EA047007B1 - A NEW EFFECTIVE METHOD FOR SYNTHESIS OF 2-AMINO-5-CHLORO-N,3-DIMETHYLBENZAMIDE - Google Patents

Abstract

The present invention describes new methods for the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide. The compounds obtained by the methods disclosed in this invention are useful for the preparation of certain anthranilamide compounds that are of interest as insecticides, such as, for example, the insecticides chlorantraniliprole and cyantraniliprole.

Description

Cross reference to related application

This application claims priority to U.S. Provisional Patent Application No. 62/929138, filed November 1, 2019.

Field of technology to which the invention relates

The present invention is directed to new methods for the synthesis of 2-amino-5-chloro-K3dimethylbenzamide. The compounds produced by the methods disclosed herein are useful for the preparation of certain anthranilamide compounds that are of interest as insecticides, such as, for example, the insecticides chlorantraniliprole and cyantraniliprole.

State of the art

Traditional processes for the production of 2-amino-5-chloro-H,3-dimethylbenzamide suffer from several manufacturing problems, such as the use of hazardous materials, high costs, relatively lengthy process steps, and complex operations.

The present invention provides new methods useful for the preparation of 2-amino-5chloro-N,3-dimethylbenzamide and its derivatives. The methods of the present invention have a number of advantages over previous methods and these include reduced costs, elimination of the need to separate mixed solvents, reduced waste, relatively short process steps, simplified operation and reduced process risks.

Short description

In one aspect, this document provides a method for preparing a compound of formula VI,

(formula VI) wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated Cj-C'5-alkyl and C'i-C'5-alkyl;

where at least one of R7-R10 is halogen; and where R11 is selected from branched C ₁ -C ₁₀ -alkyl and straight-chain C ₁ -C ₁₀ -alkyl, the method comprising

I) forming a mixture containing

A) a compound of formula V,

(formula V) wherein each of R7-R ₁₀ is independently selected from hydrogen, halogen, halogenated C.'rC.'5-alkyl and C.'rC.'5-alkyl;

where at least one of R7-R ₁₀ is halogen; and wherein the compound of formula V is prepared in accordance with a method comprising:

i) forming a first mixture containing

a) a compound of formula III,

b) solvent and

c) halogenating reagent;

ii) causing the first mixture to react;

- 1 047007 iii) introducing a second mixture into the first mixture to form a third mixture, wherein the second mixture contains

d) an oxidizing agent and

e) catalyst; and iv) allowing the third mixture to react;

B) an alkylamine and

C) solvent; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a method for preparing a compound of formula V,

Ry

^R c ⁰ (formula V), wherein each of R7-R10 is independently selected from hydrogen, halogen, halogenated C'i-C'5-alkyl and

C'i-C'5-alkyl; and wherein at least one of R7-R10 is halogen, the method comprising

I) formation of the first mixture containing

A) a compound of formula III;

B) solvent and

C) halogenating reagent;

ii) providing a reaction in the first mixture;

III) introducing a second mixture into the first mixture to form a third mixture, wherein the second mixture contains

D) oxidizing agent and

E) catalyst; And

IV) ensuring the reaction in the third mixture.

In one aspect, this document provides a method for preparing a compound of formula VI,

Rr

^{ι: 0} (Formula VI) wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated Cj-C.'5-alkyl and C.'rC'5-alkyl;

wherein at least one of R7-Ri0 is halogen; and where R11 is selected from branched C ₁ -C ₁₀ -alkyl and straight-chain C ₁ -C ₁₀ -alkyl, the method comprising

I) forming a mixture containing

A) a compound of formula V,

- 2 047007

(formula V) wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated C.'rC.'5-alkyl, C.'rC.'5-alkyl;

wherein at least one of R7-Ri0 is halogen; and wherein the compound of formula V is prepared in accordance with a method comprising:

i) forming a mixture containing

a) a compound of formula IV,

And

C1-C5 alkyl; and where at least one of R7-R10 is halogen;

b) oxidizing agent;

c) solvent and

d) a catalyst; and ii) causing a reaction in the mixture;

B) an alkylamine and

C) solvent; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a method for preparing a compound of formula V,

(formula V) wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated C.'rC'5-alkyl, C.'rC'5-alkyl; and wherein at least one of R7-R10 is halogen, the method comprising

(formula IV), wherein each of R7-R10 is independently selected from hydrogen, halogen, halogenated ^-^-alkyl C.'i-C'5-alkyl; and where at least one of R7-R10 is halogen;

B) oxidizing agent;

- 3 047007

C) solvent and

D) catalyst; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a method for preparing a compound of Formula IV,

C.'i-C.'5-alkyl;

wherein at least one of R7-R10 is a halogen, the method comprising: i) forming a mixture containing

A) a compound of formula III,

B) solvent;

C) halogenating reagent; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a method for preparing a compound of formula III,

includes

I) forming a mixture containing A) a compound of formula II,

R

(formula II) wherein R1-R5 are each independently selected from hydrogen, halogen and C.'rC.'5-alkyl; and wherein the compound of formula II is prepared in accordance with a method comprising i) forming a mixture containing a) a compound of formula I,

- 4 047007

(formula I) wherein R1-R5 are each independently selected from hydrogen, halogen and C1-C5 alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react; And

B) acid; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a process for preparing a compound of formula II,

(formula II) wherein R1-R5 are each independently selected from hydrogen, halogen and C.'rC'5-alkyl. the method includes

I) forming a mixture containing

A) a compound of formula I,

(formula I) wherein R1-R5 are each independently selected from hydrogen, halogen and C1-C5 alkyl;

B) chloral hydrate;

C) hydroxylamine derivative;

D) solvent;

E) inorganic salt and

F) acid; And

ii) ensuring the reaction in the mixture.

