Process for the preparation of polyfluoroalkyl amines from polyfluoroalkyl alcohols

Abstract

A process for the preparation of polyfluoroalkyl amines, wherein in a first step a polyfluoroalkyl alcohol is reacted with an imide in the presence of SO2F2 and a deacidifying agent and then in a second step the obtained compound is reacted with an acid, a base or a hydrazine.

Description

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

[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 flupyrfuranone.

[0003] Several methods for preparing fluoroalkylamines are known, such as (a) reacting the corresponding polyfluoroalkyl halide with ammonia (e.g., Dickey et al., Industrial and Engineering Chemistry, 1956, No. 2, 209-213, US2002 / 0183557) or reacting the corresponding alcohol with ammonia (JP2005002031A), (b) hydrogenating the corresponding nitrile or azide compound (US3532755, Mecinovic et al., Green Chem., 2018, 20, 4418–4442), and (c) reducing the corresponding polyfluoroalkyl amide (e.g., for CF3CH2NH2, Douglas et al., Chem. Commun., 2016, 52, 12195-12198; for CHF2CH2NH2, Husted & Ahlbrecht). J. Am. Chem. Soc. 1953, 75, 7, 1605-1608; for R among them F =R of -CF3, -C2F5, -C3F9 F CH2NH2, Soloshonok et al., Tetrahedron Letters, 2002, 43, 5449–5452; For FCH2CH2NH2, Papanastassiou & Bruni, J. Org. Chem. 1964, 29, 10, 2870–2872).

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

[0005] WO-A-2011 / 012243 and WO-A-2012 / 095403 disclose a method 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 difluoroacetamide is then converted into 2,2-difluoroethylamine by adding an acid suitable for cleaving difluoroacetamide.

[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 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 allyl group is removed (deallylation) from the resulting N-(2,2-difluoroethyl)prop-2-en-1-amine.

[0010] Known methods are disadvantageous because they either involve long reaction times at high temperatures and pressures with low yields, require expensive reagents or equipment, or have highly corrosive reaction mixtures, making them unsuitable for commercial-scale use.

[0011] US2012 / 0190867 (WO-A-2012 / 101044) describes the use of Gabriel synthesis to utilize HCF₂CH₂Cl (CFC 142). HCF₂CH₂Cl is environmentally unfriendly, belonging to the ozone-depleting substance (ODS) class, and its utilization is strictly limited. The reaction time in the described method is relatively short, but it requires relatively high temperatures (90-140°C). Furthermore, this method may require the use of a catalyst.

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

[0013] However, the authors (JACS, p. 16466) also found that substrates with steric hindrance at the α-position of the amine (such as cyclohexane and aniline) are poor substrates for this reaction and cannot be alkylated at high reaction rates using polyfluorools. Like other amines, aniline is a base (pKb = 9.42) and is nucleophilic, although it is a weak base and a poor nucleophile compared to structurally similar aliphatic amines.

[0014] In this invention, phthalimide is used, whose ring system has two carbonyl groups at the α-position of the amine group and is therefore considered a sterically hindered substrate. It is also known that phthalimide exhibits significant NH- acidity and no basicity due to the electron-withdrawing (-M) effect of the two carbonyl groups. The higher acidity of the imide-NH group is due to the pair of electrophilic carbonyl groups on the sides. Furthermore, it is well known that amides (such as phthalimide or succinimide used in the method of this invention) are generally less reactive to electrophilic reagents than amines (such as those used in the method of Epifanov et al.).

[0015] Therefore, surprisingly, the polyfluoroalkylation of phthalimide (which is acidic rather than basic) in the method of this invention can be carried out in high yields under mild conditions, while cyclohexylamine or aniline are only poor substrates for this reaction under mild conditions. This also applies when succinimide is used instead of phthalimide.

[0016] Kuwabara et al. described the synthesis of polyfluoroalkylamines (where R...) from N-polyfluoroalkyl phthalimides in "The journal of the Chemical Society of Japan, 1985 v. 1985, N 4, pp. 796-798". F =R of -CF3, -CF2CHF2, (CF2CF2)2H, -(CF2CF2)3H F (CH2NH2). The desired N-polyfluoroalkyl phthalimide was prepared from the K salt of polyfluoroalkyl o-nitrobenzenesulfonate and phthalimide under very harsh reaction conditions and long-term heating at 150°C.

