Preparation of herbicidal uracil compounds

Abstract

The present invention relates to a process for the preparation of arylethers of formula (I) comprising reacting a phenolic compound of formula (II), with an alpha-activated acetic acid or an ester thereof in aromatic hydrocarbons and in the presence of a base.

Description

[0001] Preparation of herbicidal uracil compounds

[0002] The present invention relates to a process for the preparation of arylethers of formula I comprising reacting a phenolic compound of formula II, with an alpha-activated acetic acid or an ester thereof in aromatic hydrocarbons and in the presence of a base.

[0003] WO 2017 / 202768 A1 sets out a process for the preparation of structurally related arylethers through reaction of phenolic compounds with ethyl bromoacetate in acetonitrile and potassium carbonate as base (example 5.7). It is taught that these uracilpyridines exhibit herbicidal activity.

[0004] The inventors of the present invention found that the conditions described in WO 2017 / 202768 A1 entail the formation of significant amounts of unwanted side products. They determined that, besides target compound I, tricyclic compounds of formula A are generated and that the uracil moiety in the starting material is degraded to some extent to produce amine compounds of type B and urea compounds of type C.

[0005] In quest of overcoming this disadvantage and in search for an economically viable process the inventors found that the choice of solvent plays a crucial role in the etherification of compounds of formula II. It is commonly known that suitable solvents in ether syntheses are typically selected from di-polar, aprotic solvents such as, for example, ethers, nitriles, amides or ketones. However, the inventors surprisingly found that the process of the present invention, when conducted in non-polar, aromatic hydrocarbons, produces high yields of target compounds I and low amounts of undesirable side products A, B and C. This efficiency renders the process of the present invention amenable for industrial scale production of compounds of formula I. Accordingly, the present invention relates to a process for the preparation of arylethers of formula I, wherein

[0006] R1and R2independently of each other are selected from the group consisting of fluorine, chlorine, and bromine;

[0007] R3is halogen, methyl, or methoxy; n is 0, 1 , or 2;

[0008] R4is hydrogen, Ci-C4-alkyl; the process comprising reacting a phenolic compound of formula II, wherein the variables R1, R2, R3and n are as defined for compounds of formula I, with a compound of formula III, wherein

[0009] X is chlorine, bromine or -O-S(=O)2-RX;

[0010] Rxis Ci-C4-alkyl or phenyl, and 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;

[0011] R4is as defined for compounds of formula I; the reaction mixture comprising an auxiliary solvent and a base selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; whereas the process is characterized in that the auxiliary solvent is selected from the group consisting of aromatic hydrocarbons, wherein the aromatic core is benzene or naphthalene, whereas the aromatic core may be unsubstituted or substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of Ci-C4-alkyl, C C4-alkoxy and halogen.

[0012] Compounds of formula II can be obtained as described in WO 2017 / 202768 A1. Compounds of formula III are either commercially available or they can be prepared from commercially available starting materials using synthetic procedures that are well known to the skilled person in the art.

[0013] In one aspect of the present invention the base is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

[0014] When alkali hydroxides are used as base these are employed in the presence of water giving rise to biphasic reaction media consisting of an organic, apolar phase comprising the auxiliary solvent and an aqueous phase accommodating the base.

[0015] In another aspect of the present invention the base is sodium carbonate or potassium carbonate, preferably potassium carbonate.

[0016] Typically, the amount of the base in the process of the present invention is between 0.9 and 5 equivalents, preferably between 0.9 and 3 equivalents, most preferably between 0.95 and 1 .8 equivalents, based on the amount of compound II.

[0017] In one aspect of the present invention X in compounds of formula III is chlorine, bromine or -O-S(=O)2-RX, wherein Rxis methyl or tolyl; and wherein R4is as defined for compounds of formula I.

[0018] In another aspect of the present invention X in compounds of formula III is chlorine or bromine. In a preferred embodiment the compound of formula III of the process of the invention is ethyl chloroacetate or methyl chloroacetate, most preferably ethyl chloroacetate.

