A process for the preparation of polyfluoroalkylamines from polyfluoroalkylalcohols

Abstract

A method for preparing polyfluoroalkylamines, wherein in a first step, a polyfluoroalkyl alcohol is reacted with an imine in the presence of SO₂F₂ and an acid scavenger, and then in a second step, the obtained compound is reacted with an acid, a base or hydrazine.

Description

[Technical Field]

[0001] This invention relates to a method for preparing polyfluoroalkylamines from polyfluoroalkyl alcohols using the Gabriel synthesis method. [Previous Technology]

[0002] Polyfluoroalkylamines are important intermediates in the preparation of active substances. For example, 2,2-difluoroethylamine can be used as an intermediate in the preparation of flupyradifurone.

[0003] Various methods are known for the preparation of fluoroalkylamines, such as (a) the reaction of the corresponding polyfluoroalkyl halogen with ammonia (e.g., Dickey et al., Industrial and Engineering Chemistry, 1956, No. 2, 209-213, US2002 / 0183557) or the reaction of the corresponding alcohol with ammonia (JP2005002031A), (b) the hydrogenation of the corresponding nitriles or azides (US3532755, Mecinovic et al., Green Chem., 2018, 20, 4418–4442), and (c) the reduction of the corresponding polyfluoroalkylamines (e.g., Douglas et al., Chem. Commun., 2016, 52, 12195-12198 on CF3CH2NH2, and Husted & Ahlbrecht, J. Am. Chem. on CHF2CH2NH2). Soc. 1953, 75, 7, 1605–1608; Soloshonok et al., Tetrahedron Letters, 2002, 43, 5449–5452, on RFCH2NH2 (with RF= -CF3, -C2F5, -C3F9); Papanastassiou & Bruni, J. Org. Chem. 1964, 29, 10, 2870–2872, on FCH2CH2NH2.

[0004] In addition, WO-A-2012 / 101044 discloses a method for preparing 2,2-difluoroethylamine, wherein 2,2-difluoro-1-chloroethane is reacted with aceimine in the presence of an acid scavenger (such as a base) to obtain 2,2-difluoroethylamine.

[0005] WO-A-2011 / 012243 and WO-A-2012 / 095403 disclose methods for preparing 2,2-difluoroethylamine, wherein 2,2-difluoro-1-chloroethane is reacted with ammonia to obtain 2,2-difluoroethylamine.

[0006] WO-A-2011 / 042376 discloses a method for preparing 2,2-difluoroethylamine, wherein 2,2-difluoro-1-nitroethane is hydrogenated in the presence of a catalyst to obtain 2,2-difluoroethylamine.

[0007] WO-A-2011 / 069994 discloses a method for preparing 2,2-difluoroethylamine, wherein difluoroacetonitrile is catalytically hydrogenated and the resulting difluoroethylamide is then converted to 2,2-difluoroethylamine by adding an acid suitable for cleaving difluoroethylamide.

[0008] WO-A-2012 / 062702 discloses a method for preparing 2,2-difluoroethylamine, wherein 2,2-difluoro-1-chloroethane is reacted with a benzylamine compound and the resulting N-benzyl-2,2-difluoroethylamine compound is catalytically hydrogenated to obtain 2,2-difluoroethylamine.

[0009] WO-A-2012 / 062703 discloses a method for preparing 2,2-difluoroethylamine, wherein 2,2-difluoro-1-chloroethane is reacted with prop-2-en-1-amine and then the resulting N-(2,2-difluoroethyl)prop-2-en-1-amine is freed from the allyl group (deallylation).

[0010] The known methods are disadvantageous because they have low yields due to the high temperature and pressure and very long reaction times, require expensive reagents or equipment, or have highly corrosive reaction mixtures. For these reasons, the known methods are not suitable for commercial use.

[0011] US 2012 / 0190867 (WO-A-2012 / 101044) describes the use of the Gaborite synthesis method, which utilizes HCF₂CH₂Cl (Freon 142). HCF₂CH₂Cl is environmentally unfriendly, belonging to the category of ozone-depleting substances (ODS), and its utilization is strictly limited. The reaction time in the described method is short, but high temperatures (90 to 140°C) are required. Additionally, this method may require the use of a catalyst.

