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

Abstract

This article describes a new and efficient method for synthesizing 2-amino-5-chloro-N,3-dimethylbenzamide. The compounds prepared by the methods disclosed herein can be used to prepare certain anthranilamide compounds that are of interest as insecticides, such as the insecticides chlorantraniliprole and cyantraniliprole.

Description

[0001] This application is a divisional application of the international application number PCT / US2020 / 057726 filed on October 28, 2020, the Chinese national application number 202080048608.5, and the application titled “A New Efficient Method for Synthesizing 2-Amino-5-chloro-N,3-dimethylbenzamide”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 929,138, filed on November 1, 2019. Technical Field

[0004] The present disclosure relates to novel methods for synthesizing 2-amino-5-chloro-N,3-dimethylbenzamide. The compounds prepared by the methods disclosed herein can be used to prepare certain anthranilamide compounds of interest as insecticides, such as the insecticides chlorantraniliprole and cyantraniliprole. Background Art

[0005] Conventional methods for producing 2-amino-5-chloro-N,3-dimethylbenzamide have several industrial problems such as hazardous materials, high costs, relatively long process steps, and complicated operations.

[0006] The present disclosure provides novel methods for preparing 2-amino-5-chloro-N,3-dimethylbenzamide and its derivatives. Compared with previous methods, the method of the present disclosure has many benefits and includes reduced costs, elimination of the need for mixed solvent separation, reduced waste, relatively short process steps, simplified operational complexity and reduced process hazards. Summary of the invention

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

[0008]

[0009] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0010] Where R 7 -R 10 At least one of is a halogen; and

[0011] Where R 11 Selected from branched C 1 -C 10Alkyl and unbranched C 1 -C 10 alkyl, the method comprising

[0012] I) forming a mixture comprising:

[0013] A) a compound of formula V, wherein

[0014]

[0015] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0016] Where R 7 -R 10 At least one of is a halogen; and

[0017] Wherein the compound of formula V is prepared according to a process comprising:

[0018] i) forming a first mixture, the first mixture comprising:

[0019] a) a compound of formula III, wherein

[0020]

[0021] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0022] b) solvent; and

[0023] c) halogenating agent;

[0024] ii) reacting the first mixture;

[0025] iii) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising

[0026] d) an oxidizing agent; and

[0027] e) a catalyst; and

[0028] iv) reacting the third mixture;

[0029] B) an alkylamine; and

[0030] C) a solvent; and

[0031] II) reacting the mixture.

[0032] In one aspect, provided herein is a method for preparing a compound having formula V, wherein

[0033]

[0034] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0035] Where R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0036] I) forming a first mixture, the first mixture comprising:

[0037] A) a compound of formula III, wherein

[0038]

[0039] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0040] B) a solvent; and

[0041] C) halogenating agent;

[0042] II) reacting the first mixture;

[0043] III) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising

[0044] D) an oxidizing agent; and

[0045] E) a catalyst; and

[0046] IV) reacting the third mixture.

[0047] In one aspect, provided herein is a method for preparing a compound having formula VI, wherein

[0048]

[0049] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1-C 5 Alkyl and C 1 -C 5 alkyl;

[0050] Where R 7 -R 10 At least one of is a halogen; and

[0051] Where R 11 Selected from branched C 1 -C 10 Alkyl and unbranched C 1 -C 10 alkyl, the method comprising

[0052] I) forming a mixture comprising

[0053] A) a compound of formula V, wherein

[0054]

[0055] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0056] Where R 7 -R 10 At least one of is a halogen; and

[0057] Wherein the compound of formula V is prepared according to a process comprising:

[0058] i) forming a mixture comprising

[0059] a) a compound of formula IV, wherein

[0060]

[0061] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0062] Where R 7 -R 10 At least one of is a halogen;

[0063] b) oxidizing agents;

[0064] c) solvent; and

[0065] d) a catalyst; and

[0066] ii) reacting the mixture;

[0067] B) an alkylamine; and

[0068] C) a solvent; and

[0069] II) reacting the mixture.

[0070] In one aspect, provided herein is a method for preparing a compound having formula V, wherein

[0071]

[0072] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0073] Where R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0074] I) forming a mixture comprising

[0075] A) a compound of formula IV, wherein

[0076]

[0077] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0078] Where R 7 -R 10 At least one of is a halogen;

[0079] B) oxidizing agent;

[0080] C) a solvent; and

[0081] D) a catalyst; and

[0082] II) reacting the mixture.

[0083] In one aspect, provided herein is a method for preparing a compound having formula IV, wherein

[0084]

[0085] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0086] Where R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0087] I) forming a mixture comprising

[0088] A) a compound of formula III, wherein

[0089]

[0090] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0091] B) solvent;

[0092] C) a halogenating agent; and

[0093] II) reacting the mixture.

[0094] In one aspect, provided herein is a method for preparing a compound having formula III, wherein

[0095]

[0096] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl, the method comprising:

[0097] I) forming a mixture comprising

[0098] A) a compound of formula II, wherein

[0099]

[0100] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0101] Wherein the compound of formula II is prepared according to a process comprising:

[0102] i) forming a mixture comprising

[0103] a) a compound of formula I, wherein

[0104]

[0105] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0106] b) chloral hydrate;

[0107] c) Hydroxylamine derivatives;

[0108] d) solvent;

[0109] e) inorganic salts; and

[0110] f) acid; and

[0111] ii) reacting the mixture; and

[0112] B) acid; and

[0113] II) reacting the mixture.

[0114] In one aspect, provided herein is a method for preparing a compound having formula II, wherein

[0115]

[0116] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl, the method comprising:

[0117] I) forming a mixture comprising

[0118] A) a compound of formula I, wherein

[0119]

[0120] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0121] B) chloral hydrate;

[0122] C) Hydroxylamine derivatives;

[0123] D) solvent;

[0124] E) inorganic salts; and

[0125] F) acid; and

[0126] II) reacting the mixture.

[0127] In one aspect, provided herein is a method for preparing a compound having formula IV, wherein

[0128]

[0129] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; wherein R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0130] I) forming a mixture comprising

[0131] A) a compound of formula II, wherein

[0132]

[0133] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0134] B) acid;

[0135] II) reacting the first mixture;

[0136] III) introducing a halogenating agent into the first mixture to form a second mixture; and

[0137] IV) reacting the second mixture. DETAILED DESCRIPTION

[0138] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation expressly stated otherwise. For example, a composition, mixture, process, or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0139] The conjunction "consisting of" excludes any elements, steps, or ingredients not mentioned. If in a claim, it would exclude materials other than those listed, except for impurities normally associated therewith. When the conjunction "consisting of" appears in a clause of the claim body, rather than immediately following the preamble, it limits only the elements listed in that clause; other elements are not excluded from the claim as a whole.

