WO2009040367A1 - Process for the preparation of fluorine containing organic compound - Google Patents

Process for the preparation of fluorine containing organic compound Download PDF

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WO2009040367A1
WO2009040367A1 PCT/EP2008/062734 EP2008062734W WO2009040367A1 WO 2009040367 A1 WO2009040367 A1 WO 2009040367A1 EP 2008062734 W EP2008062734 W EP 2008062734W WO 2009040367 A1 WO2009040367 A1 WO 2009040367A1
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formula
compound
process according
reaction
hydrogen bromide
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PCT/EP2008/062734
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French (fr)
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Wolfgang Wiesenhöfer
Cédric Le Fevere de Ten Hove
Véronique Mathieu
Anne Warge
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Solvay (Société Anonyme)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/07—Preparation of halogenated hydrocarbons by addition of hydrogen halides
    • C07C17/087—Preparation of halogenated hydrocarbons by addition of hydrogen halides to unsaturated halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
    • C07C29/12—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids
    • C07C29/124—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of mineral acids of halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups

Definitions

  • the invention relates to a process for the preparation of fluorine containing organic molecules, in particular 2,2-difluoroethanol.
  • the process comprises the preparation of a brominated fluorocarbon.
  • Difluorethanol is an important intermediate for the preparation of more complex fluor containing organic compounds, in particular pharmaceuticals and agrochemicals.
  • JP 622 73 925 discloses a process wherein l,l-difluoro-2-chlorethane as a raw material is heated in the presence of a carboxylic acid ester, an alkalimetalhydroxyde and water.
  • WO 99/56873 discloses a process for producing fluor alcohols in the presence of a catalyst.
  • EP-A 1 403 238 discloses a process for producing fluorinated alcohols through hydrolysis of fluorinated alkylhalides.
  • An important starting compound for these reactions is a fluorinated alkylhalide and several processes exist for producing such starting compounds.
  • GB 705 734 discloses a process for producing halogen derivatives of organic material directly from an organic material and a metal halide or an ammonium halide.
  • US-A 5,430,202 discloses a process for preparing substantially fluorinated alkyl bromides by reaction of substantially fluorinated alkyl iodides with phase transfer catalysts in the bromide form.
  • the present invention thus provides a process for the preparation of a fluorine containing organic molecule, which process comprises the steps of a) preparation of a compound of formula I
  • R 1 , R 2 and R 3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group by feeding a compound of formula II
  • R 3 R- ⁇ wherein R 1 , R 2 and R 3 are as defined above and hydrogen bromide into a reaction zone, thereby producing a reaction mixture containing the compound of formula II and hydrogen bromide and irradiating said reaction mixture with
  • an optionally fluorinated hydrocarbon group is preferably an optionally fluorinated hydrocarbon group with not more than 10 carbon atoms, more preferably it is an optionally fluorinated hydrocarbon group with 1-4 carbon atoms and in particular the hydrocarbon group is an alkyl residue that can be completely or partially fluorinated.
  • an optionally fluorinated hydrocarbon group is a Ci -C 4 alkyl group in which one or more, preferably two or more hydrogen atoms are replaced by fluorine atoms.
  • Examples of a fluorinated hydrocarbon group are a trifluoromethyl group, a difluoromethyl group or a fluoromethyl group or a pentafluoroethyl group, a tetrafluoroethyl group, a trifluoroethyl group or a difluoroethyl group.
  • the reaction of the compound of formula I with hydrogen bromide can advantageously be used in a process in an industrial scale by feeding the fluoroolefme and hydrogen bromide to a reaction zone to form a reaction mixture that is irradiated with UV light followed by a reaction step wherein the bromo atom is substituted to obtain the desired fluorine containing molecule.
  • substituted fluorocarbons and fluorohydrocarbons can be obtained in a high yield in a shortened and easy process.
  • reaction step a) can advantageously be conducted by continuously feeding the fluoroolefm and hydrogen bromide into the reaction zone to form a reaction mixture that is irradiated with UV light, and even more advantageously the products can continuously be withdrawn from the reaction zone.
  • the compound of formula II is therefore preferably continuously fed into the reaction zone and/or the compound of formula I is continuously removed from the reaction zone, and it is more preferably conducted so that the complete process of feeding the reaction zone with the starting materials and withdrawing the product from the reaction zone is continuous.
  • the reaction is carried out in the gas phase.
  • An example of a suitable solvent is the compound of formula I.
  • the process step a) is e.g. performed at a temperature and a pressure such that the compound of the formula II and the hydrogen bromide is in the gas phase and the compound of formula I is in liquid phase.
  • the reaction temperature at a pressure of from 0.5 to 3 bar, preferably 1 to 2 bar and more preferably about 1 bar (atmospheric pressure) is generally from -73 to 40 0 C, preferably from -20 to 30 0 C and more preferably from 5 to 20 0 C.
  • the compound of formula I can easily be withdrawn from the product mixture.
  • compound of formula II and hydrogen bromide can be fed into the reaction zone and reacted as described herein before in the gas phase and the compound of formula (I) is withdrawn in a liquid phase. Preferably this withdrawal is carried out continuously.
  • the process step a) is carried out in liquid phase it is preferable that it is carried out in the presence of an inert solvent, which can be the formula (I) compound itself or any of the optional by-products of the reaction.
  • the UV radiation is generally provided by an UV lamp and is preferably narrow-band UV radiation. Often the UV radiation is in the range of 160-600 nm, preferably it is from 160 to 300 nm, most preferably the UV radiation is in the range of 180-260 nm. It is possible to use a polychromatic UV lamp for carrying out the process, preferred is the use of a low-pressure UV lamp with a strong emission of hard UV light. Preferred UV lamp are e.g. UV lamps that have strong emissions at 185 and/or 254 nm. At these emission wavelengths, very excellent results are achieved.
  • the compound of the formula II and/or the hydrogen bromide are separated from the compound of formula I before conducting step b) and the compound of formula II and/or the hydrogen bromide can be recycled after separation to the reaction.