In one aspect, provided herein is a method for preparing a compound of Formula IV,

C.'i-C'5-alkyl;

wherein at least one of R7-R10 is a halogen, the method comprising: i) forming a mixture containing

- 5 047007

A) a compound of formula II,

R

and (formula II) wherein R1-R5 are each independently selected from hydrogen, halogen and C1-C5 alkyl; And

B) acid;

ii) providing a reaction in the first mixture;

III) introducing a halogenating reagent into the first mixture to form a second mixture and

IV) ensuring the reaction in the second mixture.

Detailed Description of the Present Invention

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

The transition phrase consisting of excludes any unspecified element, step or ingredient. If the said phrase is present in a claim, it will limit the inclusion in the claim of materials other than those specified, excluding impurities typically associated with them. If the phrase consisting of appears in the wording of a distinctive part of a claim rather than immediately after a restrictive part, it limits only the element set forth in that wording; other elements are not generally excluded from the claims.

The transitional phrase essentially consisting of is used to define a composition or process that includes materials, steps, features, components or elements in addition to those literally disclosed, provided that such additional materials, steps, features, components or the elements do not significantly affect the main (main) and new (new) characteristic (characteristics) of the claimed invention. The term essentially consisting of is a compromise between containing and consisting of.

If an invention or part thereof is defined by an open term such as containing, it should be understood that (unless otherwise stated) the description is to be interpreted as describing such invention using the terms essentially consisting of or consisting of.

Also, unless explicitly stated otherwise, or refers to an inclusive or rather than an exclusive or. For example, condition A or B is satisfied by any of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

Moreover, an element or component of the present invention in the singular form is intended to be non-limiting with respect to the number of representations (ie, repetitions) of the element or component. Therefore, the singular form should be considered to include one or at least one element or component, and the singular form of the element or component also includes the plural form if it is obvious that the number is not intended to be singular.

As used herein, the term approximately means plus or minus 10% of the stated value.

The term halogen, either alone or in compound words such as haloalkyl, includes fluorine, chlorine, bromine or iodine atoms. Additionally, when used in compounds such as haloalkyl, said alkyl may be partially or completely replaced by halogen atoms, which may be the same or different.

If the group contains a substituent which may be hydrogen, for example R ⁴ , then when the substituent is hydrogen, it is understood that it is equivalent to the specified group, which is unsubstituted.

The term alkyl includes, without limitation, a functional group containing straight or branched chain alkyl. In some aspects, alkyl may be methyl, ethyl, n-propyl, isopropyl, or various isomers of butyl, pentyl, or hexyl.

Some compounds of the present invention may exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereoisomers, atro

- 6 047007 poisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or separated from the other stereoisomer(s). In addition, one skilled in the art knows how to separate, enrich and/or selectively obtain said stereoisomers.

Embodiments of the present invention include the following.

Embodiment 1. Method for preparing the compound of formula VI,

(formula VI) wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated Cj-C'5-alkyl and C'i-C'5-alkyl;

where at least one of R7-R10 is halogen; and where R11 is selected from branched C ₁ -C ₁₀ -alkyl and straight-chain C ₁ -C ₁₀ -alkyl, the method comprising

I) forming a mixture containing

A) a compound of formula V,

(formula V) wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated C'rC'5-alkyl and C.'rC'5-alkyl;

where at least one of R7-R10 is halogen; and wherein the compound of formula V is prepared in accordance with a method comprising:

i) forming a first mixture containing

(formula III), wherein each of R ₁ -R ₄ is independently selected from hydrogen, halogen and Cj-C.'5-alkyl;

b) solvent and

c) halogenating reagent;

ii) causing the first mixture to react;

iii) introducing a second mixture into the first mixture to form a third mixture, wherein the second mixture contains

d) an oxidizing agent and

e) catalyst; and iv) allowing the third mixture to react;

B) an alkylamine and

C) solvent; And

ii) ensuring the reaction in the mixture.

Embodiment 2. The method of Embodiment 1, wherein the alkylamine contains a functional group selected from a branched C ₁ -C ₁₀ alkyl and a straight chain C ₁ -C ₁₀ alkyl.

- 7 047007

Embodiment 3. The method of Embodiment 2, wherein the alkylamine is selected from methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert-butylamine, and combinations thereof.

Embodiment 4: The method of Embodiment 3, wherein the alkylamine is methylamine.

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

Embodiment 6: The method of Embodiment 5, wherein solvent C) is ethyl acetate.

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

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

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

Embodiment 10. The method of Embodiment 9, wherein solvent b) is acetic acid.

Embodiment 11. The method of Embodiment 1, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

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

Embodiment 13. The method of Embodiment 12, wherein the chlorination reagent is sulfuryl chloride.

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

Embodiment 15. The method of Embodiment 14, wherein process step ii) of reacting the first mixture is carried out at a reaction temperature ranging from about 120°C to about 130°C.

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

Embodiment 17. The method of Embodiment 16, wherein the oxidizing agent is hydrogen peroxide.

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

Embodiment 19. The method of Embodiment 18, wherein the catalyst is sulfuric acid.

