EA044234B1 - METHOD FOR OBTAINING METOXYMETHYLPYRIDINE DICARBOXYLATE - Google Patents

Description

Field of technology to which the invention relates

The present application concerns an effective method for the preparation of methoxymethylpyridine dicarboxylate.

Prior Art

Imazamox is a systemic herbicide that works by inhibiting the protein acetolactate synthase (ALS) in plants. Dialkyl-5,6-dicarboxylate-3-alkoxymethylpyridine having formula (I)

is an important intermediate in the preparation of the herbicide imazamox (2-[(RS)-4-isopropyl-4-methyl5-oxo-2-imidazolin-2-yl]-5-methoxymethylnicotinic acid).

Various production methods are described in the literature. EP0548532 describes the reaction of methylpyridine with a halogenating agent to minimize the yield of the dihalogenated product, and the reaction with ammonium bromide in methanol under nitrogen at reflux for 6 hours. US5760239 describes the preparation of 2,3-disubstituted 5-methoxymethylpyridine by the reaction of ammonium bromide with a base in the presence of an alcohol at a temperature of 120-180°C under pressure in a hermetically sealed system. WO 2010066669 describes the preparation of 2,3-disubstituted 5-methoxymethylpyridine from trimethylammonium bromide, dimethyl ether in the methanol/H ₂ O system with the base being MOCH3 MOH, where the reaction is carried out under pressure in a hermetically sealed vessel at a temperature of from 75 to 110° WITH. WO 2010055139 describes the preparation of 2,3-disubstituted 5-pyridylmethylammonium bromide from 2,3-disubstituted 5-pyridylmethyl by reaction with bromine and subsequent reaction with trialkylamine.

However, there is a need to develop a more efficient synthesis route by improving various steps of the process, and there is a need to improve each step of the entire synthesis by increasing yield and conversion.

Brief description of the invention

The present invention describes a method for producing a compound having formula (I)

where each R1 represents C ₁ -C ₄ alkyl and

R ₂ represents C1- _C4 alkyl, including the following steps: (i) reaction of dialkyl-3-methylpyridine-5,6-dicarboxylate structure

with potassium peroxymonosulfate and a metal halide salt, where the metal is an alkali or alkaline earth metal, to obtain a mixture containing compounds having formulas IIa and/or IIb and/or IIc:

where n=2 and m=1 (IIa), n=1 and m=2 (IIb), or n=0 and m=3 (IIc); each R1 is C1- _C4 alkyl and

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X represents a halogen, (ii) reacting the mixture obtained in step (i) with an amine to obtain a compound having formula (III)

where each R1 represents C1- _C4 alkyl; Y+ represents

where _R3 , R4 and R5 are each independently C1-C6 alkyl; And

X is a halogen, (iii) the reaction of the compound of formula (III) obtained in step (ii) with a base that is a metal alkoxide, where the metal is an alkali or alkaline earth metal.

The present invention also describes a method for preparing a mixture containing compounds having formula IIa and/or IIb and/or IIc

where X represents halogen; each R1 is C1- _C4 alkyl;

n=2 and m=1 (IIa), n=1 and m=2 (IIb), or n=0 and m=3 (IIc), involving the reaction of dialkyl-3methylpyridine-5,6-dicarboxylate of the structure:

R1O2C

R1O2C with potassium peroxymonosulfate and a metal halide salt, where the metal is an alkali or alkaline earth metal, in the presence of a radical initiator selected from inorganic peroxides, organic peroxides and azo initiators.

The present invention also describes a method for preparing compounds having formula (III)

where each R1 represents C1-C4 alkyl; Y+ represents

where R ₃ , R ₄ and R ₅ are each independently C1-C6 alkyl and

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X is a halogen involving the reaction of a mixture containing compounds having formula IIa and/or IIb and/or IIc

where n=2 and m=1 (IIa), n=1 and m=2 (IIb), or n=0 and m=3 (IIc);

each R1 is C1- _C4 alkyl and

X is a halogen, with a dialkyl phosphite in the presence of an amine, where the amine is a nucleophilic amine, to give a compound having formula (III).

The present invention also describes a method for producing a compound having formula (I):

where each R1 represents C1-C4 alkyl;

R2 represents C1-C4 alkyl, involving the reaction of a compound having formula (III)

where each R1 represents C1-C4 alkyl; Y+ represents

where R ₃ , R 4 and R ₅ are each independently C1-C ₆ alkyl and

X is halogen, with a metal alkoxide base in the presence of a hydroxy scavenger, or with a metal alkoxide base where the metal is an alkali or alkaline earth metal that has been previously treated with a hydroxy scavenger.

The present invention also describes a method for preparing compounds having the formula

where each R1 represents C1- _C4 alkyl, involving the reaction of compounds having formula (IIb-c)

- 3 044234 where n=1 and m=2 (IIb), or n=0 and m=3 (IIc);

each R1 is C1- _C4 alkyl and

X is bromine, with dialkyl phosphite in the presence of a base to give a compound having formula (IIa).

The present invention describes a method for preparing a compound having the structure:

which includes:

(a) conversion of the diester compound of formula (I)

where each R1 represents C1- _C4 alkyl, and _R2 represents C1 alkyl; obtained by the method according to any one of claims 1-10 or 14, into the corresponding diacid under hydrolysis conditions;

(b) converting the diacid - the compound of step (a) - into an anhydride having the structure

(c) reacting the anhydride compound of step (b) with 2-amino-2,3-dimethylbutanenitrile to form a compound having the structure:

- 4 044234 (d) reaction of the compound from step (c) with an acid to form a compound having the structure

H ₃ C

base ₃

C(O)NH ₂ (e) reaction of the compound from step (d) with a base.

The present invention also describes a method for preparing a compound having the structure

which includes:

(i) preparing a compound of formula (I)

where each R1 represents C ₁ -C ₄ alkyl and R ₂ represents C ₁ alkyl, by the method according to any one of claims 1 to 10 or 14; and (iia) reacting the compound of formula (I) with (R)2-amino-2,3-dimethylbutyramide in the presence of a strong base and a non-polar, substantially water-free solvent to form a salt of the compound of formula (Im); and treating said salt with aqueous acid to obtain a chiral free carboxylic acid of formula (Im); or (iib) converting a diacid of formula (I) into an anhydride having the structure

reacting the anhydride from the previous step with 2-amino-2,3-dimethylbutyramide to give a compound having the following structure:

condensing the compound from the previous step to obtain a compound of formula (Im); or

- 5 044234 (iic) conversion of a diacid of formula (I) into an anhydride having the structure

reaction of the anhydride with 2-amino-2,3-dimethylcarbonitrile to give a compound having the following structure:

hydrolysis of the nitrile from the previous step to produce an amide with the following structure:

reacting the amide from the previous step with MOH/CH ₃ OH (where M is an alkali metal selected from Na or K) followed by acidification to form a compound of formula (Im).

Detailed Description of the Invention

Before describing the present invention in detail, it will be useful to define certain terms used herein. Unless otherwise specified, all technical and scientific terms used herein have the meaning commonly accepted by those skilled in the art.

The use of the singular in this text includes the description of both one and several items, unless specifically indicated otherwise. The terms one and at least one may be used interchangeably herein.

In this text, the term comprising is used to describe various embodiments; however, one skilled in the art will understand that in some cases an embodiment may alternatively be described using the phrase consisting primarily of or consisting of. In each such case, the terms comprising, consisting primarily of, and consisting of have the meaning they would have if used as a transitional phrase in the claims.

For a better understanding of the present invention, without in any way limiting the scope of the present invention, unless otherwise indicated, all numbers expressing amounts, percentages or ratios, and other numerical values specified in the text of the description or claims are to be understood as modified roughly a term. Accordingly, unless otherwise stated, numerical parameters set forth in the specification and claims are approximations that may vary depending on the desired properties to be achieved. At a minimum, each numerical value must be understood in light of the number of significant figures specified and using normal rounding techniques. In this regard, the use of the term approximately in this text specifically includes a deviation of ±10% from the specified value or range. In addition, the extreme points of all ranges concerning components or properties included in the specified ranges can be independently combined, and the ranges include all values and subranges included in them.

