Field of Invention

The invention relates to a new process for the manufacture of nonafluoro-tert- butyl alcohol, commonly also known as perfluoro-t-butanol (perfluoro-t-BuOH).

Background of Invention

The compound nonafluoro-tert-butyl alcohol (IUPAC name: 1,1, 1,3, 3, 3- hexafluoro-2-(trifluoromethyl)propan-2-ol) is a fluoroalcohol. Other names are perfluoro-tert-butyl alcohol, perfluoro-tert-butanol or perfluoro-t-butanol (perfluo- ro-t-BuOH), respectively.

Typical technical applications of the compound perfluoro-t-butanol (perfluoro-t- BuOH) are described in scientific or technical literature as well as in patent literature. Some older applications of perfluoro-t-butanol (perfluoro-t-BuOH) are in so- called “fluorous chemistry reactions”, for example, as disclosed in the Journal of Fluorine Chemistry (2006), 127(11), 1496-1504. The compound perfluoro-t- butanol (perfluoro-t-BuOH) is also described for use in the preparation of pharmaceutical peptides like in WO 2008/034093. Newer technical applications of the compound perfluoro-t-butanol (perfluoro-t-BuOH) in ionic liquids are described, for example, in New Journal of Chemistry (2017), 41(1), 47-50; and use as heat transfer fluid is described, for example, in CN 111792985; and use in polymer applications is described, for example, in JP 2013/006952 and in the journal Macromolecules (Washington, DC, United States) (2016), 49(10), 3706-3715. Newer patent publications like CN 110563764 describe the large scale use of the compound perfluoro-t-butanol (perfluoro-t-BuOH) as flame retardant in battery electrolyte formulations, and as starting material for stable peroxides as replacement for SFe (which has a huge global warming potential value of 23900; SFe is currently used as gaseous dielectric medium in very high industrial amounts in high voltage electricity applications e.g. as circuit breakers and switch gear). The com- pound perfluoro-t-butanol (perfluoro-t-BuOH) is also described as an additive in electronics, for example, in WO 2019/207020.

The compound perfluoro-t-butanol (perfluoro-t-BuOH) is the perfluorinated analogue of tert-butyl alcohol (t-butanol; t-BuOH). Notably, as a consequence of its electron withdrawing fluorine substituents, it is very acidic for an alcohol, with a pK _a value (acidity) of 5.4, similar to that of a carboxylic acid. As another consequence of being a perfluorinated compound, it is also one of the lowest boiling alcohols, with a boiling point lower than that of methanol. (CAS number: 2378- 02-1) Chemical formula C4F9OH Molecular mass: 236.04 g/mol. It is a colourless liquid, miscible with water, boiling point 45 °C (standard state at 25 °C and 100 kPa).

The compound perfluoro-t-butanol (perfluoro-t-BuOH) is normally prepared by addition of trichloromethyllithium to hexafluoroacetone, followed by halogen exchange with antimony pentafluoride. The aluminate derived from its alkoxide anion, tetraki s[l,l,l,3,3,3 -hexafluoro-2-(trifluoromethyl)propan-2- oxy]aluminate(l-), {A1[(CF3)3CO]4}“ is used as a weakly coordinating anion. However, the use of trichloromethyllithium is hazardous because lithium organyl compounds with halogen in the alpha-position tend to be explosive (dihalocarbene formation).

All prior art processes for the manufacture of the compound perfluoro-t-butanol (perfluoro-t-BuOH) currently known in the prior art have a number of disadvantages.

Currently the compound perfluoro-t-butanol (perfluoro-t-BuOH) is produced by the general reaction of a “CF3" anion” with hexafluoroacetone (HF A) in a nucleophilic reaction as outlined in the following reaction scheme: HFA perfluoro-t-BuOH

Hexafluoroacetone (HFA) is a gas at room temperature, and therefore besides the involved “chemistry” the costs for HFA usage are sharply increased also by logistic issues, e.g., such like handling and cleaning of pressure cylinders and safety aspects, because HFA is a very toxic gas at atmospheric pressure. Hydrates of HFA are more easily to handle. The most preferred hydrate of HFA is HFA trihydrate (HFA x 3 H2O). However, as HFA hydrates have no reactivity vs. trifluoromethyl anions, the HFA hydrates need to be converted to almost anhydrous HFA by means of dehydrating agents like P2O5 or SO3/H2SO4. As preparation and handling of suitable HFA is economically and technically the most challenging part of the Pf-t-BuOH synthesis it is outlined in more details below.

In hitherto known industrial scale processes hexafluoroacetone (HFA) usually is made out of hexafluoropropylene (HFP) followed by epoxidation to hexafluoropropylene oxide (HFPO) and subsequent isomerization to yield hexafluoroacetone (HFA), as outlined in the following reaction scheme:

The improved isomerization of HFPO to HFA is disclosed in a recent patent publication, e.g., in the Chinese patent application CN 111116342 A (published May 8, 2020). Also, the isomerization of fluorinated epoxides to related carbonyl compounds is described in an older US patent US 3321515 A (May 23, 1967).

The entire synthesis of HFA starting from HFP is disclosed with some improvements, e.g., in the recent Chinese patent application CN 111153783 A (May 15, 2020). Further a device for implementing the process is disclosed. A process for producing hexafluoroacetone trihydrate by taking hexafluoropropylene as a raw material is disclosed. The process comprises the following steps: (1) taking hexafluor opropylene and oxygen as raw materials, and carrying out oxidation reaction in an oxidation kettle in the presence of a solvent to obtain a mixture of hexafluor opropylene oxide and unreacted hexafluoropropylene; (2) carrying out solvent removal, acid removal and drying on the obtained mixture, introducing the mixture into a fixed bed reactor, and carrying out isomerization reaction on hexafluor opropylene oxide under the condition of a catalyst to generate hexafluoroacetone; and (3) carrying out multistage water absorption on the obtained product, and combining hexafluoroacetone with water to obtain hexafluoroacetone trihydrate. A mixed product obtained through the oxidation reaction is not separated, hexafluoroacetone and hexafluoroacetone trihydrate are produced directly through a reaction in the presence of a Lewis acid catalyst, separation of hexafluoropropylene and hexafluoroacetone trihydrate is realized according to the boiling point difference, and hexafluoropropylene obtained through separation can be continuously recycled after rectification, drying and impurity removal. The CN 111153783 A asserts that according to the method, high-difficulty separation of hexafluoropropylene and hexafluoropropylene oxide in the middle step is avoided, the problem that hexafluoropropylene and hexafluoroacetone are difficult to separate in the prior art is solved, the production energy consumption and wastewater discharge are reduced, and the cost is saved.

The entire synthesis of HFA is also disclosed in scientific literature, e.g., by Su- sumu Misaki in Journal of Fluorine Chemistry, 17 (1981), 159-171 (“Direct Fluorination of Phenol and Cresols”), and by Kurosaki et al. in Chemistry Letters (1988), (1), 17-20.

Even though HFP is produced by several companies like DuPont, Solvay Specialty Polymers, Daikin and Lianyungang Tetrafluor New Materials Co., Ltd. in large industrial scale and at reasonable price by pyrolysis of (as refrigerant phased out) HCFC-22 (CF2CIH), the HFPO and HFA are quite exotic and expensive compounds due to their gaseous form and toxicity. For the other component needed in the synthesis of perfluoro-t-butanol (perfluoro- t-BuOH), namely the CFs" anion, Ruppert’s reagent (CF3-TMS) is a suitable precursor, but there is no availability in large-scale production and at a reasonable price any more. In the past, large-scale production of Ruppert’s reagent at a reasonable price was achieved by a process using Halon 1301 (CFs-Br) as a suitable large-scale commercial precursor material. But this suitable precursor for CF3- TMS (Ruppert’s reagent), i.e., the Halon 1301 (CF3-Br; used in the 60ies as very efficient fire extinguishing agent) was phased out during the Montreal Protocol, and thus is not available anymore in large industrial quantities for environmental ban reasons, and not as end product, but it might remain as a niche compound for legally confined applications such as a “a declared use as intermediate only”. An alternative synthesis of Ruppert’s reagent, e.g., out of alternative precursor CF3H, which is still available, for example, is disclosed in WO 2012/148772. Another alternative synthesis of Ruppert’s reagent out of expensive CF3SO2CI (triflyl chloride; TfCl), for example, is disclosed in CN 107880069. Said alternative syntheses of Ruppert’s reagent still would be possible, but either requires very challenging special equipment, or in case of triflyl chloride (TfCl), the starting material price would be already higher than the acceptable market price of perfluoro-t-butanol (perfluoro-t-BuOH) for larger scale applications like in polymers, SFe replacements and batteries.

Further sources for the CF3" anion are trifluoroacetates, e.g., such like the sodium or potassium trifluoroacetate, which are available at reasonable price and available in large-scale). In this case, the CF3" anion is generated by thermally induced decarboxylation of the trifluoroacetate. Earlier publications with that decarboxylation reaction type describe the synthesis, e.g., of CF3I out of trifluoroacetates (Journal of the American Chemical Society (1950), 72, 3806-7), and of CF3- substituted benzenes (Chemistry Letters (1981), (12), 1719-20; Journal of Fluorine Chemistry (2010), 131(11), 1108-1112).

It is also known in the prior art that the direct contact of alcohols with elemental fluorine (F2) normally give alkylhypofluorites (see Elemental Fluorine in Organic Chemistry, Springer Verlag 1997, ISBN: 978-3-540-69197-6, DOI https://doi.org/10.1007/3-540-69197-9), and it is known that alkylhypofluorites can be explosive (J. Fluorine Chemistry 54 (1991), 1). For example, hypofluorites are formally derivatives of OF-, which is the conjugate base of hypofluorous acid. One example is trifluoromethyl hypofluorite (CF3OF); trifluoromethyl hypofluorite (CF3OF) can be regarded as a simple mixture of COF2 and F2, and among said alkylhypofluorites it is an exception because it is not explosive, and therefore it can be used as fluorinating agent.

