Process for preparing chlorine-containing benzamide derivatives

Abstract

Described herein are novel methods for the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide. Compounds prepared by the methods disclosed herein are useful for the preparation of certain anthranilamide compounds of interest as pesticides, such as the insecticides chlorantraniliprole and cyantraniliprole.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 417,409, filed October 19, 2022.

[0002] The present disclosure relates to novel methods for the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide. Compounds prepared by the methods disclosed herein are useful for the preparation of certain anthranilamide compounds of interest as pesticides, such as the insecticides chlorantraniliprole and cyantraniliprole. [Background technology]

[0003] Conventional processes for producing 2-amino-5-chloro-N,3-dimethylbenzamide are subject to several industrial problems, such as hazardous substances, high costs, relatively long process steps, and complicated operations.

[0004] Additionally, some processes use relatively large amounts of salt, water, and / or acid. Such processes result in relatively large amounts of waste solids and wastewater and suboptimal yields. Processes that overcome these environmental concerns and increase yields are desirable. Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure provides novel methods useful for the preparation of 2-amino-5-chloro-N,3-dimethylbenzamide and its derivatives. The advantages of the disclosed methods compared to conventional methods are numerous, including reduced costs, elimination of the need for mixed solvent separation, reduced waste, relatively short process steps, simplified operational complexity, and reduced process hazards. [Means for solving the problem]

[0006] In one embodiment, the compound of formula VI [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and R 11 is branched C1~C 10 Alkyl and unbranched C1-C 10 1. A process for preparing a compound of formula (I) wherein the compound is selected from the group consisting of alkyl, I) A) Formula V [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 wherein at least one of is a halogen; The compound of formula V is i) a) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1 to R4 is hydrogen; b) a solvent containing an acid; and c) Halogenating reagents forming a first mixture comprising: ii) reacting the first mixture; iii) optionally removing a portion of the acid-containing solvent; iv) First mixture; d) an oxidizing agent; and e) Additives forming a second mixture comprising: v) reacting the second mixture in the presence of a catalyst. a compound of formula V prepared according to a process comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) reacting the mixture; and III) Optionally, applying a purification step to the mixture A method is provided, comprising:

[0007] In one embodiment, the compound of formula V [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10 wherein at least one of is a halogen, I) A) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1 to R4 is hydrogen; B) a solvent containing an acid; and C) Halogenating Reagents forming a first mixture comprising: II) reacting the first mixture; III) optionally removing a portion of the acid-containing solvent; IV) First mixture; D) an oxidizing agent; and E) Additives forming a second mixture comprising: V) reacting the second mixture in the presence of a catalyst A method is provided, comprising:

[0008] In one embodiment, the compound of formula VI [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and R 11 is branched C1~C 10 Alkyl and unbranched C1-C 10 1. A process for preparing a compound of formula (I) wherein the compound is selected from the group consisting of alkyl, I) A) Formula V [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 wherein at least one of is a halogen; The compound of formula V is i) a) Formula IV [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen; b) oxidizing agent; c) a solvent; and d) Additives forming a mixture comprising: ii) reacting the mixture in the presence of a catalyst a compound of formula V prepared according to a process comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) reacting the mixture; and III) Optionally, applying a purification step to the mixture A method is provided, comprising:

[0009] In one embodiment, the compound of formula V [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10 wherein at least one of is a halogen, I) A) Formula IV [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen; B) oxidizing agent; C) a solvent; and D) Additives forming a mixture comprising: II) reacting the mixture in the presence of a catalyst A method is provided, comprising:

[0010] In one embodiment, the compound of formula IV [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10wherein at least one of is a halogen, I) A) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1 to R4 is hydrogen; B) a solvent containing an acid; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture A method is provided, comprising:

[0011] In one embodiment, the compound of formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R1 to R4 is hydrogen; I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and The compound of formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; a compound of formula II prepared according to a process comprising: B) acids; and C) Solvent forming a mixture comprising: II) Reacting the mixture A method is provided, comprising:

[0012] In one embodiment, the compound of formula II [ka] wherein each of R1 to R5 is independently selected from hydrogen, halogen, C1 to C5 haloalkyl, and C1 to C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; I) A) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) Chloral hydrate; C) hydroxylamine or a hydroxylamine derivative; D) solvent; E) optionally a pH adjuster; and F) Acid forming a mixture comprising: II) reacting the mixture at a pH in the range of about 0 to about 7; and III) Optionally, extracting the mixture with an extraction solvent. A method is provided, comprising:

[0013] In one embodiment, the compound of formula IV [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 wherein at least one of is a halogen, I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) acids; and C) Solvent forming a first mixture comprising: II) reacting the first mixture; III) removing an amount of solvent from the first mixture; IV) forming a second mixture comprising the first mixture and a halogenating reagent; and V) Reacting the Second Mixture A method is provided, comprising: DETAILED DESCRIPTION OF THE INVENTION

[0014] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any variation thereof, are intended to include a non-exclusive inclusion, subject to any limitations specified. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0015] The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. In the case of a claim, such would close the claim to the inclusion of materials other than those recited, apart from impurities normally associated therewith. When the phrase "consisting of" appears within a clause in the body of a claim rather than immediately following a preamble, it limits only the elements set forth in that clause; other elements are not excluded from the claim as a whole.

[0016] The transitional phrase "consisting essentially of" is used to define a composition 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 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."

[0017] It should be readily understood that where the invention or any portion thereof is defined in open-ended terms such as "comprising," the statement should also be construed as describing such inventions using the terms "consisting essentially of" or "consisting of" (unless otherwise stated).

[0018] Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive "or" and not an exclusive "or." For example, a condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0019] Furthermore, 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 that element or component. Thus, "a" or "an" should be read to include one or at least one, and singular forms of elements or components also include the plural, unless the number is clearly intended to be singular.

[0020] As used herein, the term "about" means ±10% of a value.

[0021] The term "halogen", alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine, or iodine. Furthermore, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms, which may be the same or different.

[0022] A group may have a substituent that may be hydrogen, e.g., R 4 and the substituent is then taken to be hydrogen, this is considered to be equivalent to the group being unsubstituted.

[0023] The term "alkyl" includes functional groups including, but not limited to, straight-chain or branched alkyl. In some embodiments, alkyl can be methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, or hexyl isomers.

[0024] The term "salts thereof" refers to suitable salts of the compound to which the term refers. Suitable salts include, but are not limited to, alkali metal salts, sodium salts, potassium salts, lithium salts, cesium salts, alkali metal salts, calcium salts, magnesium salts, halogen salts, chloride salts, bromide salts, iodide salts, sulfate salts, disulfate salts, nitrate salts, phosphate salts, divalent phosphate salts, hydrogen phosphate salts, carbonate salts, bicarbonate salts, mesylate salts, and combinations thereof. It is understood that certain compounds of the present invention can exist as the pure compound, the compound itself, its salts, and combinations thereof.

[0025] The terms "S150" and "S200" refer to high flash aromatic hydrocarbon solvents with high boiling points of about 180° C. to about 250° C. These solvents offer high solubility and controlled evaporation properties, making them excellent for use in many industrial applications such as additives.

[0026] Certain compounds of the present invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. As will be appreciated by those skilled in the art, one stereoisomer may be more active and / or exhibit advantageous effects when enriched or separated from other stereoisomers. Furthermore, those skilled in the art will recognize methods for separating, enriching, and / or selectively preparing such stereoisomers.

[0027] Embodiments of the present disclosure include the following.

[0028] Embodiment 1. Formula VI [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and R 11 is branched C1~C 10 Alkyl and unbranched C1-C 10 1. A process for preparing a compound of formula (I) wherein the compound is selected from the group consisting of alkyl, I) A) Formula V [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 wherein at least one of is a halogen; The compound of formula V is i) a) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) a solvent containing an acid; and c) Halogenating reagents forming a first mixture comprising: ii) reacting the first mixture; iii) optionally removing a portion of the acid-containing solvent; iv) First mixture; d) an oxidizing agent; and e) Additives forming a second mixture comprising: v) reacting the second mixture in the presence of a catalyst. a compound of formula V prepared according to a process comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) reacting the mixture; and III) Optionally, applying a purification step to the mixture A method comprising:

[0029] Embodiment 2. The alkylamine is a branched C1-C 10 Alkyl and unbranched C1-C 10 2. The method of embodiment 1, comprising a functional group selected from alkyl. In some embodiments, the alkylamine is selected from branched C1-C5 alkyl and unbranched C1-C5 alkyl.

[0030] Embodiment 3. The method of embodiment 2, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, and combinations thereof.

[0031] Embodiment 4. The method of embodiment 3, wherein the alkylamine is methylamine.

[0032] Embodiment 5. The method of embodiment 1, wherein the solvent C) is selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0033] Embodiment 6. The method of embodiment 5, wherein solvent C) is ethyl acetate.

[0034] Embodiment 7. The method of embodiment 1, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 100°C.

[0035] Embodiment 8. The method of embodiment 7, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

[0036] Embodiment 9. The method of embodiment 1, wherein solvent b) comprises a solvent selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0037] Embodiment 10. The method of embodiment 9, wherein solvent b) comprises sulfuric acid and methanesulfonic acid.

[0038] Embodiment 11. The method of embodiment 1, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0039] Embodiment 12. The method of embodiment 11, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0040] Embodiment 13 The method of embodiment 12, wherein the chlorinating reagent is chlorine.

[0041] Embodiment 14. The method of embodiment 1, wherein the method step ii) of reacting the first mixture is carried out at a reaction temperature ranging from about 0°C to about 140°C.

[0042] Embodiment 15. The method of embodiment 14, wherein the method step ii) of reacting the first mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0043] Embodiment 16. The method of embodiment 1, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0044] Embodiment 17. The method of embodiment 16, wherein the oxidizing agent is hydrogen peroxide.

[0045] Embodiment 18. The method of embodiment 1, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0046] Embodiment 19. The method of embodiment 18, wherein the catalyst is sulfuric acid.

[0047] Embodiment 20. The method of embodiment 1, wherein the additive is selected from alkyl acetate, ethyl acetate, isopropyl acetate, alkyl alcohol, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash aromatic hydrocarbon solvent (S150), high flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzene sulfonate (SDS), and combinations thereof.

[0048] Embodiment 21. The method of embodiment 20, wherein the additive is a combination of ethyl acetate and mesitylene.

