A novel and efficient process for the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide

Abstract

Described herein are novel methods for synthesizing 2-amino-5-chloro-N,3-dimethylbenzamide. Compounds prepared by the methods disclosed herein are useful for preparing certain anthranilamide compounds of interest as insecticides, such as the insecticides chlorantraniliprole and cyantraniliprole. [Case 1] TIFF2023501851000082.tif38170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 929,138, filed November 1, 2019.

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

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

[0004] The present disclosure provides novel methods useful for preparing 2-amino-5-chloro-N,3-dimethylbenzamide and its derivatives. The advantages of the disclosed methods compared to previous methods are numerous and include reduced costs, elimination of the need for mixed solvent separation, reduced waste, relatively short method steps, simplified operational complexity, and reduced process hazards. Summary of the Invention [Means for solving the problem]

[0005] In one aspect, provided herein is a compound of formula VI [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10at least one of is a halogen; and R 11 is branched C1~C 10 Alkyl and unbranched C1-C 10 alkyl) 1. A method for preparing I) A) A compound of formula V [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and The compound of formula V is i) a) a compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) a solvent; and c) Halogenating reagents forming a first mixture comprising: ii) reacting the first mixture; iii) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising: d) an oxidizing agent; and e) Catalyst including); and iv) reacting the third mixture; prepared according to a method comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) Reacting the mixture A method is provided that includes:

[0006] In one aspect, provided herein is a compound of formula V [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) a solvent; and C) Halogenating Reagents forming a first mixture comprising: II) reacting the first mixture; III) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising: D) an oxidizing agent; and E) Catalyst including); and IV) reacting the third mixture. A method is provided that includes:

[0007] In one aspect, provided herein is a compound of formula VI [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and R 11 is branched C1~C 10Alkyl and unbranched C1-C 10 alkyl) 1. A method for preparing I) A) A compound of formula V [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and The compound of formula V is i) a) a compound of formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen); b) oxidizing agent; c) a solvent; and d) Catalyst forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) Reacting the mixture A method is provided that includes:

[0008] In one aspect, provided herein is a compound of formula V [ka] (R7~R 10each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen); B) oxidizing agent; C) a solvent; and D) catalyst forming a mixture comprising: II) Reacting the mixture A method is provided that includes:

[0009] In one aspect, provided herein is a compound of formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) solvent; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture A method is provided that includes:

[0010] In one aspect, provided herein is a compound of formula III [ka] wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl. 1. A method for preparing I) A) A compound of formula II [ka] each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and The compound of formula II is i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture and B) acid forming a mixture comprising: II) Reacting the mixture A method is provided that includes:

[0011] In one aspect, provided herein is a compound of formula II [ka] wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl. 1. A method for preparing I) A) A compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) Chloral hydrate; C) hydroxylamine derivatives; D) solvent; E) inorganic salts; and F) Acid forming a mixture comprising: II) Reacting the mixture A method is provided that includes:

[0012] In one aspect, provided herein is a compound of formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and B) acid forming a mixture comprising: II) reacting the first mixture; III) introducing a halogenating reagent into the first mixture to form a second mixture; and IV) reacting the second mixture A method is provided that includes: DETAILED DESCRIPTION OF THE INVENTION

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

[0014] The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. When in a claim, such phrase limits the claim to include materials other than those recited, except for impurities normally accompanying the materials. When the phrase "consisting of" appears within a clause in the body of a claim rather than immediately following the preamble, the phrase limits only the elements set forth in that clause; other elements are not excluded from the claim as a whole.

[0015] The transitional phrase "consisting essentially of" is used to define a composition or method that includes materials, steps, features, components, or elements in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of" occupies intermediate ground between "comprising" and "consisting of."

[0016] It should be readily understood that where an invention or portion thereof is defined by open-ended terms such as "comprising," the description should (unless otherwise expressly stated) be construed to also describe such inventions using the terms "consisting essentially of" or "consisting of."

[0017] Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive or, not an exclusive or. For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0018] Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be open-ended regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and singular forms of elements or components also include pluralities unless the number is clearly intended to be singular.

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

[0020] The term "halogen," either alone or in compound terms such as "haloalkyl," includes fluorine, chlorine, bromine, or iodine. Additionally, when used in compound terms such as "haloalkyl," the alkyl may be partially or fully substituted with halogen atoms, which may be the same or different.

[0021] The group may be a substituent that can be hydrogen, e.g., R 4 When a group contains, it is recognized that when this substituent is taken as hydrogen, this is equivalent to said group unsubstituted.

[0022] The term "alkyl" includes functional groups including, but not limited to, straight-chain or branched alkyl. In some embodiments, alkyl can be methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, or hexyl isomers.

[0023] Certain compounds of the present invention may exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Those skilled in the art will understand that one stereoisomer may be more active and / or exhibit beneficial effects when enriched relative to other stereoisomers or separated from other stereoisomers. Furthermore, those skilled in the art know how to separate, enrich and / or selectively prepare said stereoisomers.

[0024] Embodiments of the present disclosure include the following.

[0025] Embodiment 1. Compound of Formula VI [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and R 11 is branched C1~C 10 Alkyl and unbranched C1-C 10 alkyl) 1. A method for preparing I) A) A compound of formula V [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R10 at least one of is a halogen; and The compound of formula V is i) a) a compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) a solvent; and c) Halogenating reagents forming a first mixture comprising: ii) reacting the first mixture; iii) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising: d) an oxidizing agent; and e) Catalyst including); and iv) reacting the third mixture; prepared according to a method comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) Reacting the mixture A method comprising:

[0026] Embodiment 2. The alkylamine is a branched C1-C 10 Alkyl and unbranched C1-C 10 2. The method of embodiment 1, comprising a functional group selected from alkyl.

