Process for synthesis of 2-(5-isoxazolyl)-phenol

Abstract

To provide an intermediate for preparing 2-(5-isoxazolyl)-phenol, and a preparation method thereof.SOLUTION: The invention provides an intermediate represented by formula 5B, and a preparation method thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for preparing 2-(5-isoxazolyl)-phenols and compounds therefrom. [Background technology]

[0002] A method for preparing certain pyrimidinyloxybenzene derivatives as herbicides is described in Patent Document 1. Methods for preparing pyrimidine derivatives are disclosed in Non-Patent Document 1; Non-Patent Document 2 and Non-Patent Document 3. While the methods disclosed in the aforementioned references can provide desirable compounds, continuous improvement is required, especially in the development of methods that provide materials on a commercial scale. Thus, there remains a need for new methods that are less expensive, more efficient, more flexible, or more convenient to operate. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2015 / 108779 Brochure [Non-patent literature]

[0004] [Non-Patent Document 1] Organic Synthesis 2003,80,200-206 [Non-patent document 2] Organic Process Research and Development 2005,9,141-148 [Non-patent document 3] Eur.J.Org.Chem.2014,7426-7432 Summary of the Invention [Means for solving the problem]

[0005] Embodiment A. The present invention relates to a compound of formula 1 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 The present invention is directed to a method for preparing a compound of formula (I), the method comprising: formula 2 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. in the presence of an alkali metal base to form a compound of formula 3 R 2 (C=O)LG 3 (In the formula, R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and LG is chloro, C1-C4 alkoxy or -O(C=O)R 2 is) to form a compound of formula 4 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. or an alkali metal salt thereof; A compound of formula 4 or an alkali metal salt thereof is heated to form a compound of formula 5 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 providing a compound of the formula: Compounds of formula 5 can be treated with a hydroxylamine salt to give compounds of formula 6 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 providing a compound of the formula: Treating a compound of formula 6 with an acid Includes:

[0006] Embodiment B. The present invention relates to a compound of formula 8 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 3 is halogen, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 The present invention is also directed to a method for preparing a compound of the formula: formula 2 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. in the presence of an alkali metal base to form a compound of formula 3 R 2 (C=O)LG 3 (In the formula, R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and LG is chloro, C1-C4 alkoxy or -O(C=O)R 2 is) to form a compound of formula 4 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. or an alkali metal salt thereof; A compound of formula 4 or an alkali metal salt thereof is heated to form a compound of formula 5 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 providing a compound of the formula: Compounds of formula 5 can be treated with a hydroxylamine salt to give compounds of formula 6 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 providing a compound of the formula: Compounds of formula 6 can be treated with acid to give compounds of formula 1 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 providing a compound of the formula: The compound of formula 1 is reacted with a compound of formula 7 in the presence of a second base. [ka] (In the formula, Z is a halogen or SO2R 4 and; R 3 is halogen, C1-C4 alkyl or C1-C4 haloalkyl; R 4 is C1-C4 alkyl) and treating with a compound of Includes:

[0007] Embodiment C. The present invention relates to a compound of formula 5 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl and; R 2 is C1-C4 haloalkyl; and m is 0, 1, 2 or 3 The present invention is also directed to a method for preparing a compound of the formula: formula 2 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. in the presence of an alkali metal base to form a compound of formula 3A R 2 (C=O)LG 3A (In the formula, R 2 is C1-C4 haloalkyl; and LG is chloro, C1-C4 alkoxy or -O(C=O)R 2 is) to form a compound of formula 4 [ka] (In the formula, Each R 1 are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is C1-C4 haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. or an alkali metal salt thereof; heating a compound of formula 4A or an alkali metal salt thereof; Includes:

[0008] Embodiment D. The present invention relates to a compound of formula 5A [ka] (In the formula, R 1 is halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; and R 2 is C1-C2 haloalkyl; R 1 When is fluoro, R 2 is other than trifluoromethyl) This also applies to compounds of the formula:

[0009] Embodiment E. The present invention relates to a compound of formula 4A [ka] (In the formula, R 1 is halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl; R 2 is C1-C2 haloalkyl; and X is a halogen; R 1 When is fluoro, R 2 is other than trifluoromethyl) The present invention also covers the compound or its alkali metal salt.

[0010] Embodiment F. The compound of Formula 7 is In the presence of a halogenating agent, [ka] (In the formula, R 3 is halogen, C1-C4 alkyl, or C1-C4 haloalkyl; and Q is Cl or OH. and a compound of formula 11 [ka] (In the formula, R A and R B are each independently C1-C4 alkyl; or R A and R B together form -(CH2)4-, -(CH2)5- or -CH2CH2OCH2CH2-) and a compound of formula 12 [ka] (In the formula, R 3 is halogen, C1-C4 alkyl, or C1-C4 haloalkyl; and R A and R B are each independently C1-C4 alkyl; or R A and R B taken together to form -(CH2)4-, -(CH2)5- or -CH2CH2OCH2CH2-; and Hal - is a chloride ion or a bromide ion) and providing an intermediate of; The intermediate of formula 12 is converted into a compound of formula 13 in the presence of a base. [ka] (In the formula, R 4 is C1-C4 alkyl) with the acid salt of the compound of formula 14 [ka] (In the formula, R 3 is halogen, C1-C4 alkyl or C1-C4 haloalkyl; R 4 is C1-C4 alkyl) providing a compound of the formula: treating a compound of formula 14 with an oxidizing agent; The method of embodiment B, wherein the compound is prepared by DETAILED DESCRIPTION OF THE INVENTION

[0011] As used herein, the terms "comprise," "including," "including," "including," "having," "having," "containing," "containing," "characterized by," or any other variation thereof, are intended to cover non-exclusive inclusions, subject to the clearly stated limitation. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited to only those elements, but may include other elements that are not expressly listed or that are inherent in such composition, mixture, process, or method.

[0012] The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. In a claim, it closes the claim to the inclusion of materials other than those recited, except for impurities ordinarily associated therewith. When the phrase "consisting of" appears in the characterizing clause of a claim rather than immediately following the preamble, it is limited to only the elements recited in that clause; other elements are not excluded from the claim as a whole.

[0013] The transitional phrase "consisting essentially of" is used to define a composition, process, or method that includes materials, steps, features, components, or elements in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of" occupies a middle ground between "comprising" and "consisting of."

[0014] It should be readily understood that where applicant defines an invention or portions thereof in open-ended terms, such as "comprising," the description should (unless otherwise stated) be construed to also describe such an invention using the terms "consisting essentially of" or "consisting of."

[0015] Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive or, not an exclusive or. For example, condition A or B is satisfied by any one of the following: A is true (or present) and B is not true (or absent), A is not true (or absent) and B is true (or present), or both A and B are true (or present).

[0016] Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be open-ended regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural, unless the number is clearly intended to be singular.

[0017] As used herein, the term "suitable" indicates that a described entity or condition is appropriate for use in the indicated situation or environment. As used herein, the term "treatment" or "treating" refers to the use of a chemical or chemical process to change the existing condition of another material, chemical, or compound. The terms "converting," "converted," transformation, and related terms refer to effecting a change in the structure, form, characteristics, or function of an entity, e.g., a compound. For example, a compound of a first formula or structure is converted to a compound of a second formula or structure by a chemical process involving one or more treatments as defined above.

