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

wherein R ¹ , R ² and R ³ are independently hydrogen, fluor or an optionally fluorinated hydrocarbon group by feeding a compound of formula II

F. R

R ³ R- _π 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

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 -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. 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 40 ⁰ C, preferably from -20 to 30 ⁰ C and more preferably from 5 to 20 ⁰ C.

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 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.

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 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.

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

wherein 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

wherein 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. 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 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. 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

wherein 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). 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.

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.

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 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 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.

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 130 ⁰ C 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 130 ⁰ C 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 100 ⁰ C 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 130 ⁰ C 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 100 ⁰ C 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 %).