WO2024086259A1

WO2024086259A1 - Method for preparing chlorine-containing benzamide derivatives

Info

Publication number: WO2024086259A1
Application number: PCT/US2023/035475
Authority: WO
Inventors: Yefeng FAN; Xin Liu; Jianhua Mao; Hao Wang; Ning Xu
Original assignee: FMC Agro Singapore Pte Ltd; FMC Corp
Current assignee: FMC Agro Singapore Pte Ltd; FMC Corp
Priority date: 2022-10-19
Filing date: 2023-10-19
Publication date: 2024-04-25
Anticipated expiration: 2025-04-19
Also published as: CN120265608A; CO2025006124A2; EP4605373A1; KR20250093337A; JP2025535812A; TW202421613A; IL320019A; MX2025004528A; AU2023365213A1

Abstract

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

Description

METHOD FOR PREPARING CHLORINE-CONTAINING BENZAMIDE DERIVATIVES

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 63/417,409 filed October 19, 2022.

FIELD OF INVENTION

[0001] This disclosure is directed to novel methods of synthesizing 2-amino-5- chloro-N, 3 -dimethylbenzamide. Compounds prepared by the methods disclosed herein are useful for preparation of certain anthranilamide compounds that are of interest as insecticides, such as, for example, the insecticides chlorantraniliprole and cyantraniliprole.

BACKGROUND

[0002] Conventional processes for the production of 2-amino-5-chloro-N,3- dimethylbenzamide are subject to several industrial concerns, such as hazardous materials, high cost, relatively long method steps, and complicated operations.

[0003] Further, some processes use relatively high amounts of salt, water, and/or acid. Such processes result in relatively high amounts of waste solid and waste water and nonoptimal yields. Processes that overcome these environmental concerns and increase yields are desirable.

[0004] The present disclosure provides novel methods useful for preparing 2- amino-5-chloro-N,3-dimethylbenzamide and derivatives thereof. The benefits of the methods of the present disclosure compared to previous methods are numerous and include reduced cost, eliminated need for mixed solvent separations, reduced waste, relatively short method steps, simplified operation complexity, and reduced process hazards.

BRIEF DESCRIPTION [0005] In one aspect, provided herein is a method of preparing a compound of

Formula VI, wherein

(Formula VI) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen; and wherein Rii is selected from branched C1-C10 alkyl and unbranched C1-C10 alkyl, the method comprising

I) forming a mixture comprising

A) a compound of Formula V, wherein

(Formula V) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen; and wherein the compound of Formula V is prepared according to a method comprising i) forming a first mixture comprising a) a compound of Formula III, wherein

(Formula III) each of Ri - R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1-R4 is hydrogen; b) a solvent comprising an acid; and c) a halogenation reagent; ii) reacting the first mixture; iii) optionally removing a portion of the solvent comprising an acid; iv) forming a second mixture comprising the first mixture; d) an oxidation agent; and e) an additive; and v) reacting the second mixture, wherein the second mixture is reacted in the presence of a catalyst;

B) an alkylamine; and

C) a solvent;

II) reacting the mixture; and

III) optionally applying a purification step to the mixture.

[0006] In one aspect, provided herein is a method of preparing a compound of Formula V, wherein

(Formula V) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R10 is a halogen, the method comprising

I) forming a first mixture comprising

A) a compound of Formula III, wherein

(Formula III) each of Ri - R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1-R4 is hydrogen;

B) a solvent comprising an acid; and

C) a halogenation reagent;

II) reacting the first mixture;

III) optionally removing a portion of the solvent comprising an acid;

IV) forming a second mixture comprising the first mixture;

D) an oxidation agent; and

E) an additive; and

V) reacting the second mixture, wherein the second mixture is reacted in the presence of a catalyst.

[0007] In one aspect, provided herein is a method of preparing a compound of Formula VI, wherein

(Formula VI) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen; and wherein R11 is selected from branched C1-C10 alkyl and unbranched C1-C10 alkyl, the method comprising

I) forming a mixture comprising

A) a compound of Formula V, wherein

(Formula V) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen; and wherein the compound of Formula V is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula IV, wherein

(Formula IV) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R10 is a halogen; b) an oxidation agent; c) a solvent; and d) an additive; and ii) reacting the mixture, wherein the mixture is reacted in the presence of a catalyst;

B) an alkylamine; and

C) a solvent;

II) reacting the mixture; and

III) optionally applying a purification step to the mixture.

[0008] In one aspect, provided herein is a method of preparing a compound of

Formula V, wherein

I) forming a mixture comprising

A) a compound of Formula IV, wherein

(Formula IV) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R10 is a halogen;

B) an oxidation agent;

C) a solvent; and

D) an additive; and II) reacting the mixture, wherein the mixture is reacted in the presence of a catalyst.

[0009] In one aspect, provided herein is a method of preparing a compound of

Formula IV, wherein

(Formula IV) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen, the method comprising

I) forming a mixture comprising

A) a compound of Formula III, wherein

(Formula III) each of Ri - R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1-R4 is hydrogen; B) a solvent comprising an acid;

C) a halogenation reagent; and

II) reacting the mixture.

[0010] In one aspect, provided herein is a method of preparing a compound of Formula III, wherein

(Formula III) each of Ri - R.4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl, and at least one of R1-R4 is hydrogen; the method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; and wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent;

B) an acid; and

C) a solvent; and

II) reacting the mixture.

[0011] In one aspect, provided herein is a method of preparing a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and Ci-Cs alkyl, and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen;

, the method comprising

I) forming a mixture comprising

A) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen;

B) chloral hydrate;

C) a hydroxylamine or a hydroxylamine derivative;

D) a solvent;

E) optionally a pH adjusting agent; and

F) an acid; and

II) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0bout 7; and

III) optionally extracting the mixture with an extraction solvent. [0012] In one aspect, provided herein is a method of preparing a compound of

Formula IV, wherein

I) forming a first mixture comprising

A) a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen;

B) an acid; and C) a solvent;

II) reacting the first mixture;

III) removing an amount of the solvent from the first mixture;

IV) forming a second mixture comprising the first mixture and a halogenation reagent; and

V) reacting the second mixture.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0013] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.

[0014] The transitional phrase “consisting of’ excludes any element, step, or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

[0015] 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 do not materially affect the basic and novel characteristic(s) of the claimed invention. The term “consisting essentially of’ occupies a middle ground between “comprising” and “consisting of’. [0016] Where an invention or a portion thereof is defined with an open- ended term such as “comprising,” it should be readily understood that (unless otherwise stated) the description should be interpreted to also describe such an invention using the terms “consisting essentially of’ or “consisting of.”

[0017] Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0018] Also, the indefinite articles “a” and “an” preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular.

[0019] As used herein, the term “about” means plus or minus 10% of the value.

[0020] The term “halogen”, either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, 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.

[0021] When a group contains a substituent which can be hydrogen, for example R.4, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.

[0022] The term “alkyl” includes, without limitation, a functional group comprising straight-chain or branched alkyl. In some aspects, the alkyl may be methyl, ethyl, n- propyl, i-propyl, or the different butyl, pentyl or hexyl isomers.

[0023] The term “salt thereof’ refers to a suitable salt of the compound that this term proceeds. Suitable salts include, without limitation, alkali metal salts, sodium salts, potassium salts, lithium salts, cesuim salts, alkaline metal salts, calcium salts, magnesium salts, halogen salts, chloride salts, bromide salts, iodide salts, sulfate salts, disulfate salts, nitrate salts, phosphate salts, dihydric phosphate salts, hydrophosphate salts, carbonate salts, bicarbonate salts, mesylate salts, and combinations thereof. It is understood that certain compounds of this invention can exist as pure compounds, compounds per se, salts thereof, and combinations thereof.

[0024] The terms “SI 50” and “S200” refer to high-flash aromatic hydrocarbon solvents with high boiling points of about 180°C and about 250°C, respectively. These solvents offer high solvency and controlled evaporation characteristics that make them excellent for use in many industrial applications such as additives.

[0025] Certain compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.

[0026] The embodiments of this disclosure include:

[0027] Embodiment 1. A method of preparing a compound of Formula VI, wherein

I) forming a mixture comprising

A) a compound of Formula V, wherein

each of Ri - R-i is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) a solvent comprising an acid; and c) a halogenation reagent; ii) reacting the first mixture; iii) optionally removing a portion of the solvent comprising an acid; iv) forming a second mixture comprising the first mixture; d) an oxidation agent; and e) an additive; and v) reacting the second mixture, wherein the second mixture is reacted in the presence of a catalyst;

B) an alkylamine; and

C) a solvent;

II) reacting the mixture; and

III) optionally applying a purification step to the mixture.

[0028] Embodiment 2. The method of embodiment 1, wherein the alkylamine comprises a functional group selected from branched Ci-Cio alkyl and unbranched Ci-Cio alkyl. In some embodiments, the alkylamine is selected from branched Ci-Cs alkyl and unbranched Ci- Cs alkyl. [0029] Embodiment 3. The method of embodiment 2, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, and combinations thereof.

[0030] Embodiment 4. The method of embodiment 3, wherein the alkylamine is methylamine.

[0031] Embodiment 5. The method of embodiment 1, wherein the solvent C) is selected from acetonitrile, di chloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0032] Embodiment 6. The method of embodiment 5, wherein the solvent C) is ethyl acetate.

[0033] Embodiment 7. The method of embodiment 1, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 100 °C.