[0049] Embodiment 22. The method of embodiment 1, wherein the method step v) of reacting the second mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

[0050] Embodiment 23. The method of embodiment 20, wherein the method step v) of reacting the second mixture is carried out at at least one reaction temperature selected from about 30°C to about 40°C and about 60°C to about 70°C.

[0051] Embodiment 24. The compound of Formula III is I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and The compound of formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; a compound of formula II prepared according to a process comprising: B) acids; and C) Solvent forming a mixture comprising: II) Reacting the mixture 2. The method of embodiment 1, wherein the compound is prepared according to a method comprising:

[0052] Embodiment 25. The method of embodiment 22, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0053] Embodiment 26. The method of embodiment 25, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0054] Embodiment 27. The method of claim 24, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0055] Embodiment 28. The method of embodiment 27, wherein solvent C) is 1,2-dichloroethane.

[0056] Embodiment 29. The method of embodiment 24, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0057] Embodiment 30. The method of embodiment 29, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 45°C to about 55°C.

[0058] Embodiment 31. The method of embodiment 24, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0059] Embodiment 32 The method of embodiment 31, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0060] Embodiment 33. The method of embodiment 24, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0061] Embodiment 34. The method of embodiment 33, wherein solvent d) is water.

[0062] Embodiment 35. The method of embodiment 24, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0063] Embodiment 36. The method of embodiment 35, wherein the pH adjuster is sodium carbonate.

[0064] Embodiment 37. The method of embodiment 24, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0065] Embodiment 38. The method of embodiment 37, wherein the acid f) is hydrochloric acid.

[0066] Embodiment 39. The method of embodiment 24, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0067] Embodiment 40. The method of embodiment 39, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0068] Embodiment 41. The method of embodiment 24, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0069] Embodiment 42. The method of embodiment 41, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 45°C to about 55°C.

[0070] Embodiment 43. The method of embodiment 24, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0071] Embodiment 44. The method of embodiment 43, wherein the extraction solvent is 1,2-dichloroethane.

[0072] Embodiment 45. Formula V [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10 wherein at least one of is a halogen, I) A) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1 to R4 is hydrogen; B) a solvent containing an acid; and C) Halogenating Reagents forming a first mixture comprising: II) reacting the first mixture; III) optionally removing a portion of the acid-containing solvent; IV) First mixture; D) an oxidizing agent; and E) Additives forming a second mixture comprising: V) reacting the second mixture in the presence of a catalyst A method comprising:

[0073] Embodiment 46. The method of embodiment 45, wherein the solvent comprises a solvent selected from acetonitrile, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, and combinations thereof.

[0074] Embodiment 47. The method of embodiment 46, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0075] Embodiment 48. The method of embodiment 45, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0076] Embodiment 49. The method of embodiment 48, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0077] Embodiment 50. The method of embodiment 49, wherein the chlorinating reagent is chlorine.

[0078] Embodiment 51. The method of embodiment 45, wherein the method step II) of reacting the first mixture is carried out at a reaction temperature ranging from about 0°C to about 140°C.

[0079] Embodiment 52. The method of embodiment 51, wherein the method step II) of reacting the first mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0080] Embodiment 53. The method of embodiment 45, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0081] Embodiment 54. The method of embodiment 50, wherein the oxidizing agent is hydrogen peroxide.

[0082] Embodiment 55. The method of embodiment 42, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0083] Embodiment 56. The method of embodiment 55, wherein the catalyst is sulfuric acid.

[0084] Embodiment 57. The method of embodiment 45, wherein the additive is selected from alkyl acetate, ethyl acetate, isopropyl acetate, alkyl alcohol, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash aromatic hydrocarbon solvent (S150), high flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof.

[0085] Embodiment 58. The method of embodiment 57, wherein the additive is a combination of ethyl acetate and mesitylene.

[0086] Embodiment 59. The method of embodiment 45, wherein the method step V) of reacting the second mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

[0087] Embodiment 60. The method of embodiment 59, wherein the method step V) of reacting the second mixture is carried out at at least one reaction temperature selected from about 30°C to about 40°C and about 60°C to about 70°C.

[0088] Embodiment 61. The compound of Formula III is I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and The compound of formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; a compound of formula II prepared according to a process comprising: B) acids; and C) Solvent forming a mixture comprising: II) Reacting the mixture 46. ​​The method of embodiment 45, wherein the compound is prepared according to a method comprising:

[0089] Embodiment 62. The method of embodiment 61, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0090] Embodiment 63. The method of embodiment 62, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0091] Embodiment 64. The method of claim 61, wherein the solvent C) is selected from 1,2-dichloroethane, dichloromethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0092] Embodiment 65. The method of embodiment 64, wherein solvent C) is 1,2-dichloroethane.

[0093] Embodiment 66. The method of embodiment 61, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0094] Embodiment 67. The method of embodiment 66, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 45°C to about 55°C.

[0095] Embodiment 68. The method of embodiment 61, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0096] Embodiment 69. The method of embodiment 68, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0097] Embodiment 70. The method of embodiment 61, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0098] Embodiment 71. The method of embodiment 70, wherein solvent d) is water.

[0099] Embodiment 72. The method of embodiment 61, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0100] Embodiment 73. The method of embodiment 72, wherein the pH adjuster is sodium carbonate.

[0101] Embodiment 74. The method of embodiment 61, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0102] Embodiment 75. The method of embodiment 74, wherein the acid f) is hydrochloric acid.

[0103] Embodiment 76. The method of embodiment 61, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0104] Embodiment 77. The method of embodiment 76, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0105] Embodiment 78. The method of embodiment 61, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0106] Embodiment 79. The method of embodiment 78, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0107] Embodiment 80. The method of embodiment 61, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0108] Embodiment 81. The method of embodiment 74, wherein the extraction solvent is 1,2-dichloroethane.

[0109] Embodiment 82. Formula VI [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and R 11 is branched C1~C 10 Alkyl and unbranched C1-C 10 1. A process for preparing a compound of formula (I) wherein the compound is selected from the group consisting of alkyl, I) A) Formula V [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 wherein at least one of is a halogen; The compound of formula V is i) a) Formula IV [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10at least one of which is a halogen; b) oxidizing agent; c) a solvent; and d) Additives forming a mixture comprising: ii) reacting the mixture in the presence of a catalyst a compound of formula V prepared according to a process comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) reacting the mixture; and III) Optionally, applying a purification step to the mixture A method comprising:

[0110] Embodiment 83. The alkylamine is a branched C1-C 10 Alkyl and unbranched C1-C 10 83. The method of embodiment 82, comprising a functional group selected from alkyl. In some embodiments, the alkylamine is selected from branched C1-C5 alkyl and unbranched C1-C5 alkyl.

[0111] Embodiment 84. The method of embodiment 83, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, and combinations thereof.

[0112] Embodiment 85. The method of embodiment 84, wherein the alkylamine is methylamine.

[0113] Embodiment 86. The method of embodiment 82, wherein the solvent C) is selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0114] Embodiment 87. The method of embodiment 86, wherein solvent C) is ethyl acetate.

[0115] Embodiment 88. The method of embodiment 82, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 100°C.

[0116] Embodiment 89. The method of embodiment 88, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

[0117] Embodiment 90. The method of embodiment 82, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0118] Embodiment 91. The method of embodiment 90, wherein the oxidizing agent is hydrogen peroxide.

[0119] Embodiment 92. The method of embodiment 82, wherein the solvent C) is selected from acetonitrile, methanol, ethanol, isopropanol, water, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dioxane, formic acid, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0120] Embodiment 93 The method of embodiment 92, wherein solvent C) is acetic acid.

[0121] Embodiment 94. The method of embodiment 82, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0122] Embodiment 95. The method of embodiment 94, wherein the catalyst is sulfuric acid.

[0123] Embodiment 96. The method of embodiment 82, wherein the additive is selected from alkyl acetate, ethyl acetate, isopropyl acetate, alkyl alcohol, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash aromatic hydrocarbon solvent (S150), high flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof.

[0124] Embodiment 97. The method of embodiment 96, wherein the additive is a combination of ethyl acetate and mesitylene.

[0125] Embodiment 98. The method of embodiment 82, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

[0126] Embodiment 99. The method of embodiment 98, wherein the method step ii) of reacting the mixture is carried out at at least one reaction temperature selected from about 30°C to about 40°C and about 60°C to about 70°C.

[0127] Embodiment 100. A compound of Formula IV: I) A) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1 to R4 is hydrogen; B) a solvent containing an acid; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture 83. The method of embodiment 82, wherein the compound is prepared according to a method comprising:

[0128] Embodiment 101. The method of embodiment 100, wherein the solvent comprises a solvent selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0129] Embodiment 102. The method of embodiment 101, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0130] Embodiment 103. The method of embodiment 100, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0131] Embodiment 104. The method of embodiment 103, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0132] Embodiment 105. The method of embodiment 104, wherein the chlorinating reagent is chlorine.

[0133] Embodiment 106. The method of embodiment 100, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 140°C.

[0134] Embodiment 107. The method of embodiment 106, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0135] Embodiment 108. The compound of Formula III is I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and The compound of formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; a compound of formula II prepared according to a process comprising: B) acids; and C) Solvent forming a mixture comprising: II) Reacting the mixture 101. The method of embodiment 100, wherein the compound is prepared according to a method comprising:

[0136] Embodiment 109. The method of embodiment 108, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0137] Embodiment 110. The method of embodiment 109, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0138] Embodiment 111. The method of claim 108, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0139] Embodiment 112. The method of embodiment 111, wherein the solvent C) is 1,2-dichloroethane.

[0140] Embodiment 113. The method of embodiment 108, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0141] Embodiment 114. The method of embodiment 113, wherein the method step II) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0142] Embodiment 115. The method of embodiment 108, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0143] Embodiment 116. The method of embodiment 115, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0144] Embodiment 117. The method of embodiment 108, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0145] Embodiment 118. The method of embodiment 117, wherein solvent d) is water.

[0146] Embodiment 119. The method of embodiment 108, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0147] Embodiment 120. The method of embodiment 119, wherein the pH adjuster is sodium carbonate.

[0148] Embodiment 121. The method of embodiment 108, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0149] Embodiment 122. The method of embodiment 121, wherein the acid f) is hydrochloric acid.

