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WO2015151116A2 - Process for producing 2-fluoro-6-(trifluoromethyl)pyridine compounds - Google Patents

Process for producing 2-fluoro-6-(trifluoromethyl)pyridine compounds Download PDF

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Publication number
WO2015151116A2
WO2015151116A2 PCT/IN2015/000146 IN2015000146W WO2015151116A2 WO 2015151116 A2 WO2015151116 A2 WO 2015151116A2 IN 2015000146 W IN2015000146 W IN 2015000146W WO 2015151116 A2 WO2015151116 A2 WO 2015151116A2
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Prior art keywords
fluoride
pyridine
trifluoromethyl
fluoro
process according
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WO2015151116A3 (en
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Ram Singh
Satish Kumar
Mahendra Kumar
Shailendra Kumar Singh
Ashutosh Agarwal
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Jubilant Pharmova Ltd
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Jubilant Life Sciences Ltd
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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to a novel process for the production of 2-fluoro-6- (trifluoromethyl)pyridine compounds. More particularly the present invention provides a large scale industrial process for the production of 2-fluoro-6-(trifluoromethyl)pyridine compounds with high yield and purity.
  • the (trifluoromethyl)pyridine compounds are useful intermediates for the production of agrochemicals and pharmaceuticals.
  • 2-fluoro-6-(trifluoromethyl)pyridine is useful intermediate in the production of picoxystrobin fungicide.
  • the 2,4-dichloro-6-(trifluoromethyl)pyridine obtained in first step is heated with an excess of potassium fluoride in a pressure vessel at 350 °C for 8 hours, the desired product viz., 2,4-difluoro-6-(trifluoromethyl)pyridine is recovered by taking the reaction mixture up in a solvent, filtered to remove salts, and then distilled off the solvent under vacuum.
  • European Patent No. 0063872 discloses the preparation of certain fluoromethyl pyridines where at least one of the halo groups attached to the ring is ortho or para to the fluoromethyl group of the compound.
  • the process involves the fluorination of the corresponding chloromethyl pyridine in the presence of potassium fluoride in a polar aprotic solvent under anhydrous conditions and phase transfer catalyst to produce mixture of fluoromethyl pyridine compounds. It is reported that the process is unsuitable for the preparation of the fluoromethyl pyridine compounds which do not have atleast one ring halogen atom at ortho or para to the fluoromethyl group of the compound.
  • European Patent No. 0042696 discloses the process for producing (trifluoromethyl)pyridine directly by vapour phase reaction of alpha methyl pyridine in single step in the presence of diluent and catalyst at a temperature of 300-600 °C.
  • European Patent Nos. 0110690 and 0256146 also discloses preparation of substituted (trifluoromethyl)pyridine compounds by liquid phase chlorination. The patent discloses several compounds but none of the compounds are 2-fluoro-6-(trifluoromethyl)pyridine based. EP patent 0256146 also reported recovering the (trifluoromethyl)pyridine compound by distillation and using the distillation residue to catalyze further fluorine for chlorine exchange.
  • a process for the production of 2-fluoro-6-(trifluoromethyl)pyridine comprising a liquid phase fluorination of 2-chloro-6-(trichloromethyl)pyridine or mixture of 2-chloro-6-(trichloromethyl)pyridine and , chlorofluoro pyridine compounds with hydrogen fluoride and isolating 2-fluoro-6- (trifluoromethyl)pyridine with high yield, selectivity and purity.
  • the fluorinating agent is added continuously or in a single lot.
  • the disclosed embodiments of the present invention deal with an industrial process for the production of 2-fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I), with high purity and yield.
  • the process of the present invention is industrially feasible and has the advantage of producing highly or completely fluorinated 2-fluoro-6-(trifluoromethyl)pyridine compounds at large scale.
  • the present process involves the complete conversion of organic matter of substrate into desired product by recycling of unconverted/residue containing chlorofluoro pyridine compounds. According to the present invention, fluorination is carried out in the absence of solvent.
  • process of the present invention has several advantages in that it avoids tedious extraction and purification processes, no isolation of intermediate, minimum generation of effluents thereby resulting in easy operation, high productivity and low manufacturing cost.
  • the fluorination process involves the removal of hydrochloric acid gas as generated, to facilitate the fluorine exchange over chlorine at alpha position as well as side chain, resulting in high selectivity towards 2-fluoro-6- (trifluoromethylpyridine compound.
  • the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine compounds of Formula (I), comprising fluorination of one or more pyridine compounds of Formula (II) with fluorinating agent and isolating 2-fIuoro-6- (trifluoromethyl)pyridine compound obtained.
  • n 0, 1, 2 or 3
  • m 0, 1, 2 or 3
  • Y is independently selected from the halogen groups CI, Br, I or F.
  • the compounds of Formula (II) are prepared by the processes known in the prior art.
  • the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the fluorination is carried out in vapor phase or liquid phase.
  • the fluorination is carried out in the liquid phase.
  • the fluorinating agent is selected from the group comprising of metal fluoride, hydrogen fluoride or mixtures thereof.
  • the hydrogen fluoride is anhydrous or hydrofluoric acid.
  • the metal fluoride is selected from, but not limited to the group comprising of antimony trifluorodichloride (SbF 3 Cl2) , antimony trifluoride (SbF 3 ), stannic fluoride (SnF 4 ), stannous fluoride (SnF 2 ), mercuric fluoride (HgF 2 ), silver monofluoride (AgF), silver difluoride (AgF 2 ), cadmium fluoride (CdF 2 ), potassium fluoride (KF), sodium fluoride (NaF), zinc fluoride (ZnF 2 ), cobalt difluoride (CoF 2 ), lead difluoride (PbF 2 ), cupric fluoride (CuF 2 ), bismuth trifluoride (BiF 3 ) or mixtures thereof.
  • the fluorinating agent is added continuously or in a single lot.
  • the amount of fluorinating agent used, in the process of the present invention is at least 3 moles per mole of starting material.
  • the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the catalyst is selected from the group comprising of metal chlorides, metal fluoride, phosphorous halides or mixtures thereof.
