WO2024018354A1

WO2024018354A1 - A process for the synthesis of 4-alkoxy-3-hydroxypicolinic acids and intermediates thereof

Info

Publication number: WO2024018354A1
Application number: PCT/IB2023/057261
Authority: WO
Inventors: Sanjib MAL; Parantap SARKAR; Pranab Kumar Patra; Alexander Guenther Maria KLAUSENER
Original assignee: Pi Industries Ltd.
Priority date: 2022-07-18
Filing date: 2023-07-17
Publication date: 2024-01-25

Abstract

The present invention discloses a process for the synthesis of 4- alkoxy-3-hydroxypicolinic acids of formula (I) from 2-picolinic acid. The present invention further discloses a process for preparation of compounds of formula (iii) from compounds of formula (ii). The present invention also discloses novel intermediate compounds of formula (iii).

Description

Title of the Invention: A PROCESS FOR THE SYNTHESIS OF 4-ALKOXY-3- HYDROXYPICOLINIC ACIDS AND INTERMEDIATES THEREOF

FIELD OF THE INVENTION:

The present invention relates to a process for the synthesis of 4-alkoxy-3-hydroxypicolinic acids. More particularly, the present invention relates to a simple, efficient and cost- effective process for the synthesis of 4-alkoxy-3-hydroxypicolinic acids from 2-picolinic acid. The present invention also relates to novel intermediate compounds that are used for the synthesis of 4-alkoxy-3-hydroxypicolinic acids.

BACKGROUND OF THE INVENTION:

Novel and highly efficacious fungicides that lack cross-resistance against other fungicides are extremely desirable in agriculture, especially for controlling diseases caused by Septoria spp. in cereal crops. The picolinamide class of fungicides has shown such desirable characteristics, and therefore it represents a field of interest in agrochemistry. Fenpicoxamid (Inatreq™) is the first fungicide from the picolinamide class, which was derived from the antifungal natural product UK-2A. Florylpicoxamid is another fungicide from this class that controls a wide range of pathogens including Septoria spp., powdery mildew, Botrytis spp., Anthracnose, Alternaria, scab, Monilinia, and others. A third fungicide from this class, which has been provisionally approved is Metarylpicoxamid.

3-Hydroxy-4-methoxypicolinic acid or 3-hydroxy-4-methoxy-2-picolinic acid (la) is a key building block for the synthesis of picolinamide class related fungicides, e.g., Fenpicoxamid, Florylpicoxamid and Metarylpicoxamid. Therefore, an efficient and scalable process route to obtain 3-hydroxy-4-methoxypicolinic acid from inexpensive raw materials will be of utmost interest.

Several methods for producing 3-hydroxypicolinic acids are disclosed in the prior art, such as:

US Pat. No. 9,353,060 B2 discloses a process for the preparation of 4-alkoxy-3- hydroxypicolinic acids from 2-substituted furans. In this process, 4,6-dibromo-3- hydroxypicolinate esters are prepared from furan-2-yl-aminoacetates in one chemical step by employing a rearrangement reaction involving bromination.

US Pat. No. 9,481 ,651 B2 and its divisional patent US Pat. No. 9,718,783 B2 disclose another process for the preparation of 4-alkoxy-3-hydroxypicolinic acids from furfural. In this approach, 4,6-dibromo-3-hydroxypicolinonitrile was prepared from furfural in a lengthy series of chemical steps selected from cyano-amination, amine salt formation and a rearrangement reaction involving bromination. 4-alkoxy-3-hydroxypicolinic acids are subsequently prepared from 4,6-dibromo-3-hydroxypicolinonitrile in a series of reactions, involving substitution of a bromo substituent, nitrile hydrolysis and reductive removal of the remaining bromo substituent.

US Pat. No. 9,951 ,018 B2 discloses another process for the preparation of 4-alkoxy-3- hydroxypicolinic acids from furfural.

US Pat. No. 10,259,789 B2 discloses a process for the preparation of 4-alkoxy-3- hydroxypicolinic acids from furfural. This process involves Strecker synthesis based on furfural (1 ), followed by an Aza-Achmatowicz reaction to deliver pyridine 3-hydroxy-2- carbonitrile. The hydroxypyridine is then brominated to provide the dibromo pyridine (4), which in the next step is subjected to a regioselective nucleophilic substitution in 4- position to obtain the intermediate 4-methoxy-3-hydroxy-2-cyano pyridine (5). Further debromination and hydrolysis using Zn/KOH afforded the 3-hydroxy-4-methoxy-picolinic acid.

US Pat. No. 10,550,083 B2 discloses a process for the preparation of 4-alkoxy-3- hydroxypicolinic acids from 4,6-dibromo-3-hydroxypicolinonitrile. This process comprises a series of chemical steps, comprising bromo-substitution, nitrile hydrolysis and halogen reduction that are conducted as a one-pot process. 4,6-Dibromo-3-hydroxypicolinonitrile may be prepared from furfural in a series of steps comprising of cyano-amination, amine salt formation and a rearrangement reaction involving bromination.

These processes are known in the prior art, however, there are some disadvantages, for example: (A) multi-step synthesis; (B) hazardous reaction conditions like cyanation using potassium cyanide; (C) highly alkaline hydrolysis; (D) troublesome operations such as extraction and column chromatography, and (E) low yields etc. Further, lithiation reaction in pyridine might result in metalation at positions other than ortho to the “Metal Directing Group”.

There is therefore an urgent need for a simple, and cost-effective process. Such a process should allow for the preparation of 4-alkoxy-3-hydroxypicolinic acids from cheap starting materials and under easily controllable reaction conditions. It should also solve the aforementioned problems associated with processes described in the prior art, and be suitable for large-scale preparation, in terms of simplicity, yield and purity of the product. Further, there is also a need for a process wherein ortho directed metallation is highly desired.

Accordingly, the inventors of the present invention have developed an alternative and cost-effective process for the synthesis of 4-alkoxy-3-hydroxypicolinic acids that addresses the problems associated with the processes reported in the prior art.

OBJECTIVE OF THE INVENTION:

The main objective of the present invention is to provide a process for the synthesis of 4- alkoxy-3-hydroxypicolinic acids of formula (I);

Formula (I) wherein, R¹ is alkyl, preferably Ci-Ce alkyl; Another objective of the present invention is to provide a process for the synthesis of 3- hydroxy-4-methoxypicolinic acid (la) from 2-picolinic acid.

la

Yet another objective of the present invention is to provide a process for the synthesis of compound of formula (iii),

Formula (iii) from the compound of formula (ii),

Formula (ii) Wherein R¹ and R² are independently, alkyl, preferably Ci-Ce alkyl.

