Method for preparing polyfluoroalkylamines from polyfluoroalkyl alcohols

Abstract

A method for preparing polyfluoroalkylamines, comprising the steps of: in a first step, reacting a polyfluoroalkyl alcohol with an imide in the presence of SO2F2 and an acid scavenger; and then in a second step, reacting the resulting compound with an acid, a base or hydrazine.

Description

[Technical Field]

[0001] This invention relates to a method for producing polyfluoroalkylamines starting from polyfluoroalkyl alcohols using Gabriel synthesis. [Background 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 flupyradiflon.

[0003] Various methods are known for preparing fluoroalkylamines, for example: (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 (c) Methods for reducing the corresponding polyfluoroalkylamide (Douglas et al., Chem.Commun., 2016, 52, 12195-12198 (for CF3CH2NH2), Husted & Ahlbrecht, J.Am.Chem.Soc. 1953, 75, 7, 1605-1608 (for CHF2CH2NH2), Soloshonok et al., Tetrahedron Letters, 2002, 43, 5449-5452 (R F Regarding CH2NH2, R F =-CF3, -C2F5, -C3F9), Papanastassiou & Bruni, J. Org. Chem. 1964, 29, 10, 2870-2872 (for FCH2CH2NH2)).

[0004] Furthermore, WO-A-2012 / 101044 discloses a method for preparing 2,2-difluoroethylamine, in which 2,2-difluoro-1-chloroethane is reacted with an imide 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 a method for preparing 2,2-difluoroethylamine, in which 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, in which 2,2-difluoro-1-nitroethane is hydrogenated in the presence of a catalyst to obtain 2,2-difluoroethylamine.

[0007] WO-A2011 / 069994 discloses a method for preparing 2,2-difluoroethylamine, in which difluoroacetonitrile is catalytically hydrogenated, the resulting difluoroethylamide is converted to 2,2-difluoroethylamine by adding an acid suitable for cleavage of the difluoroethylamide.

[0008] WO-A2012 / 062702 discloses a method for preparing 2,2-difluoroethylamine, in which 2,2-difluoro-1-chloroethane is reacted with a benzylamine compound, and the resulting N-benzyl-2,2-difluoroethaneamine compound is catalytically hydrogenated to obtain 2,2-difluoroethylamine.

[0009] WO-A-2012 / 062703 discloses a method for preparing 2,2-difluoroethylamine, in which 2,2-difluoro-1-chloroethane is reacted with prop-2-ene-1-amine, and the allyl group is removed (deallylated) from the resulting N-(2,2-difluoroethyl)prop-2-ene-1-amine.

[0010] Known methods are disadvantageous because they require very long reaction times at high temperature and high pressure, have low yields, have expensive reagents or equipment, or the reaction mixture is very corrosive, and thus are unsuitable for use on a commercial scale.

[0011] US2012 / 0190867 (WO-A-2012 / 101044) describes the utilization of HCF2CH2Cl (Freon 142) using the Gabriel synthesis. HCF2CH2Cl is not environmentally friendly, belongs to the class of ozone-depleting substances (ODS), and its utilization is severely restricted. The reaction time in the described method is short, but high temperatures (90 - 140 °C) are required. Furthermore, this method may require the use of a catalyst.

[0012] M. Epifanov et al. describe in JACS 2018, 140, 16464 - 16468 the process of SO2F2-mediated alkylation of primary and secondary amines with polyfluoroalcohols. In the examples described in this literature, only amines bonded to one or two alkyl-chain alkyl-NH2 or R2NH, such as cyclohexylamine, morpholine, phenylalanine, N-methylbenzylamine, etc., are shown. These amines exhibit high nucleophilicity and basicity (pKb 3.5 - 4.5) and have hitherto been successful in alkylation with low-reactivity polyfluoroalcohols.

[0013] However, the authors (JACS, p. 16466) also found that not only substrates with a steric bulk alpha to the amine such as cyclohexylamine, but also aniline, is an insufficient substrate for this reaction and cannot be alkylated at a high reaction rate using polyfluoroalcohol. Like other amines, aniline is basic (pKb = 9.42) and nucleophilic, but is a weaker base and less nucleophilic than structurally similar aliphatic amines.