  • the metal chloride catalyst is selected from, but not limited to the group comprising of ferrous chloride (FeCl 2 ), ferric chloride (FeCl 3 ), niobium pentachloride (NbCl 5 ), tantalum pentachloride (TaCl 5 ), tungsten hexachloride (WC1 6 ), stannic chloride (SnCl 4 ), antimony trichloride (SbCl 3 ), titanium tetrachloride (TiCl 4 ) and mixtures thereof.
  • the metal fluoride catalyst is selected from, but not limited to the group comprising of antimony pentafluoride (SbF 5 ), antimony trifluoride (SbF 3 ), ferrous fluoride (FeF 2 ), ferric fluoride (FeF 3 ), silver monofluoride (AgF), potassium fluoride (KF), stannic fluoride (SnF 4 ), titanium tetrafluoride (TiF 4 ), chromium difluoride (CrF 2 ), chromium trifluoride (CrF 3 ), chromium tetrafluoride (CrF 4 ), aluminium fluoride (A1F 3 ), nickel difluoride (NiF 2 ), nickel trifluoride (NiF 3 ), manganese difluoride (MnF 2 ), manganese trifluoride (MnF 3 ), manganese tetrafluoride (MnF 4 ), cobalt difluoride (
  • the present invention relates to the process for the preparation of 2- fluoro-6-(trifluoromethyl)pyridine compounds Formula (I), wherein the other reactant materials and catalyst is recovered and recycled.
  • the other reactant materials include unreacted pyridine compounds of Formula (II) and hydrogen fluoride.
  • 2-fluoro-6-(trifluoromethyl)pyridine cornpounds is purified by employing any suitable conventional techniques of distillation, known to the person skilled in the art.
  • a process for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine comprising fluorinating 2-chloro-6- (trichloromethyl)pyridine or mixture of 2-chloro-6-(trichloromethyl)pyridine and chlorofluoro pyridine compounds with a fluorinating agent and isolating the 2-fluoro-6- (trifluoromethyl)pyridine.
  • the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine, wherein the chlorofluoro pyridine compound is selected from the group comprising of 2-chloro-6-(trifluoromethyl)pyridine, 2-chloro-6- (difluorochloromethyl)pyridine, 2-chloro-6-(dichlorofluoromethyl)pyridine or mixtures thereof.
  • the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine, wherein the fluorination is carried out in vapor phase or liquid phase, preferably in the liquid p hase.
  • the fluorinating agent is selected from the group comprising of metal fluoride, hydrogen fluoride or mixtures thereof.
  • the hydrogen fluoride is anhydrous or hydrofluoric acid preferably anhydrous hydrogen fluoride.
  • the metal fluoride is selected from the group comprising of, but not limited to antimony trifluorodichloride (SbF 3 Cl 2 ) , antimony trifluoride (SbF 3 ), stannic fluoride (SnF 4 ), stannous fluoride (SnF 2 ), mercuric fluoride (HgF 2 ), silver mono fluoride (AgF), silver difluoride (AgF 2 ), cadmium fluoride (CdF 2 ), potassium fluoride (KF), sodium fluoride (NaF), zinc fluoride (ZnF 2 ), cobalt difluoride (CoF 2 ), lead difluoride (PbF 2 ), cupric fluoride (CuF 2 ), bismuth trifluor
  • the present invention relates to a process for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine, wherein the fluorinating agent is added continuously or in a single lot.
  • the amount of fluorinating agent used, in the process of the present invention is at least 3 moles per mole of the starting material.
  • the present invention relates to a process for the preparation of 2- fluoro-6-(trifluoromethyl)pyridine, wherein the fluorination is carried out in the temperature range of 90-250 °C at atmospheric, subatmospheric or super-atmospheric pressure.
  • the fluorination is carried out with hydrogen fluoride in the temperature range of 140-230 °C and at a pressure between 0-50 kg/cm 2 , preferably between 10-30 kg/cm 2 .
  • the present invention relates to a process for the preparation of 2- fluoro-6-(trifluoromethyl)pyridine, wherein the fluorination is carried out optionally in the presence of a catalyst.
  • the catalyst is selected from the group comprising of metal chlorides, metal fluoride, phosphorous halides or mixtures thereof.
  • the metal chloride catalyst is selected from the group comprising of, but not limited to ferrous chloride (FeCl 2 ), ferric chloride (FeCl 3 ), niobium pentachloride (NbCl 5 ), tantalum pentachloride (TaCl 5 ), tungsten hexachloride (WC1 6 ), stannic chloride (SnCl 4 ), antimony trichloride (SbCl 3 ), titanium tetrachloride (T1CI4) or mixtures thereof.
  • the metal fluoride catalyst is selected from the group comprising of, but not limited to antimony trifluoride (SbF 3 ), ferrous fluoride (FeF 2 ), ferric fluoride (FeF 3 ), silver monofluoride (AgF), potassium fluoride (KF), stannic fluoride (SnF 4 ), titanium tetrafluoride (T1F 4 ), chromium difluoride (CrF 2 ), chromium trifluoride (CrF 3 ), chromium tetrafluoride (CrF 4 ), aluminium fluoride (A1F 3 ), nickel difluoride (NiF 2 ), nickel trifluoride (NiF 3 ), manganese difluoride (MnF 2 ), manganese trifluoride (MnF 3 ), manganese tetrafluoride (MnF 4 ), cobalt difluoride (CoF 2 ), cobalt trifluoride (CoF
  • the gases like excess HF and HC1 generated are vented and scrubbed in chilled water and neutralized with caustic soda or calcium hydroxide.
  • the excess HF and vent gases are separated and purified by conventional distillation method and recovered HF is recycled.
  • Hydrochloric acid gas is scrubbed in chilled water to make concentrated hydrochloric acid which may be useful for other suitable processes.
  • an industrial process for isolating 2-fluoro-6-(trifluoromethyl)pyridine compounds wherein the process comprises fluorinating one or more pyridine compounds of Formula (II), depressurizing the reactor to atmospheric pressure, flushing with inert gas, optionally distilling the reaction product, diluting, neutralizing followed by distillation to obtain corresponding 2-fluoro-6- (trifluoromethyl)pyridine product with high purity.
  • isolation process involves distillation and neutralization of the reaction mass.