Embodiment 20. The method of Embodiment 1, wherein process step iv) of reacting the third mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

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

Embodiment 22. The method of Embodiment 1, wherein the compound of formula III is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula II, wherein R1-R5 are each independently selected from hydrogen, halogen and C.'i-C.'5-alkyl; and (formula II),

- 8 047007 where the compound of formula II is prepared in accordance with a method comprising i) forming a mixture containing

a) a compound of formula I,

(formula I) wherein R1-R5 are each independently selected from hydrogen, halogen and C'i-C'5-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react; And

B) acid; And

ii) ensuring the reaction in the mixture.

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.

Embodiment 24. The method of Embodiment 23, wherein acid B) is hydrochloric acid.

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

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

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

Embodiment 28. The method of Embodiment 27, wherein the hydroxylamine derivative is hydroxylamine sulfate.

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

Embodiment 30. The method of Embodiment 29, wherein the solvent is water.

Embodiment 31. The method of Embodiment 22, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

Embodiment 32. The method of Embodiment 31, wherein the inorganic salt is sodium sulfate.

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.

Embodiment 34. The method of Embodiment 33, wherein the acid f) is hydrochloric acid.

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%.

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%.

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

Embodiment 38. The method of Embodiment 37, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 39. Process for preparing a compound of formula V,

- 9 047007

R

^R ' ^c ° (formula V), wherein each of R7-R10 is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl and C1-C5 alkyl; and wherein at least one of R7-R10 is halogen, the method comprising

I) formation of the first mixture containing

A) a compound of formula III;

B) solvent and

C) halogenating reagent;

ii) providing a reaction in the first mixture;

III) introducing a second mixture into the first mixture to form a third mixture, wherein the second mixture contains

D) oxidizing agent and

E) catalyst; And

IV) ensuring the reaction in the third mixture.

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.

Embodiment 41 The method of Embodiment 40, wherein the solvent is acetic acid.

Embodiment 42. The method of Embodiment 39, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

Embodiment 43. The method of Embodiment 42, wherein the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

Embodiment 44. The method of Embodiment 43, wherein the chlorination reagent is sulfuryl chloride.

Embodiment 45. The method of Embodiment 39, wherein process step II) of reacting the first mixture is carried out at a reaction temperature ranging from about 20°C to about 140°C.

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

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

Embodiment 48. The method of Embodiment 47, wherein the oxidizing agent is hydrogen peroxide.

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

Embodiment 50. The method of Embodiment 49, wherein the catalyst is sulfuric acid.

Embodiment 51. The method according to embodiment 39, where stage IV) of the method, which

- 10 047007 which provide the reaction in the third mixture is carried out at a reaction temperature ranging from about 20°C to about 100°C.

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

Embodiment 53. The method of Embodiment 39, wherein the compound of formula III is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula II,

(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 in accordance with a method comprising i) forming a mixture containing a) a compound of formula I,

(formula I) wherein R1-R5 are each independently selected from hydrogen, halogen and Cj-C.'5-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react; And

B) acid; And

ii) ensuring the reaction in the mixture.

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.

Embodiment 55 The method of Embodiment 54, wherein acid B) is hydrochloric acid.

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

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

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

Embodiment 59. The method of Embodiment 58, wherein the hydroxylamine derivative is hydroxylamine sulfate.

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

Embodiment 61 The method of Embodiment 60, wherein the solvent is water.

Embodiment 62. The method of Embodiment 53, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

- 11 047007

Embodiment 63. The method of Embodiment 62, wherein the inorganic salt is sodium sulfate.

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.

Embodiment 65. The method of Embodiment 64, wherein the acid f) is hydrochloric acid.

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%.

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%.

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

Embodiment 69. The method of Embodiment 68, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 70. Process for preparing a compound of formula VI,

(formula VI) wherein each of R ₇ -R ₁₀ is independently selected from hydrogen, halogen, halogenated Cj-C.'5-alkyl and Cj-C.'5-alkyl;

where at least one of R ₇ -R ₁₀ is halogen; and where R11 is selected from branched C ₁ -C ₁₀ -alkyl and straight-chain C ₁ -C ₁₀ -alkyl, the method comprising

I) forming a mixture containing

A) a compound of formula V,

(formula V) wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated C'i-C'5-alkyl and Cj-C'5-alkyl;

where at least one of R7-R10 is halogen; and wherein the compound of formula V is prepared in accordance with a method comprising:

i) forming a mixture containing

a) a compound of formula IV,

Cj-C'5-alkyl; and where at least one of R7-R10 is halogen;

- 12 047007

b) oxidizing agent;

c) solvent and

d) a catalyst; and ii) causing a reaction in the mixture;

B) an alkylamine and

C) solvent; And

ii) ensuring the reaction in the mixture.

Embodiment 71. The method of Embodiment 70, wherein the alkylamine contains a functional group selected from branched C ₁ -C ₁₀ alkyl and straight chain C ₁ -C ₁₀ alkyl.

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

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

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

Embodiment 75. The method of Embodiment 74, wherein solvent C) is ethyl acetate.

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

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

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

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

Embodiment 80. The method of Embodiment 70, wherein solvent c) is selected from acetonitrile, methanol, ethanol, isopropanol, water, dimethylformamide, dimethyl sulfoxide, Nmethylpyrrolidone, tetrahydrofuran, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

Embodiment 81 The method of Embodiment 80, wherein solvent c) is acetic acid.

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

Embodiment 83. The method of Embodiment 82, wherein the catalyst is sulfuric acid.

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

Embodiment 85. The method of Embodiment 84, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

Embodiment 86. The method of Embodiment 70, wherein the compound of formula IV is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula III, wherein each of R ₁ -R ₄ is independently selected from hydrogen, halogen and C.'iC.'5-alkyl;

B) solvent;

C) halogenating reagent; And

ii) ensuring the reaction in the mixture.

