HK40080089A - Triflazoles and methods of making the same - Google Patents

Description

Trifluozole and preparation method thereof

Priority and cross-reference

This application claims priority to U.S. provisional application serial No. 62/968,243, filed on 31/1/2020, which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates generally to the chemical synthesis of azole derivatives. More particularly, the presently disclosed subject matter relates to methods of producing trifluoroazoles or related derivatives thereof, and the resulting trifluoroazoles and/or derivatives thereof.

Background

The conversion of phenol or enolate functions into trifluoromethylsulfonyl ethers ("triflates") is known in the fine chemistry industry. The most commonly used agents are two: trifluoromethyl sulfonic anhydride (Tf) ₂ O) and aromatic triflimides, e.g. N, N-bis (trifluoromethylsulfonyl) aniline (PhNTf) ₂ ) And N, N-bis (trifluoromethylsulfonyl) -5-chloro-2-aminopyridine ("kommins reagent"). Both reagent groups were derived from the industrial starting material trifluoromethylsulfonyl fluoride (CF) ₃ SO ₂ F)。CF ₃ SO ₂ F is derived from CH using Simons electrochemical process ₃ SO ₂ F or CH ₃ SO ₂ Cl is obtained by scale production, and CH ₃ SO ₂ Cl is in turn made from methane and sulfuryl chloride. CF (compact flash) ₃ SO ₂ F itself is a highly toxic gas, which, although well known as a triflating agent for phenolic compounds, is at present not considered suitable for the production of fine chemicals. Tf ₂ O ratio CF ₃ SO ₂ F has some advantages because it is a liquid at room temperature and is less toxic. However, Tf ₂ O itself is made of CF ₃ SO ₂ F is prepared in an expensive multi-step process. Tf ₂ O is toxic, easily hydrolyzed, and reacts with some common solvents such as THF. The triflating agent is preferably a triflimide. They are composed of Tf ₂ O the prepared desktop stable compound was reacted with phenols at room temperature and enolate at low temperature. The main drawback of such triflating agents is their cost. 4 moles of CF were consumed to produce 1 mole of trifluoromethanesulfonimide ₃ SO ₂ F and using multiple steps, although a recent Chinese patent (CN110627691) claims to reduce it to 2 moles and one step.

However, these two classes of triflating agents are not the only options. In 1970, the drug was prepared from imidazole and Tf ₂ O preparation of reagent l- (trifluoromethylsulfonyl) imidazole ('CF') ₃ SO ₂ Im ") and shows that the reaction with phenols at 20-90 ℃ leads to the phenolic tris-compounds in good yieldsFluorine methanesulfonate (Effenberger, F.; Mack, K.E. tetrahedron Letters 1970,11, 3947-. CF ₃ SO ₂ Im is mentioned in this patent document about thirty times: as triflating agents for protic amines and phenolic compounds, as coupling agents, as graphene doping agents, and in the production of lithium battery electrolytes. In the non-patent literature, since 1970, CF ₃ SO ₂ Im is mentioned only six times as a successful reagent.

Disclosure of Invention

The present disclosure provides methods for producing trifluoxazole or its related derivatives, and the resulting products.

According to some embodiments, the present disclosure provides a compound prepared by trifluoromethylsulfonyl fluoride (CF) ₃ SO ₂ F) A process for obtaining trifluoxazole by reaction with oxazole, an azole anion compound ("azolate"), N-silylazole, or a combination thereof. Examples of suitable oxazoles, azole anion compounds, or N-silyl oxazoles are given in the detailed description.

One or more of the reactions described herein optionally may be carried out in the presence of an aprotic solvent. Examples of suitable aprotic solvents are given in the detailed description. In some embodiments, the reactants may be suspended or dissolved in a solvent.

In some embodiments, the azole anionic compound or azole salt has a metal cation. Examples of suitable metals are included in the detailed description.

In some embodiments, the azole salt is derived from the free azole and the protic or aprotic base, respectively, or in situ. The terms "protic" and "aprotic" are defined in the detailed description. Examples of suitable bases are given in the detailed description.

In some embodiments, the azolium salt is derived in situ from a protic azole as the base, wherein the protic azole reacts with itself to form an azolium (azolium) azolium salt.

In some embodiments, the azole salt is derived in situ from an N-silylazole having an azole structure. For example, in some embodiments, the N-silylazole is an N- (trimethylsilyl) azole.

In some embodiments, the azole salt is derived in situ from an N-silylazole having an azole structure in the presence of a catalyst. Examples of suitable catalysts are given in the detailed description.

According to some embodiments, an exemplary method includes causing a CF to ₃ SO ₂ F is reacted with N-silylazole and the trifluozole is isolated, wherein the N-silylazole has the azole structure. The azole structure is in the proton form in the free state.

Examples of azole structures or azoles include, but are not limited to, imidazole, pyrazole, 1,2, 4-triazole, benzimidazole, benzotriazole, indazole, 2-methylimidazole, 2-methylbenzimidazole, 3, 5-dimethylpyrazole, and substituted derivatives thereof.

The N-silylazole can be an N- (trialkylsilyl) azole, such as an N- (trimethylsilyl) azole.

CF in the presence of a catalyst and/or optionally in the presence of an aprotic solvent as described herein ₃ SO ₂ F may be reacted with N-silylazole. The catalyst may be a basic catalyst. The catalyst or basic catalyst is as described herein. In some embodiments, the catalyst or basic catalyst comprises a reactive fluoride containing compound as described herein. In some embodiments, the catalyst is a protic azole or azole anion thereof.

In some embodiments, the catalyst is basic and comprises an aprotic organic base, which may be selected from tertiary amines, amidines such as bicyclic amidines, isothioureas, phosphazenes, guanidines, and combinations thereof.

In some embodiments, the catalyst is basic and comprises a compound selected from the group consisting of metal carbonates, metal fluorides, metal hydrides, alkyl lithiums, grignard reagents, hydroxides, alkoxide anionic compounds, and combinations thereof.

