about 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, or 1:5.

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[0115] The reaction can be carried out in the presence of an additive.

[0116] Suitable additives are for example quaternary ammonium salts and phosphonium salts. These act generally as phase transfer catalysts.

[0117] Suitable quaternary ammonium salts comprise, for example, tetra-(Ci-Ci8)-alkylammonium fluorides, chlorides, bromides, iodides, tetrafluoroborates, diborates, hydrogensulfates, perchlorates and borates, such as tetramethylammonium fluoride tetrahydrate, tetramethylammonium fluoride, tetrabutylammonium fluoride, tetrabutylammonium fluoride trihydrate, tetramethylammonium chloride (TMAC), tetraethylammonium chloride, tetrapropylammonium chloride, tetrabu-tylammionium chloride, dodecyltrimethylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride, methyltricaprylammonium chloride; tetramethylammonium bromide, tetraethylammonium chloride hydrate, tetraethylammonium bromide, tetrapropylammonium bromide (TPAB), tetrabutylammonium bromide (TEAB), tetrahexylammonium bromide, tetraoctylammonium bromide, hexadecyltrimethylammonium bromide (CTAB), dodecyltrimethylammonium bromide, tetramethylammonium bromide tetrabutylammonium iodide, tetrahexylammonium iodide, tetrabutylammonium tetrafluoroborate, Ci2-Ci4-trimethylammonium diborate, tetrabutylammonium hydrogensulfate (TBAHS), tetrabutylammonium perchlorate, Ci2-Ci4-alkyltrimethylammonium borate, Ci2-Ci4-alkyltrimethylammonium diborate; N-benzyltri-(Ci-Ci8)-alkylammonium chlorides, bromides or fluorides, such as benzyltrimethylammonium chloride (BTMAC), benzyltriethylammonium chloride (BTEAC), benzyltriethylammonium bromide, benzyltributylammonium chloride, benzyltributylammonium bromide; phenyltri-(Ci-Cis)-alkylammonium chlorides, bromides or fluorides, such as phenyltrimethylammonium chloride (PTMAC); aromatic ammonium salts, such as hexadecylpyridinium chloride, N,N-dimethylpiperi-dinium hydroxide, pyridinium fluorides, chlorides or bromides, such as, for example, 1 -cetylpyridinium chloride monohydrate, cetylpyridinium bromide.

[0118] Among these, preference is given to tetramethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium bromide, tetrahexylammonium bromide, tetraoctylammonium bromide, tetrabutylammonium iodide, tetrahexylammonium iodide, tetrabutylammonium hydrogensulfate and tetrabutylammonium hydroxide.

[0119] Suitable phosphonium salts comprise, for example, Ci-Ci8-alkyltriphenylphosphonium chlorides, bromides, acetates, such as methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, ethyltriphenylphosphonium acetate, butyltriphenylphosphonium chloride, butyltriphenylphosphonium bromide, tetra-(Ci-Ci8)-alkylphospho-nium chloride or bromide, such as tetrabutylphosphonium bromide, tetraphenylphosphonium chloride or bromide, benzyltriphenylphosphonium chloride or bromide.

[0120] Among the quaternary ammonium and phosphonium salts, preference is given to the ammonium salts. Among the ammonium salts, preference is given to the tetra-(Ci-Ci8)-alkylammo-nium salts, in particular to the to the tetra-(Ci-Ci8)-alkylammonium halogenides, especially to the tetra-(Ci-Ci8)-alkylammonium chlorides. Specifically, tetra-(Ci-C4-alkyl)-ammonium

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[0123] halogenides are used; more specifically tetra-(Ci-C4-alkyl)-ammonium chlorides.

[0124] In general, the additive is employed in an amount of up to 50 mol%, preferably between 1 and 40 mol%, more preferably between 2 and 30 mol%, even more particularly between 2 and 25 mol% and in particular between 3 and 25 mol%, based on the amount of the compounds of formula (II). In a specific embodiment, especially if the additive is an ammonium salt, this is employed in an amount of 15 to 25 mol%, based on the amount of the compounds of formula (II).

[0125] For the reaction, the compounds of formula (II), HBr, water and, if appropriate, the additive can principally be brought into contact in any way per se.

[0126] This means that the reaction partners, water and, if appropriate, the additive may be introduced into the reaction vessel and reacted separately, simultaneously or successively.

[0127] For example, it is possible to introduce the major part or the entirety of the compounds of formula (II), optionally in a solvent, into a reaction vessel and subsequently add HBr (optionally dissolved in a solvent). Water can be added before the addition of HBr, simultaneously or subsequently. If only a part of the compounds of formula (II) has been introduced into the reaction vessel before HBr is added, the remaining part thereof is added either during HBr addition of subsequently or both.

[0128] It might be advantageous to add HBr by and by, either continually or portion-wise.

[0129] In a preferred embodiment of the invention, the major part, in particular at least 80% and more preferably the entirety or virtually the entirety (> 95%) of the compounds of formula (II), optionally in a solvent, and water are initially charged, and the major part, in particular at least 80% and more preferably the entirety or virtually the entirety (> 95%) of HBr, optionally dissolved in an appropriate solvent, is added thereto, preferably by and by, for example over a period from 0.5 to 20 min and in particular from 1 to 10 min.

[0130] Alternatively, it is also possible to introduce the major part or the entirety of HBr into the reaction vessel, generally dissolved in an organic solvent or in water or both, and subsequently add water (if this has not been introduced together with HBr or not entirely) and the compounds of formula (II), optionally with or in a solvent.

[0131] In yet another alternative, it is possible to introduce the major part or the entirety of the compounds of formula (II) and of HBr into the reaction vessel, optionally in a solvent, and subsequently add the water.

[0132] In yet another alternative, the compounds of formula (II), optionally in a solvent, HBr, also optionally in a solvent, and water are introduced simultaneously into a reaction vessel.

[0133] More preference is however given to introduce the entirety of the compounds of formula (II), a solvent and water into a reaction vessel, and subsequently add the entirety of HBr, optionally

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[0136] dissolved in an organic solvent. As said above, it might be advantageous to add HBr by and by.

[0137] The desired reaction temperature can be adjusted during the addition of the components or only after all components have been added. The former variant is for example indicated if the compound (II) is initially charged and reacted in form of a melt, to which HBr and water are added. Preference is however given to adjust the temperature only after all components have been added.