[0027] Embodiment 3. The method of embodiment 2, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, and combinations thereof.

[0028] Embodiment 4. The method of embodiment 3, wherein the alkylamine is methylamine.

[0029] Embodiment 5. The method of embodiment 1, wherein the solvent C) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0030] Embodiment 6 The method of embodiment 5, wherein solvent C) is ethyl acetate.

[0031] Embodiment 7. The method of embodiment 1, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 100°C.

[0032] Embodiment 8. The method of embodiment 7, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0033] Embodiment 9. The method of embodiment 1, wherein the solvent b) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0034] Embodiment 10 The method of embodiment 9, wherein solvent b) is acetic acid.

[0035] Embodiment 11. The method of embodiment 1, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0036] Embodiment 12. The method of embodiment 11, wherein the chlorinating reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

[0037] Embodiment 13 The method of embodiment 12, wherein the chlorinating reagent is sulfuryl chloride.

[0038] Embodiment 14. The method of embodiment 1, wherein step ii) of the method of reacting the first mixture is carried out at a reaction temperature ranging from about 20°C to about 140°C.

[0039] Embodiment 15. The method of embodiment 14, wherein step ii) of the method of reacting the first mixture is carried out at a reaction temperature in the range of about 120°C to about 130°C.

[0040] Embodiment 16 The method of embodiment 1, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0041] Embodiment 17 The method of embodiment 16, wherein the oxidizing agent is hydrogen peroxide.

[0042] Embodiment 18 The method of embodiment 1, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof.

[0043] Embodiment 19 The method of embodiment 18, wherein the catalyst is sulfuric acid.

[0044] Embodiment 20. The method of embodiment 1, wherein step iv) of the method of reacting the third mixture is conducted at a reaction temperature ranging from about 20°C to about 100°C.

[0045] Embodiment 21. The method of embodiment 20, wherein step iv) of the method of reacting the third mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

[0046] Embodiment 22. The compound of Formula III is I) A) A compound of formula II [ka] each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and The compound of formula II is i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture and B) acid forming a mixture comprising: II) Reacting the mixture 2. The method of embodiment 1, wherein the compound is prepared according to a method comprising:

[0047] Embodiment 23. The method of embodiment 22, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and combinations thereof.

[0048] Embodiment 24 The method of embodiment 23, wherein the acid B) is hydrochloric acid.

[0049] Embodiment 25. The method of embodiment 22, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0050] Embodiment 26. The method of embodiment 25, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

[0051] Embodiment 27 The method of Embodiment 22, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0052] Embodiment 28 The method of embodiment 27, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0053] Embodiment 29 The method of embodiment 22, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0054] Embodiment 30 The method of embodiment 29, wherein the solvent is water.

[0055] Embodiment 31. The method of embodiment 22, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0056] Embodiment 32 The method of embodiment 31, wherein the inorganic salt is sodium sulfate.

[0057] Embodiment 33 The method of embodiment 22, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0058] Embodiment 34 The method of embodiment 33, wherein acid f) is hydrochloric acid.

[0059] Embodiment 35 The method of Embodiment 22, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0060] Embodiment 36 The method of embodiment 35, wherein the concentration of the compound of formula I in the mixture ranges from about 3% to about 10%.

[0061] Embodiment 37. The method of embodiment 22, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0062] Embodiment 38. The method of embodiment 37, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0063] Embodiment 39. A compound of Formula V [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) a solvent; and C) Halogenating Reagents forming a first mixture comprising: II) reacting the first mixture; III) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising: D) an oxidizing agent; and E) Catalyst including); and IV) reacting the third mixture. A method comprising:

[0064] Embodiment 40 The method of embodiment 39, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0065] Embodiment 41 The method of embodiment 40, wherein the solvent is acetic acid.

[0066] Embodiment 42 The method of embodiment 39, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0067] Embodiment 43 The method of embodiment 42, 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.

[0068] Embodiment 44 The method of embodiment 43, wherein the chlorinating reagent is sulfuryl chloride.

[0069] Embodiment 45. The method of embodiment 39, wherein step II) of the method of reacting the first mixture is conducted at a reaction temperature ranging from about 20°C to about 140°C.

[0070] Embodiment 46. The method of embodiment 45, wherein step II) of the method of reacting the first mixture is carried out at a reaction temperature ranging from about 120°C to about 130°C.

[0071] Embodiment 47. The method of embodiment 39, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0072] Embodiment 48 The method of embodiment 47, wherein the oxidizing agent is hydrogen peroxide.

[0073] Embodiment 49 The method of embodiment 39, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof.

[0074] Embodiment 50 The method of embodiment 49, wherein the catalyst is sulfuric acid.

[0075] Embodiment 51. The method of Embodiment 39, wherein step IV) of the method of reacting the third mixture is conducted at a reaction temperature ranging from about 20°C to about 100°C.

[0076] Embodiment 52. The method of Embodiment 51, wherein step IV) of the method of reacting the third mixture is conducted at a reaction temperature ranging from about 60°C to about 65°C.

[0077] Embodiment 53. The compound of Formula III is I) A) A compound of formula II [ka] each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and The compound of formula II is i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture and B) acid forming a mixture comprising: II) Reacting the mixture 40. The method of embodiment 39, wherein the compound is prepared according to a method comprising:

[0078] Embodiment 54. The method of embodiment 53, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and combinations thereof.

[0079] Embodiment 55 The method of embodiment 54, wherein the acid B) is hydrochloric acid.

[0080] Embodiment 56. The method of embodiment 53, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0081] Embodiment 57. The method of embodiment 56, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

[0082] Embodiment 58 The method of Embodiment 53, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0083] Embodiment 59 The method of embodiment 58, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0084] Embodiment 60 The method of embodiment 53, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0085] Embodiment 61 The method of embodiment 60, wherein the solvent is water.