[0014] In the present invention, phthalimide having two carbonyl groups at the α-position relative to the amine group in the ring system is used, and thus it can also be considered a bulky substrate. Due to the electron-withdrawing (-M) effect of the two carbonyl groups, phthalimide is known to have significant NH acidity and no basicity. The high acidity of imide-NH is a result of the adjacent pair of electrophilic carbonyl groups. Furthermore, amides (such as phthalimide or succinimide used in the method according to the present invention) are generally known to be less reactive towards electrophiles than amines (similar to those used in the method of Epifanov et al.).

[0015] Therefore, it is surprising that the polyfluoroalkylation of phthalimide (which is acidic and not basic) in the method according to the present invention can be carried out in high yield under mild conditions where cyclohexylamine or aniline is merely an insufficient substrate for this reaction. The same is true when succinimide is used instead of phthalimide.

[0016] The synthesis of polyfluoroalkylamines from N-polyfluoroalkylphthalimides is described by Kuwabara et al. in "The journal of chemical society of Japan, 1985v.1985, N4, pp. 796 - 798 (R F CH2NH2, R F =-CF3, -CF2CHF2, (CF2CF2)H, -(CF2CF2)3H)". The preparation of the desired N-polyfluoroalkylphthalimides from polyfluoroalkyl o-nitrobenzenesulfonates and the K-salt of phthalimide was achieved under very harsh reaction conditions with long heating at 150 °C.

Prior Art Documents

Patent Documents

[0017]

Patent Document 1

Patent Document 2

[0018] [Non-Patent Document 1] Dickey et al., Industrial and Engineering Chemistry, 1956, No. 2, 209-213 [Non-Patent Document 2] Mecinovic et al., Green Chem, 2018, 20, 4418-4442 [Non-Patent Document 3] Douglas et al., Chem.Commun., 2016, 52, 12195-12198. [Non-Patent Document 4] Husted & Ahlbrecht, J.Am.Chem.Soc.1953, 75, 7, 1605-1608 [Non-Patent Document 5] Soloshonok et al., Tetrahedron Letters, 2002, 43, 5449-5452. [Non-Patent Document 6] Papanastassiou & Bruni, J.Org.Chem.1964, 29, 10, 2870-2872 [Non-Patent Document 7] M. Epifanov et al., JACS 2018, 140, 16464-16468 [Non-Patent Document 8] Kuwabara et al., The Journal of Chemical Society of Japan, 1985v.1985, N4, pp. 796-798. [Overview of the project] [Problems that the invention aims to solve]

[0019] Starting from known methods for preparing polyfluoroalkylamines (including 2,2-difluoroethylamine), the question arises as to how polyfluoroalkylamines, including 2,2-difluoroethylamine, can be prepared in a simple and inexpensive manner from commercially available, environmentally friendly starting materials, such as polyfluoroalkyl alcohols and inexpensive SO2F2 gas. The inventors have found that polyfluoroalkylamines can be prepared particularly advantageously from polyfluorinated alkyl alcohols when an imide intermediate is prepared first and then cleaved. [Means for solving the problem]

[0020] Therefore, the subject of the present invention is formula (IV) [ka] [In the formula, R F This is defined in step (i) below. A method for preparing polyfluoroalkylamines, comprising the following steps: Step (i): Equation (I) [ka] [In the formula, R F =CHF2, CF3, C2F5, or HCF2CF2] of a polyfluoroalkyl alcohol, of formula (II)

Chemical formula

Chemical formula

Mode for Carrying Out the Invention

[0021] 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).

[0022] The imide of formula (II) used in step (i) may also be present as a salt. Such salts are in some cases commercially available (for example, the potassium salt of phthalimide). Before using a salt in the method according to the present invention, the imide of formula (II) can also be converted to a salt by reaction with a suitable base. Suitable bases are known to those skilled in the art or include the bases mentioned herein as acid scavengers.