[0019] In another preferred embodiment the compound of formula III of the process of the invention is ethyl bromoacetate or methyl bromoacetate, most preferably ethyl bromoacetate.

[0020] Typically, the amount of the compound of formula III in the process of the present invention is between 0.9 and 2 equivalents, preferably between 0.95 and 1.5 equivalents, based on the amount of compound II.

[0021] The reaction mixture in the process of the present invention comprises an auxiliary solvent. The term “auxiliary solvent" herein refers to an inert, aprotic, organic solvent, which acts merely as a solvent and is not consumed in the course of the reaction. For the avoidance of doubt an auxiliary solvent is not identical with the reactants such as compounds II or compounds III. Suitable auxiliary solvents are selected from the group consisting of aromatic hydrocarbons, wherein the aromatic core is benzene or naphthalene, whereas the aromatic core may be unsubstituted or substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of methyl, ethyl, Ci-C4-alkoxy and halogen.

[0022] In one aspect the auxiliary solvent is selected from the group consisting of aromatic hydrocarbons, wherein the aromatic core is benzene, whereas the aromatic core may be unsubstituted or substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of Ci-C4-alkyl, methoxy and halogen.

[0023] In another aspect the auxiliary solvent is selected from the group consisting of toluene, xylenes (a mixture comprising variable amounts of o-xylene, m-xylene, p-xylene), mesitylene, chlorobenzene, or mixtures thereof.

[0024] Preferably the auxiliary solvent is selected from the group consisting of toluene or xylenes, or mixtures thereof. The most preferred auxiliary solvent is toluene. In one aspect the reaction mixture comprises at least 50% by weight of an auxiliary solvent, based on the total weight of the reaction mixture.

[0025] In yet another aspect the reaction mixture comprises at least 70% by weight of an auxiliary solvent, based on the total weight of the reaction mixture.

[0026] The inventors found that the temperature in the process of the present invention can be varied in a wide range. Theoretical considerations suggest that lower temperature results in lower conversion rates, i.e. longer reaction times. Accordingly, the reaction proceeded faster at a higher temperature, especially at reflux conditions. In one aspect the process of the present invention is conducted at a temperature in the range of from 0°C to reflux temperature, or in the range of from 90°C to reflux temperature, or at a temperature in the range of from a temperature that is 20 degrees below reflux temperature to reflux temperature .

[0027] In a particularly preferred embodiment the process of the present invention is conducted in toluene, xylenes, mesitylene, chlorobenzene, or mixtures thereof, and the reaction mixture is heated in the range of from 90°C to reflux temperature.

[0028] In a further particularly preferred embodiment the process of the present invention is conducted in toluene and the reaction mixture is heated to a temperature in the range of from 90°C to reflux temperature.

[0029] The reaction is generally carried out within 1 to 24 hours; preferably within 1 to 8 hours; more preferably within 1 to 5 hours.

[0030] In one aspect of the present invention the variables in compounds of formulae I and II are as follows: R1and R2are independently of each other bromine, chlorine, or fluorine; n is 0; R4is methyl or ethyl.

[0031] In a preferred embodiment the variables in compounds of formulae I and II are as follows: R1is fluorine; R2is chlorine; n is 0; R4is ethyl.

[0032] In a preferred embodiment (embodiment E.1) of the present invention the base is sodium carbonate or potassium carbonate.

[0033] Embodiment E.2: is based on embodiment E.1 , wherein the auxiliary solvent is toluene, xylenes, mesitylene, chlorobenzene, or mixtures thereof.

[0034] Embodiment E.3: is based on embodiment E.1 , wherein the auxiliary solvent is toluene. Embodiment E.4: is based on embodiment E.2, wherein the the amount of the base is in the range between 0.95 and 1.8 equivalents, based on the amount of compound II.

[0035] Embodiment E.5: is based on embodiment E.3, wherein the the amount of the base is in the range between 0.95 and 1.8 equivalents, based on the amount of compound II.

[0036] Embodiment E.6: is based on embodiment E.4, wherein the compound of formula III is ethyl chloroacetate or ethyl bromoacetate in an amount that is between 0.95 and 1 .5 equivalents, based on the amount of compound II.