[0034] Embodiment 8. The method of embodiment 7, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 60 °C to about 65 °C.

[0035] Embodiment 9. The method of embodiment 1, wherein the solvent b) comprises a solvent selected from acetonitrile, di chloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acids, and combinations thereof.

[0036] Embodiment 10. The method of embodiment 9, wherein the solvent b) comprises sulfuric acid and methanesulfonic acid.

[0037] Embodiment 11. The method of embodiment 1, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof. [0038] Embodiment 12. The method of embodiment 11, wherein the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, tri chloroisocyanuric acid, and combinations thereof.

[0039] Embodiment 13. The method of embodiment 12, wherein the chlorination reagent is chlorine.

[0040] Embodiment 14. The method of embodiment 1, wherein the method step ii) of reacting the first mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C.

[0041] Embodiment 15. The method of embodiment 14, wherein the method step ii) of reacting the first mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0042] Embodiment 16. The method of embodiment 1, wherein the oxidation 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.

[0043] Embodiment 17. The method of embodiment 16, wherein the oxidation agent is hydrogen peroxide.

[0044] Embodiment 18. The method of embodiment 1, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acids, methanesulfonic acid, and combinations thereof.

[0045] Embodiment 19. The method of embodiment 18, wherein the catalyst is sulfuric acid.

[0046] Embodiment 20. The method of embodiment 1, wherein the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-di chloroethane, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, di meth oxy ethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high-flash aromatic hydrocarbon solvent (SI 50), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulphonate (SDS), and combinations thereof.

[0047] Embodiment 21. The method of embodiment 20, wherein the additive is the combination of ethyl acetate and mesitylene.

[0048] Embodiment 22. The method of embodiment 1, wherein the method step v) of reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 100 °C.

[0049] Embodiment 23. The method of embodiment 20, wherein the method step v) of reacting the second mixture occurs at at least one reaction temperature selected from about 30 °C to about 40 °C and about 60 °C to about 70 °C.

[0050] Embodiment 24. The method of embodiment 1, wherein the compound of

Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and Ci-Cs alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; and wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent; B) an acid; and

C) a solvent; and

II) reacting the mixture.

[0051] 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 acids, methanesulfonic acid, and combinations thereof.

[0052] Embodiment 26. The method of embodiment of 25, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0053] Embodiment 27. The method of embodiment 24, wherein the solvent C) is selected from di chloromethane, 1,2-di chloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0054] Embodiment 28. The method of embodiment 27, wherein the solvent C) is 1,2-di chloroethane.

[0055] Embodiment 29. The method of embodiment 24, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0056] Embodiment 30. The method of embodiment 29, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0057] Embodiment 31. The method of embodiment 24, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0058] Embodiment 32. The method of embodiment 31, wherein the hydroxylamine derivative is hydroxylamine sulfate. [0059] 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.

[0060] Embodiment 34. The method of embodiment 33, wherein the solvent d) is water.

[0061] Embodiment 35. The method of embodiment 24, wherein the pH adjusting agent 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.

[0062] Embodiment 36. The method of embodiment 35, wherein the pH adjusting agent is sodium carbonate.

[0063] 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 acids, and combinations thereof.

[0064] Embodiment 38. The method of embodiment 37, wherein the acid f) is hydrochloric acid.

[0065] 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%.

[0066] Embodiment 40. The method of embodiment 39, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0067] Embodiment 41. The method of embodiment 24, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C. [0068] Embodiment 42. The method of embodiment 41, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55

[0069] Embodiment 43. The method of embodiment 24, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0070] Embodiment 44. The method of embodiment 43, wherein the extraction solvent is 1,2-di chloroethane.

[0071] Embodiment 45. A method of preparing a compound of Formula V, wherein

R₇

(Formula V) each of R.7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R10 is a halogen, the method comprising

I) forming a first mixture comprising

A) a compound of Formula III, wherein

B) a solvent comprising an acid; and

C) a halogenation reagent;

II) reacting the first mixture;

III) optionally removing a portion of the solvent comprising an acid;

IV) forming a second mixture comprising the first mixture;

D) an oxidation agent; and

E) an additive; and

[0072] Embodiment 46. The method of embodiment 45, wherein the solvent comprises a solvent selected from acetonitrile, 1,2-di chloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, and combinations thereof. [0073] Embodiment 47. The method of embodiment 46, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0074] Embodiment 48. The method of embodiment 45, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

[0075] Embodiment 49. The method of embodiment 48, wherein 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.

[0076] Embodiment 50. The method of embodiment 49, wherein the chlorination reagent is chlorine.

[0077] Embodiment 5E The method of embodiment 45, wherein the method step II) of reacting the first mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C.

[0078] Embodiment 52. The method of embodiment 51, wherein the method step II) of reacting the first mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0079] Embodiment 53. The method of embodiment 45, wherein the oxidation 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.

[0080] Embodiment 54. The method of embodiment 50, wherein the oxidation agent is hydrogen peroxide.

[0081] Embodiment 55. The method of embodiment 42, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acids, methanesulfonic acid, and combinations thereof. [0082] Embodiment 56. The method of embodiment 55, wherein the catalyst is sulfuric acid.

[0083] Embodiment 57. The method of embodiment 45, wherein the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high-flash aromatic hydrocarbon solvent (SI 50), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulphonate (SDS), and combinations thereof.

[0084] Embodiment 58. The method of embodiment 57, the additive is the combination of ethyl acetate and mesitylene.

[0085] Embodiment 59. The method of embodiment 45, wherein the method step V) of reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 100 °C.

[0086] Embodiment 60. The method of embodiment 59, wherein the method step V) of reacting the second mixture occurs at at least one reaction temperature selected from about 30 °C to about 40 °C and about 60 °C to about 70 °C.

[0087] Embodiment 61. The method of embodiment 45, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture.

[0088] 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 acids, methanesulfonic acid, and combinations thereof.

[0089] Embodiment 63. The method of embodiment of 62, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0090] Embodiment 64. The method of embodiment 61, wherein the solvent C) is selected from 1,2-di chloroethane, di chloromethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0091] Embodiment 65. The method of embodiment 64, wherein the solvent C) is 1 ,2-di chloroethane. [0092] Embodiment 66. The method of embodiment 61, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0093] Embodiment 67. The method of embodiment 66, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0094] Embodiment 68. The method of embodiment 61, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0095] Embodiment 69. The method of embodiment 68, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0096] 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.

[0097] Embodiment 71 . The method of embodiment 70, wherein the solvent d) is water.

[0098] Embodiment 72. The method of embodiment 61, wherein the pH adjusting agent 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.

[0099] Embodiment 73. The method of embodiment 72, wherein the pH adjusting agent is sodium carbonate. [0100] 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 acids, and combinations thereof.

[0101] Embodiment 75. The method of embodiment 74, wherein the acid f) is hydrochloric acid.

[0102] 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%.

[0103] Embodiment 77. The method of embodiment 76, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0104] Embodiment 78. The method of embodiment 61, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0105] Embodiment 79. The method of embodiment 78, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0106] Embodiment 80. The method of embodiment 61, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0107] Embodiment 81. The method of embodiment 74, wherein the extraction solvent is 1,2-di chloroethane.

[0108] Embodiment 82. A method of preparing a compound of Formula VI, wherein

I) forming a mixture comprising

A) a compound of Formula V, wherein

B) an alkylamine; and

C) a solvent;

II) reacting the mixture; and

III) optionally applying a purification step to the mixture.

[0109] Embodiment 83. The method of embodiment 82, wherein the alkylamine comprises a functional group selected from branched C1-C10 alkyl and unbranched C1-C10 alkyl. In some embodiments, the alkylamine is selected from branched C1-C5 alkyl and unbranched Ci- C5 alkyl.

[0110] Embodiment 84. The method of embodiment 83, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t- butylamine, and combinations thereof.

[0111] Embodiment 85. The method of embodiment 84, wherein the alkylamine is methylamine.

[0112] Embodiment 86. The method of embodiment 82, wherein the solvent C) is selected from acetonitrile, di chloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0113] Embodiment 87. The method of embodiment 86, wherein the solvent C) is ethyl acetate.

[0114] Embodiment 88. The method of embodiment 82, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 100 °C.

[0115] Embodiment 89. The method of embodiment 88, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 60 °C to about 65 °C.

[0116] Embodiment 90. The method of embodiment 82, wherein the oxidation 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.

[0117] Embodiment 91. The method of embodiment 90, wherein the oxidation agent is hydrogen peroxide. [01 18] 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.

[0119] Embodiment 93. The method of embodiment 92, wherein the solvent c) is acetic acid.

[0120] Embodiment 94. The method of embodiment 82, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acids, methanesulfonic acid, and combinations thereof.

[0121] Embodiment 95. The method of embodiment 94, wherein the catalyst is sulfuric acid.

[0122] Embodiment 96. The method of embodiment 82, wherein the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high-flash aromatic hydrocarbon solvent (SI 50), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulphonate (SDS), and combinations thereof.

[0123] Embodiment 97. The method of embodiment 96, the additive is the combination of ethyl acetate and mesitylene.

[0124] Embodiment 98. The method of embodiment 82, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 100 °C.