[0150] Embodiment 123. The method of embodiment 108, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0151] Embodiment 124. The method of embodiment 123, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0152] Embodiment 125. The method of embodiment 108, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0153] Embodiment 126. The method of embodiment 125, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0154] Embodiment 127. The method of embodiment 108, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0155] Embodiment 128. The method of embodiment 127, wherein the extraction solvent is 1,2-dichloroethane.

[0156] Embodiment 129. A compound of Formula IV is I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) acids; and C) Solvent forming a mixture comprising: II) reacting the first mixture; III) removing an amount of solvent from the first mixture; IV) forming a second mixture comprising the first mixture and a halogenating reagent; and V) Reacting the Second Mixture 83. The method of embodiment 82, wherein the compound is prepared according to a method comprising:

[0157] Embodiment 130. The method of embodiment 129, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0158] Embodiment 131. The method of embodiment 130, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0159] Embodiment 132. The method of claim 129, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0160] Embodiment 133. The method of embodiment 132, wherein solvent C) is 1,2-dichloroethane.

[0161] Embodiment 134. The method of embodiment 129, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0162] Embodiment 135. The method of embodiment 134, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0163] Embodiment 136. The method of embodiment 135, wherein the chlorinating reagent is chlorine.

[0164] Embodiment 137. The method of embodiment 129, wherein the method step V) of reacting the second mixture is carried out at a reaction temperature ranging from about 0°C to about 140°C.

[0165] Embodiment 138. The method of embodiment 137, wherein the method step V) of reacting the second mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0166] Embodiment 139. A compound of Formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; 130. The method of embodiment 129, wherein the compound is prepared according to a method comprising:

[0167] Embodiment 140. The method of embodiment 139, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0168] Embodiment 141. The method of embodiment 140, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0169] Embodiment 142. The method of embodiment 139, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0170] Embodiment 143. The method of embodiment 142, wherein the solvent d) is water.

[0171] Embodiment 144. The method of embodiment 139, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0172] Embodiment 145. The method of embodiment 144, wherein the pH adjuster is sodium carbonate.

[0173] Embodiment 146. The method of embodiment 139, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0174] Embodiment 147. The method of embodiment 146, wherein the acid f) is hydrochloric acid.

[0175] Embodiment 148. The method of embodiment 139, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0176] Embodiment 149. The method of embodiment 148, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0177] Embodiment 150. The method of embodiment 139, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0178] Embodiment 151. The method of embodiment 150, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 45°C to about 55°C.

[0179] Embodiment 152. The method of embodiment 139, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0180] Embodiment 153. The method of embodiment 152, wherein the extraction solvent is 1,2-dichloroethane.

[0181] Embodiment 154. Formula V [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10 wherein at least one of is a halogen, I) A) Formula IV [ka] (In the formula, R7~R 10 each of is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen; B) oxidizing agent; C) a solvent; and D) Additives forming a mixture comprising: II) reacting the mixture in the presence of a catalyst A method comprising:

[0182] Embodiment 155. The method of embodiment 154, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0183] Embodiment 156. The method of embodiment 155, wherein the oxidizing agent is hydrogen peroxide.

[0184] Embodiment 157. The method of embodiment 154, wherein the solvent is selected from acetonitrile, methanol, ethanol, isopropanol, water, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dioxane, formic acid, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0185] Embodiment 158. The method of embodiment 157, wherein the solvent is acetic acid.

[0186] Embodiment 159. The method of embodiment 154, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0187] Embodiment 160. The method of embodiment 159, wherein the catalyst is sulfuric acid.

[0188] Embodiment 161. The method of embodiment 154, wherein the additive is selected from alkyl acetate, ethyl acetate, isopropyl acetate, alkyl alcohol, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, S150, S200, Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof.

[0189] Embodiment 162. The method of embodiment 161, wherein the additive is a combination of ethyl acetate and mesitylene.

[0190] Embodiment 163. The method of embodiment 154, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

[0191] Embodiment 164. The method of embodiment 163, wherein the method step II) of reacting the mixture is carried out at at least one reaction temperature selected from about 30°C to about 40°C and about 60°C to about 70°C.

[0192] Embodiment 165. A compound of Formula IV is I) A) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1 to R4 is hydrogen; B) a solvent containing an acid; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture 155. The method of embodiment 154, wherein the compound is prepared according to a method comprising:

[0193] Embodiment 166. The method of embodiment 165, wherein the solvent comprises a solvent selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0194] Embodiment 167. The method of embodiment 166, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0195] Embodiment 168. The method of embodiment 165, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0196] Embodiment 169. The method of embodiment 168, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0197] Embodiment 170. The method of embodiment 169, wherein the chlorinating reagent is chlorine.

[0198] Embodiment 171. The method of embodiment 165, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 140°C.

[0199] Embodiment 172. The method of embodiment 171, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0200] Embodiment 173. A compound of Formula III: I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and The compound of formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; a compound of formula II prepared according to a process comprising: B) acids; and C) Solvent forming a mixture comprising: II) Reacting the mixture 166. The method of embodiment 165, wherein the compound is prepared according to a method comprising:

[0201] Embodiment 174. The method of embodiment 173, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0202] Embodiment 175. The method of embodiment 174, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0203] Embodiment 176. The method of claim 173, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0204] Embodiment 177. The method of embodiment 176, wherein solvent C) is 1,2-dichloroethane.

[0205] Embodiment 178. The method of embodiment 173, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0206] Embodiment 179. The method of embodiment 178, wherein the method step II) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0207] Embodiment 180. The method of embodiment 173, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0208] Embodiment 181. The method of embodiment 180, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0209] Embodiment 182. The method of embodiment 173, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0210] Embodiment 183. The method of embodiment 182, wherein solvent d) is water.

[0211] Embodiment 184. The method of embodiment 173, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0212] Embodiment 185. The method of embodiment 184, wherein the pH adjuster is sodium carbonate.

[0213] Embodiment 186. The method of embodiment 173, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0214] Embodiment 187. The method of embodiment 186, wherein the acid f) is hydrochloric acid.

[0215] Embodiment 188. The method of embodiment 173, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0216] Embodiment 189. The method of embodiment 188, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0217] Embodiment 190. The method of embodiment 173, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0218] Embodiment 191. The method of embodiment 190, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature in the range of from about 45°C to about 55°C.

[0219] Embodiment 192. The method of embodiment 173, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0220] Embodiment 193. The method of embodiment 192, wherein the extraction solvent is 1,2-dichloroethane.

[0221] Embodiment 194. A compound of Formula IV is I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) acids; and C) Solvent forming a mixture comprising: II) reacting the first mixture; III) removing an amount of solvent from the first mixture; IV) forming a second mixture comprising the first mixture and a halogenating reagent; and V) Reacting the Second Mixture 155. The method of embodiment 154, wherein the compound is prepared according to a method comprising:

[0222] Embodiment 195. The method of embodiment 194, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0223] Embodiment 196. The method of embodiment 195, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0224] Embodiment 197. The method of claim 194, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0225] Embodiment 198. The method of embodiment 197, wherein solvent C) is 1,2-dichloroethane.

[0226] Embodiment 199. The method of embodiment 194, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0227] Embodiment 200. The method of embodiment 199, wherein the method step II) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0228] Embodiment 201. The method of embodiment 194, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0229] Embodiment 202. The method of embodiment 201, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0230] Embodiment 203. The method of embodiment 202, wherein the chlorinating reagent is chlorine.

[0231] Embodiment 204. The method of embodiment 194, wherein the method step V) of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0232] Embodiment 205. The method of embodiment 204, wherein the method step V) of reacting the second mixture is carried out at a reaction temperature in the range of from about 20°C to about 30°C.

[0233] Embodiment 206. A compound of Formula II: i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; 195. The method of embodiment 194, wherein the compound is prepared according to a method comprising:

[0234] Embodiment 207. The method of embodiment 206, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0235] Embodiment 208. The method of embodiment 207, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0236] Embodiment 209. The method of embodiment 206, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0237] Embodiment 210. The method of embodiment 209, wherein solvent d) is water.

[0238] Embodiment 211. The method of embodiment 206, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0239] Embodiment 212. The method of embodiment 211, wherein the pH adjuster is sodium carbonate.

[0240] Embodiment 213. The method of embodiment 206, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0241] Embodiment 214. The method of embodiment 213, wherein the acid f) is hydrochloric acid.

[0242] Embodiment 215. The method of embodiment 206, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0243] Embodiment 216. The method of embodiment 215, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0244] Embodiment 217. The method of embodiment 206, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0245] Embodiment 218. The method of embodiment 217, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 45°C to about 55°C.

[0246] Embodiment 219. The method of embodiment 206, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0247] Embodiment 220. The method of embodiment 219, wherein the extraction solvent is 1,2-dichloroethane.

[0248] Embodiment 221. Formula IV [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 wherein at least one of is a halogen, I) A) Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1 to R4 is hydrogen; B) a solvent containing an acid; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture A method comprising:

[0249] Embodiment 222. The method of embodiment 221, wherein the solvent comprises a solvent selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0250] Embodiment 223. The method of embodiment 222, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0251] Embodiment 224. The method of embodiment 221, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0252] Embodiment 225. The method of embodiment 224, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0253] Embodiment 226. The method of embodiment 225, wherein the chlorinating agent is chlorine.

[0254] Embodiment 227. The method of embodiment 221, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 140°C.

[0255] Embodiment 228. The method of embodiment 227, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0256] Embodiment 229. A compound of Formula III is I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and The compound of formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; a compound of formula II prepared according to a process comprising: B) acids; and C) Solvent forming a mixture comprising: II) Reacting the mixture 222. The method of embodiment 221, wherein the compound is prepared according to a method comprising:

[0257] Embodiment 230. The method of embodiment 229, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0258] Embodiment 231. The method of embodiment 229, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0259] Embodiment 232. The method of claim 229, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0260] Embodiment 233. The method of embodiment 232, wherein solvent C) is 1,2-dichloroethane.

[0261] Embodiment 234. The method of embodiment 229, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0262] Embodiment 235. The method of embodiment 234, wherein the method step II) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0263] Embodiment 236. The method of embodiment 229, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0264] Embodiment 237. The method of embodiment 236, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0265] Embodiment 238. The method of embodiment 229, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0266] Embodiment 239. The method of embodiment 238, wherein solvent d) is water.

[0267] Embodiment 240. The method of embodiment 229, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0268] Embodiment 241. The method of embodiment 240, wherein the pH adjuster is sodium carbonate.

[0269] Embodiment 242. The method of embodiment 229, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0270] Embodiment 243. The method of embodiment 242, wherein the acid f) is hydrochloric acid.

