Solid alcohol solvate of a tetraalkylammonium fluoride and a method for producing the same

Abstract

The present disclosure relates to fluorinated tetra(Ci-C6alkyl)ammonium and C x solid alcohol solvate of an alcohol (where x is 3, 5, 6, 7, 8, 9, or 10). A particularly disclosed example of such a solid alcohol solvate is fluorinated tetra-n-butylammonium tetra(tert-pentanol). The present disclosure also relates to methods of making such solid alcohol solvates, as well as methods of forming a substantially water-free mixture, wherein the mixture comprises a fluorinated ammonium.

Description

Technical Field

[0001] This technology generally relates to solid alcohol solvates of tetraalkylammonium fluoride and methods for synthesizing such solid alcohol solvates, including crystalline solid alcohol solvates that are stable at room temperature (i.e., about 23°C). Summary of the Invention

[0002] In one aspect, this technology provides tetra(C1-C6) alkyl ammonium fluoride and C x A solid alcohol solvate of an alcohol, wherein x is 3, 5, 6, 7, 8, 9, or 10. In any embodiment herein, the tetra(C1-C6 alkyl)ammonium fluoride may be tetrabutylammonium fluoride. In any embodiment herein, the solid alcohol solvate may be tetra-n-butylammonium tetra(tert-amyl alcohol)fluoride. In any embodiment herein, the solid alcohol solvate may be in crystalline form. In one aspect, the present invention also provides a tetra(C1-C6 alkyl)ammonium fluoride and C x A hydrate of a solid alcohol solvate, wherein x is 3, 5, 6, 7, 8, 9 or 10.

[0003] In one aspect, the present technology provides a method comprising combining ammonium fluoride or its hydrate with a solvent containing an alcohol to form a mixture, and separating a solid alcohol solvate from the mixture.

[0004] In another aspect, the present technology provides a method comprising combining an ammonium fluoride hydrate with a solvent containing an alcohol to form a mixture, and distilling the mixture to obtain a second mixture that is substantially free of water.

[0005] It should be understood that all combinations of the foregoing concepts and the additional concepts discussed in more detail below (provided that such concepts do not contradict each other) are considered part of the subject matter disclosed herein. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are considered part of the subject matter disclosed herein. Brief description of the attached diagram Figure 1Images of solid tetra-n-butylammonium tetra(tert-amyl alcohol) fluoride are provided using a Leica DVM6A microscope at approximately 23°C (objectives: FOV 12.55; working distance: 33 mm; maximum magnification: 675:1; exposure time: 30 ms; resolution: 2 MP (1600x1200); zoom: 6.87x; numerical aperture: 0.125; TL intensity: 90; RL intensity: 30; SLI intensity: -10; CXI intensity: 80; BLI intensity: 90; color saturation: 24.31373; shift: Z-Lambda; filters: none).

[0007] Figure 2 Images of solid tetra-n-butylammonium tetra(tert-amyl alcohol) fluoride in mineral oil at approximately 23°C are provided via a Leica DVM6A microscope (objectives: FOV 12.55; working distance: 33 mm; maximum magnification: 675:1; exposure time: 30 ms; resolution: 2 MP (1600x1200); zoom: 1.8x; numerical aperture: 0.032; TL intensity: 60; RL intensity: 30; SLI intensity: -10; CXI intensity: 40; BLI intensity: 60; color saturation: 24.31373; shift: Z-Lambda; filters: none).

[0008] Detailed description Various implementation schemes are described below. It should be noted that the specific implementation scheme is not intended as an exhaustive description or as a limitation on the broader aspects discussed herein. A aspect described with a particular implementation scheme is not necessarily limited to that scheme and can be implemented in conjunction with any other implementation scheme.

[0009] As used herein and in the appended claims, singular articles such as “a”, “an”, and “the”, and similar references in the context of describing elements (especially in the context of the following claims), shall be construed as covering both singular and plural, unless otherwise specified herein or clearly contradicted by the context. Unless otherwise specified herein, the numerical ranges set forth herein are intended only for shorthand references of individual values ​​falling within the range, and each individual value is incorporated into this specification as if set forth separately herein. All methods described herein may be performed in any suitable order unless otherwise specified herein or clearly contradicted by the context. The use of any and all instances or exemplary language (e.g., “as”) provided herein is intended only to better illustrate the embodiments and, unless otherwise stated, does not constitute a limitation on the scope of the claims. No language in this specification should be construed as indicating that any non-claimed element is an essential element.

[0010] As used herein, “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where the use of a term is unclear to those skilled in the art, given the context in which it is used, “about” will mean at most plus or minus 10% of a particular term; for example, “about 10% by weight” should be understood as “9% to 11% by weight”. It should be understood that when “about” precedes a term, the term should be interpreted as disclosing both “about” and terms not modified by “about”; for example, “about 10% by weight” discloses “9% to 11% by weight” and “10% by weight”.

[0011] The phrase “and / or” as used in this disclosure should be understood to refer alone to any one of the members described or any two or more of them, for example, “A, B and / or C” would mean “A or B or C; A and B; A and C; B and C; or a combination of A, B and C”.

[0012] Generally, referring to an element such as hydrogen or H means including all isotopes of that element. For example, if the R group is defined to include hydrogen or H, then it also includes deuterium and tritium. Therefore, it includes radioactive isotopes such as tritium and carbon. 14 P 32 and S 35 The compounds are within the scope of this technology. Based on the disclosure herein, the procedure for incorporating such labels into the compounds of this technology will be readily apparent to those skilled in the art.

[0013] Generally, "substituted" means an organic group (e.g., an alkyl group) as defined below, in which one or more bonds to its contained hydrogen atoms are replaced by bonds to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to carbon or hydrogen atoms are replaced by one or more bonds to heteroatoms (including double or triple bonds). Therefore, unless otherwise stated, a substituted group is substituted by one or more substituents. In some embodiments, the substituted group is substituted by 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyl groups; alkoxy, alkenoxy, aryloxy, arylalkoxy, heterocyclic, heterocyclic alkyl, heterocyclic oxy, and heterocyclic alkoxy groups; carbonyl groups (oxo); carboxylic acid esters; esters; carbamates; oximes; hydroxylamines; alkoxyamines; arylalkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyl groups; pentafluorosulfanyl (i.e., SF5); sulfonamides; amines; N-oxides; hydrazides; acylhydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; and nitriles (i.e., CN).