Yet another objective of the present invention is to provide a novel compound of formula (iii).

Formula (iii) wherein, R¹ and R² are independently alkyl, preferably Ci-Ce alkyl.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides a process for the synthesis of 4-alkoxy-3- hydroxypicolinic acid of formula (I);

Formula (I) wherein, R¹ is Ci-Ce-alkyl; comprising the steps of: a) reacting 2-picolinic acid with a halogenation reagent, and amidation in the presence of an amine to afford a compound of formula (i);

Formula (i) wherein, X is halogen; R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached to form a heterocyclic ring; b) reacting the compound of formula (i) with an alkali metal alkoxide to afford a compound of formula (ii);

Formula (ii) wherein R¹ is Ci-Ce alkyl; R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached to form a heterocyclic ring; c) reacting the compound of formula (ii) with a lithiation reagent, borylation with a borylation reagent to afford a corresponding pyridine-3-boronic acid, and oxidation of the pyridine-3-boronic acid with an oxidizing agent to afford a compound of formula (iii);

OR¹

C o N

R2^N'R²

Formula (iii) d) subjecting the compound of formula (iii) to hydrolysis, with a hydrolysis reagent to afford the 4-alkoxy-3-hydroxypicolinic acid of formula (I).

In one embodiment, the present invention provides a process for the synthesis of 3- hydroxy-4-methoxy-2-picolinic acid (la), comprising the steps of:

la (a) reacting 2-picolinic acid with a halogenation reagent, and amidation in the presence of /V,/V-diisopropylamine, to afford 4-halo-/V,/V- diisopropylpicolinamide (iaa);

(b) reacting the 4-halo-A/,A/-diisopropylpicolinamide (iaa) with an alkali metal methoxide to afford A/,A/-diisopropyl-4-methoxy-2-picolinamide (iia);

(c) reacting the A/,A/-diisopropyl-4-methoxy-2-picolinamide with a lithiation reagent followed by borylation and oxidation to selectively afford 3-hydroxy-/V,/V- diisopropyl-4-methoxy-2-picolinamide (iiia);

(d) subjecting the 3-hydroxy-A/,A/-diisopropyl-4-methoxy-2-picolinamide to hydrolysis with a hydrolysis reagent to afford 3-hydroxy-4-methoxy-2-picolinic acid (la).

In an embodiment, X in compounds of formula (i) and iaa is a halogen, i.e. X = halogen. Preferably X = F, Cl, Br, I. More preferably, X = Cl, Br, I, and in a preferred embodiment, X = Cl.

In one embodiment, the present invention provides novel compound of formula (iii); OR¹

J^OH

( N

R2^N'R²

Formula (ill) wherein, R¹ is Ci-Ce-alkyl, and R² are independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached to form a heterocyclic ring.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

Figure 1 is a flowchart of the process for the preparation of 4-alkoxy-3-hydroxy-2-picolinic acid (I).

Figure 2 is a flowchart of the process for the preparation of 3-hydroxy-4-methoxy-2- picolinic acid (la).

Figure 3 is a flowchart of the process for the preparation of 3-hydroxy-/V,/V-dialkyl-4- alkoxy-2-picolinamide (iii).

Figure 4 is a flowchart of the process for the preparation of 3-hydroxy-/V,/V-diisopropyl-4- methoxy-2-picolinamide (iiia).

DETAILED DESCRIPTION OF THE INVENTION:

The definitions provided herein for the terminologies used in the present disclosure are for illustrative purposes only and in no manner limit the scope of the present invention disclosed in the present disclosure.

As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method. Carbon-based radical refers to a monovalent molecular component comprising a carbon atom that connects the radical to the remainder of the chemical structure through a single bond. Carbon-based radicals can optionally comprise saturated, unsaturated and aromatic groups, chains, rings and ring systems, and heteroatoms. Although carbonbased radicals are not subject to any particular limit in size, in the context of the present invention they typically comprise 1 to 16 carbon atoms and 0 to 3 heteroatoms. Of note are carbon-based radicals selected from Ci-Ce-alkyl, Ci-Ce-haloalkyl and phenyl optionally substituted with 1 -3 substituents selected from C1-C3 alkyl, halogen and nitro.

The meaning of various terms used in the description shall now be illustrated.

The term “alkyl”, used includes straight-chain or branched Ci to C12 alkyl, preferably Ci to Ce alkyl. Representative examples of alkyl include but not limited to methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1 ,1 -dimethylethyl, pentyl, 1 - methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1 ,1 - dimethylpropyl, 1 ,2-dimethylpropyl, or the different isomers.

The term “hydrolysis reagent” or “hydrolyzing reagent” mean the same thing and can be used interchangeably.

The term "heterocycle" or "heterocyclic" or "heterocyclic ring " includes "aromatic heterocycle" or "heteroaryl bicyclic ring system" and "nonaromatic heterocycle ring system" or polycyclic or bicyclic (spiro, fused, bridged, non-fused) ring compounds in which ring may be aromatic or non-aromatic, wherein the heterocycle ring contains at least one heteroatom selected from N, O, S(0)o-2, and or C ring 10 member of the heterocycle may be replaced by C(=O), C(=S), C(=CR*R*) and C=NR*, * indicates integers.

The term "non-aromatic heterocycle" or "non-aromatic heterocyclic" means three- to fifteen-membered, preferably three- to twelve-membered, saturated or partially unsaturated heterocycle containing one to four heteroatoms from the group of oxygen, nitrogen and sulphur: mono, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three nitrogen atoms and/or one oxygen or sulphur atom or one or two oxygen and/or sulphur atoms; if the ring contains more than one oxygen atom, they are not directly adjacent; for example (but not limited to) oxiranyl, azi ridinyl , oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, 1 ,2,4- oxadiazolidinyl, 1,2,4-thiadiazolidinyl, l,2,4-triazolidin-1 -yl, l,2,4-triazolidin-3-yl, l,2,3- triazolidinyl, 1,3,4-oxadiazolidinyl, 1,3,4-thiadiazolidinyl, 1 ,3,4-triazolidinyl, dihydrofuryl, dihydrothienyl, pyrrolinyl, isoxazolinyl, isothiazolinyl, dihydropyrazolyl, dihydrooxazolyl, dihydrothiazolyl, piperidinyl, pyrazynyl, morpholinyl, thiomorphlinyl, l,3-dioxan-5-yl, tetrahydropyranyl, tetrahydrothienyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl and cycloserines. This definition also applies to heterocyclyl as a part of a composite substituent, for example heterocyclylalkyl etc., unless specifically defined elsewhere.