[0271] Embodiment 244. The method of embodiment 229, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0272] Embodiment 245. The method of embodiment 244, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0273] Embodiment 246. The method of embodiment 229, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0274] Embodiment 247. The method of embodiment 246, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature in the range of from about 45°C to about 55°C.

[0275] Embodiment 248. The method of embodiment 229, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0276] Embodiment 249. The method of embodiment 248, wherein the extraction solvent is 1,2-dichloroethane.

[0277] Embodiment 250. Formula III [ka] wherein each of R1-R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R1 to R4 is hydrogen, I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and The compound of formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; a compound of formula II prepared according to a process comprising: B) acids; and C) Solvent forming a mixture comprising: II) Reacting the mixture A method comprising:

[0278] Embodiment 251. The method of embodiment 250, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0279] Embodiment 252. The method of embodiment 251, wherein the acids are sulfuric acid and methanesulfonic acid.

[0280] Embodiment 253. The method of claim 250, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0281] Embodiment 254. The method of embodiment 253, wherein solvent C) is 1,2-dichloroethane.

[0282] Embodiment 255. The method of embodiment 250, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0283] Embodiment 256. The method of embodiment 255, wherein the method step II) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0284] Embodiment 257. The method of embodiment 250, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0285] Embodiment 258. The method of embodiment 257, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0286] Embodiment 259. The method of embodiment 250, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0287] Embodiment 260. The method of embodiment 259, wherein solvent d) is water.

[0288] Embodiment 261. The method of embodiment 250, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0289] Embodiment 262. The method of embodiment 261, wherein the pH adjuster is sodium carbonate.

[0290] Embodiment 263. The method of embodiment 250, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0291] Embodiment 264. The method of embodiment 263, wherein the acid f) is hydrochloric acid.

[0292] Embodiment 265. The method of embodiment 250, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0293] Embodiment 266. The method of embodiment 265, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0294] Embodiment 267. The method of embodiment 250, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0295] Embodiment 268. The method of embodiment 267, wherein the method step ii) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0296] Embodiment 269. The method of embodiment 250, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0297] Embodiment 270. The method of embodiment 269, wherein the extraction solvent is 1,2-dichloroethane.

[0298] Embodiment 271. Formula II [ka] wherein each of R1 to R5 is independently selected from hydrogen, halogen, C1 to C5 haloalkyl, and C1 to C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen, I) A) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) Chloral hydrate; C) hydroxylamine or a hydroxylamine derivative; D) solvent; E) optionally a pH adjuster; and F) Acid forming a mixture comprising: II) reacting the mixture at a pH in the range of about 0 to about 7; and III) Optionally, extracting the mixture with an extraction solvent. A method comprising:

[0299] Embodiment 272. The method of embodiment 271, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0300] Embodiment 273. The method of embodiment 272, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0301] Embodiment 274. The method of embodiment 271, wherein the solvent D) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0302] Embodiment 275. The method of embodiment 274, wherein the solvent D) is water.

[0303] Embodiment 276. The method of embodiment 271, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0304] Embodiment 277. The method of embodiment 276, wherein the pH adjuster is sodium carbonate.

[0305] Embodiment 278. The method of embodiment 271, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0306] Embodiment 279. The method of embodiment 278, wherein the acid is hydrochloric acid.

[0307] Embodiment 280. The method of embodiment 271, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0308] Embodiment 281. The method of embodiment 280, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0309] Embodiment 282. The method of embodiment 271, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0310] Embodiment 283. The method of embodiment 282, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 45°C to about 55°C.

[0311] Embodiment 284. The method of embodiment 271, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0312] Embodiment 285. The method of embodiment 284, wherein the extraction solvent is 1,2-dichloroethane.

[0313] Embodiment 286. Formula IV [ka] (In the formula, R7~R 10 each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; R7~R 10 wherein at least one of is a halogen, I) A) Formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) acids; and C) Solvent forming a first mixture comprising: II) reacting the first mixture; III) removing an amount of solvent from the first mixture; IV) forming a second mixture comprising the first mixture and a halogenating reagent; and V) Reacting the Second Mixture A method comprising:

[0314] Embodiment 287. The method of embodiment 286, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0315] Embodiment 288. The method of embodiment 287, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0316] Embodiment 289. The method of claim 286, wherein the solvent C) is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0317] Embodiment 290. The method of embodiment 289, wherein solvent C) is 1,2-dichloroethane.

[0318] Embodiment 291. The method of embodiment 286, wherein the method step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0319] Embodiment 292. The method of embodiment 291, wherein the method step II) of reacting the mixture is carried out at a reaction temperature in the range of about 45°C to about 55°C.

[0320] Embodiment 293. The method of embodiment 286, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0321] Embodiment 294. The method of embodiment 293, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0322] Embodiment 295. The method of embodiment 294, wherein the chlorinating reagent is chlorine.

[0323] Embodiment 296. The method of embodiment 286, wherein the method step V) of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 140°C.

[0324] Embodiment 297. The method of embodiment 296, wherein the method step V) of reacting the second mixture is carried out at a reaction temperature in the range of from about 20°C to about 30°C.

[0325] Embodiment 298. A compound of Formula II is i) a) Formula I [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least two of R1 to R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; 287. The method of embodiment 286, wherein the compound is prepared according to a method comprising:

[0326] Embodiment 299. The method of embodiment 298, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0327] Embodiment 300. The method of embodiment 299, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0328] Embodiment 301. The method of embodiment 298, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0329] Embodiment 302. The method of embodiment 301, wherein the solvent d) is water.

[0330] Embodiment 303. The method of embodiment 298, wherein the pH adjuster is selected from inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; organic bases, such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, salts thereof, aqueous solutions thereof, and combinations thereof.

[0331] Embodiment 304. The method of embodiment 303, wherein the pH adjuster is sodium carbonate.

[0332] Embodiment 305. The method of embodiment 298, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0333] Embodiment 306. The method of embodiment 305, wherein the acid is hydrochloric acid.

[0334] Embodiment 307. The method of embodiment 298, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0335] Embodiment 308. The method of embodiment 307, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0336] Embodiment 309. The method of embodiment 298, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0337] Embodiment 310. The method of embodiment 309, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 45°C to about 55°C.

[0338] Embodiment 311. The method of embodiment 298, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0339] Embodiment 312. The method of embodiment 311, wherein the extraction solvent is 1,2-dichloroethane.

[0340] In one embodiment, compounds of formula VI are prepared according to the method represented by Scheme 1. The R groups are as defined anywhere in this disclosure. [ka]

[0341] In one embodiment, compounds of formula VI are prepared according to the method represented by Scheme 2. The R group is as defined anywhere in this disclosure. [ka]

[0342] In one embodiment, compounds of formula VI are prepared according to the method represented by Scheme 3. The R group is as defined anywhere in this disclosure. [ka]

[0343] In one embodiment, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 4. [ka]

[0344] In one embodiment, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 5. [ka]

[0345] In one embodiment, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 6. [ka]

[0346] In one aspect, compounds of Formula II or salts thereof are prepared according to the method represented by Scheme 7. The R group is as defined anywhere in this disclosure. [ka]

[0347] This embodiment involves forming a mixture containing a compound of Formula I or a salt thereof, chloral hydrate, hydroxylamine or a hydroxylamine derivative, a solvent, optionally a pH adjuster, and an acid, and reacting the mixture at a pH ranging from about 0 to about 7. The mixture is optionally extracted with an extraction solvent.

[0348] In some embodiments, the mixture components are added simultaneously to form a mixture. In some embodiments, the mixture components are added separately to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0349] In some embodiments, the mixture is reacted at a pH ranging from about 0 to about 7, from about 0 to about 6, from about 0 to about 5, from about 0 to about 4, from about 0 to about 3, from about 0 to about 2, from about 0 to about 1.5, from about 0 to about 1, from about 0 to about 0.5, from about 0.5 to about 1, from about 0.5 to about 1.5, or from about 0.5 to about 2. In some embodiments, the mixture is reacted at a pH of about 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, the mixture is reacted at a pH ranging from about 0.95 to about 1.05.

[0350] In some embodiments, the chloral hydrate is present in an amount of about 1.0 equivalent to about 3.0 equivalents. In some embodiments, the chloral hydrate is present in an amount of about 1.1 equivalents to about 3.0 equivalents.

[0351] In some embodiments, the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof. In some embodiments, the hydroxylamine derivative is hydroxylamine sulfate.

[0352] In some embodiments, the hydroxylamine derivative is present in an amount of about 0.5 equivalents to about 3.0 equivalents, hi some embodiments, the hydroxylamine derivative is present in an amount of about 0.6 equivalents to about 1.5 equivalents.

[0353] In some embodiments, the solvent is selected from the group consisting of methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof, hi some embodiments, the solvent is water.

[0354] In some embodiments, the solvent is present in an amount of about 5.0 w / w to about 30.0 w / w, based on the weight of the compound of Formula I. In some embodiments, the solvent is present in an amount of about 14.0 w / w to about 15.0 w / w, based on the weight of the compound of Formula I. When the solvent is water, these solvent amounts do not include water from the pH adjuster, if present.

[0355] When present, the pH adjuster controls the pH. In some embodiments, the pH adjuster is a base, an inorganic base, an organic base, a solid base, an aqueous base, an aqueous inorganic base, an aqueous inorganic salt base, an aqueous organic base, an aqueous organic salt base, a salt thereof, an aqueous solution thereof, or a combination thereof. In some embodiments, the pH adjuster is a base. In some embodiments, the pH adjuster is selected from inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and combinations thereof. In some embodiments, the pH adjuster is selected from organic bases such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and combinations thereof. In some embodiments, the pH adjuster is sodium carbonate.

[0356] In some embodiments, the sodium carbonate is added as a solid or an aqueous solution. In some embodiments, the sodium carbonate is added as an aqueous solution.

[0357] In some embodiments, the concentration of the aqueous sodium carbonate solution ranges from about 1.0% to about 33.0% by weight, and in some embodiments, the concentration of the aqueous sodium carbonate solution ranges from about 19.0% to about 33.0% by weight.

[0358] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof, hi some embodiments, the acid is hydrochloric acid.

[0359] In some embodiments, the acid is present in an amount from about 0.5 equivalents to about 2.0 equivalents, hi some embodiments, the acid is present in an amount from about 1.1 equivalents to about 2.0 equivalents.