[0140] The conjunction "consisting essentially of" is used to define compositions or methods that include materials, steps, features, components or elements other than those literally disclosed, provided that these additional materials, steps, features, components or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of" occupies a middle ground between "comprising" and "consisting of."

[0141] When an invention or a portion thereof is defined by an open-ended term such as "comprising," it should be readily understood that (unless otherwise indicated) the description should be interpreted as also using the term "consisting essentially of" or "consisting of" to describe such an invention.

[0142] In addition, unless expressly stated to the contrary, "or" refers to an inclusive or rather than an exclusive or. For example, condition A or B is satisfied by any of the following conditions: 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).

[0143] In addition, the indefinite article "a and an" before an element or component of the present invention is intended to be non-restrictive with respect to the number of instances (i.e., occurrences) of the element or component. Therefore, "a or an" should be understood to include one or at least one, and the singular word form of the element or component also includes the plural, unless the number obviously means the singular.

[0144] As used herein, the term "about" means plus or minus 10% of the value.

[0145] The term "halogen", alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. In addition, when used in compound words such as "haloalkyl", the alkyl group may be partially substituted or fully substituted by halogen atoms which may be the same or different.

[0146] When a group contains a substituent which may be hydrogen, for example R 4 When the substituent is regarded as hydrogen, this is considered to be equivalent to the group being unsubstituted.

[0147] The term "alkyl" includes, but is not limited to, functional groups comprising linear or branched alkyl groups. In some aspects, the alkyl group can be methyl, ethyl, n-propyl, isopropyl, or different butyl, pentyl, or hexyl isomers.

[0148] Certain compounds of the present invention may exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and / or may exhibit beneficial effects when enriched relative to or separated from one or more other stereoisomers. In addition, the skilled artisan knows how to separate, enrich, and / or selectively prepare the stereoisomers.

[0149] Embodiments of the present disclosure include:

[0150] Example 1. A method for preparing a compound having formula VI, wherein

[0151]

[0152] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0153] Where R 7 -R 10 At least one of is a halogen; and

[0154] Where R 11 Selected from branched C 1 -C 10 Alkyl and unbranched C 1 -C 10 alkyl, the method comprising

[0155] I) forming a mixture comprising:

[0156] A) a compound of formula V, wherein

[0157]

[0158] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0159] Where R 7 -R 10 At least one of is a halogen; and

[0160] Wherein the compound of formula V is prepared according to a process comprising:

[0161] i) forming a first mixture, the first mixture comprising:

[0162] a) a compound of formula III, wherein

[0163]

[0164] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0165] b) solvent; and

[0166] c) halogenating agent;

[0167] ii) reacting the first mixture;

[0168] iii) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising

[0169] d) an oxidizing agent; and

[0170] e) a catalyst; and

[0171] iv) reacting the third mixture;

[0172] B) an alkylamine; and

[0173] C) a solvent; and

[0174] II) reacting the mixture.

[0175] Embodiment 2. The method of embodiment 1, wherein the alkylamine comprises a branched C 1 -C 10 Alkyl and unbranched C 1 -C 10 Alkyl functional group.

[0176] Embodiment 3. The method as described in embodiment 2, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert-butylamine and combinations thereof.

[0177] Embodiment 4. The method of embodiment 3, wherein the alkylamine is methylamine.

[0178] Embodiment 5. The method as described in embodiment 1, wherein the solvent C) is selected from acetonitrile, ethylene dichloride, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate and combinations thereof.

[0179] Embodiment 6. The method of embodiment 5, wherein the solvent C) is ethyl acetate.

[0180] Embodiment 7. The method of embodiment 1, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 100°C.

[0181] Embodiment 8. The method of embodiment 7, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 20°C to about 30°C.

[0182] Embodiment 9. The method as described in embodiment 1, wherein the solvent b) is selected from acetonitrile, ethylene dichloride, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid and combinations thereof.

[0183] Embodiment 10. The method of embodiment 9, wherein the solvent b) is acetic acid.

[0184] Embodiment 11. The method as described in embodiment 1, wherein the halogenation reagent is selected from the group consisting of a chlorination reagent, a bromination reagent, an iodination reagent and a combination thereof.

[0185] Embodiment 12. The method as described in embodiment 11, 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.

[0186] Embodiment 13. The method of embodiment 12, wherein the chlorinating agent is sulfuryl chloride.

[0187] Embodiment 14. The method of embodiment 1, wherein the method step ii) of reacting the first mixture occurs at a reaction temperature in the range of about 20°C to about 140°C.

[0188] Embodiment 15. The method of embodiment 14, wherein the method step ii) of reacting the first mixture occurs at a reaction temperature in the range of about 120°C to about 130°C.

[0189] Embodiment 16. The method as described in embodiment 1, wherein the oxidant is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium peroxymonosulfate, potassium permanganate and combinations thereof.

[0190] Embodiment 17. The method of embodiment 16, wherein the oxidizing agent is hydrogen peroxide.

[0191] Embodiment 18. The method as described in embodiment 1, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid and combinations thereof.

[0192] Embodiment 19. The method of embodiment 18, wherein the catalyst is sulfuric acid.

[0193] Embodiment 20. The method of embodiment 1, wherein the method step iv) of reacting the third mixture occurs at a reaction temperature in the range of about 20°C to about 100°C.

[0194] Embodiment 21. The method of embodiment 20, wherein the method step iv) of reacting the third mixture occurs at a reaction temperature in the range of about 60°C to about 65°C.

[0195] Embodiment 22. The method of embodiment 1, wherein the compound of formula III is prepared according to a method comprising:

[0196] I) forming a mixture comprising

[0197] A) a compound of formula II, wherein

[0198]

[0199] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0200] Wherein the compound of formula II is prepared according to a process comprising:

[0201] i) forming a mixture comprising

[0202] a) a compound of formula I, wherein

[0203]

[0204] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0205] b) chloral hydrate;

[0206] c) Hydroxylamine derivatives;

[0207] d) solvent;

[0208] e) inorganic salts; and

[0209] f) acid; and

[0210] ii) reacting the mixture; and

[0211] B) acid; and

[0212] II) reacting the mixture.

[0213] 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.

[0214] Embodiment 24. The method of embodiment 23, wherein the acid B) is hydrochloric acid.

[0215] Embodiment 25. The method of embodiment 22, 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.

[0216] Embodiment 26. The method of embodiment 25, 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.

[0217] Embodiment 27. The method of embodiment 22, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and a combination thereof.

[0218] Embodiment 28. The method of embodiment 27, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0219] Embodiment 29. The method as described in Embodiment 22, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0220] Embodiment 30. The method of embodiment 29, wherein the solvent is water.

[0221] Embodiment 31. The method as described in Embodiment 22, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0222] Embodiment 32. The method of embodiment 31, wherein the inorganic salt is sodium sulfate.

