WO2000044724A1 - Improved method for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine - Google Patents

Improved method for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine Download PDF

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Publication number
WO2000044724A1
WO2000044724A1 PCT/IL2000/000061 IL0000061W WO0044724A1 WO 2000044724 A1 WO2000044724 A1 WO 2000044724A1 IL 0000061 W IL0000061 W IL 0000061W WO 0044724 A1 WO0044724 A1 WO 0044724A1
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process according
pentachloropyridine
reaction
dichloro
potassium fluoride
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PCT/IL2000/000061
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French (fr)
Inventor
Yoel Sasson
Amikam Zoran
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Makhteshim Chemical Works Ltd.
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Priority to AU21271/00A priority Critical patent/AU2127100A/en
Publication of WO2000044724A1 publication Critical patent/WO2000044724A1/en

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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
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to organic herbicides.
  • the present invention describes an improved method of preparation of 3,5-dichloro-2,4,6-trifluoropyridine from pentachloropyridine.
  • the process is know at temperatures of about 140°C in a solvent comprising of a mixture of an aprotic amide and an aromatic hydrocarbon and optionally in the presence of a tetraalkyl ammonium halide catalyst. These processes all suffer because they provide moderate yields of the desired product usually mixed with tarry degradation products and generally require an excess of potassium fluoride to be employed for good results. At temperatures of about 100°C N-methypyrrolidone has been utilized as a solvent (US Patent No. 4746744). This process provides a higher yield with very little tar formation.
  • the present invention provides a process for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine in very high yield and improved rate comprising contacting pentachloropyridine with potassium fluoride in dimethylsulfoxide as a solvent at temperatures of about 70-90°C.
  • compounds selected from among crown ethers, ammonium and phosphonium compounds, hereinafter phase transfer catalyst can be added.
  • the improved process of present invention can be conducted in conventional equipment using conventional techniques known to those in the art so long as pentachloropyridine and potassium fluoride are contacted at about 60°C to about 120°C in dimethylsulfoxide under essentially anhydrous conditions.
  • a batch reactor was employed.
  • the product was recovered by distillation at atmospheric or sub-atmospheric pressure at the conclusion of the process.
  • the order of addition of the pentachloropyridine, potassium fluoride and dimethylsulfoxide to the reaction vessel is not critical. It is however preferred to prepare a slurry of potassium fluoride in dimethylsulfoxide and subsequently add the pentachloropyridine.
  • the reaction consumes about 3.5 moles of potassium fluoride for every mole of pentachloropyridine.
  • Sufficient dimethylsulfoxide solvent is used to create a mobile slurry, but not so much as to make the process uneconomical. It is preferred to use between 5 and 10 kg of solvent for every kg of potassium fluoride.
  • the reaction is best conducted with as little water as possible. It is preferred to have a water content in the reaction mixture of between 500-1000 ppm.
  • a slurry of potassium fluoride in dimethylsulfoxide is prepared and heated to remove unwanted water by distillation before the addition of pentachloropyridine.
  • the process can be carried out at temperatures as low as about 65 °C up to about
  • reaction mixture is usually stirred to ensure good contact between the reagents and good temperature control.
  • phase transfer catalyst can be employed in the process.
  • Suitable catalysts include crown ethers, e.g. 18-crown-6-ether, and quaternary ammonium and phosphonium compounds, e.g. tetramethylphosphoniumchloride.
  • the phase transfer catalyst is a tetraalkyl ammonium halide, conveniently a tetraalkyl ammonium chloride.
  • Each alkyl moiety in such a catalyst may conveniently be a C ]-6 alkyl group, where methyl and/or butyl groups are preferred.
  • the catalyst is best added to the slurry of potassium fluoride in dimethylsulfoxide before the addition of pentachloropyridine.
  • a tetraalkylammonium chloride, specifically tetramethylammonium chloride was preferred. The reaction time was found to be halved when this catalyst was employed.
  • Residual H 2 O concentration in the potassium fluoride-dimethylsulfoxide slurry did not exceed 500-1000 ppm.
  • 31.2 g (0.12 mole) of pentachloropyridine was introduced into the slurry.
  • the mixture was then flushed with a slow stream of dry N 2 .
  • the reaction mixture was monitored by quantitative gas chromatography which measured the disappearance of pentachloropyridine, the formation and decline of the two fluoro-intermediate isomers monofluorotetrachloropyridine and difluyorotrichloropyridines, and the formation of the final product 3,5-dichloro-2,4,6-trifluoropyridine.
  • the exchange reaction reached completion with a full transformation of pentachloropyridine to 3,5-dichloro-2,4,6-trifluoropyridine.
  • the fractional distillation step was conducted as specified in the relevant part of example 1, giving after the two stages a distillate amounting to 22 J g of 98% TFP (87% yield). Filtration of the KCl + KF slurry produced a DMSO filtrate with a 96% purity which could be reused in a subsequent fluorination batch.
  • the flask content was then cooled to 100°C and vacuum was reestablished at 100 mm Hg to isolate the TFP by fractional distillation.
  • a reflux ratio of 5:1 and overhead temperature of 88-90°C a fraction of 20.5 g of colorless, irritating TFP liquid (condenser jacket at 40°C) was collected with a purity of 99% (81% yield).
  • Another small fraction (10 g) of NMP contairiing 6% TFP was then removed and the residual slurry was cooled to 50°C and filtered off the reaction mixture. The solid (3.5 g) was washed with 20 g NMP and discarded.