[0360] In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature ranging from about 10° C. to about 100° C. In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature ranging from about 45° C. to about 55° C. In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature ranging from about 50° C. to about 55° C.

[0361] In some embodiments, the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof, hi some embodiments, the extraction solvent is 1,2-dichloroethane.

[0362] In some embodiments, in the compound of Formula I, at least two of R1-R5 are hydrogen. In some embodiments, in the compound of Formula I, at least one of R1 and R5 is hydrogen. In some embodiments, in the compound of Formula I, at least two of R1-R5 are hydrogen and at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula I is o-toluidine.

[0363] In some embodiments, the compound of formula I is present in an amount of about 1% to about 30% by weight. In some embodiments, the compound of formula I is present in an amount of about 3% to about 10% by weight.

[0364] In some embodiments, in the compound of Formula II, at least one of R1 through R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1 through R5 are hydrogen. In some embodiments, in the compound of Formula II, at least one of R1 and R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1 through R5 are hydrogen and at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0365] Controlling the reaction pH avoids the addition of sodium sulfate salts and reduces water usage. For example, controlling the reaction pH to 0.95-1.05 using aqueous Na2CO3 solution avoids the addition of sodium sulfate salts and reduces water usage from approximately 50 w / w to approximately 25 w / w. This significantly reduces waste and wastewater. Furthermore, when the reaction scheme includes a filtration step to separate the product solid from the mother liquor, some of the product remains dissolved in the mother liquor and is difficult to isolate, resulting in a yield loss of approximately 5-7% in the mother liquor. In the present scheme, extraction is used instead of filtration. For example, when 1,2-dichloroethane (DCE) is used as the extraction solvent, the yield loss of the product in the aqueous phase is less than approximately 1.5%, and drying of the solid product can be achieved simultaneously. Combining the extraction step with pH control can increase the isolation yield of this scheme from 70-73% to 83-88%.

[0366] In one aspect, compounds of Formula III or salts thereof are prepared according to the method represented by Scheme 8. The R group is as defined anywhere in this disclosure. [ka]

[0367] This embodiment involves forming a mixture comprising a compound of Formula II or a salt thereof, an acid, and a solvent, and reacting the mixture.

[0368] In some embodiments, the mixture components are added simultaneously to form a mixture. In some embodiments, the mixture components are added separately to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0369] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and combinations thereof, hi some embodiments, the acid comprises sulfuric acid and methanesulfonic acid.

[0370] In some embodiments, the solvent is selected from 1,2-dichloroethane, dichloromethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof, hi some embodiments, the solvent is 1,2-dichloroethane.

[0371] In some embodiments, the solvent comprises an acid, hi some embodiments, the solvent is selected from acetic acid, sulfuric acid, methanesulfonic acid, 1,2-dichloroethane / acetic acid, 1,2-dichloroethane / sulfuric acid, 1,2-dichloroethane / methanesulfonic acid, acetonitrile / acetic acid, acetonitrile / sulfuric acid, acetonitrile / methanesulfonic acid, and combinations thereof.

[0372] In some embodiments, the acid and / or solvent acid is present in an amount of about 3.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II. In some embodiments, the acid and / or solvent acid is present in an amount of about 5.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II. In some embodiments, the methanesulfonic acid is present in an amount of about 3.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II. In some embodiments, the methanesulfonic acid is present in an amount of about 5.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II.

[0373] In some embodiments, the acid and / or solvent acid is present in an amount of about 0.1 equivalents to about 10.0 equivalents relative to the compound of Formula II. In some embodiments, the acid and / or solvent acid is present in an amount of about 1.0 equivalents to about 10.0 equivalents relative to the compound of Formula II. In some embodiments, the sulfuric acid is present in an amount of about 0.1 equivalents to about 10.0 equivalents relative to the compound of Formula II. In some embodiments, the sulfuric acid is present in an amount of about 1.0 equivalents to about 10.0 equivalents relative to the compound of Formula II.

[0374] In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature ranging from about 10° C. to about 90° C. In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature ranging from about 45° C. to about 55° C.

[0375] In some embodiments, in the compound of formula III, at least one of R1 to R4 is hydrogen. In some embodiments, the compound of formula III is 7-methylindoline-2,3-dione.

[0376] In some embodiments, in the compound of Formula II, at least one of R1 through R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1 through R5 are hydrogen. In some embodiments, in the compound of Formula II, at least one of R1 and R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1 through R5 are hydrogen and at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0377] The use of sulfonic acids such as methanesulfonic acid is particularly beneficial in this scheme. Methanesulfonic acid is a recyclable acid with a recovery rate of approximately 80-90%. This dramatically reduces waste generation. It also allows for temperature control and minimizes heat generation. Ultimately, product yields are increased.

[0378] In one embodiment, compounds of Formula IV or salts thereof are prepared according to the method represented by Scheme 9. The R group is as defined anywhere in this disclosure. [ka]

[0379] This embodiment involves forming a mixture comprising a compound of Formula III or a salt thereof, a halogenating reagent, and a solvent containing an acid, and reacting the mixture.

[0380] In some embodiments, the mixture components are added simultaneously to form a mixture. In some embodiments, the mixture components are added separately to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0381] In some embodiments, the solvent comprises a solvent selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof, hi some embodiments, the solvent comprises sulfuric acid and methanesulfonic acid.

[0382] In some embodiments, the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof. In some embodiments, the halogenating reagent is a chlorinating reagent.

[0383] In some embodiments, the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In some embodiments, the chlorinating reagent is chlorine.

[0384] In some embodiments, process step III) of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 140°C. In some embodiments, process step III) of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C. In some embodiments, process step III) of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 25°C.

[0385] In some embodiments, in the compound of formula III, at least one of R1 to R4 is hydrogen. In some embodiments, the compound of formula III is 7-methylindoline-2,3-dione.

[0386] In some embodiments, in the compound of formula IV, R 10 In some embodiments, in the compound of Formula IV, at least one of R to R 10is chlorine. In some embodiments, the compound of Formula IV is 5-chloro-7-methylindoline-2,3-dione.

[0387] In this embodiment, the use of chlorine as a chlorinating agent is particularly advantageous. Chlorine is more reactive than other chlorinating agents, such as sulfuryl chloride, and the reaction with chlorine can be carried out at room temperature. The use of chlorine also improves the yield of the compound of formula IV.

[0388] In one embodiment, a compound of Formula IV or a salt thereof is prepared according to the method represented by Scheme 10. The R group is as defined anywhere in this disclosure. [ka]

[0389] This embodiment includes forming a first mixture comprising a compound of Formula II or a salt thereof, an acid, and a solvent, reacting the first mixture, removing an amount of the solvent from the first mixture, forming a second mixture comprising the first mixture and a halogenating reagent, and reacting the second mixture.

[0390] In some embodiments, the first mixture components are added simultaneously to form the first mixture. In some embodiments, the second mixture components are added simultaneously to form the second mixture. In some embodiments, the first mixture components are added separately to form the first mixture. In some embodiments, the second mixture components are added separately to form the second mixture. In some embodiments, the first mixture components are added separately in any suitable combination to form the first mixture. In some embodiments, the second mixture components are added separately in any suitable combination to form the second mixture. In some embodiments, at least one first mixture component is added dropwise to the first mixture. In some embodiments, at least one second mixture component is added dropwise to the second mixture.

[0391] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, and combinations thereof, hi some embodiments, the acid comprises sulfuric acid and methanesulfonic acid.

[0392] In some embodiments, the solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof, hi some embodiments, the solvent is 1,2-dichloroethane.

[0393] In some embodiments, the solvent comprises an acid. In some embodiments, the solvent is selected from acetic acid, sulfuric acid, methanesulfonic acid, 1,2-dichloroethane / acetic acid, 1,2-dichloroethane / sulfuric acid, 1,2-dichloroethane / methanesulfonic acid, acetonitrile / acetic acid, acetonitrile / sulfuric acid, acetonitrile / methanesulfonic acid, and combinations thereof. In some embodiments, the solvent is 1,2-dichloroethane / methanesulfonic acid.

[0394] In some embodiments, the acid and / or solvent acid is present in an amount of about 3.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II. In some embodiments, the acid and / or solvent acid is present in an amount of about 5.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II. In some embodiments, the methanesulfonic acid is present in an amount of about 3.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II. In some embodiments, the methanesulfonic acid is present in an amount of about 5.0 w / w to about 10.0 w / w based on the weight of the compound of Formula II.

[0395] In some embodiments, the acid and / or solvent acid is present in an amount of about 0.1 equivalents to about 10.0 equivalents relative to the compound of Formula II. In some embodiments, the acid and / or solvent acid is present in an amount of about 1.0 equivalents to about 10.0 equivalents relative to the compound of Formula II. In some embodiments, the sulfuric acid is present in an amount of about 0.1 equivalents to about 10.0 equivalents relative to the compound of Formula II. In some embodiments, the sulfuric acid is present in an amount of about 1.0 equivalents to about 10.0 equivalents relative to the compound of Formula II.

[0396] In some embodiments, process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 10° C. to about 90° C. In some embodiments, process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 45° C. to about 55° C.

[0397] In some embodiments, the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof. In some embodiments, the halogenation reagent is a chlorination reagent. In some embodiments, the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In some embodiments, the chlorination reagent is chlorine.

[0398] In some embodiments, the method step of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C. In some embodiments, the method step of reacting the second mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C. In some embodiments, the method step of reacting the second mixture is carried out at a reaction temperature ranging from about 20°C to about 25°C.

[0399] In some embodiments, the method step of reacting the second mixture is carried out at a reaction temperature ranging from about 50° C. to about 60° C. In some embodiments, the method step of reacting the second mixture is carried out at a reaction temperature ranging from about 50° C. to about 55° C.

[0400] In some embodiments, the method step of removing an amount of solvent from the first mixture comprises removing all of the solvent from the first mixture, hi some embodiments, the method step of removing an amount of solvent from the first mixture comprises removing less than all of the solvent from the first mixture.

[0401] In some embodiments, in the compound of Formula II, at least one of R1 through R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1 through R5 are hydrogen. In some embodiments, in the compound of Formula II, at least one of R1 and R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1 through R5 are hydrogen and at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0402] In some embodiments, in the compound of formula IV, R 10 In some embodiments, in the compound of Formula IV, at least one of R to R 10 is chlorine. In some embodiments, the compound of Formula IV is 5-chloro-7-methylindoline-2,3-dione.