The present invention describes a method that is suitable for industrial use, is highly efficient, economical and environmentally friendly.

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The present invention describes a method for producing a compound having formula (I)

where each R1 represents C1-C4 alkyl; And

R2 represents C1-C4 alkyl, including the following steps:

(i) reacting dialkyl-3-methylpyridine-5,6-dicarboxylate with potassium peroxymonosulfate and a metal halide salt to obtain a mixture containing compounds having formulas IIa and/or IIb and/or IIc

where n=2 and m=1 (IIa), n=1 and m=2 (IIb), or n=0 and m=3 (IIc);

each R1 is C1-C4 alkyl and

X represents a halogen, (ii) reacting the mixture obtained in step (i) with an amine to obtain a compound having formula (III)

(III), where each R1 represents C1-C4 alkyl; Y+ represents

where R ₃ , R 4 and R ₅ are each independently C1-C6 alkyl or aryl and

X is a halogen, (iii) reaction of the product from step (ii) with a metal alkoxide base.

In some embodiments, step (i) takes place in the presence of a radical initiator.

In some embodiments, the radical initiator is azobisisobutyronitrile (AIBN).

In some embodiments, the radical initiator is activated by heating the reaction mixture.

In some embodiments, the radical reaction is induced using light.

The light may be visible light or ultraviolet radiation.

In some embodiments, step (i) is carried out in the presence of visible light.

In some embodiments, step (i) is carried out in the presence of ultraviolet radiation.

In some embodiments, when step (i) is carried out in the presence of light, a compound having the formula below (CPDC) is obtained.

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In some embodiments, the amount (CPDC) is less than or equal to 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, 8%, or 9%, or 10% of the resulting product.

In some embodiments, potassium peroxymonosulfate in step (i) is added to the reaction mixture gradually in two or more portions.

In some embodiments, the reaction is carried out in a first suitable solvent.

In some embodiments, the first suitable solvent is dichloromethane, chloroform, 1,2-dichloroethane, perchlorethylene, trichloroethane, chlorobenzene, 2-dichlorobenzene, 3-dichlorobenzene, 4-dichlorobenzene, benzene, carbon tetrachloride, or any combination thereof.

In some embodiments, the first suitable solvent is 1,2 dichloroethane.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is 5%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is 1%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is less than 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is less than 5%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is less than 1%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is from 4% to 6%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in step (i) in the reaction solution is from 0.5% to 1.5%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in step (i) in the reaction solution is less than or equal to 1%, or 2%, or 3%, or 4%, or 5%, or 6% , or 7%, or 8%, or 9%, or 10%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in step (i) in the reaction solution is less than 5%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in step (i) in the reaction solution is less than 1%.

In some embodiments, the concentration of the metal halide salt of step (i) in the reaction solution is less than or equal to 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8% , or 9%, or 10%.

In some embodiments, the concentration of the metal halide salt of step (i) in the reaction solution is 5%.

In some embodiments, the concentration of the metal halide salt of step (i) in the reaction solution is 1%.

In some embodiments, the concentration of the metal halide salt in the reaction solution is 1% or less, or 2% or less, or 3% or less, or 4% or less, or 5% or less, or 6% or less, or 7 % or less, or 8% or less, or 9% or less, or 10% or less.

In some embodiments, the concentration of the metal halide salt in step (i) in the reaction solution is less than 5%.

In some embodiments, the concentration of the metal halide salt of step (i) in the reaction solution is less than 1%.

In some embodiments, the concentration of the metal halide salt of step (i) in the reaction solution is from 4% to 6%.

In some embodiments, the concentration of the metal halide salt of step (i) in the reaction solution is from 0.5% to 1.5%.

In some embodiments, in step (ii), the halogenated products from step (i) are reacted with an amine in the presence of diethyl phosphite.

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In some embodiments, in step (ii), the dihalogenated and trihalogenated products IIb and IIc from step (i) are reacted with diethyl phosphite in the presence of a non-nucleophilic base before reacting with the amine.

In some embodiments, in step (ii), the dihalogenated and trihalogenated products IIb and IIc from step (i) are converted to the monohalogenated product IIa before reacting with the amine.

In some embodiments, the amine in step (ii) is trimethylamine.

In some embodiments, the amine is a gas.

In some embodiments, the amine is a liquid or solution of a gaseous amine.

In some embodiments, the metal in step (i) and/or (iii) is alkali or alkaline earth.

In some embodiments, halogen X is a bromide, chloride, fluoride, or iodide.

In some embodiments, the metal halide salt in step (i) is sodium bromide.

In some embodiments, the alcohol in step (iii) is methanol.

In some embodiments, step (iii) is carried out in the presence of a hydroxy scavenger.

In some embodiments, compound (iii) is dried before reacting with a metal alkoxide base.

In some embodiments, compound (iii) is treated with dehydrating reagents and/or substances before reacting with a metal alkoxide base.

Dehydrating reagents and/or substances include, but are not limited to, trialkyl orthoformates, highly hygroscopic inorganic salts, molecular sieves, and combinations thereof.

Trialkyl orthoformates include, but are not limited to, trimethyl orthoformate and triethyl orthoformate.

In some embodiments, the product from step (ii) is treated with a dehydrating agent in the presence of an acid. Examples of the acid include an organic acid or an inorganic acid.

Organic acids include, but are not limited to, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and acetic acid.

Inorganic acids include, but are not limited to, sulfuric acid, phosphoric acid, and hydrochloric acid.

In some embodiments of the method, the reaction is carried out at atmospheric pressure or at elevated pressure up to 6 bar.

In some embodiments, the hydroxy scavenger is methyl acetate.

In some embodiments, the hydroxy scavenger is ethyl acetate.

In some embodiments, the metal alkoxide base is treated with a hydroxy scavenger before reacting with compound (III).

In some embodiments, step (i) described above provides a mixture of the following compounds:

In some embodiments, the resulting compound has the structure

where R1 and R2 each represent methyl.

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In some embodiments, the resulting compound has the structure

In some embodiments, the potassium peroxymonosulfate source is a ternary salt having the formula KHSO ₅ -0.5KHSO ₄ -0.5K ₂ SO ₄ .

In some embodiments, the potassium peroxymonosulfate is OXONE®.

In some embodiments, the method described above further includes step (i)(a) after step (i) and before step (ii), wherein the mixture containing compounds IIa-c from step (i) is reacted with a dialkyl phosphite to obtain the compound, having formula IIa.

In some embodiments, the method described above further includes step (i)(a) after step (i) and before step (ii), wherein the mixture containing compounds IIa-c from step (i) reacts with the dialkyl phosphite such that a compound having formula IIb-c is converted to a compound having formula IIa.

The present invention also describes a method for preparing a mixture containing compounds having formula IIa and/or IIb and/or IIc:

(Pa-s), where X represents halogen;

each R1 is C ₁ -C ₄ alkyl;

n=2 and m=1 (IIa), n=1 and m=2 (IIb), or n=0 and m=3 (IIc), involving the reaction of dialkyl-3methylpyridine-5,6-dicarboxylate with potassium peroxymonosulfate and halide metal salt in the presence of a radical initiator.

In some embodiments, the radical initiator is azobisisobutyronitrile (AIBN).

In some embodiments, the radical initiator is activated by heating the reaction mixture.

In some embodiments, the reaction is induced using light. The light may be visible light and/or ultraviolet radiation.

In some embodiments, the reaction is carried out in the presence of visible light.

In some embodiments, the reaction is carried out in the presence of ultraviolet radiation.

In some embodiments, potassium peroxymonosulfate is added to the reaction mixture gradually in two or more portions.