[0086] Embodiment 62 The method of embodiment 53, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0087] Embodiment 63 The method of embodiment 62, wherein the inorganic salt is sodium sulfate.

[0088] Embodiment 64 The method of embodiment 53, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0089] Embodiment 65 The method of embodiment 64, wherein acid f) is hydrochloric acid.

[0090] Embodiment 66 The method of Embodiment 53, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0091] Embodiment 67 The method of Embodiment 66, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0092] Embodiment 68 The method of Embodiment 53, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0093] Embodiment 69. The method of Embodiment 68, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0094] Embodiment 70. A compound of Formula VI [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and R 11 is branched C1~C 10 Alkyl and unbranched C1-C 10 alkyl) 1. A method for preparing I) A) A compound of formula V [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of is a halogen; and The compound of formula V is i) a) a compound of formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R10 at least one of which is a halogen); b) oxidizing agent; c) a solvent; and d) Catalyst forming a mixture comprising: ii) reacting the mixture prepared according to a method comprising: B) alkylamines; and C) Solvent forming a mixture comprising: II) Reacting the mixture A method comprising:

[0095] Embodiment 71. The alkylamine is a branched C1-C 10 Alkyl and unbranched C1-C 10 71. The method of embodiment 70, comprising a functional group selected from alkyl.

[0096] Embodiment 72 The method of embodiment 71, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, and combinations thereof.

[0097] Embodiment 73 The method of embodiment 72, wherein the alkylamine is methylamine.

[0098] Embodiment 74 The method of embodiment 70, wherein the solvent C) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof.

[0099] Embodiment 75 The method of embodiment 74, wherein solvent C) is ethyl acetate.

[0100] Embodiment 76. The method of embodiment 70, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 0°C to about 100°C.

[0101] Embodiment 77. The method of embodiment 76, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 30°C.

[0102] Embodiment 78. The method of embodiment 70, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0103] Embodiment 79 The method of embodiment 78, wherein the oxidizing agent is hydrogen peroxide.

[0104] Embodiment 80. The method of embodiment 70, wherein the solvent c) is selected from acetonitrile, methanol, ethanol, isopropanol, water, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0105] Embodiment 81 The method of embodiment 80, wherein solvent c) is acetic acid.

[0106] Embodiment 82 The method of embodiment 70, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof.

[0107] Embodiment 83 The method of embodiment 82, wherein the catalyst is sulfuric acid.

[0108] Embodiment 84 The method of embodiment 70, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

[0109] Embodiment 85. The method of embodiment 84, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 60°C to about 65°C.

[0110] Embodiment 86. A compound of Formula IV: I) A) A compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) solvent; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture 71. The method of embodiment 70, wherein the compound is prepared according to a method comprising:

[0111] Embodiment 87 The method of embodiment 86, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0112] Embodiment 88 The method of embodiment 87, wherein the solvent is acetic acid.

[0113] Embodiment 89 The method of embodiment 86, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0114] Embodiment 90 The method of embodiment 89, 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.

[0115] Embodiment 91 The method of embodiment 90, wherein the chlorinating reagent is sulfuryl chloride.

[0116] Embodiment 92. The method of embodiment 86, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 140°C.

[0117] Embodiment 93. The method of embodiment 92, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 120°C to about 130°C.

[0118] Embodiment 94. A compound of Formula III: I) A) A compound of formula II [ka] each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and The compound of formula II is i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture and B) acid forming a mixture comprising: II) Reacting the mixture 87. The method of embodiment 86, wherein the compound is prepared according to a method comprising:

[0119] Embodiment 95. The method of embodiment 94, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and combinations thereof.

[0120] Embodiment 96 The method of embodiment 95, wherein the acid B) is hydrochloric acid.

[0121] Embodiment 97. The method of embodiment 94, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0122] Embodiment 98. The method of embodiment 97, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 60°C to about 65°C.

[0123] Embodiment 99 The method of embodiment 94, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0124] Embodiment 100 The method of embodiment 99, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0125] Embodiment 101 The method of embodiment 94, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0126] Embodiment 102 The method of embodiment 101, wherein the solvent is water.

[0127] Embodiment 103 The method of embodiment 94, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0128] Embodiment 104 The method of embodiment 103, wherein the inorganic salt is sodium sulfate.

[0129] Embodiment 105. The method of embodiment 94, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0130] Embodiment 106 The method of embodiment 105, wherein acid f) is hydrochloric acid.

[0131] Embodiment 107 The method of embodiment 94, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0132] Embodiment 108 The method of embodiment 107, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0133] Embodiment 109. The method of embodiment 94, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0134] Embodiment 110. The method of embodiment 109, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0135] Embodiment 111. A compound of Formula IV: I) A) A compound of formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and B) acid forming a mixture comprising: II) reacting the first mixture; III) introducing a halogenating reagent into the first mixture to form a second mixture; and IV) reacting the second mixture 71. The method of embodiment 70, wherein the compound is prepared according to a method comprising:

[0136] Embodiment 112 The method of embodiment 111, wherein the acid is selected from sulfuric acid, acetic acid, and combinations thereof.

[0137] Embodiment 113 The method of embodiment 112, wherein the acid is sulfuric acid.

[0138] Embodiment 114 The method of embodiment 111, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0139] Embodiment 115 The method of embodiment 114, 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.

[0140] Embodiment 116 The method of embodiment 115, wherein the chlorinating reagent is trichloroisocyanuric acid.

[0141] Embodiment 117 The method of Embodiment 111, wherein step IV) of the method of reacting the second mixture is conducted at a reaction temperature ranging from about 10°C to about 100°C.

[0142] Embodiment 118 The method of Embodiment 117, wherein step IV) of the method of reacting the second mixture is conducted at a reaction temperature ranging from about 10°C to about 65°C.