[0018] As used herein, the term "intermediate" refers to a compound or chemical entity in a chemical process that is prepared at a step after a starting material is provided and before a final product is prepared. In some cases, an intermediate is not isolated during a chemical process, but is converted in situ to a subsequent compound. A set of square brackets surrounding the chemical structure of an intermediate may be used herein to indicate that the intermediate is not isolated prior to its conversion to a subsequent compound; e.g., "[intermediate]."

[0019] As used herein, the term "reel-through" refers to a process in which at least one intermediate compound formed in the process is processed in a subsequent step of the process without its isolation. For example, the compound may be subjected to successive chemical reactions in only one reactor.

[0020] In the above list, the term "alkyl," used alone or in compounds such as "alkylthio" or "haloalkyl," includes straight-chain or branched alkyls, such as methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, or hexyl isomers. "Alkenyl" includes straight-chain or branched alkenes, such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl, and hexenyl isomers. "Alkenyl" also includes polyenes, such as 1,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes, such as ethynyl, 1-propynyl, 2-propynyl, and the different butynyl, pentynyl, and hexynyl isomers.

[0021] "Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, and the different butoxy, pentoxy, and hexyloxy isomers. "Alkoxyalkyl" indicates alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CHOCH, CHOCHCH, CHCHOCH, CHCHCHOCH, and CHCHOCHCH. "Alkylthio" includes branched or straight-chain alkylthio moieties, such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, and hexylthio isomers.

[0022] The term "halogen," when used alone or in a compound word, such as "haloalkyl," or in a description, such as "alkyl substituted with halogen," includes fluorine, chlorine, bromine, or iodine. Furthermore, when used in a compound word, such as "haloalkyl," or in a description, such as "alkyl substituted with halogen," the alkyl may be partially or fully substituted with halogen atoms, which may be the same or different. Examples of "haloalkyl" or "alkyl substituted with halogen" include CHF, F, ClCH, CF, CH, and CFCC1.

[0023] The terms "haloalkoxy" and the like are defined analogously to the term "haloalkyl." Examples of "haloalkoxy" include CFO-, CClCHO-, HCFCHCHO-, and CFCHO-. "Alkylcarbonyl" refers to a straight-chain or branched alkyl moiety attached to a C(=O) moiety. Examples of "alkylcarbonyl" include CHC(=O)-, CHCHCHC(=O)-, and (CH)CHC(=O)-. Examples of "alkoxycarbonyl" include CHOC(=O)-, CHCHOC(=O)-, CHCHCHOC(=O)-, (CH)CHOC(=O)-, and the different butoxy- or pentoxycarbonyl isomers. "Alkylcarbonyloxy" refers to a straight-chain or branched alkyl moiety attached to a C(=O)O- moiety. Examples of "alkylcarbonyloxy" include CH3C(=O)O-, CH3CH2CH2C(=O)O-, and (CH3)2CHC(=O)O-.

[0024] The total number of carbon atoms in the substituent is "C i ~C j " prefix, where, for example, i and j are numbers from 1 to 4. For example, C1-C4 alkylsulfonyl refers to methylsulfonyl to butylsulfonyl; C2 alkoxyalkyl refers to CHOCH-; C3 alkoxyalkyl refers to, for example, CH3CH(OCH3)-, CHOCH2CH2-, or CHCHOCH2-; C4 alkoxyalkyl refers to the various isomers of an alkyl group substituted with an alkoxy group containing a total of 4 carbon atoms, examples include CH3CH2CH2OCH2- and CHCHOCH2CH2-.

[0025] When a compound is substituted with a substituent having a subscript indicating that the number of said substituents may be more than one, said substituents (when there are more than one) are independently selected from the group of defined substituents (e.g., (R 3 ) mand m is 0, 1, 2, or 3. When a group contains a substituent that can be hydrogen, for example (when m=0), it is recognized that when this substituent is taken as hydrogen, this is equivalent to the group being unsubstituted. When a variable group is indicated as being optionally attached at a position (e.g., (R 1 ) m ) (where m can be 0), even if not stated in the definition of a variable, a hydrogen can be present at that position. When one or more positions on a group are said to be "unsubstituted" or "unsubstituted," a hydrogen atom is attached to occupy a free valence.

[0026] The term "optionally" as used herein means that optional conditions may or may not be present. For example, when a reaction is optionally carried out in the presence of a solvent, the solvent may or may not be present.

[0027] The term "optionally substituted" refers to a group that is unsubstituted or has at least one non-hydrogen substituent that does not abolish the chemical or biological activity of the unsubstituted analog. As used herein, the following definitions shall apply unless otherwise indicated. The term "optionally substituted" is used interchangeably with the phrase "unsubstituted or substituted" or the term "substituted (unsubstituted)." Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the others.

[0028] Embodiments of the present invention include the following.

[0029] Embodiment A1. Each R 1 The method of embodiment A, wherein is independently halogen or cyano.

[0030] Embodiment A2. Each R 1 The method of embodiment A1, wherein is independently halogen.

[0031] Embodiment A3. Each R 1 The method of embodiment A2, wherein is chlorine.

[0032] Embodiment A4. Each R 1 The method of embodiment A2, wherein is bromine.

[0033] Embodiment A5. The method of any one of Embodiments A-A4, wherein m is 0, 1 or 2.

[0034] Embodiment A6. The method of embodiment A5, wherein m is 1 or 2.

[0035] Embodiment A7. Each R 1 The method of embodiment A6, wherein is attached to the remainder of Formula 1 at the 3-position or the 4-position or both the 3- and 4-positions.

[0036] Embodiment A8. The method of embodiment A7, wherein m is 1.

[0037] Embodiment A9. R 1 The method of embodiment A8, wherein is attached to the remainder of Formula 1 at the 3-position.

[0038] Embodiment A10. R 1 The method of embodiment A8, wherein is attached to the remainder of Formula 1 at the 4-position.

[0039] Embodiment A11. R 1 The method of any one of embodiments A6-A10, wherein is chlorine.

[0040] Embodiment A12. R 2 The method of any one of embodiments A through A11, wherein is C1-C4 alkyl or C1-C4 haloalkyl.

[0041] Embodiment A13. R 2 The method of embodiment A12, wherein is C1-C4 haloalkyl.

[0042] Embodiment A14. R 2The method of embodiment A13, wherein is C1-C2 fluoroalkyl.

[0043] Embodiment A15. R 2 The method of embodiment A14, wherein is C1 fluoroalkyl.

[0044] Embodiment A16. R 2 The method of embodiment A15, wherein is CHF2.

[0045] Embodiment A17. The method of any one of Embodiments A through A16, wherein X is bromine or chlorine.

[0046] Embodiment A18. The method of embodiment A17, wherein X is chlorine.

[0047] Embodiment A19. The compound of formula 2 is represented by formula 9 [ka] (In the formula, Each R 1 are independently halogen, C1-C4 alkyl, or C1-C4 haloalkyl; X is halogen; and m is 0, 1, 2 or 3 The method of any one of embodiments A through A18, wherein the compound of formula (I) is prepared by treating the compound of formula (I) with methylmagnesium halide, followed by treatment with water or aqueous acid.

[0048] Embodiment A20. Each R 1 The method of embodiment A19, wherein is independently halogen.

[0049] Embodiment A21. Each R 1 The method of embodiment A20, wherein is chlorine.

[0050] Embodiment A22. Each R 1 The method of embodiment A20, wherein is bromine.

[0051] Embodiment A23. The method of any one of Embodiments A19-A22, wherein m is 0, 1 or 2.

[0052] Embodiment A24. The method of embodiment A23, wherein m is 1 or 2.

[0053] Embodiment A25. Each R 1 The method of embodiment A24, wherein is attached to the remainder of Formula 9 at the 2-position or the 3-position or both the 2- and 3-positions.

