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Process for preparing 2-hydroxy-6-trifluoromethylpyridine

09 Jun.,2025

Process for preparing 2-hydroxy-6-trifluoromethylpyridine

EPB1 - Process for preparing 2-hydroxy-6-trifluoromethylpyridine - Google Patents

Process for preparing 2-hydroxy-6-trifluoromethylpyridine Download PDF

Info

Publication number: EPB1
Authority: EP; European Patent Office
Prior art keywords: trifluoromethylpyridine; chloro; hydroxy; alkali metal; metal hydroxide
Prior art date: -03-07
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

EPA

Other languages

German (de)

French (fr)

Other versions

EPA1 (en

Inventor

Stephen Martin-Zeneca Huddersfield Works Brown

Ian Andrew-Zeneca Huddersfield Works Lilley

Raymond Vincent Heavon Jones

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Syngenta Ltd

Original Assignee

Syngenta Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

-03-07

Filing date

-02-09

Publication date

-12-11

-02-09 Application filed by Syngenta Ltd filed Critical Syngenta Ltd

-12-29 Publication of EPA1 publication Critical patent/EPA1/en

-12-11 Application granted granted Critical

-12-11 Publication of EPB1 publication Critical patent/EPB1/en

-02-09 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Classifications

- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

This invention relates to a chemical process and, more particularly, to a process for preparing 2-hydroxy-6-trifluoromethylpyridine which is useful in the manufacture of certain agricultural products.
US Patent No.4,942,239 describes the preparation of 2-hydroxypyridine by the hydrolysis of 2-chloropyridine with an aqueous concentrated potassium hydroxide solution in the presence of a tertiary alcohol, such as tert -butyl or tert -amyl alcohol, under reflux at atmospheric pressure.
a tertiary alcohol such as tert -butyl or tert -amyl alcohol
a solvent-based process has also been described for the preparation of 2-hydroxy-6-trifluoromethylpyridine in, for example, US Patent No. 3.609.158.
2-chloro-6-trifluoromethyl pyridine in dimethylsulphoxide (DMSO) is hydrolysed by heating with aqueous sodium hydroxide under reflux.
DMSO dimethylsulphoxide
2-Hydroxy-6-trifluoromethylpyridine can readily be prepared in good yield by the alkaline hydrolysis of 2-chloro-6-trifluoromethylpyridine in a solvent such as DMSO or tert -amyl alcohol.
a solvent such as DMSO or tert -amyl alcohol.
solvent-based processes are generally undesirable because of the environmental and safety implications and the need for solvent recovery systems.
the process of the present invention is solvent-free, high yielding and provides the product in a suitable physical form.
a process for the preparation of 2-hydroxy-6-trifluoromethylpyridine which comprises reacting 2-chloro-6-trifluoromethylpyridine with two or more equivalents of an aqueous alkali metal hydroxide whose strength is at least 10%w/v in a sealed vessel at a temperature of at least 140°C under autogenous pressure.
the alkali metal hydroxide is either sodium hydroxide or potassium hydroxide, the latter generally being the more effective.
the aqueous base solution strength should be at least 10% w/v and is suitably in the range of 10 to 50% w/v, for example, 10 to 20% w/v.
More than two equivalents of base are required to ensure full conversion of the pyridine to pyridone. About 2.2 equivalents have been found generally satisfactory, based on pure pyridine starting material. A greater excess would appear unnecessary, while it may be possible to reduce the excess slightly. Thus, the normal working range will be from 2, preferably from 2.1, to 2.3 equivalents of base to pyridine starting material.
the temperature of the reaction should be at least 140°C and is suitably 150°C - 160°C, typically 150°C. Below 150°C the rate of hydrolysis is reduced.
the reaction is carried out in a sealed vessel, for example, in an autoclave whose material of construction can withstand the effects of aqueous alkali at temperatures of up to 150°C and beyond and the autogenous pressures generated.
a sealed vessel for example, in an autoclave whose material of construction can withstand the effects of aqueous alkali at temperatures of up to 150°C and beyond and the autogenous pressures generated.
the vessel is constructed from a nickel alloy such as inconel, monel or hastelloy. Normally pressures of 4 to 5 bar are generated.
2-chloro-6-trifluoromethylpyridine is charged to an autoclave, which is sealed and pressure tested. The pressure is released, the autoclave resealed and heated to 150°C. At least two equivalents of aqueous alkali metal hydroxide are pumped to the autoclave and the reaction mixture held at 150°C - 160°C over 1 to 4 hours, for example 1 1 ⁇ 2 to 2 hours, under self-generated pressure of 4 to 5 bar. After reaction is adjudged complete, the reaction mixture is cooled, acidified and the product filtered and washed with water.
the 2-chloro-6-trifluoromethylpyridine starting material is a known compound and its preparation is described in the chemical literature. It may be prepared by the vapour phase chlorofluorination of ⁇ -picoline as described in EP-A- or by the fluorination of 2-chloro-6-trichloromethylpyridine (nitrapyrin) using hydrogen fluoride as described in EP-A- or using antimony trifluoro-dichloride as described in US-A-.
the main advantage of the present invention is that it provides a high-yielding process for the hydrolysis of 2-chloro-6-trifluoromethylpyridine in the absence of a solvent. However, it has the additional advantage of being able to consume impure pyridine starting material and produce a 'cleaned-up' product. This is achieved by the hydrolysis of impurities in the feedstock to products having a higher water solubility than 2-hydroxy-6-trifluoromethylpyridine.
2-chloro-6-trifluoromethylpyridine feedstock contains impurities in which there is an additional chlorine atom in the 3- or 5-position of the pyridine ring.
Some of these dichlorinated trifluoromethylpyridines are inseparable from 2-chloro-6-trifluoromethylpyridine by distillation. However, under the conditions of the present process, they are hydrolyzed to water-soluble hydroxypicolinic acid derivatives which are readily removed by acidification of the reaction mass and isolation of the precipitated product by filtration.
This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 150°C under autogenous pressure.
This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-chloro-6-trifluoromethylpyridine with aqueous sodium hydroxide at 150°C under autogenous pressure.
2-Chloro-6-trifluoromethylpyridine (8.05g at 98% strength; 43.2 mmol; 1 equiv) was charged to a Parr reactor, pressure tested at 100psi. The pressure was released and the reactor heated to 150°C.
Sodium hydroxide solution (9.823% strength; 40.1g; 98.5 mmol; 2.28 equiv) was added via an HPLC pump over 2 hours 20 minutes and the reaction mixture maintained at 150°C for a further 4 hours.