In some embodiments, the reaction is carried out in a first suitable solvent.

In some embodiments, the first suitable solvent is dichloromethane, chloroform, 1,2-dichloroethane, perchlorethylene, trichloroethane, chlorobenzene, 2-dichlorobenzene, 3-dichlorobenzene, 4-dichlorobenzene, benzene, carbon tetrachloride, or any combination thereof.

In some embodiments, the first suitable solvent is 1,2dichloroethane.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9 %, or 10%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is 1% or less, or 2% or less, or 3% or less, or 4% or less, or 5% or less, or 6% or less, or 7% or less, or 8% or less, or 9% or less, or 10% or less.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is 5%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is from 4% to 6%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is 1%.

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In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is from 0.5% to 1.5%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in the reaction solution is less than or equal to 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or

8%, or 9%, or 10%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in the reaction solution is less than 5%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in the reaction solution is less than 1%.

In some embodiments, the concentration of the metal halide salt in the reaction solution is 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10 %.

In some embodiments, the concentration of the metal halide salt in the reaction solution is 1% or less, or 2% or less, or 3% or less, or 4% or less, or 5% or less, or 6% or less, or 7 % or less, or 8% or less, or 9% or less, or 10% or less.

In some embodiments, the concentration of the metal halide salt in the reaction solution is 5%.

In some embodiments, the concentration of the metal halide salt in the reaction solution is 1%.

In some embodiments, the concentration of the metal halide salt in the reaction solution is from 4% to 6%.

In some embodiments, the concentration of the metal halide salt in the reaction solution is from 0.5% to 1.5%.

In some embodiments, the metal is an alkali or alkaline earth.

In some embodiments, the halogen is a bromide, chloride, fluoride, or iodide.

In some embodiments, the metal halide salt is sodium bromide.

In some embodiments, the metal halide salt is sodium chloride, sodium iodide, or potassium bromide.

In some embodiments, the potassium peroxymonosulfate source is a ternary salt having the formula KHSO ₅ -0.5KHSO ₄ O.5K ₂ SO ₄ .

In some embodiments, the potassium peroxymonosulfate is OXONE®.

In some embodiments, the method described above produces a mixture of the following compounds:

In some embodiments, the mixture obtained by reacting dialkyl-3-methylpyridine-5,6dicarboxylate with potassium peroxymonosulfate and a metal halide salt contains compounds having formula (IIa-b).

In some embodiments, the mixture obtained by reacting dialkyl-3-methylpyridine-5,6dicarboxylate with potassium peroxymonosulfate and a metal halide salt contains compounds having formula (IIa-c).

In some embodiments, when the reaction is carried out in the presence of light, a compound having the formula below (CPDC) is obtained.

- 11 044234 (CPDC).

Ri

R-

In some embodiments, the amount (CPDC) is less than or equal to 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, 8%, or 9%, or 10% of the resulting product.

In some embodiments, the total percentage of IIa and IIb obtained is greater than 90%.

In some embodiments, the total percentage of IIa, IIb, and IIc obtained is greater than 90%.

The present invention also describes a method for preparing compounds having formula (III)

where each R1 represents C1- _C4 alkyl; Y ⁺ is more than

where R ₃ , R ₄ and R5 are each independently C ₁ -C ₆ alkyl or aryl and

X is a halogen involving the reaction of a mixture containing compounds having formula IIa and/or IIb and/or IIc

where n=2 and m=1 (IIa), n=1 and m=2 (IIb), or n=0 and m=3 (IIc);

each R1 is C1- _C4 alkyl and

X is halogen, with dialkyl phosphite in the presence of an amine to produce a compound having formula (III).

In some embodiments, the amine is an organic amine.

In some embodiments, the amine is a nucleophilic amine.

In some embodiments, the amine is a non-nucleophilic amine.

In some embodiments, the amine is selected from the group consisting of trimethylamine, triethylamine, and pyridine.

In some embodiments, the amine is selected from the group consisting of tert-butyldimethylamine, isobutyldimethylamine.

In some embodiments, the amine is a gas.

In some embodiments, the amine is a liquid or solution of a gaseous amine.

In some embodiments, the described method is implemented in a single reaction vessel.

In some embodiments, the dihalogenated and trihalogenated compounds IIb and IIc are reacted with diethyl phosphite before reacting with the amine in the presence of a non-nucleophilic base.

In some embodiments, the dihalogenated and trihalogenated compounds IIb and IIc are converted to the monohalogenated product IIa before reacting with an amine in the presence of a non-nucleophilic base.

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The present invention also describes a method for preparing a compound having formula (I)

where each R ₁ represents C ₁ -C ₄ alkyl;

R2 represents C1- _C4 alkyl; involving the reaction of a compound having formula (III)

where each R1 represents C1-C4 alkyl; Y+ represents

where R ₃ , R 4 and R ₅ are each independently C1-C6 alkyl or aryl; And

X is a halogen, with a metal alkoxide base in the presence of a hydroxy scavenger, or with a metal alkoxide base that has been previously treated with a hydroxy scavenger.

In some embodiments, compound (iii) is dried before reacting with a metal alkoxide base.

In some embodiments, compound (iii) is treated with dehydrating reagents and/or substances before reacting with a metal alkoxide base.

Dehydrating reagents and/or substances include, but are not limited to, trialkyl orthoformates, highly hygroscopic inorganic salts, molecular sieves, and combinations thereof.

Trialkyl orthoformates include, but are not limited to, trimethyl orthoformate and triethyl orthoformate.

In some embodiments, the product from step (ii) is treated with a dehydrating agent in the presence of an acid. Examples of the acid include an organic acid or an inorganic acid.

Organic acids include, but are not limited to, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and acetic acid.

Inorganic acids include, but are not limited to, sulfuric acid, phosphoric acid, and hydrochloric acid.

In some embodiments of the method, the reaction is carried out at atmospheric pressure or at elevated pressure up to 6 bar.

In some embodiments, the metal is an alkali or alkaline earth.

In some embodiments, the alcohol is methanol.

In some embodiments, the alcohol is ethanol.

In some embodiments, the hydroxy scavenger is methyl acetate.

In some embodiments, the hydroxy scavenger is ethyl acetate.

In some embodiments, a compound having formula (III) is reacted with a metal alkoxide base in the presence of a hydroxy scavenger.

In some embodiments, a compound having formula (III) is reacted with a metal alkoxide base that has been previously treated with a hydroxy scavenger.

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The present invention also describes a method for preparing a compound having the formula

where each R1 represents C ₁ -C ₄ alkyl, involving the reaction of a compound having formula (IIb-c)

where n=1 and m=2 (IIb), or n=0 and m=3 (IIc);

each R1 is C ₁ -C ₄ alkyl and

X is bromine, with dialkyl phosphite to give the compound having formula (IIa).

In some embodiments, the process, namely steps (i), (ii) and (iii), is carried out in a single reaction vessel.

In some embodiments, a compound having formula (I) has the structure

In some embodiments, compounds having formulas (IIa-c) have the structures

In some embodiments, a compound having formula (III) has the structure

In some embodiments, the reaction of 3-methylpyridine-5,6-dialkyl dicarboxylate with OXONE® potassium peroxymonosulfate is carried out in a solvent.

Potassium peroxymonosulfate is used as an oxidizing agent and is commercially available from DuPont under the trade name OXONE® as a ternary salt component having the formula KHS0 ₅ -0.5KHS0 ₄ -0.5K ₂ S0 ₄ . In some embodiments, the source of potassium peroxymonosulfate is OXONE®.

In some embodiments, OXONE® means a solution of KHS0 ₅ -0.5KHS0 ₄ -0.5K ₂ S0 ₄ in water. The OXONE® concentration may be, but is not limited to, 10%, 20%, 30%, 40% or 50%.

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In some embodiments, the concentration of OXONE® in the water is 19%.

