The present invention provides a process for preparation of nicotinaldehydes of Formula I,
^\ .CHO
I
H Formula I wherein R is one or more optionally substituted C1-C2 alkyl.
BACKGROUND OF INVENTION
The derivatives of nicotinaldehyde are valuable intermediates for producing active pharmaceutical ingredients and agrochemicals.
WO2008148853A discloses a process for preparation of 6-(trifluoromethyl)nicotinaldehyde by oxidising 6-(trifluoromethyl)pyridin-3-yl)methanol in presence of manganese dioxide in dichloromethane at 0°C.
WO2007110667A discloses a process for preparation of 6-(trifluoromethyl)nicotinaldehyde by reacting a solution of [6-(trifluoromethyl)pyridine-3-yl]methanol in dichloromethane with a mixture of Dess-Martin periodinane in dichloromethane.
The above conventional methods involve manganese dioxide or Dess-Martin periodinane. These reagents are expensive and needs tedious removal treatment which further generates large quantity of effluent. Hence, these processes are not suitable for commercial scale ups due to their cost and large quantity of effluent.
CN112194616A discloses a microwave synthesis for the preparation of 6-trifluoromethylpyridinecarboxaldehyde in presence of sodium hypochlorite solution, sodium bromide, TEMPO and dichloromethane. The reaction is carried

out in a reaction tank using microwave irradiation technology. The said process requires microwave power of 200-450W and large amount of solvents. The molar ratio of solvent is 100-2000 with respect to reactant in the process. Hence, this process is not suitable for commercial scaleups.
The present invention provides an alternative and industrially feasible process for preparation of derivatives of nicotinaldehyde by using minimal quantity of solvents and by avoiding use of microwave technology for preparation of compound of formula I.
OBJECT OF THE INVENTION
The present invention provides an industrially feasible process for preparation of derivatives of nicotinaldehyde of formula I in absence of microwave radiations.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of Formula I,
CHO

Formula I wherein R is one or more optionally substituted C1-C2 alkyl, comprising a step of reacting a compound of Formula II,


Formula II
wherein R is one or more optionally substituted C1-C2 alkyl,
with an oxidising agent in presence of a catalyst and a solvent to obtain the compound of formula I; wherein, the reaction is carried out in absence of microwave radiations.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, R for compound of formula I and II refers to one or more alkyl group optionally substituted with halogen selected from chloro, fluoro, bromo. The optionally substituted alkyl may be selected from trifluoromethyl, difluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, or like.
As used herein, the compound of formula I represents 6-
(trifluoromethyl)nicotinaldehyde, 6-(difluoromethyl)nicotinaldehyde, 6-
[chloro(difluoro)methyl]nicotinaldehyde and 6-
[fluoro(dichloro)methyl]nicotinaldehyde or the like.
As used herein, the compound of Formula II represents [6-
(trifluoromethyl)pyridin-3-yl]methanol, [6-(difluoromethyl)pyridin-3-yl]methanol,
{6-[chloro(difluoro)methyl]pyridin-3-yl}methanol and {6-
[dichloro(fluoro)methyl]pyridin-3-yl}methanol or the like.
The present invention provides a process for preparation of a compound of Formula I, comprising a step of reacting a compound of Formula II with an oxidising agent in presence of a catalyst to obtain the compound of formula I; wherein, the reaction is carried out in absence of microwave radiations.
In an embodiment of the present invention, the oxidising agent is selected from hydrogen peroxide, air, oxygen, and sodium hypochlorite. The oxidising agent may be used in pure form or in solution form.

The molar ratio of the compound of formula II with respect to the oxidising agent is in the range of 1:1.5.
In preferred embodiment, sodium hypochlorite is used as an oxidising agent for preparation of compound of formula I.
In another preferred embodiment, 10% sodium hypochlorite is used as an oxidising agent for preparation of compound of formula I.
In another embodiment of the present invention, the reaction is carried out at a temperature selected in the range from 0°C to 20°C for about 1 to 2 hours.
In another embodiment of the present invention, the solvent used in the process is selected from a group comprising of dichloromethane, toluene, xylene and dimethoxyethane. The molar ratio of solvent with respect to the compound of formula II is selected in the range of 5-15.
In an embodiment, dichloromethane is used as solvent and molar ratio of dichloromethane with respect to compound of formula II is 14.
In an embodiment of the present invention, the catalyst is selected from sodium bromide, sodium bromate, potassium bromate, potassium bromide, 2,2,6,6-tetramethylpiperidin-1-oxyl radical (TEMPO) and a mixture thereof.
In another embodiment, the step of reacting compound of Formula II with an oxidising agent is carried out in presence of catalytic amount of TEMPO or/and mixture of TEMPO with potassium bromide.
The "catalytic amount" of TEMPO refers to molar ratio in the range of 0.001-0.005 with respect to the compound of Formula II.
In preferred embodiment, the catalytic amount of TEMPO refers to 0.001-0.0025 with respect to the compound of Formula II.
The "catalytic amount" of potassium bromide refers to molar ratio selected in the range of 0.1-0.5 w.r.to the compound of Formula II and preferred range is 0.1-0.2.