Abstract

3,5-dichloro-2,4,6-trifluoropyridine is produced in very high yield and improved rate by contacting pentachloropyridine with potassium fluoride in dimethylsulfoxide as a solvent at temperatures of about 60-125 °C. A phase transfer catalyst can optionally be added.

Description

Improved Method for the Preparation of 3,5-dichloro-2,4,6-trifluoropyridine
Field of the Invention
The present invention relates to organic herbicides.
Background of the Invention
The present invention describes an improved method of preparation of 3,5-dichloro-2,4,6-trifluoropyridine from pentachloropyridine.
Processes for the preparation of fluorinated pyridines in aprotic polar solvents are known (US Patent Nos. 3975424; 4031100; 4071521; 4351777; 4642398; 4745193; 4822887; 4849552; 4978769; 5237087)
The preparation of 3,5-dichloro-2,4,6-trifluoropyridine from pentachloropyridine by processes involving the reaction of pentachloropyridine and potassium fluoride at temperatures between 100°C and 170°C and higher are known. At temperatures of about 200°C dipolar and aprotic solvents have been utilized (US Patent No. 3303107). The process has also been taught to proceed satisfactorily at temperatures as low as 160°C in a dipolar, aprotic solvent if an initiator such as ethylene glycol (British Patent No. 1306517) or about 0.2 to 2 percent water (British Patent No. 1256082) is added.
The process is know at temperatures of about 140°C in a solvent comprising of a mixture of an aprotic amide and an aromatic hydrocarbon and optionally in the presence of a tetraalkyl ammonium halide catalyst. These processes all suffer because they provide moderate yields of the desired product usually mixed with tarry degradation products and generally require an excess of potassium fluoride to be employed for good results. At temperatures of about 100°C N-methypyrrolidone has been utilized as a solvent (US Patent No. 4746744). This process provides a higher yield with very little tar formation.
Improved processes for the production of 3,5-dichloro-2,4,6-trifluoropyridine are desirable as this compound is employed as an intermediate for the production of herbicides, such as 4-hydroxy-3,4-dichloro-2,6-3,5difluoropyridine and 4-amino-3,5-dichloro-6-fluoro-2-pyridinyloxyacetic acid, and is useful among other thing for fixing dyes to fabric.
In view of the aforementioned there is a long felt need to develop processes for preparing 3,5-dichloro-2,4,6-trifluoropyridine which overcome the disadvantages of the processes currently employed.
It is therefore a purpose of the present invention to provide a process for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine.
It is yet another purpose of the present invention to provide a process that overcomes the disadvantages of the known art.
Other objects of the invention will become apparent as the description proceeds.
Summary of the Invention
The present invention provides a process for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine in very high yield and improved rate comprising contacting pentachloropyridine with potassium fluoride in dimethylsulfoxide as a solvent at temperatures of about 70-90°C. Optionally, compounds selected from among crown ethers, ammonium and phosphonium compounds, hereinafter phase transfer catalyst, can be added.
Detailed Description of a Preferred Embodiment of the Invention
The following description is not to be construed as limiting, it being understood that the skilled person may carry out many obvious variations to the process.
The improved process of present invention can be conducted in conventional equipment using conventional techniques known to those in the art so long as pentachloropyridine and potassium fluoride are contacted at about 60°C to about 120°C in dimethylsulfoxide under essentially anhydrous conditions. A batch reactor was employed. The product was recovered by distillation at atmospheric or sub-atmospheric pressure at the conclusion of the process.
The order of addition of the pentachloropyridine, potassium fluoride and dimethylsulfoxide to the reaction vessel is not critical. It is however preferred to prepare a slurry of potassium fluoride in dimethylsulfoxide and subsequently add the pentachloropyridine.
The reaction consumes about 3.5 moles of potassium fluoride for every mole of pentachloropyridine. Sufficient dimethylsulfoxide solvent is used to create a mobile slurry, but not so much as to make the process uneconomical. It is preferred to use between 5 and 10 kg of solvent for every kg of potassium fluoride.