[0017] Starting from 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 raw materials such as polyfluoroalkyl alcohols and inexpensive SO2F2 gas in a simple and inexpensive manner. The inventors have discovered that polyfluoroalkylamines can be advantageously prepared from polyfluoroalkyl alcohols by first preparing an imide intermediate and then pyrolyzing it.

[0018] Therefore, the subject of this invention is a method for preparing polyfluoroalkylamines of formula (IV).

[0019] R F CH2NH2 (IV)

[0020] Where R F As defined in step (i) below, the method includes the following steps:

[0021] Step (i): Exposing the polyfluoroalkyl alcohol of formula (I) to SO2F2 and an acid-removing agent.

[0022] R F CH2OH (I)

[0023] Where R F =CHF2, CF3, C2F5 or HCF2CF2,

[0024] Reaction with imide of formula (II)

[0025]

[0026] Compound of formula (III) was obtained

[0027]

[0028] In compounds of formulas (II) and (III), R 1 and R 2 Each is independently hydrogen or C1-C6-alkyl or R 1 and R 2 Together with the carbon atoms they are attached to, they form a six-membered aromatic ring, which is optionally bonded by a halogen or C1-C. 12 -alkyl substitution;

[0029] Step (ii): React the compound of formula (III) with an acid, a base or hydrazine (i.e., cleave the compound of formula (III) by adding an acid, a base or hydrazine).

[0030] 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).

[0031] The imide of formula (II) used in step (i) may also be present in the form of a salt. Such salts are commercially available in some cases (e.g., potassium salts of phthalimide). The imide of formula (II) may also be converted into a salt by reacting it with a suitable base before using the salt in the method of the present invention. Suitable bases are those known to those skilled in the art or include those mentioned herein as scavenging agents.

[0032] In the method of the present invention, it is preferable to use a compound of formula (II), wherein R 1 and R 2 Each is hydrogen (i.e., succinimide) or R is therein. 1 and R 2 Together with the carbon atoms they are attached to, they form a six-membered aromatic ring (i.e., phthalimide). If succinimide is used as the compound of formula (II), then in step (i) the compound of formula (III-a) is obtained. If phthalimide is used as the compound of formula (II), then in step (i) the compound of formula (III-b) is obtained:

[0033]

[0034] The method of the present invention can be described by the following scheme:

[0035]

[0036] The N-alkylation of amines using SO2F2 is known. According to Epifanov et al., "JACS, 2018, 140, 16464-16468", it is possible to use R... F =CF3, CHF2, CF2CF3, CF2CF2CF3 polyfluoroalkyl alcohols R F Polyfluoroalkyl secondary or tertiary amines can be prepared by CH2OH. Cyclic tertiary amines (e.g., morpholine) can be isolated in yields up to 67%. Phthalimides readily react with various non-fluorinated aliphatic alcohols, as described by Sammis et al., Chem. Eur. J. 2020, 4958-4962. Intuitively, the inventors describe the preparation of polyfluoroalkyl primary amines by synthesizing phthalimides using SO2F2.

[0037] Similarly, surprisingly, the polyfluorinated alcohol used in step (i) can be converted into the imide of formula (III) very well and in a high yield of about 85-90%.

[0038] The compounds of formulas (I) and (II) are known, commercially available, or can be prepared by conventional methods. SO2F2 is commercially available and can be used as an insecticide.

[0039] Unless otherwise stated, the term "alkyl" (alone or in combination with other terms) refers to a straight-chain or branched saturated hydrocarbon chain having up to 12 carbon atoms, i.e., C1-C2. 12-alkyl, preferably having up to 6 carbon atoms, i.e., C1-C6-alkyl, very preferably having up to 4 carbon atoms, i.e., C1-C4-alkyl. Examples of such alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. The alkyl group may be substituted with suitable substituents (such as halogens).

[0040] Unless otherwise stated, the terms "aryl" or "six-membered aromatic ring" refer to the phenyl ring.

[0041] Unless otherwise stated, "halogen" or "halogenated" means fluorine, chlorine, bromine or iodine.

[0042] The reaction of the alcohol of formula (I) with the imide of formula (II) in step (i) is usually carried out in the presence of a solvent.

[0043] If a solvent is added to the reaction mixture in step (i), it is preferable to use an amount sufficient to maintain the reaction mixture in a satisfactory stirable state throughout the process. Advantageously, the solvent is used in an amount of 1 to 50 times, preferably 2 to 40 times, and particularly preferably 2 to 20 times, based on the volume of alcohol used. According to the invention, the term "solvent" should also be understood to refer to a mixture of pure solvents.