The total number of carbon atoms in a substituent group is indicated by the "Ci-Cj" prefix where i and j are numbers from 1 to 21. For example, C1-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C2 alkoxyalkyl designates CH3OCH2; C3 alkoxyalkyl designates, for example, CH3CH(OCH3), CH3OCH2CH2 or CH3CH2OCH2; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2 and CH3CH2OCH2CH2. In the above recitations, when a compound of formula (I) is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.

The terms “isolate,” “isolating,” or “isolation” as used herein mean to partially or completely remove the desired product from the other components of a finished chemical process mixture using standard methods such as, but not limited to, filtration, extraction, distillation, crystallization, centrifugation, trituration, liquid-liquid phase separation or other methods known to those of ordinary skill in the art. The isolated product may have a purity that ranges from =50% to = 50% and may be purified to a higher purity level using standard purification methods. The isolated product may also be used in a subsequent process step with or without purification.

The terms chlorinating or chlorination reagent, brominating or bromination reagent or iodinating or iodination reagent can be used in lieu of halogenating or halogenation reagent. A person skilled in the art would understand that a chlorinating reagent would cause chlorination, whereas a bromination reagent or an iodination will lead to bromination and iodination respectively, halogenation being a broader term encompassing chlorination, bromination and iodination. The term amidation as used herein refers to the formation of an amide using an amine as one of the reactants.

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In line with the above defined objectives, the present invention provides a process for the synthesis of 4-alkoxy-3-hydroxypicolinic acids of formula (I);

OR¹ .OH Q _o N

OH

Formula (I) wherein, R¹ is Ci-Ce-alkyl; comprising the steps of: a) reacting a 2-picolinic acid with a halogenation reagent in the presence of a metal halide, and amidation in the presence of an amine to afford a compound of formula (i); x

G N Co

R2^N'R²

Formula (ii) wherein R¹ is Ci-Ce alkyl; R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached form a heterocyclic ring; c) reacting the compound of formula (ii) with a lithiation reagent, borylation with a borylation reagent to afford a corresponding pyridine-3-boronic acid, and oxidation of the pyridine-3-boronic acid with an oxidizing agent to afford compound of formula (iii);

Formula (iii) d) subjecting the compound of formula (iii) to hydrolysis with a hydrolyzing or hydrolysis reagent to afford the 4-alkoxy-3-hydroxypicolinic acid of formula (I).

In the pyridine ring of the compounds with formula (ii) and iia, lithiation can theoretically occur at the three, five and six positions. Surprisingly, in the process of the present invention, it was observed that lithiation selectively occurred at position three of the pyridine ring to afford 3-hydroxy-/V,/V-dialkyl-4-alkoxy-2-picolinamide (iii), 3-hydroxy-/V,/V- diisopropyl-4-methoxy-2-picolinamide (iiia), 3-hydroxy-4-alkoxy-2-picolinic acid (I), and 3- hydroxy-4-methoxy-2-picolinic acid (la). In an embodiment, X in the compounds of formula (i) and iaa is a halogen, i.e. X = halogen. Preferably, X = F, Cl, Br, I, more preferably, X = Cl, Br, I, and in a preferred embodiment, X = Cl. The general process for the synthesis of 4-alkoxy-3-hydroxypicolinic acids of formula (I) as disclosed in the present invention is depicted in the general scheme 1 below: General Scheme: 1

2-Picolinic acid

wherein, X represents halogen, R¹ is Ci-Ce-alkyl, and R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached to form a heterocyclic ring.

In a preferred embodiment, the compound of formula (I) is 3-hydroxy-4-methoxypicolinic acid (la).

In one embodiment, the present invention provides a process for the synthesis of 3- hydroxy-4-methoxypicolinic acid (la)

comprising the steps of: a) reacting 2-picolinic acid with a halogenation reagent, and amidation in the presence of /V,/V-diisopropylamine, to afford 4-halo-A/,A/-diisopropylpicolinamide (iaa);

b) reacting the 4-halo-A/,A/-diisopropylpicolinamide with an alkali metal methoxide to afford A/,A/-diisopropyl-4-methoxy-2-picolinamide (iia);

c) reacting the A/,A/-diisopropyl-4-methoxy-2-picolinamide with a lithiation reagent followed by borylation with a borylation reagent and oxidation with an oxidizing agent to afford 3-hydroxy-A/,A/-diisopropyl-4-methoxy-2-picolinamide (iiia) selectively;

iiia | | d) subjecting the 3-hydroxy-A/,A/-diisopropyl-4-methoxy-2-picolinamide to hydrolysis with a hydrolysis reagent to afford 3-hydroxy-4-methoxy-2-picolinic acid (la).

The halogenation reagent as used in the instant invention, is selected from, but is not limited to phosphorus oxychloride, phosphorus tribromide, phosphorus trichloride, phosphorus triiodide, phosphorus pentachloride, phosphorus oxybromide, phosphorus pentabromide, thionyl chloride, thionyl bromide, oxalyl dichloride, oxalyl dibromide, triphosgene, diphosgene, phosgene, sulfuryl chloride, chlorine, bromine, iodine, tertbutyl hypochlorite, hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, /V-chlorosuccinimide, /V-bromosuccinimide, /V-iodosuccinimide, N- chloroglutarimide, /V-bromoglutarimide, /V-chloro-/V-cyclohexyl-benzenesulfonimide, N- bromophthalimide, 1 ,3-dibromo-5,5-dimethylhydantoin, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, acetyl chloride, carbon tetrabromide and acetyl bromide.

In a preferred embodiment, the halogenation reagent used in step (a) is selected from phosphorus oxychloride, sulfuryl chloride, thionyl chloride, phosgene, diphosgene, or triphosgene. In an embodiment, X in compounds of formula i, and iaa, is a halogen. Preferably, X = F, Cl, Br, I. More preferably, X = Cl, Br, I, and in a preferred embodiment, X = Cl.

In an embodiment, the halogenation reaction in step (a) is carried out in the presence of a metal halide. The metal halide in the halogenation reaction is selected from, but is not limited to lithium chloride, sodium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide and potassium iodide etc.

In a preferred embodiment, the metal halide used in step (a) is selected from sodium chloride, potassium bromide and sodium bromide.