[0023] In the method according to the present invention, R 1 and R 2 Either each is hydrogen (i.e., succinimide), or R 1 and R 2 However, it is preferable to use the compound of formula (II), which, together with the carbon atoms to which they are bonded, forms a six-membered aromatic ring (i.e., phthalimide). When succinimide is used as the compound of formula (II), the compound of formula (III-a) is obtained in step (i). When phthalimide is used as the compound of formula (II), the compound of formula (III-b) is obtained in step (i): [ka] The method according to the present invention can be explained by the following scheme: [ka] The use of SO2F2 for N-alkylation of amines is well known. Secondary or tertiary polyfluoroalkylamines are subjected to polyfluoroalkyl alcohol R according to Epifanov et al. "JACS, 2018, 140, 16464-16468". F CH2OH(R F It can be prepared from (=CF3, CHF2, CF2CF3, CF2CF2CF3). The cyclic tertiary amine can be isolated in a maximum yield of 67% (e.g., morpholine). Phthalimides can readily react with various non-fluorinated aliphatic alcohols, as described by Sammis et al. in "Chem. Eur. J., 2020, 4958-4962". Intuitively, the inventors have described the use of SO2F2 for the preparation of primary polyfluoroalkylamines by the synthesis of phthalimides.

[0024] Similarly, and remarkably, the polyfluorinated alcohol used in step (i) can be converted to the imide of formula (III) with very good yield, approximately 85–90%.

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

[0026] Unless otherwise specified, the term "alkyl" alone or in combination with other terms refers to a straight or branched saturated hydrocarbon chain having up to 12 carbon atoms, i.e., C1-C12. 12 -Alkyl, preferably having up to 6 carbon atoms, i.e., C1-C6-alkyl, and very preferably having up to 4 carbon atoms, i.e., C1-C4-alkyl. Examples of such alkyls are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Alkyls can be substituted with suitable substituents, such as halogens.

[0027] Unless otherwise specified, the terms "aryl" or "six-membered aromatic ring" refer to a phenyl ring.

[0028] Unless otherwise specified, "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0029] 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.

[0030] If a solvent is added to the reaction mixture in step (i), it is preferably used in an amount such that the reaction mixture remains sufficiently agitated throughout the entire process. Based on the volume of alcohol used, it is advantageous to use 1 to 50 times the volume of solvent, preferably 2 to 40 times, and particularly preferably 2 to 20 times the volume of solvent. The term “solvent” is also understood, according to the present invention, to mean a mixture of pure solvents.

[0031] All organic solvents that are inert under reaction conditions are suitable solvents according to the present invention, particularly ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl 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 polyether); compounds such as tetrahydrothiophene dioxide and dimethyl sulfoxide, tetramethylene sulfoxide, dipropyl sulfoxide, benzyl methyl sulfoxide, diisobutyl sulfoxide, dibutyl sulfoxide or diisoamyl sulfoxide; sulfones, e.g., dimethyl, diethyl, dipropyl, dibutyl, diphenyl 0, dihexyl, methyl ethyl, ethyl propyl, ethyl isobutyl and tetramethylene sulfone; aliphatic, alicyclic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, e.g., white spirits having components with boiling points within a range (e.g., 40°C to 250°C), cymene, benzine fractions with boiling points within a range of 70°C to 190°C, cyclohexane, methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene or xylene); halogenated aromatic compounds (e.g., chlorobenzene or dichloro Benzene); amides (e.g., hexamethylphosphoramide, formamide, N,N-dimethylacetamide, N-methylformamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methylpyrrolidine, N-methylcaprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine, octylpyrrolidone, octylcaprolactam, 1,3-dimethyl-2-imidazolinedione, N-formylpiperidine, or N,N'-1,4-diformylpiperazine);Nitriles (e.g., acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, or benzonitrile); ketones (e.g., acetone) or mixtures thereof.

[0032] In step (i), preferred solvents are acetonitrile, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetramethylene sulfone, and N-methylpyrrolidone.

[0033] The reaction in step (i) is carried out in the presence of one or more acid scavengers capable of binding to the hydrogen fluoride released during the reaction. In a preferred embodiment of the present 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-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-, 3- or 4- Picolin, 2-methyl-5-ethylpyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinoline, 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 hydroxides, bicarbonates, or carbonates of alkali metals or alkaline earth metals, and other inorganic aqueous bases; preferably, for example, 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.

[0036] The molar ratio of the acid scavenger used, particularly the base described above, to the imide of formula (II) is typically in the range of 1:1 to 5:1, preferably 1:1 to 4:1, and especially preferably 1:1 to 3:1. While the use of larger amounts of base is technically possible, it is not economically beneficial.

[0037] The molar ratio of the polyfluoroalkyl alcohol of formula (I) used to the imide of formula (II) is typically in the range of 1:1 to 5:1, preferably 1:1 to 3:1, and particularly preferably 1:1 to 2:5:1.