[0012] M. Epifanov et al., in JACS 2018, 140, 16464-16468, describe a method for the alkylation of primary and secondary amines with polyfluorinated alcohols via SO2F2-. In the examples given in the publication, only amines linked to one or two alkyl chains (-NH2 or R2NH) are mentioned, such as cyclohexylamine, morpholine, phenylalanine, N-methylbenzylamine, etc. These amines exhibit high nucleophilicity and basicity (pKb 3.5 to 4.5) and have so far been successfully alkylated with low-reactivity polyfluorinated alcohols.

[0013] However, the authors (JACS, p. 16466) also found that sterically hindered matrices on the α-axis of both amines (such as cyclohexylamine) and aniline are not only poor matrices for this reaction but also unlikely to alkylate polyfluorools with high reactivity. Like other amines, aniline is a base (pKb = 9.42) and a nucleophile, although it is a weaker base and a poorer nucleophile than structurally similar aliphatic amines.

[0014] In this invention, phthalimide is used, which has carbonyl groups on the α-th of two opposing amine groups in the ring system and can therefore also be considered a large matrix. It is also known that phthalimide exhibits significant NH acidity and is completely non-basic due to the electron-withdrawing (-M) effect of the two carbonyl groups. The high acidity of the phthalimide group -NH is a result of a pair of flanking electrophilic carbonyl groups. Furthermore, it is generally known that amides (such as phthalimide or succinimidide used in the method according to this invention) are generally less reactive to electrophilic agents than amines (such as amines used in the method of Epifanov et al.).

[0015] Surprisingly, the polyfluoroalkylation of phthalimide (which is acidic and not basic) in the method according to the invention can be carried out in high yield under mild conditions, while cyclohexylamine or aniline is a poor substrate for this reaction. The same applies when succinimide is used instead of phthalimide.

[0016] The synthesis of polyfluoroalkylamines from N-polyfluoroalkyl phthalimides was described by Kuwabara et al. in "The journal of the chemical society of Japan, 1985 v. 1985, N 4, p.796-798 (RFCH2NH2, having RF= -CF3, -CF2CHF2, (CF2CF2)2H, -(CF2CF2)3H)". The preparation of the desired N-polyfluoroalkyl phthalimide from polyfluoroalkyl phthalo-nitrobenzenesulfonate and the K salt of phthalimide was achieved under very harsh reaction conditions, with prolonged heating at 150°C.

[0017] Since the known methods for preparing polyfluoroalkylamines (including 2,2-difluoroethylamine), the current problem is how to prepare polyfluoroalkylamines, including 2,2-difluoroethylamine, from commercially available and environmentally friendly starting materials (e.g., polyfluoroalkyl alcohols and inexpensive SO2F2 gases) in a simple and inexpensive manner. The inventors have discovered that polyfluoroalkylamines can be advantageously prepared from polyfluoroalkyl alcohols by first preparing an imine intermediate and then pyrolyzing it. [Summary of the Invention]

[0018] The subject of this invention is therefore a method for preparing a polyfluoroalkylamine of formula (IV) RFCH2NH2 (IV) wherein RF is defined as in step (i), the method comprising the following steps: Step (i): reacting a polyfluoroalkyl alcohol of formula (I) RFCH2OH (I) wherein RF = CHF2, CF3, C2F5 or HCF2CF2 with an imine of formula (II) in the presence of SO2F2 and an acid scavenger to give a compound of formula (III) wherein in compounds of formula (II) and (III), R1 and R2 are each independently hydrogen or C1-C6-alkyl or R1 and R2 together with the carbon atoms of those bonds form a six-membered aromatic ring, which is substituted with a halogen or C1-C12-alkyl as desired; Step (ii): reacting the compound of formula (III) with an acid, a base or hydrazine (i.e., by adding an acid, a base or hydrazine to cleave the compound of formula (III)).

[0019] In a preferred embodiment of the present invention, the polyfluoroalkyl alcohol of formula (I) is CHF2CH2OH and the polyfluoroalkylamine of formula (IV) is CHF2CH2NH2 (2,2-difluoroethyl-1-amine).

[0020] The amide of formula (II) used in step (i) may also be present as a salt. Such salts are commercially available in some cases (e.g., potassium salt of phthalamide). In the method according to the invention, the amide of formula (II) may also be converted into a salt by reacting with a suitable base before using the salt. Suitable bases are those known to those skilled in the art or those included in the present invention as acid scavengers.