[0143] Embodiment 119. A compound of Formula II: i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture 112. The method of embodiment 111, wherein the compound is prepared according to a method comprising:

[0144] Embodiment 120 The method of embodiment 119, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0145] Embodiment 121 The method of embodiment 120, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0146] Embodiment 122 The method of embodiment 119, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0147] Embodiment 123 The method of embodiment 122, wherein the solvent is water.

[0148] Embodiment 124 The method of embodiment 119, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0149] Embodiment 125 The method of embodiment 124, wherein the inorganic salt is sodium sulfate.

[0150] Embodiment 126 The method of embodiment 119, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0151] Embodiment 127 The method of embodiment 126, wherein the acid is hydrochloric acid.

[0152] Embodiment 128 The method of embodiment 119, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0153] Embodiment 129 The method of embodiment 128, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0154] Embodiment 130. The method of embodiment 119, wherein the method step of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0155] Embodiment 131. The method of embodiment 130, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0156] Embodiment 132. A compound of Formula V [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; and R7~R 10 at least one of which is a halogen); B) oxidizing agent; C) a solvent; and D) catalyst forming a mixture comprising: II) Reacting the mixture A method comprising:

[0157] Embodiment 133. The method of embodiment 132, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

[0158] Embodiment 134 The method of embodiment 133, wherein the oxidizing agent is hydrogen peroxide.

[0159] Embodiment 135. The method of embodiment 132, wherein the solvent is selected from acetonitrile, methanol, ethanol, isopropanol, water, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0160] Embodiment 136 The method of embodiment 135, wherein the solvent is acetic acid.

[0161] Embodiment 137 The method of embodiment 132, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof.

[0162] Embodiment 138 The method of embodiment 137, wherein the catalyst is sulfuric acid.

[0163] Embodiment 139. The method of embodiment 132, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

[0164] Embodiment 140. The method of embodiment 139, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 60°C to about 65°C.

[0165] Embodiment 141. A compound of Formula IV: I) A) A compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) solvent; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture 133. The method of embodiment 132, wherein the compound is prepared according to a method comprising:

[0166] Embodiment 142 The method of embodiment 141, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0167] Embodiment 143 The method of embodiment 142, wherein the solvent is acetic acid.

[0168] Embodiment 144 The method of embodiment 141, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0169] Embodiment 145 The method of embodiment 144, 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.

[0170] Embodiment 146 The method of embodiment 145, wherein the chlorinating reagent is sulfuryl chloride.

[0171] Embodiment 147. The method of embodiment 141, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 140°C.

[0172] Embodiment 148. The method of embodiment 147, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 120°C to about 130°C.

[0173] Embodiment 149. A compound of Formula III: I) A) A compound of formula II [ka] each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and The compound of formula II is i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture and B) acid forming a mixture comprising: II) Reacting the mixture 142. The method of embodiment 141, wherein the compound is prepared according to a method comprising:

[0174] Embodiment 150. The method of embodiment 149, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and combinations thereof.

[0175] Embodiment 151. The method of embodiment 150, wherein the acid B) is hydrochloric acid.

[0176] Embodiment 152. The method of embodiment 149, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0177] Embodiment 153. The method of embodiment 152, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 60°C to about 65°C.

[0178] Embodiment 154 The method of embodiment 149, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0179] Embodiment 155 The method of embodiment 154, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0180] Embodiment 156 The method of embodiment 149, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0181] Embodiment 157 The method of embodiment 156, wherein the solvent is water.

[0182] Embodiment 158 ​​The method of embodiment 149, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0183] Embodiment 159 The method of embodiment 158, wherein the inorganic salt is sodium sulfate.

[0184] Embodiment 160. The method of embodiment 149, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0185] Embodiment 161. The method of embodiment 160, wherein the acid f) is hydrochloric acid.

[0186] Embodiment 162 The method of embodiment 149, wherein the concentration of the compound of formula I in the mixture ranges from about 1% to about 30%.

[0187] Embodiment 163 The method of embodiment 162, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0188] Embodiment 164 The method of embodiment 149, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0189] Embodiment 165. The method of Embodiment 164, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0190] Embodiment 166. A compound of Formula IV: I) A) A compound of formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and B) acid forming a mixture comprising: II) reacting the first mixture; III) introducing a halogenating reagent into the first mixture to form a second mixture; and IV) reacting the second mixture 133. The method of embodiment 132, wherein the compound is prepared according to a method comprising:

[0191] Embodiment 167 The method of embodiment 166, wherein the acid is selected from sulfuric acid, acetic acid, and combinations thereof.

[0192] Embodiment 168 The method of embodiment 167, wherein the acid is sulfuric acid.

[0193] Embodiment 169 The method of embodiment 166, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0194] Embodiment 170 The method of embodiment 169, 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.

[0195] Embodiment 171 The method of embodiment 170, wherein the chlorinating reagent is trichloroisocyanuric acid.

[0196] Embodiment 172 The method of Embodiment 166, wherein step IV) of the method of reacting the second mixture is conducted at a reaction temperature ranging from about 10°C to about 100°C.

[0197] Embodiment 173 The method of Embodiment 172, wherein step IV) of the method of reacting the second mixture is conducted at a reaction temperature ranging from about 10°C to about 65°C.

[0198] Embodiment 174. A compound of Formula II: i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture 167. The method of embodiment 166, wherein the compound is prepared according to a method comprising:

[0199] Embodiment 175 The method of embodiment 174, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0200] Embodiment 176 The method of embodiment 175, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0201] Embodiment 177 The method of embodiment 174, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0202] Embodiment 178 The method of embodiment 177, wherein the solvent is water.

[0203] Embodiment 179. The method of embodiment 174, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0204] Embodiment 180 The method of embodiment 179, wherein the inorganic salt is sodium sulfate.