[0125] Embodiment 99. The method of embodiment 98, wherein the method step ii) of reacting the mixture occurs at at least one reaction temperature selected from about 30 °C to about 40 °C and about 60 °C to about 70 °C. [0126] Embodiment 100. The method of embodiment 82, wherein the compound of Formula IV is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula III, wherein

B) a solvent comprising an acid;

C) a halogenation reagent; and

II) reacting the mixture.

[0127] Embodiment 101. The method of embodiment 100, wherein the solvent comprises a solvent selected from acetonitrile, di chloromethane, 1,2-di chloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acids, and combinations thereof.

[0128] Embodiment 102. The method of embodiment 101, wherein the solvent comprises sulfuric acid and methanesulfonic acid. [0129] Embodiment 103. The method of embodiment 100, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

[0130] Embodiment 104. The method of embodiment 103, wherein 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.

[0131] Embodiment 105. The method of embodiment 104, wherein the chlorination reagent is chlorine.

[0132] Embodiment 106. The method of embodiment 100, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C.

[0133] Embodiment 107. The method of embodiment 106, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0134] Embodiment 108. The method of embodiment 100, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; and wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture.

[0135] 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 acids, methanesulfonic acid, and combinations thereof.

[0136] Embodiment 110. The method of embodiment of 109, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0137] Embodiment 111. The method of embodiment 108, wherein the solvent C) is selected from dichloromethane, 1,2-di chloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0138] Embodiment 112. The method of embodiment 111, wherein the solvent C) is 1,2-dichloroethane.

[0139] Embodiment 113. The method of embodiment 108, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0140] Embodiment 114. The method of embodiment 113, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C. [0141] Embodiment 1 15. The method of embodiment 108, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0142] Embodiment 116. The method of embodiment 115, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0143] 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.

[0144] Embodiment 118. The method of embodiment 117, wherein the solvent d) is water.

[0145] Embodiment 119. The method of embodiment 108, wherein the pH adjusting agent 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.

[0146] Embodiment 120. The method of embodiment 119, wherein the pH adjusting agent is sodium carbonate.

[0147] 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 acids, and combinations thereof.

[0148] Embodiment 122. The method of embodiment 121, wherein the acid f) is hydrochloric acid.

[0149] 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%. [0150] Embodiment 124. The method of embodiment 123, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0151] Embodiment 125. The method of embodiment 108, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0152] Embodiment 126. The method of embodiment 125, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0153] Embodiment 127. The method of embodiment 108, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0154] Embodiment 128. The method of embodiment 127, wherein the extraction solvent is 1,2-di chloroethane.

[0155] Embodiment 129. The method of embodiment 82, wherein the compound of Formula IV is prepared according to a method comprising

I) forming a first mixture comprising

A) a compound of Formula II, wherein

each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen;

B) an acid; and

C) a solvent;

II) reacting the first mixture;

III) removing an amount of the solvent from the first mixture;

V) reacting the second mixture.

[0156] 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 acids, methanesulfonic acid, and combinations thereof.

[0157] Embodiment 131. The method of embodiment 130, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0158] Embodiment 132. The method of embodiment 129, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0159] Embodiment 133. The method of embodiment 132, wherein the solvent C) is 1,2-dichloroethane.

[0160] Embodiment 134. The method of embodiment 129, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof. [0161] Embodiment 135. The method of embodiment 134, wherein 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.

[0162] Embodiment 136. The method of embodiment 135, wherein the chlorination reagent is chlorine.

[0163] Embodiment 137. The method of embodiment 129, wherein the method step V) of reacting the second mixture occurs at a reaction temperature in the range of about 0°C to about 140 °C.

[0164] Embodiment 138. The method of embodiment 137, wherein the method step V) of reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0165] Embodiment 139. The method of embodiment 129, wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and Ci-Cs alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent.

[0166] Embodiment 140. The method of embodiment 139, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0167] Embodiment 141. The method of embodiment 140, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0168] 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.

[0169] Embodiment 143. The method of embodiment 142, wherein the solvent d) is water.

[0170] Embodiment 144. The method of embodiment 139, wherein the pH adjusting agent 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.

[0171] Embodiment 145. The method of embodiment 144, wherein the pH adjusting agent is sodium carbonate

[0172] 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 acids, and combinations thereof.

[0173] Embodiment 147. The method of embodiment 146, wherein the acid f) is hydrochloric acid.

[0174] 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%.

[0175] Embodiment 149. The method of embodiment 148, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0176] Embodiment 150. The method of embodiment 139, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0177] Embodiment 151. The method of embodiment 150, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0178] Embodiment 152. The method of embodiment 139, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0179] Embodiment 153. The method of embodiment 152, wherein the extraction solvent is 1,2-di chloroethane. [0180] Embodiment 154. A method of preparing a compound of Formula V, wherein

I) forming a mixture comprising

A) a compound of Formula IV, wherein

B) an oxidation agent; C) a solvent; and

D) an additive; and

II) reacting the mixture, wherein the mixture is reacted in the presence of a catalyst.

[0181] Embodiment 155. The method of embodiment 154, wherein the oxidation 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.

[0182] Embodiment 156. The method of embodiment 155, wherein the oxidation agent is hydrogen peroxide.

[0183] 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.

[0184] Embodiment 158. The method of embodiment 157, wherein the solvent is acetic acid.

[0185] Embodiment 159. The method of embodiment 154, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acids, methanesulfonic acid, and combinations thereof.

[0186] Embodiment 160. The method of embodiment 159, wherein the catalyst is sulfuric acid.

[0187] Embodiment 161. The method of embodiment 154, wherein the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, di chloromethane, 1,2-di chloroethane, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxy ethane, aryl solvents, toluene, xylene, mesitylene, surfactants, SI 50, S200, Tween 20, sodium dodecylbenzenesulphonate (SDS), and combinations thereof. [0188] Embodiment 162. The method of embodiment 161 , the additive is the combination of ethyl acetate and mesitylene.

[0189] Embodiment 163. The method of embodiment 154, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 100 °C.

[0190] Embodiment 164. The method of embodiment 163, wherein the method step II) of reacting the mixture occurs at at least one reaction temperature selected from about 30 °C to about 40 °C and about 60 °C to about 70 °C.

[0191] Embodiment 165. The method of embodiment 154, wherein the compound of Formula IV is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula III, wherein

(Formula III) each of Ri -R-i is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1-R4 is hydrogen;

B) a solvent comprising an acid;

C) a halogenation reagent; and

II) reacting the mixture. [0192] Embodiment 166. The method of embodiment 165, wherein the solvent comprises a solvent selected from acetonitrile, di chloromethane, 1,2-di chloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acids, and combinations thereof.

[0193] Embodiment 167. The method of embodiment 166, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0194] Embodiment 168. The method of embodiment 165, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

[0195] Embodiment 169. The method of embodiment 168, wherein 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.

[0196] Embodiment 170. The method of embodiment 169, wherein the chlorination reagent is chlorine.

[0197] Embodiment 171. The method of embodiment 165, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C.

[0198] Embodiment 172. The method of embodiment 171, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0199] Embodiment 173. The method of embodiment 165, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture.

[0200] 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 acids, methanesulfonic acid, and combinations thereof.

[0201] Embodiment 175. The method of embodiment of 174, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0202] Embodiment 176. The method of embodiment 173, wherein the solvent C) is selected from dichloromethane, 1,2-di chloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0203] Embodiment 177. The method of embodiment 176, wherein the solvent C) is 1,2-di chloroethane. [0204] Embodiment 178. The method of embodiment 173, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0205] Embodiment 179. The method of embodiment 178, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0206] Embodiment 180. The method of embodiment 173, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0207] Embodiment 181. The method of embodiment 180, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0208] 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.

[0209] Embodiment 183. The method of embodiment 182, wherein the solvent d) is water.

[0210] Embodiment 184. The method of embodiment 173, wherein the pH adjusting agent 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.

[0211] Embodiment 185. The method of embodiment 184, wherein the pH adjusting agent is sodium carbonate. [0212] 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 acids, and combinations thereof.

[0213] Embodiment 187. The method of embodiment 186, wherein the acid f) is hydrochloric acid.

[0214] 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%.

[0215] Embodiment 189. The method of embodiment 188, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0216] Embodiment 190. The method of embodiment 173, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0217] Embodiment 191. The method of embodiment 190, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0218] Embodiment 192. The method of embodiment 173, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0219] Embodiment 193. The method of embodiment 192, wherein the extraction solvent is 1,2-dichloroethane.

[0220] Embodiment 194. The method of embodiment 154, wherein the compound of Formula IV is prepared according to a method comprising

I) forming a first mixture comprising

A) a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen;

B) an acid; and

C) a solvent;

II) reacting the first mixture;

III) removing an amount of the solvent from the first mixture;

V) reacting the second mixture.

[0221] 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 acids, and combinations thereof.

[0222] Embodiment 196. The method of embodiment 195, wherein the acid B) comprises sulfuric acid and methanesulfonic acid. [0223] Embodiment 197. The method of embodiment 194, wherein the solvent C) is selected from dichloromethane, 1,2-di chloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0224] Embodiment 198. The method of embodiment 197, wherein the solvent C) is 1,2-dichloroethane.

[0225] Embodiment 199. The method of embodiment 194, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0226] Embodiment 200. The method of embodiment 199, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0227] Embodiment 201. The method of embodiment 194, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

[0228] Embodiment 202. The method of embodiment 201 , wherein 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.

[0229] Embodiment 203. The method of embodiment 202, wherein the chlorination reagent is chlorine.