The prior art processes for the manufacture of nonafluoro-tert-butyl alcohol, commonly also known as perfluoro-t-butanol (perfluoro-t-BuOH), for example, have the following disadvantages: HFA synthesis involves several complicated steps; HFA is a gas (under normal conditions), and therefore it is difficult to handle HFA; HFA is toxic. In addition, convenient and more environmentally friendly processes are desired as compared to syntheses routes using Ruppert’s reagent (CF3-TMS), or using alternative sources of the CF3" anion, e.g., such process as described above, and the hazards possibly related thereto. Waste waters contaminated with toxic material shall be avoided.

Object of the present invention is to overcome the disadvantages of the prior art processes, in particular to provide a more efficient and energy saving processes, also more environmentally friendly process, for the manufacture of nonafluoro- tert-butyl alcohol, commonly also known as perfluoro-t-butanol (perfluoro-t- BuOH), and providing a convenient synthesis route differently from using hexafluoroacetone (HFA) and other fluorinated building blocks as starting compounds than those presently used in the prior art processes.

BRIEF DESCRIPTION OF DRAWINGS

In Figure 1, use of TFAC (trifluoroacetylchloride) as protecting group raw material in a coil reactor (continuous process) is depicted. Reference is made to Example 1.

In Figure 2, use of TFAC (trifluoroacetylchloride) as protecting group raw material in a counter-current system (batch process) is depicted. Reference is made to Example 2a. Scheme of apparatus and process is shown with counter-current system (batch process), wherein the counter-current column is connected to the reservoir via a pipeline.

In Figure 3, use of TFAH (trifluoroacetic acid anhydride) as protecting group raw material in a coil reactor (continuous process) is depicted. Reference is made to Example 6.

In Figure 4, the continuous direct fluorination of trifluoroacetic acid tert-butyl ester with diluted F2 is depicted. The process involves two coil reactors connected in series with a cyclone in between. Each coil reactor is equipped with a PT-100 temperature measurement (T). Reference is made to Example 7.

In Figure 5, the continuous preparation of triflate protected t-butanol (t-BuOH), i.e., of tert-butyl trifluorosulfonate ester, in a coil reactor is depicted. The raw product reservoir is equipped with a pressure valve going into a basic scrubber (scrubber not shown) for allowing the formed HC1 to leave the raw product reservoir. Reference is made to Example 8.

In Figure 6, use of TFAC (trifluoroacetylchloride) as protecting group raw material in a counter-current system (batch process) is depicted. Reference is made to Example 2b. Scheme of apparatus and process is shown with counter-current system (batch process), and counter-current column which is directly placed onto the reservoir.

Summary of Invention

The objects of the invention are solved as defined in the claims, and described herein after in detail. In particular, the present invention relates to a new process for the manufacture of nonafluoro-tert-butyl alcohol, commonly also known as perfluoro-t-butanol (perfluoro-t-BuOH), involving hydroxyl group protecting groups and a direct fluorination step.

As described here above, the compound nonafluoro-tert-butyl alcohol, commonly also known as perfluoro-t-butanol (perfluoro-t-BuOH), is known in the state of the art, as well as hydroxyl group protected tert-butyl alcohol compound (hydroxyl group protected t-butanol or t-BuOR, respectively, wherein R is a hydroxyl group protecting group). However, using the hydroxyl group protecting group chemistry in combination with a direct fluorination is not known in the state of the art, hitherto.

In brief summary, the invention relates to a new process for the manufacture of the compound nonafluoro-tert-butyl alcohol, commonly also known as perfluoro- t-butanol (perfluoro-t-BuOH), and of the manufacture of a hydroxyl group protected and methyl group perfluorinated intermediate compound or precursor compound of the targeted compound perfluoro-t-butanol (perfluoro-t-BuOH).

The use of the protective groups, as described herein, for protecting the hydroxyl group in tert-butanol in combination with a subsequent direct fluorination reaction for perfluorinating the methyl groups of the targeted product compound tertbutanol is new over the prior art. This applies to all of the protective groups mentioned herein in the context of the processes of the invention.

The perfluorinated and trifluoroacetyl protected t-butanol compound, i.e., the trifluoroacetic acid tert-butyl ester, is already known is the state of the art. However, this compound has been made differently from the new process of the present invention, by reacting perfluoro-t-butanol and trifluoroacetic acid anhydride (TFAH).

The perfluorinated and trifluorosulfonyl (i.e., triflate) protected t-butanol compound, i.e., the trifluorosulfonic acid tert-butyl ester, is also already known is the state of the art. However, this compound has been made differently from the new process of the present invention, by reacting perfluoro-t-butanol and triflic anhydride (Tf2O).

Accordingly, the manufacture of the hydroxyl group protected and methyl group perfluorinated intermediate compound or precursor compound is still new, and is also claimed, In this process according to the invention the intermediate compound or precursor compound, e.g., the hydroxyl group protected and methyl group perfluorinated t-butanol (t-BuOH) compound, is obtained by subjecting a hydroxyl group protected t-butanol (t-BuOH) compound to a direct fluorination step with a fluorination gas comprising or consisting of elemental fluorine (F2). The invention also relates to a new process for the manufacture of the compound nonafluoro-tert-butyl alcohol, commonly also known as perfluoro-t-butanol (per- fluoro-t-BuOH), by deprotecting the hydroxyl group protected and methyl group perfluorinated t-butanol (t-BuOH) compound to obtain the unprotected nonafluo- ro-tert-butyl alcohol compound, i.e., in other terms the unprotected methyl group perfluorinated perfluoro-t-butanol (perfluoro-t-BuOH) compound.

Deprotecting, i.e., removing the hydroxyl group protecting group may be achieved by conventional manners known to the person skilled in the art. For example, such deprotecting may be achieved by saponification with an aqueous inorganic base, such as sodium hydroxide or potassium hydroxide dissolved in water, and phase separation of the targeted deprotected compound. Due to cost reasons, a simple inorganic base (KOH, NaOH) is the most preferred option for the deprotection, but other deprotection options like a transesterification, treatment with NaBHi/LiAlHi or even a deprotection by hydrogenation with hydrogen (H2) over metal catalysts as well as by use of water soluble amines (e.g. NEt3 with 112g/l at 20°C) are different options and technically applicable.

Next to the triethyl amine (NEts), depending on their degree of solubility in water, also other water soluble organic amines can be used for deprotecting of the protected hydroxyl group. Thus, water soluble amines suitable for deprotecting reaction in the context of the invention, for example, are alkyl amines such as alkyl amines with independently one to three Cl- to C3-alkyl chains (e.g., methyl, ethyl, propyl, iso-propyl, and combinations thereof). Accordingly, the Cl- to C3-alkyl chain bearing alkyl amines are selected from the group consisting of methylamine (MebflL), dimethylamine (Me2NH), trimethylamine (MesN), ethylamine (EtbflL), diethylamine (Et2NH), triethylamine (EtsNH), propylamine (PrbflL), dipropylamine (PnNH), iso-propylamine (i-PrbflL), and di-iso- propyl-amine (i-PnNH). In principle, aromatic amines, e.g., such like hydrox- yl-substituted amines, e.g., m-hydroyaniline (solubility of 26 g/1), are also suitable for deprotecting reaction in the context of the invention but besides water solubility less preferred than aliphatic amines also due to economic reasons.

Regarding the new process of the invention for the synthesis of the compound nonafluoro-tert-butyl alcohol, commonly also known as perfluoro-t-butanol (per- fluoro-t-BuOH), surprisingly, now it was found by the present invention, that if the hydroxyl-function (OH-function) in t-butanol firstly is reacted with a protecting group and then the protected t-butanol (t-BuOH) compound is fluorinated with a fluorination gas comprising or consisting of elemental fluorine (F2) in a special type of reactor, e.g., which especially should have excellent heat exchange properties, the compound perfluoro-t-butanol (perfluoro-t-BuOH), can be obtained in a by a convenient process also suitable for industrial scale, and allowing for manufacturing of the compound perfluoro-t-butanol (perfluoro-t-BuOH) for price sensitive mass product applications. Accordingly, this convenient process is achieved by protecting the hydroxyl-function (OH-function) in t-butanol followed by deprotecting of the hydroxyl-function (OH-function) after having performed a fluorination step with a fluorination gas comprising or consisting of elemental fluorine (F2).

The overall general inventive synthesis route is outlined in the reaction scheme below, wherein independently R and X both have the meaning as defined further below: perfluoro-t-BuOH

In the overall general inventive synthesis route in the reaction scheme here above, the group X of the protecting reagent denotes (e.g., as a leaving group), a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom, more preferably a chlorine atom) or an -O-R group (i.e., forming with the R of R-X an anhydride group R-O-R). Preferably, the group X of the protecting reagent denotes a hydrogen atom, a chlorine atom or an -O-R group (i.e., forming with the R of R-X an anhydride group R-O-R).

In the overall general inventive synthesis route in the reaction scheme here before, the substituent R of the protecting reagent and the protecting group, respectively, denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CCI3CO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-, CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSO2-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue.

More preferably the substituent R of the protecting reagent and the protecting group, respectively, denotes a substituent selected from the group consisting of CF3C0-, CF2HCO-, CF2CICO-, CH3C0-, CF3SO2-, CH3SO2-, PfCO-, PfSO ₂ -, and wherein Pf denotes a partially or perfluorinated C2-C4 residue.

Even more preferably the substituent R of the protecting reagent and the protecting group, respectively, denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CF2CICO-, CH3CO-, CF3SO2-, and CH3SO2-.

Most preferably the substituent R of the protecting reagent and the protecting group, respectively, denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CF2CICO-, and CF3SO2-.

