PROCESS FOR THE PREPARATION OF TRICHLORO METHYLPYRIDINE
Field of the invention
The present invention provides a process for the preparation of 3-trichloromethyl pyridine of Formula I.
Background of the invention Trichloromethyl aromatic compounds are useful as agricultural intermediates. Trichloromethyl N-heteroaromatic compounds, such as 3-trichloromethyl pyridine, are useful intermediates for the production of agricultural chemicals, including both insecticides and pesticides. PCT Publication No. 2014/198278 provides a process for the preparation of 2,3-dichloro-5-trichloromethyl pyridine by reacting nicotinic acid with phosphorous pentachloride at a temperature of 180°C. The PCT publication No. 2014/198278, also suggests the use of phosphorous pentachloride with chlorine and phosphorous trichloride with chlorine as chlorinating agents. The J. Chem. Soc., Perkin Trans. 1, 1989, 283-287 provides a process for the preparation of 3-trichloromethyl pyridine by reacting nicotinic acid with phosphorous pentachloride followed by heating at 115°C for 72 hours. The above processes suffer from the drawback that the reaction of nicotinic acid and phosphorous pentachloride results in highly exothermic reaction, lump formation due to stirring of reactants in solid form, thereby making the process industrially not feasible. The present inventors have observed that by adding a mixture of phosphorous oxychloride and phosphorous pentachloride instead of phosphorous pentachloride alone to nicotinic acid, the handling becomes easier and the reaction proceeds in a smooth manner thereby making the process industrially feasible. Further, the inventors have observed that when the present invention is carried out at a temperature in the range of 80°C to 130°C the formation of 2,3-dichloro-5-trichloromethyl pyridine of formula V is less than 2%.
3
NClCl3CCl
Formula V
Object of the invention
The object of the present invention is to provide a process for the preparation of 3-trichloromethyl pyridine of Formula I
NCCl3
Formula I
Summary of the invention
The present invention provides a process for the preparation of 3-trichloromethyl pyridine of Formula I, comprising; a) contacting nicotinic acid of Formula II with a mixture of phosphorous oxychloride and phosphorous pentachloride to obtain 3-trichloromethyl pyridine of Formula I, and b) isolating the compound of Formula I from step a).
NCOOH
N
CCl 3
Formula II Formula I
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The present invention also provides a process for the preparation of 3-trichloromethyl pyridine of Formula I having less than 2% of 2,3-dichloro-5-trichloromethyl pyridine of Formula V, comprising; a) contacting nicotinic acid of Formula II with a mixture of phosphorous oxychloride and phosphorous pentachloride to obtain 3-trichloromethyl pyridine of Formula I, and b) isolating the compound of Formula I from step a), wherein the compound of Formula I having less than 2% of 2,3-dichloro-5-trichloromethyl pyridine of Formula V.
N
COOH N
CCl 3
N
C Cl l3C
Cl
Formula I Formula II Formula V
Detailed description of the invention
The present invention provides a process for the preparation of 3-trichloromethyl pyridine of Formula I, comprising; a) contacting nicotinic acid of Formula II with a mixture of phosphorous oxychloride and phosphorous pentachloride to obtain 3-trichloromethyl pyridine of Formula I, and b) isolating the compound of Formula I from step a). N
COOH
N
CCl 3
Formula II Formula I
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The present invention also provides a process for the preparation of 3-trichloromethyl pyridine of Formula I having less than 2% of 2,3-dichloro-5-trichloromethyl pyridine of Formula V, comprising; a) contacting nicotinic acid of Formula II with a mixture of phosphorous oxychloride and phosphorous pentachloride to obtain 3-trichloromethyl pyridine of Formula I, and b) isolating the compound of Formula I from step a), wherein the compound of Formula I having less than 2% of 2,3-dichloro-5-trichloromethyl pyridine of Formula V. N
COOH N
CCl 3
N
C Cl l3C
Cl
Formula I Formula II Formula V
The nicotinic acid is contacted with a mixture of phosphorous pentachloride and phosphorous oxychloride at a temperature from about 80°C to 130°C and for a time period from about 20 hours to 80 hours.
In an aspect, the compound of Formula I is converted to 2-chloro-3-trifluoromethyl pyridine of Formula III by any method known in the art or as disclosed in the present application. In another aspect, the compound of Formula I is converted to 2-hydroxy-3-trifluoromethyl pyridine of Formula IV by any method known in the art or as disclosed in the present application.
NCF3Cl
NCF3OH
Formula III Formula IV
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The compound of Formula II may be obtained commercially or may be prepared by any method known in the art, for example, as disclosed in US 2,295,870.
The compound of Formula I is isolated by any of the methods known in the art, for example, distillation, evaporation, condensation and layer separation or mixture thereof.
The compound of Formula I, as obtained by the process of the present invention, has a purity greater than 96%, preferably greater 98% by gas chromatography.
The term ‘about’ refers to a variation of 10% on the higher and lower side of specified parameter.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examples
Example 1: Preparation of 3-trichloromethylpyridine
Phosphorus oxychloride (50.0g, 0.32 mole) and phosphorus pentachloride (66.4 g, 0.31 mole) were taken in a round bottom flask. Nicotinic acid (20.0 g, 0.16 mole) was added to it. Reaction mass was mixed thoroughly and heated at 115°C for 72 hours. Phosphorus oxychloride was distilled off under reduced pressure and the remaining oily reaction mass was slowly added to ice (200 g). The resulting mixture was basified with 2% sodium hydroxide. The mixture was extracted with dichloromethane (3 x 100 ml). The combined extracts were dried and the solvent was evaporated. The residual oil was distilled to give the title compound.