[0230] Embodiment 204. The method of embodiment 194, wherein the method step V) of reacting the second mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0231] Embodiment 205. The method of embodiment 204, wherein the method step V) of reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C. [0232] Embodiment 206. The method of embodiment 194, wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and Ci-Cs alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. [0233] Embodiment 207. The method of embodiment 206, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0234] Embodiment 208. The method of embodiment 207, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0235] 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.

[0236] Embodiment 210. The method of embodiment 209, wherein the solvent d) is water.

[0237] Embodiment 211. The method of embodiment 206, wherein the pH adjusting agent 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.

[0238] Embodiment 212. The method of embodiment 211, wherein the pH adjusting agent is sodium carbonate.

[0239] 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 acids, and combinations thereof.

[0240] Embodiment 214. The method of embodiment 213, wherein the acid f) is hydrochloric acid.

[0241] 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%. [0242] Embodiment 216. The method of embodiment 215, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0243] Embodiment 217. The method of embodiment 206, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0244] Embodiment 218. The method of embodiment 217, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0245] Embodiment 219. The method of embodiment 206, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0246] Embodiment 220. The method of embodiment 219, wherein the extraction solvent is 1,2-di chloroethane.

[0247] Embodiment 221. A method of preparing a compound of Formula IV, wherein

(Formula IV) each of R? - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen, the method comprising I) forming a mixture comprising

A) a compound of Formula III, wherein

B) a solvent comprising an acid;

C) a halogenation reagent; and

II) reacting the mixture.

[0248] Embodiment 222. The method of embodiment 221, wherein the solvent comprises a solvent selected from acetonitrile, di chloromethane, 1,2-di chloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acids, and combinations thereof.

[0249] Embodiment 223. The method of embodiment 222, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0250] Embodiment 224. The method of embodiment 221, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof. [0251] Embodiment 225. The method of embodiment 224, wherein 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.

[0252] Embodiment 226. The method of embodiment 225, wherein the chlorination reagent is chlorine.

[0253] Embodiment 227. The method of embodiment 221, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C.

[0254] Embodiment 228. The method of embodiment 227, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0255] Embodiment 229. The method of embodiment 221, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture.

[0256] 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 acids, methanesulfonic acid, and combinations thereof.

[0257] Embodiment 231. The method of embodiment of 229, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0258] Embodiment 232. The method of embodiment 229, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0259] Embodiment 233. The method of embodiment 232, wherein the solvent C) is 1,2-dichloroethane.

[0260] Embodiment 234. The method of embodiment 229, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0261] Embodiment 235. The method of embodiment 234, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0262] Embodiment 236. The method of embodiment 229, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof. [0263] Embodiment 237. The method of embodiment 236, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0264] 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.

[0265] Embodiment 239. The method of embodiment 238, wherein the solvent d) is water.

[0266] Embodiment 240. The method of embodiment 229, wherein the pH adjusting agent 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.

[0267] Embodiment 241. The method of embodiment 240, wherein the pH adjusting agent is sodium carbonate.

[0268] 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 acids, and combinations thereof.

[0269] Embodiment 243. The method of embodiment 242, wherein the acid f) is hydrochloric acid.

[0270] 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%.

[0271] Embodiment 245. The method of embodiment 244, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%. [0272] Embodiment 246. The method of embodiment 229, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0273] Embodiment 247. The method of embodiment 246, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0274] Embodiment 248. The method of embodiment 229, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0275] Embodiment 249. The method of embodiment 248, wherein the extraction solvent is 1,2-dichloroethane.

[0276] Embodiment 250. A method of preparing a compound of Formula III, wherein

(Formula III) each of Ri - R4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl, and at least one of R1-R4 is hydrogen, the method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture.

[0277] 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 acids, methanesulfonic acid, and combinations thereof.

[0278] Embodiment 252. The method of embodiment of 251, wherein the acid is sulfuric acid and methaneulfonic acid.

[0279] Embodiment 253. The method of embodiment 250, wherein the solvent C) is selected from dichloromethane, 1,2-di chloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0280] Embodiment 254. The method of embodiment 253, wherein the solvent C) is 1,2-di chloroethane. [0281] Embodiment 255. The method of embodiment 250, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0282] Embodiment 256. The method of embodiment 255, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0283] Embodiment 257. The method of embodiment 250, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0284] Embodiment 258. The method of embodiment 257, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0285] 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.

[0286] Embodiment 260. The method of embodiment 259, wherein the solvent d) is water.

[0287] Embodiment 261. The method of embodiment 250, wherein the pH adjusting agent 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.

[0288] Embodiment 262. The method of embodiment 261, wherein the pH adjusting agent is sodium carbonate. [0289] 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 acids, and combinations thereof.

[0290] Embodiment 264. The method of embodiment 263, wherein the acid f) is hydrochloric acid.

[0291] 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%.

[0292] Embodiment 266. The method of embodiment 265, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0293] Embodiment 267. The method of embodiment 250, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0294] Embodiment 268. The method of embodiment 267, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0295] Embodiment 269. The method of embodiment 250, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0296] Embodiment 270. The method of embodiment 269, wherein the extraction solvent is 1,2-dichloroethane.

[0297] Embodiment 271. A method of preparing a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl, and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen, the method comprising

I) forming a mixture comprising

A) a compound of Formula I, wherein

B) chloral hydrate; C) a hydroxylamine or a hydroxylamine derivative;

D) a solvent;

E) optionally a pH adjusting agent; and

F) an acid; and

II) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0 to about 7; and

III) optionally extracting the mixture with an extraction solvent.

[0298] Embodiment 272. The method of embodiment 271, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0299] Embodiment 273. The method of embodiment 272, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0300] 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.

[0301] Embodiment 275. The method of embodiment 274, wherein the solvent D) is water.

[0302] Embodiment 276. The method of embodiment 271, wherein the pH adjusting agent 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.

[0303] Embodiment 277. The method of embodiment 276, wherein the pH adjusting agent is sodium carbonate. [0304] 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 acids, and combinations thereof.

[0305] Embodiment 279. The method of embodiment 278, wherein the acid is hydrochloric acid.

[0306] 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%.

[0307] Embodiment 281. The method of embodiment 280, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0308] Embodiment 282. The method of embodiment 271, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0309] Embodiment 283. The method of embodiment 282, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0310] Embodiment 284. The method of embodiment 271, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0311] Embodiment 285. The method of embodiment 284, wherein the extraction solvent is 1,2-dichloroethane.

[0312] Embodiment 286. A method of preparing a compound of Formula IV, wherein

I) forming a first mixture comprising

A) a compound of Formula II, wherein

(Formula II) each of Ri - R5 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen;

B) an acid; and

C) a solvent; II) reacting the first mixture;

III) removing an amount of the solvent from the first mixture;

V) reacting the second mixture.

[0313] 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 acids, and combinations thereof.

[0314] Embodiment 288. The method of embodiment 287, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0315] Embodiment 289. The method of embodiment 286, wherein the solvent C) is selected from dichloromethane, 1,2-di chloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0316] Embodiment 290. The method of embodiment 289, wherein the solvent C) is 1,2-di chloroethane.

[0317] Embodiment 291. The method of embodiment 286, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C.

[0318] Embodiment 292. The method of embodiment 291, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0319] Embodiment 293. The method of embodiment 286, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof. [0320] Embodiment 294. The method of embodiment 293, wherein 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.

[0321] Embodiment 295. The method of embodiment 294, wherein the chlorination reagent is chlorine.

[0322] Embodiment 296. The method of embodiment 286, wherein the method step V) of reacting the second mixture occurs at a reaction temperature in the range of about 10 °C to about 140 °C.

[0323] Embodiment 297. The method of embodiment 296, wherein the method step V) of reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0324] Embodiment 298. The method of embodiment 286, wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

[0325] Embodiment 299. The method of embodiment 298, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof.

[0326] Embodiment 300. The method of embodiment 299, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0327] Embodiment 30E 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.

[0328] Embodiment 302. The method of embodiment 301, wherein the solvent d) is water.

[0329] Embodiment 303. The method of embodiment 298, wherein the pH adjusting agent 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.

[0330] Embodiment 304. The method of embodiment 303, wherein the pH adjusting agent is sodium carbonate.

[0331] 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 acids, and combinations thereof.

[0332] Embodiment 306. The method of embodiment 305, wherein the acid is hydrochloric acid.f

[0333] 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%.

[0334] Embodiment 308. The method of embodiment 307, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0335] Embodiment 309. The method of embodiment 298, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C.

[0336] Embodiment 310. The method of embodiment 309, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0337] Embodiment 311. The method of embodiment 298, wherein the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0338] Embodiment 312. The method of embodiment 311, wherein the extraction solvent is 1,2-di chloroethane. [0339] In one aspect, a compound of Formula VI is prepared according to a method represented by Scheme 1. The R groups are as defined anywhere in this disclosure.

Scheme 1.

[0340] In one aspect, a compound of Formula VI is prepared according to a method represented by Scheme 2. The R groups are as defined anywhere in this disclosure.

Scheme 2.

[0341] In one aspect, a compound of Formula VI is prepared according to a method represented by Scheme 3. The R groups are as defined anywhere in this disclosure.

Scheme 3.

[0342] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to a method represented by Scheme 4.

Scheme 4.

[0343] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to a method represented by Scheme 5.

Scheme 5.

[0344] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to a method represented by Scheme 6.

Scheme 6.