[0014] Substituted cyclic groups, such as substituted cycloalkyl, aryl, heterocyclic, and heteroaryl groups, also include ring systems in which the bonds bonded to hydrogen atoms are replaced by bonds bonded to carbon atoms. Therefore, substituted cycloalkyl, aryl, heterocyclic, and heteroaryl groups can also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0015] Alkyl groups include straight-chain and branched alkyl groups having 1 to 12 carbon atoms, typically 1 to 10 carbon atoms, or in some embodiments 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups may be substituted or unsubstituted. Examples of straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted once or multiple times with the substituents listed above, and include, but are not limited to, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxylalkyl, etc.

[0016] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups as used herein include monocyclic, bicyclic, and tricyclic systems. Aryl groups can be substituted or unsubstituted. Therefore, aryl groups include, but are not limited to, phenyl, azulel, heptalenyl, biphenyl, fluorenyl, phenanthrene, anthracenel, indenel, indanyl, pentalenyl, and naphthyl groups. In some embodiments, the aryl group contains 6-14 carbons in the ring portion of the group, and in other embodiments, 6 to 12 or even 6-10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The phrase "aryl group" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indenel, tetrahydronaphthyl, etc.). Representative substituted aryl groups can be monosubstituted (e.g., tolyl) or more than substituted. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be replaced by substituents as listed above.

[0017] Heterocyclic groups include aromatic (also called heteroaryl) and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Heterocyclic groups may be substituted or unsubstituted. In some embodiments, the heterocyclic group contains 1, 2, 3, or 4 heteroatoms. In some embodiments, the heterocyclic group includes monocyclic, bicyclic, and tricyclic rings having 3 to 16 ring members, while other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclic groups encompass aromatic, partially unsaturated, and saturated ring systems, such as, for example, imidazolyl, imidazolinyl, and imidazolidinyl groups. The phrase “heterocyclic group” includes fused rings, including those containing fused aromatic and non-aromatic groups, such as benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridging polycyclic ring systems containing heteroatoms, including but not limited to quinuclidyl. The phrase also includes heterocyclic groups with other groups, such as alkyl, oxo, or halogen groups bonded to one of the ring members, referred to as “substituted heterocyclic groups.”Heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolyl, imidazoalkyl, pyrazolyl, thiazolidinyl, tetrahydrothiophene, tetrahydrofuranyl, dioxacyclopentenyl, furanyl, thiophene, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and tetrahydropyranyl. Tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, piperazine, quininecycloyl, indole, indolinyl, isoindoleyl Azadolyl (pyrrolopyridyl), indazole, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxadiazolyl, benzooxazinyl, benzodithicyclohexenyl, benzoxathicyclohexenyl, benzothiazinyl, benzooxazolyl, benzothiazolyl, benzothiazolyl, benzo[1,3]dioxacyclopentenyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl The following groups are used in the production and distribution of alcohols: pyridyl, purinyl, xanthineyl, adenineyl, guanineyl, quinolinyl, isoquinolinyl, quinazinyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, naphridyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl. The representative substituted heterocyclic group can be monosubstituted or have more than one substituted group, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5- or 6-substituted by the various substituents listed above, or disubstituted by the various substituents listed above.

[0018] A heteroaryl group is an aromatic ring compound containing five or more ring members, including, but not limited to, one or more heteroatoms such as N, O, and S. The heteroaryl group may be substituted or unsubstituted. Heteroaryl groups include, but are not limited to, pyrroloyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridinyl, pyrazinyl, thiophene, benzothiophene, furanyl, benzofuranyl, indolyl, azindolyl (pyrrolopyridinyl), inzonoyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazololopyridinyl, triazololopyridinyl, benzotriazolyl, benzooxazolyl, benzothiazolyl, benzimidazolyl, etc. The groups are thiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Heteroaryl groups include all fused cyclic compounds with aromatic rings, such as indolyl groups, and include fused cyclic compounds in which only one ring is aromatic, such as 2,3-dihydroindolyl groups. Representative substituted heteroaryl groups can be substituted once or multiple times with the various substituents listed above.

[0019] As used herein, the term "halogen" or "halo" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0020] As those skilled in the art will understand, for any and all purposes, particularly for the purpose of providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily identified as sufficiently descriptive and capable of being broken down into at least equal halves, thirds, three-quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily subdivided into lower thirds, middle thirds, upper thirds, etc. As those skilled in the art will also understand, all terms such as “at most,” “at least,” “greater than,” “less than,” etc., include the stated numbers and refer to a scope that can be subsequently subdivided into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 atoms means a group having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms means a group having 1, 2, 3, 4, or 5 atoms, and so on.

[0021] As will be understood by those skilled in the art, “molecular weight” (also known as “relative molar mass”) is a dimensionless quantity, but is converted to molar mass by multiplying by 1 g / mol or by 1 Da. For example, a compound with a weight-average molecular weight of 5,000 has a weight-average molar mass of 5,000 g / mol and a weight-average molar mass of 5,000 Da.

[0022] As used herein, “substantially free of water” and “substantially water-free” refer to products or compositions containing less than 1% by weight of water.

[0023] This technology Tetramethylammonium fluoride ((CH3)4NF; "TMAF") and tetrabutylammonium fluoride ((CH3CH2CH2CH2)4NF; "TBAF"); n -Bu4NF”) is commonly used as a source of fluoride ions in organic solvents during the synthesis of organic compounds. For example, TBAF and TMAF can be used to remove silyl protecting groups and / or as mild bases.

[0024] Different methods for synthesizing TBAF and TMAF have been described. For example, TBAF can be prepared by contacting hydrofluoric acid with an ion exchange resin and then with tetrabutylammonium bromide. Similarly, TMAF can be prepared by neutralizing tetramethylammonium hydroxide with hydrofluoric acid. However, many of these synthetic methods produce trace amounts of water that are difficult to remove, as well as HF2. - Impurities, etc.

[0025] Anhydrous TBAF and TMAF are of interest because fluoride ions are stronger hydrogen bond acceptors (i.e., stronger Brønsted-Lowry bases) when not associated with water molecules. Although some methods have been proposed for the synthesis of anhydrous TBAF and anhydrous TMAF, they are not only readily degradable but must also be stored under anhydrous conditions.