[0021] In the method according to the present invention, it is preferable to use a compound of formula (II) wherein R1 and R2 are hydrogen atoms (i.e., succinimide) or a compound of formula (II) consisting of a six-membered aromatic ring (i.e., phthalimide) formed together with the carbon atoms bonded thereto. If succinimide is used as the compound of formula (II), then in step (i) a compound of formula (III-a) is obtained. If phthalimide is used as the compound of formula (II), then in step (i) a compound of formula (III-b) is obtained:

[0022] The method according to the present invention can be illustrated by the following process:

[0023] N-alkylation of amines is known to be carried out using SO2F2. According to Epifanov et al., "JACS, 2018, 140, 16464-16468", secondary or tertiary polyfluoroalkylamines can be prepared from polyfluoroalkyl alcohols RFCH2OH (with RF = CF3, CHF2, CF2CF3, CF2CF2CF3). Cyclic tertiary amines (e.g., morpholine) can be isolated in a maximum yield of 67%. In Sammis et al., Chem. Eur. J. 2020, 4958-4962, phthalimides can be readily reacted with various non-fluorinated aliphatic alcohols. The inventors intuitively demonstrate the preparation of primary polyfluoroalkylamines using SO2F2 via the synthesis of phthalimides.

[0024] Equally surprising is that the polyfluorinated alcohol used in step (i) can be well converted into aceimine of formula (III) with a high yield of about 85 to 90%.

[0025] Compounds of formula (I) and (II) are known, commercially available, or can be prepared by conventional methods. SO2F2 is commercially available and is used as an insecticide.

[0026] Unless otherwise indicated, the expression "alkyl" alone or in combination with other terms means a straight-chain or branched saturated hydrocarbon chain having up to 12 carbon atoms, i.e., C1-C12-alkyl, preferably up to 6 carbon atoms, i.e., C1-C6-alkyl, and most preferably up to 4 carbon atoms, i.e., C1-C4-alkyl. Examples of such alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Alkyl groups may be substituted with suitable substituents, for example, with halogens.

[0027] Unless otherwise indicated, the expression "aryl" or "six-membered aromatic ring" refers to a phenyl ring.

[0028] Unless otherwise indicated, "hal" means fluorine, chlorine, bromine or iodine.

[0029] In step (i), the reaction of the alcohol of formula (I) with the aceimine of formula (II) is usually carried out in the presence of a solvent.

[0030] When a solvent is added to the reaction mixture in step (i), the amount of solvent used preferably maintains satisfactory stirability of the reaction mixture throughout the process. Based on the volume of alcohol used, it is advantageous to use 1 to 50 times the amount of solvent, preferably 2 to 40 times, and most preferably 2 to 20 times. It should also be understood that, according to the invention, the term "solvent" means a mixture of pure solvents.

[0031] All organic solvents that are inert under the reaction conditions are suitable solvents. Suitable solvents according to the invention are particularly ethers (e.g., ethyl propyl ether, methyl tributyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dialkylene and ethylene oxide and / or propylene oxide polyether); Compounds, such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide; sulfoxides, such as dimethyl, diethyl, dipropyl, dibutyl, diphenyl, dihexyl, methylethyl, ethylpropyl, ethylisobutyl, and tetramethylene sulfoxide; aliphatic, cycloaliphatic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane), such as white oil solvents (white... Spirits (components having boiling points in the range of, for example, from 40°C to 250°C), isopropyltoluene, benzene fractions in the boiling point range of 70°C to 190°C, cyclohexane, methylcyclohexane, petroleum ether, petroleum ether, octane, benzene, toluene, or xylene); halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphatidylamine, methylamine, N,N-dimethylacetamide, N-methylmethamide, N,N-dimethyl... Methamide, N,N-dipropylmethamide, N,N-dibutylmethamide, N-methylpyrrolidone, N-methylcaprolactone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactone, 1,3-dimethyl-2-imidazolinide, N-methoxypiperidine or N,N'-1,4-dimethylpiperidine; nitrile (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile or benzonitrile); ketone (e.g., acetone) or mixtures thereof.