[0223] 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.

[0224] Embodiment 34. The method of embodiment 33, wherein the acid f) is hydrochloric acid.

[0225] 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%.

[0226] Embodiment 36. The method of embodiment 35, wherein the concentration of the compound of formula I in the mixture is in the range of about 3% to about 10%.

[0227] Embodiment 37. The method of embodiment 22, 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.

[0228] Embodiment 38. The method of embodiment 37, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0229] Embodiment 39. A method for preparing a compound having formula V, wherein

[0230]

[0231] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0232] Where R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0233] I) forming a first mixture, the first mixture comprising:

[0234] A) a compound of formula III, wherein

[0235]

[0236] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0237] B) a solvent; and

[0238] C) halogenating agent;

[0239] II) reacting the first mixture;

[0240] III) introducing a second mixture into the first mixture to form a third mixture, the second mixture comprising

[0241] D) an oxidizing agent; and

[0242] E) a catalyst; and

[0243] IV) reacting the third mixture.

[0244] Embodiment 40. The method as described in Embodiment 39, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid and combinations thereof.

[0245] Embodiment 41. The method of embodiment 40, wherein the solvent is acetic acid.

[0246] Embodiment 42. The method as described in Embodiment 39, wherein the halogenating agent is selected from the group consisting of a chlorinating agent, a brominating agent, an iodinating agent and a combination thereof.

[0247] Embodiment 43. The method as described in Embodiment 42, 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.

[0248] Embodiment 44. The method of embodiment 43, wherein the chlorinating agent is sulfuryl chloride.

[0249] Embodiment 45. The method of embodiment 39, wherein the method step II) of reacting the first mixture occurs at a reaction temperature in the range of about 20°C to about 140°C.

[0250] Embodiment 46. The method of embodiment 45, wherein the method step II) of reacting the first mixture occurs at a reaction temperature in the range of about 120°C to about 130°C.

[0251] Embodiment 47. The method as described in Embodiment 39, wherein the oxidant is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium permonosulfate, potassium permanganate and combinations thereof.

[0252] Embodiment 48. The method of embodiment 47, wherein the oxidizing agent is hydrogen peroxide.

[0253] Embodiment 49. The method as described in Embodiment 39, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid and a combination thereof.

[0254] Embodiment 50. The method of embodiment 49, wherein the catalyst is sulfuric acid.

[0255] Embodiment 51. The method of embodiment 39, wherein the method step IV) of reacting the third mixture occurs at a reaction temperature in the range of about 20°C to about 100°C.

[0256] Embodiment 52. The method of embodiment 51, wherein the method step IV) of reacting the third mixture occurs at a reaction temperature in the range of about 60°C to about 65°C.

[0257] Embodiment 53. The method of embodiment 39, wherein the compound of formula III is prepared according to a method comprising:

[0258] I) forming a mixture comprising

[0259] A) a compound of formula II, wherein

[0260]

[0261] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0262] Wherein the compound of formula II is prepared according to a process comprising:

[0263] i) forming a mixture comprising

[0264] a) a compound of formula I, wherein

[0265]

[0266] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0267] b) chloral hydrate;

[0268] c) Hydroxylamine derivatives;

[0269] d) solvent;

[0270] e) inorganic salts; and

[0271] f) acid; and

[0272] ii) reacting the mixture; and

[0273] B) acid; and

[0274] II) reacting the mixture.

[0275] 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.

[0276] Embodiment 55. The method of embodiment 54, wherein the acid B) is hydrochloric acid.

[0277] Embodiment 56. The method of embodiment 53, 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.

[0278] Embodiment 57. The method of embodiment 56, 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.

[0279] Embodiment 58. The method of embodiment 53, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and a combination thereof.

[0280] Embodiment 59. The method of embodiment 58, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0281] Embodiment 60. The method as described in Embodiment 53, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0282] Embodiment 61. The method of embodiment 60, wherein the solvent is water.

[0283] Embodiment 62. The method as described in Embodiment 53, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0284] Embodiment 63. The method of embodiment 62, wherein the inorganic salt is sodium sulfate.

[0285] 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.

[0286] Embodiment 65. The method of embodiment 64, wherein the acid f) is hydrochloric acid.

[0287] 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%.

[0288] Embodiment 67. The method of embodiment 66, wherein the concentration of the compound of formula I in the mixture is in the range of about 3% to about 10%.

[0289] Embodiment 68. The method of embodiment 53, 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.

[0290] Embodiment 69. The method of embodiment 68, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0291] Embodiment 70. A method for preparing a compound having formula VI, wherein

[0292]

[0293] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0294] Where R 7 -R 10 At least one of is a halogen; and

[0295] Where R 11 Selected from branched C 1 -C 10 Alkyl and unbranched C 1 -C 10 alkyl, the method comprising

[0296] I) forming a mixture comprising

[0297] A) a compound of formula V, wherein

[0298]

[0299] R 7 -R10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0300] Where R 7 -R 10 At least one of is a halogen; and

[0301] Wherein the compound of formula V is prepared according to a process comprising:

[0302] i) forming a mixture comprising

[0303] a) a compound of formula IV, wherein

[0304]

[0305] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0306] Where R 7 -R 10 At least one of is a halogen;

[0307] b) oxidizing agents;

[0308] c) solvent; and

[0309] d) a catalyst; and

[0310] ii) reacting the mixture;

[0311] B) an alkylamine; and

[0312] C) a solvent; and

[0313] II) reacting the mixture.

[0314] Embodiment 71. The method of embodiment 70, wherein the alkylamine comprises a branched C 1 -C 10 Alkyl and unbranched C 1 -C 10 Alkyl functional group.

[0315] Embodiment 72. The method as described in Embodiment 71, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert-butylamine and combinations thereof.

[0316] Embodiment 73. The method of Embodiment 72, wherein the alkylamine is methylamine.

[0317] Embodiment 74. The method as described in Embodiment 70, wherein the solvent C) is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate and combinations thereof.

[0318] Embodiment 75. The method of embodiment 74, wherein the solvent C) is ethyl acetate.

[0319] Embodiment 76. The method of embodiment 70, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 0°C to about 100°C.

[0320] Embodiment 77. The method of embodiment 76, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 20°C to about 30°C.

[0321] Embodiment 78. The method as described in Embodiment 70, wherein the oxidant is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium permonosulfate, potassium permanganate and combinations thereof.

[0322] Embodiment 79. The method of Embodiment 78, wherein the oxidizing agent is hydrogen peroxide.

[0323] Embodiment 80. A method as described in 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.

[0324] Embodiment 81. The method of Embodiment 80, wherein the solvent c) is acetic acid.

[0325] Embodiment 82. The method as described in Embodiment 70, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid and combinations thereof.

[0326] Embodiment 83. The method of embodiment 82, wherein the catalyst is sulfuric acid.