The reaction is best conducted with as little water as possible. It is preferred to have a water content in the reaction mixture of between 500-1000 ppm. In preferred procedures, a slurry of potassium fluoride in dimethylsulfoxide is prepared and heated to remove unwanted water by distillation before the addition of pentachloropyridine.
The process can be carried out at temperatures as low as about 65 °C up to about
120°C. The reaction mixture is usually stirred to ensure good contact between the reagents and good temperature control.
A phase transfer catalyst can be employed in the process. Suitable catalysts include crown ethers, e.g. 18-crown-6-ether, and quaternary ammonium and phosphonium compounds, e.g. tetramethylphosphoniumchloride. Preferably the phase transfer catalyst is a tetraalkyl ammonium halide, conveniently a tetraalkyl ammonium chloride.
Each alkyl moiety in such a catalyst may conveniently be a C]-6 alkyl group, where methyl and/or butyl groups are preferred. The catalyst is best added to the slurry of potassium fluoride in dimethylsulfoxide before the addition of pentachloropyridine. A tetraalkylammonium chloride, specifically tetramethylammonium chloride was preferred. The reaction time was found to be halved when this catalyst was employed.
The reaction of pentachloropyridine with potassium fluoride at 65 °C required about 10 hours to reach completion. The reaction at 90°C required two hours to reach completion and at 120°C required only 30 minutes to reach completion.
The reaction of pentachloropyridine with potassium fluoride with a catalyst of tetramethylarnmonium chloride at 70°C required five hours to reach completion. The reaction at 90°C required 1 hour to reach completion.
Examples
Example 1:
To 25 g (0.43 mole) dry, ground potassium fluoride powder and 170 g dimethylsulfoxide were charged into a 500 ml three necked glass flask. This flask was equipped with a mechanical stirrer, thermometer (0-200°C), a gas inlet (N2) tube and a jacketed distillation column (10 plates) which had a magnetically controlled fraction splitter. The stirred mixture (300 rpm) was subjected to vacuum fractional distillation at 70°C and 150 mmHg, removing as a light fraction 20 g of dimethylsulfoxide containing 6% H2O. Residual H2O concentration in the potassium fluoride-dimethylsulfoxide slurry did not exceed 500-1000 ppm. After vacuum release, 31.2 g (0.12 mole) of pentachloropyridine was introduced into the slurry. The mixture was then flushed with a slow stream of dry N2. The reaction mixture was monitored by quantitative gas chromatography which measured the disappearance of pentachloropyridine, the formation and decline of the two fluoro-intermediate isomers monofluorotetrachloropyridine and difluyorotrichloropyridines, and the formation of the final product 3,5-dichloro-2,4,6-trifluoropyridine. After ten hours at 70°C, the exchange reaction reached completion with a full transformation of pentachloropyridine to 3,5-dichloro-2,4,6-trifluoropyridine.
The product separation for the dimethylsulfoxide slurry was conducted in two consecutive distillation stages under diminished pressure of 25 mHg:
l.At a reflux ration of 5:1, a distillate passing at an overhead temperature of 80°C was collected with a composition of 36-64 3,5-dichloro-2,4,6-trifluoropyridine - dimethylsulfoxide (w/w) which represents 40% of the total liquid feed. The residual slurry was cooled to 50°C and filtered under suction, leaving a crude solid (4.0) g which was discarded and an dimethylsulfoxide filtrate with 98% purity that could be used with no further purification in a second fluorination batch.
2. The 6-64 3,5-dichloro-2,4,6-trifluoropyridine - dimethylsulfoxide distillate was subjected to a second distillation step at r.r=15, collecting at 55°C, 23 J g of 98% 3,5-dichloro-2,4,6-trifluoropyridi-ne (91% yield). The residual liquid has the same composition ( 15-85 3,5-dichloro-2,4,6-trifluoropyridine - dimethylsulfoxide) as the original feed and so could be recycled to the distillation first stage.
Example 2:
To 25 g (0.43 mole) dry, grounded KF powder, 170 g dimethylsulfoxide (DMSO) were charged into the vessel described in example 1 and the mixture was subjected to the same drying procedure leaving only 500-1000 ppm H2O in the KF-DMSO slurry. When the system's pressure was set to atmospheric, 31.2 g (0J2 mole) PCP was introduced into the slurry at 90°c followed by flushing the mixture with a slow stream of dry N2. Two hours after the PCP addition, TFP was monitored as the main reaction product with minor quantities of DFP and hydrolysis products of the various fluoro derivatives (2-3%). The fractional distillation step was conducted as specified in the relevant part of example 1 , giving after the two stages a distillate amounting to 24.4 g of 98% TFP (96% yield).