[0026] This technology addresses the shortcomings discussed above and provides additional advantages. Therefore, in one aspect, this technology provides tetra(C1-C6) alkylammonium fluoride with C x Solid alcohol solvates, wherein x is 3, 5, 6, 7, 8, 9, or 10. Those skilled in the art will readily understand that alcohol solvates can also be called "alcoholates". The C of solid alcohol solvates... xThe alcohol may be n-propanol, isopropanol, n-pentanol, isopentanol, tert-pentanol ((CH3)2C(OH)CH2CH3; 2-methylbut-2-ol), neopentanol, n-hexanol, branched hexanol, n-heptanol, branched heptanol, n-octanol, branched octanol, n-nonanol, branched nonanol, n-decanol, branched decanol, or any combination of two or more thereof. In any embodiment herein, the C1-C6 alkyl group of tetra(C1-C6 alkyl)ammonium fluoride may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentanol, tert-pentyl, or neopentyl.

[0027] In any embodiment herein, tetra(C1-C6 alkyl)ammonium fluoride may comprise tetramethylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, tetrapentylammonium fluoride, or any combination of two or more thereof. In any embodiment herein, ammonium fluoride or its hydrates may comprise tetramethylammonium fluoride, tetraethylammonium fluoride, tetra-n-propylammonium fluoride, tetra-isopropylammonium fluoride, tetra-n-butylammonium fluoride, tetra-isobutylammonium fluoride, tetra-tert-butylammonium fluoride, tetra-n-pentylammonium fluoride, tetra-isopentylammonium fluoride, tetra-tert-pentylammonium fluoride, tetra-neopentylammonium fluoride, or any combination of two or more thereof.

[0028] Therefore, in any embodiment herein, tetra-(C1-C6 alkyl)ammonium fluoride may be tetra-n-butylammonium fluoride. For example, the solid alcohol solvate may be tetra-n-butylammonium tetra(tert-amyl alcohol), also known as "tetra-n-butylammonium tetra(tert-amyl alcohol)". In any embodiment herein, the solid alcohol solvate may be substantially anhydrous and may include less than 0.5% by weight of water, less than 0.2% by weight of water, less than 0.18% by weight of water, less than 0.16% by weight of water, less than 0.14% by weight of water, less than 0.12% by weight of water, less than 0.10% by weight of water, less than 0.08% by weight of water, less than 0.06% by weight of water, less than 0.04% by weight of water, less than 0.02% by weight of water, less than 0.01% by weight of water, or less than 0.001% by weight of water. In any embodiment herein, the solid alcohol solvate may be anhydrous. Furthermore, in any embodiment herein, the solid alcohol solvate may be in crystalline form (e.g., crystalline tetra-n-butylammonium tetra(tert-amyl alcohol)).

[0029] In another aspect, the present technology provides a method comprising combining ammonium fluoride or its hydrate with a solvent (the solvent including an alcohol) to form a mixture; and separating a solid alcohol solvate from the mixture. Ammonium fluoride or its hydrate may include tetra(C1-C6 alkyl) fluoride and / or tetra(C1-C6 alkyl) fluoride hydrates.

[0030] In any embodiment of this method, ammonium fluoride or its hydrate may include tetramethylammonium fluoride, tetramethylammonium fluoride hydrate, tetraethylammonium fluoride, tetraethylammonium fluoride hydrate, tetrapropylammonium fluoride, tetrapropylammonium fluoride hydrate, tetrabutylammonium fluoride, tetrabutylammonium fluoride hydrate, tetrapentylammonium fluoride, tetrapentylammonium fluoride hydrate, or any combination of two or more thereof. In any embodiment of this document, ammonium fluoride or its hydrates may include tetramethylammonium fluoride, tetramethylammonium fluoride hydrate, tetraethylammonium fluoride, tetraethylammonium fluoride hydrate, tetra-n-propylammonium fluoride, tetra-n-propylammonium hydrate, tetra-isopropylammonium fluoride, tetra-isopropylammonium fluoride hydrate, tetra-n-butylammonium fluoride, tetra-n-butylammonium fluoride hydrate, tetra-isobutylammonium fluoride, tetra-isobutylammonium fluoride hydrate, tetra-tert-butylammonium fluoride, tetra-tert-butylammonium fluoride hydrate, tetra-n-pentylammonium fluoride, tetra-n-pentylammonium fluoride hydrate, tetra-isopentylammonium fluoride, tetra-tert-pentylammonium fluoride hydrate, tetra-neopentylammonium fluoride, tetra-neopentylammonium fluoride hydrate, or any combination of two or more thereof.

[0031] In any embodiment of this method herein, the alcohol may include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, tert-pentanol ((CH3)2C(OH)CH2CH3; 2-methylbut-2-ol), neopentanol, n-hexanol, branched hexanol, n-heptanol, branched heptanol, n-octanol, branched octanol, n-nonanol, branched nonanol, n-decanol, branched decanol, or any combination of two or more thereof. In any embodiment of this method herein, the solid alcohol solvate may be tetra-n-butylammonium tetrafluoride (tert-pentanol), tetra-n-butylammonium tetrafluoride (tert-butanol), or tetramethylammonium tert-pentanol fluoride.

[0032] In any embodiment of this document, the method may include heating the mixture to provide a heated mixture and to separate a solid alcohol solvate from the heated mixture. According to any embodiment of this document, heating the mixture may include heating for about 1 hour to about 10 hours. Therefore, in any embodiment of this document, heating the mixture may include heating for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or may be any range including the following and / or a range between any two of these values ​​(e.g., heating for about 3 hours to about 9 hours; heating for about 5 hours to about 7 hours). In any embodiment of this document, heating the mixture may include heating prior to combining ammonium fluoride or its hydrate to maintain the temperature of the solvent and / or heating to a temperature above about 23°C, such as about 50°C to about 100°C. Therefore, in any embodiment of this document, heating the mixture may include heating to temperatures of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, or including any of the following ranges and / or a range between any two of these values. For example, the mixture may be heated to temperatures of about 70°C to about 90°C or about 80°C to about 85°C.

[0033] In any of the embodiments discussed herein, the mixture may comprise 1 molar equivalent of ammonium fluoride or its hydrate (for ammonium fluoride hydrate, the molar equivalent is based on the molar equivalent of ammonium fluoride in the hydrate, not on the molar equivalent of the hydrate) and about 5 to about 50 molar equivalents of an alcohol; thus, the molar equivalent of the alcohol may be about 5 molar equivalents, about 10 molar equivalents, about 15 molar equivalents, about 20 molar equivalents, about 25 molar equivalents, about 30 molar equivalents, about 35 molar equivalents, about 40 molar equivalents, about 45 molar equivalents, about 50 molar equivalents, or include any of the following ranges and / or a range between any two of these values. For example, in any of the embodiments herein, the mixture may comprise 1 molar equivalent of ammonium fluoride or its hydrate and about 10 to about 15 molar equivalents of an alcohol.