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

[0039] The reaction in step (i) is, in principle, carried out in an open system or under the intrinsic pressure in a pressure vessel (autoclave). If a solvent is present in step (i), the pressure during the reaction (i.e., the intrinsic pressure) depends on the reaction temperature used, the amount of SO2F2, and the solvent used. If an increase in pressure is desired, further pressure increases can be achieved by adding an inert gas such as nitrogen or argon.

[0040] The most preferred method of operation is bubbling SO2F2 into a reaction mixture containing phthalimide, a base, and a polyfluoroalkyl alcohol of formula (I).

[0041] The method according to the present invention can be carried out continuously or in batches. Similarly, some steps of the method according to the present invention may be carried out continuously, and the remaining steps in batches. In the sense of the present invention, a continuous step is a step in which the inflow of a compound (starting material) into the reactor and the outflow of a compound (product) from the reactor occur simultaneously but spatially separately, while a batch step is a step in which the continuous inflow of a compound (starting material), possibly a chemical reaction, and the outflow of a compound (product) occur in a sequential order.

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

[0043] The reaction time in step (i) is short, ranging from 0.5 to 5 hours. Longer reaction times are possible, but not economically beneficial.

[0044] The reaction mixture from step (i) is post-treated according to the physical properties of the product. If phthalimide or 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. Subsequently, "dilution" of the reaction mixture, i.e., the addition of water in which the salt can dissolve, is usually carried out. The product can then be isolated by filtration or extracted from the aqueous phase using an organic solvent.

[0045] In step (ii), the cleavage of the compound of formula (III) to obtain a polyfluoroalkylamine or a salt thereof is carried out by the addition of an acid, a base, or hydrazine (including hydrazine hydrate). Preferably, an acid or hydrazine is used in step (ii). The use of hydrazine hydrate is particularly preferred. A typical procedure for this step is shown in US 2012 / 0190867 or "The Journal of the Chemical Society of Japan, 1985, Vol. 1985, No. 4, pp. 796-798".

[0046] The bases that can be used in step (ii) are known to those skilled in the art or include the bases referred to herein as acid scavengers. The acid used in step (ii) is an organic acid or an inorganic acid, and an inorganic acid is preferably used. Examples of such preferred inorganic acids according to the present invention are hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

[0047] The cleavage of the compound of formula (III) in step (ii) is carried out in a suitable solvent. Here again, the solvent is used in an amount such that the reaction mixture remains agitated throughout the entire process. Depending on the compound of formula (III) used, it is advantageous to use an amount of solvent of about 1 to 50 times (v / v), preferably about 2 to 40 times, and particularly preferably 2 to 10 times.

[0048] Any organic solvent that is inert under the reaction conditions can be used as a solvent. The term “solvent” is also understood, according to this invention, to mean a mixture of pure solvents.

[0049] Preferred solvents for the present invention in step (ii) are particularly water, ethers (e.g., ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenethole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl 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 propyl ether) The solvents are: benzene oxide polyethers; aliphatic, alicyclic or aromatic hydrocarbons (e.g., pentane, hexane, heptane, octane, nonane, white spirits having components with boiling points within a range (e.g., 40°C to 250°C), cymene, benzene fractions with boiling points within a range of 70°C to 190°C, cyclohexane, methylcyclohexane, petroleum ether, ligroin, octane, benzene, toluene or xylene); linear or 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. The preferred solvents according to the present invention in step (ii) are methanol, ethanol and water or mixtures thereof.

[0050] The molar ratio of the acid or hydrazine (or hydrazine hydrate) used to the compound of formula (III) is in the range of 0.8:1 to 10:1, preferably in the range of 1:1 to 5:1, and particularly preferably in the range of 1:1 to 3:1. In principle, it is possible to add a larger amount of acid or hydrazine. Due to its suitable handling properties, the acid can also be used as a solvent. Hydrazine is used in the form of its hydrate.

[0051] The cleavage in step (ii) can be carried out at a temperature in the range of 0°C to 150°C. The internal temperature is preferably in the range of 20°C to 100°C, and particularly preferably in the range of 40°C to 70°C. For cleavage by hydrazine, the temperature is preferably in the range of 50°C to 70°C.

[0052] The reaction time for cleavage is short, ranging from 0.1 to 12 hours. Longer reaction times are possible, but not economically beneficial.