(formula III),

- 13 047007

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.

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

Embodiment 89. The method of Embodiment 86, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

Embodiment 90. The method of Embodiment 89, wherein the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

Embodiment 91. The method of Embodiment 90, wherein the chlorination reagent is sulfuryl chloride.

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

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

Embodiment 94. The method of Embodiment 86, wherein the compound of formula III is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula II,

U (formula II), wherein R ₁ -R5 are each independently selected from hydrogen, halogen and C.'iC.'5-alkyl; and wherein the compound of formula II is prepared in accordance with a method comprising i) forming a mixture containing a) a compound of formula I,

% (formula I), where each of R1-R5 is independently selected from hydrogen, halogen and Cj-C.'5-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react; And

B) acid; And

ii) ensuring the reaction in the mixture.

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.

Embodiment 96. The method of Embodiment 95, wherein acid B) is hydrochloric acid.

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

- 14 047007

Embodiment 98. The method of Embodiment 97, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

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

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

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

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

Embodiment 103. The method of Embodiment 94, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

Embodiment 104 The method of Embodiment 103, wherein the inorganic salt is sodium sulfate.

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.

Embodiment 106. The method of Embodiment 105, wherein the acid f) is hydrochloric acid.

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%.

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%.

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

Embodiment 110. The method of Embodiment 109, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 111. The method of Embodiment 70, wherein the compound of formula IV is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula II,

(formula II) wherein Ri-R ₅ is each independently selected from hydrogen, halogen and C.'iC.'5-alkyl; And

B) acid;

ii) providing a reaction in the first mixture;

III) introducing a halogenating reagent into the first mixture to form a second mixture and

IV) ensuring the reaction in the second mixture.

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

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

Embodiment 114. The method of Embodiment 111, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

Embodiment 115. The method of Embodiment 114, wherein the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

Embodiment 116. The method of Embodiment 115, wherein the chlorination reagent is trichloroisocyanuric acid.

- 15 047007

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

Embodiment 118 The method of embodiment 117, wherein process step IV) of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 65°C.

Embodiment 119. The method of Embodiment 111, wherein the compound of formula II is prepared in accordance with a method comprising:

i) forming a mixture containing

a) a compound of formula I,

(formula I) wherein R1-R5 are each independently selected from hydrogen, halogen and C.'rC.'5-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react.

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

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

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

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

Embodiment 124. The method of Embodiment 119, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

Embodiment 125 The method of Embodiment 124, wherein the inorganic salt is sodium sulfate.

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.

Embodiment 127 The method of Embodiment 126, wherein the acid is hydrochloric acid.

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%.

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%.

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

Embodiment 131 The method of embodiment 130, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 132: Method for preparing a compound of formula V,

- 16 047007

R

^R ' ^c ° (formula V), wherein each of R7-R10 is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl and C1-C5 alkyl; and wherein at least one of R7-R10 is halogen, the method comprising

I) forming a mixture containing

A) a compound of formula IV;

C.'i-C'5-alkyl; and where at least one of R7-R10 is halogen;

B) oxidizing agent;

C) solvent and

D) catalyst; And

ii) ensuring the reaction in the mixture.

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

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

Embodiment 135. The method of Embodiment 132, wherein the solvent is selected from acetonitrile, methanol, ethanol, isopropanol, water, dimethylformamide, dimethyl sulfoxide, Nmethylpyrrolidone, tetrahydrofuran, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof.

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

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

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

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

Embodiment 140. The method of Embodiment 139, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

Embodiment 141. The method of Embodiment 132, wherein the compound of formula IV is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula III,

- 17 047007

B) solvent;

C) halogenating reagent; And

ii) ensuring the reaction in the mixture.

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.

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

Embodiment 144. The method of Embodiment 141, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

Embodiment 145. The method of Embodiment 144, wherein the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

Embodiment 146. The method of Embodiment 145, wherein the chlorination reagent is sulfuryl chloride.

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

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

Embodiment 149. The method of Embodiment 141, wherein the compound of formula III is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula II,

R

(formula II) wherein R1-R5 are each independently selected from hydrogen, halogen and ^-^-alkyl; and wherein the compound of formula II is prepared in accordance with a method comprising i) forming a mixture containing

a) a compound of formula I,

R

’ (formula I), wherein each of R1-R5 is independently selected from hydrogen, halogen and ^-^-alkyl; b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

- 18 047007

e) inorganic salt and

f) acid; and ii) causing the mixture to react; And

B) acid; And

ii) ensuring the reaction in the mixture.

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.

Embodiment 151 The method of Embodiment 150, wherein acid B) is hydrochloric acid.

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

Embodiment 153 The method of Embodiment 152, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

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

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

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

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

Embodiment 158. The method of Embodiment 149, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

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

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.

Embodiment 161. The method of Embodiment 160, wherein the acid f) is hydrochloric acid.

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%.

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%.

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

Embodiment 165 The method of embodiment 164, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 166. The method of Embodiment 132, wherein the compound of formula IV is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula II,

(formula II), wherein each of Ri-R ₅ is independently selected from hydrogen, halogen and C ₁ -C5 alkyl; and B) acid;

ii) providing a reaction in the first mixture;

iii) introducing a halogenating reagent into the first mixture to form a second mixture; and iv) allowing the second mixture to react.

- 19 047007

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

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

Embodiment 169. The method of Embodiment 166, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

Embodiment 170. The method of Embodiment 169, wherein the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

Embodiment 171 The method of Embodiment 170, wherein the chlorination reagent is trichloroisocyanuric acid.