[0034] In any embodiment described herein, the mixture may further contain C5-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof. For example, the mixture may further contain heptane and / or may further contain benzene, toluene, or combinations thereof. In any embodiment herein, such a C5-C 10 Alkanes, C6-C 10Aromatic hydrocarbons or combinations thereof may be included in the solvent prior to combination with ammonium fluoride or its hydrate, combined with ammonium fluoride or its hydrate prior to combination with the solvent, included concurrently with the combination of ammonium fluoride or its hydrate with the solvent, and / or included after the combination of ammonium fluoride or its hydrate with the solvent but before the solid alcohol solvate is separated from the mixture. In any embodiment, the mixture comprises C5-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof, the mixture may contain 1 molar equivalent of ammonium fluoride or its hydrate (as noted above in this disclosure, for ammonium fluoride hydrates, the molar equivalent is based on the molar equivalent of ammonium fluoride in the hydrate, not on the molar equivalent of the hydrate) and about 1 to about 10 molar equivalents of C3-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons, or combinations thereof; therefore, mixtures may contain C3-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof, in amounts of about 1 molar equivalent, about 2 molar equivalent, about 3 molar equivalent, about 4 molar equivalent, about 5 molar equivalent, about 6 molar equivalent, about 7 molar equivalent, about 8 molar equivalent, about 9 molar equivalent, about 10 molar equivalent, or including any of the following ranges and / or the range between any two of these values.

[0035] As previously disclosed, the method includes separating a solid alcohol solvate from a mixture. In any embodiment herein, separating the solid alcohol solvate may include distilling the mixture to obtain the solid alcohol solvate, for example, distilling the mixture in a Dean-Stark apparatus to collect a distillate. In any embodiment herein, separating the solid alcohol solvate may include an absolute pressure of about 50 mmHg to about 500 mmHg; therefore, in any embodiment herein, the absolute pressure may be about 50 mmHg, about 100 mmHg, about 150 mmHg, about 200 mmHg, about 250 mmHg, about 300 mmHg, about 350 mmHg, about 400 mmHg, about 450 mmHg, about 500 mmHg, or include any of the following ranges and / or a range between any two of these values.

[0036] In any embodiment of this document, separation of a solid alcohol solvate may include a substantially anhydrous solid alcohol solvate separating the ammonium fluoride and the alcohol and / or an anhydrous solid alcohol solvate separating the ammonium fluoride and the alcohol.

[0037] In another aspect, this technology also provides hydrates of solid alcohol solvates of any aspect and / or any embodiment disclosed herein. Such hydrates may form during the manufacture of the solid alcohol solvate, or, due to the hygroscopic nature of the solid alcohol solvate, may form over time. The identification and preparation of any particular hydrate are within the skill of a person skilled in synthetic organic chemistry.

[0038] In one aspect, the present technology provides a method comprising combining an ammonium fluoride hydrate with a solvent (which includes an alcohol) to form a mixture; and distilling the mixture to obtain a second mixture that is substantially anhydrous. In any embodiment of this method, the alcohol may include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isopentanol, tert-pentanol ((CH3)2C(OH)CH2CH3; 2-methylbut-2-ol), neopentanol, n-hexanol, branched hexanol, n-heptanol, branched heptanol, n-octanol, branched octanol, n-nonanol, branched nonanol, n-decanol, branched decanol, or any combination of two or more thereof. In any embodiment herein, the second mixture may contain less than 0.5% by weight of water, less than 0.2% by weight of water, less than 0.18% by weight of water, less than 0.16% by weight of water, less than 0.14% by weight of water, less than 0.12% by weight of water, less than 0.10% by weight of water, less than 0.08% by weight of water, less than 0.06% by weight of water, less than 0.04% by weight of water, less than 0.02% by weight of water, less than 0.01% by weight of water, or less than 0.001% by weight of water. In any embodiment herein, the second mixture may be anhydrous.

[0039] In any embodiment of this method, the distillation mixture may include collecting the distillate in a Dean-Starkapparatus apparatus. In any embodiment of this method, the distillation mixture may include an absolute pressure of about 50 mmHg to about 500 mmHg; therefore, in any embodiment of this method herein, the absolute pressure may be about 50 mmHg, about 100 mmHg, about 150 mmHg, about 200 mmHg, about 250 mmHg, about 300 mmHg, about 350 mmHg, about 400 mmHg, about 450 mmHg, about 500 mmHg, or include any of the following ranges and / or a range between any two of these values.

[0040] The ammonium fluoride hydrate (“hydrate”) may be a tetra(C1-C6 alkyl)ammonium fluoride hydrate. In any embodiment of the method disclosed herein, the ammonium fluoride hydrate may include a tetramethylammonium fluoride hydrate, a tetraethylammonium fluoride hydrate, a tetrapropylammonium hydrate, a tetrabutylammonium fluoride hydrate, a tetrapentylammonium fluoride hydrate, or any combination of two or more thereof. In any embodiment of the method disclosed herein, the ammonium fluoride hydrate may include a tetramethylammonium fluoride hydrate, a tetraethylammonium fluoride hydrate, a tetra-n-propylammonium hydrate, a tetra-isopropylammonium fluoride hydrate, a tetra-n-butylammonium fluoride hydrate, a tetra-isobutylammonium fluoride hydrate, a tetra-tert-butylammonium fluoride hydrate, a tetra-n-pentylammonium fluoride hydrate, a tetra-isopentylammonium fluoride hydrate, a tetra-tert-pentylammonium fluoride hydrate, a tetra-neopentylammonium fluoride hydrate, or any combination of two or more thereof.

[0041] In any embodiment of this method herein, distilling the mixture may include heating the mixture to a temperature of about 50°C to about 100°C. Therefore, in any embodiment of this method herein, heating the mixture may include heating to a temperature of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, or including any of the following ranges and / or a range between any two of these values. For example, in this method, the mixture may be heated to a temperature of about 70°C to about 90°C or about 80°C to about 85°C. According to any embodiment of this method herein, heating the mixture may include heating for about 1 hour to about 10 hours. Therefore, in any embodiment of this method herein, heating the mixture may include heating for about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or including any of the following ranges and / or a range between any two of these values ​​(e.g., heating for about 3 hours to about 9 hours; heating for about 5 hours to about 7 hours).

