WO1998050362A1 - Preparation of 2,5-dichloro-(3-trifluoromethyl)pyridine - Google Patents

Preparation of 2,5-dichloro-(3-trifluoromethyl)pyridine Download PDF

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WO1998050362A1
WO1998050362A1 PCT/US1998/009146 US9809146W WO9850362A1 WO 1998050362 A1 WO1998050362 A1 WO 1998050362A1 US 9809146 W US9809146 W US 9809146W WO 9850362 A1 WO9850362 A1 WO 9850362A1
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pyridine
trifluoromethyl
dichloro
process according
hydrazino
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PCT/US1998/009146
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French (fr)
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Alexander Paiyung Fung
Jimmy Jui Tai
James William Ringer
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Dow Agrosciences Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to a novel method of preparing 2 , 5-dichloro-3- (trifluoromethyl) pyridine, which is a valuable halopyridine chemical intermediate.
  • the invention includes a process for the preparation of 2 , 5-dichloro-3- (trifluoromethyl) pyridine which comprises the consecutive steps of
  • Alcohols such as 2-propanol
  • chlorinated hydrocarbons such as dichloromethane
  • organic solvents such as dichloromethane
  • Sodium hypochlorite is often preferred as the oxidizing agent in the second step and it is often preferred to use sodium hydroxide to keep the medium alkaline .
  • the compound 2 5-dichloro-6-hydrazino-3- (tri- fluoromethyl) pyridine is novel and is another embodiment of the invention.
  • the first chemical reaction of the process is surprising in that it produces the desired intermediate, 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine, as a highly predominant product instead of producing approximately equal amounts of it and its undesired isomer, 2 , 3-dichloro-6-hydrazino-5- (trifluoromethyl) - pyridine or producing a predominance of the undesired isomer.
  • the ratio of desired 2 , 5-dichloro-6-hydrazino-3- - (trifluoromethyl) pyridine to undesired 2 , 3-dichloro-6- -hydrazino-5- (trifluoromethyl) pyridine in the mixture initially obtained in the hydrazination reaction is at least 10:1 and is sometimes as high as 35:1.
  • the ratio of desired isomer to undesired isomer in the product recovered in the process is at least 10:1 and is often as high as 200:1, depending on the method of recovery employed.
  • the first chemical reaction of the process is generally carried out by contacting 2 , 3 , 6-trichloro-5-
  • auxiliary acid acceptor base is a base that neutralizes acids, but is not otherwise reactive under the reaction conditions.
  • Suitable bases include alkali metal carbonates, tertiary amines, and pyridine compounds.
  • Alkali metal hydroxides can also be used if they are added at a rate slower than the rate of reaction of the hydrazine with 2,3,6-tri- chloro-5- (trifluoromethyl) pyridine and, as a consequence, are neutralized quickly by hydrazine hydrochloride present in the mixture.
  • Tertiary aliphatic amines such as triethylamine, are sometimes preferred.
  • Hydrazine in any form, including the compound per se, hydrazine hydrate, or hydrazine generated in si tu by adding a base to a hydrazine salt can be used. The use of 1.05 to 1.6 moles of hydrazine and up to 1.2 mole of an auxiliary base is sometimes preferred.
  • the reaction is generally carried out in an organic solvent in which both 2 , 3 , 6-trichloro-5- (tri- fluoromethyl) pyridine and hydrazine have at least some solubility and which is not reactive with other reagents in the mixture under the reaction conditions.
  • Organic solvents that have been found to be useful for the reaction include alcohols, such as 2-propanol, n-butanol, and 2-methoxy-l-methylethanol ; hydrocarbons, such as toluene and xylene; chlorocarbons, such as tetrachloro- ethylene, dichloromethane, carbon tetrachloride, and chlorobenzene; ethers, such as 1, 2 -dimethoxyethane, dioxane, and tetrahydrofuran; esters, such as ethyl acetate; nitriles, such as acetonitrile; and the like. Alcohol solvents, such as 2-propanol, are often preferred.
  • the reaction is generally carried out at a temperature sufficiently high that the reaction takes place in a reasonable amount of time, but not so high that the critically important selectivity is lost. Temperatures of 0°C to 100°C have been found to be suitable. Temperatures of 15°C to 80°C are typically preferred. The reaction generally takes from 30 minutes to 16 hours depending on the solvent and the temperature employed.