Particular and representative examples of the above defined protecting reagents R-X, and related protecting groups R, respectively, used in the process of manufacturing nonafluoro-tert-butyl alcohol (perfluoro-t-butanol; perfluoro-t-BuOH), and of the intermediate or precursor compound nonafluoro-tert-butyl alcohol ester (perfluoro-t-butanol ester; perfluoro-t-BuOR), by direct fluorination according to the present invention are selected from the group consisting of: trifluoroacetic acid anhydride (TFAH) and trifluoroacetyl chloride (TFAC), both, TFAH and TFAC for protecting the hydroxyl group of the staring material compound tertbutyl alcohol (t-butanol; t-BuOH) by the trifluoroacetyl group; and triflic anhydride (Tf2O) and triflyl chloride (TfCl), both, Tf2O and TfCl for protecting the hydroxyl group of the staring material compound tert-butyl alcohol (t-butanol; t- BuOH) by the triflyl group CF3SO2-) forming together with the hydroxyl group oxygen a triflate group.

Particular preferred protecting reagents R-X used in the process of the present invention are TFAH, TFAC and triflate (CF3SO2-) protecting group. More preferably, the protecting reagent R-X used in the process of the present invention is TFAC and triflate (CF3SO2-) protecting group, and most preferably the protecting reagent R-X used in the process of the present invention is TFAC and TfCl (triflyl chloride). Most preferably, the protecting reagent R-X used in the process of the present invention is TFAC.

The triflyl group, more formally known as trifluoromethanesulfonyl group, is a functional group with the formula F3CSO2-. The triflyl group is often represented by -Tf. The related triflate group (trifluoromethanesulfonate) has the formula CF3SO2O-, and is represented by -OTf. Triflic anhydride (CFsSCh^O is known to be a very strong tritiating agent.

Triflic acid, the short name for trifluoromethanesulfonic acid, TFMS, TFSA, HOTf or TfOH, is a sulfonic acid with the chemical formula CF3SO3H. It is one of the strongest known acids. Triflic acid is mainly used in research as a catalyst for esterification.

Trifluoromethanesulfonic anhydride, also known as triflic anhydride, is the chemical compound with the formula (CFsSCh^O. It is the acid anhydride derived from triflic acid. This compound is a strong electrophile, useful for introducing the triflyl group, CF3SO2. Abbreviated Tf2O, triflic anhydride is the acid anhydride of the strong acid triflic acid, CF3SO2OH.

Trifluoromethanesulfonyl chloride (or triflyl chloride, CF3SO2CI), abbreviated (TfCl), can be used in a highly efficient method to introduce a trifluoromethyl group to aromatic and heteroaromatic systems. The chemistry is general and mild, and uses a photoredox catalyst and a light source at room temperature.

The protecting group preferably has to be selected out of such protecting groups which are not sensitive to elemental fluorine (F2) and hydrogen fluoride (HF). Accordingly, the usually commonly used TMS-group is not suitable for the process of the present invention.

However, some protecting groups which in principle are sensitive to a F2- fluorination, for example, such like alkyl-, benzyl, t-butyl, allyl-, trityl-, tetrahydropyranyl, methoxybenzyl-, methoxymethyl-, but in principle only, if desired for any other reason, can be used, but in this case at least partial fluorination of said protecting group fragment has to be expected, and after deprotecting recycling of the partially fluorinated protecting groups is very difficult or impossible, a disadvantage in addition to the higher F2 consumption, anyway. Hence, the use of such fluorinable protecting groups is very uncomfortable due to environmental and cost reasons.

Now, according to the present invention, for example, the trifluoroacetyl group as protecting group was identified to fulfill all requirements to be used as a protecting group. It must be noted, even if known e.g. as protecting group in general, that the trifluoroacetyl group was never used in fluorinations with elemental fluorine (F2), and never in fluorinations at all. For example, the trifluoroacetyl group as protecting group is described in the prior art only in general: in an overview of protecting groups in Journal of the Chemical Society, Perkin Transactions 1, 1999, Issue 24, 1589-1615; in amino acid synthesis (for overview see Chem. Rev. 2009, 109, 2455-2504); and with hazard conditions like nitration (see Chemistry Department, University of Bath in Propellants, Explosives, Pyrotechnics 32, No. 1 (2007), page 20-31, DOI: 10.1002/prep.200700004 and W02004076384).

The trifluoroacetyl group is stable under acid conditions, but can be quite easily removed under basic conditions. In general, any perfluoro acetyl group fulfills the protecting group requirements, but due to cost and environmental reasons, the trifluoro acetyl group is the most preferred one.

Perfluoro sulfonyl groups behave technically similar as protecting group, but are little less preferred, as compared to the trifluoroacetyl group, mainly due to cost reasons; but cost reason becomes less important if more often is recycled and depends on recycling rate. However, during deprotecting some side reactions are possible, as free perfluor sulfonic acids add a risk to induce rearrangement reac- tions and other side reactions in partial fluorinated intermediate stages and the final nonafluoro-tert-butyl alcohol (perfluoro-t-butanol; perfluoro-t-BuOH) product.

According to this invention, in tert-butyl alcohol (t-butanol; t-BuOH) can be easily acylated, for example, with the preferred trifluoro acetyl group without any catalyst or activator by using trifluoro acetyl chloride (TFAC) or trifluoro acetic acid anhydride (TFAH), whereas the use of TFAC has the advantage that gaseous HC1 leaves any reaction apparatus, and thus, a separation step to obtain the trifluoro acetylated nonafluoro-tert-butyl alcohol (perfluoro-t-butanol; perfluoro-t- BuOH) can be saved.

The synthesis of trifluoroacetic acid tert-butyl ester is well known, and using trifluoroacetic acid anhydride (TFAH) is disclosed in Tetrahedron Letters (2002), 43(48), 8687-8691. Also using trifluoroacetic acid is disclosed, e.g., in Journal of Molecular Catalysis (1986), 37(1), 45-52. The formation of trifluoroacetic acid tert-butyl ester as a side product by deprotection of CF3-CO- protected peptides in trifluoroacetic acid (TFA) is described, e.g., in International Journal of Peptide & Protein Research (1978), 12(5), 258-68.

The use of trifluoroacetylchloride (TFAC) for the synthesis of trifluoroacetic acid tert-butyl ester, or alternatively the use of triflylchloride, respectively, is new and has certain advantages as in both cases HC1 formed in the deprotecting reaction just leaves the reaction apparatus as a gas, and leaves behind the targeted product as residue, which then can be used without any need of isolation and/or further purification. However, of course if desired the residue of the targeted product can be subjected to suitable isolation and/or purification method. The deprotection, taking place after fluorination step according to the present invention, is quite simple and can be performed under basic conditions. The trifluoroacetic acid and its salts, which are formed during deprotection, can be recycled as TFA which either is transferred to TFAC or TFAH according to literature procedures, e.g., to close the loop and not to waste the valuable protecting group materials. The 1,1- dimethylethyl triflate ((CHsjsCOSChCFs) is mentioned in Journal of Organic Chemistry 47 (1982) 4577, and the perfluoro-tert-butyl triflate, the product after fluorination, and preparation was already described by 3M in 1976 in US 3981928 by reacting perfluoro-t-butanol (perfluoro-t-BuOH) with triflic anhydride. In said disclosure the perfluoro-t-butanol (perfluoro-t-BuOH) itself, i.e., the targeted product of this invention, was prepared according to the following reaction scheme:

Also the perfluoro-tert-butyl trifluoroacetate was already prepared as disclosed in US3981928 out of perfluoro-t-BuOH and TFAH, and also the perfluoro-tert-butyl trifluorosulfonate was prepared out of perfluoro-t-BuOH and triflic anhydride. But as the perfluoroisobutylene as starting material is very expensive and is quite difficult to produce, e.g., out of HCFC-124 (CF3-CFCIH), a not isolated intermediate of the synthesis of the refrigerant HFC-125 (CF3-CF2H) by pyrolysis reaction with chlorodifluormethane in a gold-lined reactor at 800 °C (W02002006193) this is not a suitable economic synthesis route for large scale industrial production.

The nonafluoro-tert-butyl alcohol, commonly also known as perfluoro-t-butanol (perfluoro-t-BuOH), made by the new process of the present application can be used in any application technical application as commonly known in the state of the art. For example, as already mentioned, it can be used to produce the peroxide of perfluoro-t-butanol which in turn can be used as a substitute for SFe. The perfluoro-t-butanol (perfluoro-t-BuOH) can also be used in batteries. The fact is that battery applications require a very high level of purity (at least 99.9 %) for the perfluoro-t-butanol (perfluoro-t-BuOH). Accordingly, here the processes of the present invention provide additional advantage in terms of yields and purities achieved. Although, the demands for using perfluoro-t-butanol (perfluoro-t- BuOH) as a substitute for SFe, and in case of using it in the field of agrochemicals or pharmaceuticals, are less than for battery application, e.g., as lower purities are sufficient as further conversions with cleaning steps follow in the manufacture of SFe and of agro-chemicals or pharmaceuticals, yet the processes of the present invention provide additional advantages by overcoming the mentioned disadvantages of the prior art processes, and also in terms of yields and purities.

DEFINITIONS

Direct Fluorination: Introducing one or more fluorine atoms into a compound by chemically reacting a starting compound with elemental fluorine (F2) such that one or more fluorine atoms are covalently bound into the reacted starting compound.

The term “liquid medium” may mean a solvent which inert to fluorination under the reaction conditions of the direct fluorination, in which the starting compound and/or fluorinated target compound may be dissolved, and/or the starting compound itself may be a liquid serving itself as liquid medium, and in which the fluorinated target compound may be dissolved if it is not a liquid, or if it is a liquid may also serve as the liquid medium.

The numerical ranges disclosed herein include all values from, and including, the lower and upper value. For ranges containing explicit values (e.g., 1 to 7), any subrange between any two explicit values is included (e.g., 1 to 2; 2 to 6; 5 to 7; 3 to 7; 5 to 6; etc.).