  • crude product from step a) is used in step (b).
  • a partial or complete separation of HBr and/or compound of formula (II) from the reaction product of step (a) can optionally be carried out to provide a crude product which contains optional by-products of the reaction of step (a).
  • Step (a) can be carried out in for example in a single photoreactor. Alternatively, two or more photoreactors in series can be used. Most preferably according to the present invention in the above formulae I and II the residue R 3 is fluorine. It is also preferred in the present invention that the fluoroolefme of formula II is vinylidene difluoride which is then reacted to l-bromo-2,2-difluoroethane in step a) and which is more preferably further reacted in step b) to obtain 2,2-difluoro-ethanol.
  • the brominated fluorocompounds of formula I are further processed in step b), in particular to fluoroalcohols by substituting the bromo atom in the compound of formula I.
  • the fluorocompounds of formula I are reacted with an O-nucleophile.
  • O-nucleophiles are salts of carboxylic acid such as sodium or potassium salts of carboxylic acids in particular formic acid, or acetic acid. It is also possible to use water or hydroxy salts such as sodium hydroxide as O-Nucleophiles.
  • step (b) of the process the bromine atom in the compound of formula I can alternatively be substituted, for example, by reaction with an N-nucleophile such as an amine, a S-nucleophile such as a sulphide, a thiol or a thioester.
  • the bromine atom in the compound of formula I is first converted into an active species by reaction with a metal such as magnesium, zinc, lithium or copper or a suitable derivative thereof and said active species is then added to an electrophilic substrate such as for example a carbonyl compound.
  • the temperature at which the substitution of the bromine atom in the compound of formula I is carried out in step (b) of the process according to the invention is generally at least 50 0 C. Often this temperature is at least 80 0 C. Preferably, this temperature is equal to or higher than 100 0 C, more preferably equal to or higher than 110 0 C and most preferably equal to or higher than l l5°C.
  • the temperature at which the substitution of the atom in the compound of formula I is carried out in step (b) of the process according to the invention is generally at most 200 0 C. Often this temperature is at most 150 0 C. Preferably, this temperature is equal to or lower than 140 0 C, more preferably equal to or lower than 130 0 C and most preferably equal to or lower than 125°C.
  • substitution of the bromine atom is preferably carried out in an inert solvent such as inert organic solvents selected for example from amide type solvents such as dimethylformamide or N-methylpyrollidone, nitrile type solvents such as acetonitrile or ether type solvents such as dioxane or THF.
  • inert organic solvents selected for example from amide type solvents such as dimethylformamide or N-methylpyrollidone, nitrile type solvents such as acetonitrile or ether type solvents such as dioxane or THF.
  • Amide type solvents give good results, in particular with O-nucleophiles.
  • substitution of the bromine atom can be carried out in the presence of an activator such as an alkali metal iodide, for example NaI or KI.
  • an activator such as an alkali metal iodide, for example NaI or KI.
  • the product of the reaction is a fluorinated ester.
  • step (b) of the process according to the invention can be a two-step sequence comprising (bl) reacting the compound of formula I with a carboxylic acid salt to provide a fluorinated ester and (b2) cleaving said fluorinated ester to produce a fluorinated alcohol.
  • the fluorinated ester obtained in step (bl) can be isolated before use in step (b2).
  • steps (bl) and (b2 ) can be carried out as one-pot reaction.
  • Cleavage methods suitable in step b2 are selected for example from transesterif ⁇ cation with another alcohol, e.g. a C1-C3 alcohol, in particular methanol, amidation with an amine, hydrolysis and destruction of the ester group, e.g. formic esters can be decomposed into alcohols and CO.
  • another alcohol e.g. a C1-C3 alcohol, in particular methanol
  • amidation with an amine amidation with an amine
  • hydrolysis and destruction of the ester group e.g. formic esters can be decomposed into alcohols and CO.
  • the bromine atom in the compound of formula I is converted into a fluorinated ester.
  • Said ester is then preferably isolated and subjected to a cleavage step under substantially anhydrous conditions.
  • the invention concerns in consequence a process for the manufacture of a fluorinated alcohol of formula III
  • R 1 , R 2 and R 3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group, which comprises cleaving a fluorinated ester of formula IV
  • R 1 , R 2 and R 3 are defined as above and R4 is hydrogen or a hydrocarbon group, in particular a methyl group under substantially anhydrous conditions.
  • Suitable cleavage methods are selected for example from transesterification with another alcohol, e.g; a C1-C3 alcohol, in particular methanol, amidation with an amine, hydrolysis and destruction of the ester group.
  • formic esters can be decomposed into alcohols and CO.
  • “Cleavage under substantially anhydrous conditions” is understood to denote a cleavage step carried out with a reaction medium containing at most 1 % by weight relative to the total weight of the reaction medium, preferably at most 0.5 wt. and more preferably at most 0.1 % by weight of water.
  • the cleavage is generally carried out at a temperature from 30 to 200 0 C, preferably from 50 to 100 0 C.
  • a preferred example of a cleavage step which can be carried out under substantially anhydrous conditions is a transesterification reaction with a second alcohol.
  • a second alcohol preferably, methanol or ethanol, most preferably methanol is used.
  • the water content of the second alcohol is controlled to allow for carrying out the transesterification under substantially anhydrous conditions.
  • substantially anhydrous alcohol in particular substantially anhydrous methanol is used.
  • the water content of the optional transesterification catalyst is controlled to allow for carrying out the transesterification under substantially anhydrous conditions. This can be accomplished, for example, by adding a solid base such as solid sodium hydroxide to the reaction medium. By this procedure it is also possible to substantially avoid the introduction of water in the reaction medium.
  • fluorinated alcohols and in particular 2,2-difluoroethanol may be very difficult to separate from water.
  • the fluorinated alcohol can be isolated from the reaction medium of the cleavage step e.g. by distillation to provide a substantially anhydrous fluorinated alcohol.