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pyridine Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Physical Or Chemical Processes And Apparatus (AREA)

Abstract

2-Hydroxy-6-trifluoromethylpyridine is prepared by reacting 2-chloro-6-trifluoromethylpyridine with an aqueous alkali metal hydroxide in a sealed vessel at a temperature of at least 140 DEG C. under autogenous pressure.

Description

This invention relates to a chemical process and, more particularly, to a process for preparing 2-hydroxy-6-trifluoromethylpyridine which is useful in the manufacture of certain agricultural products.
Processes for preparing 2-hydroxypyridines by the hydrolysis of 2-chloropyridines are described in the chemical literature. Thus, UK Patent No. 288,628 describes the preparation of 2-hydroxypyridine by the hydrolysis of 2-chloropyridine with solid potassium hydroxide at 175°C. It also describes the preparation of 2-hydroxy-5-nitropyridine by the hydrolysis of the corresponding chloropyridine with (a) concentrated hydrochloric acid in a bomb tube at 150°C and (b) 2-normal caustic soda lye under reflux.
US Patent No.4,942,239 describes the preparation of 2-hydroxypyridine by the hydrolysis of 2-chloropyridine with an aqueous concentrated potassium hydroxide solution in the presence of a tertiary alcohol, such as tert-butyl or tert-amyl alcohol, under reflux at atmospheric pressure. A solvent-based process has also been described for the preparation of 2-hydroxy-6-trifluoromethylpyridine in, for example, US Patent No. 3.609.158. In this patent 2-chloro-6-trifluoromethyl pyridine in dimethylsulphoxide (DMSO) is hydrolysed by heating with aqueous sodium hydroxide under reflux.
2-Hydroxy-6-trifluoromethylpyridine can readily be prepared in good yield by the alkaline hydrolysis of 2-chloro-6-trifluoromethylpyridine in a solvent such as DMSO or tert-amyl alcohol. On a large scale, however, solvent-based processes are generally undesirable because of the environmental and safety implications and the need for solvent recovery systems.
Unfortunately, the treatment of 2-chloro-6-trifluoromethylpyridine with 35% hydrochloric acid at 150°C results in only a trace of hydrolysis and with aqueous sodium hydroxide under reflux results in no hydrolysis at all. Treatment with solid base leads to hydrolysis but the product is obtained in an unacceptable physical form.
The process of the present invention is solvent-free, high yielding and provides the product in a suitable physical form.
Thus, according to the present invention, there is provided a process for the preparation of 2-hydroxy-6-trifluoromethylpyridine which comprises reacting 2-chloro-6-trifluoromethylpyridine with two or more equivalents of an aqueous alkali metal hydroxide whose strength is at least 10%w/v in a sealed vessel at a temperature of at least 140°C under autogenous pressure.
The alkali metal hydroxide is either sodium hydroxide or potassium hydroxide, the latter generally being the more effective. For maximum yield, the aqueous base solution strength should be at least 10% w/v and is suitably in the range of 10 to 50% w/v, for example, 10 to 20% w/v.
More than two equivalents of base are required to ensure full conversion of the pyridine to pyridone. About 2.2 equivalents have been found generally satisfactory, based on pure pyridine starting material. A greater excess would appear unnecessary, while it may be possible to reduce the excess slightly. Thus, the normal working range will be from 2, preferably from 2.1, to 2.3 equivalents of base to pyridine starting material.
The temperature of the reaction should be at least 140°C and is suitably 150°C - 160°C, typically 150°C. Below 150°C the rate of hydrolysis is reduced.
The reaction is carried out in a sealed vessel, for example, in an autoclave whose material of construction can withstand the effects of aqueous alkali at temperatures of up to 150°C and beyond and the autogenous pressures generated. Suitably the vessel is constructed from a nickel alloy such as inconel, monel or hastelloy. Normally pressures of 4 to 5 bar are generated.