Yield (%): 50.8
Purity (%): 98.98 (by gas chromatography)
Example 2: Preparation of 3-trifluoromethyl pyridine
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3-trichloromethyl pyridine (250 g, 1.27 mole, feed rate 1.24 g/min), anhydrous hydrogen fluoride (381 g, 190.9 mole, feed rate 1.66 g/min) and oxygen gas (feed rate 40cc /min) were fed in to a tubular reactor packed with pre-activated alumina catalyst (26g) at 350°C. The reactor outlet material was collected in ice-cold water. The collected mixture was basified with potassium hydroxide solution and then extracted with dichloromethane. The organic layer was separated and concentrated to obtain the title compound.
Yield (%): 49.7
Purity (%): 81.03 (by gas chromatography)
Example 3: Preparation of 3-trifluoromethyl pyridine-N-oxide
In a four-neck round bottom flask equipped with a stirrer, a thermometer and a condenser, 3-trifluoromethylpyridine (130g) and acetic acid (325g) were added. To the reaction mass, 30% hydrogen peroxide aqueous solution (150g) was added drop-wise using addition funnel within 30 minutes at temperature in the range of 20°C to 30°C. The temperature of the reaction mass was raised to 80°C to 90°C and the reaction was carried out at that temperature range for 7 hours. After completion of reaction, excess hydrogen peroxide was quenched with sodium sulphite (28g). The reaction mixture was heated under reduced pressure to remove acetic acid. The pH of the reaction mixture was adjusted to 8 using 30% sodium hydroxide solution. The reaction mass was extracted with dichloromethane, and concentrated to obtain 3-trifluoromethyl pyridine-N-oxide.
Yield (%) : 86.2
Purity (%): >99% (by gas chromatography)
Example 4: Preparation of 2-chloro-3-trifluoromethylpyridine In a four neck round bottom flask equipped with magnetic stirrer, thermometer, nitrogen inlet and addition funnel, 3-trifluoromethyl pyridine-N-oxide (115g) and dichloromethane (1516g) were added. The reaction mass was cooled to -30°C. Oxalyl chloride (90g) was added drop-wise within 1 hour to the reaction mass. The reaction mass was stirred for an hour at -30°C. To the reaction mass triethylamine (71.2g) was added drop-wise over a period of one hour. The reaction mass was maintained at the same temperature for 2 hours. After completion of reaction, the reaction mass was quenched in ice-water (1500g) and organic layer was
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separated. The organic layer was washed with saturated sodium bicarbonate solution, dried and concentrated to obtain crude 2-chloro-3-trifluoromethylpyridine (102g). The crude product was then purified by distillation under pressure to get pure 2-chloro-3-trifluoromethylpyridine (90g). Yield (%): 70.3 Purity (%) : 99.25 (by high-performance liquid chromatography)
Example 5: Preparation of 2-hydroxy-3-trifluoromethyl pyridine In a 1000 ml four neck round bottom flask 2-chloro-trifluoromethyl pyridine (62g) dissolved in acetic acid (620g) was taken. Water (62 g) was then added to the reaction mass at 25°C. The reaction mass was heated to 110℃ for 168 hours at atmospheric pressure. The reaction was monitored by high-performance liquid chromatography. After completion of reaction, the reaction mass was cooled to 30°C and was diluted with water (1300 ml). To the reaction mass, 6N aqueous sodium hydroxide was added until a pH between 5 to 6 was reached. The aqueous layer was extracted thrice using ethyl acetate (3*400ml). The upper organic layer was dried over anhydrous sodium sulphate and was concentrated on rota-vapour at 50°C under reduced pressure to give crude product (53g). The crude product was recrystallized with a mixture of ethyl acetate and hexane (150 ml: 550 ml) to give pure 2-hydroxy-3-trifluoromethyl pyridine (44g).
Yield (%): 79%
Purity (%) : >99 (by high-performance liquid chromatography)

We claim:
1. A process for the preparation of 3-trichloromethyl pyridine of Formula I, comprising;
a) contacting nicotinic acid of Formula II with a mixture of phosphorous oxychloride and phosphorous pentachloride to obtain 3-trichloromethyl pyridine of Formula I, and
b) isolating the compound of Formula I from step a).
N
COOH
N
CCl 3
Formula II Formula I
2. A process for the preparation of 3-trichloromethyl pyridine of Formula I having less than 2% of 2,3-dichloro-5-trichloromethyl pyridine of Formula V, comprising; a) contacting nicotinic acid of Formula II with a mixture of phosphorous oxychloride and phosphorous pentachloride to obtain 3-trichloromethyl pyridine of Formula I, and b) isolating the compound of Formula I from step a), wherein the compound of Formula I having less than 2% of 2,3-dichloro-5-trichloromethyl pyridine of Formula V.
N
COOH N
CCl 3
N
C Cl l3C
Cl
Formula I Formula II Formula V
3. The process as claimed in claim 1 or 2, wherein the step a) takes place at a temperature range from 80°C to 130°C.
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4. Use of compound of Formula I, as prepared by claim 1 or 2, for preparation of compound of Formula III and Formula IV.
N
CF3
Cl N
CF3
OH
Formula III Formula IV
5. The process as claimed in claim 1 or 2, wherein the compound of Formula I is isolated by distillation, evaporation, condensation and layer separation or mixture thereof.