Preparation method of chlorobenzamide-containing derivative

Abstract

The invention relates to a novel method for synthesizing 2-amino-5-chloro-N, 3-dimethylbenzamide, and particularly relates to a novel method for synthesizing 2-amino-5-chloro-N, 3-dimethylbenzamide. The compounds prepared by the methods disclosed herein are useful in the preparation of certain anthranilamide compounds of interest as insecticides, such as, for example, chlorantraniliprole and cyantraniliprole as insecticides.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 417,409, filed on October 19, 2022. Technical Field

[0003] This disclosure relates to novel methods for synthesizing 2 - amino - 5 - chloro - N,3 - dimethylbenzamide. Compounds prepared by the methods disclosed herein can be used to prepare certain anthranilic diamide compounds of interest as insecticides, such as the insecticides chlorantraniliprole and cyantraniliprole. Background Art

[0004] Conventional methods for producing 2 - amino - 5 - chloro - N,3 - dimethylbenzamide have several industrial problems, such as hazardous materials, high costs, relatively long method steps, and complex operations.

[0005] In addition, some methods use relatively large amounts of salts, water, and / or acids. Such methods generate relatively large amounts of waste solids and wastewater as well as non - optimal yields. Methods for overcoming these environmental problems and increasing yields are desirable.

[0006] This disclosure provides novel methods that can be used to prepare 2 - amino - 5 - chloro - N,3 - dimethylbenzamide and its derivatives. Compared with prior methods, the methods of this disclosure have many benefits and include reduced costs, elimination of the need for separation of mixed solvents, reduced waste, relatively short method steps, simplified operational complexity, and reduced method hazards. Summary of the Invention

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

[0008]

[0009] R7 - R 10 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0010] wherein at least one of R7 - R 10 is a halogen; and

[0011] wherein R 11 is selected from branched C1 - C 10 alkyl and unbranched C1 - C 10 alkyl, and the method comprises:

[0012] I) forming a mixture that comprises:

[0013] A) a compound having Formula V, wherein

[0014]

[0015] R7-R 10 Each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0016] wherein at least one of R7-R 10 is halogen; and

[0017] wherein the compound having Formula V is prepared according to the following method, which comprises:

[0018] i) Forming a first mixture comprising:

[0019] a) A compound having Formula III, wherein

[0020]

[0021] R1-R4 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and

[0022] at least one of R1-R4 is hydrogen;

[0023] b) A solvent comprising an acid; and

[0024] c) A halogenating agent;

[0025] ii) Reacting the first mixture;

[0026] iii) Optionally removing a portion of the solvent comprising the acid;

[0027] iv) Forming a second mixture comprising:

[0028] The first mixture;

[0029] d) An oxidizing agent; and

[0030] e) An additive; and

[0031] v) Reacting the second mixture, wherein the second mixture reacts in the presence of a catalyst;

[0032] B) An alkylamine; and

[0033] C) A solvent;

[0034] II) Reacting the mixture; and

[0035] III) Optionally subjecting the mixture to a purification step.

[0036] In one aspect, the present disclosure provides a method for preparing a compound of formula V, wherein

[0037]

[0038] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and

[0039] wherein at least one of R7 - R 10 is halogen, the method comprising:

[0040] I) forming a first mixture comprising:

[0041] A) a compound of formula III, wherein

[0042]

[0043] R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least one of R1 - R4 is hydrogen;

[0044] B) a solvent comprising an acid; and

[0045] C) a halogenating agent;

[0046] II) reacting the first mixture;

[0047] III) optionally removing a portion of the solvent comprising the acid;

[0048] IV) forming a second mixture comprising:

[0049] the first mixture;

[0050] D) an oxidizing agent; and

[0051] E) an additive; and

[0052] V) reacting the second mixture, wherein the second mixture reacts in the presence of a catalyst. In one aspect, the present disclosure provides a method for preparing a compound of formula VI, wherein

[0053]

[0054] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0055] wherein at least one of R7 - R 10 is halogen; and

[0056] wherein R11 Selected from branched C1-C 10 alkyl and unbranched C1-C 10 alkyl, the method comprising:

[0057] I) Forming a mixture comprising:

[0058] A) A compound of formula V, wherein

[0059]

[0060] R7-R 10 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl and C1-C5 alkyl;

[0061] wherein at least one of R7-R 10 is a halogen; and

[0062] wherein the compound of formula V is prepared according to the following method, the method comprising:

[0063] i) Forming a mixture comprising:

[0064] a) A compound of formula IV, wherein

[0065]

[0066] R7-R 10 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl and C1-C5 alkyl; and

[0067] wherein at least one of R7-R 10 is a halogen;

[0068] b) An oxidizing agent;

[0069] c) A solvent; and

[0070] d) An additive; and

[0071] ii) Reacting the mixture, wherein the mixture is reacted in the presence of a catalyst;

[0072] B) An alkylamine; and

[0073] C) A solvent;

[0074] II) Reacting the mixture; and

[0075] III) Optionally subjecting the mixture to a purification step.

[0076] In one aspect, provided herein is a method for preparing a compound of formula V, wherein

[0077]

[0078] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and wherein at least one of R7 - R 10 is halogen, the method comprising:

[0079] I) forming a mixture comprising:

[0080] A) a compound having formula IV, wherein

[0081]

[0082] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and wherein at least one of R7 - R 10 is halogen;

[0083] B) an oxidizing agent;

[0084] C) a solvent; and

[0085] D) an additive; and

[0086] II) reacting the mixture, wherein the mixture is reacted in the presence of a catalyst.

[0087] In one aspect, provided herein is a method for preparing a compound having formula IV, wherein

[0088]

[0089] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0090] wherein at least one of R7 - R 10 is halogen, the method comprising:

[0091] I) forming a mixture comprising:

[0092] A) a compound having formula III, wherein

[0093]

[0094] R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least one of R1 - R4 is hydrogen;

[0095] B) a solvent comprising an acid;

[0096] C) a halogenating agent; and

[0097] II) React the mixture.

[0098] In one aspect, provided herein is a method for preparing a compound of formula III, wherein

[0099]

[0100] R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl, and

[0101] at least one of R1 - R4 is hydrogen;

[0102] The method comprises:

[0103] I) Forming a mixture comprising:

[0104] A) A compound of formula II, wherein

[0105]

[0106] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0107] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0108] and

[0109] wherein the compound of formula II is prepared according to a method comprising:

[0110] i) Forming a mixture comprising:

[0111] a) A compound of formula I, wherein

[0112]

[0113] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0114] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0115] b) Chloral hydrate;

[0116] c) Hydroxylamine or a hydroxylamine derivative;

[0117] d) A solvent;

[0118] e) Optionally a pH regulator; and

[0119] f) An acid;

[0120] ii) React the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0121] iii) Optionally extract the mixture with an extraction solvent;

[0122] B) An acid; and

[0123] C) A solvent; and

[0124] II) React the mixture.

[0125] In one aspect, the present invention provides a method for preparing a compound of formula II, wherein

[0126]

[0127] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl,

[0128] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0129] , the method comprising:

[0130] I) Form a mixture comprising:

[0131] A) A compound of formula I, wherein

[0132]

[0133] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0134] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0135] B) Chloral hydrate;

[0136] C) Hydroxylamine or a hydroxylamine derivative;

[0137] D) A solvent;

[0138] E) Optionally a pH regulator; and

[0139] F) An acid; and

[0140] II) React the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0141] III) Optionally extract the mixture with an extraction solvent.

[0142] In one aspect, the present disclosure provides a method for preparing a compound of Formula IV, wherein

[0143]

[0144] R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0145] wherein at least one of R7-R 10 is halogen, and the method comprises:

[0146] I) forming a first mixture comprising:

[0147] A) a compound of Formula II, wherein

[0148]

[0149] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0150] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0151] B) an acid; and

[0152] C) a solvent;

[0153] II) reacting the first mixture;

[0154] III) removing a portion of the solvent from the first mixture;

[0155] IV) forming a second mixture comprising the first mixture and a halogenating agent; and

[0156] V) reacting the second mixture. DETAILED DESCRIPTION

[0157] 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 limitations specifically recited. 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 elements inherent to such composition, mixture, process, or method.

[0158] The connecting phrase "consisting of" excludes any unrecited element, step, or ingredient. If in a claim, this phrase renders the claim closed, excluding materials other than those recited, except for impurities normally associated therewith. When the phrase "consisting of" appears in a clause of the claim body rather than immediately following the preamble, the phrase only limits the elements recited in that clause; overall, the claim does not exclude other elements.

[0159] The connective "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 characteristics of the claimed invention. The term "consisting essentially of" lies between "comprising" and "consisting of".

[0160] When an invention or a part thereof is defined by an open - ended term such as "comprising", it should be understood (unless otherwise stated) that the description should also be interpreted as using the terms "consisting essentially of" or "consisting of" to describe such an invention.

[0161] Furthermore, unless expressly stated to the contrary, "or" means inclusive - or rather than exclusive - or. For example, the condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), and both A and B are true (or present).

[0162] Additionally, the indefinite articles "a" and "an" before an element or component of the present invention are intended to be non - restrictive with respect to the number of instances (i.e., occurrences) of that element or component. Thus, "a" or "an" should be understood to include one or at least one, and the singular word form of an element or component also includes the plural, unless the number clearly means singular.

[0163] As used herein, the term "about" means plus or minus 10% of that value.

[0164] The term "halogen", alone or in a compound word such as "haloalkyl", includes fluorine, chlorine, bromine, or iodine. Further, when used in a compound word such as "haloalkyl", the alkyl may be partially or completely substituted with halogen atoms which may be the same or different.

[0165] When a group contains a substituent that can be hydrogen, such as R 4When this is the case, when the substituent is regarded as hydrogen, it is considered equivalent to the group being unsubstituted.

[0166] The term "alkyl" includes, but is not limited to, functional groups containing straight-chain or branched-chain alkyl groups. In some aspects, the alkyl group can be methyl, ethyl, n-propyl, isopropyl, or different isomers of butyl, pentyl, or hexyl.

[0167] The term "its salts" refers to suitable salts of the compounds derived from this term. Suitable salts include, but are not limited to, alkali metal salts, sodium salts, potassium salts, lithium salts, cesium salts, alkaline metal salts, calcium salts, magnesium salts, halogen salts, chloride salts, bromide salts, iodide salts, sulfates, disulfates, nitrates, phosphates, dihydrogen phosphates, hydrogen phosphates, carbonates, bicarbonates, methanesulfonates, and combinations thereof. It should be understood that certain compounds of the present invention can exist as pure compounds, the compounds themselves, their salts, and combinations thereof.

[0168] The terms "S150" and "S200" refer to high-flash-point aromatic solvents having high boiling points of about 180 °C and about 250 °C, respectively. These solvents provide high solvency and controlled evaporation characteristics, which make them very suitable for many industrial applications such as additives.

[0169] Certain compounds of the present invention can exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Those skilled in the art will understand that a stereoisomer may be more active and / or may exhibit beneficial effects when enriched relative to one or more other stereoisomers, or when separated from one or more other stereoisomers. Additionally, those skilled in the art know how to separate, enrich, and / or selectively prepare the stereoisomers.