The amine [NH(R²)2: the two R² groups along with the N-atom may form a ring] for the amidation reaction in step (a) is selected from, but is not limited to various mono- and dialkylated amines, cyclic amines, methylamine, dimethylamine, diethylamine, diisopropylamine, di-tert butylamine, dicyclohexylamine, ethyl methylamine, pyrrolidine, 2,5-dimethyl pyrrolidine, morpholine, 3,5-dimethyl-morpholine, piperidine, 2,6-dimethyl- piperidine, piperazin, 2,5-dimethyl-pyrrole, and other cyclic or open chain alkyl amines or mixtures thereof.

Preferably, the amine used in step (a) of the present invention is selected from dimethyl amine, diethyl amine, ethyl methylamine, diisopropylamine, or di-fert butyl amine. In a most preferred embodiment, the amine is diisopropylamine.

The alkali metal alkoxide is represented by MOR¹, wherein M represents alkali metals, namely lithium, sodium or potassium, and R¹ is a Ci-Ce alkyl group. For example, an alkali metal methoxide can be represented as MOCH3, wherein M represents the alkali metals as stated above. Examples of alkali metal alkoxide useful in the present invention include but are not limited to sodium methoxide, sodium ethoxide, potassium fert-butoxide, sodium tert-butoxide, etc.

The preferred alkali metal alkoxide for use in step (b) is selected from sodium methoxide, or sodium ethoxide.

The lithiation reagent useful in the instant invention is selected from but is not limited to organo lithium compounds or alkyl lithium compounds such as n-methyllithium, n- propyllithium, /so-propyllithium, n-butyllithium, sec-butyllithium, fert-butyllithium, n- hexyllithium, cyclohexyllithium, lithium diisopropylamide (LDA) and phenyllithium.

The preferred lithiation reagent for use in step (c) is selected from n-butyllithium, lithium diisopropylamide (LDA) and n-hexyllithium.

In one embodiment of the present invention, borylation is carried out in the presence of an organoboron reagent. The organoboron reagent useful in step (c) is selected from, but is not limited to trimethyl borate, triethyl borate, triisopropyl borate, bis(pinacolato)diboron, triphenyl borate, phenylboronic acid pinacol ester, alkyl pinacol boronic esters and alkyl borates.

In one embodiment of the present invention, the oxidation is carried out in the presence of an oxidizing agent, selected from, but is not limited to manganese dioxide (MnC ), potassium permanganate (KMnC ), nitric acid (HNOs), sodium nitrite (NaNC ), oxygen, hydrogen peroxide, tertiary butyl hydrogen peroxide (TBHP) and sulfuric acid. In a preferred embodiment the oxidizing agent is hydrogen peroxide.

The hydrolysis of the amide can be carried out in the presence of base, acid, or supported acid.

In one embodiment, the hydrolysis reaction in step (d) is carried out in the presence of a basic hydrolyzing or hydrolysis reagent selected from, but not limited to ammonium hydroxide; metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide; metal carbonate, for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, barium carbonate; and a mixture thereof.

In another embodiment, the hydrolysis reaction in step (d) is carried out in the presence of an acidic hydrolysis reagent selected from, but is not limited to acids such as acetic acid, chromic acid, triflic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypochlorous acid, methane sulfonic acid, nitric acid, phosphoric acid, perchloric acid and sulphuric acid. In yet another alternative, the hydrolysis reagent useful in the instant invention may also be selected from, but is not limited to supported acids such as zeolite, SiO2, amberlyst- 15, nafion-h, montmorillonite K10, strong acidic ion exchange resins and other polymer supported acids in a flow or trickle bed reactor.

In a preferred embodiment, the hydrolysis reagent used in step (d) is selected from sulphuric acid or hydrochloric acid.

The suitable solvents as used in any of the process steps (a) to (d) of the present invention are selected from, but are not limited to aliphatic, alicyclic or aromatic hydrocarbons such as, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, toluene, xylene or decalin; aliphatic, alicyclic or aromatic halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; ethers such as diethylether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxy ethane, 1 ,2-diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile; esters such as methyl acetate, ethylacetate, propyl acetate, ethyl acetoacetate or benzyl benzoate; amides such as /V,/V-dimethylformamide, N,N- dimethylacetamide, /V-methyl formanilide, /V-methylpyrrolidone or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane; alcohols such as methanol, ethanol, isopropanol, polyethylene glycols; water and mixtures thereof.

The preferred solvents used in step (a) are selected from aliphatic, alicyclic or aromatic hydrocarbons such as, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, toluene, xylene, decalin, and mixtures thereof.

The preferred solvents used for the alkoxylation reaction (step-b) are alcohols selected from methanol, ethanol, isopropanol, polyethylene glycols, mixtures thereof and the like.

The preferred solvents used for lithiation and borylation reaction (step-c) are selected from ethers such as diethylether, diisopropylether, methyl tert-butylether, methyl tert- amylether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1 ,2-dimethoxyethane, 1 ,2- diethoxyethane, anisole, and mixtures thereof; or nitriles such as acetonitrile, propionitrile, n- or /so-butyronitrile and benzonitrile, and mixtures thereof. The hydrolysis reaction in step (d) is carried out in a solvent selected from, but not limited to water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile or a mixture thereof. Preferably, the hydrolysis reaction is carried out in water.

In one embodiment, the present invention provides a process for the preparation of compound of formula (iii),

OR¹

X .OH

( o

N

_RXR₂

Formula (iii) wherein, R¹ and R² are independently Ci-Ce-alkyl, and R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached form a heterocyclic ring; comprising the steps of: a) reacting A/,A/-dialkyl-4-alkoxy-2-picolinamide (ii) with a lithiation reagent followed by borylation with a borylation reagent to afford the corresponding pyridine-3-boronic acid compound; b) oxidizing the pyridine-3-boronic acid compound in the presence of an oxidizing agent to afford a compound of formula (iii). In another embodiment, R¹ and R² are independently Ci-Ce-alkyl in the molecule of formula (iii).

In a preferred embodiment, the compound of formula (iii) is 3-hydroxy-/V,/V-diisopropyl-4- methoxy-2-picolinamide (iiia).

In one embodiment, the present invention provides a novel compound of formula (iii),

OR¹ ZXOH ( X N

R^{2 N}'R² Formula (iii) wherein, R¹ and R² are independently Ci-Ce-alkyl, R² is independently Ci-Ce-alkyl, or the two R² groups together with the N-atom to which they are attached form a heterocyclic ring. In another embodiment, R¹ and R² are independently Ci-Ce-alkyl, in the molecule of formula (iii).

In yet another embodiment, R¹ and R² are independently ethyl, methyl, n-propyl, or iso- propyl.