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

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

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

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

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

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

[0059] Preparation Examples: Example 1 - Preparation of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione (Step (i)) [ka] Example 1.1 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 bubbling 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 reduced pressure to obtain 1.97 g of a white solid with a purity of 98% and a yield of 91%. Mp 114-116°C.

[0060] 1 H NMR (DMSO): 7.95-7-87 (m, 4H), 6.25 (tt, 1H), 4.0 (td, 2H) ppm. 13 C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm. 19 F NMR (DMSO): 121.40 (dt) ppm. Example 1.2 [ka] 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 bubbling into the reaction mixture at 40°C for 3 hours, and the reaction mixture was stirred at 40°C 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. 1.81 g of a white solid was obtained with 100% purity and 86% yield. Mp 114-116°C.

[0061] 1 H NMR (DMSO): 7.95-7-87 (m, 4H), 6.25 (tt, 1H), 4.0 (td, 2H) ppm. 13 C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm. 19 F NMR (DMSO): 121.40 (dt) ppm. Example 1.3 [ka] 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 bubbling into the reaction mixture at 40°C for 3 hours, and the reaction mixture was stirred at 40°C 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. 1.9 g of a white solid was obtained with 100% purity and 84% yield. Mp 114-116°C.

[0062] 1 H NMR (DMSO): 7.95-7-87 (m, 4H), 6.25 (tt, 1H), 4.0 (td, 2H) ppm. 13 C NMR (DMSO): 167.37, 134.93, 131.51, 123.54, 113.54 (t), 39.70 (t) ppm. 19 F NMR (DMSO): 121.40 (dt) ppm. Example 2 - Preparation of 2-(2,2,2-trifluoroethyl)-1H-isoindole-1,3(2H)-dione (Step (i)) Example 2.1. [ka] 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 bubbling at 20°C for 60 minutes. 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 was obtained with 100% purity and 92% yield. Mp 122-127°C.

[0063] 1 H NMR (DMSO): 7.99-7-90 (m, 4H), 4.43 (q, 2H) ppm. 13 C NMR (DMSO): 166.86, 135.20, 131.30, 123.86 (q), 123.82, 38.89 (q) ppm. 19 F NMR (DMSO): -68.85 (t, 3F) ppm. Example 2.2 [ka] 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 bubbling into the reaction mixture at 30°C for 40 minutes, and the reaction mixture was stirred 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. 1.98 g of a white solid was obtained with 100% purity and 86% yield. Mp 122-127°C.

[0064] 1 H NMR (DMSO): 7.99-7-90 (m, 4H), 4.43 (q, 2H) ppm. 13 C NMR (DMSO): 166.86, 135.20, 131.30, 123.86 (q), 123.82, 38.89 (q) ppm. 19 F NMR (DMSO): -68.85 (t, 3F) ppm. Example 3 - Preparation of 2-(2,2,3,3,3-pentafluoropropyl)-1H-isoindole-1,3(2H)-dione (Step (i)) [ka] 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 added to 25 mL of N,N-dimethylacetamide. 2.55 g (0.025 mol) of SO2F2 was bubbling into the reaction mixture at 20°C for 60 minutes, and the reaction mixture was stirred 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. 2.53 g of a white solid was obtained with 100% purity and 91% yield. Mp 134-135°C 1 H NMR (DMSO): 8.00-7-90 (m, 4H), 4.42 (t, 2H) ppm. 13C NMR (DMSO): 166.92, 135.30, 131.25, 123.89, 118.40 (tq), 112.60 (m), 37.00 (t) ppm. 19 F NMR (DMSO): -83.70 (s, 3F), -118.86 (t, 2F) ppm. Example 4 - Preparation of 2-(2,2,3,3-tetrafluoropropyl)-1H-isoindole-1,3(2H)-dione (Step (i)) [ka] 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 added to 25 mL of N,N-dimethylacetamide. 2.55 g (0.025 mol) of SO2F2 was bubbling into the reaction mixture at 20°C for 60 minutes, and the reaction mixture was stirred 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. 2.3 g of a white solid was obtained with 100% purity and 88% yield. Mp 129-130°C 1 H NMR (DMSO): 7.97-7-90 (m, 4H), 6.64 (tt, 1H), 4.23 (t, 2H) ppm. 13 C NMR (DMSO): 167.22, 135.08, 131.50, 123.75, 114.98 (tt), 109.54 (tt), 37.43 (t) ppm. 19 F NMR (DMSO): -120.95 (m, 2F), -138.64 (dt, 2F) ppm. Example 5 - Preparation of 2,2-difluoroethylamine (Step (ii)) [ka] 4.22 g (0.02 mol) of 2-(2,2-difluoroethyl)-1H-isoindole-1,3(2H)-dione was added to 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. 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), concentrated to dryness, and 2 g (85%) of 2,2-difluoroethylamine hydrochloride was obtained.