[0032] Acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetramethylene sulfide, and N-methylpyrrolidone are preferred solvents in step (i).

[0033] The reaction in step (i) is carried out in the presence of one or more acid scavengers capable of binding with the hydrogen fluoride released in the reaction. In a preferred embodiment of the invention, the acid scavenger used in step (i) is a base.

[0034] Organic and inorganic bases capable of binding released hydrogen fluoride are suitable acid scavengers. Examples of organic bases are tertiary nitrogen bases, such as tertiary amines, substituted or unsubstituted pyridines and substituted or unsubstituted quinolines, triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-, 3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2 4,6-Trimethylpyridine, 4-Dimethylaminopyridine, quinoline, 2-Methylquinoline (quinaldine), N,N,N,N-Tetramethylethylenediamine, N,N-Dimethyl-1,4-diazacyclohexane, N,N-Diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, and methylimidazole.

[0035] Examples of inorganic bases are alkali metal or alkaline earth metal hydroxides, bicarbonates or carbonates, and other inorganic aqueous bases; preferred are, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium acetate, KF, CsF. Potassium carbonate or sodium carbonate, KF, and CsF are most preferred.

[0036] The molar ratio of the acid scavenger (particularly the base described above) to the imidin of formula (II) used typically falls within the range of 1:1 to 5:1, preferably from 1:1 to 4:1, and most preferably from 1:1 to 3:1. Using a larger amount of base is technically feasible, but not economically useful.

[0037] The molar ratio of the polyfluoroalkyl alcohol of formula (I) to the aceimine of formula (II) used is generally in the range of 1:1 to 5:1, preferably in the range of 1:1 to 3:1, and especially preferably in the range of 1:1 to 2.5:1.

[0038] The molar ratio of SO2F2 to the imidin of formula (II) used is generally in the range of 1:1 to 5:1, preferably in the range of 1:1 to 3:1, and especially preferably in the range of 1:1 to 2:1.

[0039] The reaction in step (i) is generally carried out in an open system or at the inherent pressure in a pressure vessel (autoclave). The pressure during the reaction (i.e., the inherent pressure) depends on the reaction temperature used, the amount of SO2F2, and the solvent used (if the solvent is present in step (i)). If an increased pressure is required, the additional pressure can be achieved by adding an inert gas (such as nitrogen or argon).

[0040] The optimal operating mode is to effervesce SO2F2 into a reaction mixture containing phthalimide, base and polyfluoroalkyl alcohol of formula (I).

[0041] The method according to the invention can be carried out continuously or in batches. Similarly, it is conceivable to carry out some steps of the method according to the invention continuously and the remaining steps in batches. Within the meaning of this invention, continuous steps are those in which the inflow of the compound (starting material) into the reactor and the outflow of the compound (product) from the reactor occur simultaneously but spatially separately, while with respect to batch steps, the inflow of the compound (starting material), the desired chemical reaction, and the outflow of the compound (product) occur sequentially in time.

[0042] The preferred internal temperature for carrying out reaction step (i) is in the range of -5°C to 50°C, and more preferably in the range of 10°C to 40°C.

[0043] The reaction time in step (i) is very short and falls within the range of 0.5 to 5 hours. Longer reaction times are feasible, but not economically useful.

[0044] The reaction mixture from step (i) is post-processed depending on the physical properties of the product. If phthalimide or a substituted phthalimide is used as the compound of formula (II), the solvent is first removed under vacuum. If succinimidide is used as the compound of formula (II), the solid is first filtered off. Subsequently, the reaction mixture is typically "diluted," i.e., water, which is salt-soluble, is added. The product can then be separated by filtration or extracted from the aqueous phase using an organic solvent.

[0045] In step (ii), the cleavage of compound (III) to give a polyfluoroalkylamine or its salt system is carried out by adding an acid, a base, or hydrazine (including hydrazine hydrate). Preferably, an acid or hydrazine is used in step (ii). Hydrazine hydrate is particularly preferred. A typical procedure for this step is given in US 2012 / 0190867 or “The journal of the chemical society of Japan, 1985 v. 1985 N. 4 pp. 796-798”.

[0046] The base that can be used in step (ii) is known to those skilled in the art or is included in the present invention as an acid scavenger. The acid used in step (ii) is an organic acid or an inorganic acid, preferably an inorganic acid. According to the present invention, examples of such preferred inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid.