The terms “comprising,” “including,” “having,” and their derivatives, are not intended to exclude the presence of any additional component, step or procedure, whether or not the same is specifically disclosed. In order to avoid any doubt, all compositions claimed through use of the term “comprising” may include any additional additive, adjuvant, or compound, whether polymeric or otherwise, unless stated to the contrary. In contrast, the term, “consisting essentially of’ excludes from the scope of any succeeding recitation any other component, step, or procedure, excepting those that are not essential to operability. The term “consisting of’ excludes any component, step, or procedure not specifically delineated or listed. The term “or,” unless stated otherwise, refers to the listed members individually as well as in any combination. Use of the singular includes use of the plural and vice versa. The term “vol.-%” as used herein means “% by volume”. Unless otherwise stated, all percentages (%) as used herein denote “vol.-%” or “% by volume”, respectively.

For example, the use of the term “essentially”, in referring to a fluorination gas consisting essentially of F2-gas as it directly comes out of the F2-electrolysis reactors (fluorine cells), means that providing such F2-gas does not involve major purification and/or providing another gas, e.g., an inert gas, separate and/or in admixture in amounts and/or under conditions that would be sufficient to provide a change in the composition of an F2-gas as produced in and as it is withdrawn as gaseous product from F2-electrolysis reactors (fluorine cells) of more than about ± 5 % by volume, or preferably of more than about ± 3 % by volume. Accordingly, such a fluorination gas consisting essentially of F2-gas as it directly comes out of the F2-electrolysis reactors (fluorine cells) is meant to comprise elemental fluorine (F2) in a concentration of at least about 92 % by volume, or preferably of at least about 95 % by volume. Especially, such a fluorination gas consisting essentially of F2-gas as it directly comes out of the F2-electrolysis reactors (fluorine cells) may comprise elemental fluorine (F2) in a concentration in a range of about 92- 100 % by volume, or preferably in a range of about 95-100 % by volume, or more preferably in a range of in a range of about 92-99 % by volume, or preferably in a range of about 95-99 % by volume, or in a range of in a range of about 92 to about 97 % by volume, or preferably in a range of about 95 to about 97 % by volume.

Description of the invention

The invention as defined in the claims shall be described herein after in more detail, especially with reference to the manufacture of the methyl group perfluorinated nonafluoro-tert-butyl alcohol (perfluoro-t-butanol; perfluoro-t-BuOH) compound of formula (I), and to the manufacture of the precursor compound thereof which is the hydroxyl group protected and methyl group perfluorinated nonafluoro-tert-butyl alcohol ester (perfluoro-t-butanol ester; perfluoro-t-BuOR) compound of formula (II), and the use and the manufacture thereof. In a first aspect the invention relates to a hydroxyl group protected and methyl group perfluorinated tert-butyl alcohol ester compound of formula (II), wherein

R denotes a substituent selected from the group consisting of CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CChCO-, CCIH2CO-, CCI2HCO-,

CH3CO-, CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSO2-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue.

In a second aspect the invention relates to the use of a hydroxyl group protected tert-butyl alcohol ester compound of formula (II), wherein

R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CChCO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-, CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSO ₂ -, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, in the manufacture of a nonafluoro-tert-butyl alcohol compound of formula (I),

In a third aspect the invention relates to a process for the manufacture of a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II),

(II), wherein

R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CCI3CO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-,

CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, comprising or consisting of the steps of:

(i) a direct fluorination reaction step (B) of reacting the hydroxyl group protected tert-butyl alcohol compound of formula (III), wherein R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CChCO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-,

CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, with a fluorinating gas comprising or consisting of elemental fluorine (F2) to obtain a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II);

(ii) optionally, in parallel and/or subsequent to the direct fluorination reaction step (B), an isolating and/or purifying step (D) to obtain the isolated and/or purified hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II).

The invention also relates to such a process for the manufacture of a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II), wherein the hydroxyl group protected tert-butyl alcohol compound of formula (III) prior to its use in the direct fluorination reaction step (B) is prepared by a process comprising or consisting of the steps of a protecting reaction step (A) of reacting tert-butyl alcohol compound of formula (IV), with a hydroxyl group protecting agent of formula R-X (V), wherein

R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CChCO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-, CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, and

X denotes a hydrogen atom, a halogen atom or an -O-R group, to obtain a hydroxyl group protected tert-butyl alcohol compound of formula (III) as defined herein, and the hydroxyl group protected tert-butyl alcohol compound of formula (III) obtained in step (A), with or without isolating and/or purifying, is subjected to the direct fluorination reaction step (B) as defined herein.

In another aspect the invention relates to a process for the manufacture of a no- nafluoro-tert-butyl alcohol compound of formula (I), via a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) as defined herein, comprising or consisting of the steps of:

(i) a protecting reaction step (A) of reacting tert-butyl alcohol compound of with a hydroxyl group protecting agent of formula R-X (V), wherein

R denotes a substituent selected from the group consisting of

CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-,

CCI3CO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-, CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, and

X denotes a hydrogen atom, a halogen atom or an -O-R group, to obtain a hydroxyl group protected tert-butyl alcohol compound of formula (III), wherein the substituent R in formula (III) has the same meaning as indicated here before for the substituent R in formula (V); and with or without isolating and/or purifying hydroxyl group protected tert-butyl alcohol compound of formula (III),

(ii) a direct fluorination reaction step (B) of reacting the hydroxyl group protected tert-butyl alcohol compound of formula (III) obtained in step (A) with a fluorinating gas comprising or consisting of elemental fluorine (F2) to obtain a hydroxyl group protected nonafluoro-tert-butyl alcohol ester com- pound of formula (II), wherein the substituent R in formula (II) has the same meaning as indicated here before for the substituent R in formula (III); and with or without isolating and/or purifying the hydroxyl group protected no- nafluoro-tert-butyl alcohol ester compound of formula (II), (iii) a deprotecting reaction step (C) of removing the hydroxyl group protecting group R from the hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) obtained in step (B) to obtain the nonafluoro- tert-butyl alcohol compound of formula (I);

(iv) optionally, in parallel and/or subsequent to the deprotecting reaction step (C), an isolating and/or purifying step (D) to obtain the isolated and/or purified nonafluoro-tert-butyl alcohol compound of formula (I).

In a further aspect the invention also relates to a process for the manufacture of a nonafluoro-tert-butyl alcohol compound of formula (I), via a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) as defined herein, comprising or consisting of the steps of:

(i) a direct fluorination reaction step (B) of reacting a hydroxyl group protected tert-butyl alcohol compound of formula (III), , , or perfluorinated C2-C4 residue, with a fluorinating gas comprising or consisting of elemental fluorine (F2) to obtain a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II), wherein the substituent R in formula (II) has the same meaning as indicated here before for the substituent R in formula (III), and with or without isolating and/or purifying the hydroxyl group protected no- nafluoro-tert-butyl alcohol ester compound of formula (II),

(ii) a deprotecting reaction step (C) of removing the hydroxyl group protecting group R from the hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) obtained in step (B) to obtain the nonafluoro- tert-butyl alcohol compound of formula (I);

(iii) optionally, in parallel and/or subsequent to the deprotecting reaction step (C), an isolating and/or purifying step (D) to obtain the isolated and/or purified nonafluoro-tert-butyl alcohol compound of formula (I).

In still a further aspect the invention also relates to a process for the manufacture of a nonafluoro-tert-butyl alcohol compound of formula (I), via a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) as defined herein, comprising or consisting of the steps of: (i) a deprotecting reaction step (C) of removing the hydroxyl group protecting group R from the hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) wherein the substituent R in formula (II) has the same meaning as indicated here before for the substituent R in formula (III), to obtain the methyl group perfluorinated nonafluoro-tert-butyl alcohol compound of formula (I);

(ii) optionally, in parallel and/or subsequent to the deprotecting reaction step (C), an isolating and/or purifying step (D) to obtain the isolated and/or purified nonafluoro-tert-butyl alcohol compound of formula (I).

In still another aspect the invention relates to a process for the manufacture of a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II), wherein

R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CCI3CO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-,

CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, comprising or consisting of the steps of: (i) a protecting reaction step (A) of reacting tert-butyl alcohol compound of formula (IV), with a hydroxyl group protecting agent of formula R-X (V), wherein

R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CCI3CO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-, CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, and

X denotes a hydrogen atom, a halogen atom or an -O-R group, to obtain a hydroxyl group protected tert-butyl alcohol compound of formula (III), wherein the substituent R in formula (III) has the same meaning as indicated here before for the substituent R in formula (V); and with or without isolating and/or purifying hydroxyl group protected tert-butyl alcohol compound of formula (III),

(ii) a direct fluorination reaction step (B) of reacting the hydroxyl group protected tert-butyl alcohol compound of formula (III) obtained in step (A) with a fluorinating gas comprising or consisting of elemental fluorine (F2) to obtain a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II);

(iv) optionally, in parallel and/or subsequent to the direct fluorination reaction step (B), an isolating and/or purifying step (D) to obtain the isolated and/or purified hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II).

In still another aspect the invention relates also to a process for the manufacture of a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II),

(II), wherein

R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CCI3CO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-,

CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, comprising or consisting of the steps of:

(i) a direct fluorination reaction step (B) of reacting the hydroxyl group protected tert-butyl alcohol compound of formula (III), wherein R denotes a substituent selected from the group consisting of CF3CO-, CF2HCO-, CFH2CO-, CF2CICO-, CFCI2CO-, CCI3CO-, CCIH2CO-, CCI2HCO-, CH3CO-, CF3SO2-,

CF2CISO2-, CFCI2SO2-, CCI3SO2-, CF2HSO2-, CFH2SO2-, CH3SO2-, PfCO- and PfSCh-, and wherein Pf denotes a partially or perfluorinated C2-C4 residue, with a fluorinating gas comprising or consisting of elemental fluorine (F2) to obtain a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II);

(ii) optionally, in parallel and/or subsequent to the direct fluorination reaction step (B), an isolating and/or purifying step (D) to obtain the isolated and/or purified hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II).