[0138] Thus, in a more preferred embodiment, the entirety of the compound of formula (II), a solvent and water are introduced into a reaction vessel, subsequently the entirety of HBr, optionally dissolved in an organic solvent, is added, preferably by and by, and the reaction mixture is heated to the desired temperature. HBr and water are introduced in such amounts that the claimed molar ratio is present before heating is started. Once heating has started, preferably no more HBr and water is added. In particular, the entirety of the compound of formula (II), a solvent, preference being given to acetic acid, and water are introduced into a reaction vessel, subsequently the entirety of HBr, dissolved in an organic solvent, preferably in acetic acid, is added, preferably by and by, and the reaction mixture is heated to the desired temperature. HBr and water are introduced in such amounts that the claimed molar ratio is present before heating is started. Once heating has started, preferably no more HBr and water is added.

[0139] Preference is given to partly removing during the reaction the compound R4-Br formed during the reaction of the compounds of formula (II) with HBr, especially if R4is an alkyl group.

[0140] To this end, the reaction will be carried out in a manner known per se at a temperature and a pressure at which the compounds R4-Br, if appropriate, are distilled out of the reaction mixture, optionally as an azeotrope with the solvent.

[0141] If appropriate, fresh solvent can be introduced into the mixture for compensation, or the solvent distilled off with the compounds R4-Br can be recycled into the reaction after optional distillative depletion of the compounds R4-Br.

[0142] For these reasons, it is advantageous when the solvent used has a boiling point of at least 10°C, in particular at least 30°C, above the boiling point of the compounds R4-Br formed in the reaction (each at atmospheric pressure).

[0143] Appropriately, the reaction of the compounds of formula (II) with HBr is carried out in an apparatus which is equipped with at least one distillation or rectification apparatus, for example a distillation column or a distillation bridge, which firstly allows the compound R4-Br, if appropriate together with the solvent, to be distilled off and simultaneously enables removal and recycling of any solvent distilled off with the compound R4-Br.

[0144] Suitable reaction times depend inter alia on the nature of R4, on the applied temperature and pressure, and also on the amount of reactants used and can thus vary largely, e.g. between 15 min to 24 h or 2 h to 20 h.

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[0147] The end of the reaction can easily be determined by the skilled worker by means of routine methods.

[0148] After completion of the reaction or completion to the desired degree, the reaction mixture can be worked up by standard techniques, and the desired product can be isolated and purified, if desired, by customary methods, such as extractive, distillative or chromatographic methods or crystallization.

[0149] The preferred embodiments of the invention mentioned herein below should be understood as being preferred either independently from each other or in combination with one another.

[0150] According to a preferred embodiment of the invention preference is also given to the preparation of phenolic compounds of formula (I) wherein the variables, either independently of one another or in combination with one another, have the following meanings:

[0151] R1is preferably fluorine or chlorine; more preferably fluorine.

[0152] R2is preferably fluorine or chlorine; more preferably chlorine.

[0153] In particular, R1is fluorine and R2is chlorine.

[0154] n is preferably 0 or 1 ; more preferably 0.

[0155] Specific preference is given to the preparation of phenolic compound of formula (I. a), which correspond to phenolic compounds of formula (I), wherein R1is F, R2is Cl, and n is 0:

[0156]

[0157] According to another preferred embodiment of the invention, to manufacture the phenolic compounds of formula (I), preference is also given to those compounds of formula (II), wherein the variables, either independently of one another or in combination with one another, have the following meanings:

[0158] R1is preferably fluorine or chlorine, more preferably fluorine.

[0159] R2is preferably fluorine or chlorine, more preferably chlorine.

[0160] In particular, R1is fluorine and R2is chlorine.

[0161] M / BASFTR-4226-PCBASF SE 240191W001

[0162] 13

[0163] R4is preferably Ci-C4-alkyl or benzyl; more preferably methyl or benzyl. Specifically, R4is methyl.

[0164] n is preferably 0 or 1; more preferably 0.

[0165] Particular preference is given to the compounds of formula (II. a), which correspond to compounds of formula (II) wherein R1is F, R2is Cl, and n is 0:

[0166]

[0167] wherein the variable R4has the general meanings, in particular the preferred meanings, as defined above. In particular, R4is methyl or benzyl. Specifically, R4is methyl.

[0168] Thus, special preference is given to the compound of formula (II. a.1), which correspond to compounds of formula (II) wherein R1is F, R2is Cl, n is 0 and R4is CH3:

[0169]

[0170] Special preference is also given to the compound of formula (II. a.2), which correspond to compounds of formula (II) wherein R1is F, R2is Cl, n is 0 and R4is benzyl:

[0171]

[0172] The above-described method according to the invention is also termed method A in the following.

[0173] As already explained above, the phenolic compounds of formula (I) are useful in the synthesis of arylethers of formula (III):

[0174] M / BASFTR-4226-PCBASF SE 240191W001

[0175]

[0176] Arylethers of formula (III) can be prepared by reaction of phenolic compounds of formula (I) with alkylating agents of formula (X) in analogy to known processes (described e.g. in

[0177] WO 2011 / 137088, WO 2017 / 202768 or WO 2024 / 179911):

[0178]

[0179] wherein

[0180] R1, R2, R3and n are defined as in formula (I) above;

[0181] R5is hydrogen or Ci-C4-alkyl; and

[0182] X is a leaving group, such halogen, Ci-Ce-alkylsulfonate (to be more precise Ci-Ce-alkyl- sulfonyloxy), Ci-Ce-haloalkylsulfonate (to be more precise Ci-Ce-haloalkylsulfonyloxy) or arylsulfonate (to be more precise arylsulfonyloxy), where the aryl group may be substituted (examples see below), where X is preferably Cl, Br, I, Ci-Ce-alkylsulfonate or arylsulfonate (where the aryl group may be substituted); more preferably Cl, Br or I; in particular Cl or Br.

[0183] Accordingly, in a further preferred embodiment of the process of the invention, arylethers of formula (III) are obtained in a downstream process by

[0184] (i) preparing a compound (I) from compounds (II) with method A described above, i.e. reacting compounds of formula (II)

[0185] M / BASFTR-4226-PCBASF SE 240191W001

[0186]

[0187] wherein

[0188] R1, R2, R3and n are defined as above; and

[0189] R4is Ci-C4-alkyl or benzyl;

[0190] with HBr in the presence of water, wherein the ratio of HBr to water is from 3:1 to 1:1.7;

[0191] to give phenolic compounds of formula (I) as defined above; and

[0192] ii) reacting the phenolic compounds of formula (I) obtained in step (i) with alkylating agents of formula (X)

[0193]

[0194] wherein

[0195] R5is hydrogen or Ci-C4-alkyl; and

[0196] X is a leaving group,

[0197] to obtain arylethers of formula (III).