[0044] All organic solvents that are inert under the reaction conditions are suitable solvents. Suitable solvents for this invention are particularly ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexylmethyl ether, methyl ether, diethyl ether, dimethyl ethylene glycol, diphenyl ether, propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, isopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and ethylene oxide and / or propylene oxide polyethers). Compounds such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene sulfoxide, dipropyl sulfoxide, benzylmethyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide, or diisopentyl sulfoxide; sulfones such as dimethyl sulfone, diethyl sulfone, dipropyl sulfone, dibutyl sulfone, diphenyl sulfone, dihexyl sulfone, methyl ethyl sulfone, ethyl propyl sulfone, ethyl isobutyl sulfone, and sulfolane; aliphatic, alicyclic, or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, for example, component boiling...) The boiling points include petroleum solvents with a boiling range of 40°C to 250°C, umbelliferous hydrocarbons, volatile oil fractions with a boiling range of 70°C to 190°C, cyclohexane, methylcyclohexane, petroleum ether, light petroleum, octane, benzene, toluene, or xylene; halogenated aromatic compounds (e.g., chlorobenzene or dichlorobenzene); amides (e.g., hexamethylphosphoric triamine, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, etc.). N,N-dibutylformamide, N-methylpyrrolidone, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinide, N-formylpiperidine or N,N'-1,4-diformylpiperazine; nitrile compounds (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile or benzonitrile); ketone compounds (e.g., acetone); or mixtures thereof.

[0045] In step (i), the preferred solvents are acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, sulfolane, and N-methylpyrrolidone.

[0046] The reaction in step (i) is carried out in the presence of one or more deacidifying agents that can bind to the hydrogen fluoride released during the reaction. In a preferred embodiment of the invention, the deacidifying agent used in step (i) is a base.

[0047] Organic and inorganic bases that can bind to the 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-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-methylpyridine, 3-methylpyridine or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2, 6-Dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, quinoline, quinalidine, 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.

[0048] Examples of inorganic bases are alkali metal or alkaline earth metal hydroxides, bicarbonates or carbonates, and other aqueous inorganic bases; preferred examples include sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and sodium acetate, KF, and CsF. Potassium carbonate or sodium carbonate, KF, and CsF are particularly preferred.

[0049] The molar ratio of the scavenging agent (especially the aforementioned alkali) to the imide of formula (II) used is typically 1:1 to 5:1, preferably 1:1 to 4:1, and particularly preferably 1:1 to 3:1. Using a larger amount of alkali is technically feasible, but economically impractical.

[0050] The molar ratio of the polyfluoroalkyl alcohol of formula (I) to the imide of formula (II) used is typically 1:1 to 5:1, preferably 1:1 to 3:1 and particularly preferably 1:1 to 2.5:1.

[0051] The molar ratio of SO2F2 to the imide of formula (II) used is typically 1:1 to 5:1, preferably 1:1 to 3:1 and particularly preferably 1:1 to 2:1.

[0052] The reaction in step (i) is generally carried out in an open system or at the inherent pressure of 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 a solvent is present in step (i)). If an additional pressure is required, it can be achieved by adding an inert gas (such as nitrogen or argon).

[0053] The preferred method of operation is to bubble SO2F2 into a reaction mixture containing phthalimide, a base, and a polyfluoroalkyl alcohol of formula (I).

[0054] The method of the present invention can be carried out continuously or intermittently. It is also conceivable to perform some steps of the method of the present invention continuously and the remaining steps intermittently. A continuous step in the sense of the present invention refers to a continuous step in which the inflow of the compound (raw material) into the reactor and the outflow of the compound (product) from the reactor occur simultaneously but are spatially separate, while for an intermittent step, the sequential inflow of the compound (raw material), optionally the chemical reaction, and the outflow of the compound (product) occur sequentially in time.

[0055] Preferably, during reaction step (i), the internal temperature is -5°C to 50°C, and particularly preferably 10°C to 40°C.

[0056] The reaction time in step (i) is relatively short, ranging from 0.5 to 5 hours. Longer reaction times are possible, but they are not economically viable.

[0057] The reaction mixture from step (i) is post-processed according to 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 succinimide is used as the compound of formula (II), the solid is first filtered off. Then, the reaction mixture is typically “diluted,” i.e., water in which the salt is soluble is added. The product can then be separated by filtration or extracted from the aqueous phase using an organic solvent.