Embodiment 172 The method of embodiment 166, wherein process step IV) of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

Embodiment 173 The method of embodiment 172, wherein process step IV) of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 65°C.

Embodiment 174. The method of Embodiment 166, wherein the compound of formula II is prepared in accordance with a method comprising:

i) forming a mixture containing

a) a compound of formula I,

R

^R ' (formula I), wherein R1-R5 are each independently selected from hydrogen, halogen and Ci^-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react.

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

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

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

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

Embodiment 179. The method of Embodiment 174, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

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

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.

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

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%.

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%.

Embodiment 185. The method of Embodiment 174, wherein the process step of causing the mixture to react is carried out at a reaction temperature ranging from

- 20 047007 approximately 10°C to approximately 100°C.

Embodiment 186 The method of embodiment 185, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 187. Method for preparing a compound of formula IV,

Ry (formula IV), where each of R--R| ₀ is independently selected from hydrogen, halogen, halogenated Ci^-alkyl and C'i-C'5-alkyl;

wherein at least one of R ₇ -R _1o is halogen, the method comprising

I) forming a mixture containing

A) a compound of formula III, (formula III), wherein each of R ₁ -R ₄ is independently selected from hydrogen, halogen and C.'rC'5-alkyl;

B) solvent;

C) halogenating reagent; And

ii) ensuring the reaction in the mixture.

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.

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

Embodiment 190. The method of Embodiment 187, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

Embodiment 191. The method of Embodiment 190, wherein the chlorination reagent is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid, and combinations thereof.

Embodiment 192. The method of Embodiment 191, wherein the chlorination reagent is sulfuryl chloride.

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

Embodiment 194 The method of Embodiment 193, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 120°C to about 130°C.

Embodiment 195. The method of Embodiment 187, wherein the compound of formula III is prepared in accordance with a method comprising:

I) forming a mixture containing

A) a compound of formula II,

- 21 047007

(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 in accordance with a method comprising i) forming a mixture containing a) a compound of formula I,

% (formula I), wherein each of R1-R5 is independently selected from hydrogen, halogen and C.'rC.'5-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react; And

B) acid; And

ii) ensuring the reaction in the mixture.

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.

Embodiment 197 The method of Embodiment 196, wherein acid B) is hydrochloric acid.

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

Embodiment 199 The method of Embodiment 198, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

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

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

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

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

Embodiment 204. The method of Embodiment 195, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

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

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.

Embodiment 207 The method of embodiment 206, wherein the acid f) is hydrochloric acid.

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%.

Embodiment 209. The method of Embodiment 208, wherein the concentration of the compound

- 22 047007 of formula I in the mixture is in the range from about 3% to about 10%.

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

Embodiment 211 The method of embodiment 210, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 212. Method for preparing a compound of formula III,

includes

I) forming a mixture containing A) a compound of formula II,

(formula II) wherein R1-R5 are each independently selected from hydrogen, halogen and Cj-C.'5-alkyl; and wherein the compound of formula II is prepared in accordance with a method comprising i) forming a mixture containing a) a compound of formula I,

(formula I) wherein R1-R5 are each independently selected from hydrogen, halogen and Cj-C.'5-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react; And

B) acid; And

ii) ensuring the reaction in the mixture.

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.

Embodiment 214 The method of Embodiment 213, wherein acid B) is hydrochloric acid.

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

Embodiment 216 The method of embodiment 215, wherein process step II) of reacting the mixture is carried out at a reaction temperature ranging from about 60°C to about 65°C.

- 23 047007

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

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

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

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

Embodiment 221. The method of Embodiment 212, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

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

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.

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

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%.

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%.

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

Embodiment 228 The method of embodiment 227, wherein process step ii) of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 229: Method for preparing a compound of formula II,

(formula II), wherein each of Ri-R ₅ is independently selected from hydrogen, halogen and Ci^-alkyl, the method comprising

I) forming a mixture containing

A) a compound of formula I,

(formula I) wherein R1-R5 are each independently selected from hydrogen, halogen and C.'i-C.'5-alkyl;

B) chloral hydrate;

C) hydroxylamine derivative;

D) solvent;

E) inorganic salt and

F) acid; And

ii) ensuring the reaction in the mixture.

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

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

- 24 047007

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

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

Embodiment 234. The method of Embodiment 229, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

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

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.

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

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%.

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%.

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

Embodiment 241 The method of embodiment 240, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

Embodiment 242: Method for preparing a compound of formula IV,

Cj-C.'5-alkyl;

wherein at least one of R ₇ -Rio is a halogen, the method comprising

I) formation of the first mixture containing

A) a compound of formula II,

(formula II) wherein R1- _R5 are each independently selected from hydrogen, halogen and Cj-C.'5-alkyl; and B) acid;

ii) providing a reaction in the first mixture;

iii) introducing a halogenating reagent into the first mixture to form a second mixture; and iv) allowing the second mixture to react.

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

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

Embodiment 245. The method of Embodiment 242, wherein the halogenating reagent is selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof.

Embodiment 246. The method of Embodiment 245, wherein the chlorination reagent

- 25 047007 is selected from chlorine, thionyl chloride, phosgene, diphosgene, triphosgene, oxalyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus oxychloride, trichloroisocyanuric acid and combinations thereof.

Embodiment 247 The method of Embodiment 246, wherein the chlorination reagent is trichloroisocyanuric acid.

Embodiment 248 The method of embodiment 242, wherein process step IV) of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 100°C.

Embodiment 249 The method of embodiment 248, wherein process step IV) of reacting the second mixture is carried out at a reaction temperature ranging from about 10°C to about 65°C.