[0327] Embodiment 84. The method of embodiment 70, 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.

[0328] Embodiment 85. The method of embodiment 84, 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.

[0329] Embodiment 86. The method of embodiment 70, wherein the compound of formula IV is prepared according to a method comprising:

[0330] I) forming a mixture comprising

[0331] A) a compound of formula III, wherein

[0332]

[0333] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0334] B) solvent;

[0335] C) a halogenating agent; and

[0336] II) reacting the mixture.

[0337] Embodiment 87. The method as described in Embodiment 86, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid and combinations thereof.

[0338] Embodiment 88. The method of Embodiment 87, wherein the solvent is acetic acid.

[0339] Embodiment 89. The method as described in Embodiment 86, wherein the halogenation reagent is selected from the group consisting of a chlorination reagent, a bromination reagent, an iodination reagent and a combination thereof.

[0340] Embodiment 90. A method as described in Embodiment 89, 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.

[0341] Embodiment 91. The method of embodiment 90, wherein the chlorinating agent is sulfuryl chloride.

[0342] Embodiment 92. The method of embodiment 86, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 20°C to about 140°C.

[0343] Embodiment 93. The method of embodiment 92, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 120°C to about 130°C.

[0344] Embodiment 94. The method of embodiment 86, wherein the compound of formula III is prepared according to a method comprising:

[0345] I) forming a mixture comprising

[0346] A) a compound of formula II, wherein

[0347]

[0348] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0349] Wherein the compound of formula II is prepared according to a process comprising:

[0350] i) forming a mixture comprising

[0351] a) a compound of formula I, wherein

[0352]

[0353] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0354] b) chloral hydrate;

[0355] c) Hydroxylamine derivatives;

[0356] d) solvent;

[0357] e) inorganic salts; and

[0358] f) acid; and

[0359] ii) reacting the mixture; and

[0360] B) acid; and

[0361] II) reacting the mixture.

[0362] 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.

[0363] Embodiment 96. The method of embodiment 95, wherein the acid B) is hydrochloric acid.

[0364] Embodiment 97. The method of embodiment 94, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 90°C.

[0365] Embodiment 98. The method of embodiment 97, 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.

[0366] Embodiment 99. The method as described in Embodiment 94, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and a combination thereof.

[0367] Embodiment 100. The method of Embodiment 99, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0368] Embodiment 101. The method as described in Embodiment 94, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0369] Embodiment 102. The method of Embodiment 101, wherein the solvent is water.

[0370] Embodiment 103. A method as described in Embodiment 94, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0371] Embodiment 104. The method of embodiment 103, wherein the inorganic salt is sodium sulfate.

[0372] 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.

[0373] Embodiment 106. The method of embodiment 105, wherein the acid f) is hydrochloric acid.

[0374] 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%.

[0375] Embodiment 108. The method of Embodiment 107, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0376] Embodiment 109. The method of embodiment 94, 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.

[0377] Embodiment 110. The method of embodiment 109, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0378] Embodiment 111. The method of embodiment 70, wherein the compound of formula IV is prepared according to a method comprising:

[0379] I) forming a mixture comprising:

[0380] A) a compound of formula II, wherein

[0381]

[0382] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0383] B) acid;

[0384] II) reacting the first mixture;

[0385] III) introducing a halogenating agent into the first mixture to form a second mixture; and

[0386] IV) reacting the second mixture.

[0387] Embodiment 112. The method of embodiment 111, wherein the acid is selected from sulfuric acid, acetic acid, and combinations thereof.

[0388] Embodiment 113. The method of Embodiment 112, wherein the acid is sulfuric acid.

[0389] Embodiment 114. The method as described in Embodiment 111, wherein the halogenating agent is selected from the group consisting of a chlorinating agent, a brominating agent, an iodinating agent and a combination thereof.

[0390] Embodiment 115. A method as described in Embodiment 114, 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.

[0391] Embodiment 116. The method of Embodiment 115, wherein the chlorinating agent is trichloroisocyanuric acid.

[0392] Embodiment 117. The method of embodiment 111, wherein the method step IV) of reacting the second mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0393] Embodiment 118. The method of embodiment 117, wherein the method step IV) of reacting the second mixture occurs at a reaction temperature in the range of about 10°C to about 65°C.

[0394] Embodiment 119. The method of embodiment 111, wherein the compound of formula II is prepared according to a method comprising:

[0395] i) forming a mixture comprising:

[0396] a) a compound of formula I, wherein

[0397]

[0398] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0399] b) chloral hydrate;

[0400] c) Hydroxylamine derivatives;

[0401] d) solvent;

[0402] e) inorganic salts; and

[0403] f) acid; and

[0404] ii) reacting the mixture.

[0405] Embodiment 120. The method of embodiment 119, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and combinations thereof.

[0406] Embodiment 121. The method of Embodiment 120, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0407] Embodiment 122. The method as described in Embodiment 119, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0408] Embodiment 123. The method of Embodiment 122, wherein the solvent is water.

[0409] Embodiment 124. The method as described in Embodiment 119, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0410] Embodiment 125. The method of embodiment 124, wherein the inorganic salt is sodium sulfate.

[0411] Embodiment 126. The method as described in Embodiment 119, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid and combinations thereof.

[0412] Embodiment 127. The method of embodiment 126, wherein the acid is hydrochloric acid.

[0413] 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%.

[0414] Embodiment 129. The method of Embodiment 128, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0415] Embodiment 130. The method of Embodiment 119, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0416] Embodiment 131. The method of Embodiment 130, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0417] Embodiment 132. A method for preparing a compound having formula V, wherein

[0418]

[0419] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0420] Where R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0421] I) forming a mixture comprising:

[0422] A) a compound of formula IV, wherein

[0423]

[0424] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 Alkyl; and

[0425] Where R 7 -R 10 At least one of is a halogen;

[0426] B) oxidizing agent;

[0427] C) a solvent; and

[0428] D) a catalyst; and

[0429] II) reacting the mixture.

[0430] Embodiment 133. A method as described in Embodiment 132, wherein the oxidant is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, potassium permonosulfate, potassium permanganate and combinations thereof.

[0431] Embodiment 134. The method of Embodiment 133, wherein the oxidizing agent is hydrogen peroxide.

[0432] Embodiment 135. A method as described in 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.

[0433] Embodiment 136. The method of Embodiment 135, wherein the solvent is acetic acid.

[0434] Embodiment 137. The method as described in Embodiment 132, wherein the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid and combinations thereof.

[0435] Embodiment 138. The method of Embodiment 137, wherein the catalyst is sulfuric acid.

[0436] Embodiment 139. The method of embodiment 132, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 20°C to about 100°C.

[0437] Embodiment 140. The method of embodiment 139, 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.