In some embodiments, the concentration of OXONE® in the water is 25%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9 %, or 10%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is 5%. In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, in the reaction solution is 1%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in the reaction solution is less than 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in the reaction solution is less than 5%.

In some embodiments, the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in the reaction solution is less than 1%.

In some embodiments, the concentration of the metal halide salt in the reaction solution is 1%, or 2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10 %.

In some embodiments, the concentration of the metal halide salt in the reaction solution is 5%. In some embodiments, the concentration of the metal halide salt in the reaction solution is 1%.

In some embodiments of any of the bromination reactions described above, the solvent is a non-polar solvent.

In some embodiments, the non-polar solvent may include, but is not limited to, dichloromethane, chloroform, 1,2-dichloroethane, perchlorethylene, trichloroethane, chlorobenzene, 2-dichlorobenzene, 3-dichlorobenzene, 4-dichlorobenzene, benzene, carbon tetrachloride, or any combination thereof .

In some embodiments, the molar ratio of potassium peroxymonosulfate, such as OXONE®, and pyridine substrate is from about 0.7:1.0 to about 3.5:1.0.

In some embodiments, the molar ratio of potassium peroxymonosulfate, such as OXONE®, and pyridine substrate is 0.3:1.0, or 0.7:1.0, or 1.1:1.0, or 1.5:1 .0, or 2.0:1.0, or 2.5:1.0, or 3.0:1.0, or 3.5:1.0.

In some embodiments, the molar ratio of potassium peroxymonosulfate, such as OXONE®, and pyridine substrate is 0.37:1.0.

In some embodiments, the above molar ratios are maintained with each addition of OXONE®.

In some embodiments, the total amount of potassium peroxymonosulfate, such as OXONE®, is added to at least two portions, three portions, four portions, five portions, six portions, seven portions, eight portions, nine portions, or ten portions.

In some embodiments, the total amount of metal halide salt is added to at least two portions, three portions, four portions, five portions, six portions, seven portions, eight portions, nine portions, or ten portions.

In some embodiments, the reaction is carried out with light and in the absence of a radical initiator.

In some embodiments, the reaction is carried out with light and in the absence of a radical initiator, and the total amount of potassium peroxymonosulfate, such as OXONE®, is added in one step.

In some embodiments, the reaction is carried out in the presence of a radical initiator.

In some embodiments, the reaction is carried out in the presence of a radical initiator and the entire amount of potassium peroxymonosulfate, such as OXONE®, is added in one step.

In some embodiments, the reaction is carried out with light and in the absence of a radical initiator, and the total amount of the metal halide salt is added in one step.

In some embodiments, the reaction is carried out in the presence of a radical initiator and the entire amount of the metal halide salt is added at one time.

In some embodiments, the mole ratio of metal halide salt to pyridine substrate is from about 0.3:1.0 to about 3.5:1.0.

In some embodiments, the mole ratio of metal halide salt to pyridine substrate is from about 0.7:1.0 to about 3.5:1.0.

In some embodiments, the molar ratio of metal halide salt to pyridine substrate is 0.41:1.0.

In some embodiments, the above molar ratios are maintained with each addition of the metal halide salt.

- 15 044234

In some embodiments, the molar ratio of metal halide salt to pyridine substrate is 0.7:1.0, or 1.1:1.0, or 1.5:1.0, or 2.0:1.0, or 2.5:1.0, or 3.0:1.0, or

3.5:1.0.

In some embodiments, the total amount of metal halide salt is added to at least two portions, three portions, four portions, five portions, six portions, seven portions, eight portions, nine portions, or ten portions.

In some embodiments, any of the bromination reactions described above, the reaction is carried out at a pH value of less than 5, or less than 4.5, or less than 4, or less than 3.5, or less than 3, or less than 2.5, or less than 2, or less than 1.5, or less than 1.0, or less than 0.5.

In some embodiments, any of the bromination reactions described above, the reaction is carried out at a pH value of from about 1.0 to 2.0.

In some embodiments, any of the bromination reactions described above, the concentration of potassium peroxymonosulfate, such as OXONE®, or dialkyl-3-methylpyridine-5,6dicarboxylate and/or metal halide salt in the reaction solution is less than 10%, or less than 9%, or less 8%, or less than 7%, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.75%, or less than 0.5 %, or less than 0.2%, or less than 0.1%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, or dialkyl-3-methylpyridine-5,6-dicarboxylate and/or metal halide salt in the reaction solution is maintained during the reaction at less than 10%, or less than 9%, or less than 8%, or less than 7%, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.75%, or less than 0, 5%, or less than 0.2%, or less than 0.1%.

In some embodiments, the concentration of potassium peroxymonosulfate, such as OXONE®, or dialkyl-3-methylpyridine-5,6-dicarboxylate and/or metal halide salt in the reaction solution is maintained at about 1%, 2%, or 5% during the reaction.

In some embodiments, the reaction of 3-methylpyridine-5,6-dialkyl dicarboxylate with potassium peroxymonosulfate, for example OXONE®, and a metal halide salt is carried out in a continuous manner, i.e. Potassium peroxymonosulfate, such as OXONE®, is added slowly, and the concentration of potassium peroxymonosulfate, such as OXONE®, or dialkyl-3-methylpyridine-5,6-dicarboxylate is no more than 1%, 2% or 5% throughout the reaction time.

In some embodiments, any of the bromination reactions described above, the concentration of potassium peroxymonosulfate, such as OXONE®, in the aqueous phase of the reaction mixture is less than 10%, or less than 9%, or less than 8%, or less than 7%, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.75%, or less than 0.5%, or less than 0.2%, or less than 0.1 %.

In some embodiments, any of the bromination reactions described above, the concentration of potassium peroxymonosulfate, such as OXONE®, or dialkyl-3-methylpyridine-5,6dicarboxylate in the reaction solution is less than 10%, or less than 9%, or less than 8%, or less than 7 %, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.75%, or less than 0.5%, or less than 0, 2%, or less than 0.1%.

In some embodiments, any of the bromination reactions described above, the concentration of potassium peroxymonosulfate, such as OXONE®, and/or dialkyl-3-methylpyridine-5,6-dicarboxylate and/or metal halide salt in the solvent used in the reaction is less than 10%, or less than 9%, or less than 8%, or less than 7%, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.75% , or less than 0.5%, or less than 0.2%, or less than 0.1%.

In some embodiments, potassium peroxymonosulfate, such as OXONE®, is gradually added to the reaction flask and/or reactor in one or more portions.

In some embodiments, the metal halide salt is gradually added to the reaction flask and/or reactor in one or more portions.

In some embodiments, the metal halide salt is gradually added to the reaction flask and/or reactor in one or more portions.

In some embodiments, potassium peroxymonosulfate, such as OXONE®, is added dropwise to the reaction flask and/or reactor.

In some embodiments, the metal halide salt is added dropwise to the reaction flask and/or reactor.

In some embodiments, potassium peroxymonosulfate, such as OXONE®, is added to the reaction solution in 1-9 portions.

In some embodiments, the metal halide salt is added to the reaction solution in 1-9 portions.

In some embodiments, any of the bromination reactions described above, the reaction is carried out at a temperature of 60-80°C.

- 16 044234

In some embodiments of any of the bromination reactions described above, the reaction is carried out in the presence of a radical initiator.

The radical initiator includes, but is not limited to, inorganic peroxides, organic peroxides, and azo initiators.

Examples of azo initiators may include, but are not limited to: 2,2'-azo-bis-(2methylpropionitrile) (AIBN); 2,2'-azo-bis-(2-methylbutyronitrile) (VAZO67) and 1,1'-azo-bis-(cyclohexanecarbonitrile) (VAZO88).

Examples of organic peroxides may include, but are not limited to, tert-butyl hydroperoxide and benzoyl peroxide.

Examples of inorganic peroxides may include, but are not limited to, ammonium persulfate and sodium persulfate.

In some embodiments, the metal is an alkali metal or an alkaline earth metal.