In some embodiments, the catalyst contains a reactive fluoride. Examples of suitable catalysts containing reactive fluorides are given in the detailed description.

According to some embodimentsAn example method includes causing a CF to ₃ SO ₂ F is reacted with an azole, or an azole salt of an azole, wherein the azole is in the proton form in the free state; and the trifluozole is isolated. The azole structure is a suitable azole as described herein.

In some embodiments, the azolium salt has a metal cation selected from the group consisting of lithium, sodium, potassium, cesium, magnesium, and combinations thereof. In some embodiments, the azolium salt is derived from an azole and a metal base selected from the group consisting of metal hydrides, metal alkoxides, metal hydroxides, metal carbonates, metal fluorides, alkyl lithiums, grignard reagents, and combinations thereof. For example, the azole salt can be derived from an azole and a metal carbonate, the metal being selected from the group consisting of lithium, sodium, potassium, cesium, magnesium, and combinations thereof. The azole salt can also be derived from azoles and metal fluorides, and the metal in the metal fluoride can be sodium, potassium, cesium, or a combination thereof. In some embodiments, the azole salt is derived from an azole and an aprotic base, or the azole itself as the base. The azolium salt can be derived from an azole and an aprotic organic base as described herein.

In some embodiments, the CF is brought to atmospheric or subatmospheric pressure ₃ SO ₂ F is reacted with oxazole.

Examples of resulting compounds include, but are not limited to: 1- (trifluoromethylsulfonyl) -1,2, 4-triazole, 1- (trifluoromethylsulfonyl) benzimidazole, 1- (trifluoromethylsulfonyl) benzotriazole, 1- (trifluoromethylsulfonyl) pyrazole, 1- (trifluoromethylsulfonyl) -2-methylimidazole, 1- (trifluoromethylsulfonyl) -3, 5-dimethylpyrazole.

Drawings

The disclosure is best understood from the following detailed description when read with the accompanying drawing figures. It is emphasized that, according to common practice, the various features of the drawings are not necessarily to scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Like reference numerals refer to like features throughout the specification and drawings.

Figure 1 illustrates an exemplary process for preparing trifluoxazole according to some embodiments.

Figure 2 illustrates an exemplary process for preparing trifluoxazole according to some embodiments.

Detailed Description

For the purposes of the following description, it is to be understood that the embodiments described below may assume alternative variations and embodiments. It should also be understood that the specific articles, compositions, and/or methods described herein are illustrative and should not be considered as limiting.

In this disclosure, the singular forms "a," "an," and "the" include plural references and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. Thus, for example, reference to a "ring structure" is a reference to one or more such structures and their counterparts known to those skilled in the art, and so forth. When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. As used herein, "about X" (wherein X is a numerical value) preferably means ± 10% of the stated value, inclusive. For example, the phrase "about 8" preferably refers to a value of 7.2 to 8.8, including 7.2 and 8.8; as another example, the phrase "about 8%" preferably (but not always) refers to a value of 7.2% to 8.8%, including 7.2% and 8.8%. All ranges are inclusive of the endpoints at the point of occurrence and combinable. For example, when recited in the range of "1 to 5", the recited range should be understood to include ranges of "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", "2 to 5", and the like. Further, when a list of alternatives is provided in the forward direction, such list may be construed as, for example, meaning that any alternatives may be excluded by a reverse limitation in the claims. For example, when recited in the range "1 to 5", the recited range can be understood to include the reverse exclusion of any of 1,2, 3,4, or 5; thus, a recitation of "1 to 5" may be understood as "1 and 3 to 5, but excluding 2", or simply as "excluding 2" therein. It is intended to expressly exclude in the claims any component, element, attribute or step expressly referenced herein whether or not such component, element, attribute or step is listed as an alternative or whether or not it is individually recited.

Although CF ₃ SO ₂ Im is available from a number of merchants, but is currently quite expensive.The inventors expect if CF ₃ SO ₂ Im may be composed of CF ₃ SO ₂ F is prepared by one step with 1 molar equivalent of gas, CF ₃ SO ₂ The cost of Im will be reduced.

There is no known CF ₃ SO ₂ Reaction of F with the ring nitrogen of any protic azole, such as imidazole, pyrazole, 1,2, 4-triazole, indazole, benzimidazole, or benzotriazole. There is no known CF ₃ SO ₂ Reaction of F with the ring nitrogen of any N-silylimidazole, N-silylpyrazole, or N-silyl-1, 2, 4-triazole, N-silylindazole, N-silylbenzimidazole, or N-silylbenzotriazole.

The present invention provides a process for the production of trifluoroazole or related derivatives thereof, and the resulting trifluoroazoles and/or derivatives thereof.

The terms "protic" and "aprotic" as used herein refer to the presence or absence, respectively, of labile hydrogen atoms in the molecule. The term "protic" is used because the labile hydrogen atom generally moves as a proton, but it is not necessarily acidic to become protic. For example, diethylamine is both protic and a very weak acid. Its N-H hydrogen can only be removed with butyl lithium or the like, but its N-H hydrogen is highly unstable in many solvents. Protic hydrogen is primarily bound to a nitrogen or oxygen atom, and aprotic hydrogen is primarily bound to a carbon atom. The term "aprotic solvent" is well known and broadly refers to a solvent that does not have an-OH or-NH moiety. For example, diethyl ether and dimethylformamide are aprotic solvents, while ethanol and formamide are protic solvents.

The base may be protic or aprotic. Triethylamine is an aprotic base and diethylamine is a protic base. Tetramethylguanidine is a protic base and pentamethylguanidine is an aprotic base. Some fluorides (NaF, KF, CsF) can act as aprotic bases. The anion (and cation) may be protic or aprotic. The difluoride is in the protic form. The carbonate is aprotic. The bicarbonate is in the protic form. The hydroxide is of the protic type. The alkoxide is aprotic.