[0205] Embodiment 181. The method of embodiment 174, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0206] Embodiment 182 The method of embodiment 181, wherein the acid is hydrochloric acid.

[0207] Embodiment 183 The method of embodiment 174, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0208] Embodiment 184 The method of embodiment 183, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0209] Embodiment 185. The method of embodiment 174, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0210] Embodiment 186. The method of embodiment 185, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0211] Embodiment 187. A compound of Formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula III [ka] (wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) solvent; C) Halogenating Reagents forming a mixture comprising: II) Reacting the mixture A method comprising:

[0212] Embodiment 188 The method of embodiment 187, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

[0213] Embodiment 189 The method of embodiment 188, wherein the solvent is acetic acid.

[0214] Embodiment 190 The method of embodiment 187, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0215] Embodiment 191. The method of embodiment 190, 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.

[0216] Embodiment 192 The method of embodiment 191, wherein the chlorinating reagent is sulfuryl chloride.

[0217] Embodiment 193. The method of embodiment 187, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 20°C to about 140°C.

[0218] Embodiment 194. The method of embodiment 193, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 120°C to about 130°C.

[0219] Embodiment 195. A compound of Formula III: I) A) A compound of formula II [ka] each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and The compound of formula II is i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture and B) acid forming a mixture comprising: II) Reacting the mixture 188. The method of embodiment 187, wherein the compound is prepared according to a method comprising:

[0220] Embodiment 196. The method of embodiment 195, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and combinations thereof.

[0221] Embodiment 197. The method of embodiment 196, wherein the acid B) is hydrochloric acid.

[0222] Embodiment 198. The method of embodiment 195, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0223] Embodiment 199. The method of embodiment 198, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 60°C to about 65°C.

[0224] Embodiment 200 The method of embodiment 195, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0225] Embodiment 201 The method of embodiment 200, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0226] Embodiment 202 The method of embodiment 195, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0227] Embodiment 203 The method of embodiment 202, wherein the solvent is water.

[0228] Embodiment 204 The method of embodiment 195, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0229] Embodiment 205 The method of embodiment 204, wherein the inorganic salt is sodium sulfate.

[0230] Embodiment 206 The method of embodiment 195, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0231] Embodiment 207 The method of embodiment 206, wherein acid f) is hydrochloric acid.

[0232] Embodiment 208 The method of embodiment 195, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0233] Embodiment 209 The method of embodiment 208, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0234] Embodiment 210. The method of embodiment 195, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0235] Embodiment 211. The method of embodiment 210, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0236] Embodiment 212. A compound of Formula III [ka] wherein each of R1 to R4 is independently selected from hydrogen, halogen, and C1 to C5 alkyl. 1. A method for preparing I) A) A compound of formula II [ka] each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and The compound of formula II is i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture and B) acid forming a mixture comprising: II) Reacting the mixture A method comprising:

[0237] Embodiment 213 The method of embodiment 212, wherein the acid B) is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and combinations thereof.

[0238] Embodiment 214 The method of embodiment 213, wherein the acid B) is hydrochloric acid.

[0239] Embodiment 215. The method of embodiment 212, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 90°C.

[0240] Embodiment 216. The method of Embodiment 215, wherein step II) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 60°C to about 65°C.

[0241] Embodiment 217 The method of embodiment 212, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0242] Embodiment 218 The method of embodiment 217, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0243] Embodiment 219 The method of embodiment 212, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0244] Embodiment 220 The method of embodiment 219, wherein the solvent is water.

[0245] Embodiment 221. The method of embodiment 212, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0246] Embodiment 222 The method of embodiment 221, wherein the inorganic salt is sodium sulfate.

[0247] Embodiment 223. The method of embodiment 212, wherein the acid f) is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0248] Embodiment 224 The method of embodiment 223, wherein the acid f) is hydrochloric acid.

[0249] Embodiment 225 The method of embodiment 212, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0250] Embodiment 226 The method of embodiment 225, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0251] Embodiment 227 The method of Embodiment 212, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

[0252] Embodiment 228. The method of Embodiment 227, wherein step ii) of the method of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0253] Embodiment 229. A compound of Formula II [ka] wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl. 1. A method for preparing I) A) A compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); B) Chloral hydrate; C) hydroxylamine derivatives; D) solvent; E) inorganic salts; and F) Acid forming a mixture comprising: II) Reacting the mixture A method comprising:

[0254] Embodiment 230 The method of embodiment 229, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0255] Embodiment 231 The method of embodiment 230, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0256] Embodiment 232 The method of embodiment 229, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0257] Embodiment 233 The method of embodiment 232, wherein the solvent is water.

[0258] Embodiment 234 The method of embodiment 229, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0259] Embodiment 235 The method of embodiment 234, wherein the inorganic salt is sodium sulfate.

[0260] Embodiment 236 The method of embodiment 229, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0261] Embodiment 237 The method of embodiment 236, wherein the acid is hydrochloric acid.

[0262] Embodiment 238 The method of embodiment 229, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0263] Embodiment 239 The method of embodiment 238, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0264] Embodiment 240. The method of embodiment 229, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0265] Embodiment 241. The method of embodiment 240, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0266] Embodiment 242. A compound of Formula IV [ka] (R7~R 10 each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl, and C1-C5 alkyl; R7~R 10 at least one of which is a halogen) 1. A method for preparing I) A) A compound of formula II [ka] wherein each of R1-R5 is independently selected from hydrogen, halogen, and C1-C5 alkyl; and B) acid forming a first mixture comprising: II) reacting the first mixture; III) introducing a halogenating reagent into the first mixture to form a second mixture; and IV) reacting the second mixture A method comprising:

[0267] Embodiment 243 The method of embodiment 242, wherein the acid is selected from sulfuric acid, acetic acid, and combinations thereof.