  • the 2 , 5-dichloro-6-hydrazino-3- (trifluoro- methyl) pyridine produced in the first reaction of the process can be recovered by conventional means, such as by extracting out the by-product salts with water and then, in the case of water insoluble solvents, removing the solvents by evaporation under reduced pressure and, in the case of water soluble solvents, collecting the insoluble solids that form by filtration or centri- fugation.
  • water soluble solvents it is often beneficial to remove at least a portion of the solvent by distillation before dilution with water. A portion of the undesired isomer that is formed in the process is typically removed from the product recovered when aqueous recovery methods are used.
  • the reaction is generally carried out in a medium consisting essentially of an aqueous alkaline solution; that is, an aqueous medium that has a pH greater than 7.0.
  • An alkali metal or alkaline earth hydroxide is typically added to ensure that the mixture remains alkaline throughout the reaction time.
  • Approximately one mole of the hydroxide compound per mole of hydrazinopyridine compound is usually added, but the only important thing is that the medium remain alkaline.
  • Sodium hydroxide is usually preferred as the hydroxide compound.
  • An inert, water-immiscible organic solvent can be and typically is used in conjunction with the aqueous solvent .
  • An alkali metal or alkaline earth hypochlorite salt compound is generally used as the oxidizing agent.
  • Sodium hypochlorite is generally preferred and is often used in the form of household or industrial bleach.
  • the hypochlorite salts used can be prepared by the addition of chlorine to an aqueous alkali or alkaline earth hydroxide solution either prior to their addition to the reaction mixture or, under some circumstances, in si tu .
  • the reaction requires one mole of hypochlorite ion (1 molar equivalent of hypochlorite salt) per mole of 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine and at least one molar equivalent is typically used. It is generally preferred to use 1.0 to 1.5 molar equivalents of hypochlorite salt per mole of hydrazinopyridine compound.
  • Suitable organic solvents for the second reaction step of the process are those that are inert under the reaction conditions, are immiscible with water, and in which 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine and 2 , 5-dichloro-3- (trifluoromethyl) - pyridine are at least somewhat soluble.
  • Solvents that can be used include hydrocarbons, such as toluene and xylene; chlorocarbons, such as tetrachloroethylene, chloroform, dichloromethane, 1, 2-dichloroethane, and chlorobenzene; esters, such as ethyl acetate; nitriles, such as acetonitrile; and the like.
  • hydrocarbons such as toluene and xylene
  • chlorocarbons such as tetrachloroethylene, chloroform, dichloromethane, 1, 2-dichloroethane, and chlorobenzene
  • esters such as ethyl acetate
  • nitriles such as acetonitrile
  • Dichloromethane is sometimes preferred.
  • the reaction is generally carried out by adding an aqueous hypochlorite salt solution to 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine suspended or at least partially dissolved in water or an inert organic solvent or a mixture of water and an inert organic solvent.
  • An aqueous alkali or alkaline earth metal hydroxide solution can be added to the 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine/solvent mixture before the addition of the hypochlorite salt solution, simultaneously with it, or subsequent to it, to assure that the mixture remains alkaline during the reaction period. It is often preferred to mix an aqueous alkaline solution with an aqueous hypochlorite salt solution and to add the mixture obtained to the 2 , 5-dichloro-6-
  • hypochlorite salt solution is generally made slowly so that the concentration of hypochlorite ion in the reaction medium does not build up appreciably.
  • the procedure for carrying out the reaction by forming the hypochlorite salt in si tu would involve the addition of chlorine slowly and with good agitation to a mixture of an aqueous alkaline solution and the 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine/solvent mixture.
  • the reaction of the second step is generally carried out at a temperature of between 0°C and 70 °C. Temperatures between 10 °C and 40 °C are generally preferred and it is often convenient to carry out the reaction at between 20°C and 30°C.
  • the reaction is mildly exothermic and cooling is generally employed to keep the reacting mixture at the desired temperature.
  • the major product of the process, 2 5-dichloro- -3- (trifluoromethyl) pyridine can be recovered by conventional means.
  • the aqueous phase is separated from the organic phase by decantation or other suitable means.
  • Sodium or potassium bisulfite is often advantageously added before the separation to decompose any excess hypochlorite salt. It is, further, often advantageous to make the aqueous phase acidic with an inorganic acid, such as hydrochloric acid, or an organic acid, such as formic acid before phase separation.
  • Any organic solvents or other lower boiling constituents present are then, typically, removed by evaporation or by distillation leaving 2 , 5-dichloro-3- (trifluoromethyl) - pyridine in a partially purified form as a residue.