[0042] In any embodiment of this method disclosed herein, the mixture may comprise 1 molar equivalent of ammonium fluoride (based on the molar equivalent of ammonium fluoride in the hydrate, not on the molar equivalent of the hydrate) and about 5 to about 50 molar equivalents of alcohol; thus, the molar equivalent of alcohol may be about 5 molar equivalents, about 10 molar equivalents, about 15 molar equivalents, about 20 molar equivalents, about 25 molar equivalents, about 30 molar equivalents, about 35 molar equivalents, about 40 molar equivalents, about 45 molar equivalents, about 50 molar equivalents, or include any of the following ranges and / or a range between any two of these values. For example, in any embodiment of this method disclosed herein, the mixture may comprise about 10 to about 15 molar equivalents of alcohol.

[0043] In any embodiment of this method herein, the mixture may further contain C5-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof. For example, the mixture may further contain heptane and / or may further contain benzene, toluene, or combinations thereof. In any embodiment of this method herein, such C5-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof may be contained in the solvent prior to combination with the hydrate, combined with the hydrate prior to combination with the solvent, contained concurrently with the combination of the hydrate and the solvent, and / or contained after the combination of the hydrate and the solvent but before distillation of the mixture. In any embodiment of this method, the mixture comprises C5-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof, the mixture may contain 1 molar equivalent of ammonium fluoride (as previously noted in this disclosure, based on the molar equivalent of ammonium fluoride in the hydrate, not on the molar equivalent of the hydrate) and about 1 to about 10 molar equivalents of C3-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof; therefore, the mixture may contain C3-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof, in amounts of about 1 molar equivalent, about 2 molar equivalent, about 3 molar equivalent, about 4 molar equivalent, about 5 molar equivalent, about 6 molar equivalent, about 7 molar equivalent, about 8 molar equivalent, about 9 molar equivalent, about 10 molar equivalent, or in amounts including any of the following ranges and / or between any two of these values.

[0044] The present technology, which is so generally described, will be more readily understood by referring to the following embodiments, which are provided by way of illustration and are not intended to limit the present technology. Example

[0045] Example 1 – TBAF ( t Preparation of -AmOH)4 Scheme I—Preparation of tetra-n-butylammonium tetrafluoride (tert-amyl alcohol) A 250 mL jacketed four-necked round-bottom flask equipped with a top-mounted stirrer, a nitrogen inlet, a thermocouple, and a reflux condenser with a Dean-Stark trap was filled with tetra-n-butylammonium fluoride trihydrate (15.0 g, 1.0 equivalent), tert-amyl alcohol (62.9 g, 15.0 equivalent), and heptanes (mixed isomers, 19.1 g, 4.0 equivalent). The resulting stirred mixture was heated to reflux for 4 hours under reduced pressure (180 mmHg, 55 to 60 °C) and / or until the water content of the reaction mixture was reduced to less than 0.2% by Karl-Fischer titration. All volatiles were then removed under reduced pressure (15 mmHg, 40 °C) to give tetra-n-butylammonium fluoride tetra(tert-amyl alcohol) as a white solid (29.1 g, >99% yield). 1 H NMR (400 MHz, CDCl3) δ 3.46-3.41 (m, 8H), 1.72-1.63 (m, 8H), 1.54-1.40 (m, 16H), 1.20 (s, 12H), 1.19 (s, 12H), 1.02-0.98 (m, 12H), 0.94-0.89 (m,12H) ppm. 19 F NMR (376 MHz, CDCl3) δ -123.9 ppm.

[0046] Tetra-n-butylammonium fluoride (tert-amyl alcohol) was found to be a solid and crystalline at 23°C. This is purely for illustrative purposes. Figure 1 Images of tetra-n-butylammonium tetrafluoride (tert-amyl alcohol) in ambient air at 23°C are provided using a Leica DVM6A microscope (objectives: FOV 12.55; working distance: 33 mm; maximum magnification: 675:1; exposure time: 30 ms; resolution: 2 MP (1600x1200); zoom: 6.87x; numerical aperture: 0.125; TL intensity: 90; RL intensity: 30; SLI intensity: -10; CXI intensity: 80; BLI intensity: 90; color saturation: 24.31373; shift: Zn-Lambda; filters: none). Similarly, purely for illustrative purposes... Figure 2Images of tetra-n-butylammonium tetrafluoride (tert-amyl alcohol) in mineral oil, taken at 23°C using a Leica DVM6A microscope (objectives: FOV 12.55; working distance: 33 mm; maximum magnification: 675:1; exposure time: 30 ms; resolution: 2 MP (1600x1200); zoom: 1.8x; numerical aperture: 0.032; TL intensity: 60; RL intensity: 30; SLI intensity: -10; CXI intensity: 40; BLI intensity: 60; color saturation: 24.31373; movement: Z-Lambda; filter: none). Further analysis revealed that the crystalline tetra-n-butylammonium tetrafluoride (tert-amyl alcohol) remains stable for over 6 months in ambient air and a desiccator at 23°C.

[0047] Example 2 – Preparation of a substantially anhydrous TMAF solution Scheme II—Exemplary generation of a substantially anhydrous TMAF solution A 100 mL three-necked round-bottom flask was fitted with a nitrogen inlet, a thermocouple, and a Dean-Stark apparatus with a reflux condenser. Tetramethylammonium fluoride tetrahydrate (3.78 g, 22.9 mmol, 1.0 equivalent), tert-amyl alcohol (69.9 g, 34 equivalent), and heptanes (14.5 g, 6 equivalent) were added to the flask at room temperature. Stirring was initiated, a vacuum was applied to reduce the pressure to 180 mmHg, and the solution was refluxed to 60–70 °C. These conditions were maintained for 4 hours to obtain a solution that was 0.08% water by Karl Fischer titration. The vacuum was broken with nitrogen, and the reaction was cooled to room temperature under nitrogen to give tetramethylammonium fluoride (2.13 g, 22.9 mmol, 100%, 5.32 wt%), which served as the... t -A substantially anhydrous solution in the AmOH / heptane class. Characteristic data for substantially anhydrous solutions in the t-AmOH / heptane class. 1 H NMR (400 MHz, MeOH-d4) δ 3.10 (s, 12H), 1.40 (q, J = 7.56 Hz, 38.4H), 1.07 (s, 113.6H), 0.82 (t, J =7.52 Hz, 55.0H) ppm. 19 F NMR (376 MHz, MeOH-d4) δ -149.4 ppm.

[0048] Example 3 – Solid TMAF(t-AmOH) n Preparation The portions of the solution from Example 2 were further subjected to reduced pressure (15 mmHg, 40°C) to provide TMAF as a crystalline solid. t -AmOH) n The value of n varies between 0.9 and 1.7 depending on the amount of residual solvent.