[0438] Embodiment 141. The method of embodiment 132, wherein the compound of formula IV is prepared according to a method comprising:

[0439] I) forming a mixture comprising:

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

[0441]

[0442] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0443] B) solvent;

[0444] C) a halogenating agent; and

[0445] II) reacting the mixture.

[0446] Embodiment 142. The method as described in Embodiment 141, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid and combinations thereof.

[0447] Embodiment 143. The method of Embodiment 142, wherein the solvent is acetic acid.

[0448] Embodiment 144. The method as described in Embodiment 141, wherein the halogenation reagent is selected from the group consisting of a chlorination reagent, a bromination reagent, an iodination reagent and a combination thereof.

[0449] Embodiment 145. A method as described in Embodiment 144, 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.

[0450] Embodiment 146. The method of Embodiment 145, wherein the chlorinating agent is sulfuryl chloride.

[0451] Embodiment 147. The method of embodiment 141, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 20°C to about 140°C.

[0452] Embodiment 148. The method of embodiment 147, wherein the method step II) of reacting the mixture occurs at a reaction temperature in the range of about 120°C to about 130°C.

[0453] Embodiment 149. The method of embodiment 141, wherein the compound of formula III is prepared according to a method comprising:

[0454] I) forming a mixture comprising:

[0455] A) a compound of formula II, wherein

[0456]

[0457] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0458] Wherein the compound of formula II is prepared according to a process comprising:

[0459] i) forming a mixture comprising:

[0460] a) a compound of formula I, wherein

[0461]

[0462] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0463] b) chloral hydrate;

[0464] c) Hydroxylamine derivatives;

[0465] d) solvent;

[0466] e) inorganic salts; and

[0467] f) acid; and

[0468] ii) reacting the mixture; and

[0469] B) acid; and

[0470] II) reacting the mixture.

[0471] 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.

[0472] Embodiment 151. The method of embodiment 150, wherein the acid B) is hydrochloric acid.

[0473] Embodiment 152. The method of embodiment 149, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 90°C.

[0474] Embodiment 153. The method of embodiment 152, 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.

[0475] Embodiment 154. The method of embodiment 149, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and a combination thereof.

[0476] Embodiment 155. The method of Embodiment 154, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0477] Embodiment 156. The method as described in Embodiment 149, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0478] Embodiment 157. The method of Embodiment 156, wherein the solvent is water.

[0479] Embodiment 158. The method as described in Embodiment 149, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0480] Embodiment 159. The method of Embodiment 158, wherein the inorganic salt is sodium sulfate.

[0481] 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.

[0482] Embodiment 161. The method of embodiment 160, wherein the acid f) is hydrochloric acid.

[0483] 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%.

[0484] Embodiment 163. The method of Embodiment 162, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0485] Embodiment 164. The method of embodiment 149, wherein step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0486] Embodiment 165. The method of Embodiment 164, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0487] Embodiment 166. The method of embodiment 132, wherein the compound of formula IV is prepared according to a method comprising:

[0488] I) forming a mixture comprising:

[0489] A) a compound of formula II, wherein

[0490]

[0491] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0492] B) acid;

[0493] II) reacting the first mixture;

[0494] III) introducing a halogenating agent into the first mixture to form a second mixture; and

[0495] IV) reacting the second mixture.

[0496] Embodiment 167. The method of Embodiment 166, wherein the acid is selected from sulfuric acid, acetic acid, and combinations thereof.

[0497] Embodiment 168. The method of Embodiment 167, wherein the acid is sulfuric acid.

[0498] Embodiment 169. The method as described in Embodiment 166, wherein the halogenation reagent is selected from the group consisting of a chlorination reagent, a bromination reagent, an iodination reagent and a combination thereof.

[0499] Embodiment 170. A method as described in Embodiment 169, 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.

[0500] Embodiment 171. The method of Embodiment 170, wherein the chlorinating agent is trichloroisocyanuric acid.

[0501] Embodiment 172. The method of embodiment 166, wherein the method step IV) of reacting the second mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0502] Embodiment 173. The method of embodiment 172, wherein the method step IV) of reacting the second mixture occurs at a reaction temperature in the range of about 10°C to about 65°C.

[0503] Embodiment 174. The method of embodiment 166, wherein the compound of formula II is prepared according to a method comprising:

[0504] i) forming a mixture comprising:

[0505] a) a compound of formula I, wherein

[0506]

[0507] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0508] b) chloral hydrate;

[0509] c) Hydroxylamine derivatives;

[0510] d) solvent;

[0511] e) inorganic salts; and

[0512] f) acid; and

[0513] ii) reacting the mixture.

[0514] Embodiment 175. The method of embodiment 174, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and a combination thereof.

[0515] Embodiment 176. The method of Embodiment 175, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0516] Embodiment 177. The method as described in Embodiment 174, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0517] Embodiment 178. The method of Embodiment 177, wherein the solvent is water.

[0518] Embodiment 179. A method as described in Embodiment 174, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0519] Embodiment 180. The method of Embodiment 179, wherein the inorganic salt is sodium sulfate.

[0520] Embodiment 181. The method as described in Embodiment 174, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid and combinations thereof.

[0521] Embodiment 182. The method of Embodiment 181, wherein the acid is hydrochloric acid.

[0522] 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%.

[0523] Embodiment 184. The method of Embodiment 183, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0524] Embodiment 185. The method of Embodiment 174, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0525] Embodiment 186. The method of Embodiment 185, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0526] Embodiment 187. A method for preparing a compound having formula IV, wherein

[0527]

[0528] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0529] Where R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0530] I) forming a mixture comprising:

[0531] A) a compound of formula III, wherein

[0532]

[0533] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0534] B) solvent;

[0535] C) a halogenating agent; and

[0536] II) reacting the mixture.

[0537] Embodiment 188. The method as described in Embodiment 187, wherein the solvent is selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid and combinations thereof.

[0538] Embodiment 189. The method of Embodiment 188, wherein the solvent is acetic acid.

[0539] Embodiment 190. The method as described in Embodiment 187, wherein the halogenation reagent is selected from the group consisting of a chlorination reagent, a bromination reagent, an iodination reagent and a combination thereof.

[0540] Embodiment 191. A method as described in Embodiment 190, 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.

[0541] Embodiment 192. The method of Embodiment 191, wherein the chlorinating agent is sulfuryl chloride.

[0542] Embodiment 193. The method of embodiment 187, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 20°C to about 140°C.

[0543] Embodiment 194. The method of embodiment 193, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 120°C to about 130°C.

[0544] Embodiment 195. The method of embodiment 187, wherein the compound of formula III is prepared according to a method comprising:

[0545] I) forming a mixture comprising:

[0546] A) a compound of formula II, wherein

[0547]

[0548] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0549] Wherein the compound of formula II is prepared according to a process comprising:

[0550] i) forming a mixture comprising:

[0551] a) a compound of formula I, wherein

[0552]

[0553] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0554] b) chloral hydrate;

[0555] c) Hydroxylamine derivatives;

[0556] d) solvent;

[0557] e) inorganic salts; and

[0558] f) acid; and

[0559] ii) reacting the mixture; and

[0560] B) acid; and

[0561] II) reacting the mixture.