In a preferred embodiment R¹ is methyl and R² is /so-propyl.

The compound of formula (ill) is used for the synthesis of 4-alkoxy-3-hydroxypicolinic acid compounds of formula (I).

In an embodiment there is provided a process for the preparation of the compound of formula (iiia),

Formula (iiia); comprising the steps of: a) reacting A/,A/-diisopropyl-4-methoxy-2-picolinamide (iia) with a lithiation reagent followed by borylation with a borylation reagent to afford a corresponding pyridine-3-boronic acid; b) oxidizing the pyridine-3-boronic acid with an oxidizing agent to afford a compound of formula (iiia).

The 4-alkoxy-3-hydroxypicolinic acids of formula (I) prepared by the process of the present invention are used for the synthesis of picolinamide class of fungicides viz. fenpicoxamid, florylpicoxamid and metarylpicoxamid. In one embodiment, the present invention provides a process usable for the synthesis of fenpicoxamid from the compounds of formula (I).

In one embodiment, the present invention provides a process usable for the synthesis of florylpicoxamid from the compound of formula (I). In one embodiment, the present invention provides a process usable for the synthesis of metarylpicoxamid from the compound of formula (I).

In an embodiment, the above process further comprises the following step;

Wherein (#) represents the point of attachment of R³ to the Oxygen atom. Halogenation of the 2-picolinic acid (1 molar equivalent) in step a is conducted using about 0.05 to 1 molar equivalent of a metal halide, preferably 0.15 molar equivalent of the metal halide, and 1 to 10 molar equivalent of halogenation reagent, preferably 5 molar equivalent of the halogenation reagent. The halogenation reaction is conducted at a temperature of between 25 and 100 °C, preferably between 65 to 85 °C, and more preferably at a temperature of 75 °C. Thereafter, the amidation reaction in step (a) is conducted using about 1 to 5 molar equivalent of the amine, preferably 2.5 molar equivalent of the amine. The amidation reaction is conducted at a temperature in the range of -10 to 50 °C, more preferably at a temperature in the range of -2 to 27 °C, and most preferably at 0 °C.

Alkoxylation of the 4-halo-/V,/V-dialkyl-2-picolinamide (1 molar equivalent) in step (b) is conducted using about 1 to 10 molar equivalent of the metal alkoxide, preferably 5 molar equivalent of the metal alkoxide. The reaction was carried out at a temperature in the range of 20 to 80 °C, more preferably in the range of 50 to 70 °C, and most preferably at a temperature of 55 to 65 °C.

Lithiation of the /V,/V-dialkyl-4-alkoxy-2-picolinamide (1 molar equivalent) or molecule of formula (ii) (1 molar equivalent) in step (c) is conducted using about 1 to 5 molar equivalent of lithiation reagent, preferably 2.5 molar equivalent of the lithiation reagent. Lithiation is carried out at a temperature of between 30 to -80 °C, preferably from -80 to 0 °C, more preferably at a temperature in the range of -80 to -50 °C, still more preferably at a temperature in the range of -65 to -80 °C, and most preferably at a temperature in the range of -75 to -65 °C. Thereafter, the borylation reaction is conducted using about 1 to 10 molar equivalent of the borylation reagent, preferably 3 molar equivalent of the borylation reagent. The borylation reaction was carried out at a temperature of above -75 °C, more preferably at a temperature in the range of -65 to 50 °C, and most preferably in the range of -65 to 25 °C. Thereafter, the oxidation reaction in step (c) is conducted using 1 to 10 molar equivalent of the oxidizing agent, preferably 5 molar equivalent of the oxidizing agent. The oxidation reaction was carried out at a temperature in the range of - 10 to 50 °C, more preferably at a temperature in the range of -5 to 40 °C, and most preferably in the range of 0 to 25 °C.

Hydrolysis of the 3-hydroxy-/V,/V-dialkyl-4-alkoxy-2-picolinamide (1 molar equiv.) is conducted using about 1 to 20 molar equivalents of an acid, preferably 9.5 to 10 molar equivalents of an acid. The hydrolysis reaction was carried out at a temperature in the range of 0 to 150 °C, more preferably at a temperature in the range of 25 to 120 °C, and most preferably at 80 to 120 °C.

The processes as disclosed in the present invention are preferably carried out batch-wise. However, semi-continuous, continuous, or flow reaction passages are also possible. The processes disclosed in the present invention can be run in the absence of a solvent or in the presence of one or more solvents. When used, the solvents should be resistant against oxidation (i.e., a solvent will be preferred, whose stability against oxidation is substantially higher than that of the compounds of formula I, la, i, ia, ii, iia, ill, iiia, iaa, iiiaa) and suitable for suspending, or preferably dissolving the reactants.

The solvent can, likewise be separated off by means of conventional techniques, for example by distillation, and can, if desired, be recycled. The product can be purified in a manner known to any person skilled in the art, for instance by distillation or crystallization.

Following completion of the reaction, typical post-processing operations or product purification may be performed. There are no particular limitations on the purification method used, and conventional methods such as distillation, recrystallization or column chromatography may be used.

The isolation of the reaction product can be carried out by a technique which includes but is not limited to decantation, filtration, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography and the like or a combination thereof.

The process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under increased or reduced pressure. To achieve pressures greater than atmospheric pressure, the continuous flow reactor, and in particular instances the microreactor, may be equipped with one or more pumps (e.g., peristaltic HPLC pumps to deliver various reagents to the reactor) and one or more back pressure regulators (to restrict the flow). As will be appreciated by those of skill in the art, by performing reactions under high pressure, it is possible to perform such reactions at temperatures above the normal boiling point of any solvents (or starting materials or additives) employed in the continuous flow process. Accordingly, increased reaction rates may be obtained. Additionally, the use of elevated pressures and temperatures may facilitate conversion of starting materials to products, without the need for additives or promoters. The reaction time is not critical and depends on the batch size, temperature, reagent and solvent employed. Typically, the reaction time may vary from a few minutes to several hours.

Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product by filtration, and optionally washing with solvent, further optionally drying of the product if required.

The process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to carry out the reaction under increased or reduced pressure.