[0403] This embodiment is particularly beneficial if excess solvent is removed before the halogenation step is introduced. Overall yields are as high as 90%, and the individual yields for both reactions in this embodiment are each about 95%.

[0404] This embodiment is a single-pot process and has several advantages. First, it eliminates the need to separate intermediates, such as compounds of Formula III, produced from compounds of Formula II prior to subsequent reaction. Second, it reduces potential losses of intermediates, such as compounds of Formula III, produced from compounds of Formula II. Third, it increases overall yield. Fourth, it reduces the number of reaction steps and work-up steps. Fifth, it reduces overall costs.

[0405] In one embodiment, compounds of Formula V or salts thereof are prepared according to the method represented by Scheme 11. The R group is as defined anywhere in this disclosure. [ka]

[0406] This embodiment involves forming a mixture comprising a compound of Formula IV or a salt thereof, an oxidizing agent, a solvent, and an additive, and reacting the mixture in the presence of a catalyst.

[0407] In some embodiments, the mixture components are added simultaneously to form a mixture. In some embodiments, the mixture components are added separately to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0408] In some embodiments, the catalyst is added to the mixture before any mixture components are added to the mixture. In some embodiments, the catalyst is added to the mixture before all of the mixture components are added to the mixture. In some embodiments, the catalyst is added to the mixture after some, but not all, of the mixture components have been added to the mixture. In some embodiments, the catalyst is added to the mixture after all of the mixture components have been added to the mixture.

[0409] In some embodiments, the catalyst is inherently present in the mixture upon reaction with the oxidant and solvent and / or additive.

[0410] In some embodiments, the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof, hi some embodiments, the oxidizing agent is hydrogen peroxide.

[0411] In some embodiments, the oxidizing agent is present in an amount ranging from about 1.0 equivalent to about 5.0 equivalents, hi some embodiments, the oxidizing agent is present in an amount ranging from about 3.0 equivalents to about 5.0 equivalents.

[0412] In some embodiments, the solvent is selected from acetonitrile, methanol, ethanol, isopropanol, water, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dioxane, formic acid, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof, hi some embodiments, the solvent is acetic acid.

[0413] In some embodiments, the solvent is present in an amount ranging from about 10.0 equivalents to about 30.0 equivalents, hi some embodiments, the solvent is present in an amount ranging from about 13.0 equivalents to about 30.0 equivalents.

[0414] In some embodiments, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof, hi some embodiments, the catalyst is sulfuric acid.

[0415] In some embodiments, the catalyst is present in an amount ranging from about 0.1 equivalents to about 1.0 equivalents. In some embodiments, the catalyst is present in an amount ranging from about 0.3 equivalents to about 1.0 equivalents.

[0416] In some embodiments, the additive comprises an additive selected from toluene, xylene, mesitylene, high-flash aromatic hydrocarbon solvent (S150), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof. In some embodiments, the additive comprises a co-solvent. In some embodiments, the additive comprises a co-solvent selected from methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, and combinations thereof.

[0417] In some embodiments, the additive is selected from alkyl acetate, ethyl acetate, isopropyl acetate, alkyl alcohol, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, polyethylene glycol (PEG) 400, sulfolane, dimethoxyethane, aryl solvent, toluene, xylene, mesitylene, surfactant, high-flash aromatic hydrocarbon solvent (S150), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof. In some embodiments, the additive comprises mesitylene. In some embodiments, the additive comprises ethyl acetate. In some embodiments, the additive is a combination of ethyl acetate and mesitylene.

[0418] In some embodiments, the additive is present in an amount ranging from about 0.1 equivalents to about 1.0 equivalents. In some embodiments, the additive is present in an amount ranging from about 0.35 equivalents to about 1.0 equivalents. In some embodiments, the additive is present in an amount ranging from about 0.45 equivalents to about 1.0 equivalents. In some embodiments, the additive is present in an amount ranging from about 0.80 equivalents to about 1.0 equivalents.

[0419] In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature in the range of about 20°C to about 100°C. In some embodiments, the method step of reacting the mixture is carried out at at least one reaction temperature selected from about 30°C to about 40°C and about 60°C to about 70°C. In some embodiments, the method step of reacting the mixture is carried out at at least two different reaction temperatures. In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature in the range of about 30°C to about 40°C and / or about 60°C to about 70°C. In some embodiments, the method step of reacting the mixture is carried out at a first reaction temperature in the range of about 30°C to about 40°C and a second reaction temperature in the range of about 60°C to about 70°C.

[0420] In some embodiments, in the compound of formula IV, R 10 In some embodiments, in the compound of Formula IV, at least one of R to R 10 is chlorine. In some embodiments, the compound of Formula IV is 5-chloro-7-methylindoline-2,3-dione.

[0421] In some embodiments, in the compound of formula V, R 10 In some embodiments, in the compound of Formula V, at least one of R to R 10 is chlorine. In some embodiments, the compound of Formula V is 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione.

[0422] In this embodiment, the use of mesitylene as an additive and ethyl acetate as an additive co-solvent is particularly beneficial, increasing the conversion of the compound of Formula IV. This improved conversion increases the yield to about 85-90%. Additionally, the amount of unreacted compound of Formula IV is reduced from about 5% by weight to about 1-2% by weight.

[0423] In one embodiment, a compound of Formula VI or a salt thereof is prepared according to the method represented by Scheme 12. The R group is as defined anywhere in this disclosure. [ka]

[0424] This aspect includes forming a mixture including a compound of formula V or a salt thereof, an alkylamine, and a solvent, reacting the mixture, and optionally applying a purification step to the mixture.

[0425] In some embodiments, the mixture components are added simultaneously to form a mixture. In some embodiments, the mixture components are added separately to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0426] In some embodiments, the alkylamine is a branched C1-C 10 Alkyl and unbranched C1-C 10In some embodiments, the alkylamine comprises a functional group selected from branched C1-C5 alkyl and unbranched C1-C5 alkyl. In some embodiments, the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, and combinations thereof. In some embodiments, the alkylamine is methylamine.

[0427] In some embodiments, the solvent is selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof, hi some embodiments, the solvent is ethyl acetate.

[0428] In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature ranging from about 0° C. to about 100° C. In some embodiments, the method step of reacting the mixture is carried out at a reaction temperature ranging from about 60° C. to about 65° C.

[0429] In some embodiments, the method steps of applying a purification step to the mixture include a purification step selected from phase separation, acidification, precipitation, neutralization, filtration, and combinations thereof. In some embodiments, the method steps of applying a purification step to the mixture include a phase separation step, an acidification step comprising adding an acid, a precipitation step, a first filtration step, a neutralization step comprising adding a base, and a second filtration step.

[0430] In some embodiments, the method steps of applying a purification step to the mixture include adding an aqueous solvent (e.g., water), performing a phase separation, adding an acid to precipitate a salt of Formula VI, filtering the precipitated salt of Formula VI, adding a base to neutralize the salt of Formula VI, and filtering the neutralized compound of Formula VI.

[0431] In some embodiments, the method step of applying a purification step to the mixture is performed at a reaction temperature ranging from about 0° C. to about 100° C. In some embodiments, the method step of applying a purification step to the mixture is performed at a reaction temperature ranging from about 20° C. to about 30° C. In some embodiments, the method step of applying a purification step to the mixture is performed at a reaction temperature ranging from about 20° C. to about 25° C.

[0432] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfonic acid, and combinations thereof, hi some embodiments, the acid is hydrochloric acid.

[0433] In some embodiments, the acid is present in an amount ranging from about 0.8 equivalents to about 3.0 equivalents, hi some embodiments, the acid is present in an amount ranging from about 1.2 equivalents to about 3.0 equivalents.

[0434] In some embodiments, the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and combinations thereof, hi some embodiments, the base is sodium hydroxide.

[0435] In some embodiments, in the compound of formula V, R 10 In some embodiments, in the compound of Formula V, at least one of R to R 10 is chlorine. In some embodiments, the compound of Formula V is 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione.

[0436] In some embodiments, in the compound of Formula VI, R 10 In some embodiments, in the compound of Formula VI, at least one of R to R 10is chlorine. In some embodiments, the compound of Formula VI is 2-amino-5-chloro-N,3-dimethylbenzamide.

[0437] This aspect is particularly useful for purifying the compound of formula VI. In some embodiments, this aspect provides a high yield of the compound of formula VI. In some embodiments, this aspect provides a yield of the compound of formula VI of at least 94%.

[0438] In one embodiment, compounds of Formula V or salts thereof are prepared according to the method represented by Scheme 13. The R group is as defined anywhere in this disclosure. [ka]

[0439] This aspect includes forming a first mixture including a compound of Formula III or a salt thereof, a solvent including an acid, and a halogenating reagent, reacting the first mixture, optionally removing a portion of the solvent including the acid, forming a second mixture including the first mixture, an oxidizing agent, and an additive, and reacting the second mixture, wherein the second mixture is reacted in the presence of a catalyst.

[0440] In some embodiments, the first mixture components are added simultaneously to form the first mixture. In some embodiments, the second mixture components are added simultaneously to form the second mixture. In some embodiments, the first mixture components are added separately to form the first mixture. In some embodiments, the second mixture components are added separately to form the second mixture. In some embodiments, the first mixture components are added separately in any suitable combination to form the first mixture. In some embodiments, the second mixture components are added separately in any suitable combination to form the second mixture. In some embodiments, at least one first mixture component is added dropwise to the first mixture. In some embodiments, at least one second mixture component is added dropwise to the second mixture.

[0441] In some embodiments, the catalyst is added to the second mixture before any of the second mixture components are added to the second mixture. In some embodiments, the catalyst is added to the second mixture before all of the second mixture components are added to the second mixture. In some embodiments, the catalyst is added to the second mixture after some, but not all, of the second mixture components are added to the second mixture. In some embodiments, the catalyst is added to the second mixture after all of the second mixture components are added to the second mixture.

[0442] In some embodiments, the catalyst is essentially present in the first mixture and / or the second mixture during the reaction of at least two mixture components, hi some embodiments, the catalyst is essentially present in the second mixture during the reaction of the oxidizing agent and the halogenating reagent.

[0443] In some embodiments, the solvent comprises a solvent selected from acetonitrile, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, and combinations thereof. In some embodiments, the solvent comprises sulfonic acid. In some embodiments, the solvent comprises methanesulfonic acid. In some embodiments, the solvent comprises sulfuric acid. In some embodiments, the solvent comprises methanesulfonic acid and sulfuric acid. In some embodiments, the solvent is a combination of methanesulfonic acid and sulfuric acid.