[0562] 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.

[0563] Embodiment 197. The method of Embodiment 196, wherein the acid B) is hydrochloric acid.

[0564] Embodiment 198. The method of embodiment 195, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 90°C.

[0565] Embodiment 199. The method of embodiment 198, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 60°C to about 65°C.

[0566] Embodiment 200. The method of Embodiment 195, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and combinations thereof.

[0567] Embodiment 201. The method of Embodiment 200, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0568] Embodiment 202. The method as described in Embodiment 195, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0569] Embodiment 203. The method of Embodiment 202, wherein the solvent is water.

[0570] Embodiment 204. A method as described in Embodiment 195, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0571] Embodiment 205. The method of Embodiment 204, wherein the inorganic salt is sodium sulfate.

[0572] 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.

[0573] Embodiment 207. The method of Embodiment 206, wherein the acid f) is hydrochloric acid.

[0574] 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%.

[0575] Embodiment 209. The method of Embodiment 208, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0576] Embodiment 210. The method of Embodiment 195, wherein step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0577] Embodiment 211. The method of Embodiment 210, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0578] Embodiment 212. A method for preparing a compound having formula III, wherein

[0579]

[0580] R 1 -R 4 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl, the method comprising:

[0581] I) forming a mixture comprising:

[0582] A) a compound of formula II, wherein

[0583]

[0584] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0585] Wherein the compound of formula II is prepared according to a process comprising:

[0586] i) forming a mixture comprising:

[0587] a) a compound of formula I, wherein

[0588]

[0589] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0590] b) chloral hydrate;

[0591] c) Hydroxylamine derivatives;

[0592] d) solvent;

[0593] e) inorganic salts; and

[0594] f) acid; and

[0595] ii) reacting the mixture; and

[0596] B) acid; and

[0597] II) reacting the mixture.

[0598] 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.

[0599] Embodiment 214. The method of Embodiment 213, wherein the acid B) is hydrochloric acid.

[0600] Embodiment 215. The method of embodiment 212, 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.

[0601] Embodiment 216. The method of Embodiment 215, wherein step II) of reacting the mixture occurs at a reaction temperature in the range of about 60°C to about 65°C.

[0602] Embodiment 217. The method of Embodiment 212, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and combinations thereof.

[0603] Embodiment 218. The method of Embodiment 217, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0604] Embodiment 219. The method as described in Embodiment 212, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0605] Embodiment 220. The method of Embodiment 219, wherein the solvent is water.

[0606] Embodiment 221. A method as described in Embodiment 212, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0607] Embodiment 222. The method of Embodiment 221, wherein the inorganic salt is sodium sulfate.

[0608] 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.

[0609] Embodiment 224. The method of embodiment 223, wherein the acid f) is hydrochloric acid.

[0610] 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%.

[0611] Embodiment 226. The method of Embodiment 225, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0612] Embodiment 227. The method of Embodiment 212, wherein step ii) of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0613] Embodiment 228. The method of Embodiment 227, wherein the method step ii) of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0614] Embodiment 229. A method for preparing a compound having formula II, wherein

[0615]

[0616] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl, the method comprising:

[0617] I) forming a mixture comprising:

[0618] A) a compound of formula I, wherein

[0619]

[0620] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0621] B) chloral hydrate;

[0622] C) Hydroxylamine derivatives;

[0623] D) solvent;

[0624] E) inorganic salts; and

[0625] F) acid; and

[0626] II) reacting the mixture.

[0627] Embodiment 230. The method of embodiment 229, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and combinations thereof.

[0628] Embodiment 231. The method of Embodiment 230, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0629] Embodiment 232. The method as described in Embodiment 229, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0630] Embodiment 233. The method of Embodiment 232, wherein the solvent is water.

[0631] Embodiment 234. A method as described in Embodiment 229, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0632] Embodiment 235. The method of Embodiment 234, wherein the inorganic salt is sodium sulfate.

[0633] Embodiment 236. The method as described in Embodiment 229, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid and combinations thereof.

[0634] Embodiment 237. The method of Embodiment 236, wherein the acid is hydrochloric acid.

[0635] 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%.

[0636] Embodiment 239. The method of Embodiment 238, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0637] Embodiment 240. The method of Embodiment 229, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0638] Embodiment 241. The method of Embodiment 240, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0639] Embodiment 242. A method for preparing a compound having formula IV, wherein

[0640]

[0641] R 7 -R 10 are each independently selected from hydrogen, halogen, halogenated C 1 -C 5 Alkyl and C 1 -C 5 alkyl;

[0642] Where R 7 -R 10 At least one of the elements is a halogen, the method comprising:

[0643] I) forming a first mixture, the first mixture comprising:

[0644] A) a compound of formula II, wherein

[0645]

[0646] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 Alkyl; and

[0647] B) acid;

[0648] II) reacting the first mixture;

[0649] III) introducing a halogenating agent into the first mixture to form a second mixture; and

[0650] IV) reacting the second mixture.

[0651] Embodiment 243. The method of Embodiment 242, wherein the acid is selected from sulfuric acid, acetic acid, and combinations thereof.

[0652] Embodiment 244. The method of Embodiment 243, wherein the acid is sulfuric acid.

[0653] Embodiment 245. The method as described in Embodiment 242, wherein the halogenating agent is selected from the group consisting of a chlorinating agent, a brominating agent, an iodinating agent and combinations thereof.

[0654] Embodiment 246. A method as described in Embodiment 245, 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.

[0655] Embodiment 247. The method of Embodiment 246, wherein the chlorinating agent is trichloroisocyanuric acid.

[0656] Embodiment 248. The method of Embodiment 242, wherein the method step IV) of reacting the second mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0657] Embodiment 249. The method of Embodiment 248, wherein the method step IV) of reacting the second mixture occurs at a reaction temperature in the range of about 10°C to about 65°C.

[0658] Embodiment 250. The method of embodiment 242, wherein the compound of formula II is prepared according to a method comprising:

[0659] i) forming a mixture comprising:

[0660] a) a compound of formula I, wherein

[0661]

[0662] R 1 -R 5 are each independently selected from hydrogen, halogen and C 1 -C 5 alkyl;

[0663] b) chloral hydrate;

[0664] c) Hydroxylamine derivatives;

[0665] d) solvent;

[0666] e) inorganic salts; and

[0667] f) acid; and

[0668] ii) reacting the mixture.

[0669] Embodiment 251. The method of embodiment 250, wherein the hydroxylamine derivative is selected from hydroxylamine sulfate, hydroxylamine hydrochloride and combinations thereof.