[0268] Embodiment 244 The method of embodiment 243, wherein the acid is sulfuric acid.

[0269] Embodiment 245 The method of embodiment 242, wherein the halogenating reagent is selected from a chlorinating reagent, a brominating reagent, an iodinating reagent, and combinations thereof.

[0270] Embodiment 246 The method of embodiment 245, 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.

[0271] Embodiment 247 The method of embodiment 246, wherein the chlorinating reagent is trichloroisocyanuric acid.

[0272] Embodiment 248 The method of Embodiment 242, wherein step IV) of the method of reacting the second mixture is conducted at a reaction temperature ranging from about 10°C to about 100°C.

[0273] Embodiment 249. The method of Embodiment 248, wherein step IV) of the method of reacting the second mixture is conducted at a reaction temperature ranging from about 10°C to about 65°C.

[0274] Embodiment 250. A compound of Formula II: i) a) a compound of formula I [ka] (wherein each of R1 to R5 is independently selected from hydrogen, halogen, and C1 to C5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture 243. The method of embodiment 242, wherein the compound is prepared according to a method comprising:

[0275] Embodiment 251 The method of embodiment 250, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof.

[0276] Embodiment 252 The method of embodiment 251, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0277] Embodiment 253 The method of embodiment 250, wherein the solvent is selected from methanol, ethanol, toluene, water, and combinations thereof.

[0278] Embodiment 254 The method of embodiment 253, wherein the solvent is water.

[0279] Embodiment 255. The method of embodiment 250, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

[0280] Embodiment 256 The method of embodiment 255, wherein the inorganic salt is sodium sulfate.

[0281] Embodiment 257. The method of embodiment 250, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof.

[0282] Embodiment 258 The method of embodiment 257, wherein the acid is hydrochloric acid.

[0283] Embodiment 259 The method of Embodiment 250, wherein the concentration of the compound of Formula I in the mixture ranges from about 1% to about 30%.

[0284] Embodiment 260 The method of embodiment 259, wherein the concentration of the compound of Formula I in the mixture ranges from about 3% to about 10%.

[0285] Embodiment 261. The method of embodiment 250, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of from about 10°C to about 100°C.

[0286] Embodiment 262. The method of embodiment 261, wherein the method step of reacting the mixture is carried out at a reaction temperature in the range of about 50°C to about 55°C.

[0287] In one aspect, compounds of formula VI are prepared according to the method represented by Scheme 1. The R groups are as defined elsewhere in this disclosure. Scheme 1. [ka]

[0288] In one aspect, compounds of formula VI are prepared according to the method represented by Scheme 2. The R groups are as defined elsewhere in this disclosure. Scheme 2. [ka]

[0289] In one aspect, compounds of formula VI are prepared according to the method represented by Scheme 3. The R groups are as defined elsewhere in this disclosure. Scheme 3. [ka]

[0290] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 4. Scheme 4. [ka]

[0291] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 5. Scheme 5. [ka]

[0292] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 6. Scheme 6. [ka]

[0293] In one aspect, compounds of Formula II are prepared according to the method represented by Scheme 7. The R group is as defined elsewhere in this disclosure. Scheme 7. [ka]

[0294] This aspect involves reacting a compound of Formula I with chloral hydrate and hydroxylamine sulfate in a solvent at a reaction concentration in the presence of an inorganic salt and an acid. In one embodiment, the compound of Formula I is toluidine. In one embodiment, the solvent is selected from MeOH, EtOH, toluene, water, and combinations thereof. In another embodiment, the solvent is water. In one embodiment, the inorganic salt is selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof. In another embodiment, the inorganic salt is sodium sulfate. In one embodiment, the acid is selected from hydrogen chloride, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid, and combinations thereof. In another embodiment, the acid is hydrogen chloride. In one embodiment, the reaction concentration is in the range of about 1% to about 30% with respect to the compound of Formula I. In another embodiment, the reaction concentration is in the range of about 3% to about 10% with respect to the compound of Formula I. In one embodiment, the reaction temperature is in the range of about 10°C to about 100°C. In another embodiment, the reaction temperature ranges from about 50°C to about 55°C.

[0295] When the reaction conditions of 90°C in water are applied to the compound of Formula I (the compound of Formula I is toluidine), (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide is obtained as a sticky solid, resulting in difficult and insufficient separation. Furthermore, a rapid increase in temperature occurs when the crude (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide is added in small portions in the next reaction step. This problem is overcome in the present disclosure by lowering the reaction temperature in water from 90°C to a temperature in the range of about 50°C to about 55°C. This change not only results in pure (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide with good morphology, but also advantageously increases the reaction concentration. This higher reaction concentration reduces wastewater and costs.

[0296] In one aspect, compounds of Formula III are prepared according to the method represented by Scheme 8. The R group is as defined elsewhere in this disclosure. Scheme 8. [ka]

[0297] This aspect involves reacting a compound of Formula II with an acid, which also serves as a solvent. In one embodiment, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and combinations thereof. In another embodiment, the acid is sulfuric acid. In one embodiment, the reaction temperature ranges from about 10°C to about 90°C. In another embodiment, the reaction temperature ranges from about 60°C to 65°C.

[0298] In one aspect, compounds of Formula IV are prepared according to the method represented by Scheme 9. The R group is as defined elsewhere in this disclosure. Scheme 9. [ka]

[0299] This aspect includes reacting a compound of Formula III with a halogenating reagent in a solvent. In one embodiment, the halogenating reagent is selected from a fluorinating agent, a chlorinating agent, a brominating agent, an iodinating agent, and combinations thereof. In one embodiment, the halogenating reagent is a chlorinating reagent selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In another embodiment, the chlorinating reagent is sulfuryl chloride. In one embodiment, the solvent is selected from acetonitrile (ACN), 1,2-dichloroethane (DCE), toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof. In another embodiment, the solvent is acetic acid. In one embodiment, the reaction temperature is in the range of about 20° C. to about 140° C. In another embodiment, the reaction temperature is in the range of about 120° C. to about 130° C.