The azoles may be protic or aprotic. Examples of aprotic azoles are thiazole and oxazole. Examples of protic azoles include, but are not limited to, imidazole, pyrazole, 1,2, 4-triazole, benzimidazole, benzotriazole, indazole, 2-methylimidazole, 2-methylbenzimidazole, and 3, 5-dimethylpyrazole. Protic oxazoles may be treated with a base to give aprotic azole salts. Protic oxazoles are commonly referred to as "free oxazoles," and these terms are interchangeable. For example, "protic imidazole" and "free imidazole" both refer to the same chemical species, formally known as 1H-imidazole. Unless otherwise indicated, reference herein to "azoles" will be understood to include protic, rather than aprotic, azoles.

Suffixes "Im", "Pz", "Tz", "BzIm", "Bztz", and "Me ₂ Pz "refers to the radical structures of imidazole, pyrazole, 1,2, 4-triazole, benzimidazole, benzotriazole, and 3, 5-dimethylpyrazole, respectively, and the abbreviations given after the prefixes of trifluoromethylsulfonyl and silyl radicals, as described below.

The prefix "CF" in this text ₃ SO ₂ "refers to a trifluoromethylsulfonyl radical. Thus, "CF ₃ SO ₂ F "is trifluoromethanesulfonyl fluoride and" CF ₃ SO ₂ Im "means 1- (trifluoromethylsulfonyl) imidazole, and the like.

The prefix "Me" herein ₃ Si "means a trimethylsilyl radical. For example, "Me ₃ Siim "refers to 1- (trimethylsilyl) imidazole," Me ₃ SiF "refers to fluorotrimethylsilane, and the like.

The term "trifluoxazole" as used herein generally refers to N- (trifluoromethylsulfonyl) azole.

Unless otherwise indicated, reference herein to "vessel" means a flask, autoclave or other vessel used to carry out the reaction or to contain the transferred contents.

The term "reactive fluoride" herein refers to a fluorine atom or ion in a compound that can react with N-silylazole to form a fluorosilane and azole anion compound.

Unless otherwise indicated, reference herein to "low pressure" means conditions at or below atmospheric pressure. Unless otherwise indicated, reference herein to "elevated pressure" means conditions above atmospheric pressure. The term "under pressure" may be used to describe an unspecified high pressure.

As used herein, unless otherwise indicated, the term "refrigerated storage" refers to a process in which a container is cooled in a mixture of ice and water to a temperature in the range of 0 to +5 ℃.

The term "GCMS" as used herein refers to a gas chromatography-mass spectrometry analysis method. The mass to charge ratio value is provided by the term "m/e" followed by an integer. The quality detection is by electron impact.

According to some embodiments, the present invention provides methods of producing trifluoxazole and its related derivatives, as well as the resulting products.

In a broader aspect, the inventors have discovered at least two exemplary methods for producing trifluozole or its related derivatives.

In a first exemplary method, as shown in FIG. 1, CF ₃ SO ₂ And F reacts with oxazole or an oxazole salt to form trifluozole. This reaction is optionally carried out in the presence of an aprotic solvent. The vessel temperature is preferably below 50 ℃. CF (compact flash) ₃ SO ₂ F is reacted with the oxazole or oxazole salt under any pressure. In some embodiments, CF ₃ SO ₂ F is reacted with oxazole at a pressure equal to or less than atmospheric pressure. The trifluozole can be isolated.

Any suitable protic azole may be used. Examples include, but are not limited to, imidazole, benzimidazole, pyrazole, 1,2, 4-triazole, benzotriazole, indazole, 2-methylimidazole, 2-methylbenzimidazole, and 3, 5-dimethylpyrazole. These descriptions apply to all oxazoles in each of the exemplary methods described herein.

One or more of the reactions described herein may optionally be carried out in the presence of an aprotic solvent. Examples of suitable aprotic solvents include, but are not limited to, acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, methyl tert-butyl ether, propionitrile, butyronitrile, toluene, saturated hydrocarbon solvents such as hexane, heptane, pentane, cyclohexane, decalin, and the like, and any combination thereof. In some embodiments, the reactants may be suspended or dissolved in a solvent.

In some embodiments, the azolium salt has a metal cation. Examples of suitable metals include, but are not limited to, lithium, sodium, potassium, cesium, magnesium, and combinations thereof.

In some embodiments, the azolium salt is derived from a protic azole and a metal base, such as a metal hydride, a metal alkoxide, a metal hydroxide, a metal carbonate, a metal fluoride, an alkyl lithium, a grignard reagent, and combinations thereof.

In some embodiments, the azolium salt is derived from a protic azole and a metal carbonate. Examples of metals in the metal carbonate include, but are not limited to, lithium, sodium, potassium, cesium, and magnesium. The derivatives can be prepared alone or in situ.

In some embodiments, the azolium salt is derived from a protic azole and a metal fluoride. Examples of the metal in the metal fluoride include sodium, potassium and cesium. The derivatives can be prepared alone or in situ.

In some embodiments, the azole salt is derived from a protic azole and an aprotic organic base, or a protic azole as a base. Examples of suitable aprotic organic bases include, but are not limited to, alkylamines such as triethylamine and the like, 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU), heteroaromatic amines such as pyridine, 4- (dimethylamino) pyridine and the like, aprotic guanidines such as pentamethylguanidine, tetramethyl-t-butylguanidine, 1-methyl-1, 3,4,6,7, 8-hexahydro-2H-pyrimido [1,2-a ] pyrimidine, 1-methyl-2, 3,5, 6-tetrahydro-1H-imidazo [1,2-a ] imidazole and the like, phosphazenes, and combinations thereof.

In a second exemplary process, as shown in FIG. 2, the trifluoxazole is from an N-silylazole. In some embodiments, the N-silylazole is an N- (trialkylsilyl) azole. In some embodiments, the N- (trialkylsilyl) azole is an N- (trimethylsilyl) azole. The azole structure can be from any suitable azole. Examples include, but are not limited to, imidazole, benzimidazole, pyrazole, 1,2, 4-triazole, benzotriazole, indazole, 2-methylimidazole, 2-methylbenzimidazole, and 3, 5-dimethylpyrazole, and substituted derivatives thereof. These descriptions apply to all oxazoles in each of the exemplary methods described herein.