[0170] Examples of the present disclosure include:

[0171] Example 1. A method for preparing a compound having the formula VI, wherein,

[0172]

[0173] R7-R 10 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0174] wherein at least one of R7-R 10 is halogen; and

[0175] wherein R 11 is selected from branched C1-C 10 alkyl and unbranched C1-C 10an alkyl group, the method comprising:

[0176] I) forming a mixture comprising:

[0177] A) a compound of formula V, wherein

[0178]

[0179] R7 - R 10 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0180] wherein at least one of R7 - R 10 is halogen; and

[0181] wherein the compound of formula V is prepared according to the following method, the method comprising:

[0182] i) forming a first mixture comprising:

[0183] a) a compound of formula III, wherein

[0184]

[0185] R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0186] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0187] b) a solvent comprising an acid; and

[0188] c) a halogenating reagent;

[0189] ii) reacting the first mixture;

[0190] iii) optionally removing a portion of the solvent comprising the acid;

[0191] iv) forming a second mixture comprising:

[0192] the first mixture;

[0193] d) an oxidizing agent; and

[0194] e) an additive; and

[0195] v) reacting the second mixture, wherein the second mixture reacts in the presence of a catalyst;

[0196] B) an alkylamine; and

[0197] C) a solvent;

[0198] II) React the mixture; and

[0199] III) Optionally, perform a purification step on the mixture.

[0200] Example 2. The method according to Example 1, wherein the alkylamine comprises a functional group selected from branched C1-C 10 alkyl and unbranched C1-C 10 alkyl. In some embodiments, the alkylamine is selected from branched C1-C5 alkyl and unbranched C1-C5 alkyl.

[0201] Example 3. The method according to Example 2, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert-butylamine, and combinations thereof.

[0202] Example 4. The method according to Example 3, wherein the alkylamine is methylamine.

[0203] Example 5. The method according to Example 1, wherein the solvent C) is selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0204] Example 6. The method according to Example 5, wherein the solvent C) is ethyl acetate.

[0205] Example 7. The method according to Example 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.

[0206] Example 8. The method according to Example 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.

[0207] Example 9. The method according to Example 1, wherein the solvent b) comprises a solvent selected from the following: acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0208] Example 10. The method according to Example 9, wherein the solvent b) contains sulfuric acid and methanesulfonic acid.

[0209] Example 11. The method according to Example 1, wherein the halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof.

[0210] Example 12. The method according to Example 11, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0211] Example 13. The method according to Example 12, wherein the chlorinating reagent is chlorine.

[0212] Example 14. The method according to Example 1, wherein step ii) of the method for reacting the first mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C.

[0213] Example 15. The method according to Example 14, wherein step ii) of the method for reacting the first mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0214] Example 16. The method according to Example 1, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0215] Example 17. The method according to Example 16, wherein the oxidizing agent is hydrogen peroxide.

[0216] Example 18. The method according to Example 1, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0217] Example 19. The method according to Example 18, wherein the catalyst is sulfuric acid.

[0218] Example 20. The method according to Example 1, wherein the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash point aromatic solvents (S150), high flash point aromatic solvents (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof.

[0219] Example 21. The method according to Example 20, wherein the additive is a combination of ethyl acetate and mesitylene.

[0220] Example 22. The method according to Example 1, wherein step v) of the method for reacting the second mixture occurs at a reaction temperature in the range of about 20 °C to about 100 °C.

[0221] Example 23. The method according to Example 20, wherein the method step v) of reacting the second mixture occurs at a reaction temperature of at least one selected from about 30 °C to about 40 °C and about 60 °C to about 70 °C.

[0222] Example 24. The method according to Example 1, wherein the compound having formula III is prepared according to the following method, which comprises:

[0223] I) Forming a mixture comprising:

[0224] A) A compound having formula II, wherein

[0225]

[0226] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0227] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0228] and

[0229] wherein the compound having formula II is prepared according to the following method, which comprises:

[0230] i) Forming a mixture comprising:

[0231] a) A compound having formula I, wherein

[0232]

[0233] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0234] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0235] b) Chloral hydrate;

[0236] c) Hydroxylamine or a hydroxylamine derivative;

[0237] d) A solvent;

[0238] e) Optionally a pH regulator; and

[0239] f) An acid;

[0240] ii) Reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0241] iii) Optionally extracting the mixture with an extraction solvent;

[0242] B) an acid; and

[0243] C) a solvent; and

[0244] II) reacting the mixture.

[0245] Example 25. The method according to Example 22, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0246] Example 26. The method according to Example 25, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0247] Example 27. The method according to Example 24, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0248] Example 28. The method according to Example 27, wherein the solvent C) is 1,2-dichloroethane.

[0249] Example 29. The method according to Example 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.

[0250] Example 30. The method according to Example 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.

[0251] Example 31. The method according to Example 24, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0252] Example 32. The method according to Example 31, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0253] Example 33. The method according to Example 24, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0254] Example 34. The method according to Example 33, wherein the solvent d) is water.

[0255] Example 35. The method according to Example 24, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0256] Example 36. The method according to Example 35, wherein the pH regulator is sodium carbonate.

[0257] Example 37. The method according to Example 24, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0258] Example 38. The method according to Example 37, wherein the acid f) is hydrochloric acid.

[0259] Example 39. The method according to Example 24, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0260] Example 40. The method according to Example 39, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0261] Example 41. The method according to Example 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.

[0262] Example 42. The method according to Example 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 °C.

[0263] Example 43. The method according to Example 24, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0264] Example 44. The method according to Example 43, wherein the extraction solvent is 1,2-dichloroethane.

[0265] Example 45. A method for preparing a compound of formula V, wherein,

[0266]

[0267] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and

[0268] wherein at least one of R7 - R 10 is halogen, the method comprising:

[0269] I) forming a first mixture, the first mixture comprising:

[0270] A) a compound of formula III, wherein

[0271]

[0272] R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and

[0273] at least one of R1 - R4 is hydrogen;

[0274] B) a solvent containing an acid; and

[0275] C) a halogenating reagent;

[0276] II) reacting the first mixture;

[0277] III) optionally removing a portion of the solvent containing the acid;

[0278] IV) forming a second mixture, the second mixture comprising:

[0279] the first mixture;

[0280] D) an oxidizing agent; and

[0281] E) an additive; and

[0282] V) reacting the second mixture, wherein the second mixture reacts in the presence of a catalyst.

[0283] Example 46. The method according to Example 45, wherein the solvent comprises a solvent selected from: acetonitrile, 1,2 - dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, and combinations thereof.

[0284] Example 47. The method according to Example 46, wherein the solvent contains sulfuric acid and methanesulfonic acid.

[0285] Example 48. The method according to Example 45, wherein the halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof.

[0286] Example 49. The method according to Example 48, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0287] Example 50. The method according to Example 49, wherein the chlorinating reagent is chlorine.

[0288] Example 51. The method according to Example 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.

[0289] Example 52. The method as described in Example 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.

[0290] Example 53. The method as described in Example 45, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0291] Example 54. The method as described in Example 50, wherein the oxidizing agent is hydrogen peroxide.

[0292] Example 55. The method as described in Example 42, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0293] Example 56. The method as described in Example 55, wherein the catalyst is sulfuric acid.

[0294] Example 57. The method as described in Example 45, wherein the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash point aromatic solvents (S150), high flash point aromatic solvents (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof.

[0295] Example 58. The method as described in Example 57, wherein the additive is a combination of ethyl acetate and mesitylene.

[0296] Example 59. The method as described in Example 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.

[0297] Example 60. The method as described in Example 59, wherein the method step V) of reacting the second mixture occurs at a reaction temperature selected from at least one of about 30 °C to about 40 °C and about 60 °C to about 70 °C.

[0298] Example 61. The method as described in Example 45, wherein the compound having formula III is prepared by a method comprising:

[0299] I) forming a mixture, the mixture comprising:

[0300] A) a compound having formula II, wherein

[0301]

[0302] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0303] and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0304] and

[0305] wherein the compound of formula II is prepared according to the following method, which comprises:

[0306] i) forming a mixture comprising:

[0307] a) a compound of formula I, wherein

[0308]

[0309] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0310] and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0311] b) chloral hydrate;

[0312] c) hydroxylamine or a hydroxylamine derivative;

[0313] d) a solvent;

[0314] e) optionally a pH regulator; and

[0315] f) an acid;

[0316] ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0317] iii) optionally extracting the mixture with an extraction solvent;

[0318] B) an acid; and

[0319] C) a solvent; and

[0320] II) reacting the mixture.

[0321] Example 62. The method according to Example 61, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0322] Example 63. The method according to Example 62, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0323] Example 64. The method according to Example 61, wherein the solvent C) is selected from 1,2-dichloroethane, dichloromethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0324] Example 65. The method according to Example 64, wherein the solvent C) is 1,2-dichloroethane.

[0325] Example 66. The method according to Example 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.

[0326] Example 67. The method according to Example 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.

[0327] Example 68. The method according to Example 61, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0328] Example 69. The method according to Example 68, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0329] Example 70. The method according to Example 61, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0330] Example 71. The method according to Example 70, wherein the solvent d) is water.

[0331] Example 72. The method according to Example 61, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0332] Example 73. The method according to Example 72, wherein the pH regulator is sodium carbonate.

[0333] Example 74. The method according to Example 61, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0334] Example 75. The method according to Example 74, wherein the acid f) is hydrochloric acid.

[0335] Example 76. The method according to Example 61, wherein the concentration range of the compound of formula I in the mixture is from about 1% to about 30%.

[0336] Example 77. The method according to Example 76, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0337] Example 78. The method according to Example 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.

[0338] Example 79. The method according to Example 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.

[0339] Example 80. The method according to Example 61, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0340] Example 81. The method according to Example 74, wherein the extraction solvent is 1,2-dichloroethane.

[0341] Example 82. A method for preparing a compound of formula VI, wherein,

[0342]

[0343] R7-R 10 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R 10 is halogen; and

[0344] wherein R 11 is selected from branched C1-C 10 alkyl and unbranched C1-C 10 alkyl, the method comprising: I) forming a mixture comprising:

[0345] A) a compound of formula V, wherein

[0346]

[0347] R7-R 10 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R 10 is halogen; and

[0348] wherein the compound of formula V is prepared according to the following method, the method comprising:

[0349] i) forming a mixture comprising:

[0350] a) A compound of formula IV, wherein

[0351]

[0352] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and

[0353] wherein at least one of R7 - R 10 is halogen;

[0354] b) An oxidizing agent;

[0355] c) A solvent; and

[0356] d) An additive; and

[0357] ii) Reacting the mixture, wherein the mixture is reacted in the presence of a catalyst;

[0358] B) An alkylamine; and

[0359] C) A solvent;

[0360] II) Reacting the mixture; and

[0361] III) Optionally, performing a purification step on the mixture.

[0362] Example 83. The method according to Example 82, wherein the alkylamine comprises a functional group selected from branched C1 - C 10 alkyl and unbranched C1 - C 10 alkyl. In some embodiments, the alkylamine is selected from branched C1 - C5 alkyl and unbranched C1 - C5 alkyl.

[0363] Example 84. The method according to Example 83, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert - butylamine, and combinations thereof.

[0364] Example 85. The method according to Example 84, wherein the alkylamine is methylamine.

[0365] Example 86. The method according to Example 82, wherein the solvent C) is selected from acetonitrile, dichloromethane, 1,2 - dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0366] Example 87. The method according to Example 86, wherein the solvent C) is ethyl acetate.

[0367] Example 88. The method according to Example 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.

[0368] Example 89. The method according to Example 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.