[0037] Embodiment E.7: is based on embodiment E.5, wherein the compound of formula III is ethyl chloroacetate or ethyl bromoacetate in an amount that is between 0.95 and 1 .5 equivalents, based on the amount of compound II.

[0038] Embodiment E.8: is based on embodiment E.6, wherein the reaction mixture is heated to a temperature in the range of from 90°C to reflux temperature.

[0039] Embodiment E.9: is based on embodiment E.7, wherein the reaction mixture is heated to a temperature in the range of from 90°C to reflux temperature.

[0040] Embodiment E.10: is based on embodiment E.8, wherein the reaction mixture comprises at least 50% by weight of an auxiliary solvent, based on the total weight of the reaction mixture. Embodiment E.11 : is based embodiment E.9, wherein the reaction mixture comprises at least 50% by weight of an auxiliary solvent, based on the total weight of the reaction mixture.

[0041] Embodiment E.12: is based on any one of embodiments E.1 to E.11 , wherein the variables in compounds of formulae I and II are as follows: R1and R2are independently of each other bromine, chlorine, or fluorine; n is 0; R4is methyl or ethyl.

[0042] Embodiment E.13: is based on any one of embodiments E.1 to E.11 , wherein the variables in compounds of formulae I and II are as follows: R1is fluorine; R2is chlorine; n is 0; R4is ethyl.

[0043] In another preferred embodiment (embodiment E.13) of the present invention the base is sodium hydroxide or potassium hydroxide.

[0044] Embodiment E.14: is based on embodiment E.13, wherein the auxiliary solvent is toluene, xylenes, mesitylene, chlorobenzene, or mixtures thereof

[0045] Embodiment E.15: is based on embodiment E.13, wherein the auxiliary solvent is toluene.

[0046] Embodiment E.16: is based on embodiment E.14, wherein the the amount of the base is in the range between 0.95 and 1.8 equivalents, based on the amount of compound II.

[0047] Embodiment E.17: is based on embodiment E.15, wherein the the amount of the base is in the range between 0.95 and 1.8 equivalents, based on the amount of compound II.

[0048] Embodiment E.18: is based on embodiment E.16, wherein the compound of formula III is ethyl chloroacetate or ethyl bromoacetate in an amount that is between 0.95 and 1 .5 equivalents, based on the amount of compound II.

[0049] Embodiment E.19: is based on embodiment E.17, wherein the compound of formula III is ethyl chloroacetate or ethyl bromoacetate in an amount that is between 0.95 and 1 .5 equivalents, based on the amount of compound II.

[0050] Embodiment E.20: is based on embodiment E.18, wherein the reaction mixture is heated to a temperature in the range of from 90°C to reflux temperature.

[0051] Embodiment E.21 : is based on embodiment E.19, wherein the reaction mixture is heated to a temperature in the range of from 90°C to reflux temperature.

[0052] Embodiment E.22: is based on embodiment E.20, wherein the reaction mixture comprises at least 50% by weight of an auxiliary solvent, based on the total weight of the reaction mixture. Embodiment E.23: is based on embodiment E.21 , wherein the reaction mixture comprises at least 50% by weight of an auxiliary solvent, based on the total weight of the reaction mixture. Embodiment E.24: is based on any one of embodiments E.13 to E.23, wherein the variables in compounds of formulae I and II are as follows: R1and R2are independently of each other bromine, chlorine, or fluorine; n is 0; R4is methyl or ethyl.

[0053] Embodiment E.25: is based on any one of embodiments E.13 to E.23, wherein the variables in compounds of formulae I and II are as follows: R1is fluorine; R2is chlorine; n is 0; R4is ethyl.

[0054] In the definitions of the variables given above, collective terms are used which are generally representative for the substituents in question. The term “halogen” refers to fluorine, chlorine, bromine and iodine.

[0055] The term “Ci-Cn-alkyl” refers to a straight-chained or branched saturated hydrocarbon group having 1 to n carbon atoms, for example methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, and 1 ,1 -dimethylethyl.