  • the invention concerns in consequence also substantially anhydrous 2,2-difluoroethanol.
  • the substantially anhydrous 2,2-difluoroethanol contains generally at most 1 % by weight, preferably at most 0.5 % by weight more preferably at most 0.1 % by weight and most preferably at most 500 mg/kg of water.
  • the substantially anhydrous 2,2-difluoroethanol contains generally at least 10 mg/kg and often at least 50 mg/kg of water.
  • the invention concerns also the use of the substantially anhydrous 2,2-difluoroethanol as reagent in synthesis of organic molecules, in particular by reaction with a compound having functional groups which can react with water.
  • 2,2-difluoroethanol is produced by continuously feeding vinylidene difluoride and hydrogen bromide into a reaction zone, thereby producing a reaction mixture, irradiating the reaction mixture with UV light, withdrawing a product mixture containing l-bromo-2,2-difluoroethane from the reaction zone, optionally separating the l-bromo-2,2-difluoroethane from the product mixture and substituting the bromo atom with a hydroxyl group.
  • 2,2-difluoroethanol is produced by continuously feeding vinylidene difluoride and hydrogen bromide into a reaction zone, thereby producing a reaction mixture, irradiating the reaction mixture with UV light, withdrawing a product mixture containing l-bromo-2,2-difluoroethane from the reaction zone, optionally separating the l-bromo-2,2-difluoroethane from the product mixture and substituting the bromo atom with an acetyl group to provide the
  • the brominated compounds are particularly useful as intermediate products for preparing e.g. fluorinated alcohols.
  • the present invention thus also provides a process for the preparation of a compound of formula I
  • R 1 , R 2 and R 3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group, which process comprises a step of continuously feeding a compound of the formula II
  • R 8 R l Ii wherein R 1 , R 2 and R 3 are defined as above and hydrogen bromide into a reaction zone, thereby producing a reaction mixture containing the compounds of formula II and hydrogen bromide and irradiating said reaction mixture with UV light.
  • the preferred embodiment of said process corresponds to those as described above for reaction step a).
  • the compound of the formual I is preferably continuously removed from the reaction zone so that the complete process of feeding the reaction zone with the starting materials and withdrawing the product from the reaction zone is continuous.
  • the reaction is carried out in the gas phase, but it is also possible to conduct the process in the liquid phase.
  • the process is e.g. performed at a temperature and a pressure such that the compound of formula II and the hydrogen bromide is in the gas phase and the compound of the formula I is in the liquid phase. With such a setup the compound of the formula I can be easily withdrawn from the product mixture.
  • reaction is carried out in the liquid phase, it is preferred that it is carried out in the present of an inert solvent. Most preferred the reaction is conducted such that the compound of formula II is vinylidene difluoride which is then reacted to l-bromo-2,2-difluoroethane.
  • Example 1 Preparation of l-bromo-2,2-difluoroethane using a polychromatic
  • UV lamp with strong excitation of hard UV at 254 nm In a standard photo reactor equipped with a water cooled Quartz headlight wells and a low-pressure UV lamp (15W, Heraeus, TNN 15/32) and a reflux cooler before the gas outlet a mixture of hydrogen bromide (HBr) and vinylidene difluoride (VF2) were introduced at ambient pressure and temperature at the bottom of the apparatus (see table). The introduced reactants passed the UV-reaction zone, where a liquid phase was immediately condensed. The so formed product l-bromo-2,2-difluoroethane was obtained at the bottom of the reactor and obtained in high purity and yield.
  • HBr hydrogen bromide
  • VF2 vinylidene difluoride
  • UV lamp with strong excitation of hard UV at 185 nm and 254 nm In a continuous photo reactor equipped with a cooled Quartz headlight wells and a low-pressure UV lamp (125 W, NIQ 125/84 XL) and a reflux cooler before the gas outlet a mixture of hydrogen bromide (HBr) and vinylidene difluoride (VF2) were introduced at ambient pressure and temperature at the bottom of the apparatus (see table).
  • the introduced reactants passed the UV-reaction zone, where a liquid phase was immediately condensed.
  • the effective reaction temperature was 10 0 C.
  • the liquid phase was collected in a vessel heated at 60 0 C and equipped with a condenser to remove dissolved reactants. The so formed l-bromo-2,2-difluoroethane was obtained in high purity, yield and productivity.
  • Example 6 Trans esterification of 2 ,2-difluoroethyl acetate with methanol In a 250 ml three necked flask equipped with a reflux condenser and drying tube 76 g of 2,2-difluoroethyl acetate (content ca. 70 wt. %), 1 g of sodium hydroxide and 47 g of methanol were heated to reflux and stirring. After 30 min the conversion was complete the mixture was distilled. By doing so at atmospheric pressure 25 g of 2,2-difluoroethanol with a purity >99 % were isolated.
  • Example 7 reaction of l-bromo-2,2-difluoroethane with sodium formiate
  • Example 8 trans esterification of 2,2-difluoroethyl formiate with methanol
  • a 250 ml three necked flask equipped with a reflux condenser and drying tube 59.1 g of 2,2-difluoroethyl formiate, 1 g of sodium hydroxide and 51.7 g of methanol were heated to reflux under stirring. After 2 h the conversion was complete. By distillation at atmospheric pressure 28.6 g of 2,2-difluoroethanol with a purity >98.5 % were isolated (65 % isolated yield).
  • Example 9 difluoroethanol preparation via acetylation and hydrolysis (steps bl and b2) in a one pot operation Step bl
  • step bl Acetylation of l-bromo-2,2-difluoroethane with sodium acetate
  • Example 11 The experiment has been conducted according to the conditions described in example 9 step bl, with an equimolar ratio of brominated derivative (0.42 mole) and sodium acetate (0.42 mole) and a smaller quantity of solvent (123 g of DMF or 1.7 moles).
