FIELD OF THE INVENTION

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of substituted 2-hydroxypyridine compounds.

BACKGROUND OF THE INVENTION

Substituted 2-hydroxypyridine compounds are valuable intermediates for preparation of halo-containing pyridine heterocycles. Substituted 2-hydroxypyridine compounds, such as 2-hydroxy-3-halo or methylhalopyridine compounds, are useful intermediates for the production of agricultural chemicals, including both insecticides and pesticides.
PCT Publication No. 2008/056677 provides a process for preparation of 2-hydroxy-3-trifluoromethylpyridine by reacting 2-hydroxypyridine with trifluoromethyl iodide.
Chinese Publication No. 103601671 provides a process for preparation of 2-hydroxy-3-trifluoromethylpyridine by hydrolysis of iodine substituted 2-trifluoromethylpyridine.
Thus the prior processes disclose the use of reactants substituted with iodo group. These iodo compounds are very costly and also difficult to prepare. It also results in handling issues at commercial scale.
Therefore, there is an urgent need to develop a commercially viable and cost effective process for preparation of substituted 2-hydroxypyridine compounds.
The present invention provides a commercially viable and cost effective process for preparation of substituted 2-hydroxypyridine compounds with good yield and high purity using simple reagents and less reaction steps.

OBJECT OF THE INVENTION
The object of the present invention is to provide a process for preparation of substituted 2-hydroxypyridine compounds of formula I using improved reaction parameters.

Formula I
wherein R1 is halogen, C1-C3 alkyl group substituted by at least one halogen atom.

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R1 is halogen, C1-C3 alkyl group substituted by at least one halogen atom.
comprising the steps of:
a) contacting a compound of formula II with an activator to form a reaction mixture;

Formula II
b) contacting the reaction mixture obtained from step a) with water to obtain substituted 2-hydroxypyridine compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “C1-C3 alkyl” refers to methyl, ethyl propyl or isopropyl groups.
As used herein, the term “halogen” refers to fluorine, chlorine, bromine and iodine atoms.
As used herein, the term “activator” refers to acid anhydride such as acetic acid anhydride, trifluoroacetic acid anhydride or the like and acyl halides such as acetyl fluoride, acetyl chloride, trifluoroacetyl fluoride, trifluoroacetyl chloride or the like.
The preferred activator used in the present invention is selected from acetic anhydride or trifluoroacetic anhydride.
The acyl halides are either used as activators under pressure or in presence of a solvent selected from chlorinated solvents or polar aprotic solvents such as DMF, DMSO, DMA or the like.
The quantity of activator used in the present invention is selected in a range of 1 to 4 moles with respect to each mole of compound of formula II.
In an embodiment, the quantity of activator is selected in a range of 1 to 3 moles.
The reaction of compound of formula II with activator is carried out at a temperature ranging from 70-140°C.
In a preferred embodiment, the reaction is carried out at a temperature of 70-100°C.
In another embodiment, the activator is used in excess and recycled after the reaction is completed. The use of excess activator eliminates the need of solvent thereby makes the process cost effective. The excess of activator is recovered and reused in the process.
The residue containing acetylated derivative of compound of formula II, obtained by reaction of compound of formula II with activator, is directly converted to compound of formula I by hydrolysing using water without isolating it.
This prevents the possible exposure of said derivative to the environment thereby eliminates the possible formation of undesired impurities.
In an embodiment, the crude compound of formula II is of pale yellow colour. This crude product was dissolved in a mixture of ethyl acetate and hexane (10:90) by heating at a temperature of 70-100°C. The solution thus obtained was cooled to precipitate out pure compound of formula I.
The precipitated product was filtered and dried to get pure compound of formula I.
In an embodiment of the present invention, the purity of compound of formula I is greater than 98%. In another embodiment of the present invention, the purity of the compound of formula I is greater than 99%.
In an embodiment of the present invention, the yield of compound of formula I is greater than 60%. In another embodiment, the yield of the compound of formula I is greater than 80%.
In an embodiment, the conversion of compound of formula II to compound of formula I is carried out without using any solvent.
In another embodiment, the present invention involves recrystallization of the compound of formula I using a mixture of solvents selected from a group consisting of water, methanol, ethanol, isopropanol, n-propanol, ethylacetate, acetone, dichloromethane, chloroform, carbon tetrachloride, pentane, hexane, cyclohexane, heptane, toluene, diethylether or the like.
In another embodiment, the present invention involves recrystallization of the compound of formula I using a mixture of ethylacetate and hexane.
In an embodiment, the present invention provides a one pot process for preparation of a compound of formula I,

Formula I
comprising the steps of:
a) contacting a compound of formula II,

Formula II
with an activator to form a reaction mixture containing acetylated compound of formula II; and
b) recovering the activator from the reaction mixture of step a);
c) contacting the reaction mixture of step b) with water to obtain the compound of formula I.
wherein the whole process is carried out without isolating any intermediate.