[0054] Embodiment A26. The method of embodiment A24, wherein m is 1.

[0055] Embodiment A27. R 1 The method of embodiment A26, wherein is attached to the remainder of Formula 9 at the 2-position.

[0056] Embodiment A28. R 1 The method of embodiment A27, wherein is chlorine.

[0057] Embodiment A29 The method of any one of Embodiments A19-A28, wherein the methylmagnesium halide is methylmagnesium chloride.

[0058] Embodiment A30. A compound of Formula 1 is reacted with a compound of Formula 7 in the presence of a second base. [ka] (In the formula, Z is a halogen or SO2R 4 and; R 3 is halogen, C1-C4 alkyl, or C1-C4 haloalkyl; and R 4 is C1-C4 alkyl) to give a compound of formula 8 [ka] (In the formula, Each R 1are independently halogen, cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 2 is cyano, C1-C4 alkyl, or C1-C4 haloalkyl; R 3 is halogen, C1-C4 alkyl, or C1-C4 haloalkyl; and m is 0, 1, 2 or 3 The method of any of embodiments A through A29, further comprising providing a compound of formula:

[0059] Embodiment A31 The method of Embodiment A30 wherein Z is chlorine.

[0060] Embodiment A32. Z is SO2R 4 The method of embodiment A30, wherein

[0061] Embodiment A33. R 4 The method of embodiment A32, wherein is C1-C2 alkyl.

[0062] Embodiment A34. R 4 The method of embodiment A33, wherein is methyl.

[0063] Embodiment A35. R 3 The method of any one of embodiments A30-A34, wherein is a halogen.

[0064] Embodiment A36. R 3 The method of embodiment A35, wherein is chlorine.

[0065] Embodiment A37. A compound of Formula 8 2-[2-(3-bromo-5-isoxazolyl)phenoxy]-5-chloropyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, and 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-bromophenoxy]pyrimidine The method of any of embodiments A30 to A36, selected from the group consisting of:

[0066] Embodiment A38. The compound of Formula 8 is represented by Formula 8A [ka] The method according to A37, wherein the compound is 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine (alternative name 5-chloro-2-[3-chloro-2-[3-(difluoromethyl)-5-isoxazolyl]-phenoxy]-pyrimidine; CAS number 1801862-02-1).

[0067] Embodiment B1. Each R 1 The method of embodiment B, wherein is independently halogen or cyano.

[0068] Embodiment B2. Each R1 The method of embodiment B1, wherein is independently halogen.

[0069] Embodiment B3. Each R 1 The method of embodiment B2, wherein is chlorine.

[0070] Embodiment B4. Each R 1 The method of embodiment B3, wherein is bromine.

[0071] Embodiment B5. The method of any one of Embodiments B-B4, wherein m is 0, 1, or 2.

[0072] Embodiment B6 The method of embodiment B5, wherein m is 1 or 2.

[0073] Embodiment B7. Each R 1 The method of embodiment B6, wherein is attached to the remainder of Formula 8 at the 3-position or the 4-position or both the 3- and 4-positions.

[0074] Embodiment B8. The method of embodiment B6, wherein m is 1.

[0075] Embodiment B9. R 1 The method of embodiment B8, wherein is attached to the remainder of Formula 8 at the 3 position.

[0076] Embodiment B10. R 1 The method of embodiment B8, wherein is attached to the remainder of Formula 1 at the 4-position.

[0077] Embodiment B11. R 1 The method of any one of embodiments B6-B10, wherein is chlorine.

[0078] Embodiment B12. R 2 The method of any one of embodiments B-B11, wherein is C1-C4 alkyl or C1-C4 haloalkyl.

[0079] Embodiment B13. R 2The method of embodiment B12, wherein is C1-C4 haloalkyl.

[0080] Embodiment B14. R 2 The method of embodiment B13, wherein is C1-C2 fluoroalkyl.

[0081] Embodiment B15. R 2 The method of embodiment B14, wherein is C1 fluoroalkyl.

[0082] Embodiment B16. R 2 The method of embodiment B15, wherein is CHF2.

[0083] Embodiment B17. The method of any one of Embodiments B-B16, wherein X is bromine or chlorine.

[0084] Embodiment B18. The method of embodiment B17, wherein X is chlorine.

[0085] Embodiment B19. The compound of formula 2 is represented by formula 9 [ka] (In the formula, Each R 1 are independently halogen, C1-C4 alkyl, or C1-C4 haloalkyl; X is halogen; and m is 0, 1, 2 or 3 The method of any one of embodiments B through B18, wherein the compound of formula (I) is prepared by treating the compound of formula (I) with a methylmagnesium halide, followed by treatment with water or aqueous acid.

[0086] Embodiment B20. Each R 1 The method of embodiment B19, wherein is independently halogen.

[0087] Embodiment B21. Each R 1 The method of embodiment B20, wherein is chlorine.

[0088] Embodiment B22. Each R1 The method of embodiment B20, wherein is bromine.

[0089] Embodiment B23. The method of any one of Embodiments B19-B22, wherein m is 0, 1 or 2.

[0090] Embodiment B24. The method of embodiment B23, wherein m is 1 or 2.

[0091] Embodiment B25. Each R 1 The method of embodiment B24, wherein is attached to the remainder of Formula 9 at the 2-position or the 3-position or both the 2- and 3-positions.

[0092] Embodiment B26. The method of embodiment B24, wherein m is 1.

[0093] Embodiment B27. R 1 The method of embodiment B26, wherein is attached to the remainder of Formula 9 at the 2-position.

[0094] Embodiment B28. R 1 The method of embodiment B27, wherein is chlorine.

[0095] Embodiment B29. The method of any one of Embodiments B19-B28, wherein the methylmagnesium halide is methylmagnesium chloride.

[0096] Embodiment B30. The method of any one of Embodiments B-B29, wherein Z is chlorine.

[0097] Embodiment B31. Z is SO2R 4 The method of any one of embodiments B to B29, wherein

[0098] Embodiment B32. R 4 The method of embodiment B31, wherein is C1-C2 alkyl.

[0099] Embodiment B33. R 4 The method of embodiment B32, wherein is methyl.

[0100] Embodiment B34. R 3 The method of any one of embodiments B through B33, wherein is a halogen.

[0101] Embodiment B35. R 3 The method of embodiment B34, wherein is chlorine.

[0102] Embodiment B36. A compound of formula 8 2-[2-(3-bromo-5-isoxazolyl)phenoxy]-5-chloropyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, and 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-bromophenoxy]pyrimidine The method of any of embodiments B-B35, selected from the group consisting of:

[0103] Embodiment B37. The compound of formula 8 is represented by formula 8A [ka] The method according to B36, wherein the compound is 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine (alternative name 5-chloro-2-[3-chloro-2-[3-(difluoromethyl)-5-isoxazolyl]-phenoxy]-pyrimidine; CAS number 1801862-02-1).

[0104] Embodiment C1. Each R 1 The method of embodiment C, wherein is independently halogen or cyano.

[0105] Embodiment C2. Each R 1 The method of embodiment C, wherein is independently a halogen.

[0106] Embodiment C3. Each R 1 The method of embodiment C2, wherein is chlorine.

[0107] Embodiment C4. Each R 1 The method of embodiment C2, wherein is bromine.

[0108] Embodiment C5. The method of any one of Embodiments C-C4, wherein m is 0, 1, or 2.

[0109] Embodiment C6. The method of embodiment C5, wherein m is 1 or 2.