In some embodiments, by CF ₃ SO ₂ Reaction of F with N-silylazole in the presence of a catalyst gives the trifluoxazole.

In some embodiments, by CF ₃ SO ₂ Reaction of F with N-silylazole in the presence of a basic catalyst gives the trifluoroazole.

In some embodiments, this basic catalyst is the protic azole itself, or the azole anion thereof.

In some embodiments, such basic catalysts are aprotic bases. Examples of suitable basic catalysts include, but are not limited to, aprotic organic bases, and combinations thereof.

In some embodiments, examples of suitable aprotic organic bases for use as catalysts include, but are not limited to, tertiary amines, such as triethylamine and the like.

In some embodiments, examples of suitable aprotic organic bases for use as catalysts include, but are not limited to, bicyclic amidines and isothioureas, such as 1, 8-diazabicyclo (5.4.0) undecyl-7-ene (DBU), 2,3,5,6,7, 8-hexahydro-imidazo [1,2-a ] pyridine (DBN), 2,3,6, 7-tetrahydro-5H-thiazolo [3,2-a ] pyrimidine (THTP), and the like. Birman et al (Birman, V.B.; Li, X.; Han, Z.organic Letters 2007,9,37-40) give a partial listing of such bicyclic amidines and isothioureas, which are incorporated herein by reference in their entirety.

In some embodiments, examples of suitable aprotic organic bases for use as catalysts include, but are not limited to, heteroaromatic amines such as pyridine, 4- (dimethylamino) pyridine, 1-methylimidazole, and the like.

In some embodiments, examples of suitable aprotic organic bases for use as catalysts include, but are not limited to, phosphazene bases such as N "'-tert-butyl-N, N', N" -hexamethylphosphoramidite (i.e., t-BuN ═ P [ NMe) ₂ ] ₃ ) N, N ', N ", N'" -heptamethylphosphinetriamide (i.e. MeN ═ P [ NMe ═ N ″) ₂ ] ₃ ) And so on.

In some embodiments, examples of suitable aprotic organic bases for use as catalysts include, but are not limited to, aprotic guanidines such as pentamethylguanidine, tetramethyl-t-butylguanidine, 1-methyl-1, 3,4,6,7, 8-hexahydro-2H-pyrimido [1,2-a ] pyrimidine (mesbd), 1-methyl-2, 3,5, 6-tetrahydro-1H-imidazo [1,2-a ] imidazole, and the like.

Further examples of suitable basic catalysts include, but are not limited to, carbonates of lithium, sodium, potassium, magnesium, and cesium.

Further examples of suitable basic catalysts include, but are not limited to, metal hydrides, alkyl lithium, grignard reagents, and combinations thereof.

Further examples of suitable basic catalysts include, but are not limited to, hydroxide or alkoxide anionic compounds. These include, but are not limited to, potassium hydroxide, potassium t-butoxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, and the like.

Further examples of suitable basic catalysts include, but are not limited to, trialkylsiloxy anionic compounds. These include, but are not limited to, potassium trimethylsiloxy oxide (KOSiMe) ₃ ) Tetramethylammonium trimethylsiloxy oxide, tetraethylammonium trimethylsiloxy oxide, and the like.

Further examples of suitable catalysts include, but are not limited to, compounds containing reactive fluorides.

In some embodiments, examples of suitable catalysts containing reactive fluorides are fluorides or bifluorides of sodium, potassium, cesium, and tetraalkylammonium, such as tetraethylammonium difluoride, tetraethylammonium fluoride, and the like.

In some embodiments, examples of suitable catalysts containing reactive fluorides are certain types of anionic compounds containing unbound or "bare" fluoride as the anion. Examples of naked fluoroanion compounds include tetramethylammonium fluoride, tetrabutylammonium fluoride, phosphazenes fluoride such as [ P (NMe) ₂ ) ₄ ] ⁺ F ^- (i.e., tris (dimethylamino) -N, N-dimethyl-lambda) ⁵ -phosphamidofluoride), and the like.

In some embodiments, examples of suitable catalysts containing reactive fluorides are complexes containing pentavalent or hexavalent silicon, sulfur, tin, or other main group anions, anionic compounds having at least one fluorine atom in the anion, such as tris (dimethylamino) sulfonium difluorotrimethicosilicate, tris (dimethylamino) methyldifluoromethyl-trimethylorthosilicate, tetrabutylammonium difluorotriphenylsilicate, tetrabutylammonium difluorotriphenylstannate, and the like.

In some embodiments, examples of suitable catalysts containing reactive fluorides are compounds containing reactive sulfur-fluorine or phosphorus-fluorine bonds, such as sulfur tetrafluoride, sulfur methyltrifluoride, sulfur dimethyldifluoride, (diethylamino) sulfur trifluoride, phenylsulfur pentafluoride, phosphorus trifluoride, phosphorus pentafluoride, and the like.

In some embodiments, examples of suitable catalysts containing reactive fluorides are cationic compounds containing a sulfur-fluorine bond in the cation, such as (diethylamino) difluorosulfonium tetrafluoroborate, (4-morpholino) difluorosulfonium tetrafluoroborate, and the like.

In some embodiments, examples of suitable catalysts containing reactive fluorides are activated gem-difluorides such as 2, 2-difluoro-1, 3-dimethylimidazolidine, 1-difluoro-N, N' -tetramethylethylenediamine, and the like.

In some embodiments, a tetravalent organosilicon compound such as fluorotrimethylsilane (Me) ₃ SiF), tetramethylsilane (Me) ₄ Si), ethyltrimethylsilane (EtSiMe) ₃ ) Difluorodiethylsilane (Et) ₂ SiF ₂ ) And the like into the container. These organosilanes can reversibly bind to the fluoride, dissolve it as a coordination complex, and increase its reactivity.

In some embodiments, when a metal cation compound is used as the catalyst, a crown ether such as 18-crown-6, 15-crown-5, etc. may be added to the vessel to make the catalyst more effective than the metal cation compound alone.