  • 2-fluoro-6-(trifluoromethyl)pyridine can be purified by employing any suitable conventional techniques of distillation, known to the person skilled in the art. According to the process of the present invention, unreacted starting material and other reactant materials (chlorofluoro pyridine compounds) obtained are recovered and recycled. *
  • the other reactant materials include unreacted pyridine compounds from the group 2-chloro-6-(trichloromethyl)pyridine, 2- chloro-6-(trifluoromethyl)pyridine, 2-chloro-6-(difluorochloromethyl)pyridine, 2-chloro-6- (dichlorofluoromethyl)pyridine or mixtures thereof and hydrogen fluoride.
  • the process is used to obtain pure 2-chloro-6- (trifluoromethylpyridine from the mixture of 2-chloro-6-(trichloromethyl)pyridine, 2-chloro- 6-(trifluoromethyl)pyridine, 2-chloro-6-(difluorochloromethyl)pyridine, 2-chloro-6- (dichlorofluoromethyl)pyridine by employing conventional distillation technique.
  • embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
  • Example -1 A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical stirrer was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm) and ferric chloride (11 gm). The mixture was heated and anhydrous hydrogen fluoride (264 gm) was added into the reaction mixture under agitation in approx 14 hours at 170 ⁇ 10 °C and 20 ⁇ 5 kg/cm pressure. Reaction mixture was maintained further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen.
  • the reaction mass was distilled, diluted with water, neutralized with 5% aqueous solution of sodium carbonate, organic layer separated and analysed.
  • the results obtained as per gas chromatography were: 2-fluoro-6- (trifluoromethyl)pyridine: 57.25%; 2-chloro-6-(trifluoromethyl)pyridine: 41.94%; 2-chloro-6- (trichloromethyl)pyridine: 0.06%.
  • the obtained product was distilled to get 2-fluoro-6- (trifluoromethyl)pyridine with 99.97% GC purity.
  • the distillation residue containing partially fluorinated chlorofluoropyridine compounds was recycled back.
  • the product was confirmed by mass spectroscopy and 1H NMR.
  • Example -2 A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, mechanical stirrer and pressure gauge was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm) and ferric chloride (11 gm). The mixture was heated and anhydrous hydrogen fluoride was added into the reaction mixture under agitation. The temperatures of the mixture was maintained at 170 ⁇ 10 °C and at a pressure of 20 ⁇ 5 kg/cm for 18 hours with continuous feeding of anhydrous hydrogen fluoride at the rate of 20 gm/hr. Reaction mixture was maintained further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography.
  • the reactor was charged with 53 gm of chlorofluoropyridine residue obtained in example 2, fresh 2-chloro-6-(trichloromethyl)pyridine (178 gm) and ferric chloride (10 gm). The mixture was heated and anhydrous hydrogen fluoride was introduced into this reaction mixture under agitation. The temperatures of the reaction mixture was maintained at 170 ⁇ 10 °C and pressure at 20 ⁇ 5 kg/cm for 12 hours with feeding of anhydrous hydrogen fluoride at the rate of 20 gm/hr. Reaction mixture was maintained at above temperature and pressure conditions further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography.
  • the reactor was depressurized to atmospheric pressure and flushed with nitrogen.
  • the reaction product was distilled, diluted with water, neutralized with 5% aqueous sodium carbonate, layer separated and analysed.
  • the obtained product was distilled to obtain 2-fluoro-6- (trifluoromethyl)pyridine with 80.2 % yield and 99.96% GC purity.
  • the product was confirmed by mass spectroscopy and ⁇ NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound was recycled back.
  • a 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical stirrer was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm).
  • the solution was heated and anhydrous hydrogen fluoride (260 gm) was added into the reaction mixture under agitation in approx 20 hours at 190 ⁇ 10 °C and 20-30 kg/cm pressure.
  • Reaction mixture was maintained further for 8 hours.
  • the excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled.
  • the completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen.
  • Reaction product was distilled, diluted with water, neutralized with 5% aqueous solution of sodium carbonate and layer separated.
  • the obtained product layer was analyzed by gas chromatography and the results obtained were: 2-fluoro-6- (trifluoromethyl)pyridine:- 51.87%; 2-chloro-6-(trifluoromethyl)pyridine: 38.66%; 2-chloro-6- (difluorochloromethyl)pyridine: 8.22%.
  • the obtained product was distilled to get 2-fluoro-6- (trifluoromethyl)pyridine with 99.97% GC purity.
  • the product was confirmed by mass spectroscopy and 1H NMR.
  • the distillation residue containing partially fluorinated chlorofluoropyridine compound was recycled back.
  • the pressure reactor was charged with 150 gm of chlorofluoropyridine residue obtained as per process of example 4.
  • the mixture was heated and anhydrous hydrogen fluoride (297 gm) was added into this reaction mixture under agitation in 18 hours at a temperature of 170 ⁇ 10 °C and pressure of 20 ⁇ 5 kg/cm .
  • Reaction mixture was maintained further for 4 hours.
  • the excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional and recycled.
  • the completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. Reaction product was distilled, diluted with water, neutralized with 5% aqueous sodium carbonate, layer separated and analysed.
  • a 300 ml high pressure reactor equipped with overhead condenser with controlled valve, mechanical stirrer and pressure gauge was charged with 2-chloro-6-(trichloromethyl)pyridine (1 16 gm).
  • the solution was heated and anhydrous hydrogen fluoride (55 gm) was added into the reaction mixture in one lot under agitation.
  • the reaction was maintained at a temperature 150-175 °C under autogenously developed pressure for 12 hours.
  • the reactor was depressurized to atmospheric pressure and flushed with nitrogen.
  • the reaction product was diluted in ice water, neutralized with soda ash aqueous solution, followed by steam distillation and analysed.
  • a 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical * stirrer is charged with 2,3-dichloro-6- (trichloromethyl)pyridine (231 gm) and antimony trifluoride (1 1 gm) and KF.