[0110] Embodiment C7. Each R 1 The method of embodiment C6, wherein is attached to the remainder of formula 2 at the 2-position or the 3-position or both the 2- and 3-positions.

[0111] Embodiment C8. The method of embodiment C6, wherein m is 1.

[0112] Embodiment C9. R1 The method of embodiment C8, wherein is attached to the remainder of Formula 2 at the 2 position.

[0113] Embodiment C10. 1 The method of embodiment C8, wherein is attached to the remainder of Formula 2 at the 3 position.

[0114] Embodiment C11. R 1 The method of any one of embodiments C6 to C10, wherein is chlorine.

[0115] Embodiment C12. The method of any of Embodiments C-C11, wherein a compound of Formula 2 is prepared by treating a compound of Formula 9.

[0116] Embodiment C13. The compound of Formula 2 is represented by Formula 9 [ka] (In the formula, Each R 1 are independently halogen, C1-C4 alkyl, or C1-C4 haloalkyl; X is halogen; and m is 0, 1, 2 or 3 The method of any of embodiments C-C13, wherein the compound of formula (I) is prepared by treating the compound of formula (I) with methylmagnesium halide, followed by treatment with water or aqueous acid.

[0117] Embodiment C14. Each R 1 The method of embodiment C13, wherein is independently halogen.

[0118] Embodiment C15. Each R 1 The method of embodiment C14, wherein is chlorine.

[0119] Embodiment C16. Each R 1 The method of embodiment C15, wherein is bromine.

[0120] Embodiment C17. The method of any of Embodiments C13-C16, wherein m is 0, 1 or 2.

[0121] Embodiment C18. The method of embodiment C17, wherein m is 1 or 2.

[0122] Embodiment C19. Each R 1 The method of embodiment C18, wherein is attached to the remainder of formula 9 at the 2-position or the 3-position or both the 2- and 3-positions.

[0123] Embodiment C20. The method of embodiment C18, wherein m is 1.

[0124] Embodiment C21. R 1 The method of embodiment C20, wherein is attached to the remainder of Formula 9 at the 2-position.

[0125] Embodiment C22. R 1 The method of embodiment C21, wherein is chlorine.

[0126] Embodiment C23 The method of any of Embodiments C13-C22 wherein the methylmagnesium halide is methylmagnesium chloride.

[0127] Embodiment C24. Formula 5B [ka] The method of embodiment C, wherein the compound of formula (I) is prepared.

[0128] Embodiment D1. 1 A compound according to embodiment D, wherein is halogen or cyano.

[0129] Embodiment D2. 1 A compound according to embodiment D1, wherein is halogen.

[0130] Embodiment D3. 1 The compound according to embodiment D2, wherein is chlorine.

[0131] Embodiment D4. 1The compound according to embodiment D2, wherein is bromine.

[0132] Embodiment D5. R 2 The compound of any one of embodiments D-D4, wherein is C1-C2 fluoroalkyl.

[0133] Embodiment D6. 2 A compound according to embodiment D5, wherein is C1 fluoroalkyl.

[0134] Embodiment D7. 2 The compound of embodiment D6, wherein is CHF2.

[0135] Embodiment D8. Formula 5B [ka] The compound of embodiment D7, wherein

[0136] Embodiment E1.R 1 A compound according to embodiment E, wherein is halogen or cyano.

[0137] Embodiment E2.R 1 A compound according to embodiment E1, wherein is cyano.

[0138] Embodiment E3.R 1 A compound according to embodiment E1, wherein is halogen.

[0139] Embodiment E4. 1 A compound according to embodiment E3, wherein is chlorine.

[0140] Embodiment E5.R 1 A compound according to embodiment E3, wherein is bromine.

[0141] Embodiment E6. A compound according to any one of Embodiments E through E5, wherein X is bromine or chlorine.

[0142] Embodiment E7. A compound according to Embodiment E6 wherein X is chlorine.

[0143] Embodiment E8. R 2 The compound of any one of embodiments E-E7, wherein is C1-C2 fluoroalkyl.

[0144] Embodiment E9. R 2 A compound according to embodiment E8, wherein is C1 fluoroalkyl.

[0145] Embodiment E10. R 2 The compound of embodiment E9, wherein is CHF2.

[0146] Embodiment E11. Sodium salts, i.e., of Formula 4B [ka] The compound of any one of embodiments E-E10, wherein the compound is:

[0147] Embodiment E12. Formula 4C [ka] or a sodium salt thereof.

[0148] Embodiment F1.R 4 The method of embodiment F, wherein is C1-C2 alkyl.

[0149] Embodiment F2. 4 The method of embodiment F1, wherein is methyl.

[0150] Embodiment F3.R 3 The method of any one of embodiments F-F2, wherein is a halogen.

[0151] Embodiment F4.R 3 The method of embodiment F3, wherein is chlorine.

[0152] Embodiment F5 The method of any one of Embodiments F-F4, wherein the halogenating agent is POCl3.

[0153] Embodiment F5a The method of embodiment F5, wherein the halogenating agent is a Vilsmeier-Haack reagent.

[0154] Embodiment F6 The method of any one of Embodiments F-F5, wherein Q is Cl.

[0155] Embodiment F7 The method of any one of embodiments F-FC5, wherein Q is OH.

[0156] Embodiment F8. Each R A and R B The method of any one of embodiments F-F7, wherein is independently C1-C4 alkyl.

[0157] Embodiment F9. Each R A and R B The method of embodiment F8, wherein is independently C1-C2 alkyl.

[0158] Embodiment F10. Each R A and R B The method of embodiment F9, wherein is methyl.

[0159] Embodiment F11. Any of Embodiments F-F10, wherein the salt of the compound of Formula 13 is a hemisulfate salt. The method according to any one of the preceding claims.

[0160] The embodiments of the present invention, including the above embodiments A-A38, B-B37, C-C24, D-D8, E-E12, and F-F11, as well as any other embodiments described herein, may be combined in any manner, and the descriptions of variables in the embodiments relate not only to compounds of formula 8, but also to starting compounds useful in preparing compounds of formula 8, and intermediate compounds of formulas 1-7 and 9-14.

[0161] Preferred embodiments include the following:

[0162] Embodiment P1.R 2 is C1-C4 haloalkyl; and The method of embodiment A, B or F, wherein m is 0, 1 or 2.

[0163] Embodiment P2. Each R 1 are independently halogen or cyano; and R 2 The method of embodiment P1, wherein is C1-C2 fluoroalkyl.

[0164] Embodiment P3.R 1 is a halogen; R 2 is C1 fluoroalkyl; m is 1; and R 1 The method of embodiment P2, wherein is attached to the remainder of Formula 1 at the 3-position.

[0165] Embodiment P4.R 1 is chlorine; and R 2 The method of embodiment P2, wherein is CHF2.

[0166] Embodiment P5.R 3 The method of any one of embodiments P1-P4, wherein is chlorine.

[0167] Embodiment P6. Z is chlorine or SO2R 4 The method of any of embodiments P1 to P5, wherein

[0168] Embodiment P7 The method of embodiment P6, wherein Z is SO2CH3.

[0169] Embodiment P8.R 2 The compound of embodiment D or E, wherein is C1-C2 fluoroalkyl.

[0170] Embodiment P9.R 1 is a halogen; and R 2The compound according to embodiment P8, wherein is C1 fluoroalkyl.

[0171] Embodiment P10.R 1 is chlorine; and R 2 The compound according to embodiment P9, wherein is CHF2.