In another aspect, the invention provides trifluoxazole. The azoles are from the group of protic azoles selected from the group consisting of pyrazole, 1,2, 4-triazole, benzimidazole, benzotriazole, indazole, 2-methylimidazole, 2-methylbenzimidazole, and 3, 5-dimethylpyrazole. Examples of the resulting compounds include, but are not limited to, 1- (trifluoromethylsulfonyl) -1,2, 4-triazole, 1- (trifluoromethylsulfonyl) benzimidazole, 1- (trifluoromethylsulfonyl) benzotriazole, 1- (trifluoromethylsulfonyl) pyrazole, 1- (trifluoromethylsulfonyl) -2-methylimidazole, and 1- (trifluoromethylsulfonyl) -3, 5-dimethylpyrazole.

CF ₃ SO ₂ Reaction of F with protic oxazoles.

In some embodiments, the CF is reacted at low pressure ₃ SO ₂ F is introduced into a sealed vessel containing a suspension of an acetonitrile solution of imidazole and a metal base such as a metal carbonate or fluoride under anhydrous conditions. The dissolved imidazole exists in equilibrium with its anion, possibly at or near the surface of the solid. Some freely soluble imidazolium salts may also be present. Adding CF to the vessel ₃ SO ₂ F can lead to an exothermic reaction. Theoretically, the molar ratio of imidazole to carbonate and imidazole to fluoride is 1:1 and 1:2, respectively. In practice, an excess of carbonate or fluoride is preferred. The reaction may preferably be carried out at a temperature of-10 ℃ to +50 ℃. The container may be filled with an amount of imidazole of up to 2 moles or more. However, 2 moles of imidazole are only completely dissolved in acetonitrile above about 20 ℃. At the end of the reaction, the insoluble salt is separated, the solvent is removed and the product is distilled. If the vessel is well cooled, high pressure can be used; however, the use of low pressure means better safety and also enables the use of large reactors with the same capital costs as much smaller autoclaves. In addition, better temperature control and more accurate endpoint can be achieved using lower pressures, thereby minimizing the addition of CF ₃ SO ₂ Any excess of F.

In some embodiments, imidazole is added with CF ₃ SO ₂ F was previously fully deprotonated and the resulting imidazolium salt was used. Suitable cations for the imidazolide anion include lithium, sodium, potassium, cesium, and magnesium. Sodium imidazolide is preferred. It is readily heated to 200 ℃ under dynamic vacuum and<50Pa was made from imidazole and sodium hydroxide in anhydrous form. The treatment yielded a loose solid that easily formed a fine suspension in acetonitrile. When the container is being charged with CF ₃ SO ₂ The feed was carried out rapidly at low pressure while a vacuum was drawn before F. The vessel is maintained at the process temperature by cooling. In some embodiments of the present invention, the substrate is,at low pressure, when using the fully deprotonated imidazolium metal salt and with addition of CF ₃ SO ₂ When the vessel is suitably vented prior to F, the pressure of the vessel near the endpoint can be reduced below the vapor pressure of the pure solvent.

In allowing imidazole to react with CF ₃ SO ₂ In some embodiments of the F reaction, the aprotic organic base is used in a stoichiometric manner.

In some embodiments, wherein imidazole is allowed with CF ₃ SO ₂ F reaction, CF ₃ SO ₂ Im is the target product and using an aprotic organic base, an excess of imidazole may be beneficial.

In some embodiments, wherein imidazole is allowed with CF ₃ SO ₂ F reaction, CF ₃ SO ₂ Im is the target product and an aprotic organic base, preferably DBU or an aprotic guanidine, is used. These strong bases can be used at low pressures. Unlike DBU, the aprotic guanidine can be recovered by treatment with aqueous hydroxide, whereas DBU cannot be so recovered and is a disposable reagent.

In some embodiments, wherein imidazole is allowed with CF ₃ SO ₂ F reaction, CF ₃ SO ₂ Im is the target product, preferably triethylamine as base. In some embodiments, wherein imidazole is allowed with CF ₃ SO ₂ F, preferably dichloromethane and triethylamine are used under high pressure.

In some embodiments, using azoles other than imidazole, the azole or azole salt may be reacted with CF under the conditions described above for imidazole ₃ SO ₂ F reacts to form other trifluozoles. For example, metal salts of pyrazole, 1,2, 4-triazole, benzimidazole, and benzotriazole can be used to produce TfPz, TfTz, tfbzmi, and TfBzTz, respectively. These and other metal salts of oxazol, if anhydrous, may be used. Some oxazoles can be easily deprotonated with sodium or potassium hydroxide to give anhydrous azolium salts. Other anhydrous azolium salts are not readily obtainable by simple reaction of azoles with sodium hydroxide or potassium hydroxide. In this case, stronger bases can be used, for example sodium or potassium tert-butoxide, GecA reagent, a metal hydride or an alkyl lithium.

In some embodiments, reactors made of metal or plastic are preferred over glass, which corrodes in the presence of fluoride.

CF ₃ SO ₂ Reaction of F with N-silylazole.

In some embodiments, CF ₃ SO ₂ F may be reacted with N-silylazole. The reaction may be carried out without a solvent or catalyst, but a solvent and/or catalyst may be preferred.

In some embodiments, CF ₃ SO ₂ F may be reacted with N-silylazole, preferably N- (trimethylsilyl) azole. When the N-silylazole is Me ₃ When SiIm is used, the product is CF ₃ SO ₂ Im and Me ₃ SiF。

In some embodiments, CF ₃ SO ₂ F is reacted with N-silylazole and a basic catalyst can be used to produce a catalytic cycle, as shown in FIG. 2. Strong bases can be used at low pressures. The preferred catalyst is the aprotic strong base DBU. DBU is quite inexpensive and miscible with polar solvents and all the N-silylazole pure liquids currently tested. DBU in CF ₃ SO ₂ F is a very effective catalyst in the reaction with N-silylazoles. The molar ratio of DBU to oxazole can be as low as 0.001:1 or less depending on the cooling capacity of the oxazole and the vessel. Aprotic guanidines may also be preferred. Aprotic guanidines cost more than DBU, but they are also effective catalysts, are more heat resistant than DBU, and if necessary, can be recovered by treatment with aqueous hydroxide solutions, unlike DBU.