Furthermore, the invention pertains also to the use of hydroxyl group protected and methyl group perfluorinated nonafluoro-tert-butyl alcohol ester compound of formula (II) as defined herein, or the process for the manufacture of a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) as defined herein, or the process for the manufacture of a nonafluoro-tert-butyl alcohol compound of formula (I) as defined herein, independently, R denotes a substituent selected from the group consisting of CF3CO-, CF2HCOCF2CICO-, and CF3SO2-.

In a further aspect the invention pertains to a process for the manufacture of a hydroxyl group protected nonafluoro-tert-butyl alcohol ester compound of formula (II) as defined herein, or the process for the manufacture of a nonafluoro-tert- butyl alcohol compound of formula (I) as defined herein, independently, in the protecting reagent of formula R-X (V), independently, the group X denotes a hydrogen atom, a halogen atom or an -O-R group; preferably, wherein in the protecting reagent of formula R-X (V), independently, the group X denotes a hydrogen atom, a chlorine atom or an -O-R group. In still a further aspect the invention pertains to a process as defined herein, wherein the direct fluorination reaction is carried out until no exothermic activity is observed in the reaction mixture.

In still a further aspect the invention pertains also to a process as defined herein, wherein the direct fluorination reaction is carried out at a temperature which does not exceed a temperature of about 55 °C, preferably does not exceed a temperature of about 50 °C, more preferably does not exceed a temperature of about 45 °C, even more preferably does not exceed a temperature of about 40 °C, in the reaction mixture.

In still another aspect the invention pertains also to a process as defined herein, wherein the process is carried out such that HF (hydrogen fluoride) formed in the direct fluorination reaction is eliminated from the reaction mixture by purging the reaction mixture with an inert gas stream until no HF (hydrogen fluoride) is detected in the inert gas stream after it has passed through the reaction mixture.

Accordingly, in the processes as each described above and in the compounds used therein, and in the intermediate or product compounds, respectively, as each described above, independently, R preferably denotes a substituent selected from the group consisting of CF3CO-, CF2HCOCF2CICO-, and CF3SO2-.

Preferably, in the processes as each described above, in the protecting reagent of formula R-X (V), independently, the group X denotes a hydrogen atom, a halogen atom (preferably a fluorine atom or a chlorine atom, more preferably a chlorine atom) or an -O-R group (i.e., forming with the R of R-X an anhydride group R-O-R). More preferably, the group X of the protecting reagent denotes a hydrogen atom, a chlorine atom or an -O-R group (i.e., forming with the R of R-X an anhydride group R-O-R). Thus, preferably, in the process for the manufacture of a hydroxyl group protected and methyl group perfluorinated nonafluoro-tert-butyl alcohol ester compound of formula (II) as described above, or the process for the manufacture of a methyl group perfluorinated nonafluoro-tert-butyl alcohol (per- fluoro-t-BuOH) compound of formula (I) as described above, independently, in the protecting reagent of formula R-X (V), independently, the group X denotes a hydrogen atom, a halogen atom or an -O-R group; more preferably, wherein in the protecting reagent of formula R-X (V), independently, the group X denotes a hydrogen atom, a chlorine atom or an -O-R group.

Any of the above processes of manufacture of compounds according to the invention, e.g., the protection reaction, the direct fluorination reaction, the deprotection reaction, and the purification and/or isolation of compounds, each independently can be performed in a batch manner or in a continuous manner, and in any suitable reactor type and under suitable conditions known to the person skilled in the art.

Especially, any of the above processes of manufacture of compounds according to the invention, each can be performed in any suitable conventional reactor type, but herein below, the reactor types preferably used for the purpose of the present invention are described in more detail.

Especially, e.g., the protection reaction, the deprotection reaction, and the purification and/or isolation of compounds, each can be performed in a conventional manner known in the prior art. In principle, the same applies to the direct fluorination reaction, but herein below, the direct fluorination reaction (e.g., reaction conditions) is described in more detail for the purpose of the present invention.

The Direct Fluorination Process and Reactor Types

In this regard, the invention advantageously also provides for large-scale and/or industrial production processes without forming large amounts of waste water and non-recyclable salts which can contain very toxic particles, avoiding the formation of salts that cannot be economically recycled.

The fluorination reaction can be done in a batch reactor or even continuously in a series of STRs, plug flow or in so called coil reactor. For work up, the equimolar formed HF can be removed out of the final solution after fluorination by applying a slight vacuum or using a small inert gas stream into a cooling trap to condense the HF or at least at part of it into an efficient loop (scrubber) system. In a batch system using a state of the art STR, only F2 diluted with inert gas is economically practicable (an inert gas helps to avoid hot spots). In a counter-current system, and coil reactor system, high concentrated F2, optionally directly out of an F2 electrolysis cell gives good yields and is applicable.

In case of high concentrated F2, a microreactor system can also be used. Especially, a microreactor system works the better the less inert gases are present because they can form bubbles in the channels which then inhibit heat transfer/heat exchanger efficiency of the microreactor system.

However, in the present invention F2 diluted with inert gas as a fluorination gas is economically practicable and therefore preferred, especially as an inert gas helps to avoid hot spots in the reactor.

In the processes of the invention, a turbulent reaction state is preferred, for example, for allowing high production capacity and better selectivity. But, the skilled person will understand that turbulence is not intended to limit the process of the invention, especially as chemistry -wise turbulence is not mandatory for the reaction systems, such as counter-current reactor system, or coil reactor system, respectively.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out until no exothermic activity is observed in the reaction mixture.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out at a temperature which does not exceed a temperature of about 55 °C, preferably does not exceed a temperature of about 50 °C, more preferably does not exceed a temperature of about 45 °C, even more preferably does not exceed a temperature of about 40 °C, in the reaction mixture.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the process is carried out such that HF (hydrogen fluoride) formed in the direct fluorination reaction is eliminated from the reaction mixture by purging the reaction mixture with an inert gas stream until no HF (hydrogen fluoride) is detected in the inert gas stream after it has passed through the reaction mixture. The invention relates to a direct fluorination process, as mentioned herein above, wherein the elemental fluorine (F2) is present in the fluorination gas of b) in a (“lower”) concentration in the range of up to about 20 % by volume (vol.-%), or approximately about 20 % by volume (vol.-%), each based on the total volume of the fluorination gas as 100 % by volume.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the elemental fluorine (F2) is present in the fluorination gas of b) in a concentration in the “lower” range of from 0.1 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 0.5 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 1 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 5 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 10 % by volume (vol.- %) up to about 20 % by volume (vol.-%), in the range of from 15 % by volume (vol.-%) up to about 20 % by volume (vol.-%), or in a concentration of approximately about 20 % by volume (vol.-%), each based on the total volume of the fluorination gas as 100 % by volume.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a (closed) column reactor, optionally either operated in a batch manner or operated in a continuous manner, wherein a liquid starting material compound is circulated in a loop, while the fluorination gas comprising or consisting of elemental fluorine (F2) in a high concentration is fed into the column reactor and is passed through the liquid medium to react with the starting compound to form a reaction mixture containing the targeted intermediate compound or product compound, respectively, and further circulating in a loop until the fluorination reaction is completed; preferably wherein the loop is operated with a circulation velocity of from 500 1/h to 5,000 1/h, more preferably of from 3,500 1/h to 4,500 1/h.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the column reactor is equipped with at least one of the following:

(i) at least one cooler (system), at least one liquid reservoir, with inlet and outlet for, and containing as a liquid medium the starting material com- pound, and as the direct fluorination reaction proceeds also the reaction mixture containing the targeted fluorinated compound;

(ii) a pump for pumping and circulating the liquid medium of (i) in the column reactor;

(iii) one or more (nozzle) jets, preferably wherein the one or more (nozzle) jets are placed at the top of the column reactor, for spraying the circulating liquid medium of (i) into the column reactor; or alternatively a perforated metal sheet placed at the top of the column reactor, for circulating the liquid medium of (i) into the column reactor, used together with a high-efficiency pump;

(iv) one or more feeding inlets for introducing the fluorination gas comprising or consisting of elemental fluorine (F2) in a high concentration into the column reactor;

(v) optionally one or more sieves, preferably two sieves, preferably the one or more sieves placed at the bottom of the column reactor;

(vi) and at least one gas outlet equipped with a pressure valve, and at least one outlet for withdrawing the reaction mixture containing the targeted fluorinated compound.

The invention relates to a direct fluorination process, as mentioned herein above, wherein column reactor is a packed bed tower reactor, preferably a packed bed tower reactor which is packed with fillers resistant to elemental fluorine F2) and hydrogen fluoride (HF), e.g. with Raschig fillers and/or metal fillers, more preferably wherein the packed bed tower reactor is a gas loop (scrubber) system (tower) which is packed with fillers resistant to elemental fluorine (F2) and hydrogen fluoride (HF), e.g. HDPTFE Raschig fillers and/or metal fillers; the said fillers should have a diameter of not smaller than about 10 mm (not smaller that about 1 cm; e.g., not smaller than about 1 ± 0.05 cm).

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out with a counter-current flow of the circulating liquid medium of a) comprising or consisting of the starting compound and of the fluorination gas of b) fed into the column reactor and which fluorination gas of b) is comprising or consisting of elemental fluorine (F2) in a high concentration.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a (closed) column reactor, operated in a continuous manner. The term “closed” is not meant to exclude safety valves, which may be present, or to exclude effluent means, for example, to provide (controlled) escape of inert gas, optionally together with at least a part or, alternatively, major or even substantial parts, if desired, of hydrogen fluoride (HF) gas. Of course, as stated above, if desired, at least a part or, alternatively, a major or even substantial part of hydrogen fluoride (HF) may be maintained in the reactor system as a solvent for the direct fluorination reaction.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a (closed) column reactor, which is made out of Hastelloy, preferably which is made out of Hastelloy C4.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a coil reactor, operated in a continuous manner.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a coil reactor, which is made out of Hastelloy, preferably which is made out of Hastelloy C4.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a continuous flow reactor with upper lateral dimensions of about < 5 mm, or of about < 4 mm, operated in a continuous manner.

The invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a microreactor, operated in a continuous manner.

Table 1 : Chemical composition of Hastelloy C4 (nickel alloy).

Next to preferred Hastelloy® C4 described here before, as stated already above, also Hastelloy® C22 is preferred, but has a slightly different composition than Hastelloy® C4. Hastelloy® C is an alloy represented by the formula NiCr21Mol4W, alternatively also known as “alloy 22” or “Hastelloy® C22. The said alloy is well known as a highly corrosion resistant nickel-chromium- molybdenum-tungsten alloy and has excellent resistance to oxidizing reducing and mixed acids.

In case of limited scale production, e.g., laboratory scale or pilot plant scale, possibly also stainless steel materials may be used for the direct fluorination reaction, if it is worked under essentially water-free conditions. The term “essentially water-free” in the context of the present invention means that any water still present is less than 100 ppm (< 100 ppm).

Reactor Design and Direct Fluorination:

In this invention it was also found that the fluorination reaction can be carried out beneficially and preferably in special equipment and with special reactor design such as, e.g., a microreactor or a packed bed tower (preferably made of Hastelloy), especially a packed bed tower containing fillers, e.g., metal fillers (e.g. Hastelloy) or plastic fillers, preferably wherein the tower (e.g., made out of Hastelloy) is filled either with E-TFE or metal fillings (Hastelloy), for example each of about 10 mm diameter as available from Raschig (http://www.raschig.de/Fllkrper). The type of fillings is quite flexible, Raschigs Pall-Rings made out of Hastelloy can be used, and advantageously E-TFE- fillings, and especially HDPTFE-fillings.

In the said special equipment and with special reactor design such as, e.g., a microreactor or a packed bed tower (preferably made of Hastelloy), a fluorine gas with concentrations, as defined above and in the claims, can be used for chemical synthesis especially for the preparation of the fluorinated compound.

In a applying the present fluorination process it is possible to also perform chemistry with F2 as it comes directly out of the F2-electrolysis reactors (fluorine cells). A representative composition of fluorine gas produced by a fluorine cell is 97 % F2, up to 3 % CF4 (formed from damage of the electrodes), for example, traces of HF, NO2, OF2, COF2, each % by volume and based on the total volume of the fluorine containing gas as 100 % by volume.

In the fluorination gas the elemental fluorine (F2) may be diluted by an inert gas. The inert gas then constitutes the substantial difference (e.g., there may be only minor quantities of by-products (e.g., CF4) of no more than about 5 % by volume, preferably of no more than about 3 % by volume, and only traces impurities (e.g., such like HF, NO2, OF2, COF2), in the fluorination gas).

An inert gas is a gas that does not undergo chemical reactions under a set of given conditions. The noble gases often do not react with many substances and were historically referred to as the inert gases. Inert gases are used generally to avoid unwanted chemical reactions degrading a sample. These undesirable chemical reactions are often oxidation and hydrolysis reactions with the oxygen and moisture in air.

Typical inert gases are noble gases, and the very common inert gas nitrogen (N2). The noble gases (historically also the inert gases; sometimes referred to as aerogens) make up a group of chemical elements with similar properties; under standard conditions, they are all odorless, colorless, monatomic gases with very low chemical reactivity. The six noble gases that occur naturally are helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe), and the radioactive radon (Rn). Purified argon and nitrogen gases are most commonly used as inert gases due to their high natural abundance (78.3% N2, 1% Ar in air) and low relative cost. The preferred is nitrogen (N2) as the inert gas for diluting the elemental fluorine (F2) in the fluorination gas to the desired but still high concentration, as defined herein. Preferred is a fluorination gas, wherein the elemental fluorine (F2) is diluted by nitrogen (N2). An example composition of a fluorination gas, using nitrogen (N2) as the inert gas, is as follows (here as purified composition (fluorine-nitrogen gas mixture) as filled in a steel gas cylinder):

Fluorination Reactions with or without Solvent:

The starting material compounds subjected to the direct fluorination reaction for the purpose of the present invention are liquid. Therefore, no solvent is required in the direct fluorination process step of the present invention. Accordingly it is preferred to perform the direct fluorination process step of the present invention without any solvent,

However, if desired for any reason, the direct fluorination reactions of the current invention can be also performed by adding a suitable solvent, preferably only in a small quantity, e.g., of no more than 10 wt.-%, more preferably of no more than 5 wt.-%, as compared to the liquid starting material as 100 wt.-%, which suitable solvent is inert to fluorination under the reaction conditions. For example, the suitable inert solvent can be acetonitrile (CH3CN), fluorinated alkane, pentafluorobutane (365mfc), fluorinated ether CF3-CH2-OCHF2 (E245, perhalogenated ether CF3-O-CF2-CCI3, octafluorotetrahydrofurane, perhalogenated compound CFCh, and perhalogenated compound CF2CI-CFCI2 (113). All these inert solvents have good solubility for the materials, and inertness against elemental fluorine (F2) and hydrogen fluoride (HF).

The process according to the invention in one aspect is such that the direct fluorination reaction is carried out until no exothermic activity is observed in the reaction mixture.

The process according to the invention in one aspect is such that the direct fluorination reaction is carried out at a temperature which does not exceed a temperature of about 55 °C, preferably does not exceed a temperature of about 50 °C, more preferably does not exceed a temperature of about 45 °C, even more preferably does not exceed a temperature of about 40 °C, in the reaction mixture.

The process according to the invention in one aspect is such that the process is carried out such that HF (hydrogen fluoride) formed in the direct fluorination reaction is eliminated from the reaction mixture by purging the reaction mixture with an inert gas stream until no HF (hydrogen fluoride) is detected in the inert gas stream after it has passed through the reaction mixture.

The process according to the invention in one aspect is such that the elemental fluorine (F2) is present in the fluorination gas of b) in a (“lower”) concentration in the range of up to about 20 % by volume (vol.-%), or approximately about 20 % by volume (vol.-%), each based on the total volume of the fluorination gas as 100 % by volume.

The process according to the invention in one aspect is such that the elemental fluorine (F2) is present in the fluorination gas of b) in a concentration in the “lower” range of from 0.1 % by volume (vol.-%) up to about 20 % by volume (vol.- %), in the range of from 0.5 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 1 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 5 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 10 % by volume (vol.-%) up to about 20 % by volume (vol.-%), in the range of from 15 % by volume (vol.-%) up to about 20 % by volume (vol.-%), or in a concentration of approximately about 20 % by volume (vol.-%), each based on the total volume of the fluorination gas as 100 % by volume.

Process in a Counter-Current Reactor System

The process of the present invention, in particular the direct fluorination process step, is a batchwise process or continuous process, and preferably wherein the batchwise process is carried out in a column reactor. Although, in the following reactor setting the process is described as a batch process, as preferred, for example, in case of high product concentrations, optionally the process can be performed in the said reactor setting also as a continuous process. In case of a continuous process in the said reactor setting, then, it goes without saying, the additional inlet(s) and outlet(s) are foreseen, for feeding the starting compound and withdrawing the product compound, respectively.

If the invention pertains to a batchwise process of the direct fluorination step, preferably wherein the batchwise process is carried out in a column reactor, the process, most preferably the reaction is carried out in a (closed) column reactor (system), wherein the liquid medium of a) comprising or consisting of the starting compound is circulated in a loop, while the fluorination gas comprising or consisting of elemental fluorine (F2) is fed into the column reactor and is passed through the liquid medium to react with the starting compound; preferably wherein the loop is operated with a circulation velocity of from 1,500 1/h to 5,000 1/h, more preferably of from 3,500 1/h to 4,500 1/h.

If the invention pertains to a batchwise process of the direct fluorination step, the process can be carried out such that the liquid medium comprising or consisting of the starting compound is circulated in the column reactor in a turbulent stream or in laminar stream, preferably in a turbulent stream. In one aspect, the batchwise process of the direct fluorination step, as shown in Figure 2, for example, for use of TFAC (trifluoroacetylchloride) as protecting group raw material, the batchwise process is performed in a counter-current system (batch process), wherein the counter-current column is connected to the reservoir via a pipeline. Reference is made to Example 2a.

In another, preferred aspect, the batchwise process of the direct fluorination step, as shown in Figure 6, for example, for use of TFAC (trifluoroacetylchloride) as protecting group raw material, the batchwise process is performed in a countercurrent system (batch process), wherein counter-current column which is directly placed onto the reservoir. Reference is made to Example 2b.

In the case of a counter-current system (batch process), it is preferred if the counter-current column rests directly (i.e., without diameter constriction) on the reservoir. In this case the column does not flood so easily, as compared to the process of Example 2a performed in a counter-current system (batch process) wherein the counter-current column is connected to the reservoir via a pipeline. Due to diameter of the pipeline (i.e., the narrowing of the flow diameter) the flow rate may be restricted in order to avoid undesired flooding of the counter-current column.

In general, the fluorination gas containing the elemental fluorine (F2) is fed into the loop in accordance with the required stoichiometry for the targeted fluorinated product and fluorination degree, and adapted to the reaction rate.

For example, the said process of the direct fluorination step may be performed, e.g., batchwise, wherein the column reactor is equipped with at least one of the following: at least one cooler (system), at least one liquid reservoir for the liquid medium comprising or consisting of a starting compound, a pump (for pump- ing/circulating the liquid medium), one or more (nozzle) jets, preferably placed at the top of the column reactor, for spraying the circulating medium into the column reactor, or alternatively (instead of the one or more (nozzle) jets) a perforated metal sheet placed at the top of the column reactor, for circulating the liquid medium of (i) into the column reactor, used together with a high-efficiency pump, one or more feeding inlets for introducing the fluorination gas comprising or consisting of elemental fluorine (F2), optionally one or more sieves, preferably two sieves, preferably the one or more sieves placed at the bottom of the column reactor, at least one gas outlet equipped with a pressure valve.