[0198] This method for preparing compounds (III) is also termed method B in the following.

[0199] X is preferably halogen, Ci-Ce-alkylsulfonate, Ci-Ce-haloalkylsulfonate or arylsulfonate, wherein the aryl group is unsubstituted or substituted with 1, 2 or 3 radicals independently selected from the group consisting of halogen and Ci-C4-alkyl; more preferably Cl, Br, I, Ci-Ce-alkylsulfonate, Ci-Ce-haloalkylsulfonate or arylsulfonate, wherein the aryl group is unsubstituted or substituted with 1, 2 or 3 radicals independently selected from the group consisting of halogen and C1-C4-alkyl; even more preferably Cl, Br, I or -O-S(=O)2-RX; where Rxis Ci-C4-alkyl, Ci-C4-haloalkyl or phenyl, wherein the phenyl group is unsubstituted or substituted with 1, 2 or 3 identical or different radicals selected from the group consisting of methyl, chlorine and bromine; in particular Cl, Br or I; and is especially Cl or Br.

[0200] The reaction in step (ii) is preferably carried out in the presence of a base. Suitable bases are inorganic bases, such as alkali metal hydroxides, e.g. lithium, sodium, potassium or caesium hydroxide, alkali metal carbonates, such as lithium, sodium, potassium or caesium carbonate,

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[0202] 16

[0203] or alkali metal hydrogencarbonates, such as lithium, sodium, potassium or caesium hydrogencarbonate; and organic bases, such as pyridine, lutidine and the like. Preference is however given to inorganic bases, among which the alkali metal hydroxides and carbonates and especially sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate are preferred. Specifically, the base is sodium carbonate or potassium carbonate, very specifically potassium carbonate.

[0204] Within the process for obtaining arylethers of formula (III), the reaction mixture may comprise a solvent selected from the group consisting of aromatic hydrocarbons, wherein the aromatic core is benzene or naphthalene, and wherein the aromatic core may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkoxy and halogen.

[0205] In one aspect the solvent is preferably selected from the group consisting of toluene, xylenes, mesitylene, chlorobenzene, or mixtures thereof. Preferably the solvent is selected from the group consisting of toluene or xylenes, or mixtures thereof. The most preferred solvent is toluene.

[0206] More preferably, step (ii) is carried in the presence of both a base and a solvent.

[0207] Accordingly, in a further preferred embodiment of the process of the invention arylethers of formula (III) are obtained by

[0208] (i) preparing compounds (I) from compounds (II) by method A described above; and

[0209] ii) reacting the phenolic compounds of formula (I) obtained in step (i) with alkylating agents of formula (X) in the presence of a solvent selected from the group consisting of aromatic hydrocarbons, wherein the aromatic core is benzene or naphthalene, wherein the aromatic core may be unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of Ci-C4-alkyl, Ci-C4-alkoxy and halogen;

[0210] and

[0211] of a base selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;

[0212] to obtain arylethers of formula (III).

[0213] HBr necessary for the process according to the invention, either gaseous or dissolved (e.g. as aqueous solution or dissolved in acetic acid) is commercially available.

[0214] The compounds of formula (II) can be prepared by methylating a compound (V) or a salt thereof with a suitable methylation agent:

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[0216] 17

[0217]

[0218] wherein R1, R2, R3, R4and n are defined as above

[0219] If the compound (V) is used in form of a salt, this means that the NH group in the pyrimidinedione ring is present as a group N'M+; M+being a suitable counter cation, e.g. an alkali metal cation. If the compound (V) is used as such (i.e. in non-deprotonated NH form), and the reaction is carried out in the presence of a base (for details see below), the NH group in the pyrimidinedione ring in at least a part of the compound (V) will be converted into a group N'M+, depending on the amount and basicity of the base used. M+is this case is generally derived from the base used (e.g. Na+if a basic sodium salt, such a sodium methanolate or sodium ethanolate, is used).

[0220] Methylation of (V) can be carried out in analogy to known processes (e.g. as described in WO 2005 / 054208; WO 2006 / 125746). Suitable methylation agents are for example methyl halides or dimethyl sulfate.

[0221] Accordingly, in a further preferred embodiment of the process of the invention the compounds of formula (I) are prepared by

[0222] a) methylation of a compound of formula (V) to give a compound of formula (II); and b) subjecting the compound (II) or a salt thereof obtained in step a) to method A, i.e. reacting the compound of formula (II) from step a) with HBr in the presence of water, wherein the ratio of HBr to water is from 3:1 to 1:1.7, to give phenolic compounds of formula (I).

[0223] Preferably, the methylation agent if a methyl halogenide, more preferably methyl chloride (chloromethane) or methyl bromide (bromomethane).

[0224] Thus, preferably, compound (V) is methylated with methyl halogenide selected from methyl chloride or methyl bromide, more preferably with methyl chloride.

[0225] The compound (V) and the methyl halogenide can be used in a molar ratio of from 1.5:1 to 1:20, preferably from 1.1:1 to 1:10, more preferably from 1:1 to 1:5, in particular from 1:1 to 1:2.

[0226] In a preferred embodiment, in step a) a salt of the compound (V) is used as starting compound, preferably an alkali metal salt, more preferably the sodium or potassium salt, in particular the sodium salt.

[0227] In another preferred embodiment, in case that the compound (V) is used as such in step a), the reaction is carried out in the presence of a base.

[0228] M / BASFTR-4226-PCBASF SE 240191W001

[0229] The reaction in step a) can be carried out in an organic solvent, which is preferably a polar aprotic solvent or an aromatic solvent.

[0230] The reaction in step a) can be carried out at from 20°C to the boiling point of the reaction mixture, preferably from 40°C to the boiling point of the reaction mixture, more preferably from 60°C to the boiling point of the reaction mixture, even more preferably from 80°C to the boiling point of the reaction mixture and in particular from 90°C to 110°C.