  • the conversion yield of CHF2-CH2Br was 100 % and the yield of difluoroethyl acetate was 100 % (GC analysis). Difluoroethyl acetate at 97 % GC purity can be isolated from the reaction medium by distillation.
  • Example 11 The experiment has been conducted according to the conditions described in example 10, with equimolar ratio of brominated derivative and sodium acetate and a further reduction of solvent quantity (60 g of DMF or 0.9 mole).
  • Example 12 The experiment has been conducted according to the conditions described in example 11, with equimolar ratio of brominated derivative and sodium acetate in presence of 205 g (2.1 moles) N-methylpyrrolidone (NMP) as solvent. After a reaction time of 20 hours at 125°C, a conversion of 97.5 % (GC analysis) was observed.
  • Example 13 Trans esterification of 2,2-difluoroethylacetate into

Abstract

Process for the preparation of a fluorine containing organic molecule, which process comprises the steps of a) preparation of a compound of the formula (I) wherein R1, R2 and R3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group by feeding a compound of the formula (II) wherein R1, R2 and R3 are defined as above, and hydrogen bromide into a reaction zone, thereby producing a reaction mixture containing the compound of formula (II) and hydrogen bromide and irradiating said reaction mixture with UV light, and b) substituting the bromo atom in the compound of the formula (I) with another functional group to obtain the fluorine containing organic molecule. The invention allows also in particular for obtaining substantially anhydrous fluoroalcohols. The preparation of alcohols analogous to the bromides of formula (I) from the corresponding esters is also disclosed.

Description

Process for the Preparation of Fluorine Containing Organic Compound
The invention relates to a process for the preparation of fluorine containing organic molecules, in particular 2,2-difluoroethanol. The process comprises the preparation of a brominated fluorocarbon. Difluorethanol is an important intermediate for the preparation of more complex fluor containing organic compounds, in particular pharmaceuticals and agrochemicals.
There exist several industrial methods for producing fluorinated alcohols such as difluoroethanol that is an important compound for the production of e.g. pharmaceuticals such as inhalation anaesthetics. For example JP 622 73 925 discloses a process wherein l,l-difluoro-2-chlorethane as a raw material is heated in the presence of a carboxylic acid ester, an alkalimetalhydroxyde and water. WO 99/56873 discloses a process for producing fluor alcohols in the presence of a catalyst. EP-A 1 403 238 discloses a process for producing fluorinated alcohols through hydrolysis of fluorinated alkylhalides.
An important starting compound for these reactions is a fluorinated alkylhalide and several processes exist for producing such starting compounds. For example it can be referred to GB 705 734 which discloses a process for producing halogen derivatives of organic material directly from an organic material and a metal halide or an ammonium halide. US-A 5,430,202 discloses a process for preparing substantially fluorinated alkyl bromides by reaction of substantially fluorinated alkyl iodides with phase transfer catalysts in the bromide form.
It is also known that hydrogen bromide can be added to difluoroethylene under irradiation with sun light. This reaction was disclosed in 1956 by Haszeldine and Osborne (J Chem Soc (1956) 61,69). However, if such a process is industrially not very feasible, in particular when this reaction step is part of an industrial process and is followed by one or more reaction steps.
There exists the need for an improved process, in particular a process comprising less reaction steps, for the preparation of fluorine containing organic molecules with a high space time yield and a good productivity that allows for an easy processing. Preferably, it should be possible to carry out the process continuously. The present invention thus provides a process for the preparation of a fluorine containing organic molecule, which process comprises the steps of a) preparation of a compound of formula I
Figure imgf000003_0001
wherein R1, R2 and R3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group by feeding a compound of formula II
F. R
R3 R- π wherein R1, R2 and R3 are as defined above and hydrogen bromide into a reaction zone, thereby producing a reaction mixture containing the compound of formula II and hydrogen bromide and irradiating said reaction mixture with
UV light, and b) substituting the bromo atom in the compound of formula I with another functional group to obtain the fluorine organic molecule.
In the above formulae I and II an optionally fluorinated hydrocarbon group is preferably an optionally fluorinated hydrocarbon group with not more than 10 carbon atoms, more preferably it is an optionally fluorinated hydrocarbon group with 1-4 carbon atoms and in particular the hydrocarbon group is an alkyl residue that can be completely or partially fluorinated. Most preferably an optionally fluorinated hydrocarbon group is a Ci -C4 alkyl group in which one or more, preferably two or more hydrogen atoms are replaced by fluorine atoms. Examples of a fluorinated hydrocarbon group are a trifluoromethyl group, a difluoromethyl group or a fluoromethyl group or a pentafluoroethyl group, a tetrafluoroethyl group, a trifluoroethyl group or a difluoroethyl group. Surprisingly, the reaction of the compound of formula I with hydrogen bromide can advantageously be used in a process in an industrial scale by feeding the fluoroolefme and hydrogen bromide to a reaction zone to form a reaction mixture that is irradiated with UV light followed by a reaction step wherein the bromo atom is substituted to obtain the desired fluorine containing molecule. By this reaction substituted fluorocarbons and fluorohydrocarbons can be obtained in a high yield in a shortened and easy process.
It has also been surprisingly found that the reaction step a) can advantageously be conducted by continuously feeding the fluoroolefm and hydrogen bromide into the reaction zone to form a reaction mixture that is irradiated with UV light, and even more advantageously the products can continuously be withdrawn from the reaction zone.
In the process step a) of the present invention the compound of formula II is therefore preferably continuously fed into the reaction zone and/or the compound of formula I is continuously removed from the reaction zone, and it is more preferably conducted so that the complete process of feeding the reaction zone with the starting materials and withdrawing the product from the reaction zone is continuous. Preferably the reaction is carried out in the gas phase. It is also possible to conduct the process in the liquid phase, e.g. by irradiating the reactants dissolved in a solvent. An example of a suitable solvent is the compound of formula I. The process step a) is e.g. performed at a temperature and a pressure such that the compound of the formula II and the hydrogen bromide is in the gas phase and the compound of formula I is in liquid phase. As an example, when vinylidene difluoride is used as compound of formula II, the reaction temperature at a pressure of from 0.5 to 3 bar, preferably 1 to 2 bar and more preferably about 1 bar (atmospheric pressure) is generally from -73 to 400C, preferably from -20 to 300C and more preferably from 5 to 200C.