  • the 2, 5-dichloro-3- (trifluoromethyl) pyridine obtained can be purified by conventional means, such as by distillation under reduced pressure, if desired.
  • the resulting mixture was twice extracted with 500 mL of dichloromethane and the combined extracts were washed with 500 mL of water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure.
  • the residue was distilled through a 5-plate Oldershaw column at 20 mm (millimeter) Hg (2.7 kilo- Pascals) to obtain 268 g (95 percent of theory) of the title compound.
  • the title compound has a boiling point of 107-108°C under 25 mm Hg (3.3 kiloPascals) pressure and is typically obtained as a colorless liquid that solidifies on standing to a white solid melting at 52 °C.
  • iH NMR (CDCI3) ⁇ ppm (tetramethylsilane) : 8.48(s); 19p NMR (hexafluorobenzene) 0 ppm: -98.2 (s).
  • Triethylamine (96 g) was added to a solution of 200 g of 2 , 3 , 6-trichloro-5- (trifluoromethyl) - pyridine in 800 mL of 2-propanol with stirring at 25 °C and then 60 g of hydrazine hydrate was added slowly with cooling as required to maintain a 25 °C temperature. The reaction mixture was stirred at 25°C for another 8 hours to allow the reaction to complete. Water (1.6 L) was added slowly to the resulting slurry over a 2 -hour period to dissolve the triethylamine hydrochloride salt and to cause the product to precipitate.
  • a 5.25 percent aqueous solution of sodium hypochlorite (110 mL, 80 mmol) was added to a mixture of 20 g (81 mmol) of 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine, 155 mL of tetrachlorethylene, and 75 mL of IN aqueous sodium hydroxide solution over a 20-min period with stirring at ambient temperature. There was a small exotherm and gas evolution. After stirring 2 hours, the phases were separated. The organic phase was filtered, washed with dilute aqueous hydrochloric acid, dried over sodium sulfate, and concentrated by evaporation under reduced pressure.

Abstract

The compound 2,5-dichloro-3-(trifluoromethyl)pyridine is prepared economically and in good yield by the regio-selective reaction of 2,3,6-trichloro-5-(trifluoromethyl)pyridine with hydrazine to produce the intermediate 2,5-dichloro-6-hydrazino-3-(trifluoromethyl)pyridine and the subsequent reaction of this intermediate with a hypochlorite salt, such as sodium hypochlorite.

Description

PREPARATION OF 2 , 5-DICHLORO- (3 -TRIFLUOROMETHYL) PYRIDINE
The present invention relates to a novel method of preparing 2 , 5-dichloro-3- (trifluoromethyl) pyridine, which is a valuable halopyridine chemical intermediate.
The use of 2 , 5-dichloro-3- (trifluoromethyl) - pyridine as an intermediate to prepare potent herbicides and fungicides was disclosed in, for example, U.S. Patent 4,491,648, U.S. Patent 5,185,342 and EP Application 760363, published March 5, 1997. The commercial develop- ment of agricultural and pharmaceutical products derived from this compound as an intermediate, however, has been impeded because of its lack of availability.
No convenient and economical method of preparation of 2 , 5-dichloro-3- (trifluoromethyl) pyridine has been reported. The chlorination of 3- (trifluoromethyl) pyridine in the vapor phase was disclosed in U.S. Patent 4,448,967 to produce a mixture of chlorinated 3- (trifluoromethyl) pyridine compounds, ten percent of which was 2 , 5-dichloro-3- (trifluoromethyl) pyridine . The preparation of 2 , 5-dichloro-3- (trifluoromethyl) pyridine from trichloroacetaldehyde and - (trifluoromethyl) acrylo- nitrile by a cyclization process was disclosed in U.S. Patent 4,469,896. This process requires a starting material that is not readily available and a high yield would not be expected based on the disclosed information.
A method of replacing some chloro substituents on some pyridine compounds with hydrogen by means of the conversion of the chloropyridine compound to a hydrazino- pyridine compound and subsequent treatment of the hydrazinopyridine compound obtained with sodium hypochlorite was disclosed in U.S. Patent 4,127,575. Mixtures of products were obtained when chloropyridine compounds containing two or more differently oriented reactive chloro substituents were used.
The discovery of a commercially attractive method for the preparation of 2 , 5-dichloro-3- (trifluoro- methyl) pyridine would be highly desirable.