[0231] The reaction in step a) can be carried out at a pressure of from atmospheric pressure to 20 bar (2 MPa), preferably from atmospheric pressure to 10 bar (1 MPa), in particular from atmospheric pressure to 6 bar (0.6 MPa) or from atmospheric pressure to 2 bar (0.2 MPa).

[0232] Compounds (V), in turn, can be prepared by reacting carbamate compounds of formula (VI) with enamine compounds of formula (VII) in analogy to known processes (e.g. WO 99 / 31091; WO 2011 / 057935, WO 2006 / 010474 (and US 2008 / 0033174 respectively) or WO 2017 / 202768):

[0233]

[0234] R1, R2, R3, R4and n have one of the above general or preferred meanings. Hal is a halogen atom, such as Cl, Br or I, preferably Br or I. L1and L2are nucleophilically displaceable groups. The wavy line in compound (VII) indicates that the compound can be the Z isomer (in which the NH2 group and the C(O)L2group are on the same side of the C-C double bond), the E isomer (in which the NH2 group and the C(O)L2group are on opposite sides of the C-C double bond) or can be a mixture of the Z and the E isomer. Among the Z and the E isomer of the compound (VII), preference is given to the Z isomer or to mixtures of the Z and the E isomer with a molar ratio of the Z to the E isomer of at least 9:1. The Z isomer has the following formula:

[0235]

[0236] Accordingly, in a specific embodiment, the present method for preparing compounds of the formula (I) or a salt thereof comprises

[0237] (a) reacting compound of formula (VI) with a compound of formula (VII), preferably in the presence of a compound (IV) (see below), to obtain a compound (V) or a salt thereof; (b) methylating the compound (V) or a salt thereof obtained in step (a), as described above, preferably with chloromethane or bromomethane, to obtain a compound (II); and

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[0239] 19

[0240] (c) subjecting the compound (II) or a salt thereof obtained in step (b) to method A, i.e. reacting the compound of formula (II) from step (b) with HBr in the presence of water, wherein the ratio of HBr to water is from 3:1 to 1:1.7, to give phenolic compounds of formula (I).

[0241] Preferably, L1and L2are independently of each other Ci-Ce-alkoxy, Ci-Ce-haloalkoxy, phenoxy or benzyloxy, where the phenyl ring in phenoxy and benzyloxy may carry 1 to 3 methyl groups. More preferably, L1and L2are independently of each other Ci-Ce-alkoxy or benzyloxy and are in particular independently of each other Ci-C4-alkoxy.

[0242] Preferably, and especially if L1and L2have one of these preferred, more preferred and particular meanings, the reaction is carried out in the presence of a compound (IV) selected from compounds (IV. a) or (IV.b)

[0243]

[0244] wherein

[0245] RAis halogen, Ci-Ce-alkyl, OH or Ci-Ce-alkoxy;

[0246] RBand RD, independently of each other, are hydrogen, halogen, Ci-Ce-alkyl, OH or Ci-Ce- alkoxy,

[0247] Rcis hydrogen, Ci-Ce-alkyl, OH or Ci-Ce-alkoxy (specifically hydrogen, OH or Ci-Ce-alkoxy); where at least one of RA, RB, Rcand RDis OH.

[0248] Preferably, one of RA, RB, Rcand RDis OH. Preferably, one of RA, RB, Rcand RDis OH; and the other three of RA, RB, Rcand RDare hydrogen or one thereof is halogen, Ci-C4-alkyl or or Ci-C4-alkoxy. To express this preferred embodiment more illustratively, RAis OH, RBis hydrogen, halogen, Ci-C4-alkyl or or Ci-C4-alkoxy, and Rcand RDare hydrogen. In particular, one of RA, RB, Rcand RDis OH, and the other three of RA, RB, Rcand RDare hydrogen or one thereof is Cl, methyl or methoxy. To express this latter embodiment more illustratively, RAis OH, RBis hydrogen, Cl, methyl or methoxy, and Rcand RDare hydrogen. Specifically, RAis OH, RBis hydrogen or Ci-C4-alkoxy (specifically methoxy), and Rcand RDare hydrogen. In this specific embodiment, RAand RBare preferably in ortho-position to each other. Preferably the compound (IV) is a compound of the formula (IV.a). More specifically, the compound (IV) is guaiacol.

[0249] Preferably, the compound of the formula (IV) is used in an amount of from 0.001 mol to 5 mol, more preferably from 0.01 mol to 1 mol, even more preferably from 0.01 mol to 0.5 mol, in particular from 0.01 to 0.3 mol and more particularly from 0.01 mol to 0.2 mol, per 1 mol of compound (VI).

[0250] Preferably, the compound of the formula (VI) and the compound of the formula (VII) are used in a molar ratio of from 3:1 to 1:5, more preferably from 1.5:1 to 1:3, even more preferably from 1.1:1 to 1:2, and in particular from 1:1 to 1:1.5.

[0251] M / BASFTR-4226-PCBASF SE 240191W001

[0252] 20

[0253] Preferably, the reaction is carried out in the presence of a base, where the base is preferably an alkali metal Ci-C4-alkanolate or a non-nucleophilic organic base, more preferably an alkali metal Ci-C4-alkanolate or an amidine base, in particular sodium methanolate, sodium ethanolate, potassium methanolate, potassium ethanolate, 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabi-cyclo[4.3.0]non-5-ene.

[0254] Preferably, the reaction is carried out in an organic solvent, preferably in the presence of a polar aprotic solvent, an aromatic solvent or a mixture of a polar aprotic solvent with an apolar aprotic solvent. In case that L1and / or L2are Ci-Ce-alkoxy or Ci-Ce-haloalkoxy, the organic solvent has preferably a boiling point of at least 65°C.

[0255] The reaction is preferably carried out at from 60°C to the boiling point of the reaction mixture, preferably from 80°C to the boiling point of the reaction mixture, more preferably from 90°C the boiling point of the reaction mixture, and in particular from 90°C to 110°C.

[0256] Carbamate compounds (VI), in turn, can be prepared by reacting aminopyridines of formula (VIII) with compounds of formula (IX) in analogy to known processes ((i.e. Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], E5, 1985, p. 972-980, and also VIII, p. 655 and XI part 2, p. 10):

[0257]

[0258] R1, R2, R3, R4, L1and n have one of the above general or preferred meanings. Hal is a halogen atom, such as Cl, Br or I, preferably Cl.