[0065] 19 F NMR (DMSO): -122.10 (dt, 2F) ppm. 13 C NMR (DMSO): 132.77, 125.32, 113.51 (t) ppm. 1 H NMR (DMSO): 6.39 (tt, 1H), 3.31 (m, 2H) ppm. Example 6 - Preparation of 2,2,3,3-tetrafluoropropan-1-amine (Step (ii)) [ka] 5.22 g (0.02 mol) of 2-(2,2,3,3-tetrafluoropropyl)-1H-isoindole-1,3(2H)-dione was added to 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 hours. 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), concentrated to dryness, and 3.1 g of 2,2,3,3-tetrafluoropropan-1-amine hydrochloride was obtained (yield 92%).

[0066] 19 F NMR (DMSO): -121.08 (m, 2F), -137.84 (dt, 2F) ppm. 13 C NMR (DMSO): 114.93 (tt), 109.24 (tt), 38.23 ppm. 1H NMR (DMSO): 6.73 (tt, 1H), 3.62 (t, 2H) ppm. Example 7 - Preparation of 2,2,3,3,3-pentafluoropropan-1-amine (Step (ii)) [ka] 5.58 g (0.02 mol) of 2-(2,2,3,3,3-pentafluoropropyl)-1H-isoindole-1,3(2H)-dione was added to 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 hours. 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), concentrated to dryness, and 3.37 g (91%) of 2,2,3,3,3-pentafluoropropan-1-amine hydrochloride was obtained.

[0067] 19 F NMR (DMSO): -83.37 (3F), -119.01 (t, 2F) ppm. 1 H NMR (DMSO): 3.91 (t, 2H) ppm. Example 8 - Preparation of 2,2,2-trifluoroethylamine (Step (ii)) [ka] 4.58 g (0.02 mmol) of 2-(2,2,2-trifluoroethyl)-1H-isoindole-1,3(2H)-dione was added to 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 hours. 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), concentrated to dryness, and 2.45 g (90%) of 2,2-difluoroethylamine hydrochloride was obtained.

[0068] 19 F NMR (DMSO): -67.89 (t, 3F) 1 ¹H NMR (DMSO): 3.87 (q, 2H)

Claims

1. Formula (IV) 【Chemistry 1】 [In the formula, R Ｆ [This is defined as in step (i) below] A method for preparing polyfluoroalkylamines, comprising the following steps: Step (i): Equation (I) 【Chemistry 2】 [In the formula, R Ｆ = CHF ２ CF ３ , C ２ F ５ or HCF ２ CF ２ ] Polyfluoroalkyl alcohols, Formula (II) 【Transformation 3】 with imide, SO ２ F ２ and in the presence of an acid scavenger, of formula (III) 【Chemistry 4】 [In the formulas, in the compounds of formulas (II) and (III), R １ and R ２ Each of them is independent of the other, either hydrogen or C １ -C ６ - Alkyl or R １ and R ２ Together with the carbon atoms to which they are bonded, they form halogens or C １ -C １２ - Forms a six-membered aromatic ring which may be substituted with alkyl. Reaction to obtain the compound; Step (ii): Reaction of the compound of formula (III) with an acid, base, or hydrazine. The method, including the method described above.

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 or 2, 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 acid scavenger in step (i) is a tertiary amine, a substituted or unsubstituted pyridine, a substituted or unsubstituted quinoline, 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-,3- or 4-picoline, 2-methyl-5-ethylpyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, or quinoline. The method according to any one of claims 1 to 4, wherein the base is selected from 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, 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 any one of claims 1 to 4, wherein the acid scavenger in step (i) is a base which 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 used to the imide of formula (II) is in the range of 1:1 to 5:

1.

8. The method according to any one of claims 1 to 7, 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 according to any one of claims 1 to 7, wherein hydrazine hydrate is used in step (ii).

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

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