In some embodiments, the halogen is a bromide, chloride, iodide, or fluoride.

In some embodiments, the yield in the bromination reaction is greater than 60%, 70%, 80%, or 90%.

In some embodiments, the yield of monobrominated product (IIa) in the bromination reaction is greater than 40%.

In some embodiments, the yield of dibrominated product (IIb) in the bromination reaction is greater than 40%.

In some embodiments, the yield of tribrominated product (IIc) in the bromination reaction is less than 5%.

In some embodiments, the conversion to product in the reaction of 3-methylpyridine-5,6-dialkyl dicarboxylate with OXONE® and the metal halide salt is at least 99.9%.

In some embodiments, the conversion to product in the reaction of 3-methylpyridine-5,6-dialkyl dicarboxylate with OXONE® and the metal halide salt is at least 95%.

In some embodiments, the conversion to product in the reaction of 3-methylpyridine-5,6-dialkyl dicarboxylate with OXONE® and the metal halide salt is at least 90%.

In some embodiments, the conversion to product IIa in the reaction of 3-methylpyridine-5,6-dialkyl dicarboxylate with OXONE® and the metal halide salt is at least 40%.

In some embodiments, the conversion to product IIb in the reaction of 3-methylpyridine-5,6-dialkyl dicarboxylate with OXONE® and the metal halide salt is at least 40%.

The amine may be a nucleophilic amine or a non-nucleophilic amine. In some embodiments, the nucleophilic amine is, but is not limited to, trimethylamine, triethylamine, or pyridine. Examples of non-nucleophilic amines may include, but are not limited to, ethyldiisopropylamine.

In some embodiments, a mixture containing compounds having formula IIb and/or IIc is reacted with a dialkyl phosphite in the presence of an amine.

Dialkyl phosphite includes, but is not limited to, diethyl phosphite (DEP).

In some embodiments, a mixture containing compounds having formula IIb and/or IIc is reacted with a dialkyl phosphite in the presence of a nucleophilic amine to produce compound (IIa), which reacts with a nucleophilic amine to produce compound (III).

In some embodiments, a mixture containing compounds having formula (IIb) and/or (IIc) is reacted with a dialkyl phosphite in the presence of trimethylamine to produce compound (IIa), which reacts with a nucleophilic amine to produce compound (III).

In some embodiments, compound (IIa) is prepared prior to reaction with a nucleophilic amine.

In some embodiments, compound (IIa) is prepared prior to reaction with the amine by reaction with a dialkyl phosphite in the presence of a non-nucleophilic amine.

In some embodiments, the nucleophilic amine is selected from the group consisting of trimethylamine, triethylamine, and pyridine.

In some embodiments, the non-nucleophilic amine is selected from the group consisting of tert-butyldimethylamine, isobutyldimethylamine.

In one embodiment, the nucleophilic amine is triethylamine.

In some embodiments, the amine is a gas.

In some embodiments, the amine is a liquid or solution of a gaseous amine.

In some embodiments, the mixture containing compounds having formula IIb and/or IIc is reacted with an amine and a dialkyl phosphite in a single reaction vessel.

In some embodiments, the reaction of compounds having formula IIb and/or IIc with an amine and a dialkyl phosphite is carried out in the same reaction vessel.

- 17 044234

In some embodiments, a mixture containing compounds having formula IIb and/or IIc is reacted with diethyl phosphite before reacting IIa with the amine, and product IIa is not isolated before reacting with the amine.

In some embodiments, a mixture containing compounds having formula IIa and/or IIb and/or IIc is reacted with diethyl phosphite before reacting IIa with the amine.

In some embodiments, a mixture containing compounds having formula IIa and/or IIb and/or IIc is reacted with diethyl phosphite before reacting IIa with the amine, increasing the amount of IIa, and product IIa is not isolated before reacting with the amine.

In some embodiments, compound IIa is prepared by reacting compound IIb and/or IIc with a dialkyl phosphite in the presence of an amine.

In some embodiments, the reaction of a mixture containing compounds IIa and/or IIb and/or IIc with an amine is carried out in the presence of a solvent.

In some embodiments, the reaction of compound (IIa) with an amine is carried out in the presence of a solvent.

In some embodiments, a mixture containing compounds IIa and/or IIb and/or IIc is reacted with a dialkyl phosphite in the presence of an amine to convert the amount of IIb and IIc present in the mixture to pure compound IIa before forming a tetraalkylammonium salt.

In some embodiments of the amination reaction, the reaction is carried out in the presence of a solvent.

In some embodiments, the reaction of compound (III) with a metal alkoxide base is carried out in the presence of a solvent.

In some embodiments, the reaction of compound (III) with a metal alkoxide base is carried out in the presence of an alcohol solvent.

The solvent includes, but is not limited to, dichloromethane, chloroform, 1,2dichloroethane, perchlorethylene, trichloroethane, chlorobenzene, 2-dichlorobenzene, 3-dichlorobenzene, 4-dichlorobenzene, toluene, xylene, methanol, ethanol, 2-propanol or acetonitrile, benzene , carbon tetrachloride, or any combination thereof.

In some embodiments, any of the amination reactions described above, the reaction is carried out at a temperature between about 0°C and 25°C.

In some embodiments, any of the amination reactions described above, the reaction is conducted at a temperature of about 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80° C, 90°C or 100°C.

In some embodiments, the reaction of a compound having formula (III) with a metal alkoxide base is carried out in the presence of a hydroxy scavenger.

In some embodiments, the reaction of a compound having formula (III) with a metal alkoxide base is carried out in the presence of a solvent. In some embodiments, the solvent is an alcohol solvent.

The solvent is, but is not limited to, methanol or ethanol.

In some embodiments, the reaction of a compound having formula (III) with a metal alkoxide base is carried out under anhydrous conditions.

In some embodiments, the reaction of a compound having formula (III) with a metal alkoxide base is carried out under a nitrogen atmosphere.

In some embodiments, the reaction of a compound having formula (III) with a metal alkoxide base is carried out under an argon atmosphere.

In some embodiments, the solvent is dried before reacting with the metal alkoxide base.

The hydroxide scavenger agent includes, but is not limited to, methyl acetate, ethyl acetate.

The metal in the metal alkoxide base may be an alkali or alkaline earth metal.

The alcohol in the metal alkoxide base may be methanol, ethanol or phenol.

An alkali metal includes, but is not limited to, sodium or potassium.

The alkaline earth metal includes, but is not limited to, magnesium.

In some embodiments, the reaction of a compound having formula (III) with a metal alkoxide base is carried out at a temperature of 50-90°C.

Isolation of compound (I)-(III) can be carried out in a standard manner known to those skilled in the art.

The method described in the present invention has the advantage that it gives the desired product in higher yield with less complex purification.

The method described in the present invention has the advantage that it gives the target product in higher yield in less time, with cheaper and environmentally friendly purification.

- 18 044234

The method described in the present invention has the advantage that it produces the desired product at a lower cost.

The method described in the present invention has the advantage that it avoids the use of toxic reagents, which are undesirable for industrial use due to the risks associated with the use of such reagents.

The method described in the present invention also has the advantage that it can be carried out in a single reaction vessel.

Stage (i).

In the present invention, bromination is a one-step reaction in which 3methylpyridinium-5,6-dialkyl dicarboxylate is converted to the corresponding brominated products using NaBr as a bromine source of more than 90% in one reaction cycle (without workup of the reaction mixture and isolation of the product). When bromine (Br ₂ ) is applied as a bromine source, bromine is converted to bromine anion and only 40% is used in the reaction. Therefore, only 50% conversion is achieved (see, for example, WO 2010/0055139). The present invention uses 80% bromine source. To achieve high conversions, multi-cycle reactions are required. Multicyclic reactions lead to a huge overconsumption of the starting material (excess bromine) and complex processing of the reaction mixture, which produces a huge amount of waste.