[0345] In one aspect, a compound of Formula II or a salt thereof is prepared according to a method represented by Scheme 7. The R groups are as defined anywhere in this disclosure.

Scheme 7.

[0346] This aspect includes forming a mixture comprising a compound of Formula I or a salt thereof, chloral hydrate, a hydroxylamine or a hydroxylamine derivative, a solvent, optionally a pH adjusting agent, and an acid, and reacting the mixture. The mixture is reacted at a pH in a range of from about 0 to about 7. The mixture is optionally extracted with an extraction solvent. [0347] In some embodiments, the mixture components are concurrently added to form the mixture. In some embodiments, the mixture components are individually added to form the mixture. In some embodiments, the mixture components are individually added in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dr op wise to the mixture.

[0348] In some embodiments, the mixture is reacted at a pH in a range of from about 0 to about 7, about 0 to about 6, about 0 to about 5, about 0 to about 4, about 0 to about 3, about 0 to about 2, about 0 to about 1.5, about 0 to about 1, about 0 to about 0.5, about 0.5 to about 1, about 0.5 to about 1.5, or 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 in a range of from 0.95 to about 1.05.

[0349] In some embodiments, chloral hydrate is present in an amount of from about 1.0 eq to about 3.0 eq. In some embodiments, chloral hydrate is present in an amount of from about 1.1 eq to about 3.0 eq.

[0350] In some embodiments, the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solution, and combinations thereof. In some embodiments, the hydroxylamine derivative is hydroxylamine sulfate.

[0351] In some embodiments, the hydroxylamine derivative is present in an amount of from about 0.5 eq to about 3.0 eq. In some embodiments, the hydroxylamine derivative is present in an amount of from about 0.6 eq to about 1.5 eq.

[0352] In some embodiments, the solvent is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof. In some embodiments, the solvent is water.

[0353] In some embodiments, the solvent is present in an amount of from about 5.0 w/w to about 30.0 w/w relative to the weight of the compound of Formula I. In some embodiments, the solvent is present in an amount of from about 14.0 w/w to about 15.0 w/w relative to the weight of the compound of Formula I. When the solvent is water, these amounts of solvent do not include water from the pH adjusting agent when the pH adjusting agent is present.

[0354] When present, the pH adjusting agent controls pH. In some embodiments, the pH adjusting agent is a base, an inorganic base, an organic base, a solid base, an aqueous base solution, an aqueous inorganic base solution, an aqueous inorganic salt base solution, an aqueous organic base solution, an aqueous organic salt base solution, a salt thereof, an aqueous solution thereof, or a combination thereof. In some embodiments, the pH adjusting agent is a base. In some embodiments, the pH adjusting agent 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 adjusting agent is selected from organic bases, such as tri ethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and combinations thereof. In some embodiments, the pH adjusting agent is sodium carbonate.

[0355] In some embodiments, sodium carbonate is added as a solid or as an aqueous solution. In some embodiments, sodium carbonate is added as an aqueous solution.

[0356] In some embodiments, the concentration of sodium carbonate aqueous solution is in a range of from about 1.0 wt% to about 33.0 wt%. In some embodiments, the concentration of sodium carbonate aqueous solution is in a range of from about 19.0 wt% to about 33.0 wt%.

[0357] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acids, and combinations thereof. In some embodiments, the acid is hydrochloric acid.

[0358] In some embodiments, the acid is present in an amount of from about 0.5 eq to about 2.0 eq. In some embodiments, the acid is present in an amount of from about 1.1 eq to about 2.0 eq.

[0359] In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C. In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C. In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range of about 50 °C to about 55 °C.

[0360] In some embodiments, the extraction solvent is selected from di chloromethane, 1,2-di chloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof. In some embodiments, the extraction solvent is 1,2-dichloroethane.

[0361] 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 Ri and Rs is hydrogen. In some embodiments, in the compound of Formula I, at least two of R1-R5 are hydrogen, wherein at least one of Ri and Rs is hydrogen. In some embodiments, the compound of Formula I is o-toluidine.

[0362] In some embodiments, the compound of Formula I is present in an amount of from about 1 wt% to about 30 wt%. In some embodiments, the compound of Formula I is present in an amount of from about 3 wt% to about 10 wt%.

[0363] In some embodiments, in the compound of Formula II, at least one of Ri- Rs is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1-R5 are hydrogen. In some embodiments, in the compound of Formula II, at least one of Ri and Rs is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1-R5 are hydrogen, wherein at least one of Ri and Rs is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0364] Controlling the reaction pH avoids addition of sodium sulfate salt and reduces the usage of water. For example, controlling the reaction pH between 0.95-1.05 through the use of NaiCCh aqueous solution avoids addition of sodium sulfate salt and reduces the usage of water from about 50 w/w to about 25 w/w. In this way, waste solid and waste water are dramatically reduced. Further, when the reaction scheme includes a filtration step to separate the product solid and mother liquid, some product remains dissolved in the mother liquid and is difficult to isolate, thereby leading to about 5-7% yield lost in the mother liquid. In the present scheme, extraction is used to replace filtration. For example, when 1,2-dichloroethane (DCE) is used as an extraction solvent, the yield loss of product in the aqueous phase is less than about 1.5% and drying for solid product can be simultaneously achieved. When the extraction step is combined with pH control, the isolation yield for this scheme can be increased from 70-73% to 83-88%.

[0365] In one aspect, a compound of Formula III or a salt thereof is prepared according to a method represented by Scheme 8. The R groups are as defined anywhere in this disclosure.

Scheme 8.

[0366] This aspect includes forming a mixture comprising a compound of Formula II or a salt thereof, an acid, and a solvent, and reacting the mixture.

[0367] In some embodiments, the mixture components are concurrently added to form the mixture. In some embodiments, the mixture components are individually added to form the mixture. In some embodiments, the mixture components are individually added in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dr op wise to the mixture.

[0368] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, sulfonic acids, methanesulfonic acid, /?-toluenesulfonic acid, and combinations thereof. In some embodiments, the acid comprises sulfuric acid and methanesulfonic acid.

[0369] In some embodiments, the solvent is selected from 1,2-di chloroethane, dichloromethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof. In some embodiments, the solvent is 1,2-di chloroethane. [0370] 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.

[0371] In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 3.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II. In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 5.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II. In some embodiments, methanesulfonic acid is present in an amount of from about 3.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II. In some embodiments, methanesulfonic acid is present in an amount of from about 5.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II.

[0372] In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 0.1 eq to about 10.0 eq relative to the compound of Formula II. In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 1.0 eq to about 10.0 eq relative to the compound of Formula II. In some embodiments, sulfuric acid is present in an amount of from about 0.1 eq to about 10.0 eq relative to the compound of Formula II. In some embodiments, sulfuric acid is present in an amount of from about 1.0 eq to about 10.0 eq relative to the compound of Formula II.

[0373] In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C. In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C.

[0374] In some embodiments, in the compound of Formula III, at least one of Ri-

R4 is hydrogen. In some embodiments, the compound of Formula III is 7-methylindoline-2,3- dione. [0375] In some embodiments, in the compound of Formula II, at least one of Ri- R? is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1-R5 are hydrogen. In some embodiments, in the compound of Formula II, at least one of Ri and Rs is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1-R5 are hydrogen, wherein at least one of Ri and Rs is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0376] In this scheme, the use of a sulfonic acid, such as methanesulfonic acid, is particularly beneficial. Methanesulfonic acid is a recyclable acid and the recovery rate is about 80-90%. It can dramatically reduce the generation of waste solid. In addition, temperature control is achieved and heat release is minimized. Finally, product yield is increased.

[0377] In one aspect, a compound of Formula IV or a salt thereof is prepared according to a method represented by Scheme 9. The R groups are as defined anywhere in this disclosure.

Scheme 9.

[0378] This aspect includes forming a mixture comprising a compound of Formula III or a salt thereof, a halogenation reagent, and a solvent comprising an acid, and reacting the mixture.

[0379] In some embodiments, the mixture components are concurrently added to form the mixture. In some embodiments, the mixture components are individually added to form the mixture. In some embodiments, the mixture components are individually added in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dr op wise to the mixture. [0380] In some embodiments, the solvent comprises a solvent selected from acetonitrile, di chloromethane, 1,2-di chloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acids, and combinations thereof. In some embodiments, the solvent comprises sulfuric acid and methanesulfonic acid.

[0381] 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.

[0382] 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.

[0383] In some embodiments, the method step III) of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C. In some embodiments, the method step III) of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C. In some embodiments, the method step III) of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 25 °C.

[0384] In some embodiments, in the compound of Formula III, at least one of Ri- R4 is hydrogen. In some embodiments, the compound of Formula III is 7-methylindoline-2,3- dione.

[0385] In some embodiments, in the compound of Formula IV, at least one of R7- R10 is a halogen. In some embodiments, in the compound of Formula IV, at least one of R7-R10 is a chlorine. In some embodiments, the compound of Formula IV is 5-chloro-7-methylindoline-2,3- dione.

[0386] In the present aspect, the use of chlorine as a chlorination agent is particularly beneficial. Chlorine is more reactive than other chlorination agents, such as sulfuryl chloride, and reactions with chlorine may be conducted at room temperature. The use of chlorine also improves yield of the compound of Formula IV. [0387] In one aspect, a compound of Formula IV or a salt thereof is prepared according to a method represented by Scheme 10. The R groups are as defined anywhere in this disclosure.