[0047] In step (ii), the cleavage of the compound of formula (III) is carried out in a suitable solvent. The amount of solvent used also preferably keeps the reaction mixture stirable throughout the process. Based on the compound of formula (III) used, it is advantageous to use about 1 to 50 times (v / v) the amount of solvent, more preferably about 2 to 40 times the amount of solvent, and particularly preferably 2 to 10 times the amount of solvent.

[0048] All organic solvents that are inert under the reaction conditions may be used as solvents. It should also be understood that the term "solvent" according to the present invention means a mixture of pure solvents.

[0049] In step (ii), suitable solvents according to the present invention are particularly water, ethers (e.g., ethyl propyl ether, methyl tributyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dialkylene and ethylene oxide and / or propylene oxide polyether); aliphatic, cycloaliphatic or aromatic Hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane; white oil solvents (having components with boiling points in the range of, for example, from 40°C to 250°C); isopropyltoluene; benzene fractions in the boiling point range of 70°C to 190°C; cyclohexane; methylcyclohexane; petroleum ether; petroleum ether; octane; benzene; toluene; or xylene); straight-chain and branched carboxylic acids (e.g., formic acid, acetic acid, propionic acid, butyric acid, and isobutyric acid) and their esters (e.g., ethyl acetate and butyl acetate); alcohols (e.g., methanol, ethanol, isopropanol, n-butanol, and isobutanol) or mixtures thereof. In step (ii), the preferred solvent according to the invention is methanol, ethanol, and water or mixtures thereof.

[0050] The molar ratio of acid or hydrazine (or hydrazine hydrate) to the compound of formula (III) used falls within the range of 0.8:1 to 10:1, preferably from 1:1 to 5:1, and most preferably from 1:1 to 3:1. Adding larger amounts of acid or hydrazine is generally feasible. An acid with suitable handleability can also be used as a solvent. Hydrazine is used in its hydrated form.

[0051] The pyrolysis in step (ii) can be carried out at a temperature ranging from 0°C to 150°C. The internal temperature preferably falls within the range of 20°C to 100°C; particularly preferably within the range of 40°C to 70°C. The hydrazine pyrolysis temperature preferably falls within the range of 50 to 70°C.

[0052] The reaction time used for pyrolysis is very short and falls within the range of 0.1 to 12 hours. Longer times are feasible, but not economically useful.

[0053] After the reaction is complete, the obtained polyfluoroalkylamine of formula (IV) can be purified by distillation. Alternatively, 2,2-difluoroethylamine can also be isolated and purified as a salt (e.g., hydrochloride). The 2,2-difluoroethylamine salt can then be released by adding a base (preferably NaOH).

[0054] In the preferred embodiment of the present invention, the polyfluoroalkyl alcohol of formula (I) is CHF2CH2OH and the polyfluoroalkylamine of formula (IV) is 2,2-difluoroethyl-1-amine.

[0055] Furthermore, in the preferred embodiment of the present invention, the compound of formula (II) is phthalimide and the compound of formula (III) is compound of formula (III-b).

[0056] Furthermore, in the preferred embodiment of the present invention, diazabicycloundecane is used as a base (acid scavenger) in step (i).

[0057] Furthermore, in the preferred embodiment of the present invention, hydrochloric acid is used in step (ii).

[0058] Furthermore, in the preferred embodiment of the present invention, hydrazine hydrate is used in step (ii).

Implementation Method

[0060] Preparation Example:

[0061] Example 1 – Preparation of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione (step (i))

[0062] Example 1.1

[0063] 1.47 g (0.01 mmol) of phthalimide, 1.45 mL (0.02 mol) of 2,2-difluoroethanol, and 6 g (0.04 mol) of diazabicycloundecane were added to 25 mL of N,N-dimethylacetamide. 2.2 g (0.02 mol) of SO2F2 was slowly bubbled through the reaction mixture at 20 °C for 40 min. The solvent was removed under a vacuum of 1 mbar. The concentrated solution was diluted with methyl tributyl ether and washed with water. The organic layer was collected, dried over magnesium sulfate, and filtered. The ether was removed under vacuum to give 1.97 g of a white solid with 98% purity and 91% yield. Mp 114 to 116 °C.