[0172] In the following scheme, X and R in the compounds of the following formulas 1 to 14 A , R B , R 1 , R 2 , R 3 , R 4 The definitions of and m are as defined above in the Summary of the Invention and the Description of the Preferred Embodiments, unless otherwise indicated.

[0173] The methods described herein provide an efficient and robust synthesis of 2-(isoxazol-5-yl)-phenols of formula 1, which are useful in the preparation of herbicidal compounds of formula 8. Compounds of formula 1 and 8 have previously been prepared as described in WO 2015 / 108779.

[0174] As shown in Scheme 1, the compound of Formula 1 can be prepared by reacting 4H-1-benzopyran-4 of Formula 5 1-(2-hydroxyphenyl)-butane-1,3-dione-3-oxime of formula 6 can be prepared in a round-robin fashion by treating the resulting 1-(2-hydroxyphenyl)-butane-1,3-dione-3-oxime with a hydroxylamine salt, preferably hydroxylamine hydrochloride, in the presence of a base, and treating the resulting 1-(2-hydroxyphenyl)-butane-1,3-dione-3-oxime of formula 6 with an acid. In some cases, the compound of formula 6 can be treated with an acid to effect cyclization of the isoxazole to form the compound of formula 1 without isolation from the reaction mixture. [ka]

[0175] Compounds of formula 5 are prepared as shown in Scheme 2. Compounds of formula 2 are reacted with an acylating agent LG(C=O)R of formula 3 in the presence of an alkali metal base.2 wherein LG is chloro, alkoxy, or —O(C═O)R 2 (Figure imgf000012_0001) provides a compound of Formula 4 or its alkali metal salt, a compound of Formula 4B. Suitable alkali metal bases for the reaction include alkali metal alkoxides, such as sodium methoxide, sodium isopropoxide, and potassium tert-butoxide; or alkali metal hydroxides, such as potassium hydroxide and sodium hydroxide; or alkali metal carbonates and alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate. A preferred base is sodium methoxide. Suitable solvents include toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, or N,N-dimethylacetamide. A preferred solvent is N,N-dimethylacetamide. A person skilled in the art will recognize that a compound of Formula 4B can exist in multiple tautomeric forms, and that any tautomeric form of a compound of Formula 4B is contemplated in the present invention. For simplicity, only one tautomer is shown. Acidification of the reaction mixture, if necessary, allows for isolation of a compound of Formula 4. Preferably, the following steps are promoted by a base so that the compound of formula 4 is not isolated.

[0176] The compound of Formula 4 or 4B can be cyclized with ortho-halogen substitution to provide a compound of Formula 5. In some embodiments, the compound of Formula 4B is cyclized to a compound of Formula 5 under the conditions for acylation of the compound of Formula 2 and / or by further heating the compound of Formula 4B at a temperature of, for example, about 100 to 200°C, or about 120 to about 180°C, or about 140 to about 160°C. In any of these embodiments, the compound of Formula 4 or 4B does not need to be isolated. If the compound of Formula 4 is isolated from the first reaction mixture, the addition of a base may be necessary to facilitate its cyclization to a compound of Formula 5. Alternatively, the reaction sequences shown in Schemes 1 and 2 can be carried out in a single reactor without isolating the compound of Formula 5. [ka]

[0177] Treatment of nitriles of formula 9 with a methylmagnesium halide, such as methylmagnesium chloride, followed by hydrolysis can provide ortho-haloacetophenones of formula 2, as shown in Scheme 3. In particular, X is chloro or bromo, more particularly chloro. In some cases, compounds of formula 2 may be commercially available. [ka]

[0178] As shown in Scheme 4, the present invention also relates to a method for preparing a compound of Formula 8 by coupling a pyrimidine of Formula 7A or 7B with a phenol of Formula 1, typically in the presence of a base and a solvent. Suitable solvents include acetonitrile, toluene, isopropanol, tetrahydrofuran, dimethyl sulfoxide, or N,N-dimethylformamide. Suitable bases for the reaction include alkali metal hydrides, such as sodium hydride; or alkali metal alkoxides, such as sodium isopropoxide and potassium tert-butoxide; or alkali metal hydroxides, such as potassium hydroxide and sodium hydroxide; or alkali metal carbonates, such as potassium carbonate and cesium carbonate; or amide bases, such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium diisopropylamide; or tertiary amines, such as triethylamine and diisopropylethylamine. Preferably, the compound of formula 8 is obtained by nucleophilic substitution by heating the compound of formula 1 with the compound of formula 7A or 7B in the presence of a base, such as potassium carbonate or cesium carbonate, in a suitable solvent, such as acetonitrile or N,N-dimethylformamide, at a temperature in the range of 20-110°C or 50-110°C. It can be prepared by the following method. [ka]

[0179] As shown in Schemes 5 and 6, the compound of formula 7B can be prepared in a round-robin manner. This method involves treating a compound of formula 10 and a compound of formula 11 with a halogenating agent, optionally in a suitable solvent, to give an intermediate of formula 12, which is then treated with an acid salt of a compound of formula 13 in the presence of a base, without isolation, to provide a compound of formula 14. A preferred salt of the compound of formula 13 is the hemisulfate salt (formula 13A shown in Scheme 5). Suitable halogenating agents include POCl3, POBr3, SOCl2, SOBr2, (COCl)2, or COCl2, preferably POCl3, SOCl2, (COCl)2, or COCl2. When a brominating agent is used, Hal in formula 12 is preferably brominated. - is a bromide ion, and when a chlorinating agent is used, Hal in Equation 12 - is the chloride ion. Phosphorus oxychloride (POCl3) is a more preferred halogenating agent. Alternatively, the halogenating agent can be pre-prepared as the Vilsmeier-Haack reagent by reacting COCl2 with N,N-dimethylformamide. Suitable solvents include N,N-dimethylformamide, dichloroethane, toluene, or acetonitrile. Suitable bases for this reaction include alkali metal alkoxides, such as sodium methoxide and sodium isopropoxide; or alkali metal acetates, such as sodium acetate and potassium acetate; or tertiary amines, such as triethylamine and diisopropylethylamine. N,N-dimethylformamide is a preferred compound of Formula 11. In some embodiments, especially when the compound of Formula 11 is N,N-dimethylformamide, excess compound of Formula 11 can be used in place of additional solvent. The compound of Formula 10 and the halogenating agent can be added sequentially in any order or simultaneously to the compound of Formula 11. [ka]

[0180] As shown in Scheme 6, alkylsulfonylpyrimidine compounds of formula 7B can be prepared by oxidizing compounds of formula 14 with an oxidizing agent such as m-chloroperbenzoic acid, sodium periodate, potassium permanganate, potassium peroxomonosulfate (Oxone®), or hydrogen peroxide in a suitable solvent or mixture of solvents such as water, dichloromethane, methanol, acetonitrile, acetic acid, or ethyl acetate. [ka]

[0181] It is recognized that some of the reagents and reaction conditions described above for preparing compounds of Formulas 1-14 may not be compatible with particular functional groups present in the intermediates. In these cases, incorporating a protection / deprotection sequence or functional group interconversion into the synthesis will aid in obtaining the desired product. The use and selection of protecting groups will be apparent to those skilled in chemical synthesis (see, for example, Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New (See, York, 1991). Those skilled in the art will recognize that, in some cases, after the introduction of a given reagent as shown in any individual scheme, it may be necessary to perform additional routine synthetic steps as detailed to complete the synthesis of compounds of Formulas 1-14. Those skilled in the art will also recognize that, to prepare compounds of Formulas 1-14, it may be necessary to perform combinations of the steps illustrated in the above schemes in an order other than that indicated by the specific order presented. Those skilled in the art will also recognize that compounds of Formulas 1-14 and the intermediates described herein can be subjected to a variety of electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.