Figure 1 represents a flow chart of an embodiment of the present invention for the preparation of 3-hydroxy-4-alkoxy-2-picolinic acid (I). Step a: 2-picolinic acid is halogenated with a halogenation reagent in the presence of a metal halide. Thereafter, the resulting 4-halo-picolinoyl halide is subjected to amidation in the presence of an amine to afford 4-halo-A/, /V-dialkylpicolinamide (i) (10). Step b: Next, the 4-halo-/\Z, /- dialkylpicolinamide (i) is reacted with an alkali metal alkoxide to afford N, /V-dialkyl-4- alkoxy-2-picolinamide (ii) (20). Step c: After that, /,/\/-dialky l-4-al koxy-2-picolinamide (ii) is reacted with a lithiation reagent, followed by borylation and oxidation to afford 3- hydroxy-/V,/\/-dialkyl-4-alkoxy-2-picolinamide (iii) (30). Step d: Finally, the 3-hydroxy-/\/,/\/- dialkyl-4-alkoxy-2-picolinamide is subjected to hydrolysis to afford 3-hydroxy-4-alkoxy-2- picolinic acid (I) (40).

Figure 2 represents a flow chart of an embodiment of the present invention for the preparation of 3-hydroxy-4-methoxy-2-picolinic acid (la). Step a: 2-picolinic acid is halogenated with a halogenation reagent in the presence of a metal halide. Thereafter, the resulting 4-halo-2-picolinoyl halide (iab) is subjected to amidation in the presence of diisopropylamine to afford 4-halo-A/, /V-diisopropylpicolinamide (iaa) (110). Step b: The 4- halo-/V,/V-diisopropylpicolinamide (iaa) is then reacted with an alkali metal methoxide to afford /V,/V-diisopropyl-4-methoxy-2-picolinamide (iia) (120). Step c: After that, N,N- diisopropyl-4-methoxy-2-picolinamide (iia) is reacted with a lithiation reagent, followed by borylation and oxidation to afford 3-hydroxy-/V,/V-diisopropyl-4-methoxy-2-picolinamide (iiia) (130). Step d: Finally, the 3-hydroxy-/V,/V-diisopropyl-4-methoxy-2-picolinamide (iiia) is subjected to hydrolysis to afford 3-hydroxy-4-methoxy-2-picolinic acid (la) (140).

Figure 3 represents a flow chart of an embodiment of the present invention for the preparation of 3-hydroxy-/V,/V-dialkyl-4-alkoxy-2-picolinamide (iii). Step a: the N, /V-dialkyl- 4-alkoxy-2-picolinamide (ii) is reacted with a lithiation reagent, followed by reaction with a borylation reagent to obtain a corresponding pyridine-3-boronic acid (230). Step b: The pyridine-3-boronic acid is subjected to oxidation to obtain 3-hydroxy-A/, /-dialkyl-4-alkoxy-

2-picolinamide (iii).

Figure 4 represents a flow chart of an embodiment of the present invention for the preparation of 3-hydroxy-/V,/V-diisopropyl-4-methoxy-2-picolinamide (iiia). Step a: the /V,/V-diisopropyl-4-methoxy-2-picolinamide (iia) is reacted with a lithiation reagent, followed by reaction with a borylation reagent to obtain a corresponding pyridine-3- boronic acid (330). Step b: The pyridine-3-boronic acid is subjected to oxidation to obtain

3-hydroxy-/V,/V-diisopropyl-4-methoxy-2-picolinamide (iiia) (340).

It is apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The starting materials according to the present invention are known compounds that are commercially available or can be prepared in a known manner.

Examples:

The following examples are therefore to be interpreted as merely illustrative and not limiting of the disclosure in any way whatever.

Example 1 : Synthesis of 4-methoxy-3-hydroxypicolinic acid (la). a) Step 1 : Synthesis of 4-chloro-/V,/V-diisopropylpicolinamide (ia); 2-Pi

colinic acid

To a mixture of 2-picolinic acid (100 g, 812 mmol, 1 equiv.) and sodium bromide (12.5 g, 122 mmol, 0.15 equiv.), thionyl chloride (483 g, 4061 mmol, 5 equiv.) was added at 27 °C. The reaction mixture was refluxed at 75 °C for 24 h. After completion, the reaction mixture was cooled to 25 °C and excess thionyl chloride was distilled off via a downward distillation under reduced pressure to obtain 4-chloropicolinoyl chloride (iab). To an ice cold solution of 4-chloropicolinoyl chloride (iab) in toluene (1000 mL), a solution of N,N- diisopropylamine (205 g, 205 mmol, 2.5 equiv.) in toluene (500 mL) was added dropwise over a period of 30 min under a nitrogen atmosphere, and the reaction mixture was stirred further for 2-3 h. After completion, 1 N HCI (1000 mL) was added slowly to the reaction mixture, which was further stirred for 10-15 min. The reaction mixture was extracted with ethyl acetate (3x500 mL); the combined organic layer was washed with saturated aq. sodium bicarbonate solution (1000 mL), followed by brine (500 mL). The combined organic phase was concentrated under reduced pressure to obtain 4-chloro-/V,/V- diisopropylpicolinamide (ia) (198 g, yield = 89 %, assay by qNMR = 87.68 %) as a white solid. ¹H NMR (400 MHz, CDCI₃): 6 8.44 (dd, J = 5.5 Hz, 0.7 Hz, 1 H), 7.44 (dd, J = 2.1 Hz, 0.7 Hz, 1 H), 7.27 (dd, J = 5.5 Hz, 2.1 Hz, 1 H), 3.78 (m, 1 H), 3.52 (m, 1 H), 1 .53 (d, J - 6.7 Hz, 6H), 1.16 (d, J - 6.7 Hz, 6H) ppm. ¹³C NMR (100MHz, CDCI3): 6 167.3, 157.6, 149.5, 144.9, 123.9, 122.5, 50.7, 46.1 , 20.6 (2 carbons), 20.3 (2 carbons) ppm. MS: m/z 240.9 [M+H]⁺. b) Step 2: Synthesis of /V,/V-diisopropyl-4-methoxy-2-picolinamide (iia);