With such a setup the compound of formula I can easily be withdrawn from the product mixture. For example, compound of formula II and hydrogen bromide can be fed into the reaction zone and reacted as described herein before in the gas phase and the compound of formula (I) is withdrawn in a liquid phase. Preferably this withdrawal is carried out continuously. If the process step a) is carried out in liquid phase it is preferable that it is carried out in the presence of an inert solvent, which can be the formula (I) compound itself or any of the optional by-products of the reaction.
The UV radiation is generally provided by an UV lamp and is preferably narrow-band UV radiation. Often the UV radiation is in the range of 160-600 nm, preferably it is from 160 to 300 nm, most preferably the UV radiation is in the range of 180-260 nm. It is possible to use a polychromatic UV lamp for carrying out the process, preferred is the use of a low-pressure UV lamp with a strong emission of hard UV light. Preferred UV lamp are e.g. UV lamps that have strong emissions at 185 and/or 254 nm. At these emission wavelengths, very excellent results are achieved.
In one embodiment in the process step a) of the present invention the compound of the formula II and/or the hydrogen bromide are separated from the compound of formula I before conducting step b) and the compound of formula II and/or the hydrogen bromide can be recycled after separation to the reaction.
In another embodiment, crude product from step a) is used in step (b). In this embodiment a partial or complete separation of HBr and/or compound of formula (II) from the reaction product of step (a) can optionally be carried out to provide a crude product which contains optional by-products of the reaction of step (a).
Step (a) can be carried out in for example in a single photoreactor. Alternatively, two or more photoreactors in series can be used. Most preferably according to the present invention in the above formulae I and II the residue R3 is fluorine. It is also preferred in the present invention that the fluoroolefme of formula II is vinylidene difluoride which is then reacted to l-bromo-2,2-difluoroethane in step a) and which is more preferably further reacted in step b) to obtain 2,2-difluoro-ethanol. The brominated fluorocompounds of formula I are further processed in step b), in particular to fluoroalcohols by substituting the bromo atom in the compound of formula I.
In a preferred embodiment, the fluorocompounds of formula I are reacted with an O-nucleophile. Preferred O-nucleophiles are salts of carboxylic acid such as sodium or potassium salts of carboxylic acids in particular formic acid, or acetic acid. It is also possible to use water or hydroxy salts such as sodium hydroxide as O-Nucleophiles.
In step (b) of the process the bromine atom in the compound of formula I can alternatively be substituted, for example, by reaction with an N-nucleophile such as an amine, a S-nucleophile such as a sulphide, a thiol or a thioester. In another embodiment, the bromine atom in the compound of formula I is first converted into an active species by reaction with a metal such as magnesium, zinc, lithium or copper or a suitable derivative thereof and said active species is then added to an electrophilic substrate such as for example a carbonyl compound. The temperature at which the substitution of the bromine atom in the compound of formula I is carried out in step (b) of the process according to the invention is generally at least 500C. Often this temperature is at least 800C. Preferably, this temperature is equal to or higher than 1000C, more preferably equal to or higher than 1100C and most preferably equal to or higher than l l5°C.
The temperature at which the substitution of the atom in the compound of formula I is carried out in step (b) of the process according to the invention is generally at most 2000C. Often this temperature is at most 1500C. Preferably, this temperature is equal to or lower than 1400C, more preferably equal to or lower than 1300C and most preferably equal to or lower than 125°C.
The substitution of the bromine atom is preferably carried out in an inert solvent such as inert organic solvents selected for example from amide type solvents such as dimethylformamide or N-methylpyrollidone, nitrile type solvents such as acetonitrile or ether type solvents such as dioxane or THF. Amide type solvents give good results, in particular with O-nucleophiles.
The substitution of the bromine atom can be carried out in the presence of an activator such as an alkali metal iodide, for example NaI or KI.
When a carboxylic acid salt is used as the O-nucleophile, the product of the reaction is a fluorinated ester.
In this case, if the desired product is a fluorinated alcohol, step (b) of the process according to the invention can be a two-step sequence comprising (bl) reacting the compound of formula I with a carboxylic acid salt to provide a fluorinated ester and (b2) cleaving said fluorinated ester to produce a fluorinated alcohol. The fluorinated ester obtained in step (bl) can be isolated before use in step (b2). Alternatively, steps (bl) and (b2 ) can be carried out as one-pot reaction.
Cleavage methods suitable in step b2 are selected for example from transesterifϊcation with another alcohol, e.g. a C1-C3 alcohol, in particular methanol, amidation with an amine, hydrolysis and destruction of the ester group, e.g. formic esters can be decomposed into alcohols and CO.
In a particularly preferred embodiment, the bromine atom in the compound of formula I is converted into a fluorinated ester. As described herein before. Said ester is then preferably isolated and subjected to a cleavage step under substantially anhydrous conditions. The invention concerns in consequence a process for the manufacture of a fluorinated alcohol of formula III
Figure imgf000007_0001
wherein R1, R2 and R3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group, which comprises cleaving a fluorinated ester of formula IV
Figure imgf000007_0002
wherein R1, R2 and R3 are defined as above and R4 is hydrogen or a hydrocarbon group, in particular a methyl group under substantially anhydrous conditions.
Suitable cleavage methods are selected for example from transesterification with another alcohol, e.g; a C1-C3 alcohol, in particular methanol, amidation with an amine, hydrolysis and destruction of the ester group. In particular, formic esters can be decomposed into alcohols and CO. "Cleavage under substantially anhydrous conditions" is understood to denote a cleavage step carried out with a reaction medium containing at most 1 % by weight relative to the total weight of the reaction medium, preferably at most 0.5 wt. and more preferably at most 0.1 % by weight of water. The cleavage is generally carried out at a temperature from 30 to 2000C, preferably from 50 to 1000C.