[0369] Example 90. The method according to Example 82, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0370] Example 91. The method according to Example 90, wherein the oxidizing agent is hydrogen peroxide.

[0371] Example 92. The method according to Example 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.

[0372] Example 93. The method according to Example 92, wherein the solvent c) is acetic acid.

[0373] Example 94. The method according to Example 82, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0374] Example 95. The method according to Example 94, wherein the catalyst is sulfuric acid.

[0375] Example 96. The method according to Example 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-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash point aromatic solvents (S150), high flash point aromatic solvents (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof.

[0376] Example 97. The method according to Example 96, wherein the additive is a combination of ethyl acetate and mesitylene.

[0377] Example 98. The method according to Example 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.

[0378] Example 99. The method according to Example 98, wherein the method step ii) of reacting the mixture occurs at a reaction temperature selected from at least one of about 30°C to about 40°C and about 60°C to about 70°C.

[0379] Example 100. The method according to Example 82, wherein the compound of formula IV is prepared according to the following method, which comprises:

[0380] I) forming a mixture comprising:

[0381] A) a compound of formula III, wherein

[0382]

[0383] R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and

[0384] at least one of R1 - R4 is hydrogen;

[0385] B) a solvent comprising an acid;

[0386] C) a halogenating reagent; and

[0387] II) reacting the mixture.

[0388] Example 101. The method according to Example 100, wherein the solvent comprises a solvent selected from: acetonitrile, dichloromethane, 1,2 - dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0389] Example 102. The method according to Example 101, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0390] Example 103. The method according to Example 100, wherein the halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof.

[0391] Example 104. The method according to Example 103, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0392] Example 105. The method according to Example 104, wherein the chlorinating reagent is chlorine.

[0393] Example 106. The method according to Example 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.

[0394] Example 107. The method according to Example 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.

[0395] Example 108. The method according to Example 100, wherein the compound of formula III is prepared according to the following method, which comprises:

[0396] I) forming a mixture comprising:

[0397] A) a compound of formula II, wherein

[0398]

[0399] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0400] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0401] and

[0402] wherein the compound of formula II is prepared according to the following method, which comprises:

[0403] i) forming a mixture comprising:

[0404] a) a compound of formula I, wherein

[0405]

[0406] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0407] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0408] b) chloral hydrate;

[0409] c) hydroxylamine or a hydroxylamine derivative;

[0410] d) a solvent;

[0411] e) optionally a pH regulator; and

[0412] f) an acid;

[0413] ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0414] iii) optionally extracting the mixture with an extraction solvent;

[0415] B) acid; and

[0416] C) a solvent; and

[0417] II) reacting the mixture.

[0418] Example 109. The method according to Example 108, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0419] Example 110. The method according to Example 109, wherein the acid comprises sulfuric acid and methanesulfonic acid.

[0420] Example 111. The method according to Example 108, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0421] Example 112. The method according to Example 111, wherein the solvent C) is 1,2-dichloroethane.

[0422] Example 113. The method according to Example 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.

[0423] Example 114. The method according to Example 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.

[0424] Example 115. The method according to Example 108, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0425] Example 116. The method according to Example 115, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0426] Example 117. The method according to Example 108, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0427] Example 118. The method according to Example 117, wherein the solvent d) is water.

[0428] Example 119. The method according to Example 108, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0429] Example 120. The method according to Example 119, wherein the pH regulator is sodium carbonate.

[0430] Example 121. The method according to Example 108, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0431] Example 122. The method according to Example 121, wherein the acid f) is hydrochloric acid.

[0432] Example 123. The method according to Example 108, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0433] Example 124. The method according to Example 123, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0434] Example 125. The method according to Example 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.

[0435] Example 126. The method according to Example 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.

[0436] Example 127. The method according to Example 108, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0437] Example 128. The method according to Example 127, wherein the extraction solvent is 1,2-dichloroethane.

[0438] Example 129. The method according to Example 82, wherein the compound of formula IV is prepared according to the following method, which comprises:

[0439] I) forming a first mixture, the first mixture comprising:

[0440] A) a compound of formula II, wherein

[0441]

[0442] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0443] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0444] B) acid; and

[0445] C) a solvent;

[0446] II) reacting the first mixture;

[0447] III) removing a certain amount of the solvent from the first mixture;

[0448] IV) forming a second mixture, the second mixture comprising the first mixture and a halogenating reagent; and

[0449] V) reacting the second mixture.

[0450] Example 130. The method according to Example 129, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0451] Example 131. The method according to Example 130, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0452] Example 132. The method according to Example 129, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0453] Example 133. The method according to Example 132, wherein the solvent C) is 1,2-dichloroethane.

[0454] Example 134. The method according to Example 129, wherein the halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof.

[0455] Example 135. The method according to Example 134, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0456] Example 136. The method according to Example 135, wherein the chlorinating reagent is chlorine.

[0457] Example 137. The method according to Example 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.

[0458] Example 138. The method according to Example 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.

[0459] Example 139. The method according to Example 129, wherein the compound having Formula II is prepared according to the following method, which comprises:

[0460] i) forming a mixture comprising:

[0461] a) a compound having Formula I, wherein

[0462]

[0463] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0464] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0465] b) chloral hydrate;

[0466] c) hydroxylamine or a hydroxylamine derivative;

[0467] d) a solvent;

[0468] e) optionally a pH regulator; and

[0469] f) an acid;

[0470] ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0471] iii) optionally extracting the mixture with an extraction solvent.

[0472] Example 140. The method according to Example 139, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0473] Example 141. The method according to Example 140, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0474] Example 142. The method according to Example 139, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0475] Example 143. The method according to Example 142, wherein the solvent d) is water.

[0476] Example 144. The method according to Example 139, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0477] Example 145. The method according to Example 144, wherein the pH regulator is sodium carbonate.

[0478] Example 146. The method according to Example 139, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0479] Example 147. The method according to Example 146, wherein the acid f) is hydrochloric acid.

[0480] Example 148. The method according to Example 139, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0481] Example 149. The method according to Example 148, wherein the concentration of the compound of formula I in the mixture is in the range of about 3% to about 10%.

[0482] Example 150. The method according to Example 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.

[0483] Example 151. The method according to Example 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.

[0484] Example 152. The method according to Example 139, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0485] Example 153. The method according to Example 152, wherein the extraction solvent is 1,2-dichloroethane.

[0486] Example 154. A method for preparing a compound of formula V, wherein,

[0487]

[0488] R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and

[0489] wherein at least one of R7-R 10 is halogen, the method comprising:

[0490] I) forming a mixture comprising:

[0491] A) a compound of formula IV, wherein

[0492]

[0493] R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and

[0494] wherein at least one of R7-R 10 is halogen;

[0495] B) an oxidizing agent;

[0496] C) a solvent; and

[0497] D) an additive; and

[0498] II) reacting the mixture, wherein the mixture is reacted in the presence of a catalyst.

[0499] Example 155. The method according to Example 154, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0500] Example 156. The method according to Example 155, wherein the oxidizing agent is hydrogen peroxide.

[0501] Example 157. The method according to Example 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.

[0502] Example 158. The method according to Example 157, wherein the solvent is acetic acid.

[0503] Example 159. The method according to Example 154, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0504] Example 160. The method according to Example 159, wherein the catalyst is sulfuric acid.

[0505] Example 161. The method according to Example 154, wherein the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, S150, S200, Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof.

[0506] Example 162. The method according to Example 161, wherein the additive is a combination of ethyl acetate and mesitylene.

[0507] Example 163. The method according to Example 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.

[0508] Example 164. The method according to Example 163, wherein the method step II) of reacting the mixture occurs at a reaction temperature selected from at least one of about 30 °C to about 40 °C and about 60 °C to about 70 °C.

[0509] Example 165. The method according to Example 154, wherein the compound having formula IV is prepared according to the following method, which comprises:

[0510] I) forming a mixture comprising:

[0511] A) a compound having formula III, wherein

[0512]

[0513] R1-R4 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and

[0514] at least one of R1-R4 is hydrogen;

[0515] B) a solvent comprising an acid;

[0516] C) a halogenating reagent; and

[0517] II) reacting the mixture.

[0518] Example 166. The method according to Example 165, wherein the solvent comprises a solvent selected from: acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0519] Example 167. The method according to Example 166, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0520] Example 168. The method according to Example 165, wherein the halogenating agent is selected from chlorinating agents, brominating agents, iodinating agents, and combinations thereof.

[0521] Example 169. The method according to Example 168, wherein the chlorinating agent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0522] Example 170. The method according to Example 169, wherein the chlorinating agent is chlorine.

[0523] Example 171. The method according to Example 165, wherein step II) of the method of reacting the mixture occurs at a reaction temperature in the range of about 0 °C to about 140 °C.

[0524] Example 172. The method according to Example 171, wherein step II) of the method of reacting the mixture occurs at a reaction temperature in the range of about 20 °C to about 30 °C.

[0525] Example 173. The method according to Example 165, wherein the compound having Formula III is prepared by a method comprising:

[0526] I) forming a mixture comprising:

[0527] A) a compound having Formula II, wherein

[0528]

[0529] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0530] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0531] and

[0532] wherein the compound having Formula II is prepared by a method comprising:

[0533] i) forming a mixture comprising:

[0534] a) a compound having Formula I, wherein

[0535]

[0536] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0537] and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0538] b) chloral hydrate;

[0539] c) hydroxylamine or a hydroxylamine derivative;

[0540] d) a solvent;

[0541] e) optionally a pH regulator; and

[0542] f) an acid;

[0543] ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0544] iii) optionally extracting the mixture with an extraction solvent;

[0545] B) an acid; and

[0546] C) a solvent; and

[0547] II) reacting the mixture.

[0548] Example 174. The method according to Example 173, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0549] Example 175. The method according to Example 174, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0550] Example 176. The method according to Example 173, wherein the solvent C) is selected from dichloromethane, 1,2 - dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0551] Example 177. The method according to Example 176, wherein the solvent C) is 1,2 - dichloroethane.

[0552] Example 178. The method according to Example 173, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range from about 10 °C to about 90 °C.

[0553] Example 179. The method according to Example 178, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range from about 45 °C to about 55 °C.

[0554] Example 180. The method according to Example 173, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0555] Example 181. The method according to Example 180, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0556] Example 182. The method according to Example 173, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0557] Example 183. The method according to Example 182, wherein the solvent d) is water.

[0558] Example 184. The method according to Example 173, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0559] Example 185. The method according to Example 184, wherein the pH regulator is sodium carbonate.

[0560] Example 186. The method according to Example 173, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0561] Example 187. The method according to Example 186, wherein the acid f) is hydrochloric acid.

[0562] Example 188. The method according to Example 173, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0563] Example 189. The method according to Example 188, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0564] Example 190. The method according to Example 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.

[0565] Example 191. The method according to Example 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.

[0566] Example 192. The method according to Example 173, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0567] Example 193. The method according to Example 192, wherein the extraction solvent is 1,2-dichloroethane.

[0568] Example 194. The method according to Example 154, wherein the compound having Formula IV is prepared according to the following method, which comprises:

[0569] I) forming a first mixture comprising:

[0570] A) a compound having Formula II, wherein

[0571]

[0572] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0573] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0574] B) an acid; and

[0575] C) a solvent;

[0576] II) reacting the first mixture;

[0577] III) removing a portion of the solvent from the first mixture;

[0578] IV) forming a second mixture comprising the first mixture and a halogenating reagent; and

[0579] V) reacting the second mixture.