Embodiment 250. The method of Embodiment 242, wherein the compound of formula II is prepared in accordance with a method comprising:

i) forming a mixture containing

a) a compound of formula I,

(formula I), wherein each of R ₁ -R ₅ is independently selected from hydrogen, halogen and Q^-alkyl;

b) chloral hydrate;

c) hydroxylamine derivative;

d) solvent;

e) inorganic salt and

f) acid; and ii) causing the mixture to react.

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

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

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

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

Embodiment 255. The method of Embodiment 250, wherein the inorganic salt is selected from sodium sulfate, sodium hydrogensulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride, and combinations thereof.

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

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.

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

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%.

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%.

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

Embodiment 262 The method of embodiment 261, wherein the process step of reacting the mixture is carried out at a reaction temperature ranging from about 50°C to about 55°C.

In one aspect, a compound of formula VI is prepared in accordance with the method presented in Scheme 1. R groups are as defined elsewhere herein.

- 26 047007

Scheme 1.

In one aspect, a compound of formula VI is prepared in accordance with the method presented in Scheme 2. R groups are as defined elsewhere herein.

Scheme 2.

In one aspect, a compound of formula VI is prepared in accordance with the method presented in Scheme 3. R groups are as defined elsewhere herein.

Scheme 3.

In one aspect, 2-amino-5-chloro-H,3-dimethylbenzamide is prepared according to the method presented in Scheme 4.

Scheme 4.

In one aspect, 2-amino-5-chloro-H,3-dimethylbenzamide is prepared according to the method presented in Scheme 5.

Scheme 5.

In one aspect, 2-amino-5-chloro-H,3-dimethylbenzamide is prepared according to the method presented in Scheme 6.

Scheme 6.

In one aspect, a compound of formula II is prepared in accordance with the method presented in Scheme 7. R groups are as defined elsewhere herein.

Scheme 7.

This aspect involves causing the compound of formula I to react with chloral hydrate and hydroxylamine sulfate in a solvent at a concentration to react in the presence of an inorganic salt and 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 hydrogensulfate, 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 from about 1% to about 30% for a compound of Formula I. In another embodiment, the reaction concentration is in the range from about 3% to about 10% for a compound of Formula I. In one embodiment, the reaction concentration is in the range from about 3% to about 10% for a compound of Formula I. In an embodiment, the temperature re

- 27 047007 shares range from approximately 10°C to approximately 100°C. In another embodiment, the reaction temperature is in the range from about 50°C to about 55°C.

If reaction conditions with a reaction temperature of 90°C in water are applied to a compound of formula I, where the compound of formula I is toluidine, then (E)-2-(hydroxyimino)-N-(otolyl)acetamide is obtained as a sticky solid, resulting in difficult and poor separation. In addition, a rapid increase in temperature occurs due to the addition of this crude (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide in portions in subsequent reaction steps. This problem is overcome in the present invention by reducing the reaction temperature in water from 90°C to a temperature in the range of about 50 to about 55°C. This change not only results in pure (E)-2-(hydroxyimino)-N-(o-tolyl)acetamide with good morphotype, but also effectively increases the concentration to achieve the reaction. This high reaction concentration reduces wastewater and costs.

In one aspect, a compound of Formula III is prepared in accordance with the method presented in Scheme 8. R groups are as defined elsewhere herein.

Scheme 8.

N n

XI I --- ΧΧζ°

R, Ι< O (II; (III)

This aspect involves causing the compound of formula II to react with an acid, which is also used 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 from about 10°C to about 90°C. In another embodiment, the reaction temperature is in the range from about 60°C to 65°C.

In one aspect, a compound of Formula IV is prepared in accordance with the method presented in Scheme 9. R groups are as defined elsewhere herein.

Scheme 9.

R,R,

I ΗО I Н

D G > ^C) ---- D J I

R:!^TA ^R s'Tli η O pO “4 (HI)

This aspect involves causing the compound of Formula III to react with a halogenating reagent in a solvent. In one embodiment, the halogenating agent is selected from fluorination agents, chlorination agents, bromination agents, iodination agents, and combinations thereof. In one embodiment, the halogenating reagent is a chlorination 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 chlorination reagent is sulfuryl chloride. In one embodiment, the solvent is selected from acetonitrile (ACN), 1,2dichloroethane (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 from about 20°C to about 140°C. In another embodiment, the reaction temperature is in the range from about 120°C to about 130°C.

In one aspect, a compound of Formula IV is prepared in accordance with the method presented in Scheme 10. R groups are as defined elsewhere herein.

Scheme 10.

This aspect involves, in a first reaction, reacting a compound of formula II with an acid, which is also used as a solvent, followed by the addition of a halogenating agent, and in a second reaction, forming a compound of formula IV. In one embodiment, the acid is selected from acetic acid, sulfuric acid, and combinations thereof. In another embodiment, implement

- 28 047007 leniya acid is sulfuric acid. In one embodiment, the halogenating agent is selected from fluorination agents, chlorination agents, bromination agents, iodination agents, and combinations thereof. In one embodiment, the halogenating reagent is a chlorination 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 chlorination reagent is trichloroisocyanuric acid. In one embodiment, the reaction temperature of the first reaction is in the range from about 0°C to about 100°C. In another embodiment, the reaction temperature of the first reaction is in the range from about 10°C to about 65°C. In one embodiment, the reaction temperature of the second reaction is in the range from about 10°C to about 100°C. In another embodiment, the reaction temperature of the second reaction is in the range from about 10°C to 65°C.