[0058] In step (ii), the compound of formula (III) is cleaved by adding an acid, a base, or hydrazine (including hydrazine hydrate) to obtain a polyfluoroalkylamine or a salt thereof. Preferably, an acid or hydrazine is used in step (ii). Hydrazine hydrate is particularly preferred. Typical method steps for this step are given in US2012 / 0190867 or "The journal of the chemical society of Japan, 1985 v. 1985 N. 4, pp. 796-798".

[0059] The base that can be used in step (ii) is known to those skilled in the art or is included in this document as an acid remover. The acid used in step (ii) is an organic or inorganic acid, preferably an inorganic acid. According to the invention, examples of such preferred inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

[0060] The cleavage of the compound of formula (III) in step (ii) is carried out in a suitable solvent. It is also preferred that the solvent be used in an amount such that the reaction mixture remains stirable throughout the process. Based on the compound of formula (III) used, it is advantageous to use about 1 to 50 times (v / v) of the solvent, preferably about 2 to 40 times, and particularly preferably 2 to 10 times.

[0061] All organic solvents that are inert under the reaction conditions can be used as solvents. According to the present invention, the term "solvent" should also be understood to mean a mixture of pure solvents.

[0062] According to the present invention, suitable solvents in step (ii) are, in particular, water, ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexylmethyl ether, methyl ether, diethyl ether, dimethyl ethylene glycol, diphenyl ether, propyl ether, isopropyl ether, n-butyl ether, isobutyl ether, isopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and ethylene oxide and / or propylene oxide polyethers); aliphatic, alicyclic or aromatic Hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, petroleum solvents with a component boiling point of 40°C to 250°C, umbelliferous hydrocarbons, volatile oil fractions with a boiling range of 70°C to 190°C, cyclohexane, methylcyclohexane, petroleum ether, light petroleum, 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. According to the invention, the preferred solvent in step (ii) is methanol, ethanol, and water or mixtures thereof.

[0063] The molar ratio of acid or hydrazine (or hydrazine hydrate) to the compound of formula (III) used is from 0.8:1 to 10:1, preferably from 1:1 to 5:1, and particularly preferably from 1:1 to 3:1. Larger amounts of acid or hydrazine may be added in principle. The acid may also be used as a solvent under proper management. Hydrazine is used in its hydrated form.

[0064] The pyrolysis in step (ii) can be carried out at a temperature of 0°C to 150°C. The internal temperature is preferably 20°C to 100°C; particularly preferably 40°C to 70°C. For pyrolysis using hydrazine, the temperature is preferably 50-70°C.

[0065] The pyrolysis reaction time is relatively short, ranging from 0.1 to 12 hours. Longer reaction times are also possible, but they are not economically viable.

[0066] At the end of the reaction, the obtained polyfluoroalkylamine of formula (IV) can be purified by filtration. Alternatively, 2,2-difluoroethylamine can be separated and purified as a salt (such as hydrochloride). The 2,2-difluoroethylamine salt can then be released by adding a base (preferably NaOH).

[0067] In a most 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.

[0068] Furthermore, in a most preferred embodiment of the invention, the compound of formula (II) is phthalimide and the compound of formula (III) is the compound of formula (III-b).

[0069] Furthermore, in a most preferred embodiment of the invention, in step (i), diazabicycloundecane is used as a base (acid remover).

[0070] Furthermore, in a most preferred embodiment of the invention, hydrochloric acid is used in step (ii).

[0071] Furthermore, in a most preferred embodiment of the invention, hydrazine hydrate is used in step (ii).

[0072] Preparation Example:

[0073] Example 1 - Preparation of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione (Step (i))

[0074]

[0075] Example 1.1

[0076] 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 placed in 25 mL of N,N-dimethylacetamide. 2.2 g (0.02 mol) of SO₂F₂ was slowly bubbled into the reaction mixture at 20 °C for 40 minutes. The solvent was removed under a vacuum of 1 mbar. The concentrated solution was diluted with methyl tert-butyl 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 a purity of 98%, a yield of 91%, and a melting point of 114–116 °C.

[0077] 1 H NMR(DMSO):7.95-7-87(m,4H),6.25(tt,1H),4.0(td,2H)ppm.

[0078] 13C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm.

[0079] 19 F NMR (DMSO): 121.40 (dt) ppm.

[0080] Example 1.2

[0081]

[0082] 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 placed in 25 mL of N,N-dimethylacetamide. 3.06 g (0.03 mol) of SO₂F₂ was slowly bubbled into the reaction mixture at 40 °C for 3 hours, and the mixture was stirred at 40 °C under an SO₂F₂ atmosphere for 5 hours. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered and dried. 1.81 g of a white solid with a purity of 100%, a yield of 86%, and a melting point of 114–116 °C was obtained.