[0259] Accordingly, in a specific embodiment, the present method for preparing compounds of the formula (I) or a salt thereof comprises

[0260] (a) reacting an amino-pyridine of formula (VIII) with a compound of formula (IX) to give a pyridyl-carbamate of formula (VI);

[0261] (b) reacting the compound of formula (VI) obtained in step (a) with a compound of formula (VII), preferably in the presence of a compound (IV), as described above, to obtain a compound (V) or a salt thereof;

[0262] (c) methylating the compound (V) or a salt thereof obtained in step (b), as described above, preferably with chloromethane or bromomethane, to obtain a compound (II); and

[0263] (d) subjecting the compound (II) or a salt thereof obtained in step (c) to method A, i.e. reacting the compound of formula (II) from step (b) with HBr in the presence of water, wherein the ratio of HBr to water is from 3:1 to 1:1.7, to give phenolic compounds of formula (I).

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[0265] 21

[0266] In step (a), the compound of formula (IX) is typically used in an amount of at least 1 mol, preferably of 1.1 to 10 mol; more preferably of 1.2 to 9 mol in particular of 1.5 to 8 mol, per 1 mol of the aminopyridine of formula (VIII).

[0267] In another embodiment of step (a), the compound of formula (IX) is used in an amount of at least 2 mol, preferably of 2 to 10 mol, more preferably of 2.5 to 9 mol, in particular of 2.5 to 7 mol, per 1 mol of the aminopyridine of formula (VIII).

[0268] In yet another embodiment of step (a), the compound of formula (IX) is used in an amount of at least 3 mol, preferably of 3 to 10 mol, more preferably of 3 to 9 mol, in particular of 3 to 7 mol, per 1 mol of the aminopyridine of formula (VIII).

[0269] In another embodiment the preparation of the pyridylcarbamates of formula (VI) is conducted in the presence of an additive selected from aliphatic or cyclic ethers, aliphatic alcohols or phenol. Aliphatic alcohols are usually selected from alcohols having Ci-C4-alkyl chains. Examples of the suitable alcohol additives are methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol. According to one specific embodiment the additive is ethanol.

[0270] The amount of the additive can vary. Usually, it is used in an amount of 0.01 to 5 mol, preferably in an amount of 0.05 to 3 mol, more preferably in an amount of 0.1 to 1 mol per 1 mol of aminopyridine of formula (VIII).

[0271] In another embodiment the preparation of the pyridyl-carbamates of formula (VI) is conducted at high concentrations.

[0272] The preparation of the pyridyl-carbamates of formula (VI) can be carried out with or without a solvent. According to one embodiment, the reaction is carried out without a solvent. According to another embodiment the reaction is carried out with a solvent.

[0273] The amount of aminopyridine of formula (VIII) in a solvent is with respect to the total of weight of aminopyridine of formula (VIII) and solvent from 30 to 100% by weight, preferably from 40 to 100% by weight.

[0274] In another embodiment, the amount of aminopyridine of formula (VIII) in a solvent is

[0275] 30 to 99 % by weight, preferably from 40 to 99 % by weight.

[0276] Ranges from 50 to 99 %, from 60 to 99 %, from 70 to 99 %, from 80 to 99% and from 90 to 99% by weight of aminopyridine of formula (VIII) with respect to the total weight of aminopyridine of formula (VIII) and solvent are also possible.

[0277] Enamine compounds (VII) can be prepared according to known methods, e.g. as described in A. Lutz, A. and S. Trotto, J. of Heterocyclic Chem. 1972, 9, 3, 513-522.

[0278] The invention is illustrated by the following examples without being limited thereto or thereby.

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[0280] 22

[0281] Examples

[0282] Analytical HPLC Method:

[0283] Unless specified otherwise, following HPLC apparatus and method was used:

[0284] Apparatus: Agilent 1200 Series

[0285] Column: Agilent Phenyl Hexyl; 4.5 x 50 mm, 1.8 pm; flow: see below; time: 12 min + 2 min post time; pressure: start 130 bar, end 80 bar; temperature: 20°C; wavelength: 230 nm; injector volume: 3 ml; eluent: start acetonitrile / H2O = 50 / 50, then linear gradient to acetonitrile / H2O = 100 / 0 in 12 min as follows:

[0286]

[0287] I. Preparation of phenolic compounds of formula (I)

[0288] Example 1 :

[0289] Preparation of 3-[5-chloro-3-fluoro-6-(2-hydroxyphenoxy)-2-pyridyl]-1-methyl-6-(trifluoromethyl)-pyrimidine-2, 4-dione (compound (I) wherein R1is F, R2is Cl and n is 0) starting from the corresponding methyl ether (compound (II) wherein R1is F, R2is Cl, R4is methyl and n is 0)

[0290]

[0291] Example 1.1:

[0292] 68 g (150 mmol; 1.0 eq.) of 3-[5-chloro-3-fluoro-6-(2-methoxyphenoxy)-2-pyridyl]-1-methyl-6-(trifluoromethyl)pyrimidine-2, 4-dione (compound (II) wherein R1is F, R2is Cl, R4is methyl and n is 0; 98.8 % purity), 148.6 g (2475 mmol; 16.5 eq.) of glacial acetic acid as solvent (100% purity) and 8.1 g (450 mmol; 3.0 eq.) of water were charged into a reactor and stirred. Subsequently, 101 g of 30 % HBr in acetic acid (corresponds to 375 mmol; 2.5 eq. HBr) were dosed in 10 min. The reaction mixture was slowly heated to 105°C.

[0293] The conversion was checked by HPLC analysis at 230 nm which showed 96.2 area-% of the desired title compound and 0.2 area-% of the starting material.

[0294] The byproduct off-gas bromomethane was quenched with 20% aq. ethanolamine solution, and the reaction mixture was distilled under vacuum. The remainder was dissolved in toluene,

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[0296] 23

[0297] washed with water, and the organic phase was concentrated under reduced pressure, affording 456.9 g of the title compound as a suspension in toluene (14.04 w / w % HPLC; 99.0 % yield).

[0298] 1H-NMR (400 MHz, DMSO-d6, ppm): 59.69 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.14 -6.99 (m, 2H), 6.91 (dd, J = 7.8, 1.5 Hz, 1H), 6.79 (td, J = 7.6, 1.6 Hz, 1H), 6.51 (s, 1H), 3.33 (s, 3H).