A preferred example of a cleavage step which can be carried out under substantially anhydrous conditions is a transesterification reaction with a second alcohol. In that case, preferably, methanol or ethanol, most preferably methanol is used. The water content of the second alcohol is controlled to allow for carrying out the transesterification under substantially anhydrous conditions.
In that case, preferably, substantially anhydrous alcohol, in particular substantially anhydrous methanol is used.
The water content of the optional transesterification catalyst is controlled to allow for carrying out the transesterification under substantially anhydrous conditions. This can be accomplished, for example, by adding a solid base such as solid sodium hydroxide to the reaction medium. By this procedure it is also possible to substantially avoid the introduction of water in the reaction medium.
In fact, it has been found that fluorinated alcohols and in particular 2,2-difluoroethanol may be very difficult to separate from water. The fluorinated alcohol can be isolated from the reaction medium of the cleavage step e.g. by distillation to provide a substantially anhydrous fluorinated alcohol.
The invention concerns in consequence also substantially anhydrous 2,2-difluoroethanol. The substantially anhydrous 2,2-difluoroethanol contains generally at most 1 % by weight, preferably at most 0.5 % by weight more preferably at most 0.1 % by weight and most preferably at most 500 mg/kg of water. The substantially anhydrous 2,2-difluoroethanol contains generally at least 10 mg/kg and often at least 50 mg/kg of water.
The invention concerns also the use of the substantially anhydrous 2,2-difluoroethanol as reagent in synthesis of organic molecules, in particular by reaction with a compound having functional groups which can react with water.
In first a particularly preferred process of the present invention 2,2-difluoroethanol is produced by continuously feeding vinylidene difluoride and hydrogen bromide into a reaction zone, thereby producing a reaction mixture, irradiating the reaction mixture with UV light, withdrawing a product mixture containing l-bromo-2,2-difluoroethane from the reaction zone, optionally separating the l-bromo-2,2-difluoroethane from the product mixture and substituting the bromo atom with a hydroxyl group.
In a second particularly preferred process of the present invention, 2,2-difluoroethanol is produced by continuously feeding vinylidene difluoride and hydrogen bromide into a reaction zone, thereby producing a reaction mixture, irradiating the reaction mixture with UV light, withdrawing a product mixture containing l-bromo-2,2-difluoroethane from the reaction zone, optionally separating the l-bromo-2,2-difluoroethane from the product mixture and substituting the bromo atom with an acetyl group to provide the
2,2-difluoroethyl acetate which is subsequently converted into hydroxyl group according to the process according to the invention. This sequence is illustrated by examples 3, 5 and 6.
The brominated compounds are particularly useful as intermediate products for preparing e.g. fluorinated alcohols. The present invention thus also provides a process for the preparation of a compound of formula I
Figure imgf000009_0001
wherein R1, R2 and R3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group, which process comprises a step of continuously feeding a compound of the formula II
Figure imgf000009_0002
R8 R l Ii wherein R1, R2 and R3 are defined as above and hydrogen bromide into a reaction zone, thereby producing a reaction mixture containing the compounds of formula II and hydrogen bromide and irradiating said reaction mixture with UV light.
The preferred embodiment of said process corresponds to those as described above for reaction step a). In particular in the process for the preparation of compounds of the formula I of the present invention the compound of the formual I is preferably continuously removed from the reaction zone so that the complete process of feeding the reaction zone with the starting materials and withdrawing the product from the reaction zone is continuous. Preferably, the reaction is carried out in the gas phase, but it is also possible to conduct the process in the liquid phase. The process is e.g. performed at a temperature and a pressure such that the compound of formula II and the hydrogen bromide is in the gas phase and the compound of the formula I is in the liquid phase. With such a setup the compound of the formula I can be easily withdrawn from the product mixture. If the reaction is carried out in the liquid phase, it is preferred that it is carried out in the present of an inert solvent. Most preferred the reaction is conducted such that the compound of formula II is vinylidene difluoride which is then reacted to l-bromo-2,2-difluoroethane.
The following examples are not intended to limit the scope of the invention. Example 1 : Preparation of l-bromo-2,2-difluoroethane using a polychromatic
UV lamp
In a standard photo reactor equipped with a water cooled Quartz headlight wells and a polychromatic UV lamp (150W, Heraeus, TQ150) and a reflux cooler before the gas outlet a mixture of hydrogen bromide (HBr) and vinylidene difluoride (VF2) were introduced at ambient pressure and temperature at the bottom of the apparatus (see table). The introduced reactants passed the UV-reaction zone, where a liquid phase was immediately condensed. The so formed product 2-bromo-l,l-difluoroethane was obtained at the bottom of the reactor in high purity and yield.
Figure imgf000010_0001
Example 2 : Preparation of l-bromo-2,2-difluoroethane using a low-pressure
UV lamp with strong excitation of hard UV at 254 nm In a standard photo reactor equipped with a water cooled Quartz headlight wells and a low-pressure UV lamp (15W, Heraeus, TNN 15/32) and a reflux cooler before the gas outlet a mixture of hydrogen bromide (HBr) and vinylidene difluoride (VF2) were introduced at ambient pressure and temperature at the bottom of the apparatus (see table). The introduced reactants passed the UV-reaction zone, where a liquid phase was immediately condensed. The so formed product l-bromo-2,2-difluoroethane was obtained at the bottom of the reactor and obtained in high purity and yield.