[0300] In one aspect, compounds of Formula IV are prepared according to the method represented by Scheme 10. The R group is as defined elsewhere in this disclosure. Scheme 10. [ka]

[0301] This aspect involves reacting a compound of Formula II with an acid, which also serves as a solvent, in a first reaction, followed by adding a halogenating agent in a second reaction to form a compound of Formula IV. In one embodiment, the acid is selected from acetic acid, sulfuric acid, and combinations thereof. In another embodiment, the acid is sulfuric acid. In one embodiment, the halogenating reagent is selected from a fluorinating agent, a chlorinating agent, a brominating agent, an iodinating agent, and combinations thereof. In one embodiment, the halogenating reagent is a chlorinating reagent selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In another embodiment, the chlorinating reagent is trichloroisocyanuric acid. In one embodiment, the reaction temperature of the first reaction is in the range of about 0° C. to about 100° C. In another embodiment, the reaction temperature of the first reaction is in the range of about 10° C. to about 65° C. In one embodiment, the reaction temperature of the second reaction ranges from about 10°C to about 100°C. In another embodiment, the reaction temperature of the second reaction ranges from about 10°C to about 65°C.

[0302] This embodiment is a single-pot process and has several advantages. First, it eliminates the need to isolate intermediates produced from compounds of Formula II, such as compounds of Formula III, prior to subsequent reactions. Second, it reduces potential losses of intermediates produced from compounds of Formula II, such as compounds of Formula III. Third, it increases overall yield. Fourth, it reduces the number of reaction steps and work-up operations. Fifth, it reduces overall costs.

[0303] In one aspect, compounds of formula V are prepared according to the method represented by Scheme 11. The R group is as defined elsewhere in this disclosure. Scheme 11. [ka]

[0304] This aspect involves adding an oxidizing agent to an aqueous solution containing a compound of Formula IV in the presence of a catalyst. In one embodiment, the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof. In another embodiment, the oxidizing agent is hydrogen peroxide. In one embodiment, the solvent is selected from acetonitrile (ACN), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (i-PrOH), water (HO), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF), acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof. In another embodiment, the solvent is acetic acid. In one embodiment, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof. In another embodiment, the catalyst is sulfuric acid. In one embodiment, the reaction temperature is in the range of about 20° C. to about 100° C. In another embodiment, the reaction temperature ranges from about 60°C to about 65°C.

[0305] In one aspect, compounds of Formula VI are prepared according to the method represented by Scheme 12. The R group is as defined elsewhere in this disclosure. Scheme 12. [ka]

[0306] This aspect involves reacting a compound of formula V with an alkylamine in a solvent. In one embodiment, the alkylamine is a branched C1-C 10 Alkyl and unbranched C1-C 10The reaction mixture comprises a functional group selected from alkyl. In another embodiment, the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, t-butylamine, and combinations thereof. In one embodiment, the solvent is selected from acetonitrile (ACN), 1,2-dichloroethane (DCE), toluene, chlorobenzene, xylene, methanol (MeOH), ethanol (EtOH), isopropyl alcohol (i-PrOH), ethyl acetate (EtOAc), isopropyl acetate (IPA), and combinations thereof. In another embodiment, the solvent is EtOAc. In one embodiment, the reaction temperature ranges from about 0° C. to about 100° C. In another embodiment, the reaction temperature ranges from about 20° C. to about 30° C.

[0307] In one aspect, compounds of formula V are prepared according to the method represented by Scheme 13. The R group is as defined elsewhere in this disclosure. Scheme 13. [ka]

[0308] This aspect includes reacting a compound of Formula III with a halogenating agent in a solvent, followed by adding an oxidizing agent to the solution in the presence of a catalyst. In one embodiment, the halogenating agent is selected from a fluorinating agent, a chlorinating agent, a brominating agent, an iodinating agent, and combinations thereof. In another embodiment, the halogenating agent is a chlorinating agent selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. In another embodiment, the halogenating agent is sulfuryl chloride. In one embodiment, the solvent is selected from ACN, DCE, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, and butyric acid. In another embodiment, the solvent is acetic acid. In one embodiment, the reaction temperature for the halogenation is in the range of about 20° C. to about 140° C. In another embodiment, the reaction temperature for the halogenation is in the range of about 120° C. to about 130° C. In one embodiment, the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof. In another embodiment, the oxidizing agent is hydrogen peroxide. In one embodiment, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, potassium hydroxide, and combinations thereof. In another embodiment, the catalyst is sulfuric acid. In one embodiment, the reaction temperature for the oxidation ranges from about 20°C to about 100°C. In another embodiment, the reaction temperature for the oxidation ranges from about 60°C to about 65°C.

[0309] This embodiment is a single-pot process and has several advantages. First, it eliminates the need to isolate intermediates produced from compounds of formula III, such as compounds of formula IV, prior to subsequent reactions. Second, it reduces potential losses of intermediates produced from compounds of formula III, such as compounds of formula IV. Third, it increases overall yield. Fourth, it reduces the number of reaction steps and work-up operations. Fifth, it reduces overall costs. [Example]

[0310] Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. Therefore, the following examples should be construed as merely illustrative and in no way limit the present disclosure. The starting materials for the following examples may not necessarily be prepared by the specific preparative practices whose procedures are described in other examples. It is also understood that any numerical range recited herein includes all values ​​from the lower limit to the upper limit. For example, if a range is expressed as 10 to 50, values ​​such as 12 to 30, 20 to 40, or 30 to 50 are also intended to be specifically recited herein. These are merely specifically intended examples, and all possible combinations of numerical values ​​between the lowest and highest recited values ​​should be considered to be expressly recited in this application.