[0299] Table 1 summarizes the results of examples according to the invention, where examples 1.2 to 1.8 were carried out in analogy to example 1.1, but varying the reaction conditions, e.g. using different ratios of HBr to water:

[0300] Table 1

[0301]

[0302] a%: area-%

[0303] * 30 % HBr in acetic acid

[0304] ** tetramethylammonium chloride (TMACI; 0.2 eq. to (II)) was used as additive

[0305] *** tetramethylammonium chloride (TMACI; 0.05 eq. to (II)) was used as additive

[0306] Tables 2 and 3 summarizes the results of comparative examples not according to the invention, carried out in analogy to example 1.1, but using HBr / water ratios outside the ranges according to the invention.

[0307] Table 2 - aqueous HBr solution (48%)

[0308]

[0309] no extra added water; water only introduced via aqueous HBr

[0310] Table 3

[0311]

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[0313] 24

[0314]

[0315] * 30 % HBr in acetic acid

[0316] ** tetramethylammonium chloride (TMACI; 0.2 eq. to (II)) was used as additive

[0317] Example 2:

[0318] Preparation of 3-[5-chloro-3-fluoro-6-(2-hydroxyphenoxy)-2-pyridyl]-1-methyl-6-(trifluoromethyl)-pyrimidine-2, 4-dione (compound (I) wherein R1is F, R2is Cl and n is 0) starting from the corresponding benzyl ether (compound (II) wherein R1is F, R2is Cl, R4is benzyl and n is 0)

[0319] 5 g (9.39 mmol; 1.0 eq.) of 3-[6-(2-benzyloxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]-1-methyl-6-(trifluoromethyl)pyrimidine-2, 4-dione (compound (II) wherein R1is F, R2is Cl, R4is benzyl and n is 0; 98 % purity), 9.30 g (155 mmol; 16.5 eq.) of glacial acetic acid as solvent (100% purity) and 0.51 g (28.2 mmol; 3.0 eq.) of water were charged into a flask and stirred. Subsequently, 6.33 g of 30 % HBr in acetic acid (corresponds to 23.5 mmol; 2.5 eq. HBr) were added slowly. The reaction mixture was heated to 95°C (oil bath temperature).

[0320] The conversion was controlled by HPLC analysis at 230 nm which after 15 min showed 91.1 area-% of the desired title compound and no more starting material.

[0321] Comparative example 7

[0322] Preparation of 3-[5-chloro-3-fluoro-6-(2-hydroxyphenoxy)-2-pyridyl]-1-methyl-6-(trifluoromethyl)-pyrimidine-2, 4-dione (compound (I) wherein R1is F, R2is Cl and n is 0) starting from the corresponding methyl ether (compound (II) wherein R1is F, R2is Cl, R4is methyl and n is 0) and using BBra

[0323] In analogy to example 5.6 of WO 2017 / 202768, a stirred solution of 9 g (20 mmol) of 3-[5-chloro-3-fluoro-6-(2-methoxyphenoxy)-2-pyridyl]-1-methyl-6-(trifluoromethyl)pyrimidine-2,4-dione (compound (II) wherein R1is F, R2is Cl, R4is methyl and n is 0) in 200 mL of dichloromethane was cooled to -78°C. To this, 32 mL of a solution of BBra in dichloromethane (1.0 molar in dichloromethane, 32 mmol) was added within 20 min. The reaction mixture was warmed to room temperature within 5 h, poured into ice water and extracted 4 times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and the solvent was removed under reduced pressure to give 9.2 g (33.7 % w / w purity, 36% yield) of the desired title compound.

[0324] II. Preparation of downstream compounds

[0325] Example 3: Ethyl 2-[2-[[3-chloro-5-fluoro-6-[3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1-yl]-2-pyridyl]oxy]phenoxy]acetate (compound (III) wherein R1is F, R2is Cl, R5is ethyl and n is 0)

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[0327]

[0328] Qualitative HPLC method used:

[0329] Column: Agilent Extend C18, 4.6x50mm, 1.8 pm, flow: 1 mL / min, time: 13 min, pressure: 400 bar; temperature: 25°C, wavelength 280 nm; injector volume: 4 pL; Eluent: A: Water with 0.1 vol% formic acid; B: Acetonitrile with 0.1 vol% formic acid; gradient as follows:

[0330]

[0331] 25 g (55.5 mmol, 1.0 equiv.) of 3-[5-chloro-3-fluoro-6-(2-hydroxyphenoxy)-2-pyridyl]-1-methyl-6-(trifluoromethyl)pyrimidine-2, 4-dione (compound of example 1; 95.8% purity) was charged into a glass-reactor.

[0332] 9.3 g (66.6 mmol, 1.2 equiv.) of potassium carbonate was added in one portion followed by 150 g toluene. To this suspension 10.2 g (82.4 mmol, 1.5 equiv.) of ethyl chloroacetate was added. The reaction mixture was heated to 120°C. Conversion was checked by qualitative HPLC analysis at 280 nm: 0.1 a% of the starting material, 95.9 a% of the title compound.

[0333] After cooling to 50°C, two extractions with water were done at 50°C. The organic phase was concentrated under reduced pressure. The crude product was purified by crystallization from ethanol. 28.2 g (91% yield, 93.4% purity) of the product and 43.7 g of mother liquor (3.3% yield of product) are obtained leading to an overall yield of 94.3%.

[0334] 1H-NMR (CDCI3, ppm): 7.76 (d, J=7.28 Hz, 1 H); 7.22 (d, J=7.72 Hz, 1 H); 7.17 (t, J=7.83 Hz, 1 H); 6.99 - 7.06 (m, 1 H); 6.88 (d, J=7.94 Hz, 1 H); 6.25 (s, 1 H); 4.49 (s, 2 H); 4.19 (q, J=7.20 Hz, 2 H); 3.47 (s, 3 H); 1.25 (t, J=7.17 Hz, 3 H).