[0049] After separation into solid form, TMAF(t-AmOH) 1.6 Feature data. 1 H NMR (400 MHz, MeOH-d4) δ 3.11(s, 12H), 1.40 (q, J = 8.02 Hz, 3.3H), 1.07 (s, 9.9H), 0.82 (t, J = 7.72 Hz, 4.8H) ppm. 19 F NMR (376 MHz, MeOH-d4) δ -151.9 ppm.

[0050] Exemplary General Method AE The fluorination reaction was carried out according to the general method AE described below. Examples 4-9 thereafter disclose a subset of specific fluorination reactions performed and their results.

[0051] General Method A: Fluorination is performed using an in-situ prepared, essentially anhydrous TBAF solution.

[0052] Option III To a 100 mL three-necked round-bottom flask equipped with a magnetic stirrer, nitrogen inlet, thermocouple, and reflux condenser with a Dean-Stark trap, add tetra-n-butylammonium fluoride trihydrate (15.0 g, 1.2 equivalents), tert-amyl alcohol (8.5 V), and heptanes (mixed isomers, 3 V). Heat the resulting stirred mixture under reduced pressure (180 mmHg, 55 to 60 °C) to reflux for 4 hours and / or until the water content of the reaction mixture is reduced to less than 0.2% by Karl Fischer titration. Release the vacuum and adjust the temperature to 65 to 75 °C. Add bromide or methanesulfonate (1.0 equivalents) and stir the mixture at 65 to 75 °C for 1 hour. Then cool the mixture to ambient temperature, quench with water (10 V), and dilute with heptanes (mixed isomers, 3 V). Separate the phases and extract the aqueous layer with heptanes (mixed isomers, 3 V). The combined organic compounds were washed with water (2 × 5 V), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the alkyl fluoride product.

[0053] General Method B: Fluorination using an in-situ prepared, essentially anhydrous TMAF solution. Option IV At room temperature, the sample containing the solution prepared according to Example 2 was subjected to... t The matrix (1.0 equivalent) was added in a single step to a nitrogen-purged 100 mL round-bottom flask containing a substantially anhydrous solution of TMAF (1.2 to 1.5 equivalents) in AmOH / heptane (0.2–0.3 M). The reaction was heated to 70 °C and subjected to... 1 H NMR monitoring conversion.

[0054] General method C: Fluorination using solid TMAF(t-AmOH) Scheme V—TMAF( t The reaction of -AmOH) in DMSO to provide the fluorinated product Add the matrix (1.0 equivalent) to a nitrogen-purged 50 mL round-bottom flask equipped with a stir bar, followed by the addition of solid TMAF ( t -AmOH) n (1.2 to 1.5 equivalents of fluoride; prepared according to Example 2), and then anhydrous DMSO (0.2-0.3 M) was added. The reaction was heated to 70°C and passed through... 1 H NMR monitoring conversion.

[0055] General Method D: Fluorination of Aryl Halides in Alcohol / Heptane Solutions Scheme VI—Aryl halides and heteroaryl halides in t Reactions in AmOH / heptane derivatives At room temperature, the sample containing the solution prepared according to Example 2 was subjected to... t The matrix (1.0 equivalent) was added in a single step to a nitrogen-purged 100 mL round-bottom flask containing a substantially anhydrous solution of TMAF (1.2 to 1.5 equivalents) in AmOH / heptane (0.2–0.3 M). The reaction was heated to 80 °C and subjected to... 1 H NMR monitoring conversion.

[0056] General Method E: Fluorination of Aryl Halides in DMSO Scheme VII—Aryl halides and heteroaryl halides with TMAF ( t The reaction of -AmOH) in DMSO An aryl halide (1.0 equivalent) was added to a nitrogen-purged 50 mL round-bottom flask equipped with a stir bar, followed by the addition of solid TMAF. t -AmOH) n (1.2 to 1.5 equivalents of fluoride; prepared according to Example 2), and then anhydrous DMSO (0.2-0.3 M) was added. The reaction was heated to 80°C and... 1 H NMR monitoring conversion.

[0057] Example 4 – Synthesis of ethyl 6-fluorohexanoate Scheme VIII—The reaction of ethyl 6-(methanesulfonyloxy)hexanoate using general method A or general method B to provide ethyl 6-fluorohexanoate.

[0058] Ethyl 6-(methanesulfonyloxy)hexanoate (2.00 g) was converted to ethyl 6-fluorohexanoate (1.14 g, 84% yield, colorless oil) according to general method A. 1 H NMR (400 MHz, CDCl3) δ 4.43 (dt, J = 47.3, 6.1 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.78-1.64 (m, 4H), 1.48-1.41(m, 2H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 19 F NMR (376 MHz, CDCl3) δ -218.4 ppm.

[0059] According to general method B, at room temperature, [the following is applied] to [the environment / the environment]... t Alkyl methanesulfonate (0.90 g, 3.8 mmol, 1.0 equivalent) was added in a single step to a substantially anhydrous solution of TMAF (0.47 g, 5.1 mmol, 1.3 equivalent) in AmOH / heptanes (15.66 g, 0.3 M). The solution was heated to 70 °C for 1 hour. The reaction was then cooled and analyzed without further purification to obtain the product as... t Fluorination products in solutions of -AmOH / heptanes (0.55 g, 3.4 mmol, 90.3%, 3.1 wt%).

[0060] Example 5 – Synthesis of 4-Methoxybenzyl Fluorine Scheme IX—The reaction of 4-methoxybenzyl bromide using general method A or general method C to provide 4-methoxybenzyl fluoride.

[0061] 4-Methoxybenzyl bromide (2.00 g) was converted to 4-methoxybenzyl fluoride (1.09 g, 78% yield, colorless oil) according to general method A. 1 H NMR (400 MHz, DMSO) δ 7.04-7.01 (m, 2H), 6.62-6.60 (d, J =7.95 Hz, 2H) 4.99 (d, J = 48.78 Hz, 2H), 3.52 (s, 3H) ppm. 19 F NMR (376 MHz, DMSO) δ -59.7 ppm.

[0062] According to general method C, 4-(bromomethyl)anisole (1.11 g, 5.5 mmol, 1.0 equivalent) was added to a round-bottom flask at room temperature under nitrogen atmosphere, followed by the addition of solid TMAF ( t -AmOH) 1.1 (1.28 g, 6.7 mmol, 1.2 equivalents) and DMSO (27.41 g, 0.2 M). The solution was heated to 70 °C for 1 hour. The reaction was then cooled and analyzed without further purification to give the fluorinated product as a solution in DMSO (0.63 g, 4.5 mmol, 80.7%, 1.8 wt%).