Figure imgf000010_0002
Example 3 : Preparation of l-bromo-2,2-difluoroethane using a low-pressure
UV lamp with strong excitation of hard UV at 185 nm and 254 nm In a continuous photo reactor equipped with a cooled Quartz headlight wells and a low-pressure UV lamp (125 W, NIQ 125/84 XL) and a reflux cooler before the gas outlet a mixture of hydrogen bromide (HBr) and vinylidene difluoride (VF2) were introduced at ambient pressure and temperature at the bottom of the apparatus (see table). The introduced reactants passed the UV-reaction zone, where a liquid phase was immediately condensed. The effective reaction temperature was 100C. The liquid phase was collected in a vessel heated at 600C and equipped with a condenser to remove dissolved reactants. The so formed l-bromo-2,2-difluoroethane was obtained in high purity, yield and productivity.
Figure imgf000011_0001
Example 4 : Preparation of l-bromo-2,2-difluoroethane by removing the product by distillation
In a heat stable photo reactor equipped with an air cooled Quartz headlight wells and a polychromatic UV lamp (150W, Heraeus, TQ150), a Liebig cooler before the gas outlet a mixture of hydrogen bromide (HBr) and vinylidene difluoride (VF2) were introduced at ambient pressure at 65°C at the bottom of the apparatus (see table). The introduced reactants passed the UV-reaction zone, were condensed in the Liebig cooler and caught in balloons.
Figure imgf000011_0002
Example 5 : Reaction of 2-bromo-l ,1-difluoroethane with sodium acetate
In a IL three necked flask equipped with a mechanical stirrer, a reflux condenser and drying tube 108 g of l-bromo-2,2-difluoroethane, 92 g of sodium acetate, 600 ml of DMF and 11.3 g of sodium iodide were heated to 1300C under stirring for 18 h. The produced 2,2-difluoroethyl acetate was removed by distillation from the DMF. Finally 105.5 g of crude material were obtained with a content of 2,2-difluoroethyl acetate ca 70 % by weight (main impurity DMF). That results in a yield of 75.2 g of 2,2-difluoroethyl acetate (80 % yield). The material was used in the next step without further purification. Example 6 : Trans esterification of 2 ,2-difluoroethyl acetate with methanol In a 250 ml three necked flask equipped with a reflux condenser and drying tube 76 g of 2,2-difluoroethyl acetate (content ca. 70 wt. %), 1 g of sodium hydroxide and 47 g of methanol were heated to reflux and stirring. After 30 min the conversion was complete the mixture was distilled. By doing so at atmospheric pressure 25 g of 2,2-difluoroethanol with a purity >99 % were isolated. Example 7 : reaction of l-bromo-2,2-difluoroethane with sodium formiate
In a IL three necked flask equipped with a mechanical stirrer, a reflux condenser and drying tube 145 g of l-bromo-2,2-difluoroethane, 102.6 g of sodium formiate, 300 ml of DMF was heated to 1300C under stirring for 40 h. The produced 2,2-difluoroethyl formiate was removed by distillation from the DMF. 59 g of 2,2-difluoroethyl formiate were obtained (purity 98 %, 55 % isolated yield). Additional 2,2-difluoroethyl formiate was obained in mixed fractions.
Example 8 : trans esterification of 2,2-difluoroethyl formiate with methanol In a 250 ml three necked flask equipped with a reflux condenser and drying tube 59.1 g of 2,2-difluoroethyl formiate, 1 g of sodium hydroxide and 51.7 g of methanol were heated to reflux under stirring. After 2 h the conversion was complete. By distillation at atmospheric pressure 28.6 g of 2,2-difluoroethanol with a purity >98.5 % were isolated (65 % isolated yield). Example 9 : difluoroethanol preparation via acetylation and hydrolysis (steps bl and b2) in a one pot operation Step bl
In a 0.5 L glass reactor, equipped with a mechanical stirrer, a reflux condenser and a temperature probe, 59.2 g (0.41 mole) of l-bromo-2,2- difluoroethane were mixed with 46.2 g (0.56 mole) of sodium acetate and 6.2 g of potassium iodide in 300 g of dimethylformamide (DMF) and heated under stirring at 125°C for 20 hours. After cooling, a sample was analyzed by GC. The conversion of CHF2-CH2Br is 100 % and the yield of difluoroethyl acetate is 100 %. Step b2
To the reaction medium obtained in step bl, 100 g of methanol and 3 g of NaOH (solid) were added. After heating at 65°C (methanol boiling point at atmospheric pressure) during 2 hours, the conversion was complete and the yield to difluoroethanol was 100 % as evidenced by GC analysis. Example 10 : Acetylation of l-bromo-2,2-difluoroethane with sodium acetate (step bl)
The experiment has been carried out according to the conditions described in example 9 step bl, with an equimolar ratio of brominated derivative (0.42 mole) and sodium acetate (0.42 mole) and a smaller quantity of solvent (123 g of DMF or 1.7 moles). The conversion yield of CHF2-CH2Br was 100 % and the yield of difluoroethyl acetate was 100 % (GC analysis). Difluoroethyl acetate at 97 % GC purity can be isolated from the reaction medium by distillation. Example 11 : The experiment has been conducted according to the conditions described in example 10, with equimolar ratio of brominated derivative and sodium acetate and a further reduction of solvent quantity (60 g of DMF or 0.9 mole). A conversion of 100 % (GC analysis) of difluoroethyl bromide into difluoroethyl acetate was observed after 40 hours. Example 12 : The experiment has been conducted according to the conditions described in example 11, with equimolar ratio of brominated derivative and sodium acetate in presence of 205 g (2.1 moles) N-methylpyrrolidone (NMP) as solvent. After a reaction time of 20 hours at 125°C, a conversion of 97.5 % (GC analysis) was observed. Example 13 : Trans esterification of 2,2-difluoroethylacetate into
2 ,2-difluoroethanol (step b2)
In a 0.5 L glass reactor, equipped with a mechanical stirrer, a reflux condenser and a temperature probe, 164 g of 2,2-difluoroethylacetate (95 % GC purity) were added to 106 g of methanol and 3 g of solid NaOH. After 2 hours at 65°C, the conversion was complete. After distillation, the isolated yield in 2,2-difiuoroethanol (96.3 % GC purity) was 87 %. Example 14 : Amidation of 2 ,2-difluoroethyl formiate with dimethylamine
In a 20 ml sealed tube 1 g of 2,2-difluoroethyl formiate and 1 g of dimethylamine were heated under stirring to 1000C for 15 h. After that time the conversion to difluoroethanol was complete (GC- Analysis).