[0083] 1 H NMR(DMSO):7.95-7-87(m,4H),6.25(tt,1H),4.0(td,2H)ppm.

[0084] 13 C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm.

[0085] 19 F NMR (DMSO): 121.40 (dt) ppm.

[0086] Example 1.3

[0087]

[0088] 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 placed in 25 mL of N,N-dimethylacetamide. 3.06 g (0.03 mol) of SO₂F₂ was slowly bubbled into the reaction mixture at 40 °C for 3 hours, and the mixture was stirred at 40 °C under an SO₂F₂ atmosphere for 12 hours. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered and dried. 1.9 g of a white solid with a purity of 100%, a yield of 84%, and a melting point of 114–116 °C was obtained.

[0089] 1 H NMR(DMSO):7.95-7-87(m,4H),6.25(tt,1H),4.0(td,2H)ppm.

[0090] 13 C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm.

[0091] 19 F NMR (DMSO): 121.40 (dt) ppm.

[0092] Example 2 - Preparation of 2-(2,2,2-trifluoroethyl)-1H-isoindole-1,3(2H)-dione (Step (i))

[0093] Example 2.1

[0094]

[0095] 1.47 g (0.01 mol) phthalimide, 1.8 mL (0.02 mol) 2,2,2-trifluoroethanol, and 4.5 g (0.03 mol) diazabicycloundecane were placed in 25 mL of N,N-dimethylacetamide. 2.2 g (0.02 mol) SO₂F₂ was bubbled into the reaction mixture at 20 °C for 60 minutes. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered and dried. 2.1 g of a white solid with 100% purity, 92% yield, and melting point of 122–127 °C was obtained.

[0096] 1 H NMR (DMSO): 7.99-7-90 (m, 4H), 4.43 (q, 2H) ppm.

[0097] 13 C NMR (DMSO): 166.86, 135.20, 131.30, 123.86 (q), 123.82, 38.89 (q) ppm.

[0098] 19 F NMR(DMSO):-68.85(t,3F)ppm.

[0099] Example 2.2

[0100]

[0101] 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 placed in 25 mL of N,N-dimethylacetamide. 2.2 g (0.02 mol) of SO₂F₂ was bubbled into the reaction mixture at 30 °C for 40 minutes, and the reaction mixture was stirred for 12 hours under an SO₂F₂ atmosphere. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered and dried. 1.98 g of a white solid with a purity of 100%, a yield of 86%, and a melting point of 122–127 °C was obtained.

[0102] 1 H NMR (DMSO): 7.99-7-90 (m, 4H), 4.43 (q, 2H) ppm.

[0103] 13 C NMR (DMSO): 166.86, 135.20, 131.30, 123.86 (q), 123.82, 38.89 (q) ppm.

[0104] 19 F NMR(DMSO):-68.85(t,3F)ppm.

[0105] Example 3 - Preparation of 2-(2,2,3,3,3-pentafluoropropyl)-1H-isoindole-1,3(2H)-dione (step (i))

[0106]

[0107] 1.47 g (0.01 mol mmol) 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 into the reaction mixture at 20 °C for 60 minutes, and the reaction mixture was stirred for 5 hours under an SO₂F₂ atmosphere. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered and dried. 2.53 g of a white solid with a purity of 100%, a yield of 91%, and a melting point of 134–135 °C was obtained.

[0108] 1H NMR(DMSO):8.00-7-90(m,4H),4.42(t,2H)ppm.

[0109] 13 C NMR (DMSO): 166.92, 135.30, 131.25, 123.89, 118.40 (tq), 112.60 (m), 37.00 (t) ppm.

[0110] 19 F NMR(DMSO):-83.70(s,3F),-118.86(t,2F)ppm.

[0111] Example 4 - Preparation of 2-(2,2,3,3-tetrafluoropropyl)-1H-isoindole-1,3(2H)-dione (Step (i))

[0112]

[0113] 1.47 g (0.01 mol) phthalimide, 3.3 g (0.02 mol) 2,2,3,3-tetrafluoropropanol, and 4.5 g (0.03 mol) diazabicycloundecane were placed in 25 mL of N,N-dimethylacetamide. 2.55 g (0.025 mol) SO₂F₂ was bubbled into the reaction mixture at 20 °C for 60 minutes, and the reaction mixture was stirred for 5 hours under an SO₂F₂ atmosphere. The solvent was removed under vacuum, and the reaction mixture was diluted with water. The precipitate was filtered and dried. 2.3 g of a white solid with a purity of 100%, a yield of 88%, and a melting point of 129–130 °C was obtained.