[0063] Example 6 – Synthesis of 1-(fluoromethyl)-4-(trifluoromethyl)benzene Scheme X—The reaction of 1-(bromomethyl)-4-(trifluoromethyl)benzene using general method C to provide 1-(fluoromethyl)-4-(trifluoromethyl)benzene.

[0064] According to general method C, 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.92 g, 3.8 mmol, 1.0 equivalent) and solid TMAF were added to a round-bottom flask at room temperature under nitrogen atmosphere. t -AmOH) 1.1(0.92 g, 4.8 mmol, 1.3 equivalents) and DMSO (23.05 g, 0.20 M). The solution was heated to 70 °C for 1 hour. The reaction was then cooled and analyzed without further purification to give the fluorinated product as a solution in DMSO (0.62 g, 3.5 mmol, 90.3%, 2.5 wt%). 1 H NMR (400 MHz, DMSO) δ 7.38 (d, J = 8.04 Hz, 2H), 7.24 (d, J = 7.96 Hz, 2H), 5.19 (d, J = 47.18 Hz, 2H) ppm.

[0065] Example 7 – Synthesis of 2-(fluoromethyl)naphthalene Scheme XI—Using general method A, general method B or general method C to react 2-(bromomethyl)naphthalene to provide 2-(fluoromethyl)naphthalene.

[0066] 2-(bromomethyl)naphthalene (2.00 g) was converted to 2-(fluoromethyl)naphthalene (1.29 g, 89% yield, white solid) according to general method A. 1 H NMR (400 MHz, DMSO) δ 7.92-7.87 (m, 4H), 7.56-7.51 (m, 3H), 5.58 (d, J = 47.74 Hz, 2H) ppm. 19 F NMR (376 MHz, CDCl3) δ -206.7 ppm.

[0067] According to general method B, at room temperature under nitrogen atmosphere, [the substance] contains [the following]. t In a round-bottom flask, a substantially anhydrous solution of TMAF (0.52 g, 5.6 mmol, 1.3 equivalence) in AmOH / heptane (15.36 g, 0.2 M) was added once. The solution was heated to 70 °C for 1 hour. The reactants were concentrated under reduced pressure, diluted with heptane, and then filtered to remove the salt. The reaction yielded 2-(fluoromethyl)naphthalene (0.56 g, 3.5 mmol, 84.2%, 54.2% by weight in heptane) as a solution in heptane.

[0068] According to general method C, 2-(bromomethyl)naphthalene (0.99 g, 4.5 mmol, 1.0 equivalent) and solid TMAF were added to a round-bottom flask at room temperature under nitrogen atmosphere. t -AmOH) 1.1 (1.06 g, 5.5 mmol, 1.2 equivalents) and anhydrous DMSO (22.44 g, 0.2 M). The solution was heated to 70 °C for 1 hour. The reaction was then cooled and analyzed without further purification to obtain the product as... t Fluorination products in solutions of -AmOH / heptanes (0.62 g, 3.9 mmol, 86.0%, 2.6 wt%).

[0069] Example 8 – Synthesis of tert-butyl 4-(2-fluoropyrimidin-4-yl)piperazine-1-carboxylate Scheme XII—The reaction of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate using general method E to provide tert-butyl 4-(2-fluoropyrimidin-4-yl)piperazine-1-carboxylate.

[0070] Following general method E, tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (0.20 g, 0.7 mmol, 1.0 equivalent) was added to a round-bottom flask, followed by the addition of TMAF ( t -AmOH) 1.6 (0.21 g, 0.9 mmol, 1.3 equivalents) and anhydrous DMSO (3.70 g, 0.2 M). The temperature was increased to 80 °C. After 0.5 hours, the reaction was cooled to give tert-butyl 4-(2-fluoropyrimidin-4-yl)piperazine-1-carboxylate (0.18 g, 0.6 mmol, 97.3%, 4.4 wt%) as a solution in DMSO. 1 H NMR (400 MHz, DMSO) δ 8.23 ​​(dd, 1H, J = 6.12, 2.60 Hz), 6.92 (dd, 1H, J = 6.04, 4.72Hz), 3.75 (br s, 4H), 3.54-3.52 (m, 4H), 1.53 (s, 9H) ppm. 19 F NMR (376 MHz, DMSO) δ -45.6 ppm.

[0071] Example 9 – Synthesis of 6-fluoronicotinonitrile Scheme XIII—Reaction of 6-chloronicotinonitrile using general method D or general method E to provide 6-fluoronicotinonitrile.

[0072] According to general method D, at room temperature, to contain... t In a nitrogen-purged 50 mL round-bottom flask, a substantially anhydrous solution of TMAF (0.24 g, 2.6 mmol, 1.8 equivalents) in AmOH / heptane (0.3 M) was added in a single addition of 6-chloronicotinonitrile (0.20 g, 1.4 mmol, 1.0 equivalents). The reaction was heated to 80 °C. After 2 hours, the reaction was cooled to give the product as a... t Products from solutions of -AmOH / heptanes (0.10 g, 0.8 mmol, 57.1%, 2.04 wt%).

[0073] Following general method E, 6-chloronicotinonitrile (0.20 g, 1.4 mmol, 1.0 equivalent) was added to a round-bottom flask, followed by the addition of TMAF ( t -AmOH) 1.6 (0.45 g, 1.9 mmol, 1.3 equivalents) and anhydrous DMSO (5.30 g, 0.3 M). The temperature was increased to 80 °C. After 10 minutes, the reaction was cooled to give 6-fluoronicotinonitrile (0.13 g, 1.1 mmol, 75.2%, 2.18 wt%) as a solution in DMSO. 1 H NMR (400 MHz, DMSO) δ 8.90 (d, 1H, J = 2.32 Hz), 8.65-8.61 (m, 1H), 7.56 (dd, 1H, J = 8.60, 2.48 Hz) ppm. 19 F NMR (376 MHz, DMSO) δ -59.8 ppm.

[0074] Although certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made to them based on the knowledge of those skilled in the art without departing from the broader aspects of the technology defined in the following claims.

[0075] The embodiments described illustratively herein may be suitably implemented in the absence of any one or more elements or limitations not expressly disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be broadly understood and not limited. Furthermore, the terms and expressions used herein have been used as descriptive rather than restrictive terms, and their use is not intended to exclude any equivalents of the features shown and described, or portions thereof, but recognizes that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consistently composed of” will be understood to include those elements specifically described, as well as additional elements that do not materially affect the fundamental and novel features of the claimed technology. The phrase “consisting of” excludes any unspecified elements. Finally, it will be understood that disclosure using one of the foregoing terms also discloses embodiments using any of the other two terms or their equivalents.