Filtration of the KC1 + KF slurry produced a DMSO filtrate with a 96% purity which could be reused in a subsequent fluorination batch.
Example 3:
To 25 g (0.43 mole) dry, grounded KF powder, 170 g dimethylsulfoxide (DMSO) were charged into the vessel described in Example 1 and the mixture was subjected to the same drying procedure leaving only 500-1000 ppm H O in the KF-DMSO slurry. When the system's pressure was set to atmospheric, 31.2 g (0J2 mole) PCP was introduced into the slurry at 120°c followed by flushing the mixture with a slow stream of dry N2. 0.5 hour after the PCP addition, TFP was monitored as the main reaction product with minor quantities of DFP and hydrolysis products of the various fluoro derivatives (4-5%). The fractional distillation step was conducted as specified in the relevant part of example 1, giving after the two stages a distillate amounting to 22 J g of 98% TFP (87% yield). Filtration of the KCl + KF slurry produced a DMSO filtrate with a 96% purity which could be reused in a subsequent fluorination batch.
Example 4:
To 25 g (0.43 mole) dry, ground potassium fluoride powder, 170 g dimethylsulfoxide and 0.65 g (6.2 * 10"3 mole) tetramethylammonium chloride were charged into the vessel described in example 1 and the mixture was subjected to the same drying procedure leaving only 500-1000 ppm H2O in the potassium fluoride - dimethylsulfoxide slurry. When the system's pressure was set to atmospheric, 31.2 g (0J2 mole) pentachloropyridine was introduced into the slurry at 70°C followed by flushing the mixture with a slow stream of dry N2. Five hours after the pentachloropyridine addition, 3,5-dichloro-2,4,6-trifluoropyridine was monitored as the only reaction product. The fractional distillation step was conducted as specified in the relevant part of Example 1 , giving after the two stages a distillate amounting to 23.9 g of 98% 3,5-dichloro-2,4,6-trifluoropyridine (94% yield). Filtration of the potassium chloride + potassium fluoride slurry produced a dimethylsulfoxide filtrate with a 96% purity which could be reused in a subsequent fluorination batch with a new portion of tetramethylammonium.
Example 5:
To 25 g (0.43 mole) dry, grounded KF powder, 170 g dimethylsulfoxide (DMSO) and 0.65 g (6.2* 10"3 mole) tetramethylammonium chloride (TMAC) were charged into the vessel described in example 1 and the mixture was subjected to the same drying procedure leaving only 500-1000 ppm H2O in the KF-DMSO slurry. When the system's pressure was set to atmospheric, 31.2 g (0J 2 mole) PCP was introduced into the slurry at 90°c followed by flushing the mixture with a slow stream of dry N2. 1 hour after the PCP addition, TFP was monitored as the main reaction product with minor quantities of DFP and hydrolysis products of the various fluoro derivatives (3-4%). The fractional distillation step was conducted as specified in the relevant part of Example 1, giving after the two stages a distillate amounting to 23.9 g of 98% TFP
(94% yield).
Filtration of the KCl + KF slurry produced a DMSO filtrate with a 96% purity which could be reused in a subsequent fluorination batch with a new portion of TMAC.
Example 6
(Comparative Example to Example 3 - At the same temperature of 120°C. NMP takes eight times longer for reaction to reach completion.)
A 500 ml. Flask equipped as described in example 1 was charged with 25 g (0.43 mole) dry, grounded KF powder and 170 g dry NMP. The heterogeneous, stirred (300 rpm) mixture was dried by vacuum distillation (150 mm Hg, 70°C), removing a wet NMP fraction (29g) containing 4-6% H2O) and leaving 500-1000 ppm H2O in the KF-NMP slurry. After breaking the vacuum with N2, 31.2 g (0J2 mole) PCP was introduced into the stirred system followed by heating its content to 120°c.
Chlorine-fluorine substitution stops after four hours (GC monitoring) of 99% (81% yield)
The flask content was then cooled to 100°C and vacuum was reestablished at 100 mm Hg to isolate the TFP by fractional distillation. At a reflux ratio of 5:1 and overhead temperature of 88-90°C a fraction of 20.5 g of colorless, irritating TFP liquid (condenser jacket at 40°C) was collected with a purity of 99% (81% yield). Another small fraction (10 g) of NMP contairiing 6% TFP was then removed and the residual slurry was cooled to 50°C and filtered off the reaction mixture. The solid (3.5 g) was washed with 20 g NMP and discarded. The combined filtrate was distilled under reduced pressure (60mm Hg, 80-100°C) to recover most of the NMP (95%) for a subsequent usage. While embodiments of the invention have been described by way of illustration, it will be apparent that the invention may be carried out with many modifications, variations and adaptations, without departing from its spirit or exceeding the scope of the claims.