  • the solution is heated under agitation at 170 ⁇ 10 °C and 20 ⁇ 5 kg/cm pressure. Reaction mixture is maintained further for 4 hours. The excess HF and hydrochloric acid gas generated are vented, scrubbed and separated and recycled. The completion of reaction is monitored by gas chromatography. After the completion of reaction, the reactor is depressurized to atmospheric pressure and flushed with nitrogen. Reaction product is diluted with water, neutralized with 5% aqueous solution of sodium carbonate and layer separated.
  • Example -8 The obtained product layer is analyzed by gas chromatography. The obtained product is distilled to get 2,3-difluoro-6- (trifluoromethyl)pyridine. The product is confirmed by mass spectroscopy and ⁇ NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound is recycled back.
  • Example -8 The obtained product layer is analyzed by gas chromatography. The obtained product is distilled to get 2,3-difluoro-6- (trifluoromethyl)pyridine. The product is confirmed by mass spectroscopy and ⁇ NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound is recycled back.
  • Example -8 The obtained product layer is analyzed by gas chromatography. The obtained product is distilled to get 2,3-difluoro-6- (trifluoromethyl)pyridine. The product is confirmed by mass spectroscopy and ⁇ NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound is recycled back.
  • a 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical stirrer is charged with , 2,5-dichloro-6- (trichloromethyl)pyridine (23 ⁇ gm) and antimony pentafluoride (1 1 gm).
  • the solution is heated and recycled anhydrous hydrogen fluoride obtained is added into the reaction mixture under agitation in approx 20 hours at 170 ⁇ 10 °C and 20 ⁇ 5 kg/cm 2 pressure. Reaction mixture is maintained further for 4 hours.
  • the excess HF and hydrochloric acid gas generated are vented, scrubbed and separated and recycled.
  • the completion of reaction is monitored by gas chromatography. After the completion of reaction, the reactor is depressurized to atmospheric pressure and flushed with nitrogen.
  • Reaction product is diluted with water, neutralized with 5% aqueous solution of sodium carbonate and layer separated.
  • the obtained product layer is analyzed by gas chromatography.
  • the obtained product is distilled to get 2,5-difiuoro-6- (trifiuoromethyl)pyridine.
  • the product is confirmed by mass spectroscopy and 1H NMR.
  • the distillation residue containing partially fluorinated chlorofluoropyridine compound is recycled back.

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Abstract

The present invention relates to an industrially feasible and economically viable process for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I). The process comprises fluorination of one or more pyridine compounds of Formula (II) with a fluorinating agent and isolating 2-fluoro-6-(trifluoromethylpyridine compound of Formula (I) obtained, which are useful as intermediates in the synthesis of many agrochemical and pharmaceutical products.

Description

PROCESS FOR PRODUCING 2-FLUORO-6-(TRIFLUOROMETHYL)PYRIDINE
COMPOUNDS
Field of the Invention
The present invention relates to a novel process for the production of 2-fluoro-6- (trifluoromethyl)pyridine compounds. More particularly the present invention provides a large scale industrial process for the production of 2-fluoro-6-(trifluoromethyl)pyridine compounds with high yield and purity.
Background of the Invention
The (trifluoromethyl)pyridine compounds are useful intermediates for the production of agrochemicals and pharmaceuticals. For e.g. 2-fluoro-6-(trifluoromethyl)pyridine is useful intermediate in the production of picoxystrobin fungicide.
Few processes are reported in the prior art for the production of (trifluoromethyl)pyridines, however no prior art is available for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine.
US Patent Nos. 3,682,936 and 3,609,158 reported two step process for the preparation of (trifluoromethyl)pyridine compounds by reacting corresponding chloro- (trichloromethyl)pyridine compound first with antimony trifluoridedichloride to give chloro- (trifluoromethyl)pyridine followed by replacement of chlorine atom in the ring with fluorine using potassium fluoride. Thus, 2,4-difluoro-6-(trifluoromethyl)pyridine is prepared by first contacting 2,4-dichloro-6-(trichloromethyl)pyridine with antimony trifluoridedichloride to obtain 2,4-dichloro-6-(trifluoromethyl)pyridine. The 2,4-dichloro-6-(trifluoromethyl)pyridine obtained in first step is heated with an excess of potassium fluoride in a pressure vessel at 350 °C for 8 hours, the desired product viz., 2,4-difluoro-6-(trifluoromethyl)pyridine is recovered by taking the reaction mixture up in a solvent, filtered to remove salts, and then distilled off the solvent under vacuum. European Patent No. 0063872 discloses the preparation of certain fluoromethyl pyridines where at least one of the halo groups attached to the ring is ortho or para to the fluoromethyl group of the compound. The process involves the fluorination of the corresponding chloromethyl pyridine in the presence of potassium fluoride in a polar aprotic solvent under anhydrous conditions and phase transfer catalyst to produce mixture of fluoromethyl pyridine compounds. It is reported that the process is unsuitable for the preparation of the fluoromethyl pyridine compounds which do not have atleast one ring halogen atom at ortho or para to the fluoromethyl group of the compound.
European Patent No. 0042696 discloses the process for producing (trifluoromethyl)pyridine directly by vapour phase reaction of alpha methyl pyridine in single step in the presence of diluent and catalyst at a temperature of 300-600 °C.
European Patent Nos. 0110690 and 0256146 also discloses preparation of substituted (trifluoromethyl)pyridine compounds by liquid phase chlorination. The patent discloses several compounds but none of the compounds are 2-fluoro-6-(trifluoromethyl)pyridine based. EP patent 0256146 also reported recovering the (trifluoromethyl)pyridine compound by distillation and using the distillation residue to catalyze further fluorine for chlorine exchange.
Some of the processes reported for the preparation of (trifluoromethyl)pyridine in the prior art are carried out at very high pressure and temperature whereas others involve the use of expensive catalyst. Also, these processes disclosed in the prior art include multiple steps for extraction and isolation to obtain the desired products.
There is a need to develop a commercially and economically viable process for large scale industrial manufacturing of 2-fluoro-6-(trifluoromethyl)pyridine compounds with high purity and yield.