Example 15 : Amidation of 2,2-difluoroethyl formiate with dimethylamine using crude formiate
In a 100 ml three neck flask equipped with a mechanical stirrer, a reflux condenser and drying tube 14.5 g of 2-bromo-l,l-difluoroethane, 10.3 g of sodium formiate, 30 ml of DMF were heated to 1300C under stirring for 40 h. The solution was then cooled to room temperature and the liquid phase was decanted from solids. 12 g of the crude liquid (containing 25 % by weight 2,2-difluoroethyl formiate) were placed into a 20 ml sealed tube, 1.5 g of dimethylamine was added and is the mixture heated under stirring to 1000C for 6 h. Afterwards aqueous HCl was added and the content of difluoroethanol was determined by GC analysis content 13.1 %, corresponding to a conversion of 74 %).

Claims

C L A I M S
1. Process for the preparation of a fluorine containing organic molecule, which process comprises the steps of
a) preparation of a compound of the formula I
Figure imgf000014_0001
wherein R1, R2 and R3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group by feeding a compound of the formula II
Figure imgf000014_0002
R R3 R K1 n
wherein R1, R2 and R3 are defined as above, and hydrogen bromide into a reaction zone, thereby producing a reaction mixture containing the compound of formula II and hydrogen bromide and irradiating said reaction mixture with UV light, and
b) substituting the bromo atom in the compound of the formula I with another functional group to obtain the fluorine containing organic molecule.
2. Process according to claim 1, wherein the optionally fluorinated hydrocarbon groups have 1 to 10 carbon atoms.
3. Process according to any of the preceding claims, wherein the compound of formula II is continuously fed into the reaction zone and/or the compound of formula I is continuously removed from the reaction zone.
4. Process according any of the preceding claims, wherein the step a) is conducted at a temperature and pressure such that the compound of the formula II and the hydrogen bromide are in gas phase and the compound of the formula I is in liquid phase.
5. Process according to claims 1-3, wherein the step a) is carried out in the liquid phase.
6. Process according to any of the preceding claims, wherein the UV irradiation wavelength is in the range of 160 to 600 nm, preferably from 180 to 260 nm.
7. Process according to any of the preceding claims, which process further comprises the step of separating the compound of the formula II and/or the hydrogen bromide from the compound of the formula I before conducting step b).
8. Process according to claim 7, which further comprises the step of recycling the compound of the formula II and/or the hydrogen bromide after separation from the compound of formula I.
9. Process according to any of the preceding claims, wherein R3 is F.
10. Process according to any of the preceding claims, wherein R1 and R2 are H.
11. Process according to any of the preceding claims, wherein the fluorine containing organic molecule is a fluoroalcohol.
12. Process according to any of the preceding claims for producing 2,2-difluorethanol by continuously feeding vinylidene difluoride and hydrogen bromide into a reaction zone, thereby producing a reaction mixture, irradiating the reaction mixture with UV light, withdrawing a product mixture containing 2~bromo-l,l-difluoroethane from the reaction zone, optionally separating the 2~bromo-l,l-difluoroethane from the product mixture and substituting the bromo atom with a hydroxyl group.
13. Process according to anyone of claims 1 to 10 wherein in step (b) of the process the bromine atom in the compound of formula I is substituted by reaction with an N-nucleophile such as an amine, a S-nucleophile such as a sulphide, a thiol or a thioester.
14. Process according to anyone of claims 1 to 10 wherein in step (b) the compound of formula I is first converted into an active species by reaction with a metal such as magnesium, zinc, lithium or copper or a suitable derivative thereof and said active species is then added to an electrophilic substrate.
15. Process according to anyone of claims 1 to 14 wherein the temperature at which the substitution of the bromine atom in the compound of formula I is carried out in step (b) is from 500C to 2000C, preferably from 1100C to 1300C.
16. Process for the preparation of a compound of the formula I
Figure imgf000016_0001
wherein R1, R2 and R3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group, which process comprises the step of continuously feeding a compound of the formula II
\ / R2
R R3 R K1 n
wherein R1, R2 and R3 are defined as above, and hydrogen bromide into a reaction zone, thereby producing a reaction mixture containing the compound of formula II and hydrogen bromide and irradiating said reaction mixture with UV light.
17. Process for the manufacture of a fluorinated alcohol of formula III
Figure imgf000017_0001
wherein R1, R2 and R3 are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group, which comprises (a) cleaving a fluorinated ester of formula IV
Figure imgf000017_0002
wherein R1, R2 and R3 are defined as above and R4 is hydrogen or a hydrocarbon group, in particular a methyl group under substantially anhydrous conditions.
18. Process according to claim 17, wherein the cleavage is carried out by transesterification, with a second alcohol, preferably with a non fluorinated alcohol.
19. Process according to claim 18, wherein the second alcohol is selected from methanol and ethanol.
20. Process according to claim 18 or 19 wherein the transesterification is catalysed by addition of a solid base.
21. Process according to anyone of claims 17 to 20, further comprising isolating the fluorinated alcohol in substantially anhydrous form by distillation of the reaction medium of step (c).
22. Process according to anyone of claims 17 to 21 wherein the cleavage is carried out at a temperature from 30 to 2000C, preferably from 50 to 1000C.
23. Process according to anyone of claims 17 to 22, wherein the fluorinated alcohol is 2,2-difluoroethanol.
24. Substantially anhydrous 2,2-difluoroethanol.
25. Use of substantially anhydrous 2,2-difluoroethanol as reagent in synthesis of organic molecules.
26. Use according to claim 25 wherein the organic molecule is synthesized by reaction of the 2,2-difluoroethanol with a compound having functional groups which can react with water.
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