Scheme 10.

[0388] This aspect 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 halogenation reagent, and reacting the second mixture.

[0389] In some embodiments, the first mixture components are concurrently added to form the first mixture. In some embodiments, the second mixture components are concurrently added to form the second mixture. In some embodiments, the first mixture components are individually added to form the first mixture. In some embodiments, the second mixture components are individually added to form the second mixture. In some embodiments, the first mixture components are individually added in any suitable combination to form the first mixture. In some embodiments, the second mixture components are individually added 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.

[0390] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acids, and combinations thereof. In some embodiments, the acid comprises sulfuric acid and methanesulfonic acid. [0391] In some embodiments, the solvent is selected from dichloromethane, 1 ,2- di chloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof. In some embodiments, the solvent is 1,2-di chloroethane.

[0392] 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-di chloroethane/methanesulfonic acid, acetonitrile/acetic acid, acetonitrile/sulfuric acid, acetonitrile/methanesulfonic acid, and combinations thereof. In some embodiments, the solvent is 1,2-di chloroethane/methanesulfonic acid.

[0393] In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 3.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II. In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 5.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II. In some embodiments, methanesulfonic acid is present in an amount of from about 3.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II. In some embodiments, methanesulfonic acid is present in an amount of from about 5.0 w/w to about 10.0 w/w relative to the weight of the compound of Formula II.

[0394] In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 0.1 eq to about 10.0 eq relative to the compound of Formula II. In some embodiments, the acid and/or the acid of the solvent is present in an amount of from about 1.0 eq to about 10.0 eq relative to the compound of Formula II. In some embodiments, sulfuric acid is present in an amount of from about 0.1 eq to about 10.0 eq relative to the compound of Formula II. In some embodiments, sulfuric acid is present in an amount of from about 1.0 eq to about 10.0 eq relative to the compound of Formula II.

[0395] In some embodiments, the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 10 °C to about 90 °C. In some embodiments, the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 45 °C to about 55 °C. [0396] 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.

[0397] In some embodiments, the method step of reacting the second mixture occurs at a reaction temperature in the range of about 10 °C to about 100 °C. In some embodiments, the method step of reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C. In some embodiments, the method step of reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 25 °C.

[0398] In some embodiments, the method step of reacting the second mixture occurs at a reaction temperature in the range of about 50 °C to about 60 °C. In some embodiments, the method step of reacting the second mixture occurs at a reaction temperature in the range of about 50 °C to about 55 °C.

[0399] In some embodiments, the method step of removing an amount of the solvent from the first mixture comprises removing all the solvent from the first mixture. In some embodiments, the method step of removing an amount of the solvent from the first mixture comprises removing less than all the solvent from the first mixture.

[0400] In some embodiments, in the compound of Formula II, at least one of Ri- Rs is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1-R5 are hydrogen. In some embodiments, in the compound of Formula II, at least one of Ri and Rs is hydrogen. In some embodiments, in the compound of Formula II, at least two of Ri-Rs are hydrogen, wherein at least one of Ri and Rs is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0401] In some embodiments, in the compound of Formula IV, at least one of R7- R10 is a halogen. In some embodiments, in the compound of Formula IV, at least one of R7-R10 is a chlorine. In some embodiments, the compound of Formula IV is 5-chloro-7-methylindoline-2,3- dione.

[0402] This aspect is particularly beneficial when excess solvent is removed before introduction of the halogenation step. The overall yield is as much as 90% and the individual yields of both reactions of this aspect are each about 95%.

[0403] This aspect is a single-pot process and possesses several advantages. First, the need to separate intermediates produced from the compound of Formula II, such as the compound of Formula III, before subsequent reactions is eliminated. Second, potential losses of intermediates produced from the compound of Formula II, such as the compound of Formula III, are reduced. Third, the total yield is increased. Fourth, the number of reaction steps and workup operations is reduced. Fifth, overall cost is reduced.

[0404] In one aspect, a compound of Formula V or a salt thereof is prepared according to a method represented by Scheme 11. The R groups are as defined anywhere in this disclosure.

Scheme 11.

[0405] This aspect includes forming a mixture comprising a compound of Formula IV or a salt thereof, an oxidation agent, a solvent, and an additive, and reacting the mixture in the presence of a catalyst.

[0406] In some embodiments, the mixture components are concurrently added to form the mixture. In some embodiments, the mixture components are individually added to form the mixture. In some embodiments, the mixture components are individually added in any suitable combination to form the mixture. In some embodiments, the mixture components are individually added in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0407] In some embodiments, a catalyst is added to the mixture before any of the mixture components are added to the mixture. In some embodiments, a catalyst is added to the mixture before all the mixture components are added to the mixture. In some embodiments, a catalyst is added to the mixture after some, but not all, of the mixture components are added to the mixture. In some embodiments, a catalyst is added to the mixture after all the mixture components are added to the mixture.

[0408] In some embodiments, a catalyst is inherently present in the mixture upon the reaction of the oxidation agent and the solvent and/or additive.

[0409] In some embodiments, the oxidation 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. In some embodiments, the oxidation agent is hydrogen peroxide.

[0410] In some embodiments, the oxidation agent is present in an amount in a range of from about 1.0 eq to about 5.0 eq. In some embodiments, the oxidation agent is present in an amount in a range of from about 3.0 eq to about 5.0 eq.

[0411] 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. In some embodiments, the solvent is acetic acid.

[0412] In some embodiments, the solvent is present in an amount in a range of from about 10.0 eq to about 30.0 eq. In some embodiments, the solvent is present in an amount in a range of from about 13.0 eq to about 30.0 eq. [0413] In some embodiments, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acids, methanesulfonic acid, and combinations thereof. In some embodiments, the catalyst is sulfuric acid.

[0414] In some embodiments, the catalyst is present in an amount in a range of from about 0.1 eq to about 1.0 eq. In some embodiments, the catalyst is present in an amount in a range of from about 0.3 eq to about 1.0 eq.

[0415] In some embodiments, the additive comprises an additive selected from toluene, xylene, mesitylene, high-flash aromatic hydrocarbon solvent (SI 50), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulphonate (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, di chloromethane, 1,2-di chloroethane, ethyl acetate, isopropyl acetate, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethylacetamide, N- methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, and combinations thereof.

[0416] In some embodiments, the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidone, polyethylene glycol (PEG) 400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high-flash aromatic hydrocarbon solvent (SI 50), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulphonate (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 the combination of ethyl acetate and mesitylene.

[0417] In some embodiments, the additive is present in an amount in a range of from about 0.1 eq to about 1.0 eq. In some embodiments, the additive is present in an amount in a range of from about 0.35 eq to about 1.0 eq. In some embodiments, the additive is present in an amount in a range of from about 0.45 eq to about 1.0 eq. In some embodiments, the additive is present in an amount in a range of from about 0.80 eq to about 1.0 eq. [0418] In some embodiments, the method step of reacting the mixture occurs 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 occurs 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 occurs at at least two different reaction temperatures. In some embodiments, the method step of reacting the mixture occurs 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 occurs 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.

[0419] In some embodiments, in the compound of Formula IV, at least one of R7- R10 is a halogen. In some embodiments, in the compound of Formula IV, at least one of R7-R10 is a chlorine. In some embodiments, the compound of Formula IV is 5-chloro-7-methylindoline-2,3- dione.

[0420] In some embodiments, in the compound of Formula V, at least one of R7- R10 is a halogen. In some embodiments, in the compound of Formula V, at least one of R7-R10 is a chlorine. In some embodiments, the compound of Formula V is 6-chloro-8-methyl-2H- benzofd] [ 1 ,3 ]oxazine-2,4( lH)-dione.

[0421] In this aspect, the use of mesitylene as an additive and ethyl acetate as an additive co-solvent is particularly beneficial and increase the conversion of the compound of Formula IV. This improved conversion increases yield up to about 85-90%. In addition, the unreacted compound of Formula IV is decreased from about 5 wt% to about 1-2 wt%.

[0422] In one aspect, a compound of Formula VI or a salt thereof is prepared according to a method represented by Scheme 12. The R groups are as defined anywhere in this disclosure.

Scheme 12.

(V) (VI)

[0423] This aspect includes forming a mixture comprising 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.

[0424] In some embodiments, the mixture components are concurrently added to form the mixture. In some embodiments, the mixture components are individually added to form the mixture. In some embodiments, the mixture components are individually added in any suitable combination to form the mixture. In some embodiments, the mixture components are individually added in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0425] In some embodiments, the alkylamine comprises a functional group selected from branched Ci-Cio alkyl and unbranched Ci-Cio alkyl. In some embodiments, the alkylamine is 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.

[0426] In some embodiments, the solvent is selected from acetonitrile, di chloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof. In some embodiments, the solvent is ethyl acetate.

[0427] In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 100 °C. In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range of about 60 °C to about 65 °C. [0428] In some embodiments, the method step of applying a purification step to the mixture comprises a purification step selected from phase separation, acidification, precipitation, neutralization, filtration, and combinations thereof. In some embodiments, the method step of applying a purification step to the mixture comprises 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.

[0429] In some embodiments, the method step of applying a purification step to the mixture comprises adding an aqueous solvent (e g. water), performing a phase separation, adding an acid to precipitate out 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.