Summary of the Invention
According to one aspect of the present invention, there is provided a process for preparation of 2-fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I),
Figure imgf000003_0001
(I)
said process comprising fluorination of one or more pyridine compounds of Formula (II) with a fluorinating agent and isolating 2-fluoro-6-(trifluoromethyl)pyridine compound obtained,
Figure imgf000004_0001
(II) wherein, n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; X is CI or F with the proviso that when n=3 then X≠F; Y is independently selected from the halogen groups CI, Br, I or F.
According to another aspect of the present invention, there is provided a process for the production of 2-fluoro-6-(trifluoromethyl)pyridine comprising a liquid phase fluorination of 2-chloro-6-(trichloromethyl)pyridine or mixture of 2-chloro-6-(trichloromethyl)pyridine and , chlorofluoro pyridine compounds with hydrogen fluoride and isolating 2-fluoro-6- (trifluoromethyl)pyridine with high yield, selectivity and purity.
According to one aspect of the present invention, there is provided a process for the production of 2-fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the fluorination is carried out optionally in the presence of a catalyst.
According to one other aspect of the present invention, the fluorinating agent is added continuously or in a single lot.
According* to yet another aspect of the present invention, there is provided a process for the production of 2-fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the process further involves the venting of excess hydrogen fluoride and hydrochloric acid gas.
Other aspects will be set forth in the description which follows, and in part will be apparent from the description or may be learnt by the practice of the invention.
Detailed Description of the Invention
While the specification concludes with claims defining the features of the invention that are regarded as novel, it is believed that the invention will be better understood from a consideration of the following description.
The disclosed embodiments of the present invention deal with an industrial process for the production of 2-fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I), with high purity and yield. The process of the present invention is industrially feasible and has the advantage of producing highly or completely fluorinated 2-fluoro-6-(trifluoromethyl)pyridine compounds at large scale. The present process involves the complete conversion of organic matter of substrate into desired product by recycling of unconverted/residue containing chlorofluoro pyridine compounds. According to the present invention, fluorination is carried out in the absence of solvent.
Thus, process of the present invention has several advantages in that it avoids tedious extraction and purification processes, no isolation of intermediate, minimum generation of effluents thereby resulting in easy operation, high productivity and low manufacturing cost. According to the process of the invention, the fluorination process involves the removal of hydrochloric acid gas as generated, to facilitate the fluorine exchange over chlorine at alpha position as well as side chain, resulting in high selectivity towards 2-fluoro-6- (trifluoromethylpyridine compound.
In one embodiment, the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine compounds of Formula (I), comprising fluorination of one or more pyridine compounds of Formula (II) with fluorinating agent and isolating 2-fIuoro-6- (trifluoromethyl)pyridine compound obtained.
Figure imgf000005_0001
wherein , n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; X is CI or F with the proviso that when n=3 then X≠F; and Y is independently selected from the halogen groups CI, Br, I or F.
According to the present invention, the compounds of Formula (II) are prepared by the processes known in the prior art.
In one embodiment, the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the fluorination is carried out in vapor phase or liquid phase. According to one of the preferred embodiments of the present invention, the fluorination is carried out in the liquid phase. According to the present invention, the fluorinating agent is selected from the group comprising of metal fluoride, hydrogen fluoride or mixtures thereof. In another preferred embodiment, the hydrogen fluoride is anhydrous or hydrofluoric acid. The metal fluoride is selected from, but not limited to the group comprising of antimony trifluorodichloride (SbF3Cl2) , antimony trifluoride (SbF3), stannic fluoride (SnF4), stannous fluoride (SnF2), mercuric fluoride (HgF2), silver monofluoride (AgF), silver difluoride (AgF2), cadmium fluoride (CdF2), potassium fluoride (KF), sodium fluoride (NaF), zinc fluoride (ZnF2), cobalt difluoride (CoF2), lead difluoride (PbF2), cupric fluoride (CuF2), bismuth trifluoride (BiF3) or mixtures thereof. According to one other aspect of the present invention, the fluorinating agent is added continuously or in a single lot.
The amount of fluorinating agent used, in the process of the present invention, is at least 3 moles per mole of starting material.
According to one aspect of the present invention, there is provided a process for preparing 2- fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the fluorination is carried out optionally in the presence of a catalyst.
In one embodiment, the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the catalyst is selected from the group comprising of metal chlorides, metal fluoride, phosphorous halides or mixtures thereof.
According to one of the preferred embodiments of the present invention, the metal chloride catalyst is selected from, but not limited to the group comprising of ferrous chloride (FeCl2), ferric chloride (FeCl3), niobium pentachloride (NbCl5), tantalum pentachloride (TaCl5), tungsten hexachloride (WC16), stannic chloride (SnCl4), antimony trichloride (SbCl3), titanium tetrachloride (TiCl4) and mixtures thereof. The metal fluoride catalyst is selected from, but not limited to the group comprising of antimony pentafluoride (SbF5), antimony trifluoride (SbF3), ferrous fluoride (FeF2), ferric fluoride (FeF3), silver monofluoride (AgF), potassium fluoride (KF), stannic fluoride (SnF4), titanium tetrafluoride (TiF4), chromium difluoride (CrF2), chromium trifluoride (CrF3), chromium tetrafluoride (CrF4), aluminium fluoride (A1F3), nickel difluoride (NiF2), nickel trifluoride (NiF3), manganese difluoride (MnF2), manganese trifluoride (MnF3), manganese tetrafluoride (MnF4), cobalt difluoride (CoF2), cobalt trifluoride (CoF3) or mixtures thereof In one embodiment, the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine compounds of Formula (I), wherein the fluorination is carried out in the temperature range of 90-250 °C at atmospheric, subatmospheric or superatmospheric pressure/ In a preferred embodiment, the fluorination is carried out in the temperature range of 140-230 °C at atmospheric, subatmospheric or super-atmospheric pressure.
In another embodiment, the present invention relates to the process for the preparation of 2- fluoro-6-(trifluoromethyl)pyridine compounds Formula (I), wherein the other reactant materials and catalyst is recovered and recycled. The other reactant materials include unreacted pyridine compounds of Formula (II) and hydrogen fluoride.
According to the process of the invention, 2-fluoro-6-(trifluoromethyl)pyridine cornpounds is purified by employing any suitable conventional techniques of distillation, known to the person skilled in the art.