In a typical small-scale process according to the present invention, 2-chloro-6-trifluoromethylpyridine is charged to an autoclave, which is sealed and pressure tested. The pressure is released, the autoclave resealed and heated to 150°C. At least two equivalents of aqueous alkali metal hydroxide are pumped to the autoclave and the reaction mixture held at 150°C - 160°C over 1 to 4 hours, for example 1 ½ to 2 hours, under self-generated pressure of 4 to 5 bar. After reaction is adjudged complete, the reaction mixture is cooled, acidified and the product filtered and washed with water.
The 2-chloro-6-trifluoromethylpyridine starting material is a known compound and its preparation is described in the chemical literature. It may be prepared by the vapour phase chlorofluorination of α-picoline as described in EP-A- or by the fluorination of 2-chloro-6-trichloromethylpyridine (nitrapyrin) using hydrogen fluoride as described in EP-A- or using antimony trifluoro-dichloride as described in US-A-.
The main advantage of the present invention is that it provides a high-yielding process for the hydrolysis of 2-chloro-6-trifluoromethylpyridine in the absence of a solvent. However, it has the additional advantage of being able to consume impure pyridine starting material and produce a 'cleaned-up' product. This is achieved by the hydrolysis of impurities in the feedstock to products having a higher water solubility than 2-hydroxy-6-trifluoromethylpyridine.
Commonly, 2-chloro-6-trifluoromethylpyridine feedstock contains impurities in which there is an additional chlorine atom in the 3- or 5-position of the pyridine ring. Some of these dichlorinated trifluoromethylpyridines are inseparable from 2-chloro-6-trifluoromethylpyridine by distillation. However, under the conditions of the present process, they are hydrolyzed to water-soluble hydroxypicolinic acid derivatives which are readily removed by acidification of the reaction mass and isolation of the precipitated product by filtration.
It should be noted, however, that additional base is required to hydrolyze these impurities. Four equivalents of base are needed for dichlorinated species. Therefore, the precise amount of base used in the process should be calculated according to the level of impurities in the feedstock.
The invention is illustrated by the following Examples in which :- g = grammes mmol = millimoles °C = degrees centigrade ml = millilitre HPLC = high performance liquid equiv = equivalent chromatography psi = pounds per square inch
This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 150°C under autogenous pressure.
2-Chloro-6-trifluoromethylpyridine (10.0g; 55.1 mmol; 1 equiv) was charged to a 100 ml Hastelloy C Parr reactor, the reactor sealed and pressure tested with nitrogen. When a sealed system had been achieved, the pressure was released, the reactor resealed, and heated to 150°C. Potassium hydroxide solution (10% strength; 68.0 g; 121.1 mmol; 2.2 equiv) was added via an HPLC pump over 1 hour, while the mixture was maintained at 150°C. Addition of base caused the pressure to rise to 5 bar. The reaction mixture was held at this temperature and pressure for a further 5 hours . Following this period the reactor was cooled, dismantled and sodium chloride (5g) added. The solution was cooled to 5°C, acidified to pH 5-6 by the addition of concentrated sulphuric acid, filtered and pulled dry. The filter cake was washed with water (10g), pulled dry, discharged and allowed to dry overnight to afford 2-hydroxy-6-trifluoromethylpyridine as a colourless powder (9.5 g: 95% strength; 92% isolated yield).
This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting 2-chloro-6-trifluoromethylpyridine with aqueous sodium hydroxide at 150°C under autogenous pressure.
2-Chloro-6-trifluoromethylpyridine (8.05g at 98% strength; 43.2 mmol; 1 equiv) was charged to a Parr reactor, pressure tested at 100psi. The pressure was released and the reactor heated to 150°C. Sodium hydroxide solution (9.823% strength; 40.1g; 98.5 mmol; 2.28 equiv) was added via an HPLC pump over 2 hours 20 minutes and the reaction mixture maintained at 150°C for a further 4 hours. The mixture was cooled, unreacted 2-chloro-6-trifluoromethylpyridine extracted with methylene chloride, and the aqueous phase acidified with hydrochloric acid and filtered to afford 2-hydroxy-6-trifluoromethylpyridine (5.615g; 93% strength; 73% isolated yield). Further product was obtained by extraction of the filtrates with methylene chloride.