[0335] [M+H] = 518.0; Rt = 1.217 min

[0336] III. Preparation of precursor compounds

[0337] 4. Preparation of methyluracils of formula (II)

[0338] Example 4.1: 3-[6-(2-methoxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]-1-methyl-6-(trifluoromethyl)-pyrimidine-2, 4-dione

[0339] M / BASFTR-4226-PCBASF SE 240191W001

[0340]

[0341] 255.4 g (562.9 mmol) of sodium 3-(5-chloro-3-fluoro-6-(2-methoxyphenoxy)pyridin-2-yl)-2,4-di-oxo-6-(trifluoromethyl)-3,4-dihydro-2 / 7-pyrimidin-1-ide (sodium salt of compound of example 5.1) together with 971 g of dimethylformamide (DMF) were added into the reactor. The temperature was raised to 100°C, a vacuum of 200 mbar abs was applied and this vacuum was broken with methyl chloride to reach 1.0-1.1 bar abs. 54 g (1066 mmol, 1.89 equiv.) methyl chloride were added over the course of 6.5 h.

[0342] The progress of the methylation was monitored by HPLC (conditions see above). After 7 hours, conversion was complete. Excess methyl chloride was removed by stripping with nitrogen for 10 min. The reaction mixture was distilled under vacuum to remove volatiles, xylene was added, the mixture was washed with water, and xylene was removed distillatively. The residue was crystallized from ethanol, filtered and dried to afford 240 g of the title compound in form of a beige solid (98.6 % purity; 95.7% yield).

[0343] LC / MS (LC: Shimadzu LC-30AD, ESI; Column: Kinetex EVO C18.5pm 2.1x30mm; Mobile phase: A: water + 0.04% TFA; B: ACN + 0.02% TFA; Temperature: 40°C; Gradient: 5% B to 100% B in 2.5 min; 100% B to 5% B in 0.02min; 5% B for 0.5min; Flow: 0.8mL / min; MS: ESI positive; Mass range: 100-2000.): tret = 1 29 min, 445.9 m / z (M+).

[0344] Example 4.2: 3-[6-(2-benzyloxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]-1-methyl-6-(trifluorome-thyl)-pyrimidine-2, 4-dione

[0345]

[0346] To a solution of 6.5 g (12.8 mmol) of 3-[6-(2-benzyloxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-1H-pyrimidine-2, 4-dione (compound of example 5.3) in 65 mL acetonitrile was added 5.3 g (38 mmol) K2CO3 followed by 7.3 g (51 mmol) methyl iodide at 0°C with stirring. The mixture was stirred at 15°C for 16 hours, then water (80 mL) was added, and the pH was adjusted to pH=5 by using 2N HCI. The mixture was extracted with ethyl acetate, the combined organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure yielding 7 g of the crude product.

[0347] 1H-NMR (CDCh, ppm): 7.63 (d, J=7.28 Hz, 1 H); 7.21 - 7.25 (m, 4 H); 7.12 - 7.17 (m, 2 H); 6.98 (t, J=7.03 Hz, 3 H); 6.26 (s, 1 H); 4.99 (s, 2 H); 3.47 (s, 3 H).

[0348] M / BASFTR-4226-PCBASF SE 240191W001

[0349] 27

[0350] [M+H] = 522.0; Rt = 1.323 min

[0351] 5. Preparation of NH-uracils (V)

[0352] Example 5.1 : 3-[6-(2-methoxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-pyrimi-dine-2, 4-dione

[0353]

[0354] At room temperature, sodium methoxide (41.4 g, 0.73 mol, 1.07 eq) was added to ethyl 3-amino-4,4,4-trifluorocrotonate (syn. ethyl (Z)-3-amino-4,4,4-trifluoro-but-2-enoate; (Z isomer of the compound (VII) wherein L2= ethoxy) 133.5 g, 0.73 mol, 1.07 eq) in N,N-dimethylformamide (DMF) (400 g) and stirred for 30 minutes. Ethyl N-[5-chloro-3-fluoro-6-(2-methoxyphenoxy)-2-pyridyl]carbamate (compound of example 6.1; 232 g, 0.680 mol, 1.00 eq) as a DMF solution (388 g of DMF) was added over a period of 15 minutes. To this, guaiacol (7.8 g, 0.06 mol, 0.09 eq) was added. The reaction mixture was then heated gradually to 100°C internal temperature under distillative conditions under reduced pressure (175-200 mbar). During the reaction, DMF was gradually added to replace the mass distilled off. The reaction was maintained at this temperature for 8 hours until HPLC-analysis (A = 275 nm) confirmed complete transformation, indicated by less than 1% remaining starting material.

[0355] Quantitative HPLC (column Advanced Material Technology, Halo Phenyl-Hexyl 2.1 x 1002.0 Micron, 600 bar; flow: 0.7 mL / min; temperature: 45 °C; wavelength: 275 nm; injector volume: 2 ml + needle wash; eluent and gradient as follows:

[0356]

[0357] shows 19.2 wt.-% product content in 1496 g of crude mass corresponding to 98% yield.

[0358] LC / MS (LC: Shimadzu LC-30AD, ESI; Column: Kinetex EVO C18.5pm 2.1x30mm; Mobile phase: A: water + 0.04% TFA; B: ACN + 0.02% TFA; Temperature: 40°C; Gradient: 5% B to

[0359] M / BASFTR-4226-PCBASF SE 240191W001

[0360] 28

[0361] 100% B in 2.5 min; 100% B to 5% B in 0.02min; 5% B for 0.5min; Flow: 0.8mL / min; MS: ESI positive; Mass range: 100-2000.): tret = 1 12 min, 431.8 m / z (M+).

[0362] Example 5.2: 3-[6-(2-methoxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-pyrimi-dine-2, 4-dione

[0363] The reaction was carried out in analogy to example 5.1, using however 0.06 mol of phenol instead of guaiacol. The titled compound was obtained in 98% yield (quantitative HPLC).

[0364] Example 5.3: 3-[6-(2-benzyloxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]-6-(trifluoromethyl)-1H-pyri-midine-2, 4-dione

[0365]

[0366] To a solution of 1.7 g (43 mmol) NaH in NMP (N-methyl-2-pyrrolidone) (60 mL) at 0°C was added 6 g (14 mmol) of ethyl N-[6-(2-benzyloxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]carbamate (compound of example 6.2) and the mixture was stirred for 30 minutes at 35°C. Then 3.9 g (21 mmol) of ethyl (E)-3-amino-4,4,4-trifluoro-but-2-enoate (CAS: 372-29-2) was added and the reaction mixture was stirred at 100°C for 3 days. The resulting mixture was quenched with ice water, acidified to pH=2 by using 6N HCI and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated.