The bromination reaction with N-bromosuccinimide using 150% (1.5 eq.) brominating agent provided 70% conversion, while using 1.5 eq. NaBr in the present invention provides a conversion of more than 90%. After 6 cycles of adding oxidant, the conversion is more than 94.0%.

In the present invention, the conversion in the bromination reaction is greater than 90%, without the need to isolate excess starting material and repeat the reaction (taking into account the total amount of mono-, di- and tribrominated products).

The brominated product was found to be stable under the reaction conditions and did not decompose. Both the product and the starting material can undergo hydrolysis at the ester group in an aqueous environment.

In addition, it was unexpectedly found that when the bromination reaction is carried out without light and in the presence of a radical initiator, mainly bromination products are formed with a very limited amount of benzylic oxidation product (see, for example, Moriyama et al., 2012). Surprisingly, it was discovered that both light and OXONE® were required to obtain the oxidation product.

Stage (ii).

This step allows the use of polybrominated by-products and makes it possible to achieve high conversion without requiring the isolation of unreacted starting material, which is essential for low conversion; and higher yields become achievable because polybrominated by-products (mainly dibrominated) result in lower yields if not used.

Stage (iii).

Debromination of the monobrominated intermediate requires the use of a dialkyl phosphite and a base that is not nucleophilic enough to react with the monobrominated intermediate. Since the monobrominated intermediate reacts with a tertiary amine or pyridine derivative in the next step, such a reagent can be used as a debrominating base, allowing both steps to be combined in a single process in a single reaction vessel and eliminating the need for an additional non-nucleophilic base, which can be an expensive reagent.

In addition, in step (iii), where a trapping agent such as methyl acetate is used, the reaction conditions are mild and therefore there is no need to use high temperature or pressure (sealed reactor) to produce the ether product.

In a method for preparing a compound having the structure

O (Im),

- 19 044234 which involves the conversion of dialkyl-3-methylpyridine-5,6-dicarboxylate into a compound having the structure

wherein each R1 is C1-C4 alkyl, the improvement is the conversion of dialkyl-3-methylpyridine-5,6-dicarboxylate to the compound having formula (I) by a method according to any embodiment of the present invention.

In some embodiments, a method is described for preparing a compound having the structure

which includes:

(a) preparing a compound having formula (I)

wherein each R1 is C1- _C4 alkyl, according to any embodiment of the present invention.

In some embodiments, the method further includes:

(b) converting a compound having formula (I) into a compound having formula (Im).

In some embodiments, the method further includes:

(b) converting the diester compound having formula (I) into the corresponding anhydride;

(c) reacting the anhydride with 2-amino-2,3-dimethylbutanenitrile, followed by base-catalyzed condensation to form a compound having formula (Im).

In some embodiments, the method further includes:

(b) converting the diester compound having formula (I) into the corresponding anhydride;

(c) reacting the anhydride with 2-amino-2,3-dimethylbutanenitrile, followed by acid-catalyzed hydrolysis of the nitrile to the primary amide, and then base-catalyzed condensation to form the compound having formula (Im).

In some embodiments, the method further comprises: (b) reacting a diester compound having formula (I) with 2-amino-2,3-dimethylbutyramide to form a compound having formula (Im).

In some embodiments, the method further includes:

(b) reacting a diester compound having formula (I) with 2-amino-2,3-dimethylbutyramide in the presence of a base to form a compound having formula (Im).

In some embodiments, the method further includes:

(b) reacting a diester compound having formula (I) with 2-amino-2,3-dimethylbutyramide in the presence of a base; and (c) acid treatment to form a compound having formula (Im).

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In some embodiments, a method is described for preparing a compound having the structure

which includes:

(a) conversion of a diester compound having formula (I)

wherein each R1 represents a C1- _C4 alkyl prepared according to any embodiment of the present invention to the corresponding diacid under hydrolysis conditions;

(b) converting the diacid product of step (a) into an anhydride having the structure

(c) reacting the anhydride product of step (b) with 2-amino-2,3-dimethylbutanenitrile to form a compound having the structure

(d) reacting the product from step (c) with an acid to form a compound having the structure

(e) reacting the product from step (d) with a base to form a compound having formula ^(Im) .

- 21 044234

In some embodiments, a method is described for preparing a compound having the structure

which includes:

(a) conversion of a diester compound having formula (I)

(I) wherein each R1 represents a C ₁ -C ₄ alkyl obtained according to any embodiment of the present invention to the corresponding diacid under hydrolysis conditions;

(b) converting the diacid product of step (a) into an anhydride having the structure

(c) reacting the anhydride product of step (b) with 2-amino-2,3-dimethylbutanenitrile to form a compound having the structure

(c) reacting the anhydride product of step (b) with 2-amino-2,3-dimethylbutyramide to form a compound having the structure

(d) reacting the product from step (c) with a base to form a compound having formula ^(Im) .

In some embodiments, the use of a compound having formula (I) prepared according to any embodiment of the present invention for the preparation of imazamox is described.

- 22 044234

Method for converting a compound having formula (I)

where each R1 represents C1-C4 alkyl and

R2 is C1- _C4 alkyl, in the corresponding herbicide having the formula

described in the following documents: US 5973154, US 2011/0245506 A1, WO 2010/055042 A1, WO 2010/066669 A1 and/or EP 0166907, the contents of each of which are incorporated herein by reference.

Method for converting a compound having formula (I)

where each R1 represents C ₁ -C ₄ alkyl and

R2 represents methyl, in the corresponding herbicide having the formula

described in the following documents: US 5973154, US 2011/0245506 A1, WO 2010/055042 A1, WO 2010/066669 A1 and/or EP 0166907, the contents of each of which are incorporated herein by reference.

These reactions take place under conditions that ensure the production of the target compound. Such conditions, for example, temperature, reaction time, molar concentration, etc., may be varied by those skilled in the art based on the methods and techniques described herein.

Where ranges are specified in this text, it should be understood that the specified range includes all integer and decimal values included in the range, as well as any subranges. For example, the range from 77 to 90% includes values of 77, 78, 79, 80, 81%, etc.

As used herein, the term approximately, with respect to a stated numerical value, covers the range from +1% to -1% of the stated value. For example, approximately 100 mg/kg includes values of 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9, 100, 100 ,1, 100.2, 100.3, 100.4, 100.5, 100.6, 100.7, 100.8, 100.9 and 101 mg/kg. Accordingly, about 100 mg/kg in one embodiment includes 100 mg/kg.

It should be understood that in cases where a range is specified for a parameter, all integer values and decimal fractions included in that range are also covered by the present invention.

- 23 044234

As used herein, the term alkyl includes branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, _C1Cn , for example in the term _C1 - _Cn alkyl, includes groups containing 1, 2..., n-1 or n carbon atoms in a linear or branched chain, and more specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, secbutyl, etc. Options may include C1 _{- C12} alkyl, _C2 - _C12 alkyl, _C3C12 alkyl, _C4 - _C12 alkyl, etc. Options may include C ₁ -C ₈ alkyl, C ₂ -C ₈ alkyl, C ₃ -C ₈ alkyl, C ₄ -C ₈ alkyl, etc. The term alkoxy means an alkyl group as described above attached via a bridging oxygen atom.

Each embodiment described herein is applicable to each other embodiment described. Thus, all combinations of the various elements described herein are within the scope of the present invention.

The present invention will be better understood by consideration of the experimental data presented below, but those skilled in the art will understand that the specific examples detailed herein are merely illustrative of the present invention, which is more fully described in the claims.

The present invention is illustrated by the following examples, but is not limited to them.

experimental part

Example 1.