[0580] Example 195. The method according to Example 194, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0581] Example 196. The method according to Example 195, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0582] Example 197. The method according to Example 194, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0583] Example 198. The method according to Example 197, wherein the solvent C) is 1,2-dichloroethane.

[0584] Example 199. The method according to Example 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.

[0585] Example 200. The method according to Example 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.

[0586] Example 201. The method according to Example 194, wherein the halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof.

[0587] Example 202. The method according to Example 201, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0588] Example 203. The method according to Example 202, wherein the chlorinating reagent is chlorine.

[0589] Example 204. The method according to Example 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.

[0590] Example 205. The method according to Example 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.

[0591] Example 206. The method according to Example 194, wherein the compound of formula II is prepared according to the following method, the method comprising:

[0592] i) forming a mixture, the mixture comprising:

[0593] a) a compound of formula I, wherein

[0594]

[0595] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0596] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0597] b) chloral hydrate;

[0598] c) Hydroxylamine or hydroxylamine derivatives;

[0599] d) A solvent;

[0600] e) Optionally, a pH regulator; and

[0601] f) An acid;

[0602] ii) Reacting the mixture, wherein the mixture is reacted at a pH in the range from about 0 to about 7; and

[0603] iii) Optionally extracting the mixture with an extraction solvent.

[0604] Example 207. The method according to Example 206, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0605] Example 208. The method according to Example 207, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0606] Example 209. The method according to Example 206, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0607] Example 210. The method according to Example 209, wherein the solvent d) is water.

[0608] Example 211. The method according to Example 206, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0609] Example 212. The method according to Example 211, wherein the pH regulator is sodium carbonate.

[0610] Example 213. The method according to Example 206, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0611] Example 214. The method according to Example 213, wherein the acid f) is hydrochloric acid.

[0612] Example 215. The method according to Example 206, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0613] Example 216. The method according to Example 215, wherein the concentration of the compound of formula I in the mixture is in the range of about 3% to about 10%.

[0614] Example 217. The method as described in Example 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.

[0615] Example 218. The method as described in Example 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.

[0616] Example 219. The method as described in Example 206, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0617] Example 220. The method as described in Example 219, wherein the extraction solvent is 1,2-dichloroethane.

[0618] Example 221. A method for preparing a compound of formula IV, wherein,

[0619]

[0620] R7 - R 10 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0621] wherein at least one of R7 - R 10 is halogen, and the method comprises:

[0622] I) forming a mixture comprising:

[0623] A) a compound of formula III, wherein

[0624]

[0625] R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and

[0626] at least one of R1 - R4 is hydrogen;

[0627] B) a solvent comprising an acid;

[0628] C) a halogenating reagent; and

[0629] II) reacting the mixture.

[0630] Example 222. The method according to Example 221, wherein the solvent comprises a solvent selected from the group consisting of acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof.

[0631] Example 223. The method according to Example 222, wherein the solvent comprises sulfuric acid and methanesulfonic acid.

[0632] Example 224. The method according to Example 221, wherein the halogenating agent is selected from the group consisting of chlorinating agents, brominating agents, iodinating agents, and combinations thereof.

[0633] Example 225. The method according to Example 224, wherein the chlorinating agent is selected from the group consisting of chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0634] Example 226. The method according to Example 225, wherein the chlorinating agent is chlorine.

[0635] Example 227. The method according to Example 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.

[0636] Example 228. The method according to Example 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.

[0637] Example 229. The method according to Example 221, wherein the compound having formula III is prepared according to the following method, which comprises:

[0638] I) forming a mixture comprising:

[0639] A) a compound having formula II, wherein

[0640]

[0641] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0642] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0643] and

[0644] wherein the compound having formula II is prepared according to the following method, which comprises:

[0645] i) Form a mixture comprising:

[0646] a) A compound of formula I, wherein

[0647]

[0648] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0649] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0650] b) Chloral hydrate;

[0651] c) Hydroxylamine or a hydroxylamine derivative;

[0652] d) A solvent;

[0653] e) Optionally a pH regulator; and

[0654] f) An acid;

[0655] ii) React the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0656] iii) Optionally extract the mixture with an extraction solvent;

[0657] B) An acid; and

[0658] C) A solvent; and

[0659] II) React the mixture.

[0660] Example 230. The method according to Example 229, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0661] Example 231. The method according to Example 229, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0662] Example 232. The method according to Example 229, wherein the solvent C) is selected from dichloromethane, 1,2 - dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0663] Example 233. The method according to Example 232, wherein the solvent C) is 1,2 - dichloroethane.

[0664] Example 234. The method according to Example 229, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range from about 10 °C to about 90 °C.

[0665] Example 235. The method according to Example 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.

[0666] Example 236. The method according to Example 229, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0667] Example 237. The method according to Example 236, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0668] Example 238. The method according to Example 229, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0669] Example 239. The method according to Example 238, wherein the solvent d) is water.

[0670] Example 240. The method according to Example 229, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0671] Example 241. The method according to Example 240, wherein the pH regulator is sodium carbonate.

[0672] Example 242. The method according to Example 229, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0673] Example 243. The method according to Example 242, wherein the acid f) is hydrochloric acid.

[0674] Example 244. The method according to Example 229, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0675] Example 245. The method according to Example 244, wherein the concentration of the compound of formula I in the mixture is in the range of about 3% to about 10%.

[0676] Example 246. The method according to Example 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.

[0677] Example 247. The method according to Example 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.

[0678] Example 248. The method according to Example 229, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0679] Example 249. The method according to Example 248, wherein the extraction solvent is 1,2-dichloroethane.

[0680] Example 250. A method for preparing a compound of formula III, wherein,

[0681]

[0682] R1-R4 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl, and at least one of R1-R4 is hydrogen, and the method comprises:

[0683] I) forming a mixture comprising:

[0684] A) a compound of formula II, wherein

[0685]

[0686] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0687] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0688] and

[0689] wherein the compound of formula II is prepared according to the following method, the method comprising:

[0690] i) forming a mixture comprising:

[0691] a) a compound of formula I, wherein

[0692]

[0693] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0694] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0695] b) chloral hydrate;

[0696] c) hydroxylamine or a hydroxylamine derivative;

[0697] d) a solvent;

[0698] e) optionally a pH regulator; and

[0699] f) an acid;

[0700] ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0701] iii) optionally extracting the mixture with an extraction solvent;

[0702] B) an acid; and

[0703] C) a solvent; and

[0704] II) reacting the mixture.

[0705] Example 251. The method according to Example 250, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, methanesulfonic acid, and combinations thereof.

[0706] Example 252. The method according to Example 251, wherein the acid is sulfuric acid and methanesulfonic acid.

[0707] Example 253. The method according to Example 250, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0708] Example 254. The method according to Example 253, wherein the solvent C) is 1,2-dichloroethane.

[0709] Example 255. The method according to Example 250, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range from about 10 °C to about 90 °C.

[0710] Example 256. The method according to Example 255, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range from about 45 °C to about 55 °C.

[0711] Example 257. The method according to Example 250, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0712] Example 258. The method according to Example 257, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0713] Example 259. The method as described in Example 250, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0714] Example 260. The method as described in Example 259, wherein the solvent d) is water.

[0715] Example 261. The method as described in Example 250, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0716] Example 262. The method as described in Example 261, wherein the pH regulator is sodium carbonate.

[0717] Example 263. The method as described in Example 250, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0718] Example 264. The method as described in Example 263, wherein the acid f) is hydrochloric acid.

[0719] Example 265. The method as described in Example 250, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0720] Example 266. The method as described in Example 265, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0721] Example 267. The method as described in Example 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.

[0722] Example 268. The method as described in Example 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.

[0723] Example 269. The method as described in Example 250, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0724] Example 270. The method as described in Example 269, wherein the extraction solvent is 1,2-dichloroethane.

[0725] Example 271. A method for preparing a compound of formula II, wherein,

[0726]

[0727] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl,

[0728] and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen,

[0729] The method comprises:

[0730] I) forming a mixture comprising:

[0731] A) a compound having formula I, wherein

[0732]

[0733] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0734] and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0735] B) chloral hydrate;

[0736] C) hydroxylamine or a hydroxylamine derivative;

[0737] D) a solvent;

[0738] E) optionally a pH regulator; and

[0739] F) an acid; and

[0740] II) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0741] III) optionally extracting the mixture with an extraction solvent.

[0742] Example 272. The method according to Example 271, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0743] Example 273. The method according to Example 272, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0744] Example 274. The method according to Example 271, wherein the solvent D) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0745] Example 275. The method according to Example 274, wherein the solvent D) is water.

[0746] Example 276. The method according to Example 271, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0747] Example 277. The method according to Example 276, wherein the pH regulator is sodium carbonate.

[0748] Example 278. The method according to Example 271, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0749] Example 279. The method according to Example 278, wherein the acid is hydrochloric acid.

[0750] Example 280. The method according to Example 271, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0751] Example 281. The method according to Example 280, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0752] Example 282. The method according to Example 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.

[0753] Example 283. The method according to Example 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.

[0754] Example 284. The method according to Example 271, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0755] Example 285. The method according to Example 284, wherein the extraction solvent is 1,2-dichloroethane.

[0756] Example 286. A method for preparing a compound of formula IV, wherein,

[0757]

[0758] R7 - R 10 each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0759] wherein at least one of R7-R 10 is a halogen, and the method comprises:

[0760] I) forming a first mixture comprising:

[0761] A) a compound of formula II, wherein

[0762]

[0763] R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl;

[0764] and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0765] B) an acid; and

[0766] C) a solvent;

[0767] II) reacting the first mixture;

[0768] III) removing a portion of the solvent from the first mixture;

[0769] IV) forming a second mixture comprising the first mixture and a halogenating reagent; and

[0770] V) reacting the second mixture.

[0771] Example 287. The method according to Example 286, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0772] Example 288. The method according to Example 287, wherein the acid B) comprises sulfuric acid and methanesulfonic acid.

[0773] Example 289. The method according to Example 286, wherein the solvent C) is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof.

[0774] Example 290. The method according to Example 289, wherein the solvent C) is 1,2-dichloroethane.

[0775] Example 291. The method according to Example 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.

[0776] Example 292. The method according to Example 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.

[0777] Example 293. The method according to Example 286, wherein the halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof.

[0778] Example 294. The method according to Example 293, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0779] Example 295. The method according to Example 294, wherein the chlorinating reagent is chlorine.

[0780] Example 296. The method according to Example 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.

[0781] Example 297. The method according to Example 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.

[0782] Example 298. The method according to Example 286, wherein the compound having Formula II is prepared by a method comprising:

[0783] i) forming a mixture comprising:

[0784] a) a compound having Formula I, wherein

[0785]

[0786] R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl;

[0787] and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen;

[0788] b) chloral hydrate;

[0789] c) hydroxylamine or a hydroxylamine derivative;

[0790] d) a solvent;

[0791] e) optionally a pH regulator; and

[0792] f) an acid;

[0793] ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and

[0794] iii) optionally extracting the mixture with an extraction solvent.

[0795] Example 299. The method as described in Example 298, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof.

[0796] Example 300. The method as described in Example 299, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0797] Example 301. The method as described in Example 298, wherein the solvent d) is selected from methanol, ethanol, toluene, ethyl acetate, formic acid, acetic acid, water, and combinations thereof.