[0444] In some embodiments, the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof. In some embodiments, the halogenation reagent is a chlorination reagent. In some embodiments, the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In some embodiments, the chlorination reagent is chlorine.

[0445] In some embodiments, the method step of reacting the first mixture is carried out at a reaction temperature ranging from about 0° C. to about 140° C. In some embodiments, the method step of reacting the first mixture is carried out at a reaction temperature ranging from about 20° C. to about 30° C.

[0446] In some embodiments, the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof, hi some embodiments, the oxidizing agent is hydrogen peroxide.

[0447] In some embodiments, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof. In some embodiments, the catalyst comprises sulfuric acid. In some embodiments, the catalyst is sulfuric acid.

[0448] In some embodiments, the additive is selected from alkyl acetate, ethyl acetate, isopropyl acetate, alkyl alcohol, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvent, toluene, xylene, mesitylene, surfactant, high-flash aromatic hydrocarbon solvent (S150), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof. In some embodiments, the additive comprises ethyl acetate and mesitylene. In some embodiments, the additive is a combination of ethyl acetate and mesitylene.

[0449] In some embodiments, the method step of reacting the second mixture is carried out at a reaction temperature in the range of about 20°C to about 100°C. In some embodiments, the method step of reacting the second mixture is carried out at at least one reaction temperature selected from about 30°C to about 40°C and about 60°C to about 70°C. In some embodiments, the method step of reacting the mixture is carried out at at least two different reaction temperatures. In some embodiments, the method step of reacting the second mixture is carried out at a reaction temperature in the range of about 30°C to about 40°C and / or about 60°C to about 70°C. In some embodiments, the method step of reacting the second mixture is carried out at a first reaction temperature in the range of about 30°C to about 40°C and a second reaction temperature in the range of about 60°C to about 70°C.

[0450] In some embodiments, in the compound of formula III, at least one of R1 to R4 is hydrogen. In some embodiments, the compound of formula III is 7-methylindoline-2,3-dione.

[0451] In some embodiments, in the compound of formula V, R 10 In some embodiments, in the compound of Formula V, at least one of R to R 10 At least one of is chlorine. In some embodiments, the compound of formula V is 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. [Please confirm and elaborate as necessary]

[0452] This embodiment is a single-pot process and has several advantages. First, it eliminates the need to separate intermediates, such as compounds of Formula IV, produced from compounds of Formula III prior to subsequent reaction. Second, it reduces potential losses of intermediates, such as compounds of Formula IV, produced from compounds of Formula III. Third, it increases overall yield. Fourth, it reduces the number of reaction steps and work-up steps. Fifth, it reduces overall costs. [Example]

[0453] Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. Accordingly, the following examples are intended to be merely illustrative and are not intended to limit the present disclosure in any way. The starting materials in the following examples may not necessarily have been prepared by the specific preparation procedures described in other examples. Furthermore, any numerical range recited herein is understood to include all values ​​from the lower value to the upper value. For example, if a range is stated as 10 to 50, it is intended that values ​​such as 12 to 30, 20 to 40, or 30 to 50 are expressly recited herein. These are merely examples of what is specifically intended, and all possible combinations of numerical values ​​between the lowest and highest recited values ​​should be considered to be expressly stated in this application.

[0454] Example 1. Reaction of o-toluidine. 16.2 g of o-toluidine, 16.8 g of hydrochloric acid, 27.6 g of chloral hydrate, 24.8 g of hydroxylamine sulfate, and 238.0 g of water were charged into a reactor at room temperature. The reactor was heated and the reaction temperature was controlled at 50-55°C. The reaction pH decreased with reaction time. When the reaction pH became less than 0.95, 19% aqueous Na2CO3 solution was added to control the pH at 0.95-1.05. After the reaction, 150 g of 1,2-dichloroethane was added three times and extracted at 50-55°C. 430.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-dichloroethane solution was obtained, which could be used directly in other examples. The weight percent of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-dichloroethane was 5.2%. The yield of (E)-3-hydroxy-N-(o-tolyl)acrylamide was 83.8%.

[0455] Example 2. Reaction of o-toluidine. 66.1 g of hydroxylamine sulfate and 360.0 g of water were charged into a reactor at room temperature. The reactor was heated and the reaction temperature was controlled at 50-55°C. 43.3 g of o-toluidine, 44.8 g of hydrochloric acid, and 130.0 g of water were mixed and charged into dropping funnel A. 73.6 g of chloral hydrate and 130.0 g of water were mixed and charged into dropping funnel B. The solutions from funnels A and B were added dropwise to the reactor. The reaction pH decreased over time. When the reaction pH fell below 0.95, 19% aqueous Na2CO3 solution was added to control the pH at 0.95-1.05. After the reaction, 1050.0 g of 1,2-dichloroethane was charged three times and extracted at 50-55°C. 1092.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide was obtained in 1,2-dichloroethane solution, which could be used directly in other examples. The weight percent of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-dichloroethane was 5.8%. The yield of (E)-3-hydroxy-N-(o-tolyl)acrylamide was 88.9%.

[0456] Example 3. Cyclization. 404.6 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide (wt % = 5.6%) in 1,2-dichloroethane solution was charged to a reactor at room temperature. A portion of the 1,2-dichloroethane (approximately 2 / 3 of the total 1,2-dichloroethane) was distilled off from the reaction mixture under pressure (100-200 mbar) at 40-45°C. A mixture of methanesulfonic acid (113.5 g) and sulfuric acid (12.7 g) was then added dropwise to the reaction mixture at atmospheric pressure and 40-45°C. Upon completion of this addition, the reaction was heated and the temperature of the mixture was controlled at 50-55°C under 300-330 mbar. The reaction mixture was refluxed under these conditions. Upon completion of the reaction, the remaining 1,2-dichloroethane was distilled off at 50-55°C under 100-50 mbar. The mixture was cooled to 20-25°C and added dropwise to water in a separate reactor, where the temperature was controlled at approximately 40°C until a solid precipitated. The mixture was cooled to room temperature and stirred at room temperature. The slurry was filtered, and the filter cake was washed twice with water. The solid was dried to obtain 20.1 g of crude 7-methylindoline-2,3-dione. The crude 7-methylindoline-2,3-dione could be used directly in other examples. The weight percent of 7-methylindoline-2,3-dione was 95.9%. The yield of this step was 94.1%.

[0457] Example 4. Halogenation. 20.0 g of 7-methylindoline-2,3-dione (weight % = 95.9%), 95.9 g of methanesulfonic acid, and 9.81 g of 98% sulfuric acid were charged into a reactor at room temperature. Chlorine gas was bubbled into the reaction solution at 20-25°C. Upon completion of the reaction, nitrogen gas was bubbled into the reaction solution to purge the chlorine gas. The reaction mixture was added dropwise to water in a separate reactor (temperature controlled at approximately 40°C), and a solid precipitated during the quench. The reaction mixture was cooled to room temperature and stirred at room temperature. The slurry was filtered, and the filter cake was washed twice with water. The solid was dried to obtain 24.5 g of crude 5-chloro-7-methylindoline-2,3-dione. The crude 5-chloro-7-methylindoline-2,3-dione could be used directly in other examples. The weight percent of 5-chloro-7-methylindoline-2,3-dione was 90.0%. The yield of this step was 94.7%.

[0458] Example 5. Cyclization and halogenation. 1690.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide (wt% = 5.22%) in 1,2-dichloroethane solution was charged to a reactor at room temperature. A portion of the 1,2-dichloroethane (approximately 2 / 3 of the total 1,2-dichloroethane) was distilled off from the reaction mixture under pressure (100-200 mbar) at 40-45°C. A mixture of methanesulfonic acid (441.0 g) and sulfuric acid (50.0 g) was then added dropwise to the reaction mixture at atmospheric pressure and 40-45°C. Upon completion of this addition, the reaction was heated and the temperature of the mixture was controlled at 50-55°C under 300-330 mbar. The reaction mixture was refluxed under these conditions. Upon completion of the reaction, the remaining 1,2-dichloroethane was distilled off at 50-55°C under 100-50 mbar. The mixture was cooled to 20-25°C, and chlorine gas was bubbled into the reaction solution at 20-25°C. Upon completion of the reaction, nitrogen gas was bubbled into the reaction solution to purge the chlorine gas. The reaction mixture was then added dropwise to water in a separate reactor (temperature controlled at approximately 40°C), and a solid precipitated during the quench. The mixture was cooled to room temperature and stirred at room temperature. The slurry was filtered, and the filter cake was washed twice with water. The solid was dried to obtain 96.4 g of crude 5-chloro-7-methylindoline-2,3-dione. The crude 5-chloro-7-methylindoline-2,3-dione could be used directly in other examples. The weight percent of 5-chloro-7-methylindoline-2,3-dione was 91.4%. The yield of this step was 91.0%.

[0459] Example 6. Oxidation. 52.0 g of 5-chloro-7-methylindoline-2,3-dione (wt % = 83.0%), 170.0 g of acetic acid, 23.0 g of HO, 6.60 g of sulfuric acid, and 8.0 g of mesitylene were charged into a reactor at room temperature. The reaction mixture was heated and the temperature of the mixture was controlled at 25-35°C. 75.0 g of 30% hydrogen peroxide solution was added dropwise at 25-35°C. After 3 hours, 8.0 g of ethyl acetate was added, and the mixture was stirred for an additional 2 hours. The reaction mixture was then heated again and the temperature of the mixture was controlled at 60-70°C. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium sulfite solution was added to quench the peroxide until the KI test paper no longer turned blue. The slurry was filtered, and the filter cake was washed twice with water. The solid was dried to give 47.5 g of crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. The crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione could be used directly in other examples. The weight percent of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione was 89.5%. The yield for this step was 91.1%.