A so-called perforated metal sheet in particular can be used if the pump performance allows for it, e.g., in case of a high-efficiency pump. In case, the use of a so-called perforated metal sheet can be advantageous, for example, is there is a potential risk of clogging (nozzle) jets.

In one embodiment, the process of the direct fluorination step can be performed in a column reactor is a packed bed tower reactor, preferably a packed bed tower reactor which is packed with fillers resistant to elemental fluorine (F2) and hydrogen fluoride (HF), e.g. with Raschig fillers and/or metal fillers, more preferably wherein the packed bed tower reactor is a gas loop (scrubber) system (tower) which is packed with fillers resistant to elemental fluorine (F2) and hydrogen fluoride (HF), e.g. Raschig fillers and/or metal fillers.

In a further embodiment, in the process of the direct fluorination step the reaction is carried out with a counter-current flow of the circulating liquid medium comprising or consisting of the starting compound and of the fluorination gas fed into the column reactor and which fluorination gas is comprising or consisting of elemental fluorine (F2).

The pressure valve functions to keep the pressure, as required in the reaction, and to release any effluent gas, e.g. inert carrier gas contained in the fluorination gas, if applicable together with any hydrogen fluoride (HF) released for the reaction.

The said process of the direct fluorination step may be performed, e.g., batchwise, such that in the said process of the direct fluorination step the column reactor is a packed bed tower reactor, preferably a packed bed tower reactor which is packed with metal fillers.

The packed tower, e.g., according to Figure 2 or 6, respectively, can have a diameter of 100 or 200 mm (depending on the circulating flow rate and scale) made out of high grade stainless steel (1.4571) or Hastelloy (preferred Hastelloy C4) and a length of 3 meters for the 100mm and a length of 6 meters for the 200 mm diameter tower (latter if higher capacities are needed). The tower made is filled either with E-TFE- or HDPTFE-fillings, or metal fillings each of 10 mm diameter as available from Raschig (http://www.raschig.de/Fllkrper). The type of fillings is quite flexible, Raschig Pall-Rings made out of Hastelloy were used in the trials disclosed hereunder, also E-TFE-fillings showed same performance, both not causing too much pressure reduction (pressure loss) while feeding F2-gas in counter-current manner. Plastics (e.g. HD-PTFE) as construction material for the tower are also suitable but for lower pressures only. If plastics are used, measures have to be taken to avoid electrostatic charges.

Process in a Coil Reactor System

In case it is desired to perform any of the processes of the present invention, e.g., the protection reaction, the direct fluorination reaction, the deprotection reaction, and the purification and/or isolation of compounds, each independently can be performed in a continuous manner in a coil reactor system, in a manner and under conditions known to the person skilled in the art.

Especially, in one aspect the invention relates to a direct fluorination process, as mentioned herein above, wherein the direct fluorination reaction is carried out in a coil reactor, operated in a continuous manner.

Here, the skilled person is well aware that the use of inert gas in larger ratios of inert gas to elemental fluorine has disadvantages in terms of process controllability of the fluorination reaction, for example, in terms of effective mixing of the elemental fluorine F2) with the liquid compound to be fluorinated, heat transfer control, e.g., poor heat exchange, and maintenance of desired reaction conditions in the micro-environments in the reaction mixture. For example, in a coil reactor, at high inert gas concentrations, e.g., low fluorine (F2) concentrations, in addition to the poor heat exchange, there may be ineffective (reaction) zones with (inert) gas bubbles, which could nullify the advantages of using a coil reactor technology-

Therefore, in case of continuous direct fluorination with diluted F2 it is preferred that the process also employs a cyclone. For example, if the continuous process of protecting the tert-butyl alcohol (t-BuOH) compound and subsequent direct fluor- ination of the hydroxyl group protected tert-butyl alcohol ester (t-BuOR) compound involves two coil reactors connected in series, then a cyclone is installed in between the first coil reactor (for the protection step) and the second coil reactor (for the subsequent direct fluorination step). Reference is made to Example 6. As the reaction of F2 with C-H bonds is very exothermic (> 100 kcal/mol) heat transfer is a key parameter for good yields. In contrary to that, inert gas (N2) from diluted F2 is in contradiction as this lowers heat exchange efficiency. To overcome this efficiency lowering a cyclone installed between the two coil reactors allows to get rid of some inert gas and getting the process back to full heat exchange efficiency in the second coil reactor.

The following examples are intended to further illustrate the invention without limiting its scope.

Examples

Example 1:

TFAC (trifluoroacetylchloride) as protecting group raw material in a coil reactor (continuous process).

See Figure 1 for scheme of apparatus and process.

Apparatus: A coil reactor made out of Hastelloy C4 (1 m length, diameter: 0.5 cm), raw material reservoir (1 1), TFAC feed out of a gas cylinder, raw material reservoir (2 1, 145.71 stainless steel). Both feeds were equipped with Bronk- horst mass flow controllers; raw product reservoir was equipped with a pressure valve going into a basic scrubber.

Raw materials: Trifluoroacetylchloride (supplier Sinochem Lantian) and t-BuOH (technical grade, supplier Sigma Aldrich Taufkirchen).

In the coil reactor apparatus above, 96.4 g (1.3 mol) t-BuOH from Aldrich were placed into the raw material reservoir and the dosage pump started with a feed of 100 g/h. Right after start of the pump, TFAC (185.5 g/h; 1.4 mol/h) was fed as gas out of a cylinder into the coil reactor (kept with a water bath at 30 °C, pressure valve set to 3 bar abs.). An exothermic reaction could be observed immediately, the material after the coil reactor was collected in the raw material reservoir kept at 0 °C by external cooling. After 58 minutes, all t-BUOH was consumed, all the feeds were stopped. Most of the formed HC1 had left already into the scrubber, and the pressure of raw material reservoir was released to atmospheric pressure. A sample taken for HPLC-MS analysis indicated a quantitative conversion of t- BuOH to trifluoroacetic acid tert-butyl ester, as confirmed by GC-MS.

Example 2a:

TFAC (trifluoroacetylchloride) as protecting group raw material in a countercurrent system (batch process).

See Figure 2 for scheme of apparatus and process.

In a batch counter-current apparatus out of Hastellloy C4 steel having a pressure valve at the top which is set to 3 bar abs. and with a liquid reservoir volume of 5 1 (see drawing), a column is set on the reservoir (length 50 cm, diameter 100 mm, filled with HDPTFE fillings with diameter 10 mm) 3.0 1 (2.3 kg, 31.0 mol) of t- BUOH (technical grade from Aldrich) was filled in and the pump was started with a performance of 500 1/h. For the heat exchanger, a water cooling system with a water temperature of 8 °C was used. When the temperature of the t-BuOH reached 10 °C (coming from 26 °C after start of the loop), gaseous TFAC out of a cylinder was fed with a feed rate of 1000 g/h; 7.55 mol/h over a Bronkhorst mass flow controller into the gas inlet installed between raw material reservoir and column as drawn above, same inlet as used for the F2-feed later on. After feed of 4.2 kg (32.0 mol) the TFAC the feed was stopped, 20 1 N2-inert gas was inserted at the inert gas inlet as drawn to draw out some HCl-gas residues, then the pump also was stopped after further 10 min, the pressure was released to atmospheric pressure and the content in the reservoir was analyzed by GC which showed a quantitative conversion of t-BuOH and quantitative presence of trifluoroacetic acid tert-butyl ester. Example 2b:

TFAC (trifluoroacetylchloride) as protecting group raw material in a countercurrent system (batch process), and counter-current column is directly placed onto the reservoir.

The reaction is carried out like described here before in Example 2a, in a batch counter-current apparatus as described, except for the variation that the countercurrent column is directly placed onto the reservoir.

In the case of a counter-current system (batch process), it is preferred if the counter-current column rests directly (i.e., without diameter constriction) on the reservoir. In this case the column does not flood so easily, as compared to the process of Example 2a performed in a counter-current system (batch process) wherein the counter-current column is connected to the reservoir via a pipeline. Due to diameter of the pipeline (i.e., the narrowing of the flow diameter) the flow rate may be restricted in order to avoid undesired flooding of the counter-current column.

See Figure 6 for scheme of apparatus and process with counter-current system (batch process), and counter-current column is directly placed onto the reservoir.

Example 3:

Fluorination of trifluoroacetic acid tert-butyl ester (batch process) with F2 to yield perfluoro-tert-butyl trifluoroacetate.

In the same apparatus as in Example 2, a F2-gas cylinder (20 % F2 in 80 % N2) was now connected instead of TFAC to the gas inlet below the column part.

The reservoir is containing the liquid raw material out of Example 2 and was used without further purification. The pressure during the fluorination is kept by the pressure valve on top of the column. The inert gas together with (only) very little traces of HF leave as a purge gas during reaction. The cooler (Lauda Kryomat refrigeration machine) was fed with a cooling system with a cooling media with a temperature of -10 °C. In the counter-current apparatus the pressure valve at the top was set to 3 bar abs., and the pump was started again. When the temperature of the looping media reached 5 °C (coming from 26 °C after start of the loop over the cooler), the 20 % F2 dosage valve (mass flow meter from Bronkhorst) was opened with a dosage of 20 mol F2-gas (20 % in N2) /h, a very strong exothermic activity was observed. All purge gas (N2) together with most of the formed HF leaves the apparatus over the pressure valve into a basic scrubber system (made out of plastics) together with very little (most of the time no) F2 only. In total after 14 h, 10.9 kg (288.0 mol) F2 gas (20 %) was fed into that looping reaction mixture. Reaction media samples were taken every hour and very carefully with a stainless steel cylinder (a completely sealed sampling system), and analyzed by GC to observe progress of the reaction by trifluoroacetic acid tert-butyl ester consumption (amounts of HF in the samples were degassed by brief evaporation at a vacuum pump). After finishing the F2-feed, the analysis showed that starting material trifluoroacetic acid tert-butyl ester had disappeared completely. Now the pressure in the apparatus was released to atmospheric pressure, N2 inert gas was fed into the system for 30 min to get rid of the HF residues. GC analysis showed presence of 95 % perfl uoro-tert-butyl trifluoroacetate. Without purification this material was used for the next step as described in Example 4 and without stopping the loop.