[0182] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are merely illustrative and are not intended to limit the disclosure in any way. The steps in the following examples illustrate the procedure for each step in the overall synthetic transformation, and the starting material for each step may not necessarily have been prepared by the particular preparative procedure whose procedure is described in another example or step. Percentages are by weight. The abbreviation "h" means "hours." "HPLC" means high performance liquid chromatography. 1 H NMR spectra are reported in ppm downfield from tetramethylsilane; s is a singlet, d is a doublet, dd is a doublet of a doublet, t is a triplet, and m is a multiplet. [Example]

[0183] Synthesis Example 1 Preparation of 3-chloro-2-[3-(difluoromethyl)isoxazol-5-yl]-phenol Step A: Preparation of 5-chloro-2-(difluoromethyl)-4H-1-benzopyran-4-one A 250 mL round-bottom flask equipped with an overhead stirrer, distillation head, and nitrogen inlet was charged with sodium methoxide (10.8 g, 200 mmol) and N,N-dimethylacetamide (50 mL) at 25 °C. Premixed 2,6-dichloroacetophenone (3 A solution of ethyl difluoroacetate (5 g, 181 mmol) and ethyl difluoroacetate (27 g, 218 mmol) in N,N-dimethylacetamide (20 mL) was added dropwise to the sodium methoxide slurry, and the reaction temperature was maintained at 25–35°C. After 1 h at 35°C, the methanol and ethanol produced from the reaction were removed by distillation under reduced pressure. N,N-dimethylacetamide (80 mL) was added to a separate 1 L round-bottom flask equipped with an overhead stirrer, reflux condenser, and nitrogen inlet, and this was heated to 150°C. The reaction mixture was added to the hot N,N-dimethylacetamide over 2.5 h, while the temperature was maintained at 150°C. Upon completion, as judged by HPLC analysis, the reaction mixture was cooled to 50°C. Water (200 mL) was slowly added to the reactor, and the resulting slurry was slowly cooled to 20°C and stirred for 1 h. The solid was then collected by filtration, washed with water (100 mL), and dried at ambient temperature to give 38 g of crude product. The crude product was treated with activated carbon to remove colored impurities and recrystallized from toluene to give 31.7 g of the title compound as a pale yellow solid (76% yield from 2,6-dichloroacetophenone). 1 H NMR δ 7.79(t,1H),7.70(dd,1H),7.76(dd,1H),7.15-6.89(t,1H),6.68(s,1H).MP=113℃.

[0184] Step B: Preparation of 3-chloro-2-[3-(difluoromethyl)-5-isoxazolyl]-phenol A 500 mL jacketed reactor equipped with an overhead stirrer and temperature probe was charged with 5-chloro-2-(difluoromethyl)-4H-1-benzopyran-4-one (i.e., the product of Step A, Synthesis Example 1; 50 g, 217 mmol), hydroxylamine hydrochloride (18.1 g, 260 mmol), and methanol (150 mL) at ambient temperature. Solid sodium acetate (21.3 g, 260 mmol) was added to the reaction mixture in one portion, and the resulting slurry was stirred overnight. Concentrated hydrogen chloride solution (34 g, 325 mmol) was then added slowly, and the resulting slurry was stirred for 1 hour. Upon completion, as determined by HPLC, water (220 mL) was added to the reactor, and the slurry was stirred at ambient temperature for 2 hours. The solid was then collected by filtration, washed with 10% methanol in water (150 mL), and dried at ambient temperature to give 49.1 g of the title compound (93% by weight, 91% yield from 5-chloro-2-(difluoromethyl)-4H-1-benzopyran-4-one). 1 H NMR δ 10.7(s,1H),7.48-7.22(t,1H),7.40(t,1H),7.09(d,1H),7.05(s,1H),7.01(d,1H).MP=139.7℃.

[0185] Synthesis Example 2 Preparation of 5-chloro-2-(methylthio)-pyrimidine (CAS number 38275-42-2). A 100 mL jacketed reactor equipped with an overhead stirrer, thermocouple, recirculating heating and cooling bath, nitrogen inlet, and scrubber was charged with 41 mL of N,N-dimethylformamide and heated to 50 °C. Chloroacetyl chloride (10 g, 88.5 mmol) was added dropwise, and the reaction mixture was held at 50 °C for 1 h. The resulting mixture was then heated to 70 °C, followed by the dropwise addition of phosphorus oxychloride (13.6 g, 88.5 mmol), maintaining the temperature at 70–75 °C. The reaction was held at 70 °C for 4 h and then cooled to 50 °C. S-methylisothiourea hemisulfate (12.3 g, 88.5 mmol) was added to the reaction mixture, followed by solid sodium methoxide (23.9 g, 443 mmol). The resulting mixture was heated to 60 °C for 2 h and then cooled to 40 °C. Water (60 mL) was added dropwise to the reactor, and the resulting slurry was slowly cooled to 20° C. and stirred for 2 hours. The solid was then collected by filtration, washed with 20 mL of water, and dried at ambient temperature to give the title compound of Formula 1 (8.5 g, 60% yield from chloroacetyl chloride). 1 H NMR(400MHz,DMSO-d6)δ 8.76(s,2H),2.53(s,3H).MP=61.6℃.

[0186] Synthesis Example 3 Alternative preparation of 5-chloro-2-(methylthio)-pyrimidine (CAS no. 38275-42-2) A 100 mL jacketed reactor equipped with an overhead stirrer, thermocouple, recirculating heating and cooling bath, nitrogen inlet, and scrubber was charged with 12.3 g (92.9 mmol) of Vilsmeier-Haack reagent and 30 mL of N,N-dimethylformamide. The resulting slurry was then heated to 50 °C. 10 g (88.5 mmol) of chloroacetyl chloride was added dropwise, maintaining a reaction temperature of 50–52 °C. The reaction mixture was held at 50 °C overnight. The resulting solution was cooled to ambient temperature and transferred to an addition funnel. 17.6 g (177 mmol) of triethylamine and 30 mL of N,N-dimethylformamide were added to the reactor, and the mixture was cooled to 10 °C. The solution in the addition funnel was then added dropwise, while maintaining the temperature below 25 °C, and 13.3 g (97.4 mmol) of S-methylisothiourea hemisulfate was added in one portion. The resulting reaction mixture was then heated to 70° C. for 4 hours and cooled to 20° C. Water (100 mL) was added dropwise to the reactor and the resulting slurry was stirred for 2 hours. The solid was then collected by filtration, washed twice with water (30 mL), and dried at room temperature to give 10.1 g of the title product (99.3 wt %, 72% yield from chloroacetyl chloride). 1 H NMR(400MHz,DMSO-d6)δ 8.76(s,2H),2.52(s,3H).MP=61.6℃.