In an embodiment, preparation of compound of formula I from the compound of formula II is carried out using a mixture of TEMPO and potassium bromide, as catalyst.
The crude product is washed with sodium thiosulfate solution and recrystallized using a solvent selected from alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, tert-butanol, and hydrocarbons selected from hexane, heptane and toluene, and isolated purified compound of Formula I.
In a preferred embodiment, the present invention provides a process for preparation of 6-(trifluoromethyl)nicotinaldehyde, comprising a step of reacting (6-(trifluoromethyl)pyridin-3-yl)methanol with sodium hypochlorite in presence of a catalyst and solvent, wherein the reaction is carried out in absence of microwave radiations.
In a preferred embodiment, the present invention provides a process for preparation of 6-(trifluoromethyl)nicotinaldehyde, comprising a step of reacting (6-(trifluoromethyl)pyridin-3-yl)methanol with 10% sodium hypochlorite in presence of a catalytic mixture of TEMPO and potassium bromide in dichloromethane, wherein the reaction is carried out in absence of microwave radiations.
In a preferred embodiment, the present invention provides a process for preparation of 6-(difluoromethyl)nicotinaldehyde, comprising a step of reacting (6-(difluoromethyl)pyridin-3-yl)methanol with 10% sodium hypochlorite in presence of a catalytic mixture of TEMPO and potassium bromide in dichloromethane, wherein the reaction is carried out in absence of microwave radiations.
The compound of Formula I is obtained with a yield greater than 65% and preferably in the range of 65 to 90%.
The compound of formula I is isolated with a purity greater than 90% and preferably in a range of 90-99%.
In another embodiment, the present invention provides efficient recycling and recovery of solvents, with minimal use of organic solvent. Therefore, it is an

environment friendly process and alternative to the known processes for commercial production of compound of Formula I.
The compound of the present invention can be isolated using various isolation techniques known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
In an embodiment of the present invention, the isolation is conducted by means of filtration followed by vacuum distillation.
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 (GC), liquid chromatography (LC) and alike.
The compound of Formula II used as starting material may be obtained commercially or may be prepared by any method known in the art. The reagents used in the above process are obtained commercially.
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 6-(trifluoromethyl)nicotinaldehyde:
Dichloromethane (170g, 1.98 moles), (6-(trifluoromethyl)pyridin-3-yl)methanol (27.4g, 0.141 moles), 2,2,6,6-tetramethylpiperidin-l-oxyl (0.26g, 0.0014 moles) and aqueous solution of potassium bromide (20%, 8.4g, 0.014 moles) were added

in a reactor at 25-30°C. The reaction mass was cooled to 0-15°C and aqueous solution of sodium hypochlorite (10.3%, 170g, 0.177 moles) was added over 45 minutes at 0-15°C. The reaction mass was stirred for an hour at the same temperature and monitored by GC. After reaction completion, the organic layer was separated and washed with aqueous solution of hydrogen chloride (10%, 68g, 0.186 moles) containing potassium iodide (l.lg, 0.006 moles). The organic layer was further washed with sodium thiosulfate (10%), The solvent was distilled out from organic layer to obtain the crude product (79%, 19.62g). The crude product was recrystallised with isopropyl alcohol/n-heptane (1%) to obtain the purified titled compound.
Purity: 99.4%; Yield: 75%
Example 2. Preparation of 6-(difluoromethyl)nicotinaldehyde
Dichloromethane (1.98 moles), [6-(difluoromethyl)pyridin-3-yl]methanol (0.141 moles), 2,2,6,6-tetramethylpiperidin-l-oxyl (0.0014 moles) and aqueous solution of potassium bromide (20%, 0.014 moles) were added in a reactor at 25-30°C. The reaction mass was cooled to 0-15°C and aqueous solution of sodium hypochlorite (10.3%), 0.177 moles) was added over 45 minutes at 0-15°C. The reaction mass was stirred for an hour at the same temperature and monitored by GC. After reaction completion, the organic layer was separated and washed with aqueous solution of hydrogen chloride (10%, 0.186 moles) containing potassium iodide (0.006 moles). The organic layer was further washed with sodium thiosulfate (10%), The solvent was distilled out from organic layer to obtain the crude product (78%). The crude product was recrystallised with isopropyl alcohol/n-heptane (1%) to obtain the purified titled compound.
Purity: 99.4%; Yield: 70.5%

WE CLAIM

1. A process for preparation of a compound of Formula I,
,CHO

Formula I wherein R is one or more optionally substituted C1-C2 alkyl, comprising a step of reacting a compound of Formula II

Formula II
wherein R is one or more optionally substituted C1-C2 alkyl,
with an oxidising agent in presence of a catalyst and a solvent to obtain the compound of formula I; wherein, the reaction is carried out in absence of microwave radiations.
2. The process as claimed in claim 1, wherein the oxidising agent is selected from a group consisting of hydrogen peroxide, air, oxygen, and sodium hypochlorite.
3. The process as claimed in claim 1, wherein the solvent is selected from a group consisting of dichloromethane, toluene, xylene and dimethoxyethane.
4. The process as claimed in claim 1, wherein molar ratio of solvent with respect to compound of formula II is selected in the range of 5-15.
5. The process as claimed in claim 1, wherein the catalyst is selected from a group consisting of sodium bromide, sodium bromate, potassium bromate, potassium

bromide, (2,2,6,6-tetramethylpiperidin-l-oxyl) radical (TEMPO) and a mixture thereof.
6. The process as claimed in claim 1 and 5, wherein catalyst used is a mixture of potassium bromide and (2,2,6,6-tetramethylpiperidin-l-oxyl) radical (TEMPO).
7. The process as claimed in claim 1, wherein the reaction is carried out at a temperature selected from 0-20°C.