[0076] This disclosure is not limited to the specific embodiments described herein. Many modifications and variations are possible without departing from its spirit and scope, as will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent methods and compositions within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terminology of the appended claims and the full scope of their equivalents. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, which are, of course, subject to variation. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0077] Furthermore, when the features or aspects of this disclosure are described in accordance with the Markush Group, those skilled in the art will recognize that this disclosure is also described in accordance with any individual member or subgroup of the Markush Group.

[0078] As those skilled in the art will understand, for any and all purposes, particularly for the purpose of providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope will be readily recognized as sufficiently descriptive and capable of being subdivided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily subdivided into lower thirds, middle thirds, upper thirds, etc. As those skilled in the art will also understand, all language such as “at most,” “at least,” “greater than,” “less than,” etc., includes the stated number and refers to a scope that may be further subdivided into subscopes as discussed above. Finally, as those skilled in the art will understand, a scope includes each individual member.

[0079] All publications, patent applications, granted patents and other documents mentioned in this specification are incorporated herein by reference as if each publication, patent application, granted patent or other document were specifically and individually indicated to be incorporated herein by reference in its entirety. Definitions contained in the text incorporated by reference that conflict with definitions in this disclosure are excluded.

[0080] Other embodiments are set forth in the following claims.

Claims

1. A tetra(C1-C6) alkyl ammonium fluoride and C x A solid alcohol solvate of an alcohol, wherein x is 3, 5, 6, 7, 8, 9 or 10.

2. The solid alcohol solvate of claim 1, wherein the tetra(C1-C6 alkyl) fluoride is tetrabutylammonium fluoride.

3. The solid alcohol solvate of claim 1 or claim 2, wherein the solid alcohol solvate is tetra-n-butylammonium tetra(tert-amyl alcohol) fluoride.

4. The solid alcohol solvate of any one of claims 1-3, wherein the solid alcohol solvate is in crystalline form.

5. A hydrate of the alcohol solvate according to any one of claims 1-4.

6. A method comprising: Ammonium fluoride or its hydrate is combined with a solvent containing an alcohol to form a mixture; and Separate the solid alcohol solvate from the mixture.

7. The method of claim 6, wherein separating the solid alcohol solvate comprises distilling the mixture to obtain the solid alcohol solvate.

8. The method of claim 6 or claim 7, wherein the ammonium fluoride or its hydrate is tetra(C1-C6 alkyl) fluoride or tetra(C1-C6 alkyl) fluoride hydrate.

9. The method of any one of claims 6-8, wherein the ammonium fluoride or its hydrate is tetrabutylammonium fluoride, tetrabutylammonium fluoride hydrate, tetramethylammonium fluoride or tetramethylammonium fluoride hydrate.

10. The method of any one of claims 6-9, wherein the mixture further comprises C5-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof.

11. The method of claim 10, wherein the C5-C 10 Alkanes include heptane.

12. The method of claim 10 or claim 11, wherein the C6-C 10 Aromatic hydrocarbons include benzene, toluene, or combinations thereof.

13. The method of any one of claims 6-12, wherein the method comprises: The ammonium fluoride or its hydrate is combined with the solvent containing the alcohol to form the mixture; Heating the mixture to a temperature of about 50°C to about 100°C to provide a heated mixture; and Separate the solid alcohol solvate from the heated mixture.

14. The method of claim 13, wherein heating the mixture comprises heating for about 1 hour to about 10 hours.

15. The method of any one of claims 6-14, wherein the mixture comprises 1 molar equivalent of the ammonium fluoride or its hydrate and about 5 to about 50 molar equivalents of the alcohol.

16. The method of any one of claims 6-15, wherein the mixture comprises 1 molar equivalent of the ammonium fluoride or its hydrate and about 10 to about 20 molar equivalents of the alcohol.

17. The method of any one of claims 6-16, wherein the mixture comprises 1 molar equivalent of the ammonium fluoride or its hydrate and about 10 to about 15 molar equivalents of the alcohol.

18. The method of any one of claims 10-17, wherein the mixture comprises 1 molar equivalent of the ammonium fluoride or its hydrate and about 1 to about 10 molar equivalents of the C3-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof.

19. The method of any one of claims 6-18, wherein separating the solid alcohol solvate from the mixture comprises distilling the mixture in a Dean-Stark apparatus to collect the distillate.

20. The method of any one of claims 6-19, wherein separating the solid alcohol solvate comprises an absolute pressure of about 50 mmHg to about 500 mmHg.

21. The method of any one of claims 6-20, wherein the alcohol comprises tert-butanol or tert-amyl alcohol.

22. The method of any one of claims 6-21, wherein the solid alcohol solvate is tetra-n-butylammonium tetra(tert-ammonium alcohol), tetra-n-butylammonium tetra(tert-butanol), or tetramethylammonium tert-ammonium alcohol.

23. The method of any one of claims 6-22, wherein separating the solid alcohol solvate comprises separating the solid alcohol solvate which is substantially anhydrous.

24. The method of any one of claims 6-23, wherein separating the solid alcohol solvate comprises separating the ammonium fluoride and the anhydrous solid alcohol solvate of the alcohol.

25. A method comprising: Ammonium fluoride hydrate is combined with a solvent containing an alcohol to form a mixture; and The mixture is distilled to obtain a second mixture that is substantially free of water.

26. The method of claim 25, wherein the hydrate comprises a hydrate of tetra(C1-C6) alkyl ammonium fluoride.

27. The method of claim 25 or claim 26, wherein the hydrate is a hydrate of tetrabutylammonium fluoride or a hydrate of tetramethylammonium fluoride.

28. The method of any one of claims 25-27, wherein the mixture further comprises C5-C 10 Alkanes, C6-C 10 Aromatic hydrocarbons or combinations thereof.

29. The method of any one of claims 25-28, wherein distilling the mixture comprises heating the mixture to a temperature of about 50°C to about 100°C.

30. The method of any one of claims 25-29, wherein distilling the mixture comprises collecting the distillate in a Dean-Stark apparatus.

31. The method of any one of claims 25-30, wherein distilling the mixture comprises an absolute pressure of about 50 mmHg to about 500 mmHg.

32. The method of any one of claims 25-31, wherein the alcohol comprises tert-butanol and / or tert-amyl alcohol.

33. The method of any one of claims 25-32, wherein the second mixture contains less than 0.2% by weight of water.

34. The method of any one of claims 25-33, wherein the second mixture is anhydrous.

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