[0460] Example 7. Halogenation and oxidation 20.9 g of 7-methylindoline-2,3-dione (weight % = 95.9%), 100.0 g of methanesulfonic acid, and 12.4 g of 98% sulfuric acid were charged into a reactor at room temperature. Chlorine gas was bubbled into the reaction solution at 20-25°C. Upon completion of the reaction, nitrogen gas was bubbled into the reaction solution to purge the chlorine gas. The mixture was then heated to 25-35°C. 6.0 g of mesitylene was charged into the mixture. 40.0 g of 30% hydrogen peroxide solution was added dropwise at 25-35°C. After 3 hours, 6.0 g of ethyl acetate was added, and the mixture was stirred for an additional 2 hours. The reaction was then heated and the temperature of the mixture was controlled at 60-70°C. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium sulfite solution was added to quench the peroxide until the KI test paper no longer turned blue. The slurry was filtered, and the filter cake was washed twice with water. The solid was dried to give 14.5 g of crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. The crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione could be used directly in other examples. The weight percent of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione was 69.3%. The yield for this step was 38.2%.

[0461] Example 8. Reaction with methanamine. 21.2 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (wt % = 89.9%), 89.00 g of ethyl acetate, and 9.2 g of acetic acid were charged to a reactor. Gaseous methaneamine was bubbled through the reaction mixture at 55-60 °C. Upon completion of the reaction, nitrogen gas was bubbled through the reaction mixture to purge the methylamine gas. Water was then added, and phase separation was performed twice at 55-60 °C. The organic phase was cooled to room temperature. 13.2 g of 30% aqueous hydrogen chloride solution was added to the organic phase, precipitating 2-amino-5-chloro-N,3-dimethylbenzamide hydrochloride. 2-amino-5-chloro-N,3-dimethylbenzamide salt and water were added to a separate reactor, and sodium hydroxide solution was added to neutralize and liberate 2-amino-5-chloro-N,3-dimethylbenzamide. Filtration was performed again, and the filter cake was washed twice with water. The solid was dried to obtain 17.3 g of 2-amino-5-chloro-N,3-dimethylbenzamide. The weight percent of 2-amino-5-chloro-N,3-dimethylbenzamide was 98.3%. The yield of this step was 94.9%.

[0462] This specification uses examples to illustrate the disclosure, including the best mode, and to enable those skilled in the art to practice the disclosure, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

Claims

1. Formula VI 【Chemistry 1】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; R ７ ~R １０ at least one of is a halogen; and R １１ is a branched C １ ~C １０ Alkyl and unbranched C １ ~C １０ 1. A process for preparing a compound of formula (I) wherein the compound is selected from the group consisting of: I) A) Formula V 【Chemistry 2】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; R ７ ~R １０ wherein at least one of is a halogen; wherein the compound of formula V is i) a) Formula III 【Transformation 3】 (In the formula, R １ ~R ４ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R １ ~R ４ wherein at least one of is hydrogen; b) a solvent containing an acid; and c) Halogenating Reagents forming a first mixture comprising: ii) reacting the first mixture; iii) optionally removing a portion of the solvent containing the acid; iv) the first mixture; d) an oxidizing agent; and e) Additives forming a second mixture comprising: v) reacting the second mixture in the presence of a catalyst a compound of formula V prepared according to a process comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) reacting the mixture; and III) Optionally, applying a purification step to said mixture A method comprising:

2. 2. The method of claim 1, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

3. 3. The method of claim 2, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

4. 4. The method of claim 3 wherein the chlorinating agent is chlorine.

5. wherein the compound of formula III is I) A) Formula II 【Chemistry 4】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; and The compound of formula II is i) a) Formula I 【Transformation 5】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. a compound of formula II prepared according to a process comprising: B) an acid; and C) Solvent forming a mixture comprising: II) reacting the mixture 10. The method of claim 1, wherein the composition is prepared according to a method comprising:

6. Formula V 【Transformation 6】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R ７ ~R １０ wherein at least one of is a halogen, I) A) Formula III 【Transformation 7】 (In the formula, R １ ~R ４ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R １ ~R ４ wherein at least one of is hydrogen; B) a solvent containing an acid; and C) Halogenating Reagents forming a first mixture comprising: II) reacting the first mixture; III) optionally removing a portion of the solvent containing the acid; IV) the first mixture; D) an oxidizing agent; and E) Additives forming a second mixture comprising: V) reacting the second mixture in the presence of a catalyst. A method comprising:

7. wherein the compound of formula III is I) A) Formula II 【Transformation 8】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; and The compound of formula II is i) a) Formula I 【Chemistry 9】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. a compound of formula II prepared according to a process comprising: B) an acid; and C) Solvent forming a mixture comprising: II) reacting the mixture 7. The method of claim 6, wherein the composition is prepared according to a method comprising:

8. Formula VI 【Chemistry 10】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; R ７ ~R １０ at least one of is a halogen; R １１ is a branched C １ ~C １０ Alkyl and unbranched C １ ~C １０ 1. A process for preparing a compound of formula (I) wherein the compound is selected from the group consisting of: I) A) Formula V 【Chemistry 11】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; R ７ ~R １０ wherein at least one of is a halogen; wherein the compound of formula V is i) a) Formula IV 【Chemistry 12】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R ７ ~R １０ wherein at least one of is a halogen; b) an oxidizing agent; c) a solvent; and d) Additives forming a mixture comprising: ii) reacting said mixture in the presence of a catalyst a compound of formula V prepared according to a process comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) reacting the mixture; and III) Optionally, applying a purification step to said mixture A method comprising:

9. The compound of formula IV is I) A) Formula III 【Chemistry 13】 (In the formula, R １ ~R ４ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R １ ~R ４ wherein at least one of is hydrogen; B) a solvent containing an acid; C) Halogenating Reagents forming a mixture comprising: II) reacting the mixture 9. The method of claim 8, wherein the composition is prepared according to a method comprising:

10. wherein the compound of formula III is I) A) Formula II 【Chemistry 14】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; and The compound of formula II is i) a) Formula I 【Chemistry 15】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. a compound of formula II prepared according to a process comprising: B) an acid; and C) Solvent forming a mixture comprising: II) reacting the mixture 10. The method of claim 9, wherein the composition is prepared according to a method comprising:

11. The compound of formula IV is I) A) Formula II 【Chemistry 16】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; B) an acid; and C) Solvent forming a first mixture comprising: II) reacting the first mixture; III) removing an amount of solvent from the first mixture; IV) forming a second mixture comprising the first mixture and a halogenating reagent; and V) reacting the second mixture 9. The method of claim 8, wherein the composition is prepared according to a method comprising:

12. The compound of formula II is i) a) Formula I 【Chemistry 17】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the first mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent.

12. The method of claim 11 , prepared according to a method comprising:

13. Formula V [Chemistry 18] (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R ７ ~R １０ wherein at least one of is a halogen, I) A) Formula IV 【Chemistry 19】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R ７ ~R １０ wherein at least one of is a halogen; B) an oxidizing agent; C) a solvent; and D) Additives forming a mixture comprising: II) reacting the mixture in the presence of a catalyst A method comprising:

14. The compound of formula IV is I) A) Formula III 【Chemistry 20】 (In the formula, R １ ~R ４ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R １ ~R ４ wherein at least one of is hydrogen; B) a solvent containing an acid; C) Halogenating Reagents forming a mixture comprising: II) reacting the mixture 14. The method of claim 13, wherein the composition is prepared according to a method comprising:

15. wherein the compound of formula III is I) A) Formula II 【Chemistry 21】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; and The compound of formula II is i) a) Formula I 【Chemistry 22】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. a compound of formula II prepared according to a process comprising: B) an acid; and C) Solvent forming a mixture comprising: II) reacting the mixture 15. The method of claim 14, wherein the composition is prepared according to a method comprising:

16. The compound of formula IV is I) A) Formula II 【Chemistry 23】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; B) an acid; and C) Solvent forming a first mixture comprising: II) reacting the first mixture; III) removing an amount of solvent from the first mixture; IV) forming a second mixture comprising the first mixture and a halogenating reagent; and V) reacting the second mixture 14. The method of claim 13, wherein the composition is prepared according to a method comprising:

17. The compound of formula II is i) a) Formula I 【Chemistry 24】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent.

17. The method of claim 16, prepared according to a method comprising:

18. Formula IV 【Chemistry 25】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; and R ７ ~R １０ wherein at least one of is a halogen, I) A) Formula III 【Chemistry 26】 (In the formula, R1 to R ４ each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R １ ~R ４ wherein at least one of is hydrogen; B) a solvent containing an acid; C) Halogenating Reagents forming a mixture comprising: II) reacting the mixture A method comprising:

19. wherein the compound of formula III is I) A) Formula II 【Chemistry 27】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; and The compound of formula II is i) a) Formula I 【Chemistry 28】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. a compound of formula II prepared according to a process comprising: B) an acid; and C) Solvent forming a mixture comprising: II) reacting the mixture 20. The method of claim 18, wherein the composition is prepared according to a method comprising:

20. Formula III 【Chemistry 29】 (In the formula, R １ ~R ４ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl, and R １ ~R ４ wherein at least one of is hydrogen, I) A) Formula II 【Transformation 30】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; and The compound of formula II is i) a) Formula I 【Chemistry 31】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. a compound of formula II prepared according to a process comprising: B) an acid; and C) Solvent forming a mixture comprising: II) reacting the mixture 20. The method of claim 18, wherein the composition is prepared according to a method comprising:

21. Formula II 【Chemistry 32】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl, R １ ~R ５ at least two of are hydrogen; １ and R ５ wherein at least one of is hydrogen, I) A) Formula I 【Transformation 33】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; B) Chloral hydrate; C) hydroxylamine or a hydroxylamine derivative; D) solvent; E) optionally a pH adjuster; and F) Acid forming a mixture comprising: II) reacting the mixture at a pH in the range of about 0 to about 7; and III) Optionally, extracting the mixture with an extraction solvent. A method comprising:

22. Formula IV 【Transformation 34】 (In the formula, R ７ ~R １０ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; R ７ ~R １０ wherein at least one of is a halogen, I) A) Formula II 【Chemistry 35】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; B) an acid; and C) Solvent forming a first mixture comprising: II) reacting the first mixture; III) removing an amount of solvent from the first mixture; IV) forming a second mixture comprising the first mixture and a halogenating reagent; and V) reacting the second mixture A method comprising:

23. The compound of formula II is i) a) Formula I 【Transformation 36】 (In the formula, R １ ~R ５ Each of the groups independently represents hydrogen, halogen, C １ ~C ５ Haloalkyl and C １ ~C ５ alkyl; And R １ ~R ５ at least two of are hydrogen; and R １ and R ５ wherein at least one of is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) solvent; e) optionally a pH adjuster; and f) acid forming a mixture comprising: ii) reacting the mixture at a pH in the range of about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent.

23. The method of claim 22, prepared according to a method comprising:

Images