Example 4:

Deprotection of of perfluoro-tert-butyl trifluoroacetate with NaOH.

(Continuation after Example 3)

Over the inlet before the cooler and a media temperature of at 5°C (cooling liquid still -10 °C) now a saturated NaOH solution in water was slowly fed into the looping mixture to achieve a basic environment of the solution. The feed is done in that manner that the temperature is kept below 40 °C. Afterwards the pump was stopped and all the material out of the reservoir was transferred into a settler and extracted with CH2CI2. Perfluoro-t-BuOH was distilled out of the extracted organic phases at 1 bar abs., and with a transition temperature of 45 °C using an 30 cm Vigreux column. The isolated yield was 71 %, the purity 99.9 % (GC). The residue (water phase) containing TFA and water was acidified with HCl-gas out of a cylinder and TFA was recycled as trifluoroacetic acid - water azeotrope of 80:20 with a boiling point of: 104 °C. In another trial, 1,1,1,3,3-pentafhiorobutane (365mfc) was used as more environmental extraction agent and gave an isolated yield of 91 % perfluoro-t-BuOH. The structure and purity were confirmed by GC- MS and 'H-NMR in CDCh (6= 3,55 vs. TMS).

Example 5:

Alternative deprotection of peril uoro-/c/7-butyl trifluoroacetate with lO wt % amine in water.

50 g (0.15 mol) perfluoro-/c77-butyl trifluoroacetate was topped with a dropping funnel into a 10:90 vol-% water solution of NEt3 in H2O at 90 °C in a state of the art stirred glass flask. After 15 min, perfluoro-t-BuOH was detected at the installed reflux condenser and isolated as colorless liquid with boiling point of 44.5 °C. The isolated yield of perfluoro-t-BuOH was 97 %.

Example 6:

Trifluoroacetic acid anhydride (TFAH) as protecting group raw material in a coil reactor (continuous process).

See Figure 3 for scheme of apparatus and process.

This reaction is described in Tetrahedron Letters (2002), 43(48), 8687-8691 but with standard equipment. In this trial according to the invention, a coil reactor was used. Apparatus: A coil reactor made out of Hastelloy C4 (1 m length, diameter: 0.5 cm) (same as in Example 1), a raw material reservoir (1 1) with the TFAH raw material, another raw material cylinder with the t-BuOH, both raw materials connected each with a piston pump to the coil reactor. Both feeds are equipped with Bronkhorst mass flow controllers, raw product reservoir (raw product trap) is equipped with a pressure valve set to 2 bar abs., going into a basic scrubber; but in contrast to Example 1, no material is leaving over that valve as trifluoroacetic acid (TFA) is formed in equimolar amounts instead of HC1.

Raw materials: TFAH (from Sigma Aldrich Taufkirchen) and t-BuOH (technical grade)

In the coil reactor apparatus above, 96.4 g (1.3 mol) t-BuOH from Aldrich were placed into the raw material reservoir and the dosage pump started with a feed of 1.3 mol/h. Right after start of the pump, TFAH (273.0 g/h; 1.3 mol/h) was also fed into the coil reactor. The reactor was kept with a simple water bath at 30 °C, pressure valve set to 2 bar abs.). An exothermic reaction could be observed immediately, the material after the coil reactor was collected in the raw material reservoir kept at 0 °C by external cooling. After 1 h all the feeds were stopped. The pressure of raw material reservoir was released to atmospheric pressure. A sample taken for GC analysis indicated a quantitative conversion of t-BuOH to trifluoroacetic acid tert-butyl ester which was purified by distillation.

Example 7:

Continuous fluorination of trifluoroacetic acid tert-butyl ester with diluted F2

See Figure 4 for scheme of apparatus and process.

Two coil reactors out of Hastelloy C4 (each 1 m length, diameter: 0.5 cm), each with PT- 100 temperature measurement (T), were connected in series with a cyclone in between. As the reaction of F2 with C-H bonds is very exothermic (> 100 kcal/mol) heat transfer is a key parameter for good yields. In contrast to that, inert gas (N2) from diluted F2 is in contradiction as this lowers heat exchange efficiency. To overcome this lowering a cyclone is installed between the two coil reactors to get rid of some inert gas and getting back to full heat exchange efficiency in the second coil reactor.

The starting reservoir is containing the liquid raw material trifluoroacetic acid tert-butyl ester as prepared in Example 1. The pressure during the fluorination is kept by the pressure valve on the gas phase exit of the cyclone set to 10 bar abs., and another one on the exit of the raw product reservoir set to 9 bar abs. The inert gas together with (only) very little traces of HF leaves as a purge gas during reaction to the scrubber over the two gas exits after the pressure valves. For cooling, the coils were put into a cooling liquid bath (temperature -10 °C). The 20 % F2 in 80 % N2 dosage valve for the first coil reactor (with a mass flow meter from Bronkhorst) was opened with a dosage of 4.5 mol F2-gas/in N2 /h, the feed for the trifluoroacetic acid tert-butyl ester was set to 1.0 mol/h. After 5 min, the F2 dosage (with a mass flow meter from Bronkhorst) before the 2 ^nd coil was opened too and also set to 4.5 mol/h. The temperature in the first coil reactor raised to 30 °C, the temperature in second coil reactor only to 20 °C. In total, 510 g (3.0 mol) trifluoroacetic acid tert-butyl ester and 1,026 g (27.0 mol) F2 gas (20 %) was fed over 3 h over the two inlet positions into the system. All the material was collected in the raw product reservoir which was cooled with dry ice/EtOH. Under strict safety behavior the material collected in the raw product reservoir was purged with a N2-stream to get rid of HF and then distilled. The perfluoro-tert-butyl trifluoroacetate product was distilled off using a 20 cm Vigreux column at 1 bar abs., and at a transition temperature of 58.5 °C and a purity > 99.0 % (GC), the yield was 81 %.

Example 8:

Continuous preparation of tert-butyl trifluorosulfonate in a coil reactor.

See Figure 5 for scheme of apparatus and process. Apparatus: Same equipment as in example 6. Both feeds equipped with Bronk- horst mass flow controllers, raw product reservoir is equipped with a pressure valve going into a basic scrubber for allowing the formed HC1 to leave.

Raw materials: Triflyl chloride (product No 164798) and t-BuOH from Sigma Aldrich Taufkirchen.

In the coil reactor apparatus above, 96.4 g (1.3 mol) t-BuOH from Aldrich were placed into the raw material reservoir and the dosage pump started with a feed of 1.3 mol/h. Right after start of the pump, 219.1 g (1.3 mol) CF3SO2CI was also fed into the coil reactor. The reactor was kept with a simple water bath at 26 °C, pressure valve set to 3 bar absol. An exothermic reaction could be observed immediately, the material after the coil reactor was collected in the raw material reservoir kept at 0 °C by external cooling. After 1 h the raw material tanks were empty and all the feeds were stopped. The pressure of raw material reservoir was released to atmospheric pressure. A sample taken for GC (and GC-MS) analysis indicated a quantitative conversion of t-BuOH to tert-butyl trifluorosulfonate.

Example 9:

Fluorination of perfluoro-tert-butyl trifluorosulfonate with 20 % F2 in N2.

The same equipment as in Example 7 was used.

The starting reservoir is containing a liquid raw material tert-butyl trifluorosulfonate as prepared in Example 8. The pressure during the fluorination is kept by the pressure valve on the gas phase exit of the cyclone and is set to 10 bar abs., and another one on the exit of the raw product reservoir after the two reactors is set to 9 bar abs. The inert gas together with quite little traces of HF leaves as a purge gas during reaction to the scrubber over the two gas exits after the pressure valves. For cooling, the coil reactors were put into a cooling liquid bath (temperature -20 °C). The 20 % F2 in 80 % N2 dosage valve for the first coil reactor (with a mass flow meter from Bronkhorst) was opened with a dosage of 4.5 mol F2-gas/in N2 /h, the feed for the perfluoro-tert-butyl trifluorosulfonate was set to 1.0 mol/h. After 5 min, the F2 dosage (with a mass flow meter from Bronkhorst) before the second coil reactor was opened too and also set to 4.5 mol/h. The temperature in the first coil reactor raised to 33°C, the temperature in the second coil reactor only to 24 °C. In total, 1,104 g (3.0 mol) perfluoro-tert-butyl trifluorosulfonate and 1,026 g (27.0 mol) F2 gas (20 %) was fed over 3 h over the two inlet positions into the system. All the material was collected in the raw product reservoir which was cooled with dry ice/EtOH. Under strict safety behavior the material collected in the raw product reservoir was purged with a N2-stream to get rid of HF and then distilled. The perfluoro-tert-butyl trifluoroacetate product was distilled off using a 20 cm Vigreux column at 1 bar abs., and at a transition temperature of 93 °C (1 bar abs.). The isolated yield was 74 %, the achieved purity > 98.5 % (GC).

Example 10:

Deprotection of perfluoro-tert-butyl trifluorosulfonate.

55 g (0.15 mol) perfluoro-tert-butyl trifluorosulfonate was topped with a dropping funnel into a 10:90 vol-% water solution of NEt3 in H2O at 90 °C in a state of the art stirred glass flask. After 28 min, perfluoro-t-BuOH was detected at the installed reflux condenser and isolated as colorless liquid with boiling point of 44.5 °C. The isolated yield of perfluoro-t-BuOH was 81 %.