In a preferred embodiment, the present invention provides a one pot process for preparation of 2-hydroxy-3-(trifluoromethyl)pyridine,
comprising the steps of:
a) contacting 3-trifluoromethylpyridine-1-oxide with an activator to form a reaction mixture;
b) recovering the activator from the reaction mixture of step a);
c) contacting the reaction mixture of step b) with water to obtain 3-trifluoromethyl-2-hydroxypyridine.
The compound of formula II used as a reactant in present invention can be easily prepared or can be procured commercially.
The activator used is easily available at commercial scale.
The isolation of a compound from the reaction mixture can be performed by the process of extraction, distillation, filtration, decantation, washing, dryings or combination thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), gas chromatography (GS), liquid chromatography (LC) and alike.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example: 1 Preparation of 2-hydroxy-3-(trifluoromethyl)pyridine
3-trifluoromethylpyridine-N-oxide (25g, 0.153mol) and acetic anhydride (289g, 2.83mol) were refluxed for 12 hours. The unreacted acetic anhydride was evaporated and recovered under vacuum. Water (200g, 11.11mol) was added to the residue and the resulting mixture was heated at 100? for 6 hours. The mixture was neutralized with saturated solution of sodium bicarbonate. Product was extracted with ethyl acetate (3*100ml) and dried over rota vapour to get 17.0g of yellow solid crude product. The crude product was further purified by recrystallization in a mixture of ethyl acetate and hexane to get 10g of off white solid product.
Yield: 60 %.
Purity: 99.22 %.

Example: 2 Preparation of 2-hydroxy-3-(trifluoromethyl)pyridine
3-trifluoromethylpyridine-N-oxide (22g, 0.134mol) and trifluoroacetic anhydride (286g, 2.80mol) was refluxed for 15 hours. The unreacted trifluoroacetic anhydride was evaporated and recovered under vacuum. Water (198g, 10.99mol) was added to the residue and the resulting mixture was heated at 80? for 4 hours. The mixture was neutralized with saturated solution of sodium bicarbonate. Product was extracted with ethyl acetate (3*100ml) and dried over rota vapour to get yellow solid crude product, which was further purified by recrystallization in a mixture of ethyl acetate and hexane to get white solid product.
Yield: 60%.
Purity: 98.4 %.

Example: 3 Preparation of 2-hydroxy-3-(trifluoromethyl)pyridine
3-trifluoromethylpyridine-N-oxide (22g, 0.134mol) and acetic anhydride (286g, 2.80mol) was heated to 90 to 100? for 14 hours. The unreacted acetic anhydride was evaporated and recovered under vacuum. Water (208g, 10.99mol) was added to the residue and the resulting mixture was heated at 90? for 4 hours. The mixture was neutralized with saturated solution of sodium bicarbonate. Product was extracted with ethyl acetate (3*100ml) and dried over rota vapour to get yellow solid crude product, which was further purified by recrystallization in a mixture of ethyl acetate and hexane to get white solid product.
Yield: 85%.
Purity: 99.4 %.

CLAIMS:

WE CLAIM:

1. A process for preparation of a compound of formula I,

Formula I
comprising the steps of:
a) contacting a compound of formula II with an activator to form a reaction mixture;

Formula II
wherein R1 is halogen, C1-C3 alkyl group substituted by at least one halogen atom.
b) contacting the reaction mixture obtained from step a) with water to obtain the compound of formula I.
2. The process as claimed in claim 1, wherein the activator is selected from a group consisting of acetic acid anhydride, trifluoroacetic acid anhydride, acetyl fluoride, acetyl chloride, trifluoroacetyl fluoride, trifluoroacetyl chloride or a mixture thereof.
3. The process as claimed in claim 1, wherein the reaction of compound of formula II with activator is carried out at a temperature ranging from 70-140°C.
4. The process as claimed in claim 1, wherein the activator is used in a range of 1 to 4 moles with respect to each mole of compound of formula II.
5. The process as claimed in claim 1, wherein the compound of formula I is obtained with a purity greater than 98%.
6. The process as claimed in claim 1, wherein the compound of formula I is obtained with a yield greater than 80%.
7. The process as claimed in claim 1, wherein the conversion of compound of formula II to compound of formula I is carried out without using any solvent.
8. The process as claimed in claim 1, wherein the conversion of compound of formula II to compound of formula I is carried out one pot without isolating any intermediate in-between.
9. The process in claim 1, wherein the compound of formula I is recrystallized using a mixture of solvents.
10. The process in claim 1, wherein the activator is recovered for further use from the reaction mixture of step a).