[0798] Example 302. The method as described in Example 301, wherein the solvent d) is water.

[0799] Example 303. The method as described in Example 298, wherein the pH regulator 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, their salts, their aqueous solutions, and combinations thereof.

[0800] Example 304. The method as described in Example 303, wherein the pH regulator is sodium carbonate.

[0801] Example 305. The method as described in Example 298, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof.

[0802] Example 306. The method as described in Example 305, wherein the acid is hydrochloric acid.

[0803] Example 307. The method as described in Example 298, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0804] Example 308. The method as described in Example 307, wherein the concentration of the compound of formula I in the mixture is in the range of about 3% to about 10%.

[0805] Example 309. The method as described in Example 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.

[0806] Example 310. The method as described in Example 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.

[0807] Example 311. The method as described in Example 298, wherein the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof.

[0808] Example 312. The method as described in Example 311, wherein the extraction solvent is 1,2-dichloroethane.

[0809] In one aspect, a compound of Formula VI is prepared according to the method represented by Scheme 1. The R group is defined anywhere in this disclosure.

[0810] Scheme 1.

[0811]

[0812] In one aspect, a compound of Formula VI is prepared according to the method represented by Scheme 2. The R group is defined anywhere in this disclosure.

[0813] Scheme 2.

[0814]

[0815] In one aspect, a compound of Formula VI is prepared according to the method represented by Scheme 3. The R group is defined anywhere in this disclosure.

[0816] Scheme 3.

[0817]

[0818] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 4.

[0819] Scheme 4.

[0820]

[0821] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 5.

[0822] Scheme 5.

[0823]

[0824] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 6.

[0825] Scheme 6.

[0826]

[0827] In one aspect, a compound of formula II or a salt thereof is prepared according to the method represented by Scheme 7. The R group is defined anywhere in this disclosure.

[0828] Scheme 7.

[0829]

[0830] This aspect includes: forming a mixture that comprises a compound of formula I or a salt thereof, chloral hydrate, hydroxylamine or a hydroxylamine derivative, a solvent, optionally a pH regulator, and an acid; and reacting the mixture. The mixture is reacted at a pH in the range from about 0 to about 7. The mixture is optionally extracted with an extraction solvent.

[0831] In some embodiments, the mixture components are added simultaneously to form the mixture. In some embodiments, the mixture components are added separately to form the mixture. In some embodiments, the mixture components are added separately in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0832] In some embodiments, the mixture is reacted at a pH in the range 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 the range from 0.95 to about 1.05.

[0833] In some embodiments, chloral hydrate is present in an amount from about 1.0 equivalent to about 3.0 equivalents. In some embodiments, chloral hydrate is present in an amount from about 1.1 equivalents to about 3.0 equivalents.

[0834] In some embodiments, the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine salts, hydroxylamine solutions, and combinations thereof. In some embodiments, the hydroxylamine derivative is hydroxylamine sulfate.

[0835] In some embodiments, the hydroxylamine derivative is present in an amount from about 0.5 equivalent to about 3.0 equivalents. In some embodiments, the hydroxylamine derivative is present in an amount from about 0.6 equivalent to about 1.5 equivalents.

[0836] 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.

[0837] In some embodiments, the solvent is present in an amount from about 5.0 w / w to about 30.0 w / w, based on the weight of the compound of Formula I. In some embodiments, the solvent is present in an amount from about 14.0 w / w to about 15.0 w / w, based on the weight of the compound of Formula I. When the solvent is water, these amounts of solvent do not include water from the pH regulator when a pH regulator is present.

[0838] When present, the pH regulator controls the pH. In some embodiments, the pH regulator is a base, an inorganic base, an organic base, a solid base, an aqueous base, an aqueous inorganic base, an aqueous inorganic salt base, an aqueous organic base, an aqueous organic salt base, its salt, its aqueous solution, or a combination thereof. In some embodiments, the pH regulator is a base. In some embodiments, the pH regulator 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 regulator is selected from organic bases such as triethylamine, pyridine, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and combinations thereof. In some embodiments, the pH regulator is sodium carbonate.

[0839] In some embodiments, sodium carbonate is added in solid or aqueous solution form. In some embodiments, sodium carbonate is added in aqueous solution form.

[0840] In some embodiments, the concentration of the aqueous sodium carbonate solution ranges from about 1.0 wt% to about 33.0 wt%. In some embodiments, the concentration of the aqueous sodium carbonate solution ranges from about 19.0 wt% to about 33.0 wt%.

[0841] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, formic acid, acetic acid, sulfonic acid, and combinations thereof. In some embodiments, the acid is hydrochloric acid.

[0842] In some embodiments, the acid is present in an amount from about 0.5 equivalents to about 2.0 equivalents. In some embodiments, the acid is present in an amount from about 1.1 equivalents to about 2.0 equivalents.

[0843] 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.

[0844] In some embodiments, the extraction solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, petroleum ether, toluene, chlorobenzene, xylene, methyl isobutyl ketone, and combinations thereof. In some embodiments, the extraction solvent is 1,2-dichloroethane.

[0845] In some embodiments, in a compound of Formula I, at least two of R1 - R5 are hydrogen. In some embodiments, in a compound of Formula I, at least one of R1 and R5 is hydrogen. In some embodiments, in a compound of Formula I, at least two of R1 - R5 are hydrogen, wherein at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula I is o - toluidine.

[0846] In some embodiments, the compound of Formula I is present in an amount from about 1 wt% to about 30 wt%. In some embodiments, the compound of Formula I is present in an amount from about 3 wt% to about 10 wt%.

[0847] In some embodiments, in a compound of Formula II, at least one of R1 - R5 is hydrogen. In some embodiments, in a compound of Formula II, at least two of R1 - R5 are hydrogen. In some embodiments, in a compound of Formula II, at least one of R1 and R5 is hydrogen. In some embodiments, in a compound of Formula II, at least two of R1 - R5 are hydrogen, wherein at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula II is (E) - 3 - hydroxy - N - (o - tolyl)acrylamide.

[0848] Controlling the reaction pH avoids the addition of sodium sulfate salts and reduces the use of water. For example, by using an aqueous solution of Na2CO3 to control the reaction pH between 0.95 - 1.05, the addition of sodium sulfate salts is avoided and the use of water is reduced to from about 50 w / w to about 25 w / w. In this way, waste solids and wastewater are significantly reduced. Additionally, when the reaction scheme includes a filtration step to separate product solids and mother liquor, some of the product remains dissolved in the mother liquor and is difficult to separate, resulting in a yield loss of about 5% - 7% in the mother liquor. In this scheme, extraction is used instead of filtration. For example, when 1,2 - dichloroethane (DCE) is used as the extraction solvent, the yield loss of the product in the aqueous phase is less than about 1.5% and drying of the solid product can be achieved simultaneously. When the extraction step is combined with pH control, the separation yield of this scheme can be increased from 70% - 73% to 83% - 88%.

[0849] In one aspect, a compound of Formula III or a salt thereof is prepared according to the method represented by Scheme 8. The R group is defined anywhere in this disclosure.

[0850] Scheme 8.

[0851]

[0852] This aspect includes: forming a mixture that comprises a compound of Formula II or a salt thereof, an acid, and a solvent; and reacting the mixture.

[0853] In some embodiments, the mixture components are added simultaneously to form a mixture. In some embodiments, the mixture components are added separately to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0854] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and combinations thereof. In some embodiments, the acid comprises sulfuric acid and methanesulfonic acid.

[0855] In some embodiments, the solvent is selected from 1,2-dichloroethane, dichloromethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof. In some embodiments, the solvent is 1,2-dichloroethane.

[0856] In some embodiments, the solvent contains 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.

[0857] In some embodiments, the acid and / or the acid in the solvent is present in an amount from about 3.0 w / w to about 10.0 w / w relative to the weight of the compound having Formula II. In some embodiments, the acid and / or the acid in the solvent is present in an amount from about 5.0 w / w to about 10.0 w / w relative to the weight of the compound having Formula II. In some embodiments, methanesulfonic acid is present in an amount from about 3.0 w / w to about 10.0 w / w relative to the weight of the compound having Formula II. In some embodiments, methanesulfonic acid is present in an amount from about 5.0 w / w to about 10.0 w / w relative to the weight of the compound having Formula II.

[0858] In some embodiments, the acid and / or the acid in the solvent is present in an amount from about 0.1 equivalent to about 10.0 equivalents relative to the compound having Formula II. In some embodiments, the acid and / or the acid in the solvent is present in an amount from about 1.0 equivalent to about 10.0 equivalents relative to the compound having Formula II. In some embodiments, sulfuric acid is present in an amount from about 0.1 equivalent to about 10.0 equivalents relative to the compound having Formula II. In some embodiments, sulfuric acid is present in an amount from about 1.0 equivalent to about 10.0 equivalents relative to the compound having Formula II.

[0859] 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.

[0860] In some embodiments, in the compound of Formula III, at least one of R1-R4 is hydrogen. In some embodiments, the compound of Formula III is 7-methylindoline-2,3-dione.

[0861] In some embodiments, in the compound of Formula II, at least one of R1-R5 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 R1 and R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1-R5 are hydrogen, wherein at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0862] In this scenario, it is particularly beneficial to use a sulfonic acid such as methanesulfonic acid. Methanesulfonic acid is a recyclable acid and the recovery rate is about 80%-90%. It can significantly reduce the generation of waste solids. Additionally, temperature control is achieved and heat release is minimized. Finally, the product yield is increased.

[0863] In one aspect, a compound of Formula IV or a salt thereof is prepared according to the method represented by Scheme 9. The R group is defined anywhere in this disclosure.

[0864] Scheme 9.

[0865]

[0866] This aspect includes: forming a mixture that contains a compound of Formula III or a salt thereof, a halogenating reagent, and a solvent containing an acid; and reacting the mixture.

[0867] In some embodiments, the mixture components are added simultaneously to form the mixture. In some embodiments, the mixture components are added separately to form the mixture. In some embodiments, the mixture components are added separately in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0868] In some embodiments, the solvent includes a solvent selected from: acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, sulfonic acid, and combinations thereof. In some embodiments, the solvent contains sulfuric acid and methanesulfonic acid.

[0869] In some embodiments, the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof. In some embodiments, the halogenating reagent is a chlorinating reagent.

[0870] In some embodiments, the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In some embodiments, the chlorinating reagent is chlorine.

[0871] 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.

[0872] In some embodiments, in the compound of formula III, at least one of R1-R4 is hydrogen. In some embodiments, the compound of formula III is 7-methylindoline-2,3-dione.

[0873] In some embodiments, in the compound of formula IV, at least one of R7-R 10 is a halogen. In some embodiments, in the compound of formula IV, at least one of R7-R 10 is chlorine. In some embodiments, the compound of formula IV is 5-chloro-7-methylindoline-2,3-dione.

[0874] In this aspect, the use of chlorine as the chlorinating agent is particularly beneficial. Chlorine is more reactive than other chlorinating agents such as sulfuryl chloride, and the reaction with chlorine can be carried out at room temperature. The use of chlorine also increases the yield of the compound of formula IV.

[0875] In one aspect, the compound of formula IV or a salt thereof is prepared according to the method represented by Scheme 10. The R group is defined as anywhere in this disclosure.

[0876] Scheme 10.