[0430] In some embodiments, the method step of of applying a purification step to the mixture occurs at a reaction temperature in the range of about 0 °C to about 100 °C. In some embodiments, the method step of of applying a purification step to the mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C. In some embodiments, the method step of of applying a purification step to the mixture occurs at a reaction temperature in the range of about 20 °C to about 25 °C.

[0431] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfonic acid, and combinations thereof. In some embodiments, the acid is hydrochloric acid.

[0432] In some embodiments, the acid is present in an amount in a range of from about 0.8 eq to about 3.0 eq. In some embodiments, the acid is present in an amount in a range of from about 1.2 eq to about 3.0 eq.

[0433] 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. In some embodiments, the base is sodium hydroxide.

[0434] In some embodiments, in the compound of Formula V, at least one of R7-

R10 is a halogen. In some embodiments, in the compound of Formula V, at least one of R7-R10 is a chlorine. In some embodiments, the compound of Formula V is 6-chloro-8-methyl-2H- benzo[d] [ 1 ,3 ]oxazine-2,4( lH)-dione.

[0435] In some embodiments, in the compound of Formula VI, at least one of R7- R10 is a halogen. In some embodiments, in the compound of Formula VI, at least one of R7-R10 is a chlorine. In some embodiments, the compound of Formula VI is 2-amino-5-chloro-N,3- dimethylbenzamide.

[0436] This aspect is particularly beneficial to purifiy 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%.

[0437] In one aspect, a compound of Formula V or a salt thereof is prepared according to a method represented by Scheme 13. The R groups are as defined anywhere in this disclosure.

Scheme 13.

(Hi) (V)

[0438] This aspect includes forming a first mixture comprising a compound of Formula III or a salt thereof, a solvent comprising an acid, and a halogenation reagent, reacting the first mixture, optionally removing a portion of the solvent comprising an acid, forming a second mixture comprising the first mixture, an oxidation agent, and an additive, and reacting the second mixture, wherein the second mixture is reacted in the presence of a catalyst.

[0439] In some embodiments, the first mixture components are concurrently added to form the first mixture. In some embodiments, the second mixture components are concurrently added to form the second mixture. In some embodiments, the first mixture components are individually added to form the first mixture. In some embodiments, the second mixture components are individually added to form the second mixture. In some embodiments, the first mixture components are individually added in any suitable combination to form the first mixture. In some embodiments, the second mixture components are individually added 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.

[0440] In some embodiments, a catalyst is added to the second mixture before any of the second mixture components are added to the second mixture. In some embodiments, a catalyst is added to the second mixture before all the second mixture components are added to the second mixture. In some embodiments, a 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, a catalyst is added to the second mixture after all the second mixture components are added to the second mixture.

[0441] In some embodiments, a catalyst is inherently present in the first mixture and/or the second mixture upon the reaction of at least two mixture components. In some embodiments, a catalyst is inherently present in the second mixture upon the reaction of the oxidation agent and the halogenation reagent.

[0442] In some embodiments, the solvent comprises a solvent selected from acetonitrile, 1,2-di chloroethane, 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 a 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 the combination of methanesulfonic acid and sulfuric acid.

[0443] 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.

[0444] In some embodiments, the method step of reacting the first mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C. In some embodiments, the method step of reacting the first mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0445] In some embodiments, the oxidation agent is selected from oxygen, chlorine, sodium hypochlorite, chromium tri oxide, 3 -chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof. In some embodiments, the oxidation agent is hydrogen peroxide.

[0446] In some embodiments, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acids, methanesulfonic acid, and combinations thereof. In some embodiments, the catalyst comprises sulfuric acid. In some embodiments, the catalyst is sulfuric acid.

[0447] In some embodiments, the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, di chloromethane, 1,2-di chloroethane, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high-flash aromatic hydrocarbon solvent (SI 50), high-flash aromatic hydrocarbon solvent (S200), Tween 20, sodium dodecylbenzenesulphonate (SDS), and combinations thereof. In some embodiments, the additive comprises ethyl acetate and mesitylene. In some embodiments, the additive is the combination of ethyl acetate and mesitylene.

[0448] In some embodiments, the method step of reacting the second mixture occurs 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 occurs 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 occurs at at least two different reaction temperatures. In some embodiments, the method step of reacting the second mixture occurs 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 occurs 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.

[0449] In some embodiments, in the compound of Formula III, at least one of Ri- R4 is hydrogen. In some embodiments, the compound of Formula III is 7-methylindoline-2,3- dione.

[0450] In some embodiments, in the compound of Formula V, at least one of R7- R10 is a halogen. In some embodiments, in the compound of Formula V, at least one of R7-R10 is chlorine. In some embodiments, the compound of Formula V is 6-chloro-8-methyl-2H- benzo[d][l,3]oxazine-2,4(lH)-dione. [please confirm and elaborate as desired]

[0451] This aspect is a single-pot process and possesses several advantages. First, the need to separate intermediates produced from the compound of Formula III, such as the compound of Formula IV, before subsequent reactions is eliminated. Second, potential losses of intermediates produced from the compound of Formula III, such as the compound of Formula IV, are reduced. Third, the total yield is increased. Fourth, the number of reaction steps and workup operations is reduced. Fifth, overall cost is reduced.

EXAMPLES

[0452] 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. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. The starting material for the following Examples may not have necessarily been prepared by a particular preparative run whose procedure is described in other Examples. It also is understood that any numerical range recited herein includes all values from the lower value to the upper value. For example, if a range is stated as 10-50, it is intended that values such as 12- 30, 20-40, or 30-50, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.

[0453] Example 1. Reaction of o-toluidine.

[0454] 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 to 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 was lower than 0.95, 19% NaiCCh aqueous solution was added to control pH between 0.95-1.05. After reaction, 150 g 1,2- dichloroethane was charged three times to extract at 50-55 °C. 430.0 g of (E)-3 -hydroxy -N-(o- tolyl)acrylamide in 1,2-dichloroethane solution was obtained, which was usable directly in other Examples. The wt% 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.

[0456] 66.1 g of hydroxylamine sulfate and 360.0 g of water were charged to 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 hydrochloric acid and 130.0 g of water were mixed and charged in dropping funnel A. 73.6 g of chloral hydrate and 130.0 g of water were mixed and charged in dropping funnel B. The solution in funnel A and B were added dropwise to the reactor. The reaction pH decreased with reaction time. When the reaction pH was lower than 0.95, 19% Na CCh aqueous solution was added to control pH between 0.95-1.05. After reaction, 1050.0 g 1,2-dichloroethane was charged three times to extract at 50-55 °C. 1092.0 g of (E)-3 -hydroxy -N- (o-tolyl)acrylamide in 1,2-dichloroethane solution was obtained, which was usable directly in other Examples. The wt% 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%.

[0457] Example 3. Cyclization.

[0458] 404.6 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-di chloroethane solution (wt%=5.6%) was charged in a reactor at room temperature. A portion of the 1,2- di chloroethane (about 2/3 of the total 1,2-dichloroethane) was distilled out from the reaction mixture at 40-45 °C under pressure (100-200 mbar). A mixture of methanesulfonic acid (113.5 g) and sulfuric acid (12.7 g) was then added dropwise to the reaction mixture at 40-45 °C under atmospheric pressure. When this addition was complete, the reaction was heated, and the temperature of the mixture was controlled at 50-55 °C under 300-330 mbar. The reaction mixture refluxed under these conditions. When the reaction was complete, the residual 1,2-di chloroethane was distilled out at 50-55 °C under 100-50 mbar. The mixture was cooled to 20-25 °C and added dropwise to the water in another reactor, where the temperature was controlled at about 40 °C, and the solid precipitated out. The mixture was cooled to room temperature and stirred at room temperature. The slurry was filtered, and the filter cake was washed twice by water. The solid was dried and 20.1 g of crude 7 -methylindoline-2, 3-dione was obtained. The crude 7- methylindoline-2, 3-dione was usable directly in other Examples. The wt% of 7-methylindoline- 2, 3-dione was 95.9%. The yield of this step was 94.1%.

[0459] Example 4. Halogenation.

[0460] 20.0 g of 7-methylindoline-2, 3-dione (wt%=95.9%) and 95.9 g of methanesulfonic acid and 9.81 g 98% sulfuric acid were charged to a reactor at room temperature. Chlorine gas was bubbled into the reaction solution at 20-25 °C. When the reaction was complete, nitrogen gas was bubbled into the reaction solution to purge the chlorine gas. The reaction mass was added dropwise to the water in another reactor (temperature was controlled at about 40 °C), and solid precipitated out during quenching. The reaction was cooled to room temperature and stirred at room temperature. The slurry was fdtered, and the fdter cake was washed twice by water. The solid was dried and 24.5 g of crude 5-chloro-7-methylindoline-2, 3-dione was obtained. The crude 5 -chloro-7-m ethylindoline-2, 3-dione was usable directly in other Examples. The wt% of 5- chloro-7-methylindoline-2, 3-dione was 90.0%. The yield of this step was 94.7%

[0461] Example 5. Cyclization and Halogenation.