This aspect is a one-pot process and has several advantages. First, it eliminates the need to separate intermediates derived from a compound of formula II, such as a compound of formula III, before subsequent reactions. Secondly, the potential losses of intermediates derived from a compound of formula II, such as a compound of formula III, are reduced. Third, the overall yield increases. Fourth, the number of reaction steps and processing operations is reduced. Fifthly, the overall cost is reduced.

In one aspect, a compound of Formula V is prepared in accordance with the method presented in Scheme 11. R groups are as defined elsewhere herein.

Scheme 11.

(IV) (V)

This aspect involves adding an oxidizing agent to an aqueous solution that contains 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-chloroperoxybenzoic acid, hydrogen peroxide, peroxyacetic 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 (H2O), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), Nmethyl-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 from about 20°C to about 100°C. In another embodiment, the reaction temperature is in the range from about 60°C to about 65°C.

In one aspect, a compound of Formula VI is prepared in accordance with the method presented in Scheme 12. R groups are as defined elsewhere herein.

Scheme 12.

Ri; About Rio About

This aspect involves causing a compound of formula V to react with an alkylamine in a solvent. In one embodiment, the alkylamine contains a functional group selected from branched u-alkyl and straight-chain u-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 acetates (IPAc) and combinations thereof. In another embodiment, the solvent is EtOAc. In one embodiment, the reaction temperature is in the range from about 0°C to about 100°C. In another embodiment, the reaction temperature is in the range from about 20°C to about 30°C.

- 29 047007

In one aspect, a compound of Formula V is prepared in accordance with the method presented in Scheme 13. R groups are as defined elsewhere herein.

Scheme 13.

This aspect involves allowing a compound of Formula III to react with a halogenating reagent 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 fluorination agents, chlorination agents, bromination agents, iodination agents, and combinations thereof. In another embodiment, the halogenating agent is a chlorination 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 reagent 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 from about 20°C to about 140°C. In another embodiment, the reaction temperature for halogenation is in the range from about 120°C to about 130°C. In one embodiment, the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide, peroxyacetic 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 oxidation is in the range from about 20°C to about 100°C. In another embodiment, the reaction temperature for oxidation is in the range from about 60°C to about 65°C.

This aspect is a one-pot process and has several advantages. First, it eliminates the need to separate intermediates derived from a compound of formula III, such as a compound of formula IV, before subsequent reactions. Secondly, the potential losses of intermediates derived from a compound of formula III, such as a compound of formula IV, are reduced. Third, the overall yield increases. Fourth, the number of reaction steps and processing operations is reduced. Fifthly, the overall cost is reduced.

Examples

Without further qualification, it is believed that one skilled in the art, with the aid of the above description, can implement the present invention to its fullest extent. Therefore, the following examples should be considered solely as illustrative and absolutely not limiting the present invention in any way. The starting material for the following examples does not necessarily have to be prepared through a specific preparation cycle, the procedure for which is described in the other examples. It should also be understood that any numerical range given herein includes all values in the range from the lower value to the upper value. For example, if the range is specified as 10-50, then it is assumed that values such as 12-30, 20-40 or 30-50, etc., are explicitly listed in that specification. These are examples only of what is specifically stated, and all possible combinations of numerical values between and inclusive of the listed smallest value and the largest value are to be considered as expressly stated in this application.

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 the 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 (E)-3-hydroxy-N-(otolyl)acrylamide of high purity were obtained.

Example 2. Cyclization.

20.0 g of (E)-3-hydroxy-N-(o-tolyl)acrylamide was charged in portions to control the reaction temperature into the sulfuric acid in the reactor. The reaction temperature was controlled at 60°C to 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. Received 16.0 g 7

- 30 047007 methylindoline-2,3-dione. This crude product can be used for subsequent reactions without further processing.

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 the 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 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 were obtained.

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 the 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 in the range of 60-65°C. After the reaction, water was loaded into 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-8methyl-211-be11zo[c1][1,3]oxazine-2,4(111)-dione were obtained.

Example 5. Reaction with methamine.

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

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 the reactor. The reaction temperature was controlled at 120-125°C. After consumption of 7methylindoline-2,3-dione, the reaction temperature was reduced to 60-65°C. 41.4 g of 30% hydrogen peroxide solution was added dropwise to control the temperature in the range of 60-65°C. After the reaction, water was loaded into 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-2Hbenzo[d][1,3]oxazine-2,4(1N-dione) were obtained.

In this written description, examples are used to illustrate the present invention, including the best mode, and to enable any person skilled in the art to practice the present invention, including making and using any devices or systems and performing any methods provided. The scope of patentability of the present invention is defined by the claims and may include such other examples as may be apparent 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 claims, or if they include equivalent structural elements with minor differences from the literal claims.

Claims (6)