In some embodiments, a weak base such as triethylamine is used. In these embodiments, high pressure, elevated temperature, or both may be beneficial.

It is not clear whether the DBU or the aprotic guanidine reacts directly with the N-silylazole or whether only traces of the free azole are deprotonated. A small amount of free oxazole can be added to the vessel. This is not presently necessary.

In some embodiments, most preferably noneAnd (4) solvent reaction. For example, CF ₃ SO ₂ F and pure Me ₃ Sitz/DBU (example 1) or Me ₃ The low pressure reaction of the SiIm/DBU (example 2) produced a product in 97% yield.

In some embodiments, when pure Me is allowed ₃ Si-azoles and CF ₃ SO ₂ F reaction at low pressure, keeping the vessel at a low temperature to allow the by-product Me to form ₃ The vapor pressure of SiF (bp ═ 16.4 ℃) does not cause the pressure in the container to be higher than atmospheric pressure.

In some embodiments, the optimal yield is obtained by using the aprotic reactant and the catalyst.

In all embodiments, the best yields are obtained by using anhydrous reactants, catalysts and solvents throughout the process.

Experiment of

All reactions were carried out in a fume hood. The pressure gate, which regulates the pressure in the vessel, performs the addition of low pressure. When the vessel pressure drops below the set pressure, more gas is added until the set pressure is reached. A fluid pressure gauge was also used as the pressure gate display. The course of the reaction is typically monitored by GCMS, which is most reliable for identifying each peak in the trace, but only for its relative amount in the vessel. When a liquid product is obtained, the removal of the more volatile components of the reaction is omitted from the examples and only the product boiling point is provided. The N-silylazole is prepared by reacting oxazole with hexamethyldisilazane.

Example 1: 1- (trifluoromethylsulfonyl) -1,2, 4-triazole (CF) ₃ SO ₂ Tz): to a 250mL, single neck round bottom flask equipped with an air inlet and thermometer was added 1-trimethylsilyl-1, 2, 4-triazole (Me) ₃ Sitz, 79 g, 0.56 mole) and diazabicyclo [5.4.0]Undec-7-ene (DBU, 0.44 g, 2.9 mmol). The container was refrigerated and evacuated to a constant static pressure (1.3 kPa). Adding trifluoromethylsulfonyl fluoride (CF) at 5-16 deg.C under low pressure stirring for more than 1 hr ₃ SO ₂ F, 92.6 g, 0.609 mol). Distilling off the volatile by-product trimethylfluorosilane (Me) in a 40 ℃ water bath under reduced pressure ₃ SiF). The residue is distilled at 63 ℃/2kPa to give the product CF ₃ SO ₂ TZ (109.4 g, 0.54 mol, 97%). GCMS m/e 201, singlet.

Example 2: 1- (trifluoromethylsulfonyl) -imidazole (CF) ₃ SO ₂ Im): to a 250mL, single neck round bottom flask equipped with an air inlet and thermometer was added 1- (trimethylsilyl) imidazole (Me) ₃ SiIm, 57.9 g, 0.41 mol) and DBU (0.26 g, 1.7 mmol). The container was refrigerated and evacuated to a constant static pressure (1.3 kPa). Adding CF under stirring at 3-11 deg.C under low pressure for more than 46 min ₃ SO ₂ F (66.4 g, 0.436 mol). The volatile by-product Me was distilled off under reduced pressure using a 40 ℃ water bath ₃ And (4) SiF. The residue is distilled at 40 ℃/1.3kPa to obtain the product CF ₃ SO ₂ Im (79.7 g, 0.4 mol, 97%). GCMS m/e 200, singlet.

Example 3: CF (compact flash) ₃ SO ₂ TZ. Me was added to a 600mL stirred autoclave ₃ SiTz (38.9 g, 0.28 mol), DBU (0.6g, 0.004 mol) and acetonitrile (200mL), sealed, refrigerated and evacuated to a constant static pressure (4 kPa). Adding CF under pressure over 1 minute ₃ SO ₂ F (41.9g, 0.276 mol), the vessel was raised from 2 ℃ to 17 ℃. The vessel was rapidly reduced to low pressure and stirred overnight at ambient temperature. The next morning, the vessel was evacuated at 8 ℃/33kPa and the majority of volatiles (200g) were distilled into a dry ice trap at 6 ℃ and low pressure. The vessel was then charged with nitrogen, opened, and the contents distilled at 54-57 deg.C/2-2.5 kPa to give a clear colorless liquid product, CF ₃ SO ₂ TZ (43g, 0.21 mol, 78%). GCMS m/e 201, with trace solvent.

Example 4: CF (compact flash) ₃ SO ₂ Im is taken as the reference. A1 liter 4-neck round bottom flask was equipped with an air inlet with 1 thermometer and connected to 1 bubbler, 1 thermometer, 1 large stirrer, 1 powder funnel and stopper. The flask was purged with freshly dried potassium carbonate (K) using a nitrogen flow ₂ CO ₃ 138g, 1 mole), and the funnel was replaced with a septum. Stirring K ₂ CO ₃ And a solution of imidazole (35g, 0.5 mol) in acetonitrile (400mL) was transferred to a stirred vessel via cannula. Replacing the septum with a plug and removing the bubbler from the lineAnd (5) disconnecting. The container was refrigerated and evacuated at 5 ℃ to a constant static pressure (4 kPa). Adding CF at 5-7 deg.C/40-53 kPa for more than 30 minutes ₃ SO ₂ F (80g, 0.53 mol). At the end of the reaction, the vessel was filled with nitrogen, the contents were filtered in a fume hood, and the solid was washed with acetonitrile (250 mL). The combined filtrates were slightly distilled at 30 deg.C/1.2 kPa to give the crude product (64g, 0.32mol, 63%), which was combined with other reactions and then distilled to give the purified product.