It has now been found that 2 , 5-dichloro-3- (tri- fluoromethyl) pyridine can be prepared simply and in high yield by sequential treatment of 2 , 3 , 6-trichloro-5- (tri- fluoromethyl) pyridine with hydrazine and an oxidizing agent. The process is surprisingly selective, very little isomeric 2 , 3-dichloro-5- (trifluoromethyl) pyridine being produced as a by-product.
The invention includes a process for the preparation of 2 , 5-dichloro-3- (trifluoromethyl) pyridine which comprises the consecutive steps of
1) contacting 2 , 3 , 6-trichloro-5- (trifluoromethyl) - pyridine with hydrazine and, optionally, an auxiliary acid acceptor base in an inert organic solvent at a temperature of between 0°C and 100°C to obtain 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine, and
2) contacting 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine with an alkali metal or alkaline earth hypochlorite salt in a medium comprising an aqueous alkaline solution and, optionally, an inert, water- -immiscible organic solvent.
Alcohols, such as 2-propanol, are typically preferred as solvents in the first reaction step and chlorinated hydrocarbons, such as dichloromethane, are typically employed as organic solvents in the second reaction step. Sodium hypochlorite is often preferred as the oxidizing agent in the second step and it is often preferred to use sodium hydroxide to keep the medium alkaline .
The compound 2 , 5-dichloro-6-hydrazino-3- (tri- fluoromethyl) pyridine is novel and is another embodiment of the invention.
The preparation of 2 , 5-dichloro-3- (trifluoromethyl) pyridine (Formula I):
Figure imgf000005_0001
by the process of the present invention involves two chemical reactions, a first reaction wherein 2,3,6-tri- chloro-5- (trifluoromethyl) pyridine (Formula II):
Figure imgf000005_0002
is converted to 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine (Formula III) :
Figure imgf000005_0003
and a second reaction wherein 2 , 5-dichloro-6-hydrazino-3- - (trifluoromethyl) pyridine is converted to 2 , 5-dichloro- -3- (trifluoromethyl) pyridine.
The first chemical reaction of the process is surprising in that it produces the desired intermediate, 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine, as a highly predominant product instead of producing approximately equal amounts of it and its undesired isomer, 2 , 3-dichloro-6-hydrazino-5- (trifluoromethyl) - pyridine or producing a predominance of the undesired isomer. The ratio of desired 2 , 5-dichloro-6-hydrazino-3- - (trifluoromethyl) pyridine to undesired 2 , 3-dichloro-6- -hydrazino-5- (trifluoromethyl) pyridine in the mixture initially obtained in the hydrazination reaction is at least 10:1 and is sometimes as high as 35:1. The ratio of desired isomer to undesired isomer in the product recovered in the process is at least 10:1 and is often as high as 200:1, depending on the method of recovery employed.
The first chemical reaction of the process is generally carried out by contacting 2 , 3 , 6-trichloro-5-
- (trifluoromethyl) pyridine with hydrazine and, when less than two of hydrazine per mole of chloropyridine compound of Formula II is used, an auxiliary acid acceptor base. Excellent results are obtained when either at least 2 moles of hydrazine is used per mole of 2 , 3 , 6-trichloro-5- - (trifluoromethyl) pyridine or at least one mole of hydrazine and at least one mole of an auxiliary acid acceptor base are used. A suitable auxiliary acid acceptor base is a base that neutralizes acids, but is not otherwise reactive under the reaction conditions.
Suitable bases include alkali metal carbonates, tertiary amines, and pyridine compounds. Alkali metal hydroxides can also be used if they are added at a rate slower than the rate of reaction of the hydrazine with 2,3,6-tri- chloro-5- (trifluoromethyl) pyridine and, as a consequence, are neutralized quickly by hydrazine hydrochloride present in the mixture. Tertiary aliphatic amines, such as triethylamine, are sometimes preferred. Hydrazine in any form, including the compound per se, hydrazine hydrate, or hydrazine generated in si tu by adding a base to a hydrazine salt, can be used. The use of 1.05 to 1.6 moles of hydrazine and up to 1.2 mole of an auxiliary base is sometimes preferred.