Claims

l.An improved process for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine by reacting pentachloropyridine and potassium fluoride wherein the improvement comprises contacting the pentachloropyridine and potassium fluoride in dimethylsulfoxide as solvent
2. A process according to Claim 1 wherein a phase transfer catalyst is added.
3. A process according to Claim 2 wherein the phase transfer catalyst is selected from among crown-ethers, ammonium compounds and phosphonium compounds.
4. A process according to Claim 3 wherein the phase transfer catalyst is a tetraalkyl ammonium halide wherein the alkyl moiety is a Ci to C, group.
5. A process according to claim 4 wherein the alkyl moiety is methyl or butyl.
6. A process according to claim 4 wherein the halide is chloride.
7. A process according to Claim 4 wherein the tetraalkylammonium chloride is tetramethylammonium chloride.
8. A process according to claim 3 wherein the phosphonium compound is tetramethyl- phosphoniumchloride.
9. A process according to claim 3 wherein the crown ether is 18 crown 6 ether.
10. A process according to Claim 1 wherein the reaction is run at temperature of 65°C to 125°C.
11. A process according to Claim 10 wherein the reaction is run at temperature of 65°C to 75°C.
12. A process according to Claim 1 wherein the reaction is at atmospheric pressure.
13. A process according to Claim 1 wherein water is present in the reaction in an amount of about 500 ppm to about 1000 ppm.
14. A process according to Claim 1 wherein the mole ratio of potassium fluoride to pentachloropyridine is about 3.5 to 1.
PCT/IL2000/000061 1999-02-01 2000-01-30 Improved method for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine WO2000044724A1 (en)

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IL12839799A IL128397A0 (en) 1999-02-01 1999-02-01 Improved method for the preparation of 3,5-dichloro-2,4,6-trifluoropyridine

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
US8805019B2 (en) 2009-03-06 2014-08-12 Koninklijke Philips N.V. Processing images of at least one living being
CN106008331A (en) * 2016-07-21 2016-10-12 四川福思达生物技术开发有限责任公司 Preparation method of 3, 5-dichloro-2, 4, 6-trifluoropyridine

Citations (4)

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GB1306517A (en) * 1970-06-08 1973-02-14 Ici Ltd Manufacture of halogenated pyridine derivatives
GB1340421A (en) * 1971-01-14 1973-12-12 Ici Ltd Manufacture of chlorofluoropyridines
US4031100A (en) * 1976-08-23 1977-06-21 The Dow Chemical Company Process for making 2,6-difluoropyridine
US4822887A (en) * 1983-12-23 1989-04-18 The Dow Chemical Company Preparation of difluoropyridine compounds

Patent Citations (4)

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GB1306517A (en) * 1970-06-08 1973-02-14 Ici Ltd Manufacture of halogenated pyridine derivatives
GB1340421A (en) * 1971-01-14 1973-12-12 Ici Ltd Manufacture of chlorofluoropyridines
US4031100A (en) * 1976-08-23 1977-06-21 The Dow Chemical Company Process for making 2,6-difluoropyridine
US4822887A (en) * 1983-12-23 1989-04-18 The Dow Chemical Company Preparation of difluoropyridine compounds

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8805019B2 (en) 2009-03-06 2014-08-12 Koninklijke Philips N.V. Processing images of at least one living being
CN106008331A (en) * 2016-07-21 2016-10-12 四川福思达生物技术开发有限责任公司 Preparation method of 3, 5-dichloro-2, 4, 6-trifluoropyridine

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