According to yet another embodiment of the present invention, there is provided a process for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine, comprising fluorinating 2-chloro-6- (trichloromethyl)pyridine or mixture of 2-chloro-6-(trichloromethyl)pyridine and chlorofluoro pyridine compounds with a fluorinating agent and isolating the 2-fluoro-6- (trifluoromethyl)pyridine.
In one embodiment, the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine, wherein the chlorofluoro pyridine compound is selected from the group comprising of 2-chloro-6-(trifluoromethyl)pyridine, 2-chloro-6- (difluorochloromethyl)pyridine, 2-chloro-6-(dichlorofluoromethyl)pyridine or mixtures thereof.
In one embodiment, the present invention relates to a process for the preparation of 2-fluoro- 6-(trifluoromethyl)pyridine, wherein the fluorination is carried out in vapor phase or liquid phase, preferably in the liquid p hase.
According to the present invention, the fluorinating agent is selected from the group comprising of metal fluoride, hydrogen fluoride or mixtures thereof. The hydrogen fluoride is anhydrous or hydrofluoric acid preferably anhydrous hydrogen fluoride. The metal fluoride is selected from the group comprising of, but not limited to antimony trifluorodichloride (SbF3Cl2) , antimony trifluoride (SbF3), stannic fluoride (SnF4), stannous fluoride (SnF2), mercuric fluoride (HgF2), silver mono fluoride (AgF), silver difluoride (AgF2), cadmium fluoride (CdF2), potassium fluoride (KF), sodium fluoride (NaF), zinc fluoride (ZnF2), cobalt difluoride (CoF2), lead difluoride (PbF2), cupric fluoride (CuF2), bismuth trifluoride (B1F3) or mixtures thereof.
According to yet other embodiment, the present invention relates to a process for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine, wherein the fluorinating agent is added continuously or in a single lot.
The amount of fluorinating agent used, in the process of the present invention, is at least 3 moles per mole of the starting material.
In another embodiment, the present invention relates to a process for the preparation of 2- fluoro-6-(trifluoromethyl)pyridine, wherein the fluorination is carried out in the temperature range of 90-250 °C at atmospheric, subatmospheric or super-atmospheric pressure.
In a preferred embodiment, the fluorination is carried out with hydrogen fluoride in the temperature range of 140-230 °C and at a pressure between 0-50 kg/cm2, preferably between 10-30 kg/cm2. In another embodiment, the present invention relates to a process for the preparation of 2- fluoro-6-(trifluoromethyl)pyridine, wherein the fluorination is carried out optionally in the presence of a catalyst.
According to the present invention, the catalyst is selected from the group comprising of metal chlorides, metal fluoride, phosphorous halides or mixtures thereof. According to one of the preferred embodiments of the present invention, the metal chloride catalyst is selected from the group comprising of, but not limited to ferrous chloride (FeCl2), ferric chloride (FeCl3), niobium pentachloride (NbCl5), tantalum pentachloride (TaCl5), tungsten hexachloride (WC16), stannic chloride (SnCl4), antimony trichloride (SbCl3), titanium tetrachloride (T1CI4) or mixtures thereof. The metal fluoride catalyst is selected from the group comprising of, but not limited to antimony trifluoride (SbF3), ferrous fluoride (FeF2), ferric fluoride (FeF3), silver monofluoride (AgF), potassium fluoride (KF), stannic fluoride (SnF4), titanium tetrafluoride (T1F4), chromium difluoride (CrF2), chromium trifluoride (CrF3), chromium tetrafluoride (CrF4), aluminium fluoride (A1F3), nickel difluoride (NiF2), nickel trifluoride (NiF3), manganese difluoride (MnF2), manganese trifluoride (MnF3), manganese tetrafluoride (MnF4), cobalt difluoride (CoF2), cobalt trifluoride (CoF3), or mixtures thereof. According to one of the embodiment of the present invention, the fluorination process may be carried out batch-wise or continuously.
In a preferred embodiment, the gases like excess HF and HC1 generated are vented and scrubbed in chilled water and neutralized with caustic soda or calcium hydroxide. - According to the process of the invention, the excess HF and vent gases are separated and purified by conventional distillation method and recovered HF is recycled. Hydrochloric acid gas is scrubbed in chilled water to make concentrated hydrochloric acid which may be useful for other suitable processes.
According to the process of the invention, there is provided an industrial process for isolating 2-fluoro-6-(trifluoromethyl)pyridine compounds, wherein the process comprises fluorinating one or more pyridine compounds of Formula (II), depressurizing the reactor to atmospheric pressure, flushing with inert gas, optionally distilling the reaction product, diluting, neutralizing followed by distillation to obtain corresponding 2-fluoro-6- (trifluoromethyl)pyridine product with high purity. According to the process of the invention, isolation process involves distillation and neutralization of the reaction mass.
According to the process of the invention, 2-fluoro-6-(trifluoromethyl)pyridine can be purified by employing any suitable conventional techniques of distillation, known to the person skilled in the art. According to the process of the present invention, unreacted starting material and other reactant materials (chlorofluoro pyridine compounds) obtained are recovered and recycled. *
According to the process of the present invention, the other reactant materials include unreacted pyridine compounds from the group 2-chloro-6-(trichloromethyl)pyridine, 2- chloro-6-(trifluoromethyl)pyridine, 2-chloro-6-(difluorochloromethyl)pyridine, 2-chloro-6- (dichlorofluoromethyl)pyridine or mixtures thereof and hydrogen fluoride.
According to the process of the invention, the process is used to obtain pure 2-chloro-6- (trifluoromethylpyridine from the mixture of 2-chloro-6-(trichloromethyl)pyridine, 2-chloro- 6-(trifluoromethyl)pyridine, 2-chloro-6-(difluorochloromethyl)pyridine, 2-chloro-6- (dichlorofluoromethyl)pyridine by employing conventional distillation technique. In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
Example -1 A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical stirrer was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm) and ferric chloride (11 gm). The mixture was heated and anhydrous hydrogen fluoride (264 gm) was added into the reaction mixture under agitation in approx 14 hours at 170±10 °C and 20±5 kg/cm pressure. Reaction mixture was maintained further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. The reaction mass was distilled, diluted with water, neutralized with 5% aqueous solution of sodium carbonate, organic layer separated and analysed. The results obtained as per gas chromatography were: 2-fluoro-6- (trifluoromethyl)pyridine: 57.25%; 2-chloro-6-(trifluoromethyl)pyridine: 41.94%; 2-chloro-6- (trichloromethyl)pyridine: 0.06%. The obtained product was distilled to get 2-fluoro-6- (trifluoromethyl)pyridine with 99.97% GC purity. The distillation residue containing partially fluorinated chlorofluoropyridine compounds was recycled back. The product was confirmed by mass spectroscopy and 1H NMR.