The reaction is generally carried out in an organic solvent in which both 2 , 3 , 6-trichloro-5- (tri- fluoromethyl) pyridine and hydrazine have at least some solubility and which is not reactive with other reagents in the mixture under the reaction conditions. Organic solvents that have been found to be useful for the reaction include alcohols, such as 2-propanol, n-butanol, and 2-methoxy-l-methylethanol ; hydrocarbons, such as toluene and xylene; chlorocarbons, such as tetrachloro- ethylene, dichloromethane, carbon tetrachloride, and chlorobenzene; ethers, such as 1, 2 -dimethoxyethane, dioxane, and tetrahydrofuran; esters, such as ethyl acetate; nitriles, such as acetonitrile; and the like. Alcohol solvents, such as 2-propanol, are often preferred.
The reaction is generally carried out at a temperature sufficiently high that the reaction takes place in a reasonable amount of time, but not so high that the critically important selectivity is lost. Temperatures of 0°C to 100°C have been found to be suitable. Temperatures of 15°C to 80°C are typically preferred. The reaction generally takes from 30 minutes to 16 hours depending on the solvent and the temperature employed.
The 2 , 5-dichloro-6-hydrazino-3- (trifluoro- methyl) pyridine produced in the first reaction of the process can be recovered by conventional means, such as by extracting out the by-product salts with water and then, in the case of water insoluble solvents, removing the solvents by evaporation under reduced pressure and, in the case of water soluble solvents, collecting the insoluble solids that form by filtration or centri- fugation. In the case of water soluble solvents, it is often beneficial to remove at least a portion of the solvent by distillation before dilution with water. A portion of the undesired isomer that is formed in the process is typically removed from the product recovered when aqueous recovery methods are used.
In the second reaction of the process,
2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine is converted into 2 , 5-dichloro-3- (trifluoromethyl) pyridine by means of a suitable oxidizing agent. Nitrogen gas is evolved.
The reaction is generally carried out in a medium consisting essentially of an aqueous alkaline solution; that is, an aqueous medium that has a pH greater than 7.0. An alkali metal or alkaline earth hydroxide is typically added to ensure that the mixture remains alkaline throughout the reaction time. Approximately one mole of the hydroxide compound per mole of hydrazinopyridine compound is usually added, but the only important thing is that the medium remain alkaline. Sodium hydroxide is usually preferred as the hydroxide compound. An inert, water-immiscible organic solvent can be and typically is used in conjunction with the aqueous solvent .
An alkali metal or alkaline earth hypochlorite salt compound is generally used as the oxidizing agent. Other water soluble hypochlorite salts and water soluble oxidizing agents that are equivalent in terms of oxidizing power, including copper II salts and silver I oxide, can be used as well. Sodium hypochlorite is generally preferred and is often used in the form of household or industrial bleach. The hypochlorite salts used can be prepared by the addition of chlorine to an aqueous alkali or alkaline earth hydroxide solution either prior to their addition to the reaction mixture or, under some circumstances, in si tu . The reaction requires one mole of hypochlorite ion (1 molar equivalent of hypochlorite salt) per mole of 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine and at least one molar equivalent is typically used. It is generally preferred to use 1.0 to 1.5 molar equivalents of hypochlorite salt per mole of hydrazinopyridine compound.
Suitable organic solvents for the second reaction step of the process are those that are inert under the reaction conditions, are immiscible with water, and in which 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine and 2 , 5-dichloro-3- (trifluoromethyl) - pyridine are at least somewhat soluble. Solvents that can be used include hydrocarbons, such as toluene and xylene; chlorocarbons, such as tetrachloroethylene, chloroform, dichloromethane, 1, 2-dichloroethane, and chlorobenzene; esters, such as ethyl acetate; nitriles, such as acetonitrile; and the like. Dichloromethane is sometimes preferred.
The reaction is generally carried out by adding an aqueous hypochlorite salt solution to 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine suspended or at least partially dissolved in water or an inert organic solvent or a mixture of water and an inert organic solvent. An aqueous alkali or alkaline earth metal hydroxide solution can be added to the 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine/solvent mixture before the addition of the hypochlorite salt solution, simultaneously with it, or subsequent to it, to assure that the mixture remains alkaline during the reaction period. It is often preferred to mix an aqueous alkaline solution with an aqueous hypochlorite salt solution and to add the mixture obtained to the 2 , 5-dichloro-6-
-hydrazino-3- (trifluoromethyl) pyridine . The addition of hypochlorite salt solution is generally made slowly so that the concentration of hypochlorite ion in the reaction medium does not build up appreciably. The procedure for carrying out the reaction by forming the hypochlorite salt in si tu, would involve the addition of chlorine slowly and with good agitation to a mixture of an aqueous alkaline solution and the 2 , 5-dichloro-6- -hydrazino-3- (trifluoromethyl) pyridine/solvent mixture.