[0056] The term "Ci-C6-alkoxy" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as defined above) which is bonded via an oxygen, at any position in the alkyl group, for example methoxy, ethoxy, n-propoxy, 1 -methylethoxy, butoxy, 1 -methylpropoxy, 2- methylpropoxy or 1 ,1 -dimethylethoxy.

[0057] Working Examples

[0058] The present invention is further illustrated by means of the following working examples.

[0059] Analytical Methods

[0060] Qualitative HPLC method, used for examples 1.1-1.5

[0061] Column: Agilent Extend C18, 4,6x50mm, 1 ,8 m, 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.

[0062] Example 1.1 : Preparation of ethyl 2-[2-[[3-chloro-5-fluoro-6-[3-methyl-2,6-dioxo-4-

[0063] (trifluoromethyl)pyrimidin-1-yl]-2-pyridyl]oxy]phenoxy]acetate

[0064] 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 (95.8% purity) was charged into a glass-reactor. 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 jacket temperature and stirred for 6 hours. Conversion was checked by qualitative HPLC analysis at 280 nm: 0.1 a% of the starting material, 95.9 a% of the title compound. 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 title compound and 43.7 g of mother liquor (3.3% yield of title compound) are obtained leading to an overall yield of 94.3%.

[0065] Table 1 summarizes the results of experiments using different solvents. The data demonstrate that, when toluene is employed, the reaction proceeds with high yields and producing comparatively small amounts of by-products A, B and C as defined herein. Table 1 : a)example corresponds to Example 1.1 as described in detail aboveb)example not according to the present invention

Claims

Claims1 . A process for the preparation of arylethers of formula I,whereinR1and R2independently of each other are selected from the group consisting of fluorine, chlorine, and bromine;R3is halogen, methyl, or methoxy; n is 0, 1 , or 2;R4is hydrogen, Ci-C4-alkyl; the process comprising reacting a phenolic compound of formula II,wherein the variables R1, R2, R3and n are as defined for compounds of formula I, with a compound of formula III,whereinX is chlorine, bromine or -0-S(=0):-Rx;Rxis methyl or phenyl, and 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;R4is as defined for compounds of formula I; the reaction mixture comprising an auxiliary solvent and a base selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; whereas the process is characterized in that the auxiliary solvent is selected from the group consisting of aromatic hydrocarbons, wherein the aromatic core is benzene or naphthalene, whereas 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.

2. The process according to claim 1 , wherein the auxiliary solvent is selected from the groupconsisting of toluene, xylenes, mesitylene, chlorobenzene, or mixtures thereof.

3. The process according to claim 1 or 2, wherein the reaction mixture comprises at least 50% by weight of an auxiliary solvent, based on the total weight of the reaction mixture.

4. The process according to any one of claims 1 to 3, wherein the base is sodium carbonate or potassium carbonate.

5. The process according to any one of claims 1 to 4, wherein the amount of the base is in the range between 0.9 and 5 equivalents, based on the amount of compound II.

6. The process according to any one of claims 1 to 5, wherein the compound of formula III of the process of the invention is ethyl chloroacetate or methyl chloroacetate.

7. The process according to any one of claims 1 to 5, wherein the compound of formula III of the process of the invention is ethyl bromoacetate or methyl bromoacetate.

8. The process according to any one of claims 1 to 7, wherein the amount of the compound III is in the range between 0.9 and 2 equivalents, based on the amount of compound II.

9. The process according to any one of claims 1 to 8, wherein the temperature is in the range of from 0°C to reflux temperature.

10. The process according to any one of claims 1 to 9, wherein the temperature is in the range of from a temperature that is 20 degrees below reflux temperature to reflux temperature.1 1 . The process according to any one of claims 1 to 10, wherein the variables in compounds of formulae I and II are as follows: R1and R2are independently of each other bromine, chlorine, or fluorine; n is 0; R4is methyl or ethyl.

12. The process according to any one of claims 1 to 1 1 , wherein the variables in compounds of formulae I and II are as follows: R1is fluorine; R2is chlorine; n is 0; R4is ethyl.

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