[0367] [M+H] = 508.0; Rt = 1.240 min

[0368] 6. Preparation of pyridyl-carbamates (VI)

[0369] Example 6.1: Ethyl N-[6-(2-methoxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]carbamate

[0370]

[0371] 187 g (694 mmol, 1 equivalent) of 2-amino-6-(2-methoxyphenoxy)-5-chloro-3-fluoro-pyridine were suspended in 187 g of xylene and 9.6 g of ethanol (208 mmol, 0.3 equivalents) as additive. To this, 226 g (2082 mmol, 3 equivalents) ethyl chloroformate were added at r.t. The mixture was heated up to 90 °C and stirred for 19 hours at 90 °C. The in situ generated HCI was stripped with a slight nitrogen flow and quenched in a scrubber with aq. NaOH. HPLC analysis showed complete conversion to the desired product. Excess of ethyl chloroformate and xylene were evaporated completely in vacuo to give 89% of the target compound.

[0372] M / BASFTR-4226-PCBASF SE 240191W001

[0373] Example 6.2: Ethyl N-[6-(2-benzyloxyphenoxy)-5-chloro-3-fluoro-2-pyridyl]carbamate

[0374]

[0375] To a solution of 8.8 g (25.6 mmol) of 2-amino-6-(2-benzyloxyphenoxy)-5-chloro-3-fluoro-pyridine in 80 ml dichloromethane was added 3 g (38 mmol) of pyridine followed by 4 g (37.5 mmol) of ethyl chloroform ate. The mixture was stirred at 25°C for 20 hours, diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated to give 14.4 g of a mixture of the desired compound and the di-substituted derivative. The crude mixture (12.4 g) was dissolved in 200 mL ethanol and aqueous NaOH (1M) was added dropwise at 0°C with stirring. The mixture was stirred at 15°C for 6 hours, diluted with brine and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SC>4, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica (petrol ether / ethyl acetate) to give 6.6 g (15.9 mmol, 62%) of the desired compound.

[0376] [M+H] = 417.1; Rt= 1.293 min

[0377] M / BASFTR-4226-PC

Claims

1. BASF SE 240191W00130Claims1. A method for preparing a compound of the formula (I)whereinR1and R2, independently of each other, are selected from the group consisting of fluorine, chlorine and bromine;R3is halogen or methyl; andn is 0, 1 or 2;comprising reacting a compound of formula (II)whereinR1, R2, R3and n are as defined above for formula (I); andR4is Ci-C4-alkyl or benzyl;with HBr in the presence of water;wherein the molar ratio of HBr to water is from 3:1 to 1:1.7.

2. The method according to claim 1, where R1and R2, independently of each other, are fluorine or chlorine.M / BASFTR-4226-PCBASF SE 240191W001313. The method according to any of the preceding claims, where n is 0.

4. The method according to any of the preceding claims, where R4is methyl or benzyl, preferably methyl.

5. The method according to any of the preceding claims, where the molar ratio of HBr to water is from 3:1 to 1:1.5, preferably from 1.5:1 to 1:1.5.

6. The method according to claim 5, where the molar ratio of HBr to water is from 1.5:1 to 1:1.3, preferably from 1:1 to 1:1.3.

7. The method according to any of the preceding claims, where the molar ratio of the compound of the formula (II) to HBr to is from 1.5:1 to 1:5, preferably from 1:1 to 1:4, in particular 1:1.5 to 1:4.

8. The method according to any of the preceding claims, where HBr is used in gaseous form or in form of a solution in an organic solvent.

9. The method according to any of the preceding claims, where the reaction is carried out in an organic solvent.

10. The method according to any of claims 8 and 9, where the solvent for HBr and the solvent in which the reaction is carried out are, independently of each other, selected from the group consisting of aromatic hydrocarbons, halogenated aliphatic, cycloaliphatic and aromatic hydrocarbons, carboxylic acids and mixtures thereof; preferably from benzene, toluene, the xylenes, the cresols, dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, formic acid, acetic acid, propionic acid, trifluoroacetic acid and mixtures thereof.

11. The method according to claim 10, where the solvent for HBr and the solvent in which the reaction is carried out are, independently of each other, selected from the group consisting of benzene, toluene, the xylenes, the cresols, chlorobenzene, formic acid, acetic acid, propionic acid and mixtures thereof; preferably from benzene, toluene, the xylenes, the cresols, chlorobenzene, acetic acid and mixtures thereof.

12. The method according to claim 11 , where the solvent for HBr and the solvent in which the reaction is carried out is acetic acid.M / BASFTR-4226-PCBASF SE 240191W0013213. The method according to any of the preceding claims, where the reaction is carried out at a temperature of from 50°C to the boiling point of the reaction mixture.

14. The method according to claim 13, where the reaction is carried out at a temperature of from 60°C to the boiling point of the reaction mixture.

15. The method according to claim 14, where the reaction is carried out at a temperature of from 70 to 120°C.

16. The method according to claim 15, where the reaction is carried out at a temperature of from 80 to 110°C.

17. The method according to any of the preceding claims, where the reaction is carried out in the presence of a phase transfer catalyst selected from quaternary ammonium salts and quaternary phosphonium salts.

18. The method according to claim 17, where the phase transfer catalyst is selected from quaternary ammonium salts, which are preferably selected from tetra-(Ci- C4-alkyl)-ammonium halogenides.

19. A method for preparing a compound of the formula (III)whereinR1, R2, R3and n are as defined in any of claims 1 to 3; andR5is hydrogen or Ci-C4-alkyl;comprising(i) preparing a compound (I) as defined in any of claims 1 to 3 with the method according to any of claims 1 to 18; and(ii) reacting the compound (I) obtained in step (i) with a compound (X)M / BASFTR-4226-PCBASF SE 240191W00133whereinX is a leaving group;where X is preferably halogen, Ci-Ce-alkylsulfonate, Ci-Ce- haloalkylsulfonate or arylsulfonate, wherein the aryl group is unsubstituted or substituted with 1, 2 or 3 radicals independently selected from the group consisting of halogen and Ci-C4-alkyl; where X is more preferably chlorine, bromine, iodine or -O- S(=O)2-RX; where Rxis Ci-C4-alkyl, Ci-C4-haloalkyl or phenyl, wherein the phenyl group is unsubstituted or substituted with 1 , 2 or 3 identical or different radicals selected from the group consisting of methyl, chlorine and bromine; andR5is as defined above for the compound of formula (III).M / BASFTR-4226-PC

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