The reaction of the second step is generally carried out at a temperature of between 0°C and 70 °C. Temperatures between 10 °C and 40 °C are generally preferred and it is often convenient to carry out the reaction at between 20°C and 30°C. The reaction is mildly exothermic and cooling is generally employed to keep the reacting mixture at the desired temperature.
The major product of the process, 2 , 5-dichloro- -3- (trifluoromethyl) pyridine can be recovered by conventional means. Typically, the aqueous phase is separated from the organic phase by decantation or other suitable means. Sodium or potassium bisulfite is often advantageously added before the separation to decompose any excess hypochlorite salt. It is, further, often advantageous to make the aqueous phase acidic with an inorganic acid, such as hydrochloric acid, or an organic acid, such as formic acid before phase separation. Any organic solvents or other lower boiling constituents present are then, typically, removed by evaporation or by distillation leaving 2 , 5-dichloro-3- (trifluoromethyl) - pyridine in a partially purified form as a residue. The 2, 5-dichloro-3- (trifluoromethyl) pyridine obtained can be purified by conventional means, such as by distillation under reduced pressure, if desired.
EXAMPLES
1. Preparation of 2.3.6-Trichloro-5- (trifluoromethyl) - pyridine
Solid 2,3, 6-trichloro-5- (trichloromethyl) - pyridine (338 g (gram), 1.13 mol (mole)) was placed in a 2 L (liter) flask equipped with a stirrer, a reflux condenser, and a water cooling bath. Antimony penta- fluoride (200 g, 0.92 mol) was slowly added to the mixture with cooling to maintain the temperature below about 40°C. The mixture was stirred another hour at 40°C and was then poured into 500 mL (milliliters) of ice water. The resulting mixture was twice extracted with 500 mL of dichloromethane and the combined extracts were washed with 500 mL of water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was distilled through a 5-plate Oldershaw column at 20 mm (millimeter) Hg (2.7 kilo- Pascals) to obtain 268 g (95 percent of theory) of the title compound. The title compound has a boiling point of 107-108°C under 25 mm Hg (3.3 kiloPascals) pressure and is typically obtained as a colorless liquid that solidifies on standing to a white solid melting at 52 °C. iH NMR (CDCI3) , δ ppm (tetramethylsilane) : 8.48(s); 19p NMR (hexafluorobenzene) 0 ppm: -98.2 (s).
2. Preparation of 2.5-Dichloro-6-hydrazino-3- (trifluoromethyl) pyridine
A) 2,3, 6-Trichloro-5- (trifluoromethyl) pyridine (10 g, 40 mmol) was dissolved in 80 mL of 2-propanol and 4.8 g (96 mmol) of hydrazine hydrate was added. The mixture was heated at 80°C with stirring for 3 hours. Most of the solvent was removed by evaporation under reduced pressure and then 80 mL of water was added. The insoluble solids were collected by filtration, washed with water, and dried to obtain 9.3 g (93 percent of theory) of the title compound as a pale yellow solid. The ratio of the title compound to its undesired isomer, 2 , 3-dichloro-6-hydrazino-5- (trifluoromethyDpyridine in this solid was 33:1 as determined by gas-liquid chromato- graphy. After purification by recrystallization from carbon tetrachloride, the title compound was a pale yellow solid melting at 140°C. Elemental Analysis (C6H4CI2F3N3)
%C, 29.3; %H, 1.64; %N, 17.1; %C1 , 28.8; %F, 23.2 %C, 29.3; %H, 1.64; %N, 16.8; %C1 , 28.5; %F, 23.2 H NMR (D6-dimethylsulfoxide (DMSO) ) , δ ppm: 7.73 (s, 1H) , 6.60(brs, 3H) ; 19F NMR (DMSO), 0 ppm (CHF3): -61. Ms).