To a stirred solution of 4-chloro-/V,/V-diisopropylpicolinamide (ia) (100 g, 364 mmol, 1 equiv.) in methanol (1000 mL), sodium methoxide (100 g, 1821 mmol, 5 equiv.) was added portion-wise over a period of 15 min under stirring at 27 °C. The reaction mixture was refluxed under nitrogen for 18-20 h. After completion, the reaction mixture was cooled to 25 °C and methanol was evaporated under reduced pressure. The reaction mixture was poured into ice-cold water (1000 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layer was evaporated under reduced pressure to obtain N,N- diisopropyl-4-methoxy-2-picolinamide (iia) as a white powder (89.8 g, yield = 96 %, qNMR assay - 92.34 %). ¹H-NMR (400 MHz, CDCI₃): 58.25 (dd, J - 5.9 Hz, 0.5 Hz, 1 H), 6.82 (dd, J - 2.2 Hz, 0.5 Hz, 1 H), 6.69 (dd, J - 5.9 Hz, 2.2 Hz, 1 H), 3.61 (s, 3H), 3.76-3.61 (m, 1 H), 3.43 (m, 1 H), 1.58 (s, 1 H), 1.43 (d, J- 6.7 Hz, 6H), 1 .15 (d, J- 6.7 Hz, 6H) ppm. ¹³C NMR (100 MHz, CDCI3): 5168.5, 166.2, 158.0, 149.8, 110.1 , 107.3, 55.2, 50.5, 45.8, 21.2 (2 carbons), 20.5 (2 carbons) ppm. MS: m/z 237.30 [M+H]⁺. c) Step 3: Synthesis of 3-hydroxy-/V,/V-diisopropyl-4-methoxypicolinamide (iiia);

To a solution of A/,A/-diisopropyl-4-methoxy-2-picolinamide (iia) (100 g, 389 mmol, 1 equiv.) in tetrahydrofuran (1500 mL), n-butyllithium (2.5M in cyclohexane, 389 mL, 973 mmol, 2.5 equiv.) was added slowly under nitrogen at -75 °C. After complete addition, the reaction mixture was stirred below -65 °C for 1 h. Then, triisopropyl borate (121 g, 1 168 mmol, 3 equiv.) was added dropwise to the reaction mixture at the same temperature. After stirring for 15 min, the reaction mixture was gradually warmed to 25 °C and further stirred for 1 .5 h. The reaction mixture, containing the corresponding pyridine boronic acid (iiiaa) was cooled again to 0 °C and 30% aq. hydrogen peroxide (221 g, 1947 mmol, 5 equiv.) was added dropwise maintaining the reaction temperature below 5 °C, followed by stirring at 25 °C for 4 h. The reaction mixture was cooled to 0 °C and the pH of the solution was adjusted to 6.5 - 7 with 1 N hydrochloric acid (1000 mL). Ethyl acetate (600 mL) was added to the mixture, which was then quenched by the addition of solid sodium thiosulphate (386 g) and further stirred for 1 h at 27 °C. The solid precipitate thus obtained was filtered to afford the desired compound as a white solid. The organic layer was separated and the aq. layer was extracted with ethyl acetate (2x400 mL). The organic layer was combined and concentrated under reduced pressure and the crude product was washed with acetonitrile (100 mL). The solid was collected via filtration followed by drying under reduced pressure to obtain 3-hydroxy-A/,A/-diisopropyl-4-methoxy-2- picolinamide (iiia) as an off white solid (95 g, yield = 91 %, assay by qNMR = 94.39 %). ¹H NMR (400 MHz, DMSO-d₆): 69.33 (s, 1 H), 7.91 (d, J - 5.5 Hz, 1 H), 6.98 (d, J - 5.5 Hz, 1 H), 3.86 (s, 3H), 3.53 (m, 2H), 1.41 (d, J - 6.7 Hz, 6H), 1.05 (d, J - 6.7 Hz, 6H) ppm. ¹³C NMR (100MHz, DMSO-d₆): 6 166.6, 153.8, 144.5, 141.3, 139.1 , 107.1 , 55.8, 50.1 , 44.6, 20.34 (2 carbons), 20.30 (2 carbons) ppm. MS: m/z 253.35 [M+H]⁺. d) Step 4: Synthesis of 3-hydroxy-4-methoxy-2-picolinic acid (la);

To a solution of sulfuric acid (679 g, 3464 mmol, 9.5 equiv.) in water (188 mL) at 25 °C, 3-hydroxy-A/,A/-diisopropyl-4-methoxy-2-picolinamide (iiia) (100 g, 365 mmol, 1 equiv.) was added portion wise. After complete addition, the reaction mixture was heated at 120 °C for 16 h. On completion, the reaction mixture was cooled to 0 °C and pH was adjusted to 3 - 3.5 by dropwise addition of aq. 4.5 N sodium hydroxide. The obtained solid was isolated via filtration and washed with water (200 mL) followed by drying under reduced pressure to obtain 3-hydroxy-4-methoxy-2-picolinic acid (la) (46.45 g, yield - 68.90 %, qNMR assay - 91.37 %) as a white powder. HPLC and NMR data of the product (la) showed formation of a single product, i.e., 3-hydroxy-4-methoxy-2-picolinic acid (la). ¹H NMR (400 MHz, DMSO-d₆): 617.0 (brs, 1 H), 14.5 (brs, 1 H), 8.03 (d, J- 6.4 Hz, 1 H), 7.39 (d, J - 6.4 Hz, 1 H), 4.03 (s, 3H) ppm. ¹³C NMR (100 MHz, DMSO-d₆): 6 164.2, 162.1 , 152.5, 132.4, 126.6, 109.2, 57.4 ppm. MS: m/z 169.60 [M+H]⁺.

The advantages of the processes to prepare 3-hydroxy-4-alkoxy-2-picolinic acid (I), 3- hydroxy-4-methoxy-2-picolinic acid (la), A/,A/-dialkyl-3-hydroxy-4-alkoxy-2-picolinamide (iii), or A/,A/-diisopropyl-3-hydroxy-4-methoxy-2-picolinamide (iiia) are as follows:

1. The process uses abundant and commercially cheap starting material, i.e. 2- piconolic acid.

2. Selective lithiation at position three of the pyridine ring is achieved with excellent yield. This results in the exclusive formation of /V,/V-dialkyl-3-hydroxy-4-alkoxy-2- picolinamide (iii), and A/,A/-diisopropyl-3-hydroxy-4-methoxy-2-picolinamide (iiia), without the formation of other regioisomers.

3. As step c results in the regioselective formation of /V,/V-dialkyl-3-hydroxy-4-alkoxy- 2-picolinamide (iii), or A/,A/-diisopropyl-3-hydroxy-4-methoxy-2-picolinamide (iiia), pure 3-hydroxy-4-alkoxy-2-picolinic acid (I), or 3-hydroxy-4-methoxy-2-picolinic acid (la), is obtained in step d.