[0877]

[0878] This aspect includes: forming a first mixture that contains a compound of formula II or a salt thereof, an acid, and a solvent; reacting the first mixture; removing a certain amount of the solvent from the first mixture; forming a second mixture that contains the first mixture and a halogenating reagent; and reacting the second mixture.

[0879] In some embodiments, the first mixture components are added simultaneously to form a first mixture. In some embodiments, the second mixture components are added simultaneously to form a second mixture. In some embodiments, the first mixture components are added individually to form a first mixture. In some embodiments, the second mixture components are added individually to form a second mixture. In some embodiments, the first mixture components are added individually in any suitable combination to form a first mixture. In some embodiments, the second mixture components are added individually in any suitable combination to form a 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.

[0880] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, sulfonic acid, and combinations thereof. In some embodiments, the acid includes sulfuric acid and methanesulfonic acid.

[0881] In some embodiments, the solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, toluene, acetonitrile, chlorobenzene, xylene, ethyl acetate, and combinations thereof. In some embodiments, the solvent is 1,2-dichloroethane.

[0882] In some embodiments, the solvent contains an acid. In some embodiments, the solvent is selected from acetic acid, sulfuric acid, methanesulfonic acid, 1,2-dichloroethane / acetic acid, 1,2-dichloroethane / sulfuric acid, 1,2-dichloroethane / methanesulfonic acid, acetonitrile / acetic acid, acetonitrile / sulfuric acid, acetonitrile / methanesulfonic acid, and combinations thereof. In some embodiments, the solvent is 1,2-dichloroethane / methanesulfonic acid.

[0883] In some embodiments, the acid and / or the acid in the solvent is present in an amount from about 3.0 w / w to about 10.0 w / w based on the weight of the compound having Formula II. In some embodiments, the acid and / or the acid in the solvent is present in an amount from about 5.0 w / w to about 10.0 w / w based on the weight of the compound having Formula II. In some embodiments, methanesulfonic acid is present in an amount from about 3.0 w / w to about 10.0 w / w based on the weight of the compound having Formula II. In some embodiments, methanesulfonic acid is present in an amount from about 5.0 w / w to about 10.0 w / w based on the weight of the compound having Formula II.

[0884] In some embodiments, the acid and / or the acid of the solvent are present in an amount from about 0.1 equivalent to about 10.0 equivalents relative to the compound having Formula II. In some embodiments, the acid and / or the acid of the solvent are present in an amount from about 1.0 equivalent to about 10.0 equivalents relative to the compound having Formula II. In some embodiments, sulfuric acid is present in an amount from about 0.1 equivalent to about 10.0 equivalents relative to the compound having Formula II. In some embodiments, sulfuric acid is present in an amount from about 1.0 equivalent to about 10.0 equivalents relative to the compound having Formula II.

[0885] 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.

[0886] In some embodiments, the halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof. In some embodiments, the halogenating reagent is a chlorinating reagent. In some embodiments, the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In some embodiments, the chlorinating reagent is chlorine.

[0887] 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.

[0888] 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.

[0889] In some embodiments, the method step of removing a certain amount of solvent from the first mixture includes removing all of the solvent from the first mixture. In some embodiments, the method step of removing a certain amount of solvent from the first mixture includes removing less than all of the solvent from the first mixture.

[0890] In some embodiments, in the compound of Formula II, at least one of R1 - R5 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 R1 and R5 is hydrogen. In some embodiments, in the compound of Formula II, at least two of R1 - R5 are hydrogen, wherein at least one of R1 and R5 is hydrogen. In some embodiments, the compound of Formula II is (E)-3-hydroxy-N-(o-tolyl)acrylamide.

[0891] In some embodiments, in the compound of Formula IV, at least one of R7 - R 10 is halogen. In some embodiments, in the compound of Formula IV, at least one of R7 - R 10 is chlorine. In some embodiments, the compound of Formula IV is 5-chloro-7-methylindoline-2,3-dione.

[0892] This aspect is particularly beneficial when excess solvent is removed prior to introducing the halogenation step. The overall yield is up to 90%, and the individual yields of the two reactions in this aspect are each approximately 95%.

[0893] This aspect is a one-pot method and has several advantages. First, the need to isolate the intermediate (such as the compound of Formula III) produced from the compound of Formula II prior to subsequent reactions is eliminated. Second, the potential loss of the intermediate (such as the compound of Formula III) produced from the compound of Formula II is reduced. Third, the overall yield is increased. Fourth, the number of reaction steps and post-treatment operations is reduced. Fifth, the total cost is reduced.

[0894] In one aspect, a compound of Formula V or a salt thereof is prepared according to the method represented by Scheme 11. The R group is defined anywhere in this disclosure.

[0895] Scheme 11.

[0896]

[0897] This aspect includes: forming a mixture that contains a compound of Formula IV or a salt thereof, an oxidant, a solvent, and an additive; and reacting the mixture in the presence of a catalyst.

[0898] In some embodiments, the mixture components are added simultaneously to form a mixture. In some embodiments, the mixture components are added separately to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, the mixture components are added separately in any suitable combination to form a mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0899] 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 of 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 of the mixture components are added to the mixture.

[0900] In some embodiments, the catalyst is inherently present in the mixture when the oxidant and the solvent and / or additive react.

[0901] In some embodiments, the oxidant is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof. In some embodiments, the oxidant is hydrogen peroxide.

[0902] In some embodiments, the oxidant is present in an amount in the range from about 1.0 equivalent to about 5.0 equivalents. In some embodiments, the oxidant is present in an amount in the range from about 3.0 equivalents to about 5.0 equivalents.

[0903] 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.

[0904] In some embodiments, the solvent is present in an amount in the range from about 10.0 equivalents to about 30.0 equivalents. In some embodiments, the solvent is present in an amount in the range from about 13.0 equivalents to about 30.0 equivalents.

[0905] In some embodiments, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof. In some embodiments, the catalyst is sulfuric acid.

[0906] In some embodiments, the catalyst is present in an amount in the range from about 0.1 equivalent to about 1.0 equivalent. In some embodiments, the catalyst is present in an amount in the range from about 0.3 equivalent to about 1.0 equivalent.

[0907] In some embodiments, the additive includes an additive selected from toluene, xylene, mesitylene, high flash point aromatic solvent (S150), high flash point aromatic solvent (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof. In some embodiments, the additive contains a co-solvent. In some embodiments, the co-solvent contained in the additive is selected from methanol, ethanol, isopropanol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, and combinations thereof.

[0908] 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-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, polyethylene glycol (PEG) 400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash point aromatic solvent (S150), high flash point aromatic solvent (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof. In some embodiments, the additive contains mesitylene. In some embodiments, the additive contains ethyl acetate. In some embodiments, the additive is a combination of ethyl acetate and mesitylene.

[0909] In some embodiments, the additive is present in an amount in the range from about 0.1 equivalent to about 1.0 equivalent. In some embodiments, the additive is present in an amount in the range from about 0.35 equivalent to about 1.0 equivalent. In some embodiments, the additive is present in an amount in the range from about 0.45 equivalent to about 1.0 equivalent. In some embodiments, the additive is present in an amount in the range from about 0.80 equivalent to about 1.0 equivalent.

[0910] In some embodiments, the method step of reacting the mixture occurs at a reaction temperature in the range from about 20 °C to about 100 °C. In some embodiments, the method step of reacting the mixture occurs at a reaction temperature selected from at least one of 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 from about 30 °C to about 40 °C and / or in the range from 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 from about 30 °C to about 40 °C and at a second reaction temperature in the range from about 60 °C to about 70 °C.

[0911] In some embodiments, in a compound having Formula IV, at least one of R7 - R 10 is a halogen. In some embodiments, in a compound having Formula IV, at least one of R7 - R 10 is chlorine. In some embodiments, the compound having Formula IV is 5 - chloro - 7 - methylindoline - 2,3 - dione.

[0912] In some embodiments, in a compound having Formula V, at least one of R7 - R 10 is a halogen. In some embodiments, in a compound having Formula V, at least one of R7 - R 10 is chlorine. In some embodiments, the compound having Formula V is 6 - chloro - 8 - methyl - 2H - benzoxazine - 2,4(1H) - dione.

[0913] In this regard, using mesitylene as an additive and ethyl acetate as an additive co - solvent is particularly beneficial and increases the conversion rate of the compound having Formula IV. This improved conversion rate increases the yield up to about 85% - 90%. Additionally, the unreacted compound having Formula IV is reduced from about 5 wt% to about 1 - 2 wt%.

[0914] In one aspect, a compound having Formula VI or a salt thereof is prepared according to the method represented by Scheme 12. The R group is defined anywhere in this disclosure.

[0915] Scheme 12.

[0916]

[0917] This aspect includes: forming a mixture that includes a compound having Formula V or a salt thereof, an alkylamine, and a solvent; reacting the mixture; and optionally performing a purification step on the mixture.

[0918] In some embodiments, the mixture components are added simultaneously to form the mixture. In some embodiments, the mixture components are added separately to form the mixture. In some embodiments, the mixture components are added separately in any suitable combination to form the mixture. In some embodiments, the mixture components are added separately in any suitable combination to form the mixture. In some embodiments, at least one mixture component is added dropwise to the mixture.

[0919] In some embodiments, the alkylamine includes a branched C1 - C 10 alkyl and an unbranched C1 - C 10Functional groups of 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, tert-butylamine, and combinations thereof. In some embodiments, the alkylamine is methylamine.

[0920] In some embodiments, the solvent is selected from acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof. In some embodiments, the solvent is ethyl acetate.

[0921] 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.

[0922] In some embodiments, the method step of purifying the mixture includes purification steps selected from the following: phase separation, acidification, precipitation, neutralization, filtration, and combinations thereof. In some embodiments, the method step of purifying the mixture includes a phase separation step, an acidification step including adding an acid, a precipitation step, a first filtration step, a neutralization step including adding a base, and a second filtration step.

[0923] In some embodiments, the method step of purifying the mixture includes adding an aqueous solvent (such as water), performing phase separation, adding an acid to precipitate a salt of formula VI, filtering the precipitated salt of formula VI, adding a base to neutralize the salt of formula VI, and filtering the neutralized compound of formula VI.

[0924] In some embodiments, the method step of purifying 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 purifying 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 purifying the mixture occurs at a reaction temperature in the range of about 20 °C to about 25 °C.

[0925] 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.

[0926] In some embodiments, the acid is present in an amount in the range of about 0.8 equivalent to about 3.0 equivalents. In some embodiments, the acid is present in an amount in the range of about 1.2 equivalents to about 3.0 equivalents.

[0927] 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.

[0928] In some embodiments, in the compound of Formula V, at least one of R7-R 10 is a halogen. In some embodiments, in the compound of Formula V, at least one of R7-R 10 is chlorine. In some embodiments, the compound of Formula V is 6-chloro-8-methyl-2H-benzo[d][1,3]oxazin-2,4(1H)-dione.

[0929] In some embodiments, in the compound of Formula VI, at least one of R7-R 10 is a halogen. In some embodiments, in the compound of Formula VI, at least one of R7-R 10 is chlorine. In some embodiments, the compound of Formula VI is 2-amino-5-chloro-N,3-dimethylbenzamide.

[0930] This aspect is particularly beneficial for purifying the compound of Formula VI. In some embodiments, this aspect provides a high yield of the compound of Formula VI. In some embodiments, this aspect provides a yield of at least 94% of the compound of Formula VI.