[0670] Embodiment 252. The method of Embodiment 251, wherein the hydroxylamine derivative is hydroxylamine sulfate.

[0671] Embodiment 253. The method as described in Embodiment 250, wherein the solvent is selected from methanol, ethanol, toluene, water and combinations thereof.

[0672] Embodiment 254. The method of Embodiment 253, wherein the solvent is water.

[0673] Embodiment 255. A method as described in Embodiment 250, wherein the inorganic salt is selected from sodium sulfate, sodium bisulfate, sodium chloride, sodium bisulfite, potassium sulfate, potassium chloride and combinations thereof.

[0674] Embodiment 256. The method of Embodiment 255, wherein the inorganic salt is sodium sulfate.

[0675] Embodiment 257. The method as described in Embodiment 250, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid and combinations thereof.

[0676] Embodiment 258. The method of Embodiment 257, wherein the acid is hydrochloric acid.

[0677] 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%.

[0678] Embodiment 260. The method of Embodiment 259, wherein the concentration of the compound of Formula I in the mixture is in the range of about 3% to about 10%.

[0679] Embodiment 261. The method of Embodiment 250, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 10°C to about 100°C.

[0680] Embodiment 262. The method of Embodiment 261, wherein the method step of reacting the mixture occurs at a reaction temperature in the range of about 50°C to about 55°C.

[0681] In one aspect, compounds having Formula VI are prepared according to the method represented by Scheme 1. The R group is as defined anywhere in the disclosure.

[0682] Solution 1.

[0683]

[0684] In one aspect, compounds having Formula VI are prepared according to the method represented by Scheme 2. The R group is as defined anywhere in the disclosure.

[0685] Solution 2.

[0686]

[0687] In one aspect, compounds having Formula VI are prepared according to the method represented by Scheme 3. The R group is as defined anywhere in the disclosure.

[0688] Solution 3.

[0689]

[0690] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 4.

[0691] Solution 4.

[0692]

[0693] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 5.

[0694] Solution 5.

[0695]

[0696] In one aspect, 2-amino-5-chloro-N,3-dimethylbenzamide is prepared according to the method represented by Scheme 6.

[0697] Solution 6.

[0698]

[0699] In one aspect, compounds having Formula II are prepared according to the method represented by Scheme 7. The R group is as defined anywhere in the disclosure.

[0700] Solution 7.

[0701]

[0702] This aspect includes 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 bisulfate, sodium chloride, sodium bisulfite, 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, for a compound of formula I, the reaction concentration is in the range of from about 1% to about 30%. In another embodiment, for a compound of formula I, the reaction concentration is in the range of from about 3% to about 10%. In one embodiment, the reaction temperature is in the range of from about 10°C to about 100°C. In another embodiment, the reaction temperature is in the range of from about 50°C to about 55°C.

[0703] When the reaction conditions that the reaction temperature in water is 90 ℃ are applied to the compound with formula I (wherein the compound with formula I is toluidine), (E)-2-(hydroxyimino)-N-(o-tolyl) acetamide is obtained as a sticky solid, resulting in separation difficulties and poor. In addition, when being added to this thick (E)-2-(hydroxyimino)-N-(o-tolyl) acetamide in batches in the subsequent reactions step, a rapid increase in temperature is caused. In the present disclosure, this problem is overcome by reducing the reaction temperature in water from 90 ℃ to a temperature in the range of from about 50 ℃ to 55 ℃. This change not only produces pure (E)-2-(hydroxyimino)-N-(o-tolyl) acetamide with good morphology, but also advantageously increases reaction concentration. This high reaction concentration reduces waste water and cost.

[0704] In one aspect, compounds having Formula III are prepared according to the method represented by Scheme 8. The R group is as defined anywhere in the disclosure.

[0705] Solution 8.

[0706]

[0707] This aspect includes reacting a compound of formula II with an acid that 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 is in the range of from about 10°C to about 90°C. In another embodiment, the reaction temperature is in the range of from about 60°C to 65°C.

[0708] In one aspect, compounds having Formula IV are prepared according to the method represented by Scheme 9. The R group is as defined anywhere in the disclosure.

[0709] Solution 9.

[0710]

[0711] This aspect includes reacting a compound of formula III with a halogenating agent in a solvent. In one embodiment, the halogenating agent is selected from a fluorinating agent, a chlorinating agent, a brominating agent, an iodinating agent, and a combination thereof. In one 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 a combination thereof. In another embodiment, the chlorinating agent 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 a combination thereof. In another embodiment, the solvent is acetic acid. In one embodiment, the reaction temperature is in the range of from about 20°C to about 140°C. In another embodiment, the reaction temperature is in the range of from about 120°C to about 130°C.

[0712] In one aspect, compounds having Formula IV are prepared according to the method represented by Scheme 10. The R group is as defined anywhere in the disclosure.

[0713] Solution 10.

[0714]

[0715] This aspect includes reacting a compound of formula II with an acid also used as a solvent in a first reaction, followed by adding a halogenating agent, and forming a compound of formula IV in a second reaction. In one embodiment, the acid is selected from acetic acid, sulfuric acid, and a combination thereof. In another embodiment, the acid is sulfuric acid. In one embodiment, the halogenating agent is selected from a fluorinating agent, a chlorinating agent, a brominating agent, an iodinating agent, and a combination thereof. In one 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 a combination thereof. In another embodiment, the chlorinating agent 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 is in the range of from about 10°C to about 100°C. In another embodiment, the reaction temperature of the second reaction is in the range of from about 10°C to 65°C.

[0716] This aspect is a one-pot process and has several advantages. First, the need to separate the intermediate (such as the compound of formula III) produced by the compound of formula II before the subsequent reaction is eliminated. Second, the potential loss of the intermediate (such as the compound of formula III) produced by the compound of formula II is reduced. Third, the total output is increased. Fourth, the number of reaction steps and post-processing operations is reduced. Fifth, the total cost is reduced.

[0717] In one aspect, compounds having Formula V are prepared according to the method represented by Scheme 11. The R group is as defined anywhere in the disclosure.

[0718] Solution 11.

[0719]

[0720] This aspect includes adding an oxidant to an aqueous solution containing a compound of Formula IV in the presence of a catalyst. In one embodiment, the oxidant 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 oxidant is hydrogen peroxide. In one embodiment, the solvent is selected from acetonitrile (ACN), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (i-PrOH), water (H 2In one embodiment, the solvent is acetic acid. In one embodiment, the catalyst is selected from sulfuric acid, hydrogen chloride, nitric acid and a combination thereof. In another embodiment, the catalyst is sulfuric acid. In one embodiment, the reaction temperature is in the range of from about 20°C to about 100°C. In another embodiment, the reaction temperature is in the range of from about 60°C to about 65°C.