Example 5: CF (compact flash) ₃ SO ₂ Im is taken as the reference. A1.00N solution of imidazole (34g, 0.5 mol) in NaOH (500mL) in a 1L single neck round bottom flask was concentrated to dryness and the residue was heated at 200 deg.C/13 Pa for 30 minutes. The vessel was cooled under vacuum and filled with nitrogen. The loose contents were scraped off the flask wall, a stir bar was added, and the flask was then quickly sealed with a septum. Acetonitrile (250mL) was infused through a cannula, the vessel was stirred for a few minutes, and the septum was replaced with a gas inlet. Refrigerating container, evacuating to constant static pressure (5kPa), and adding CF at 40-93kPa for over 75 minutes ₃ SO ₂ F (80g, 0.53 mol). The last fifteen minutes of addition was done without ice and with the vessel warm. The vessel was stirred at room temperature overnight. The next morning, the vessel pressure had dropped to 36 kPa. The vessel was evacuated, filled with nitrogen, and the contents of the vessel were filtered. The filtration process takes several hours and uses a rubber dam. The filtrate was distilled at 38 deg.C/1 kPa to give a crude product (78.4g, 0.39mol, 78%), which was combined with other reactions and then distilled to give a purified product.

Example 6: 1- (trifluoromethylsulfonyl) benzimidazole (CF) ₃ SO ₂ Bzm). A500 mL three necked round bottom flask was equipped with 1 thermometer, stirrer, septum, 1 gas inlet and 1 stopper. A cannula containing 37.6% w/w Me was added to the vessel ₃ Sibzmi (156.6g, 0.31 moles) in acetonitrile, DBU (0.3g, 0.002 moles), and replacing the membrane with a plug. The vessel was stirred, refrigerated and evacuated to a constant static pressure (4 kPa). Adding CF at 5-15 deg.C/40-53 kPa for more than 16 minutes ₃ SO ₂ F (49g, 0.32 mol). The container is stirred and refrigerated for an additional 30 minutes to3 ℃/34kPa, then evacuated to 6kPa and filled with nitrogen. Direct distillation of the material was attempted to obtain solids and liquids. The residue, essentially free of acetonitrile, was dissolved in benzene (100mL) and the solid was filtered off to give a clear colorless filtrate. The filtrate was distilled (56.5 ℃ C./0.6 Pa) to give the product CF ₃ SO ₂ BzIm (72.2g, 0.29 mol, 93%). GCMS m/e 250, singlet.

Example 7: l- (trifluoromethylsulfonyl) benzotriazole (CF) ₃ SO ₂ BzTz). A1-mL 250-mL single-neck round bottom flask was equipped with a stirrer and sealed with a septum. Infusion of Me through cannula ₃ SiBztz (59.9g, 0.31 mole) and DBU (0.07g, 0.5 mmol). The septum was replaced with a gas inlet, the contents of the vessel were stirred, evacuated (0.1kPa) and refrigerated. CF addition at 93kPa for more than one hour ₃ SO ₂ F (46.8g, 0.31 mol). The container immediately turned yellow. The refrigerated container was then evacuated to 0.3kPa and the contents of the container solidified. This crude solid (78.2g, 0.31 mole, 99.5%) was lacrimatory and gave multiple GCMS peaks but showed a well-defined melting point, 37-37.2 ℃. Lit. m.p. ═ 37 ℃.

Example 8: 1- (trifluoromethylsulfonyl) pyrazole (CF) ₃ SO ₂ Pz). To a 1 500mL single neck round bottom flask was equipped with 1 stirrer and Me was added ₃ SiPz (63g, 0.45 moles) and DBU (0.11g, 0.7 mmol), rapidly sealed with a gas inlet, refrigerated and evacuated to 0.4 kPa. Adding CF to a stirred refrigerated vessel at 53-93kPa for more than 24 minutes ₃ SO ₂ F (71.3g, 0.47 mol). The vessel was stirred on ice for a further 30 minutes and the pressure was reduced to 51 kPa. The vessel was then evacuated to 0.8kPa and the contents of the vessel frozen and then melted as the flask warmed. Product CF ₃ SO ₂ Pz distilled off at 48 ℃ under 1kPa as a clear, colorless liquid. Yield, 85.9g (0.43 mol, 95%) GCMS m/e 200, single peak.

Example 9: 1- (trifluoromethylsulfonyl) -2-methylimidazole (CF) ₃ SO ₂ MeIm). To a 1 250mL single neck round bottom flask equipped with 1 stirrer and septum and added N- (trimethylsilyl) -2-methylimidazole (Me) ₃ SiMeIm, 72.7g, 0.47 moles) and DBU (0.6g,4 mmol). The diaphragm is replaced by an air inlet. The container was refrigerated and evacuated to 0.3 kPa. CF addition at 67-72kPa over two hours ₃ SO ₂ F (57.4g, 0.38 mol). The product was distilled off at 46 ℃ C./0.5 kPa as a colorless liquid, and the distillate contained some fine needles (66.8g, 0.31 mol, 82% from CF) ₃ SO ₂ F) .1. the GCMS m/e 214 is a main peak; also present are m/e 154, Me ₃ SiMeIm and other small unidentified peaks. The product is not easily separated from contaminants by further distillation.

Example 10: CF (compact flash) ₃ SO ₂ Tz. 1,2, 4-triazole (22g, 0.32 mol), potassium fluoride (40g, 0.7 mol) and acetonitrile (300mL) were charged to a 600mL stirred autoclave, sealed, refrigerated and evacuated (4.5 kPa). CF is treated at 8-24 ℃/73-80kPa for more than 1 hour ₃ SO ₂ F (50.2g, 0.33 mol) was added to a stirred vessel. The vessel was then stirred for an additional 10 minutes and lowered to 8 deg.C/46 kPa. The vessel was then evacuated, filled with nitrogen, and the contents filtered. Distilling the filtrate at 44 ℃/1.2kPa to obtain the product CF ₃ SO ₂ Tz (30.3g, 0.15 mol, 47%). The remaining solid in the vessel (13g) consisted predominantly of triazole.