[0931] In one aspect, a compound of Formula V or a salt thereof is prepared according to the method represented by Scheme 13. The R groups are defined anywhere in this disclosure.

[0932] Scheme 13.

[0933]

[0934] This aspect includes: forming a first mixture that includes a compound of Formula III or a salt thereof, a solvent containing an acid, and a halogenating reagent; reacting the first mixture; optionally removing a portion of the solvent containing the acid; forming a second mixture that includes the first mixture, an oxidizing agent, and an additive; and reacting the second mixture, wherein the second mixture reacts in the presence of a catalyst.

[0935] In some embodiments, the first mixture components are added simultaneously to form a first mixture. In some embodiments, the second mixture components are added simultaneously to form a second mixture. In some embodiments, the first mixture components are added individually to form a first mixture. In some embodiments, the second mixture components are added individually to form a second mixture. In some embodiments, the first mixture components are added individually in any suitable combination to form a first mixture. In some embodiments, the second mixture components are added individually in any suitable combination to form a 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.

[0936] 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 of 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 of the second mixture components are added to the second mixture.

[0937] In some embodiments, the catalyst is inherently present in the first mixture and / or the second mixture when at least two mixture components react. In some embodiments, the catalyst is inherently present in the second mixture when an oxidizing agent and a halogenating reagent react.

[0938] In some embodiments, the solvent includes a solvent selected from the group consisting of acetonitrile, 1,2-dichloroethane, chloroform, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, sulfuric acid, methanesulfonic acid, and combinations thereof. In some embodiments, the solvent contains a sulfonic acid. In some embodiments, the solvent contains methanesulfonic acid. In some embodiments, the solvent contains sulfuric acid. In some embodiments, the solvent contains methanesulfonic acid and sulfuric acid. In some embodiments, the solvent is a combination of methanesulfonic acid and sulfuric acid.

[0939] In some embodiments, the halogenating reagent is selected from the group consisting of chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof. In some embodiments, the halogenating reagent is a chlorinating reagent. In some embodiments, the chlorinating reagent is selected from the group consisting of chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In some embodiments, the chlorinating reagent is chlorine.

[0940] 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.

[0941] In some embodiments, the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof. In some embodiments, the oxidizing agent is hydrogen peroxide.

[0942] In some embodiments, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, phosphoric acid, sulfonic acid, methanesulfonic acid, and combinations thereof. In some embodiments, the catalyst comprises sulfuric acid. In some embodiments, the catalyst is sulfuric acid.

[0943] In some embodiments, the additive is selected from alkyl acetates, ethyl acetate, isopropyl acetate, alkyl alcohols, methanol, ethanol, isopropyl alcohol, 2-butanol, tert-butanol, acetonitrile, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, PEG-400, sulfolane, dimethoxyethane, aryl solvents, toluene, xylene, mesitylene, surfactants, high flash point aromatic solvents (S150), high flash point aromatic solvents (S200), Tween 20, sodium dodecylbenzenesulfonate (SDS), and combinations thereof. In some embodiments, the additive comprises ethyl acetate and mesitylene. In some embodiments, the additive is a combination of ethyl acetate and mesitylene.

[0944] 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 at a second reaction temperature in the range of about 60 °C to about 70 °C.

[0945] In some embodiments, in the compound of formula III, at least one of R1-R4 is hydrogen. In some embodiments, the compound of formula III is 7-methylindoline-2,3-dione.

[0946] In some embodiments, in the compound of formula V, R7-R10 at least one of which is a halogen. In some embodiments, in the compound of Formula V, R7-R 10 at least one of which is chlorine. In some embodiments, the compound of Formula V is 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. [Please confirm and elaborate as needed]

[0947] This aspect is a one-pot process and has several advantages. First, the need to isolate the intermediate (such as the compound of Formula IV) produced from the compound of Formula III before subsequent reactions is eliminated. Second, the potential loss of the intermediate (such as the compound of Formula IV) produced from the compound of Formula III is reduced. Third, the overall yield is increased. Fourth, the number of reaction steps and post-treatment operations is reduced. Fifth, the total cost is reduced.

[0948] Examples

[0949] Without further elaboration, it is believed that those skilled in the art can make the most of the present invention using the foregoing description. Accordingly, the following examples should be construed as merely illustrative and not in any way limiting of the disclosure. The starting materials for the following examples may not necessarily be prepared by a specific preparation run, the procedures of which are described in other examples. It should also be understood that any numerical range recited herein includes all values from the lower value to the upper value. For example, if the range is specified as 10 - 50, it is contemplated that values such as 12 - 30, 20 - 40, or 30 - 50 are expressly recited in this specification. These are merely examples of specific intentions, and all possible combinations of the values between (and including) the recited lowest and highest values will be considered to be clearly stated in this application.

[0950] Example 1. Reaction of o-toluidine.

[0951] 16.2 g of o-toluidine, 16.8 g of hydrochloric acid, 27.6 g of chloral hydrate, 24.8 g of hydroxylamine sulfate, and 238.0 g of water were charged into a reactor at room temperature. The reactor was heated and the reaction temperature was controlled at 50°C - 55°C. The reaction pH decreased over time. When the reaction pH was below 0.95, 19% aqueous Na2CO3 solution was added to control the pH between 0.95 - 1.05. After the reaction, 150 g of 1,2-dichloroethane was charged in three portions for extraction at 50°C - 55°C. 430.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-dichloroethane solution was obtained, which could be directly used 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%.

[0952] Example 2. Reaction of o-toluidine.

[0953] At room temperature, 66.1 g of hydroxylamine sulfate and 360.0 g of water were charged into a reactor. The reactor was heated and the reaction temperature was controlled at 50 °C - 55 °C. 43.3 g of o-toluidine, 44.8 g of hydrochloric acid and 130.0 g of water were mixed and charged into dropping funnel A. 73.6 g of chloral hydrate and 130.0 g of water were mixed and charged into dropping funnel B. The solutions in funnels A and B were added dropwise to the reactor. The reaction pH decreased over time. When the reaction pH was below 0.95, 19% aqueous Na2CO3 solution was added to control the pH between 0.95 - 1.05. After the reaction, 1050.0 g of 1,2-dichloroethane was charged in three portions for extraction at 50 °C - 55 °C. 1092.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-dichloroethane solution was obtained, which could be directly used 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%.

[0954] Example 3. Cyclization.

[0955] At room temperature, 404.6 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide in 1,2-dichloroethane solution (wt% = 5.6%) was charged into a reactor. At 40 °C - 45 °C and under a pressure of (100 - 200 mbar), a portion of 1,2-dichloroethane (about 2 / 3 of the total 1,2-dichloroethane) was distilled off from the reaction mixture. Then, a mixture of methanesulfonic acid (113.5 g) and sulfuric acid (12.7 g) was added dropwise to the reaction mixture at 40 °C - 45 °C under atmospheric pressure. When this addition was complete, the reaction was heated and the temperature of the mixture was controlled at 50 °C - 55 °C under 300 - 330 mbar. The reaction mixture was refluxed under these conditions. When the reaction was complete, the remaining 1,2-dichloroethane was distilled off at 50 °C - 55 °C under 100 - 50 mbar. The mixture was cooled to 20 °C - 25 °C and added dropwise to water in another reactor where the temperature was controlled at about 40 °C and solids 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 with 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 could be directly used in other examples. The wt% of 7-methylindoline-2,3-dione was 95.9%. The yield of this step was 94.1%.

[0956] Example 4. Halogenation.

[0957] At room temperature, 20.0 g of 7-methylindoline-2,3-dione (wt% = 95.9%) and 95.9 g of methanesulfonic acid and 9.81 g of 98% sulfuric acid were charged into a reactor. Chlorine gas was bubbled into the reaction solution at 20 °C - 25 °C. When the reaction was completed, nitrogen gas was bubbled into the reaction solution to purge chlorine gas. The reaction mass was added dropwise to water in another reactor (the temperature was controlled at about 40 °C), and solids precipitated out during quenching. The reaction was cooled to room temperature and stirred at room temperature. The slurry was filtered, and the filter cake was washed twice with water. The solid was dried to obtain 24.5 g of crude 5-chloro-7-methylindoline-2,3-dione. The crude 5-chloro-7-methylindoline-2,3-dione could be directly used in other examples. The wt% of 5-chloro-7-methylindoline-2,3-dione was 90.0%. The yield of this step was 94.7%.

[0958] Example 5. Cyclization and halogenation.

[0959] At room temperature, 1690.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide in a 1,2-dichloroethane solution (wt% = 5.22%) was charged into a reactor. A portion of 1,2-dichloroethane (about 2 / 3 of the total 1,2-dichloroethane) was distilled from the reaction mixture at 40 °C - 45 °C under a pressure of (100 - 200 mbar). Then a mixture of methanesulfonic acid (441.0 g) and sulfuric acid (50.0 g) was added dropwise to the reaction mixture at 40 °C - 45 °C under atmospheric pressure. When this addition was completed, the reaction was heated, and the temperature of the mixture was controlled at 50 °C - 55 °C under 300 - 330 mbar. The reaction mixture was refluxed under these conditions. When the reaction was completed, the remaining 1,2-dichloroethane was distilled out at 50 °C - 55 °C under 100 - 50 mbar. The mixture was cooled to 20 °C - 25 °C and chlorine gas was bubbled into the reaction solution at 20 °C - 25 °C. When the reaction ended, nitrogen gas was bubbled into the reaction solution to purge chlorine gas. Then the reaction mass was added dropwise to water in another reactor (the temperature was controlled at about 40 °C), and solids precipitated out during quenching. The mixture was cooled to room temperature and stirred at room temperature. The slurry was filtered, and the filter cake was washed twice with water. The solid was dried to obtain 96.4 g of crude 5-chloro-7-methylindoline-2,3-dione. The crude 5-chloro-7-methylindoline-2,3-dione could be directly used in other examples. The wt% of 5-chloro-7-methylindoline-2,3-dione was 91.4%. The yield of this step was 91.0%.

[0960] Example 6. Oxidation.

[0961] At room temperature, 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 of mesitylene were charged into a reactor. The reaction was heated and the temperature of the mixture was controlled at 25°C - 35°C. 75.0 g of 30% hydrogen peroxide solution was added dropwise at 25°C - 35°C. After 3 hours, 8.0 g of 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°C - 70°C. When the reaction was completed, the mixture was cooled to room temperature and an aqueous solution of sodium sulfite was charged to quench the peroxide until the KI test paper did not turn blue. The slurry was filtered and the filter cake was washed twice with water. The solid was dried to obtain 47.5 g of crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. The crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione could be directly used in other examples. The wt% of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione was 89.5%. The yield of this step was 91.1%.

[0962] Example 7. Halogenation and Oxidation

[0963] At room temperature, 20.9 g of 7-methylindoline-2,3-dione (wt% = 95.9%), 100.0 g of methanesulfonic acid, and 12.4 g of 98% sulfuric acid were charged into a reactor. Chlorine gas was bubbled into the reaction solution at 20°C - 25°C. When the reaction was completed, nitrogen gas was bubbled into the reaction solution to purge the chlorine gas. Then the mixture was heated to 25°C - 35°C. 6.0 g of mesitylene was charged into the mixture. 40.0 g of 30% hydrogen peroxide solution was added dropwise at 25°C - 35°C. After 3 hours, 6.0 g of 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°C - 70°C. After the reaction was completed, the mixture was cooled to room temperature and an aqueous solution of sodium sulfite was charged to quench the peroxide until the KI test paper did not turn blue. The slurry was filtered and the filter cake was washed twice with water. The solid was dried to obtain 14.5 g of crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione. The crude 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione could be directly used in other examples. The wt% of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione was 69.3%. The yield of this step was 38.2%.