[0064] 1H NMR (DMSO): 7.95-7-87 (m, 4H), 6.25 (tt, 1H), 4.0 (td, 2H) ppm.

[0065] 13C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm.

[0066] 19F NMR (DMSO): 121.40 (dt) ppm.

[0067] Example 1.2

[0068] 1.47 g (0.01 mmol) of phthalimide, 1.45 mL (0.02 mol) of 2,2-difluoroethanol, and 3.88 g (0.03 mol) of N-ethyldiisopropylamine were added to 25 mL of N,N-dimethylacetamide. 3.06 g (0.03 mol) of SO2F2 was slowly bubbled through the reaction mixture at 40 °C for 3 h, and the reaction mixture was stirred at 40 °C under an SO2F2 atmosphere for 5 h. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered off and dried. 1.81 g of a white solid with 100% purity and 86% yield was obtained. Mp 114 to 116 °C.

[0069] 1H NMR (DMSO): 7.95-7-87 (m, 4H), 6.25 (tt, 1H), 4.0 (td, 2H) ppm.

[0070] 13C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm.

[0071] 19F NMR (DMSO): 121.40 (dt) ppm.

[0072] Example 1.3

[0073] 1.47 g (0.01 mmol) of phthalimide, 1.45 mL (0.02 mol) of 2,2-difluoroethanol, and 3.1 g (0.03 mol) of triethylamine were added to 25 mL of N,N-dimethylacetamide. 3.06 g (0.03 mol) of SO₂F₂ was slowly bubbled through the reaction mixture at 40 °C for 3 h, and the reaction mixture was stirred at 40 °C under an SO₂F₂ atmosphere for 12 h. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered off and dried. 1.9 g of a white solid with 100% purity and 84% yield was obtained. Mp 114 to 116 °C.

[0074] 1H NMR (DMSO): 7.95-7-87 (m, 4H), 6.25 (tt, 1H), 4.0 (td, 2H) ppm.

[0075] 13C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm.

[0076] 19F NMR (DMSO): 121.40 (dt) ppm.

[0077] Example 2 – Preparation of 2-(2,2,2-trifluoroethyl)-1H-isoindole-1,3(2H)-dione (step (i))

[0078] Example 2.1.

[0079] 1.47 g (0.01 mol) of phthalimide, 1.8 mL (0.02 mol) of 2,2,2-trifluoroethanol, and 4.5 g (0.03 mol) of diazabicycloundecane were added to 25 mL of N,N-dimethylacetamide. 2.2 g (0.02 mol) of SO2F2 was bubbled through the reaction mixture at 20 °C for 60 min. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered off and dried. 2.1 g of a white solid with 100% purity and 92% yield was obtained. Mp 122 to 127 °C.

[0080] 1H NMR (DMSO): 7.99-7-90 (m, 4H), 4.43 (q, 2H) ppm

[0081] 13C NMR (DMSO): 166.86, 135.20, 131.30, 123.86 (q), 123.82, 38.89 (q) ppm.

[0082] 19F NMR (DMSO): -68.85 (t, 3F) ppm.

[0083] Example 2.2

[0084] 1.47 g (0.01 mol) of phthalimide, 1.8 mL (0.02 mol) of 2,2,2-trifluoroethanol, and 2.3 g (0.04 mol) of spray-dried KF were added to 25 mL of N,N-dimethylacetamide. 2.2 g (0.02 mol) of SO2F2 was bubbled through the reaction mixture at 30 °C for 40 min, and the reaction mixture was stirred for 12 h under an SO2F2 atmosphere. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered off and dried. 1.98 g of a white solid with 100% purity and 86% yield was obtained. Mp 122 to 127 °C.

[0085] 1H NMR (DMSO): 7.99-7-90 (m, 4H), 4.43 (q, 2H) ppm.

[0086] 13C NMR (DMSO): 166.86, 135.20, 131.30, 123.86 (q), 123.82, 38.89 (q) ppm.

[0087] 19F NMR (DMSO): -68.85 (t, 3F) ppm.