Example 11: 1- (trifluoromethylsulfonyl) -3, 5-dimethylpyrazole (CF) ₃ SO ₂ Me ₂ Pz). A1-mL 250-mL single-neck round-bottom flask was equipped with 1 stirrer and 1 septum, and N- (trimethylsilyl) -3, 5-dimethylpyrazole (65.2g, 0.39 mole) and DBU (0.27g, 0.004 mole) were added via cannula. The membrane was quickly replaced with a vacuum adapter, the container was evacuated to a constant static pressure (0.4kPa), and refrigerated. CF at 93kPa for more than 20 minutes ₃ SO ₂ F (62.6g, 0.041 mol) was added to a stirred refrigerated container. The vessel was stirred on ice for a further 15 minutes until the pressure stabilized (64 kPa). The volatiles (3kPa) were withdrawn while warming to room temperature. The vessel contents were filtered to remove a small amount of solid and a clear colorless filtrate (85g) was distilled off at 56 deg.C/0.16 kPa to give the pure product CF ₃ SO ₂ Me ₂ Pz (82.3g, 0.36 mol, 93%) as a clear colorless liquid. GCMS m/e 228, singlet.

Although the subject matter has been described in terms of exemplary embodiments, it is not so limited. Rather, the appended claims are to be construed broadly, including other variants and embodiments, which may be made by those skilled in the art.

Claims (25)

1. A method, comprising:

reacting trifluoromethane sulfonyl fluoride (CF) ₃ SO ₂ F) Reacting with an N-silylazole, wherein the N-silylazole has an azole structure, and the azole structure is protic in the free state; and

separation of having CF ₃ SO ₂ -N- (trifluoromethylsulfonyl) azoles of azole formula.

2. The method according to claim 1, wherein the azole structure is selected from the group consisting of imidazole, pyrazole, 1,2, 4-triazole, benzimidazole, benzotriazole, indazole, 2-methylimidazole, 2-methylbenzimidazole, 3, 5-dimethylpyrazole, and substituted derivatives.

3. The method of claim 1, wherein the N-silylazole is an N- (trialkylsilyl) azole.

4. The method of claim 3, wherein the N- (trialkylsilyl) azole is an N- (trimethylsilyl) azole.

5. The process of claim 1, wherein CF is reacted in the presence of a catalyst ₃ SO ₂ F is reacted with the N-silylazole.

6. The method of claim 5, wherein the catalyst comprises a compound containing reactive fluoride.

7. The process of claim 1, wherein CF is reacted in the presence of a basic catalyst ₃ SO ₂ F is reacted with the N-silylazole.

8. The process of claim 7, wherein the basic catalyst is a protic azole or an azole salt anion thereof.

9. The method of claim 7, wherein the basic catalyst comprises an organic aprotic base selected from the group consisting of tertiary amines, aprotic amidines, aprotic isothioureas, aprotic phosphazenes, aprotic guanidines, and combinations thereof.

10. The method of claim 9, wherein the organic aprotic base is selected from diazabicyclo (5.4.0) undec-7-ene, pentamethylguanidine, and tetramethyl-tert-butylguanidine.

11. The method of claim 7, wherein the basic catalyst comprises a compound selected from the group consisting of metal carbonates, metal fluorides, metal hydrides, alkyllithium, grignard reagents, hydroxides, alkoxide anionic compounds, and combinations thereof.

12. The method of claim 7, wherein the basic catalyst comprises a reactive fluoride-containing compound.

13. The process of claim 1, wherein CF is reacted in the presence of an aprotic solvent ₃ SO ₂ F is reacted with the N-silylazole.

14. A method, comprising:

reacting trifluoromethane sulfonyl fluoride (CF) ₃ SO ₂ F) With an azole, or an azole salt of the azole, wherein the azole is in the free state is protic; and

separation of a gas having CF ₃ SO ₂ -N-trifluoromethanesulfonyl azoles of azole formula.

15. The method according to claim 14, wherein the azole structure is selected from the group consisting of imidazole, pyrazole, 1,2, 4-triazole, benzimidazole, benzotriazole, indazole, 2-methylimidazole, 2-methylbenzimidazole, 3, 5-dimethylpyrazole, and substituted derivatives.

16. The method of claim 14 wherein the azolium salt has a metal cation selected from the group consisting of lithium, sodium, potassium, cesium, magnesium, and combinations thereof.

17. The process of claim 14, wherein the azolium salt is derived from an azole and a metal base selected from the group consisting of metal hydrides, metal alkoxides, metal hydroxides, metal carbonates, metal fluorides, alkyl lithiums, grignard reagents, and combinations thereof.

18. The method of claim 14, wherein the azolium salt is derived from an azole and a metal carbonate, the metal selected from the group consisting of lithium, sodium, potassium, cesium, magnesium, and combinations thereof.

19. The method of claim 14, wherein the azolium salt is derived from an azole and a metal fluoride selected from the group consisting of sodium, potassium, cesium, and combinations thereof.

20. The method of claim 14, wherein the azolium salt is from an azole and an aprotic base, or a protic azole as a base.

21. The method of claim 14, wherein the azolium salt is derived from an azole and an aprotic organic base.

22. The method of claim 14, wherein CF is brought to atmospheric or subatmospheric pressure ₃ SO ₂ F is reacted with the oxazole or oxazole salt.

23. The method of claim 14, wherein CF is reacted in the presence of an aprotic solvent ₃ SO ₂ F is reacted with the oxazole or the oxazole salt.

24. The method of claim 23, wherein the aprotic solvent is acetonitrile.

25. A compound which is 1- (trifluoromethylsulfonyl) -3, 5-dimethylpyrazole or 1- (trifluoromethylsulfonyl) -2-methylimidazole.