[0964] Example 8. Reaction with Methylamine

[0965] 21.2 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (wt% = 89.9%), 89.00 g of ethyl acetate, and 9.2 g of acetic acid were charged into a reactor. Gaseous methylamine was bubbled into the reaction at 55 °C - 60 °C. After the reaction was completed, nitrogen was bubbled into the reaction solution to purge the methylamine gas. Then water was added and phase separation was carried out twice at 55 °C - 60 °C. The organic phase was cooled to room temperature. 13.2 g of 30% aqueous hydrochloric acid solution was added to the organic phase, and 2-amino-5-chloro-N,3-dimethylbenzamide hydrochloride precipitated out. The 2-amino-5-chloro-N,3-dimethylbenzamide salt and water were added to another reactor, and a sodium hydroxide solution was added to liberate 2-amino-5-chloro-N,3-dimethylbenzamide by neutralization. Filtration was carried out again and the filter cake was washed twice with 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%.

[0966] The written description uses examples to illustrate the disclosure, including the best mode, and also enables any person skilled in the art to practice the disclosure, including making and using any device or system and performing any incorporated method. 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 these claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

Claims

1. A method for preparing a compound of formula VI, wherein, R7-R 10 Each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R 10 is a halogen; and wherein R 11 is selected from branched C1-C 10 alkyl and unbranched C1-C 10 alkyl, and the method comprises: I) A mixture is formed, which mixture comprises: A) A compound of formula V, wherein R7-R 10 Each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R 10 is a halogen; and wherein the compound of formula V is prepared according to the following method, which method comprises: i) A first mixture is formed, which first mixture comprises: a) A compound of formula III, wherein R1-R4 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1-R4 is hydrogen; b) A solvent containing an acid; and c) A halogenating reagent; ii) The first mixture is reacted; iii) Optionally, a portion of the solvent containing the acid is removed; iv) A second mixture is formed, which second mixture comprises: The first mixture; d) An oxidizing agent; and e) An additive; and v) The second mixture is reacted, wherein the second mixture is reacted in the presence of a catalyst; B) An alkylamine; and C) A solvent; II) The mixture is reacted; and III) Optionally, a purification step is performed on the mixture.

2. The method according to claim 1, wherein The halogenating reagent is selected from chlorinating reagents, brominating reagents, iodinating reagents, and combinations thereof.

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

4. The method according to claim 3, wherein The chlorinating reagent is chlorine.

5. The method according to claim 1, wherein, The compound of formula III is prepared according to the following method, which method comprises: I) A mixture is formed, which mixture comprises: A) A compound of formula II, wherein R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and wherein the compound of formula II is prepared according to the following method, which method comprises: i) A mixture is formed, which mixture comprises: a) A compound of formula I, wherein R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) Hydroxylamine or a hydroxylamine derivative; d) A solvent; e) Optionally, a pH regulator; and f) An acid; ii) The mixture is reacted, wherein the mixture is reacted at a pH in the range from about 0 to about 7; and iii) Optionally, the mixture is extracted with an extraction solvent; B) An acid; and C) A solvent; and II) The mixture is reacted.

6. A method for preparing a compound of formula V, wherein, R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R 10 is a halogen, and the method comprises: I) A first mixture is formed, which first mixture comprises: A) A compound of formula III, wherein R1-R4 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and at least one of R1-R4 is hydrogen; B) A solvent containing an acid; and C) A halogenating reagent; II) The first mixture is reacted; III) Optionally, a portion of the solvent containing the acid is removed; IV) A second mixture is formed, which second mixture comprises: The first mixture; D) An oxidizing agent; and E) An additive; V) React the second mixture, where the second mixture reacts in the presence of a catalyst.

7. The method according to claim 6, wherein, The compound having formula III is prepared according to the following method, which comprises: I) Form a mixture comprising: A) A compound having formula II, where R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and where at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and where the compound having formula II is prepared according to the following method, which comprises: i) Form a mixture comprising: a) A compound having formula I, where R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and and where at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) Hydroxylamine or a hydroxylamine derivative; d) A solvent; e) Optionally a pH regulator; and f) An acid; ii) React the mixture, where the mixture reacts at a pH in the range from about 0 to about 7; and iii) Optionally extract the mixture with an extraction solvent; B) An acid; and C) A solvent; and II) React the mixture.

8. A method for preparing a compound having formula VI, where, R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R 10 is a halogen; and wherein R 11 is selected from branched C1-C 10 alkyl and unbranched C1-C 10 alkyl, and the method comprises: I) Form a mixture comprising: A) A compound having formula V, where R7-R 10 Each is independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R 10 is a halogen; and where the compound having formula V is prepared according to the following method, which comprises: i) Form a mixture comprising: a) A compound having formula IV, where R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R 10 is a halogen; b) An oxidizing agent; c) A solvent; and d) An additive; and ii) React the mixture, where the mixture reacts in the presence of a catalyst; B) An alkylamine; and C) A solvent; II) React the mixture; and III) Optionally perform a purification step on the mixture.

9. The method according to claim 8, wherein, The compound having formula IV is prepared according to the following method, which comprises: I) Form a mixture comprising: A) A compound having formula III, where R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least one of R1 - R4 is hydrogen; B) A solvent containing an acid; C) A halogenating reagent; and II) React the mixture.

10. The method according to claim 9, wherein, The compound having formula III is prepared according to the following method, which comprises: I) Form a mixture comprising: A) A compound having formula II, where R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and and where at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and where the compound having formula II is prepared according to the following method, which comprises: i) Form a mixture comprising: a) A compound having formula I, where R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and where at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) Hydroxylamine or a hydroxylamine derivative; d) A solvent; e) Optionally, a pH regulator; and f) An acid; ii) Reacting the mixture, wherein the mixture is reacted at a pH in the range 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.

11. The method according to claim 8, wherein, The compound having formula IV is prepared according to the following method, which comprises: I) Forming a first mixture, the first mixture comprising: A) A compound having formula II, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) An acid; and C) A solvent; II) Reacting the first mixture; III) Removing a certain amount of the solvent from the first mixture; IV) Forming a second mixture, the second mixture comprising the first mixture and a halogenating reagent; and V) Reacting the second mixture.

12. The method according to claim 11, wherein, The compound having formula II is prepared according to the following method, which comprises: i) Forming a mixture, the mixture comprising: a) A compound having formula I, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) Chloral hydrate; c) Hydroxylamine or a hydroxylamine derivative; d) A solvent; e) Optionally, a pH regulator; and f) An acid; ii) Reacting the first mixture, wherein the mixture is reacted at a pH in the range from about 0 to about 7; and iii) Optionally extracting the mixture with an extraction solvent.

13. A method for preparing a compound having formula V, wherein, R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R 10 is a halogen, and the method includes: I) Forming a mixture, the mixture comprising: A) A compound having formula IV, wherein R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least one of R7-R 10 is a halogen; B) An oxidizing agent; C) A solvent; and D) An additive; and II) Reacting the mixture, wherein the mixture is reacted in the presence of a catalyst.

14. The method according to claim 13, wherein, The compound having formula IV is prepared according to the following method, which comprises: I) Forming a mixture, the mixture comprising: A) A compound having formula III, wherein R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least one of R1 - R4 is hydrogen; B) A solvent containing an acid; C) A halogenating reagent; and II) Reacting the mixture.

15. The method according to claim 14, wherein, The compound having formula III is prepared according to the following method, which comprises: I) Forming a mixture, the mixture comprising: A) A compound having formula II, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and wherein at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and wherein the compound having formula II is prepared according to the following method, which comprises: i) Forming a mixture, the mixture comprising: a) A compound having formula I, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH regulator; and f) an acid; ii) reacting the mixture, wherein the mixture reacts at a pH in the range 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.

16. The method according to claim 13, wherein, The compound having formula IV is prepared according to the following method, which comprises: I) forming a first mixture, the first mixture comprising: A) a compound having formula II, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) an acid; and C) a solvent; II) reacting the first mixture; III) removing a certain amount of the solvent from the first mixture; IV) forming a second mixture, the second mixture comprising the first mixture and a halogenating reagent; and V) reacting the second mixture.

17. The method according to claim 16, wherein, The compound having formula II is prepared according to the following method, which comprises: i) forming a mixture, the mixture comprising: a) a compound having formula I, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH regulator; and f) an acid; ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent.

18. A method for preparing a compound having formula IV, wherein, R7-R 10 each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and R7-R 10 At least one of them is a halogen, and the method includes: I) forming a mixture, the mixture comprising: A) a compound having formula III, wherein R1 - R4 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least one of R1 - R4 is hydrogen; B) a solvent containing an acid; C) a halogenating reagent; and II) reacting the mixture.

19. The method according to claim 18, wherein, The compound having formula III is prepared according to the following method, which comprises: I) forming a mixture, the mixture comprising: A) a compound having formula II, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and wherein the compound having formula II is prepared according to the following method, which comprises: i) forming a mixture, the mixture comprising: a) a compound having formula I, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH regulator; and f) an acid; ii) reacting the mixture, wherein the mixture reacts at a pH in the range 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.

20. A method for preparing a compound of formula III, wherein, R1 - R4 are each 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 R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; and wherein the compound of formula II is prepared by a method comprising: i) forming a mixture comprising: a) a compound of formula I, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH regulator; and f) an acid; ii) reacting the mixture, wherein the mixture reacts at a pH in the range 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.

21. A method for preparing a compound of formula II, wherein, R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl, and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen, the method comprising: I) forming a mixture comprising: A) a compound of formula I, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) chloral hydrate; C) hydroxylamine or a hydroxylamine derivative; D) a solvent; E) optionally a pH regulator; and F) an acid; and II) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and III) optionally extracting the mixture with an extraction solvent.

22. A method for preparing a compound of formula IV, wherein, R7-R 10 Each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; wherein at least one of R7-R 10 is a halogen, and the method includes: I) forming a first mixture comprising: A) a compound of formula II, wherein R1 - R5 are each independently selected from hydrogen, halogen, C1 - C5 haloalkyl, and C1 - C5 alkyl; and at least two of R1 - R5 are hydrogen; and at least one of R1 and R5 is hydrogen; B) an acid; and C) a solvent; II) reacting the first mixture; III) removing a certain amount of the solvent from the first mixture; IV) forming a second mixture, the second mixture comprising the first mixture and a halogenating reagent; and V) reacting the second mixture.

23. The method according to claim 22, wherein The compound having formula II is prepared according to the following method, the method comprising: i) forming a mixture, the mixture comprising: a) a compound having formula I, wherein R1-R5 are each independently selected from hydrogen, halogen, C1-C5 haloalkyl, and C1-C5 alkyl; and wherein at least two of R1-R5 are hydrogen; and at least one of R1 and R5 is hydrogen; b) chloral hydrate; c) hydroxylamine or a hydroxylamine derivative; d) a solvent; e) optionally a pH regulator; and f) an acid; ii) reacting the mixture, wherein the mixture reacts at a pH in the range from about 0 to about 7; and iii) optionally extracting the mixture with an extraction solvent.

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