B) 2 , 3 , 6-Trichloro-5- (trifluoromethyl) pyridine
(5.0 g, 20 mmol) was dissolved in 40 mL of tetrachloro- ethylene and 4.8 g (96 mmol) of hydrazine hydrate was added. The mixture was heated at 80°C with stirring for 4 hours . The aqueous phase was removed and the organic phase was washed with 2x40 mL of water. The volatiles were removed by evaporation under reduced pressure and the solid residue was diluted with water, collected by filtration, washed with water, and dried to obtain 4.5 g
(92 percent of theory) of the title compound as a pale yellow solid. The ratio of the title compound to its isomer, 2 , 3-dichloro-6-hydrazino-5- (trifluoromethyl) - pyridine as determined by gas-liquid chromatography was 14:1. Similar results were obtained when the reaction was carried out in the solvents dichloromethane, carbon tetrachloride, chlorobenzene, ethyl acetate, and n-butanol .
C) Triethylamine (96 g) was added to a solution of 200 g of 2 , 3 , 6-trichloro-5- (trifluoromethyl) - pyridine in 800 mL of 2-propanol with stirring at 25 °C and then 60 g of hydrazine hydrate was added slowly with cooling as required to maintain a 25 °C temperature. The reaction mixture was stirred at 25°C for another 8 hours to allow the reaction to complete. Water (1.6 L) was added slowly to the resulting slurry over a 2 -hour period to dissolve the triethylamine hydrochloride salt and to cause the product to precipitate. The solids that formed were collected by filtration, washed with 400 mL of water, and dried to obtain 156 g (79 percent of theory) of the title compound containing 0.7 percent of the undesired isomer (142:1 ratio of title compound to isomer) .
3. Preparation of 2.5-Dichloro-3- (trifluoromethyl) - pyridine
A) A 5.25 percent aqueous solution of sodium hypochlorite (110 mL, 80 mmol) was added to a mixture of 20 g (81 mmol) of 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine, 155 mL of tetrachlorethylene, and 75 mL of IN aqueous sodium hydroxide solution over a 20-min period with stirring at ambient temperature. There was a small exotherm and gas evolution. After stirring 2 hours, the phases were separated. The organic phase was filtered, washed with dilute aqueous hydrochloric acid, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The 10.2 g of residue obtained was distilled and the fraction boiling at 78-79°C under 20 mm Hg (2.7 kiloPascals) pressure was collected to obtain 8.3 g (47 percent of theory) of the title compound as a colorless liquid.
B) A 5.5 percent aqueous solution of sodium hypochlorite (55 mL. 0.41 mmol) was added to a mixture of 10 g (41 mmol) of 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine, 105 mL of chloroform, and 50 mL of IN aqueous sodium hydroxide solution over a 15-min period with stirring at ambient temperature. There was a small exotherm and gas evolution. After stirring 1 hour with intermittent water bath cooling to keep the temperature near ambient, the phases were separated. The organic phase was filtered, washed with dilute aqueous hydrochloric acid, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The 8.5 g of residue obtained was distilled and the fraction boiling at 80-82°C under 22 mm Hg (2.9 kiloPascals) pressure was collected to obtain 7.2 g (82 percent of theory) of the title compound as a colorless liquid. H NMR (CDCI3) , δ ppm: 8.04 (d, 1H, J=2 Hz), 8.52 (d, 1H, J=2 Hz); 19F NMR (CDCI3), ø ppm (CHF3) : -63.7(e).
C) A mixture of 780 g of 12 percent aqueous sodium hypochlorite and 290 g of 13.8 percent aqueous sodium hydroxide was prepared and was added over a 2 -hour period to a mixture of 305 g of 2 , 5-dichloro-6-hydrazino- -3- (trifluoromethyl) pyridine and 2.1 L of dichloromethane with stirring and cooling to maintain the temperature at 25°C. The mixture was allowed react with stirring at 25°C for another two hours. About 10 ml of 40 percent aqueous sodium bisulfite was then added to destroy the excess sodium hypochlorite and the pH of the mixture was adjusted to between 4 and 5 with about 54 g of 88 percent formic acid. The organic and aqueous phases were separated and the aqueous layer was extracted with 400 mL of dichloromethane. The organic phase and extract were combined and concentrated by evaporation under reduced pressure to obtain 290 g of crude product. This crude product was further purified by distillation under reduced pressure to obtain 196 g (72 percent of theory) of the title compound as a colorless liquid.

Claims

WHAT IS CLAIMED IS:
1. A process for the preparation of
2 , 5-dichloro-3- (trifluoromethyl) pyridine which comprises the consecutive steps of
1) contacting 2 , 3 , 6-trichloro-5- (trifluoromethyl) - pyridine with hydrazine and, optionally, a auxiliary acid acceptor base in an inert organic solvent at a temperature of between 0┬░C and 100┬░C to obtain 2, 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine, and
2) contacting 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine with an alkali metal or alkaline earth hypochlorite salt in a medium comprising an aqueous alkaline solution and, optionally, an inert, water- - immiscible organic solvent.