Claims (5)

A process for the preparation of 2-hydroxy-6-trifluoromethylpyridine which comprises reacting 2-chloro-6-trifluoromethylpyridine with two or more equivalents of an aqueous alkali metal hydroxide whose strength is at least 10%w/v in a sealed vessel at a temperature of at least 140°C under autogenous pressure.
A process according to claim 1 wherein the strength of the aqueous alkali metal hydroxide is in the range of 10% to 50% w/v.
A process according to claim 1 or 2 wherein the alkali metal hydroxide is potassium hydroxide.
A process according to any one of the preceding claims wherein the amount of alkali metal hydroxide used is in the range of from 2 to 2.3 equivalents of base to 2-chloro-6-trifluoromethylpyridine starting material.
A process according to any one of the preceding claims wherein the temperature is in the range of from 150°C to 160°C.

EPA -03-07 -02-09 Process for preparing 2-hydroxy-6-trifluoromethylpyridine Expired - Lifetime EPB1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title GBGB.5A GBD0 (en) -03-07 -03-07 Chemical process GB -03-07 PCT/GB/ WOA1 (en) -03-07 -02-09 Process for preparing 2-hydroxy-6-trifluoromethylpyridine

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Publication Number Publication Date EPA1 EPA1 (en) -12-29 EPB1 true EPB1 (en) -12-11

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Application Number Title Priority Date Filing Date EPA Expired - Lifetime EPB1 (en) -03-07 -02-09 Process for preparing 2-hydroxy-6-trifluoromethylpyridine

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Country Link US (1) USA (en) EP (1) EPB1 (en) JP (1) JPA (en) AT (1) ATET1 (en) AU (1) AUA (en) DE (1) DET2 (en) DK (1) DKT3 (en) ES (1) EST3 (en) GB (1) GBD0 (en) WO (1) WOA1 (en)

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* Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title GBD0 (en) * -09-03 -10-28 Zeneca Ltd Chemical process GBD0 (en) -07-03 -08-23 Zeneca Ltd Chemical process GBD0 (en) -07-03 -08-23 Zeneca Ltd Chemical process

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* Cited by examiner, † Cited by third party Publication number Priority date Publication date Assignee Title GBA (en) * -04-14 -07-03 Schering Kahlbaum Ag Process for the manufacture of hydroxypyridine compounds USA (en) * -05-06 -11-28 Dow Chemical Co Production of monohalopyridinols USA (en) * -03-17 -12-05 Dow Chemical Co Polyhalo-(trifluoromethyl)pyridyloxy amides and hydrazides USA (en) * -03-17 -01-22 Dow Chemical Co Cyanoalkoxy(trifluoromethyl)pyridines USA (en) * -03-17 -09-28 Dow Chemical Co Certain substituted (pyridyl)-oxy acetic acid derivatives GBA (en) * -06-30 -01-17 USA (en) * -02-24 -07-26 Merck & Co., Inc. Anti-inflammatory oxazole[4,5-b]pyridines USA (en) * -01-29 -02-03 Reilly Tar & Chemical Corp. Processes for preparing 2-chloro-5-trifluoromethylpyridine USA (en) * -08-20 -06-19 The Dow Chemical Company Fungicidal control employing substituted pyridinols JPSA (en) * -08-14 -02-29 Ishihara Sangyo Kaisha Ltd N-pyridyl-n'-benzoylurea compound and insecticide containing said compound JPHB2 (en) * -09-16 -03-06 北興化学工業株式会社 Method for producing 2,3,5-trichloropyridine DEA1 (en) * -04-28 -11-09 Ruetgerswerke Ag METHOD FOR PRODUCING 2-HYDROXYPYRIDINE

- -03-07 GB GBGB.5A patent/GBD0/en active Pending
- -02-09 AT ATT patent/ATET1/en active
- -02-09 EP EPA patent/EPB1/en not_active Expired - Lifetime
- -02-09 WO PCT/GB/ patent/WOA1/en active IP Right Grant
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- -02-09 DE DET patent/DET2/en not_active Expired - Lifetime
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2-Hydroxy-5-(trifluoromethyl)pyridine | C6H4F3NO - PubChem

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Process for preparing 2-hydroxy-6-trifluoromethylpyridine