[0088] Example 3 – Preparation of 2-(2,2,3,3,3-pentafluoropropyl)-1H-isoindole-1,3(2H)-dione (step (i))

[0089] 1.47 g (0.01 mol) of phthalimide, 3 g (0.02 mol) of 2,2,3,3,3-pentafluoropropanol, and 4.5 g (0.03 mol) of diazabicycloundecane were placed in 25 mL of N,N-dimethylacetamide. 2.55 g (0.025 mol) of SO2F2 was bubbled through the reaction mixture at 20 °C for 60 min, and the reaction mixture was stirred for 5 h under an SO2F2 atmosphere. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered off and dried. 2.53 g of a white solid with 100% purity and 91% yield was obtained. Mp 134 to 135 °C.

[0090] 1H NMR (DMSO): 8.00-7-90 (m, 4H), 4.42 (t, 2H) ppm.

[0091] 13C NMR (DMSO): 166.92, 135.30, 131.25, 123.89, 118.40 (tq), 112.60 (m), 37.00 (t) ppm.

[0092] 19F NMR (DMSO): -83.70 (s, 3F), -118.86 (t, 2F) ppm.

[0093] Example 4 – Preparation of 2-(2,2,3,3-tetrafluoropropyl)-1H-isoindole-1,3(2H)-dione (step (i))

[0094] 1.47 g (0.01 mol) of phthalimide, 3.3 g (0.02 mol) of 2,2,3,3-tetrafluoropropanol, and 4.5 g (0.03 mol) of diazabicycloundecane were placed in 25 mL of N,N-dimethylacetamide. 2.55 g (0.025 mol) of SO2F2 was bubbled through the reaction mixture at 20 °C for 60 min, and the reaction mixture was stirred for 5 h under an SO2F2 atmosphere. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered off and dried. 2.3 g of a white solid with 100% purity and 88% yield was obtained. Mp 129 to 130 °C.

[0095] 1H NMR (DMSO): 7.97-7-90 (m, 4H), 6.64 (tt, 1H), 4.23 (t, 2H) ppm.

[0096] 13C NMR (DMSO): 167.22, 135.08, 131.50, 123.75, 114.98 (tt), 109.54 (tt), 37.43 (t) ppm.

[0097] 19F NMR (DMSO): -120.95 (m, 2F), -138.64 (dt, 2F) ppm.

[0098] Example 5 – Preparation of 2,2-difluoroethylamine (step (ii))

[0099] 4.22 g (0.02 mol) of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione was placed in 50 mL of ethanol and treated with 1.8 g (0.036 mol) of hydrazine hydrate. The reaction mixture was stirred under reflux for 2 h. The reaction mixture was then cooled to 20 °C and the solid was filtered off. The filtrate was adjusted to pH 2 with 10 mL of hydrochloric acid (2N) and concentrated to dryness to give 2 g (85%) of 2,2-difluoroethylamine hydrochloride.

[0100] 19F NMR (DMSO): -122.10 (dt, 2F) ppm.

[0101] 13C NMR (DMSO): 132.77, 125.32, 113.51 (t) ppm.

[0102] 1H NMR (DMSO): 6.39 (tt, 1H), 3.31 (m, 2H) ppm.

[0103] Example 6 – Preparation of 2,2,3,3-tetrafluoroprop-1-amine (step (ii))

[0104] 5.22 g (0.02 mol) of 2-(2,2,3,3-tetrafluoropropyl)-1H-isoindole-1,3(2H)-dione was placed in 50 mL of ethanol and treated with 1.4 g (0.028 mol) of hydrazine hydrate. The reaction mixture was stirred under reflux for 2 h. The reaction mixture was then cooled to 20 °C and the solid was filtered off. The filtrate was adjusted to pH 2 with 10 mL of hydrochloric acid (2N) and concentrated to dryness to give 3.1 g of 2,2,3,3-tetrafluoropropyl-1-amine hydrochloride in 92% yield.

[0105] 19F NMR (DMSO): -121.08 (m, 2F), -137.84 (dt, 2F) ppm.

[0106] 13C NMR (DMSO): 114.93 (tt), 109.24 (tt), 38.23 ppm.

[0107] 1H NMR (DMSO): 6.73 (tt, 1H), 3.62 (t, 2H) ppm.