2. A process according to Claim 1 wherein the solvent in step 1) is 2-propanol.
3. A process according to Claim 1 wherein the acid acceptor base triethylamine is used in step 1) .
4. A process according to Claim 1 wherein the hypochlorite salt in step 2) is sodium hypochlorite.
5. A process according to Claim 1 wherein the organic solvent dichloromethane is employed in step 2) .
6. A process according to Claim 1 wherein in step 2) the hypochlorite salt is added as an aqueous solution and the medium is made alkaline with an alkali metal hydroxide compound added in aqueous solution either concurrently with or as a mixture with the hypochlorite salt solution.
7. A process according to Claim 1 wherein the temperature in step 1) is maintained at between 15┬░C and
80┬░C.
8. A process according to Claim 1 wherein the temperature in step 2) is maintained at 10┬░C to 40┬░C.
9. A process for the preparation of 2 , 5-dichloro-6-hydrazino-3- (trifluoromethyl) pyridine which comprises contacting 2 , 3 , 6-trichloro-5- (trifluoromethyl) pyridine with hydrazine and, optionally, an acid acceptor base in an inert organic solvent at a temperature of between 0┬░C and 100 ┬░C.
10. A process according to Claim 9 wherein the solvent is an 2-propanol.
11. A process according to Claim 9 wherein the acid acceptor base triethylamine is used.
12. A process according to Claim 9 wherein the temperature is maintained at between 15┬░C and 80┬░C.
13. The compound 2 , 5-dichloro-6-hydrazino-3- - (trifluoromethyl) pyridine .
PCT/US1998/009146 1997-05-09 1998-05-08 Preparation of 2,5-dichloro-(3-trifluoromethyl)pyridine WO1998050362A1 (en)

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EP0930300A1 (en) * 1997-12-16 1999-07-21 DAICEL CHEMICAL INDUSTRIES, Ltd. Process for preparing (poly)chloropyridines
WO2004099149A1 (en) * 2003-05-09 2004-11-18 Asahi Glass Company, Limited Processes for producing 3-substituted 2-chloro-5­fluoropyridine or salt thereof
JP2015514711A (en) * 2012-03-30 2015-05-21 ダウ アグロサイエンシィズ エルエルシー Process for preparing 3-substituted-6-trifluoromethylpyridine and process using halogenated 6-trichloromethylpyridine
CN112441966A (en) * 2020-12-09 2021-03-05 山东省农药科学研究院 Method for producing 2-chloro-3-trifluoromethylpyridine from 2,3, 6-trichloro-5-trifluoromethylpyridine
CN114728907A (en) * 2019-11-22 2022-07-08 Fmc公司 Method for synthesizing (3-chloro-2-pyridyl) hydrazine

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0930300A1 (en) * 1997-12-16 1999-07-21 DAICEL CHEMICAL INDUSTRIES, Ltd. Process for preparing (poly)chloropyridines
US5977370A (en) * 1997-12-16 1999-11-02 Daicel Chemical Industries, Ltd. Process for preparing pyridine chloride
WO2004099149A1 (en) * 2003-05-09 2004-11-18 Asahi Glass Company, Limited Processes for producing 3-substituted 2-chloro-5­fluoropyridine or salt thereof
US7414136B2 (en) 2003-05-09 2008-08-19 Asahi Glass Company, Limited Method for producing 3-substituted 2-chloro-5-fluoro-pyridine or its salt
AU2004236085B2 (en) * 2003-05-09 2010-03-25 Asahi Glass Company, Limited Processes for producing 3-substituted 2-chloro-5-fluoropyridine or salt thereof
JP2015514711A (en) * 2012-03-30 2015-05-21 ダウ アグロサイエンシィズ エルエルシー Process for preparing 3-substituted-6-trifluoromethylpyridine and process using halogenated 6-trichloromethylpyridine
CN114728907A (en) * 2019-11-22 2022-07-08 Fmc公司 Method for synthesizing (3-chloro-2-pyridyl) hydrazine
CN112441966A (en) * 2020-12-09 2021-03-05 山东省农药科学研究院 Method for producing 2-chloro-3-trifluoromethylpyridine from 2,3, 6-trichloro-5-trifluoromethylpyridine

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