Preparation of dimethyl 5,6-dicarboxylate-3-pyridinylmethyl bromide mixture having formula (IIa-c) 3-methylpyridine 5,6-dimethyldicarboxylate (286.8 mmol, 60 g) is heated until completely melted and added to 210 ml 1, 2-dichloroethane. AIBN (3.1 mmol, 0.6 g) was added to the reaction mixture, then 17.3% NaBr in water (118.7 mmol, 70.6 g) was added. The pH value is adjusted to 1.5-2.0 using 98% H ₂ SO ₄ . The reaction mixture is stirred at 70-75°C, adding 169.8 g of 19.3% OXONE® (3.4% H ₂ SO ₄ solution, 106.6 mmol KHSO ₅ ) for 30 minutes. The solution becomes colored. The solution was boiled for 2 hours, then cooled to 25°C. The aqueous phase is discarded.

An additional portion of AIBN (3.1 mmol, 0.6 g) was added to the reaction mixture, then an additional portion of 17.3% NaBr solution (118.7 mmol, 70.6 g) was added. The pH value is adjusted to 1.5-2.0 using 98% H ₂ SO ₄ . The reaction mixture is stirred at 70-75°C, adding another 169.8 g of 19.3% OXONE® (3.4% H ₂ SO ₄ solution, 106.6 mmol) over 30 minutes. The solution becomes colored. The solution was boiled for 2 hours, then cooled to 25°C. The aqueous phase is discarded.

A third portion of AIBN (3.1 mmol, 0.6 g) was added to the reaction mixture, followed by a third portion of 17.3% NaBr solution (118.7 mmol, 70.6 g). The pH value is adjusted to 1.5-2.0 using 98% H ₂ SO ₄ . The reaction mixture is stirred at 70-75°C, adding another 169.8 g of 19.3% OXONE® (3.4% H ₂ SO ₄ solution, 106.6 mmol) over 30 minutes. The solution becomes colored. The solution was boiled for 2 hours, then cooled to 25°C. The aqueous phase is discarded.

A fourth portion of AIBN (3.1 mmol, 0.6 g) was added to the reaction mixture, followed by a fourth portion of 17.3% NaBr solution (118.7 mmol, 70.6 g). The reaction mixture is stirred at 70-75°C, adding another 169.8 g of 19.3% OXONE® (3.4% H ₂ SO ₄ solution, 106.6 mmol) over 30 minutes. The solution becomes colored. The solution was boiled for 2 hours, then cooled to 25°C. The aqueous phase is discarded

A fifth portion of AIBN (3.1 mmol, 0.6 g) was added to the reaction mixture, followed by a fifth portion of 17.3% NaBr solution (118.7 mmol, 70.6 g). The reaction mixture is stirred at 70-75°C, adding another 169.8 g of 19.3% OXONE® (3.4% H ₂ SO ₄ solution, 106.6 mmol) over 30 minutes. The solution becomes colored. The solution was boiled for 2 hours, then cooled to 25°C. The aqueous phase is discarded.

A sixth portion of AIBN (3.1 mmol, 0.6 g) was added to the reaction mixture, followed by a sixth portion of 17.3% NaBr solution (118.7 mmol, 70.6 g). The reaction mixture is stirred at 70-75°C, adding another 169.8 g of 19.3% OXONE® (3.4% H ₂ SO ₄ solution, 106.6 mmol) over 30 minutes. The solution becomes colored. The solution was boiled for 2 hours and then cooled to 25°C. The aqueous phase is discarded. The organic phase is washed with 420 g of 5% NaHCO ₃ solution. The organic phase is washed with 420 g of saturated NaCl solution. The organic phase was dried over MgSO ₄ and filtered. The solvent was evaporated to dryness under reduced pressure, yielding 91.4 g of a viscous brown oil with a conversion of 96.3% (mono-, di- and tribrominated products).

Treat with sodium bisulfite by adding a 20% sodium bisulfite solution until complete neutralization (monitored using potassium iodide indicator paper).

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Table 1

Conversion per cycle [stage (i)]

Cycle no. MPDC-DME BPDC-DME DPDC-DME TPDC-DME 1 73.5% 23.7% 0.9% not onp. 2 50.1% 44.1% 3.8% not onp. 3 30.1% 57.4% 9.9% 0.8% 4 16.8% 61.4% 18.3% 1.0% 5 7.9% 57.8% 29.5% 1.9% 6 2.9% 48.8% 41.4% 3.7%

Reaction with light without an initiator.

Diethyl 3-methylpyridine-5,6-dicarboxylate (5.6 g, 23.6 mmol) was added to 1,2-dichloroethane (40 ml).

KBr (3.4 g, 28.6 mmol) was added to the resulting solution. OXONE® (14.0 g, 45.5 mmol; KHSO ₅ ) and then water (40 g) were added and the reaction mixture was irradiated with a tungsten lamp for 7.5 hours.

Table 2 ________________Conversion during irradiation [stage (i)]________________ ________1.2 eq, KVg, 1.9 eq, OXONE®, 7 hours, 30-40°C________

MPDC______BPDC______DPDC______CPDC

6.8%_________63.9%_________25.3%_________2.3%

Preparation of dimethyl 5,6-dicarboxylate-3-pyridylmethylammonium salt having formula (III).

The brominated mixture IIa-c (88.4 g) is diluted by adding 470 ml of 1,2-dichloroethane. The solution is cooled to 0-5°C and diethyl phosphite (136.9 mmol, 18.9 g) is added, followed by a 33% solution of (CH ₃ ) ₃ N (441.0 mmol, 79.0 g) in EtOH. The reaction mixture is stirred for 0.5 hours at 0-5°C, then heated to 25°C for 1 hour (the reaction mixture is stirred for 6 hours if the reaction is still not complete after adding additional diethyl phosphite (13.8 mmol, 11 .9 g) at 0-5°C, stirring at 25°C for 1 hour and then boiling for 1 hour). The resulting precipitate was dried in vacuo at 50°C, obtaining 77.0 g (221.8 mmol) of product (79.9% yield).

Preparation of dimethyl 5,6-dicarboxylate-3-methoxymethylpyridine (I).

Methyl acetate (1.35 mmol, 1.0 g) and sodium methoxide solution (30% in methanol) (23.88 mmol, 4.3 g) were added to methanol (20 g) under nitrogen atmosphere. The resulting mixture was boiled (60-65°C) for 1 hour, then cooled to 25°C and compound III (12.82 mmol, 5.0 g, 89%) was added. The reaction mixture is stirred at boiling (60-65°C) for 3 hours, then cooled to 10-15°C and acetic acid (1.45 g) is added dropwise over 10 minutes. The solvent is evaporated to dryness under reduced pressure. Add toluene (40 ml) and wash with 20 g of water. The aqueous layer is extracted with 30 ml of toluene and the combined organic phases are washed with 20 g of water. The solvent is evaporated under reduced pressure to obtain 2.7 g of the desired product (87.2% yield, 99.0% purity).

Discussion.

There is a need to develop an improved method for the synthesis of dialkyl-3-alkoxymethyl-5,6-dicarboxylate, an intermediate that is used in the synthesis of the herbicide imazamox.

The method described in the present invention works at atmospheric pressure, with easy-to-handle materials, is highly efficient, cheap and environmentally friendly. None of the currently known methods have these advantages. It has been found that the synthesis of dimethyl 5-(methoxymethyl)pyridine-2,3-dicarboxylate (and related dialkyl-3-alkoxymethyl-5,6-dicarboxylates) according to the synthesis steps described herein can significantly improve the conversion yield of the resulting target product.

Literature:

Kennedy, R. J. et al. (1960) The Oxidation of Organic Substances by Potassium Peroxymonosulfate. J. Org. Chem. 25, 1901.

Liu, Y. et al. (2001) An Efficient Method for the Preparation of Benzylic Bromides. Synthesis 14, 2078.

Moriyama, K. et al. (2014) Selective oxidation of alcohols with alkali metal bromides as bromide catalysts: experimental study of the reaction mechanism. Org. Lett. 79, 6094.

EP 0548532 A1, published June 30, 1993 (Strong).

EP 0166907 A2, published January 8, 1986 (American Cyanamid Company).

US 5760239, issued June 2, 1998 (Wu et al.).