MS (m/z): 165, 146, 1 15, 96, 76, 69; Ή NMR (400 MHZ, CDC13): δ 8.044-7.984 ppm (m, 1H), 6 7.622-7.598 ppm (m, 1H), δ 7.195-7.167 ppm (m, 1H).
Example -2 A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, mechanical stirrer and pressure gauge was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm) and ferric chloride (11 gm). The mixture was heated and anhydrous hydrogen fluoride was added into the reaction mixture under agitation. The temperatures of the mixture was maintained at 170±10 °C and at a pressure of 20±5 kg/cm for 18 hours with continuous feeding of anhydrous hydrogen fluoride at the rate of 20 gm/hr. Reaction mixture was maintained further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. Reaction product was distilled, diluted with water, neutralized with 5% aqueous solution of sodium carbonate, layer separated and analysed. The results obtained as per gas chromatography were: 2-fluoro-6- (trifluoromethyl)pyridine: 90.96 %; 2-chloro-6-(trifluoromethyl)pyridine: 7.67 %; 2-chloro-6- (trichloromethyl)pyridine: 0.001 %. The obtained product was distilled to obtain 2-fluoro-6- (trifluoromethyl)pyridine with 85% yield and 99.97% GC purity. The distillation residue containing partially fluorinated chlorofluoropyridine compounds was recycled back. The product was confirmed by mass spectroscopy and 1HNMR.
Example -3
The reactor was charged with 53 gm of chlorofluoropyridine residue obtained in example 2, fresh 2-chloro-6-(trichloromethyl)pyridine (178 gm) and ferric chloride (10 gm). The mixture was heated and anhydrous hydrogen fluoride was introduced into this reaction mixture under agitation. The temperatures of the reaction mixture was maintained at 170±10 °C and pressure at 20±5 kg/cm for 12 hours with feeding of anhydrous hydrogen fluoride at the rate of 20 gm/hr. Reaction mixture was maintained at above temperature and pressure conditions further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. The reaction product was distilled, diluted with water, neutralized with 5% aqueous sodium carbonate, layer separated and analysed. The obtained product was distilled to obtain 2-fluoro-6- (trifluoromethyl)pyridine with 80.2 % yield and 99.96% GC purity. The product was confirmed by mass spectroscopy and Ή NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound was recycled back.
Example -4
A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical stirrer was charged with 2-chloro-6-(trichloromethyl)pyridine (231 gm). The solution was heated and anhydrous hydrogen fluoride (260 gm) was added into the reaction mixture under agitation in approx 20 hours at 190±10 °C and 20-30 kg/cm pressure. Reaction mixture was maintained further for 8 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional method and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. Reaction product was distilled, diluted with water, neutralized with 5% aqueous solution of sodium carbonate and layer separated. The obtained product layer was analyzed by gas chromatography and the results obtained were: 2-fluoro-6- (trifluoromethyl)pyridine:- 51.87%; 2-chloro-6-(trifluoromethyl)pyridine: 38.66%; 2-chloro-6- (difluorochloromethyl)pyridine: 8.22%. The obtained product was distilled to get 2-fluoro-6- (trifluoromethyl)pyridine with 99.97% GC purity. The product was confirmed by mass spectroscopy and 1H NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound was recycled back.
Example -5
The pressure reactor was charged with 150 gm of chlorofluoropyridine residue obtained as per process of example 4. The mixture was heated and anhydrous hydrogen fluoride (297 gm) was added into this reaction mixture under agitation in 18 hours at a temperature of 170±10 °C and pressure of 20±5 kg/cm . Reaction mixture was maintained further for 4 hours. The excess HF and hydrochloric acid gas generated were vented, scrubbed and separated as per conventional and recycled. The completion of reaction was monitored by gas chromatography. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. Reaction product was distilled, diluted with water, neutralized with 5% aqueous sodium carbonate, layer separated and analysed. The results obtained as per gas chromatography were: 2-fluoro-6-(trifluoromethyl)pyridine: 86.32%; 2-Chloro-6-(trifluoromethyl)pyridne: 12.50 %. The product was distilled through to obtain 2-fluoro-6-(trifluoromethyl)pyridine with 99.67% GC purity. The product was confirmed by mass spectroscopy and 1H NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound was recycled back. Example -6
A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, mechanical stirrer and pressure gauge was charged with 2-chloro-6-(trichloromethyl)pyridine (1 16 gm). The solution was heated and anhydrous hydrogen fluoride (55 gm) was added into the reaction mixture in one lot under agitation. The reaction was maintained at a temperature 150-175 °C under autogenously developed pressure for 12 hours. After the completion of reaction, the reactor was depressurized to atmospheric pressure and flushed with nitrogen. The reaction product was diluted in ice water, neutralized with soda ash aqueous solution, followed by steam distillation and analysed. The results obtained as per gas chromatography were: 2-fluoro-6-(trifluoromethyl)pyridine: 40.28%; 2-chloro-6-(trifluoromethylpyriidne: 48.49%; 2-chloro-6-(difluorochloromethyl)pyrdine: 10.22%; 2-chloro-6-
(trichloromethyl)pyriditte: 0.01 1%. The product was confirmed by mass spectroscopy and 1H NMR.