[0108] Example 7 – Preparation of 2,2,3,3,3-pentafluoroprop-1-amine (step (ii))

[0109] 5.58 g (0.02 mol) of 2-(2,2,3,3,3-pentafluoropropyl)-1H-isoindole-1,3(2H)-dione was placed in 50 mL of ethanol and treated with 1.4 g (0.028 mol) of hydrazine hydrate. The reaction mixture was stirred under reflux for 2 h. The reaction mixture was then cooled to 20 °C and the solid was filtered off. The filtrate was adjusted to pH 2 with 10 mL of hydrochloric acid (2N) and concentrated to dryness to give 3.37 g of 2,2,3,3,3-pentafluoropropyl-1-amine hydrochloride (91%).

[0110] 19F NMR (DMSO): -83.37 (3F), -119.01 (t, 2F) ppm.

[0111] 1H NMR (DMSO): 3.91 (t, 2H) ppm.

[0112] Example 8 – Preparation of 2,2,2-trifluoroethylamine (step (ii))

[0113] 4.58 g (0.02 mol) of 2-(2,2,2-trifluoroethyl)-1H-isoindole-1,3(2H)-dione was placed in 50 mL of ethanol and treated with 1.6 g (0.032 mol) of hydrazine hydrate. The reaction mixture was stirred under reflux for 2 h. The reaction mixture was then cooled to 20 °C and the solid was filtered off. The filtrate was adjusted to pH 2 with 10 mL of hydrochloric acid (2N) and concentrated to dryness to give 2.45 g of 2,2-difluoroethylamine hydrochloride (90%).

[0114] 19F NMR (DMSO): -67.89 (t, 3F)

[0115] 1H NMR (DMSO): 3.87 (q, 2H) [Simplified Explanation of the Diagram]

[0059] None [Biomaterial Storage]

[0117] None

Claims

1. A method for preparing a polyfluoroalkylamine of formula (IV) RFCH2NH2 (IV) wherein RF is as defined in step (i), the method comprising the steps of: Step (i): reacting a polyfluoroalkyl alcohol of formula (I) RFCH2OH (I) wherein RF = CHF2, CF3, C2F5 or HCF2CF2 with an imine of formula (II) in the presence of SO2F2 and an acid scavenger to give a compound of formula (III) wherein in compounds of formula (II) and (III), R1 and R2 are each independently hydrogen or C1-C6-alkyl or R1 and R2 together with the carbon atoms of the latter form a six-membered aromatic ring, the six-membered aromatic ring being substituted with a halogen or C1-C12-alkyl as desired; Step (ii): reacting the compound of formula (III) with an acid, a base or hydrazine.

2. The method of claim 1, wherein the polyfluoroalkylamine of formula (IV) is 2,2-difluoroethyl-1-amine.

3. The method of claim 1 or 2, wherein the compound of formula (II) is succinimide or phthalimide.

4. The method of claim 1 or 2, wherein the compound of formula (II) is an o-phthalimide.

5. The method of claim 1 or 2, wherein the acid scavenger in step (i) is a base selected from: tertiary amines, substituted or unsubstituted pyridines and substituted or unsubstituted quinolines, triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidone, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-, 3- or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethyl... Pyridine, 4-dimethylaminopyridine, quinoline, 2-methylquinoline, N,N,N,N-tetramethylethylenediamine, N,N-dimethyl-1,4-diazacyclohexane, N,N-diethyl-1,4-diazacyclohexane, 1,8-bis(dimethylamino)naphthalene, diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), butylimidazole, methylimidazole, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, KF and CsF.

6. The method of claim 1 or 2, wherein the acid scavenger in step (i) is a base, which is diazabicycloundecane, potassium carbonate, sodium carbonate, KF or CsF.

7. The method of claim 5, wherein the molar ratio of the base to the imidin of formula (II) used is in the range of 1:1 to 5:

1.

8. The method of request item 1 or 2, wherein an inorganic acid is used in step (ii).

9. The method according to claim 8, wherein the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid.

10. The method of request item 1 or 2, wherein hydrazine hydrate is used in step (ii).

11. The method of claim 10, wherein the molar ratio of hydrazine hydrate to the compound of formula (III) is in the range of 0.8:1 to 10:

1.

12. The method of claim 8, wherein the molar ratio of the acid to the compound of formula (III) is in the range of 0.8:1 to 10:1.