4. No chromatographic purification is involved in any of the process steps.

Claims

Claims:

1 . A process for the synthesis of 4-alkoxy-3-hydroxypicolinic acids of formula (I);

Formula (I) wherein, R¹ is Ci-Ce alkyl; comprising the steps of: a) reacting 2-picolinic acid with a halogenation reagent, and amidation in the presence of an amine to afford a compound of formula (i);

Formula (i) wherein, X is halogen; R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached form a heterocyclic ring; b) reacting the compound of formula (i) with an alkali metal alkoxide to afford a compound of formula (ii);

Formula (ii) wherein R¹ is Ci-Ce alkyl; R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached form a heterocyclic ring; c) reacting the compound of formula (ii) with a lithiation reagent, borylation with a borylation reagent to afford a corresponding pyridine-3-boronic acid, and oxidation of the pyridine-3-boronic acid with an oxidizing agent to afford compound of formula (iii); and

OR¹ .OH

( ,

N

R^{2 N}'R²

Formula (iii) d) subjecting the compound of formula (iii) to hydrolysis with a hydrolysis reagent to afford the 4-alkoxy-3-hydroxypicolinic acid of formula (I). A process for the synthesis of 3-hydroxy-4-methoxy-2-picolinic acid (la), comprising the steps of:

(a) reacting 2-picolinic acid with a halogenation reagent, and amidation in the presence of /V,/V-diisopropylamine, to afford 4-halo-/V,/V- diisopropylpicolinamide (iaa);

(b) reacting the 4-halo-A/,A/-diisopropylpicolinamide (iaa) with an alkali metal methoxide (MOCH3) to afford A/,A/-diisopropyl-4-methoxy-2-picolinamide (iia);

(c) reacting the A/,A/-diisopropyl-4-methoxy-2-picolinamide (iia) with a lithiation reagent followed by borylation with a borylation reagent and oxidation with an oxidizing agent to afford 3-hydroxy-A/,A/-diisopropyl-4-methoxy-2-picolinamide (iiia); and

(d) subjecting the 3-hydroxy-A/,A/-diisopropyl-4-methoxy-2-picolinamide (iiia) to hydrolysis with a hydrolysis reagent to afford 3-hydroxy-4-methoxy-2-picolinic acid (la). A process for the preparation of the compound of formula (iii),

OR¹

( o N

R^{2 N}'R²

Formula (ill) wherein, R¹ and R² are independently Ci-Ce-alkyl, R² is independently Ci-Ce-alkyl, or the two R² groups together with the N atom to which they are attached form a heterocyclic ring; comprising the steps of: a) reacting /V,/V-dialkyl-4-alkoxy-2-picolinamide (ii) with a lithiation reagent followed by borylation with a borylation reagent to afford the corresponding pyridine-3-boronic acid; and b) oxidizing the pyridine-3-boronic acid compound in the presence of an oxidizing agent to afford a compound of formula (iii). A process for the preparation of the compound of formula (iiia),

Formula (iiia); comprising the steps of: a) reacting A/,A/-diisopropyl-4-methoxy-2-picolinamide (iia) with a lithiation reagent followed by borylation with a borylation reagent to afford a pyridine- 3-boronic acid; and b) oxidizing the pyridine-3-boronic acid with an oxidizing agent to afford a compound of formula (iiia). The process as claimed in claim 1 or claim 2, wherein the halogenation reaction in step a is carried out in the presence of a metal halide. The process as claimed in claim 5, wherein the metal halide is selected from sodium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide and potassium iodide. The process as claimed in claim 1 or claim 2, wherein the amine used in step (a) is selected from mono- and dialkylated amines, cyclic amines, methylamine, dimethylamine, diethylamine, diisopropylamine, di-tert butylamine, dicyclohexylamine, ethyl methylamine, pyrrolidine, 2,5-dimethyl pyrrolidine, morpholine, 3,5-dimethyl-morpholine, piperidine, 2,6-dimethyl-piperidine, and piperazine.

8. The process as claimed in claim 7, wherein the amine used in step (a) is selected from dimethyl amine, diethyl amine, ethyl methylamine, di-/so-propylamine, and di- tert butyl amine.

9. The process as claimed in claim 1 or claim 2, wherein the halogenation reagent is selected from phosphorous oxychloride, sulfuryl chloride, thionyl chloride, phosgene, diphosgene, and triphopsgene.

10. The process as claimed in claim 1 or claim 2, wherein the alkali metal alkoxide is MOR¹, wherein M represents an alkali metal, wherein the alkali metal can be lithium, sodium or potassium, and R¹ is Ci-Ce alkyl.

11 .The process as claimed in any of the claims 1 to 4, wherein the lithiation reagent is selected from organo lithium compounds, alkyl lithium compounds such as n- methyllithium, n-propyllithium, iso-propyllithium, n-butyllithium, sec-butyllithium, fert-butyllithium, n-hexyllithium, cyclohexyllithium; lithium diisopropylamide (LDA) and phenyllithium.

12. The process as claimed in claim 11 , wherein the lithiation reagent is selected from n-butyllithium, lithiumdiisopropylamide (LDA), and n-hexyllithium.

13. The process as claimed in any of the claims 1 to 4, wherein the borylation reagent is selected from trimethyl borate, triethyl borate, triisopropyl borate, triphenyl borate, bis(pinacolato)diboron, phenylboronic acid pinacol ester, alkyl pinacol boronic esters and alkyl borates.

14. The process as claimed in any of the claims 1 to 4, wherein the oxidation is carried out in the presence of an oxidizing agent selected from manganese dioxide (MnC ), potassium permanganate (KMnCk), nitric acid (HNOs), sodium nitrite (NaNC ), oxygen, hydrogen peroxide, tertiary butyl hydrogen peroxide (TBHP) and sulfuric acid.

15. The process as claimed in claim 14, wherein the oxidizing agent is hydrogen peroxide. 16. The process as claimed in claim 1 or claim 2, wherein the hydrolysis reagent is a base, acid, or supported acid.

17. The process as claimed in 16, wherein the hydrolysis reagent is an acid selected from sulphuric acid and hydrochloric acid.

18. The process as claimed in any of the claims 1 to 4, wherein the lithiation reagent is reacted with the compound of formula (ii) at a temperature in the range of 30 to -80 °C.

19. A compound of formula (iii);

Formula (iii) wherein, R¹ and R ² are independently Ci-Ce-alkyl, R² is independently Ci-Ce- alkyl, or the two R² groups together with the N atom to which they are attached form a heterocyclic ring.

20. The compound as claimed in claim 19, wherein R¹ and R ² are independently Ci- Ce-alkyl.

21 . The compound as claimed in claim 19, wherein R¹ and R² are independently ethyl, methyl, n-propyl, or /so-propyl.

22. The compound as claimed in claim 19, wherein R¹ is methyl and R² is /so-propyl.

23. The process as claimed in claim 1 or claim 2, wherein the process further comprises;