Example -7
A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical * stirrer is charged with 2,3-dichloro-6- (trichloromethyl)pyridine (231 gm) and antimony trifluoride (1 1 gm) and KF. The solution is heated under agitation at 170±10 °C and 20±5 kg/cm pressure. Reaction mixture is maintained further for 4 hours. The excess HF and hydrochloric acid gas generated are vented, scrubbed and separated and recycled. The completion of reaction is monitored by gas chromatography. After the completion of reaction, the reactor is depressurized to atmospheric pressure and flushed with nitrogen. Reaction product is diluted with water, neutralized with 5% aqueous solution of sodium carbonate and layer separated. The obtained product layer is analyzed by gas chromatography. The obtained product is distilled to get 2,3-difluoro-6- (trifluoromethyl)pyridine. The product is confirmed by mass spectroscopy and Ή NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound is recycled back. Example -8
A 300 ml high pressure reactor equipped with overhead condenser with controlled valve, pressure gauge and mechanical stirrer is charged with , 2,5-dichloro-6- (trichloromethyl)pyridine (23 Γ gm) and antimony pentafluoride (1 1 gm). The solution is heated and recycled anhydrous hydrogen fluoride obtained is added into the reaction mixture under agitation in approx 20 hours at 170± 10 °C and 20±5 kg/cm2 pressure. Reaction mixture is maintained further for 4 hours. The excess HF and hydrochloric acid gas generated are vented, scrubbed and separated and recycled. The completion of reaction is monitored by gas chromatography. After the completion of reaction, the reactor is depressurized to atmospheric pressure and flushed with nitrogen. Reaction product is diluted with water, neutralized with 5% aqueous solution of sodium carbonate and layer separated. The obtained product layer is analyzed by gas chromatography. The obtained product is distilled to get 2,5-difiuoro-6- (trifiuoromethyl)pyridine. The product is confirmed by mass spectroscopy and 1H NMR. The distillation residue containing partially fluorinated chlorofluoropyridine compound is recycled back.

Claims

We claim:
1. A process for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine compounds of Formula (I),
Figure imgf000015_0001
said process comprising fluorination of one or more pyridine compounds of Formula (II) with fluorinating agent and isolating 2-fluoro-6-(trifluoromethyl)pyridine compound obtained.
Figure imgf000015_0002
(II)
wherein,
n is 0, 1 , 2 or 3;
m is 0, 1 , 2 or 3;
X is CI or F with the proviso that when n=3 then X≠F
and Y is independently selected from the halogen groups CI, Br, I or F.
The process according to claim 1 , wherein the fluorination is carried out in vapor phase or liquid phase, preferably in liquid phase.
The process according to claim 1, wherein the fluorinating agent is selected from the group comprising of metal fluoride, hydrogen fluoride or mixtures thereof.
The process according to claim 1 , wherein the fluorinating agent is selected from the group comprising of antimony trifluorodichloride (SbF3Cl2), antimony trifluoride (SbF3), stannic fluoride (SnF4), stannous fluoride (SnF2), mercuric fluoride (HgF2), silver monofluoride (AgF), silver difluoride (AgF2), cadmium fluoride (CdF2), potassium fluoride (KF), zinc fluoride (ΖηΡ2), cobalt difluoride (CoF2), lead difluoride (PbF2), cupric fluoride (CuF2), bismuth trifluoride (BiF3), anhydrous hydrogen fluoride, or mixtures thereof. The process according to claim 1, wherein the fluorination is carried out optionally in the presence of a catalyst selected from the group comprising of antimony trifluoride (SbF3), antimony pentafluoride (SbF5), ferrous fluoride (FeF2), ferric fluoride (FeF3), silver monofluoride (AgF), potassium fluoride (KF), stannic fluoride (SnF4), titanium tetrafluoride (TiF4), chromium difluoride (CrF2), chromium trifluoride (CrF3), chromium tetrafluoride (CrF4), aluminium fluoride (A1F3), nickel difluoride (NiF2), nickel trifluoride (NiF3), manganese difluoride (MnF2), manganese trifluoride (ΜηΡ3), manganese tetrafluoride (MnF4), cobalt difluoride (CoF2), cobalt trifluoride (CoF3), ferrous chloride (FeCl2), ferric chloride (FeCl3), niobium pentachloride (NbCl5), tantalum pentachloride (TaCl5), tungsten hexachloride (WC16), stannic chloride (SnCl4), antimony trichloride (SbCl3), titanium tetrachloride (TiCl4) or mixtures thereof.
The process according to claim 1, wherein the reaction is carried out in the temperature range of 90-250 °C and at atmospheric, subatmospheric or superatmospheric pressure.
A process for the preparation of 2-fluoro-6-(trifluoromethyl)pyridine, comprising fluorination of 2-chloro-6-(trichloromethyl)pyridine or mixture of 2-chloro-6- (trichloromethyl)pyridine and chlorofluoro pyridine compound with fluorinating agent and isolating 2-fluoro-6-(trifluoromethyl)pyridine.
The process according to claim 7, wherein the chlorofluoro pyridine compound is selected from the group comprising of 2-chloro-6-(trifluoromethyl)pyridine, 2-chloro-6- (difluorochloromethyl)pyridine, 2-chloro-6-(dichlorofluoromethyl)pyridine or mixtures thereof.
The process according to claim 7, wherein the fluorinating agent is selected from the group comprising of metal fluoride, hydrogen fluoride or mixtures thereof wherein the metal fluoride is selected from antimony trifluorodichloride (SbF3Cl2), antimony trifluoride (SbF3), stannic fluoride (SnF4), stannous fluoride (SnF2), mercuric fluoride (HgF2), silver monofluoride (AgF), silver difluoride (AgF2), cadmium fluoride (CdF2), potassium fluoride (KF), zinc fluoride (ZnF2), cobalt difluoride (CoF2), lead difluoride (PbF2), cupric fluoride (CuF2), bismuth trifluoride (BiF3), and anhydrous hydrogen fluoride. • 10. The process according to claim 7, wherein the fluorinating agent is anhydrous hydrogen fluoride.
11. The process according to claim 7, wherein the reaction is carried out in the temperature range of 140-230 °C and pressure range of 0-50 kg/cm2.
12. The . process according to claim 1 or 7, wherein the fluorinating agent is added continuously or in a single lot.
13. The process according to claim 1 or 7, wherein the process further comprises venting of excess hydrogen fluoride and hydrochloric acid gas.
14. The process according to claim 1 or 7, wherein the fluorination process is batch- wise or continuous.
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