[0721] In one aspect, compounds having Formula VI are prepared according to the method represented by Scheme 12. The R group is as defined anywhere in the disclosure.

[0722] Solution 12.

[0723]

[0724] This aspect comprises reacting a compound having formula V with an alkylamine in a solvent. In one embodiment, the alkylamine comprises a branched C 1 -C 10 Alkyl and unbranched C 1 -C 10 In one embodiment, the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert-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), isopropanol (i-PrOH), ethyl acetate (EtOAc), isopropyl acetate (IPAc) and combinations thereof. In another embodiment, the solvent is EtOAc. In one embodiment, the reaction temperature is in the range of from about 0°C to about 100°C. In another embodiment, the reaction temperature is in the range of from about 20°C to about 30°C.

[0725] In one aspect, compounds having Formula V are prepared according to the method represented by Scheme 13. The R group is as defined anywhere in the disclosure.

[0726] Solution 13.

[0727]

[0728] This aspect includes reacting a compound with formula III with a halogenating agent in a solvent, and then adding an oxidant 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 a combination 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 a combination 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 halogenation is in the range of from about 20°C to about 140°C. In another embodiment, the reaction temperature for halogenation is in the range of from about 120°C to about 130°C. In one embodiment, the oxidant 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 oxidant 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 oxidation is in the range of from about 20°C to about 100°C. In another embodiment, the reaction temperature for oxidation is in the range of from about 60°C to about 65°C.

[0729] This aspect is a one-pot process and has several advantages. First, the need to separate the intermediate (such as the compound of formula IV) produced by the compound of formula III before the subsequent reaction is eliminated. Second, the potential loss of the intermediate (such as the compound of formula IV) produced by the compound of formula III is reduced. Third, the total output is increased. Fourth, the number of reaction steps and post-processing operations is reduced. Fifth, the total cost is reduced.

[0730] Examples

[0731] Without further elaboration, it is believed that those skilled in the art can make the most of the present invention using the previous description. Therefore, the following examples should be interpreted as being illustrative only and not limiting the present disclosure in any way. The starting materials of the following examples may not necessarily be prepared by specific preparation runs, and their procedures are described in other embodiments. It should also be understood that any numerical ranges listed herein include all values ​​from the lower limit to the upper limit. For example, if the range is specified as 10-50, it is expected that values ​​such as 12-30, 20-40 or 30-50 are explicitly listed in this specification. These are only examples of special expectations, and all possible combinations of numerical values ​​between the lowest and highest values ​​listed (and including the lowest and highest values) will be considered to be clearly stated in this application.

[0732] Example 1. Reaction of o-toluidine.

[0733] 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° C. to 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 purified (E)-3-hydroxy-N-(o-tolyl)acrylamide was obtained.

[0734] Example 2. Cyclization.

[0735] In order to control the reaction temperature, 20.0 g of (E)-3-hydroxy-N-(o-tolyl) acrylamide was added to sulfuric acid in batches in a reactor. 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. The crude product can be used for subsequent reactions without further treatment.

[0736] Example 3. Halogenation.

[0737] 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°C-125°C. After the reaction, the mixture was cooled to room temperature. Water was added to the mixture, which was 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.

[0738] Example 4. Oxidation.

[0739] 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°C-65°C. At this temperature, 13.0 g of 30% hydrogen peroxide solution was added dropwise to control the temperature between 60°C-65°C. After the reaction, water was added to the mixture, which was 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.

[0740] Example 5. Reaction with methylamine.

[0741] 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 methylamine was bubbled into the reaction at room temperature. After the reaction, the mixture was extracted with water. The organic phase solvent was removed under vacuum. 8.5 g of a crude product of 2-amino-5-chloro-N,3-dimethylbenzamide was obtained.

[0742] Example 6. One-pot synthesis.

[0743] 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°C-125°C. After 7-methylindoline-2,3-dione was consumed, the reaction temperature was cooled to 60°C-65°C. 41.4 g of 30% hydrogen peroxide solution was added dropwise to control the temperature between 60°C-65°C. After the reaction, water was added to the mixture, which was 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.

[0744] This written description uses examples to illustrate the disclosure, including the best mode, and also to enable any person skilled in the art to practice the disclosure, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.

Claims

1. A method for preparing a compound of formula VI, wherein: R7-R 10 Each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl and C1-C5 alkyl; Among them R7-R 10 At least one of is a halogen; and Where R 11 Selected from branched C1-C 10 Alkyl and unbranched C1-C 10 alkyl, the method comprising I) forming a mixture comprising A) a compound of formula V, wherein R7-R 10 Each is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl and C1-C5 alkyl; Among them R7-R 10 At least one of is a halogen; and wherein the compound of formula V is prepared according to a one-pot process comprising: i) forming a first mixture, the first mixture comprising: a) a compound of formula III, wherein R1-R4 are each independently selected from hydrogen, halogen and C1-C5 alkyl; b) solvent; and c) a halogenating agent, wherein the halogenating agent is sulfuryl chloride; 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, wherein the oxidizing agent is hydrogen peroxide; and iv) reacting the third mixture, wherein the third mixture is reacted in the presence of a catalyst, wherein the catalyst is sulfuric acid formed in situ from sulfuryl chloride and hydrogen peroxide; B) an alkylamine; and C) a solvent; and II) reacting the mixture.

2. The method of claim 1, wherein: The alkylamine comprises a branched C1-C 10 Alkyl and unbranched C1-C 10 Alkyl functional group.

3. The method of claim 1, wherein: The solvent C) is selected from acetonitrile, ethylene dichloride, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate and combinations thereof.

4. The method of claim 1, wherein: This process step II) of reacting the mixture takes place at a reaction temperature in the range from 0°C to 100°C.

5. The method of claim 1, wherein: The solvent b) is selected from acetonitrile, ethylene dichloride, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid and combinations thereof.

6. The method of claim 1, wherein: The process step ii) of reacting the first mixture takes place at a reaction temperature in the range of 20°C to 140°C.

7. The method of claim 1, wherein: This process step iv) of reacting the third mixture takes place at a reaction temperature in the range of 20°C to 100°C.

8. The method of claim 1, wherein: The compound of formula III is prepared according to a process comprising: I) forming a mixture comprising A) a compound of formula II, wherein R1-R5 are each independently selected from hydrogen, halogen and C1-C5 alkyl; and Wherein the compound of formula II is prepared according to a process comprising: i) forming a mixture comprising a) a compound of formula I, wherein R1-R5 are each independently selected from hydrogen, halogen and C1-C5 alkyl; b) chloral hydrate; c) Hydroxylamine derivatives; d) solvent; e) inorganic salts; and f) acid; as well as ii) reacting the mixture at a reaction temperature in the range of 50° C. to 55° C.; as well as B) acid; as well as II) reacting the mixture.

Images