1. Method for preparing a compound of formula V, R/ ^Rl ° ⁰ (formula V), wherein each of R ₇ -R ₁₀ is independently selected from hydrogen, halogen, halogenated C ₁ -C ₅ -αalkyl and C ₁ -C ₅ -αalkyl; wherein at least one of R ₇ -R ₁₀ is halogen, the method comprising i) forming a first mixture containing a) a compound of formula III, - 31 047007 Ri ^R 4 (formula III), wherein each of R1-R4 is independently selected from hydrogen, halogen and C1-C5 alkyl; b) a solvent selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid and combinations thereof; And c) a halogenating reagent selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof; ii) allowing the first mixture to react at a reaction temperature in the range of from about 20°C to about 140°C; iii) adding an oxidizing agent to the reacted first mixture in the presence of a catalyst selected from sulfuric acid, hydrogen chloride, nitric acid and combinations thereof, to form a further mixture wherein the oxidizing agent is selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3-chloroperoxybenzoic acid, hydrogen peroxide , peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate and combinations thereof; iv) causing the additional mixture to react at a reaction temperature ranging from about 20°C to about 100°C. 2. The method according to claim 1, wherein the compound of formula III is prepared in accordance with a method comprising: I) forming a mixture containing A) a compound of formula II, ^r 4 (formula II), where each of R1-R5 is independently selected from hydrogen, halogen and ^-^-alkyl; and wherein the compound of formula II is prepared in accordance with a method comprising: i) forming a mixture containing a) a compound of formula I, where each of R1-R5 is independently selected from hydrogen, halogen and ^-^-alkyl; b) chloral hydrate; c) a hydroxylamine derivative selected from hydroxylamine sulfate, hydroxylamine hydrochloride, and combinations thereof; d) a solvent selected from MeOH, EtOH, toluene, water and combinations thereof; e) an inorganic salt selected from sodium sulfate, sodium hydrogen sulfate, sodium chloride, sodium disulfite, potassium sulfate, potassium chloride and combinations thereof; And f) an acid selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid and combinations thereof; and ii) causing the mixture to react; And B) an acid selected from hydrogen chloride, sulfuric acid, nitric acid, hydrobromic acid, formic acid, acetic acid and combinations thereof; And ii) ensuring the reaction in the mixture. 3. Method for preparing the compound of formula V, - 32 047007 Ry ^{RlCl 0} (formula V), wherein each of R7-R10 is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl and C1-C5 alkyl; and wherein at least one of R7-R10 is halogen, the method comprising I) formation of the first mixture containing A) a compound of formula III, Ri ^R4 (formula III), wherein each of R1-R4 is independently selected from hydrogen, halogen and ^-^-alkyl; B) a solvent selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, acetic acid, acetic anhydride, propionic acid, butyric acid, and combinations thereof; And C) a halogenating reagent selected from a chlorination reagent, a bromination reagent, an iodination reagent, and combinations thereof; ii) providing a reaction in the first mixture; III) introducing a second mixture into the first mixture to form a third mixture, wherein the second mixture contains D) an oxidizing agent selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3chloroperoxybenzoic acid, hydrogen peroxide, peroxyacetic acid, potassium peroxymonosulfate, potassium permanganate, and combinations thereof; And E) a catalyst selected from sulfuric acid, hydrogen chloride, nitric acid, and combinations thereof; And IV) ensuring the reaction in the third mixture. 4. Method for preparing the compound of formula VI, ^R1 °° (Formula VI), wherein R7-R10 are each independently selected from hydrogen, halogen, halogenated ^-^-alkyl and ^-^-alkyl; where at least one of R7-R10 is halogen; and where R11 is selected from branched ^-^-alkyl and straight ^-^-alkyl, the method comprising I) forming a mixture containing A) a compound of formula V, - 33 047007 wherein each of R7-R10 is independently selected from hydrogen, halogen, halogenated C1-C5 alkyl and C1-C5 alkyl; where at least one of R7-R10 is halogen; and where the compound of formula V is obtained in accordance with the method according to claim 1; B) an alkylamine containing a functional group selected from branched C ₁ -C ₁₀ -alkyl and straight-chain C ₁ -C ₁₀ -alkyl; And C) a solvent selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof; And ii) allowing the mixture to react at a reaction temperature ranging from about 0°C to about 100°C. 5. Method for preparing the compound of formula IV, Ry I ХГ)=° I o ^R '° (formula IV), where each of R7-R10 is independently selected from hydrogen, halogen, halogenated C ₁ -C ₅ -alkyl and ^-^-alkyl; wherein at least one of R7-R10 is halogen, the method comprising I) forming a mixture containing A) a compound of formula II, Ri n r ₄ (formula II), each of R1-R5 is independently selected from hydrogen, halogen and ^-^-alkyl; B) acid; II) interaction of the first mixture; III) introducing a halogenating reagent into the first mixture to form a second mixture; And IV) interaction of the second mixture. 6. Method for preparing a compound of formula VI, where (Formula VI) each of R7-R10 is independently selected from hydrogen, halogen, halogenated ^-^-alkyl and ^-^-alkyl; where at least one of R7-R10 is halogen; And - 34 047007 where R11 is selected from branched C1-C ₁₀ -alkyl and unbranched C1-C ₁₀ -alkyl, including I) formation of a mixture containing A) a compound of formula V, where Rv (Formula V) each of R7-R10 is independently selected from hydrogen, halogen, halogenated C ₁ -C ₅ -alkyl and C ₁ -C ₅ -alkyl; where at least one of R7-R10 is halogen; and wherein the compound of formula V is prepared by a process comprising: i) formation of a mixture containing a) a compound of formula IV as defined in claim 5, and wherein the compound of formula IV is prepared as defined in claim 5; b) an oxidizing agent selected from oxygen, chlorine, sodium hypochlorite, chromium trioxide, 3chloroperoxybenzoic acid, hydrogen peroxide, potassium peroxymonosulfate, potassium permanganate and combinations thereof; c) solvent; And d) a catalyst selected from sulfuric acid, hydrogen chloride, nitric acid and combinations thereof; and ii) mixture interaction; B) an alkylamine selected from branched C ₁ -C ₁₀ -alkyl and straight-chain C ₁ -C ₁₀ -alkyl; And C) a solvent selected from acetonitrile, dichloroethane, toluene, chlorobenzene, xylene, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, and combinations thereof; And ii) reacting the mixture at a reaction temperature ranging from 0°C to 100°C.