[0311] Example 1. Reaction of o-toluidine 11.5 g of o-toluidine, 12.0 g of hydrochloric acid, 19.7 g of chloral hydrate, 27.0 g of hydroxylamine sulfate, 30.0 g of sodium sulfate, and 200.0 g of water were charged into a reactor. The reaction temperature was controlled at 55-60°C. After the reaction, the mixture was cooled to room temperature and filtered. The filter cake was washed with water and dried. 13.2 g of highly pure (E)-3-hydroxy-N-(o-tolyl)acrylamide was obtained.

[0312] Example 2. Cyclization 20.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide was added to the sulfuric acid in the reactor in small portions to control the reaction temperature. The reaction temperature was controlled between 60°C and 65°C. After the reaction, the mixture was cooled to room temperature and added to ice water. The mixture was stirred and filtered. The filter cake was washed with water and dried. 16.0 g of 7-methylindoline-2,3-dione was obtained. This crude product could be used for the subsequent reaction without further treatment.

[0313] Example 3. Halogenation 30.0 g of 7-methylindoline-2,3-dione, 50.3 g of sulfuryl chloride, and 100.0 g of acetic acid were charged into a reactor. The reaction temperature was controlled at 120-125°C. After the reaction, the mixture was cooled to room temperature. Water was added to the mixture, which was then stirred at room temperature. The mixture was filtered. The filter cake was washed with water and dried. 29.1 g of 5-chloro-7-methylindoline-2,3-dione was obtained.

[0314] Example 4. Oxidation 18.0 g of 5-chloro-7-methylindoline-2,3-dione, 100.0 g of acetic acid, and 1.0 g of sulfuric acid were charged into a reactor. The reaction temperature was controlled at 60-65°C. At this temperature, 13.0 g of 30% hydrogen peroxide solution was added dropwise to control the temperature at 60-65°C. After the reaction, water was added to the mixture, which was then stirred at room temperature. The mixture was filtered. The filter cake was washed with water and dried. 14.6 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione was obtained.

[0315] Example 5. Reaction with methanamine 10.0 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione and 100.0 g of ethyl acetate were charged into a reactor. Gaseous methanamine was bubbled through the reaction mixture at room temperature. After the reaction, the mixture was extracted with water. The solvent of the organic phase was removed under vacuum. 8.5 g of crude 2-amino-5-chloro-N,3-dimethylbenzamide was obtained.

[0316] Example 6. One-pot synthesis 30.0 g of 7-methylindoline-2,3-dione, 50.3 g of sulfuryl chloride, and 164.0 g of acetic acid were charged into a reactor. The reaction temperature was controlled at 120-125°C. After the 7-methylindoline-2,3-dione was consumed, the reaction temperature was cooled to 60-65°C. 41.4 g of 30% hydrogen peroxide solution was added dropwise to control the temperature at 60-65°C. After the reaction, water was added to the mixture, which was then stirred at room temperature. The mixture was filtered. The filter cake was washed with water and dried. 27.6 g of 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione was obtained.

[0317] This written description uses examples to explain 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 methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal wording of the claims, or if they include equivalent structural elements that have insubstantial differences from the literal wording of the claims.

Claims

1. Compound of Formula V 【Chemical 1】 (R 7 ~R 10 each independently represents hydrogen, halogen, halogenated C 1 ~C 5 alkyl, and C 1 ~C 5 alkyl; R 7 ~R 10 at least one of which is a halogen 1. A method for preparing i) a) a compound of formula III 【Chemistry 2】 (R 1 ~R 4 each independently represents hydrogen, halogen, and C 1 ~C 5 alkyl); b) a solvent; and c) a chlorinating reagent selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof. forming a first mixture comprising: ii) reacting the first mixture; iii) adding an oxidizing agent to the reacted first mixture in the presence of a catalyst to form a further mixture; and iv) reacting said further mixture; The method comprising:

2. 10. The method of claim 1, wherein step iii) comprises adding a second mixture to the first mixture to obtain a further mixture, wherein the second mixture comprises d) an oxidizing agent and e) a catalyst.

3. 10. The method of claim 1, wherein the solvent b) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

4. 10. The process of claim 1, wherein step ii) of the process of reacting the first mixture is carried out at a reaction temperature in the range of 20°C to 140°C.

5. 10. The method of claim 1, wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof.

6. 10. The method of claim 1, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof.

7. 10. The process of claim 1, wherein said process step iv) of reacting said further mixture is carried out at a reaction temperature in the range of 20°C to 100°C.

8. wherein the compound of formula III is I) A) Compound of Formula II 【Chemistry 3】 (R 1 ~R 5 each independently represents hydrogen, halogen, and C 1 ~C 5 alkyl; and The compound of formula II is i) a) a compound of formula I 【Chemistry 4】 (R 1 ~R 5 each independently represents hydrogen, halogen, and C 1 ~C 5 alkyl); b) Chloral hydrate; c) hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid forming a mixture comprising: ii) reacting the mixture (prepared according to a method comprising the steps of: B) acid forming a mixture comprising: II) reacting the mixture 10. The method of claim 1, wherein the composition is prepared according to a method comprising:

9. Compound of Formula VI 【Chemistry 5】 (R 7 ~R 10 each independently represents hydrogen, halogen, halogenated C 1 ~C 5 alkyl, and C 1 ~C 5 alkyl; R 7 ~R 10 at least one of is a halogen; R 11 is a branched C 1 ~C 10 Alkyl and unbranched C 1 ~C 10 alkyl) 1. A method for preparing I) A) a compound of formula V as defined in claim 1, wherein said compound of formula V is prepared by the method of claim 1. B) alkylamines, and C) a solvent; forming a mixture comprising: II) reacting the mixture The method comprising:

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