[0187] Synthesis Example 4 Preparation of 5-chloro-2-(methylsulfonyl)-pyrimidine (CAS number 38275-47-7). To a 100 mL jacketed reactor equipped with an overhead stirrer, thermocouple, recirculating heating and cooling bath, and nitrogen inlet, 5-chloro-2-(methylthio)-pyrimidine (i.e., the product of Synthesis Example 2 or 3; 5 g, 31.1 mmol) and sodium tungstate dihydrate (0.52 g, 1.6 mmol) were added at ambient temperature, followed by water (15 mL) and ethyl acetate (15 mL). The resulting mixture was heated to 60 °C, and then 50% aqueous hydrogen peroxide (5.3 g, 77.7 mmol) was added dropwise, maintaining the reaction temperature at 60–65 °C. After 2 h, the reaction was determined to be complete by HPLC. The reaction mixture was cooled to ambient temperature, and excess hydrogen peroxide in the reaction mixture was quenched with sodium bisulfite. The organic layer was then separated, and the aqueous layer was extracted with 15 mL of ethyl acetate. The combined organic layers were concentrated to give the crude product. Crystallization from toluene and heptane gave 5.6 g of the title compound of formula 6 (93% yield from 5-chloro-2-(methylthio)-pyrimidine). 1 H NMR(400MHz,DMSO-d6)δ 9.24(s,2H),3.42(s,3H).MP=122℃.

[0188] Synthesis Example 5 Preparation of 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]-pyrimidine (alternative name 5-chloro-2-[3-chloro-2-[3-(difluoromethyl)-5-isoxazolyl]-phenoxy]-pyrimidine; CAS number 1801862-02-1) To a 100 mL nitrogen-flushed, glass-jacketed reactor equipped with a recirculating heating / cooling bath, nitrogen inlet, temperature probe, and overhead stirrer was added 3-chloro-2-[3-(difluoromethyl)-5-isoxazolyl]-phenol (i.e., the product of Step B, Synthesis Example 1; 4.02 g, 96.5 wt %, 15.8 mmol), 5-chloro-2-(methylsulfonyl)-pyrimidine (i.e., the product of Synthesis Example 4; 3.44 g, 97.0 wt %, 17.3 mmol), potassium carbonate (3.27 g, 23.7 mmol), and isopropyl alcohol (12.1 g). The resulting slurry was heated to 65° C. for 1 hour and, upon completion as judged by HPLC analysis, water (12.1 g) was added. The mixture was added over 5 minutes. The reaction mixture was cooled to 54°C, the two liquid phases were separated, and the aqueous phase was removed. The organic solution was cooled to 0°C, and a solid crystallized from the isopropyl alcohol. The solid was collected by filtration, washed with a pre-cooled isopropyl alcohol / water mixture (4 / 1 v / v, 3.5 g), and dried under vacuum at 60°C to give the title compound, compound of Formula 8 (4.62 g, 99.4% by weight, 81.2% yield). 1 H NMR(400MHz,CDCl3)δ 8.44(s,2H),7.47-7.55(m,2H),7.22(dd,1H),6.61-6.87(t,1H),6.70(s,1H).MP=66.5℃.

[0189] By the procedures described herein, together with methods known in the art, the following compounds can be prepared using the claimed methods. The following abbreviations are used in the tables below: Et means ethyl (CH2CH3), Pr means propyl, i-Pr means isopropyl, and Bu means butyl.

[0190] [Table 1]

[0191] Each of the following tables is a comparison of the headings in Table 1 (i.e., "m is 0" (i.e., R1 It is organized in the same manner as Table 1 above, except that the "(is absent)" is replaced with the respective headings shown below. For example, the first entry in Table 2 is a compound of formula 4, where m is 1 and R 1 is 3-F, X is Cl, and R 2 is CN. The remainder of Table 2 is constructed similarly, and therefore the remainder of Tables 3-59 are constructed in the same manner.

[0192] [Table 2]

[0193] [Table 3]

[0194] Each of the following tables corresponds to the heading in Table 36 (i.e., "m is 0 (i.e., R 1 It is organized in the same manner as Table 36 above, except that the "(is not present)" column is replaced with the respective headings shown below. For example, the first entry in Table 37 is for a compound of Formula 5 (where m is 1 and R 1 is 5-F and R 2 (where CN is CN). The remainder of Table 37 is constructed similarly, and therefore the remainder of Tables 38-70 are constructed in the same way.

[0195] [Table 4]

[0196] [Table 5]

[0197] Each of the following tables corresponds to the heading in Table 71 (i.e., "m is 0 (i.e., R 1It is organized in the same manner as Table 71 above, except that the "(is not present)" column is replaced with the respective headings shown below. For example, the first entry in Table 72 is for a compound of Formula 1 (where m is 1 and R 1 is 3-F and R 2 (where CN is CN). The remainder of Table 72 is constructed similarly, and therefore the remainder of Tables 73-105 are constructed in the same manner.

[0198] [Table 6]

[0199] [Table 7]

[0200] Each of the following tables corresponds to the heading in Table 106 (i.e., "m is 0 (i.e., Wachi, R 1 For example, the first entry in Table 107 is for a compound of Formula 8 (where m is 1 and R is not present) 1 is 3-F and R 2 is CN and R 3 (where C1 is Cl). The remainder of Table 107 is constructed similarly, and therefore the remainder of Tables 108-140 are constructed in the same manner.

[0201] [Table 8]

Claims

1. Formula 1 【Chemistry 1】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3.

1. A method for preparing a compound of formula (I), comprising: Formula 2 【Chemistry 2】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. in the presence of an alkali metal base to form a compound of formula 3 R ２ (C=O)LG ３ (In the formula, R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and LG is chloro, C １ ~C ４ Alkoxy or —O(C═O)R ２ is) to form a compound of formula 4 【Transformation 3】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. or an alkali metal salt thereof; The compound of formula 4 or the alkali metal salt thereof is heated to obtain a compound of formula 5 【Chemistry 4】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3. providing a compound of formula (I); The compound of formula 5 is treated with a hydroxylamine salt to give the compound of formula 6 【Transformation 5】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3. providing a compound of formula (I); treating the compound of formula 6 with an acid; A method comprising:

2. R ２ is C １ ~C ４ haloalkyl; and m is 0, 1, or 2. The method described.

3. Each R １ are independently halogen or cyano; and R ２ is C １ ~C ２ The method of claim 2, wherein the alkyl group is a fluoroalkyl group.

4. R １ is a halogen; R ２ is C １ is fluoroalkyl; m is 1; and R １ The method of claim 3, wherein is attached to the remainder of formula 1 at the 3-position.

5. R １ is chlorine; and R ２ is CHF ２ The method of claim 4, wherein

6. The compound of formula 2 is represented by formula 9 【Transformation 6】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; X is a halogen; and m is 0, 1, 2 or 3.

10. The method of claim 1, wherein the compound of formula (I) is prepared by treating the compound of formula (I) with methylmagnesium halide followed by treatment with water or aqueous acid.

7. The compound of formula 1 is reacted with a compound of formula 7 in the presence of a second base. 【Transformation 7】 (In the formula, Z is a halogen or SO ２ R ４ and R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and R ４ is C １ ~C ４ alkyl) to give a compound of formula 8 【Transformation 8】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3.