US 5973154, issued October 26, 1999 (Drabb et al.).

US 2011/0245506 A1, published 6 October 2011 (Cortes).

WO 2010/055139 A1, published May 20, 2010 (Gebhardt et al.).

WO 2010/066669 A1, published 17 June 2010 (Rippel).

WO 2010/055042 A1, published 20 May 2010 (Cortes).

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Claims (17)

CLAIM 1. Method for preparing the compound of formula (I) where each R1 represents C1- _C4 alkyl and R2 is C1- _C4 alkyl, including the following steps: (i) reaction of dialkyl-3-methylpyridine-5,6-dicarboxylate with structure r^o ₂ c R-|O ₂ C with potassium peroxymonosulfate and a metal halide salt, where the metal is an alkali or alkaline earth metal, to obtain a mixture containing compounds of formula IIa and/or IIb and/or IIc where n=2 and m=1 (IIa), n=1 and m=2 (IIb) or n=0 and m=3 (IIc); each R1 is C ₁ -C ₄ alkyl and X represents a halogen, (ii) reacting the mixture obtained in step (i) with an amine to obtain a compound of formula (III) where each R1 represents C1- _C4 alkyl; Y+ represents where _R3 , R4 and R5 are each independently C1-C6 alkyl and X is a halogen, (iii) the reaction of the compound of formula (III) obtained in step (ii) with a base that is a metal alkoxide, where the metal is an alkali or alkaline earth metal. 2. The method according to claim 1, wherein step (i) takes place in the presence of a radical initiator selected from inorganic peroxides, organic peroxides and azo initiators, preferably wherein the radical initiator is azobisisobutyronitrile (AIBN), or where in step (i) a radical the reaction is initiated by visible light or ultraviolet radiation or carried out in the presence of visible light or ultraviolet radiation. 3. The method according to claim 1 or 2, where the source of potassium peroxymonosulfate is a triple salt having the formula KHSO5-0.5KHSO4-0.5K2SO4, preferably where potassium peroxymonosulfate is - 26 044234 dii (i) are added to the reaction mixture gradually in two or more portions or where the concentration of potassium peroxymonosulfate in the reaction solution is less than 5 or less than 1%. 4. The method according to any one of claims 1 to 3, where the reaction is carried out in a first suitable solvent selected from dichloromethane, chloroform, 1,2-dichloroethane, perchlorethylene, trichloroethane, chlorobenzene, 2-dichlorobenzene, 3-dichlorobenzene, 4-dichlorobenzene, benzene, carbon tetrachloride or any combination thereof. 5. The method according to any one of claims 3, 4, where the concentration of dialkyl-3-methylpyridine-5,6-dicarboxylate in step (i) in the reaction solution is less than 5% and/or the concentration of the metal halide salt in step (i) in the reaction solution solution less than 5%. 6. Method according to any one of claims 1 to 5, wherein in step (ii) the reaction mixture further contains diethyl phosphite and the amine is a nucleophilic amine or wherein in step (ii) the dihalogenated and trihalogenated products IIb and IIc from step (i) are converted into monohalogenated product IIa before reaction with the amine. 7. The method according to any one of claims 1 to 6, where the amine in step (ii) is trimethylamine; or halogen X is bromide, chloride, fluoride or iodide; or the metal halide salt in step (i) is sodium bromide; or the metal alkoxide in step (iii) is produced from methanol; or step (iii) is carried out in the presence of a hydroxy scavenger; or step (iii) is carried out in the presence of methyl acetate as a hydroxy scavenging agent. 8. Method according to any one of claims 1 to 7, wherein step (i) produces a mixture of the following compounds: (Pa), Vg (IIb), and Vg (Ps). 9. Method according to any one of claims 1 to 8, where the resulting compound of formula (I) has the structure 10. The method according to any one of claims 1 to 9, further comprising step (i)(a) after step (i) and before step (ii), wherein the mixture containing compounds IIa-c from step (i) is reacted with dialkyl phosphite such that the compound of formula IIb-c is converted into a compound of formula IIa. - 27 044234 11. Method for preparing a mixture containing compounds of formula IIa and/or IIb and/or IIc (Pa-s), where X represents halogen; each R1 is C ₁ -C ₄ alkyl; n=2 and m=1 (IIa), n=1 and m=2 (IIb) or n=0 and m=3 (IIc), involving the reaction of dialkyl-3-methylpyridine-5,6-dicarboxylate structure with potassium peroxymonosulfate and a metal halide salt, where the metal is an alkali or alkaline earth metal, in the presence of a radical initiator selected from inorganic peroxides, organic peroxides and azo initiators. 12. Method for preparing the compound of formula (III) where each R1 represents C1-C4 alkyl; Y+ represents where R ₃ , R 4 and R ₅ are each independently C1-C6 alkyl and X is a halogen involving the reaction of a mixture containing compounds of formula IIa and/or IIb and/or IIc where n=2 and m=1 (IIa), n=1 and m=2 (IIb) or n=0 and m=3 (IIc); each R1 is C1- _C4 alkyl and X is a halogen, with a dialkyl phosphite and an amine, where the amine is a nucleophilic amine. - 28 044234 13. The method according to claim 12, where the resulting compound has the structure 14. Method for preparing the compound of formula (I) where each R1 represents C1-C4 alkyl; R ₂ represents C ₁ -C ₄ alkyl, involving the reaction of a compound of formula (III) where each R1 represents C1-C4 alkyl; Y' represents where R ₃ , R4 and R5 are each independently C1-C ₆ alkyl and X is a halogen, with a metal alkoxide base in the presence of a hydroxy scavenger, or with a metal alkoxide base where the metal is an alkali or alkaline earth metal that has been previously treated with a hydroxy scavenger. 15. Method for preparing a compound having the structure - 29 044234 which includes: (i) preparing a compound of formula (I) where each R ₁ represents C1-C4 alkyl and R2 represents C ₁ alkyl, by the method according to any one of claims 1-10 or 14; and (iia) reacting a compound of formula (I) with (R)2-amino-2,3-dimethylbutyramide in the presence of a strong base and a non-polar, substantially water-free solvent to form a salt of the compound of formula (Im) and treating said salt with an aqueous acid with providing a chiral free carboxylic acid of formula (Im); or (iib) converting a diacid of formula (I) into an anhydride having the structure reacting the anhydride from the previous step with 2-amino-2,3-dimethylbutyramide to give a compound having the following structure: and condensing the compound from the previous step to obtain a compound of formula (Im); or (iic) converting a diacid of formula (I) into an anhydride having the structure reaction of the anhydride with 2-amino-2,3-dimethylcarbonitrile to give a compound having the following structure: - 30 044234 hydrolysis of nitrile from the previous stage to obtain an amide of the following structure: n ₃ s base ₃ ' C(O)CN O · and reaction of the amide from the previous step with MOH/CH ₃ OH (where M is an alkali metal selected from Na or K) followed by acidification to form a compound of formula (Im). 16. Method for preparing a compound having the structure which includes: (a) conversion of the diester compound of formula (I) where each R ₁ represents C ₁ -C ₄ alkyl and R2 represents C ₁ alkyl; obtained by the method according to any one of claims 1-10 or 14, into the corresponding diacid under hydrolysis conditions; (b) converting the diacid - the compound of step (a) - into an anhydride having the structure (c) reacting the anhydride of the compound of step (b) with 2-amino-2,3-dimethylbutanenitrile to form a compound having the structure - 31 044234 (d) reaction of the compound from step (c) with an acid to form a compound having the structure (e) reacting the compound from step (d) with a base. 17. Method for preparing a compound of formula (Pa) (Pa), where each R] represents C1-C4 alkyl, involving the reaction of a compound of formula (L-c) (Пь-с), where n=1 and m=2 (Пь) or n=0 and m=3 (Пс); each R is C1-C4 alkyl and X is bromine, with a dialkyl phosphite in the presence of a base. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2