[0114] 1 H NMR(DMSO):7.97-7-90(m,4H),6.64(tt,1H),4.23(t,2H)ppm.

[0115] 13 C NMR (DMSO): 167.22, 135.08, 131.50, 123.75, 114.98 (tt), 109.54 (tt), 37.43 (t) ppm.

[0116] 19 F NMR(DMSO):-120.95(m,2F),-138.64(dt,2F)ppm.

[0117] Example 5: Preparation of 2,2-difluoroethylamine (step (ii))

[0118]

[0119] 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 hours. Subsequently, the reaction mixture was cooled to 20 °C and the solids were 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.

[0120] 19 F NMR(DMSO):-122.10(dt,2F)ppm.

[0121] 13 C NMR (DMSO): 132.77, 125.32, 113.51 (t) ppm.

[0122] 1 H NMR (DMSO): 6.39 (tt, 1H), 3.31 (m, 2H) ppm.

[0123] Example 6 - Preparation of 2,2,3,3-tetrafluoropropane-1-amine (step (ii))

[0124]

[0125] 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 and refluxed for 2 hours. Subsequently, the reaction mixture was cooled to 20 °C and the solids were 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.

[0126] 19 F NMR(DMSO):-121.08(m,2F),-137.84(dt,2F)ppm.

[0127] 13 C NMR(DMSO): 114.93(tt), 109.24(tt), 38.23ppm.

[0128] 1 H NMR (DMSO): 6.73 (tt, 1H), 3.62 (t, 2H) ppm.

[0129] Example 7 - Preparation of 2,2,3,3,3-pentafluoroprop-1-amine (step (ii))

[0130]

[0131] 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 and refluxed for 2 hours. Subsequently, the reaction mixture was cooled to 20 °C and the solids were 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 (91%) of 2,2,3,3,3-pentafluoropropyl-1-amine hydrochloride.

[0132] 19 F NMR(DMSO):-83.37(3F),-119.01(t,2F)ppm.

[0133] 1 1H NMR (DMSO): 3.91 (t, 2H) ppm.

[0134] Example 8 - Preparation of 2,2,2-trifluoroethylamine (step (ii))

[0135]

[0136] 4.58 g (0.02 mmol) 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 and refluxed for 2 hours. Subsequently, the reaction mixture was cooled to 20 °C and the solids were 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 (90%) of 2,2-difluoroethylamine hydrochloride.

[0137] 19 F NMR (DMSO): -67.89 (t, 3F)

[0138] 1 ¹H NMR (DMSO): 3.87 (q, 2H).

Claims

1. Method for preparing polyfluoroalkylamines of formula (IV) R F CH2NH2 (IV) wherein R F The method comprises the following steps as defined in step (i) below: Step (i): The polyfluoroalkyl alcohol of formula (I) is subjected to the presence of SO2F2 and an acid-removing agent. R F CH2OH (I) Where R F = CHF2, CF3, C2F5 or HCF2CF2, Reaction with imide of formula (II) (II), The compound of formula (III) was obtained. (III) in, In the compounds of formulas (II) and (III), R 1 and R 2 Each is independently hydrogen or C1-C6-alkyl or R 1 and R 2 Together with the carbon atoms they are attached to, they form a six-membered aromatic ring, which is optionally bonded by a halogen or C1-C. 12 -alkyl substitution; Step (ii): React the compound of formula (III) with an acid, a base or hydrazine.

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

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

4. The method according to claim 1 or 2, wherein the compound of formula (II) is phthalimide.

5. The method according to claim 1, wherein the acid-removing agent in step (i) is a base, wherein the base is selected from triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine, N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-methylpyridine, 3-methylpyridine or 4-methylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethyl... Aminopyridine, quinoline, quinalidine, 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 according to claim 1, wherein the acid remover in step (i) is a base, wherein the base is diazabicycloundecane, potassium carbonate, sodium carbonate, KF or CsF.

7. The method according to claim 5 or 6, wherein the molar ratio of the base to the imide of formula (II) used is from 1:1 to 5:

1.

8. The method of claim 1, 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 claim 1, wherein hydrazine hydrate is used in step (ii).

11. The method according to any one of claims 1 to 8 to 10, wherein the molar ratio of the acid or hydrazine hydrate to the compound of formula (III) is 0.8:1 to 10:1.

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