10. The method of claim 1, further comprising providing a compound of formula:

8. R ３ The method of claim 7 , wherein is chlorine.

9. Z is SO ２ R ４ The method of claim 7, wherein

10. The compound of formula 7 can be reacted with a compound of formula 10 in the presence of a halogenating agent. 【Chemistry 9】 (In the formula, R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and Q is Cl or OH. and a compound of formula 11 【Chemistry 10】 (In the formula, R Ａ and R Ｂ are each independently C １ ~C ４ is alkyl; or R Ａ and R Ｂ are put together, -(CH ２ ) ４ -, -(CH ２ ) ５ - or -CH ２ CH ２ OCH ２ CH ２ - becomes and a compound of formula 12 【Chemistry 11】 (In the formula, R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and R Ａ and R Ｂ are each independently C １ ~C ４ is alkyl; or R Ａ and R Ｂ are put together, -(CH ２ ) ４ -, -(CH ２ ) ５ - or -CH ２ CH ２ OCH ２ CH ２ -becomes; and Hal － is a chloride ion or a bromide ion) providing an intermediate of The intermediate of formula 12 is converted into a compound of formula 13 in the presence of a base. 【Chemistry 12】 (In the formula, R ４ is C １ ~C ４ alkyl) to give a compound of formula 14 【Chemistry 13】 (In the formula, R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ４ is C １ ~C ４ alkyl) providing a compound of formula (I); treating the compound of formula 14 with an oxidizing agent; 10. The method of claim 9, wherein the compound is prepared by:

11. The compound of formula 8 is 2-[2-(3-bromo-5-isoxazolyl)phenoxy]-5-chloropyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, and 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-bromophenoxy]pyrimidine 8. The method of claim 7, selected from the group consisting of:

12. The compound of formula 8 is represented by formula 8A 【Chemistry 14】 The method of claim 11 , wherein the compound is

13. Formula 8 【Chemistry 15】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3.

1. A method for preparing a compound of formula (I), comprising: Formula 2 【Chemistry 16】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. in the presence of a base to form a compound of formula 3 R ２ (C=O)LG ３ (In the formula, R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and LG is chloro, C １ ~C ４ Alkoxy or —O(C═O)R ２ is) to form a compound of formula 4 【Chemistry 17】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. providing a salt of the compound of formula (I); Heating the salt of the compound of formula 4 to form a compound of formula 5 [Chemistry 18] (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3. providing a compound of formula (I); The compound of formula 5 is treated with a hydroxylamine salt to give the compound of formula 6 【Chemistry 19】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3. providing a compound of formula (I); The compound of formula 6 is treated with an acid to give a compound of formula 1 【Chemistry 20】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3. providing a compound of formula (I); The compound of formula 1 is reacted with a compound of formula 7 in the presence of a second base. 【Chemistry 21】 (In the formula, Z is a halogen or SO ２ R ４ and R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ４ is C １ ~C ４ alkyl) and treating with a compound of A method comprising:

14. R ２ is C １ ~C ４ haloalkyl; and 14. The method of claim 13, wherein m is 0, 1, or 2.

15. Each R １ are independently halogen or cyano; R ２ is C １ ~C ２ is fluoroalkyl; and R ３ The method of claim 14 , wherein is a halogen.

16. R １ is a halogen; R ２ is C １ is fluoroalkyl; m is 1; and R １ 16. The method of claim 15, wherein is attached to the remainder of Formula 1 at the 3-position.

17. R １ is chlorine; R ２ is CHF ２ and R ３ The method of claim 16 , wherein is chlorine.

18. The compound of formula 2 is represented by formula 9 【Chemistry 22】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; X is a halogen; and m is 0, 1, 2 or 3.

15. The method of claim 14, wherein the compound is prepared by treating the compound of formula (I) with methylmagnesium halide followed by treatment with water or aqueous acid.

19. Z is SO ２ R ４ The method of claim 13, wherein

20. The compound of formula 7 can be reacted with a compound of formula 10 in the presence of a halogenating agent. 【Chemistry 23】 (In the formula, R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and Q is Cl or OH. and a compound of formula 11 【Chemistry 24】 (In the formula, R Ａ and R Ｂ are each independently C １ ~C ４ is alkyl; or R Ａ and R Ｂ are put together, -(CH ２ ) ４ -, -(CH ２ ) ５ - or -CH ２ CH ２ OCH ２ CH ２ - becomes and a compound of formula 12 【Chemistry 25】 (In the formula, R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and R Ａ and R Ｂ are each independently C １ ~C ４ is alkyl; or R Ａ and R Ｂ are put together, -(CH ２ ) ４ -, -(CH ２ ) ５ - or -CH ２ CH ２ OCH ２ CH ２ -becomes; and Hal － is a chloride ion or a bromide ion) providing an intermediate of The intermediate of formula 12 is converted into a compound of formula 13 in the presence of a base. 【Chemistry 26】 (In the formula, R ４ is C １ ~C ４ alkyl) to give a compound of formula 14 【Chemistry 27】 (In the formula, R ３ is a halogen, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ４ is C １ ~C ４ alkyl) providing a compound of formula (I); treating the compound of formula 14 with an oxidizing agent; 20. The method of claim 19, wherein the compound is prepared by:

21. The compound of formula 8 is 2-[2-(3-bromo-5-isoxazolyl)phenoxy]-5-chloropyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]phenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-fluorophenoxy]pyrimidine, 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, 5-bromo-2-[2-[3-(trifluoromethyl)-5-isoxazolyl]-3-chlorophenoxy]pyrimidine, and 5-chloro-2-[2-[3-(difluoromethyl)-5-isoxazolyl]-3-bromophenoxy]pyrimidine 14. The method of claim 13, selected from the group consisting of:

22. The compound of formula 8 is represented by formula 8A 【Chemistry 28】 22. The method of claim 21 , wherein the compound is

23. Formula 5 【Chemistry 29】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is C １ ~C ４ haloalkyl; and m is 0, 1, 2 or 3.

1. A method for preparing a compound of formula (I), comprising: Formula 2 【Transformation 30】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. in the presence of an alkali metal base to form a compound of formula 3A R ２ (C=O)LG 3A (In the formula, R ２ is C １ ~C ４ haloalkyl; and LG is chloro, C １ ~C ４ Alkoxy or —O(C═O)R ２ is) to form a compound of formula 4 【Chemistry 31】 (In the formula, Each R １ are independently halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is C １ ~C ４ haloalkyl; m is 0, 1, 2 or 3; and X is a halogen. or an alkali metal salt thereof; heating said compound of formula 4A or said alkali metal salt thereof; A method comprising:

24. R ２ is C １ ~C ２ and m is 0, 1, or 2.

25. Each R １ are independently halogen or cyano; and R ２ is C １ ~C ２ 25. The method of claim 24, wherein the alkyl group is a fluoroalkyl group.

26. R １ is a halogen; R ２ is C １ is fluoroalkyl; m is 1; and R １ 26. The method of claim 25, wherein is attached to the remainder of Formula 1 at the 3-position.

27. R １ is chlorine; and R ２ is CHF ２ 27. The method of claim 26, wherein:

28. Formula 5A 【Chemistry 32】 (In the formula, R １ is halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; and R ２ is C １ ~C ２ haloalkyl; R １ When is fluoro, R ２ is other than trifluoromethyl) Compound.

29. R ２ is C １ ~C ２ 29. The compound of claim 28 which is fluoroalkyl.

30. R １ is a halogen; and R ２ is C １ 30. The compound of claim 29 which is fluoroalkyl.

31. R １ is chlorine; and R ２ is CHF ２ 31. The compound of claim 30, wherein:

32. Formula 4A 【Transformation 33】 (In the formula, R １ is halogen, cyano, C １ ~C ４ Alkyl or C １ ~C ４ haloalkyl; R ２ is C １ ~C ２ haloalkyl; and X is a halogen; R １ When is fluoro, R ２ is other than trifluoromethyl) or an alkali metal salt thereof.

33. R ２ is C １ ~C ２ 33. The compound of claim 32, which is fluoroalkyl.

34. R １ is halogen; and R ２ is C １ 34. The compound of claim 33, which is fluoroalkyl.

35. R １ is chlorine; and R ２ is CHF ２ 35. The compound of claim 34, wherein:

36. Formula 4C 【Transformation 34】 or a sodium salt thereof.

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