[0462] 1690.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-di chloroethane solution (wt%=5.22%) was charged in a reactor at room temperature. A portion of the 1,2- di chloroethane (about 2/3 of the total 1,2-dichloroethane) was distilled out from the reaction mixture at 40-45 °C under pressure (100-200 mbar). A mixture of methanesulfonic acid (441.0 g) and sulfuric acid (50.0 g) was then added dropwise to the reaction mixture at 40-45 °C under atmospheric pressure. When this addition was complete, the reaction was heated, and the temperature of the mixture was controlled at 50-55 °C under 300-330 mbar. The reaction mixture refluxed under these conditions. When the reaction was complete, the residual 1,2-di chloroethane was distilled out 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. When the reaction was over, nitrogen gas was bubbled into the reaction solution to purge the chlorine gas. The reaction mass was then added dropwise to water in another reactor (temperature was controlled at about 40 °C), and the solid precipitated out during quenching. The mixture was cooled to room temperature and was stirred at room temperature. The slurry was filtered, and the filter cake was washed by water for twice. The solid was dried and 96.4 g of crude 5-chloro-7-methylindoline-2, 3-dione was obtained. The crude 5-chloro-7-methylindoline-2, 3-dione was usable directly in other Examples. The wt% of 5- chloro-7-methylindoline-2, 3-dione was 91.4%. The yield of this step was 91.0%

[0463] Example 6. Oxidation.

[0464] 52.0 g of 5-chloro-7-methylindoline-2, 3-dione (wt%=83.0%), 170.0 g of acetic acid, 23.0 g of H2O, 6.60 g of sulfuric acid, and 8.0 g mesitylene were charged to a reactor at room temperature. The reaction 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 ethyl acetate was added and the mixture was stirred for another 2 hours. Then the reaction was heated again and the temperature of the mixture was controlled at 60-70 °C. When the reaction was complete, the mixture was cooled to room temperature and sodium sulfite aqueous solution was charged to quench the peroxide until KI test paper did not turn blue. The slurry was filtrated, and the filter cake was washed twice by water. The solid was dried and 47.5 g of crude 6-chloro-8-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dione was obtained. The crude 6-chloro-8- methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dione was usable directly in other Examples. The wt% of 6-chloro-8-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dione was 89.5%. The yield of this step was 91.1%

[0465] Example 7. Halogenation and oxidation

[0466] 20.9 g of 7-methylindoline-2, 3-dione (wt%=95.9%), 100.0 g of methanesulfonic acid, and 12.4 g 98% sulfuric acid were charged to a reactor at room temperature. Chlorine gas was bubbled into the reaction solution at 20-25 °C. When the reaction was complete, nitrogen gas was bubbled into the reaction solution to purge the chlorine gas. Then the mixture was heated to 25-35 °C. 6.0 g of mesitylene were 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 ethyl acetate was added and the mixture was stirred for another 2 hours. Then the reaction was heated and the temperature of the mixture was controlled at 60-70 °C. After the reaction was completed, the mixture was cooled to room temperature and sodium sulfite aqueous solution was charged to quench the peroxide until KI test paper did not turn blue. The slurry was filtrated, and the filter cake was washed twice by water. The solid was dried and 14.5 g of crude 6-chloro-8-methyl-2H- benzo[d][l,3]oxazine-2,4(lH)-dione was obtained. The crude 6-chloro-8-methyl-2H- benzo[d][l,3]oxazine-2,4(lH)-dione was usable directly in other Examples. The wt% of 6-chloro- 8-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dione was 69.3%. The yield of this step was 38.2%.

[0467] Example 8. Reaction with methanamine.

[0468] 21.2 g of 6-chloro-8-methyl-2H-benzo[d][l,3]oxazine-2,4(lH)-dione (wt%=89.9%), 89.00 g of ethyl acetate, and 9.2 g of acetic acid were charged to a reactor. Gaseous methanamine was bubbled to the reaction at 55-60 °C. After the reaction was complete, nitrogen gas was bubbled into the reaction solution to purge methylamine gas. Then water was added and phase separation was conducted twice at 55-60 °C. The organic phase was cooled to room temperature. 13.2 g of 30% hydrogen chloride aqueous solution was added to the organic phase and 2-amino-5-chloro-N,3-dimethylbenzamide hydrochloride salt precipitated out. The 2-amino- 5-chloro-N,3-dimethylbenzamide salt and water were added to another reactor, sodium hydroxide solution was added to free 2-amino-5-chloro-N, 3 -dimethylbenzamide through neutralization. Filtration was conducted again and the filter cake was washed twice by water. The solid was dried and 17.3 g of 2-amino-5-chloro-N,3-dimethylbenzamide was obtained. The wt% of 2-amino-5- chloro-N, 3 -dimethylbenzamide was 98.3%. The yield of this step was 94.9%.

[0469] This written description uses examples to illustrate the present disclosure, including the best mode, and also to enable any person 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 with insubstantial differences from the literal language of the claims.

Claims

WHAT IS CLAIMED IS: A method of preparing a compound of Formula VI, wherein

(Formula VI) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen; and wherein Rn is selected from branched C1-C10 alkyl and unbranched C1-C10 alkyl, the method comprising

I) forming a mixture comprising

A) a compound of Formula V, wherein

B) an alkylamine; and

C) a solvent;

II) reacting the mixture; and

III) optionally applying a purification step to the mixture. The method of claim 1, wherein the halogenation reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof. The method of claim 2, wherein 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. The method of claim 3, wherein the chlorination reagent is chlorine. The method of claim 1, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture. A method of preparing a compound of Formula V, wherein

(Formula V) each of R? - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R10 is a halogen, the method comprising

I) forming a first mixture comprising

A) a compound of Formula III, wherein

B) a solvent comprising an acid; and

C) a halogenation reagent;

II) reacting the first mixture;

III) optionally removing a portion of the solvent comprising an acid;

IV) forming a second mixture comprising the first mixture;

D) an oxidation agent; and

E) an additive; and

V) reacting the second mixture, wherein the second mixture is reacted in the presence of a catalyst. The method of claim 6, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising A) a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; and wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen,

Ci-Cs haloalkyl, and C1-C5 alkyl; and and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent;

B) an acid; and

C) a solvent; and

II) reacting the mixture. A method of preparing a compound of Formula VI, wherein

I) forming a mixture comprising

A) a compound of Formula V, wherein

B) an alkylamine; and

C) a solvent;

II) reacting the mixture; and

III) optionally applying a purification step to the mixture. The method of claim 8, wherein the compound of Formula IV is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula III, wherein

(Formula III) each of Ri - R.4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1-R4 is hydrogen;

B) a solvent comprising an acid;

C) a halogenation reagent; and

II) reacting the mixture. The method of claim 9, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

each of Ri - Rs is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; and wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture. The method of claim 8, wherein the compound of Formula IV is prepared according to a method comprising

I) forming a first mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; II) reacting the first mixture;

III) removing an amount of the solvent from the first mixture;

V) reacting the second mixture. The method of claim 11, wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the first mixture, wherein the mixture is reacted at a pH in a range of from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent. A method of preparing a compound of Formula V, wherein

I) forming a mixture comprising

A) a compound of Formula IV, wherein

each of R? - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R10 is a halogen;

B) an oxidation agent;

C) a solvent; and

D) an additive; and

II) reacting the mixture, wherein the mixture is reacted in the presence of a catalyst. The method of claim 13, wherein the compound of Formula IV is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula III, wherein

B) a solvent comprising an acid;

C) a halogenation reagent; and II) reacting the mixture. The method of claim 14, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture. The method of claim 13 wherein the compound of Formula IV is prepared according to a method comprising I) forming a first mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent;

II) reacting the first mixture;

III) removing an amount of the solvent from the first mixture;

V) reacting the second mixture. The method of claim 16, wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0t 7; and iii) optionally extracting the mixture with an extraction solvent. od of preparing a compound of Formula IV, wherein

(Formula IV) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R7-R10 is a halogen, the method comprising

I) forming a mixture comprising

A) a compound of Formula III, wherein

B) a solvent comprising an acid;

C) a halogenation reagent; and

II) reacting the mixture. The method of claim 18, wherein the compound of Formula III is prepared according to a method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent; and

II) reacting the mixture. A method of preparing a compound of Formula III, wherein

(Formula III) each of Ri - R.4 is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl, and at least one of R1-R4 is hydrogen, the method comprising

I) forming a mixture comprising

A) a compound of Formula II, wherein

B) an acid; and C) a solvent; and

II) reacting the mixture. ethod of preparing a compound of Formula II, wherein

(Formula II) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl, and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen

, the method comprising

I) forming a mixture comprising

A) a compound of Formula I, wherein

each of Ri - Rs is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen;

B) chloral hydrate;

C) a hydroxylamine or a hydroxylamine derivative;

D) a solvent;

E) optionally a pH adjusting agent; and

F) an acid; and

III) optionally extracting the mixture with an extraction solvent. A method of preparing a compound of Formula IV, wherein

(Formula IV) each of R7 - Rio is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R10 is a halogen, the method comprising I) forming a first mixture comprising

A) a compound of Formula II, wherein

B) an acid; and

C) a solvent;

II) reacting the first mixture;

III) removing an amount of the solvent from the first mixture;

V) reacting the second mixture. The method of claim 22, wherein the compound of Formula II is prepared according to a method comprising i) forming a mixture comprising a) a compound of Formula I, wherein

(Formula I) each of Ri - Rs is independently selected from hydrogen, halogen, Ci-Cs haloalkyl, and C1-C5 alkyl; and wherein at least two of Ri - Rs are hydrogen; and at least one of Ri and Rs is hydrogen; b) chloral hydrate; c) a hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH adjusting agent; and f) an acid; ii) reacting the mixture, wherein the mixture is reacted at a pH in a range of from about 0t 7; and iii) optionally extracting the mixture with an extraction solvent.