Patent Description:
The amide motif is of central importance, impacting all sciences, life, medicine and modern society. It is a preferred building block of nature and a key unit that controls stability, 3D-structure and hence function of proteins or peptides, and consequently also biological processes or related applications, such as catalysis.

The closely related compound families, e.g. carbamates and ureas, are similarly influential, finding applications as insecticides, in polymers (foams, elastomers, polyurethanes), as preservatives, cosmetics and in medical treatment as, for example, chemotherapy and HIV agents.

Fluorinated compounds play an eminent role, especially but not limited to the pharmaceutical field due to the steric similarity but different chemical/physical behaviour between fluorine and hydrogen and thus methods for the specific synthesis of fluorinated compounds are subject of immense research.

<NPL>, describes the reaction of isothiocyanates providing a new general route to difluoroazomethines and being particularly useful for preparing N-aryldifluoroazomethines which are trapped as N-(trifluoromethyl)-N-(fluoroformyl)anilines by carbonyl fluoride addition.

Due to the importance of amides and related compounds, there is a constant need for methods for the synthesis of fluorinated amides and related compounds, especially compounds which comprise an N-CF<NUM> motif. Additionally, there is a significant demand for novel compounds having such an N-CF<NUM> motif.

This object is met by the method of Claim <NUM> of the present invention. Accordingly, a method for the synthesis of N-trifluoromethylcarbonyl compounds having the structure R-N(CF<NUM>)CO-LG, whereby R is an organic moiety from isothiocyanates R-NCS and LG is a leaving group is provided, comprising the step a).

Surprisingly, it has been found that by doing so for many isothiocyanates a conversion into N-trifluoromethylcarbonyl compounds can be observed. For most applications within the present invention, at least one of the following advantages could be observed:.

The term "organic moiety" especially means and/or includes a structure whereby a carbon atom is adjacent to the N(CF<NUM>)CO-unit and bound to that unit with a single bond.

The term "leaving group" especially means and/or includes any chemical moiety which is able to depart with a pair of electrons in heterolytic bond cleavage. Especially preferred leaving groups are halogens, here especially preferred fluoride and/or chloride, sulfonic esters, especially tosylates, heterocyclic compounds, especially imidazoles. Especially preferred are fluoride and chloride.

The term "electrophilic C<NUM>-compound" especially means and/or includes a compound of the chemical structure LG<NUM>-CO-LG<NUM> whereby LG<NUM> and LG<NUM> are independently from each other leaving groups, including leaving groups as above. However, also preferred in this context are leaving groups of the structure -OCHal<NUM>, whereby Hal is halogen, especially fluoride and/or chloride. The resulting compounds, e.g. Hal<NUM>C-O(CO)O-CHal<NUM> have the advantage that they in the course of the reaction will form two compounds Hal-CO-Hal (as known e.g. from triphosgene, the compound with Hal=Cl) which themselves are electrophilic C<NUM>-compounds. Similarly a compound where only LG is -OCHal<NUM> will form additionally (only) one compound Hal-CO-Hal (e.g. known from diphosgene, Cl-CO-OCl<NUM>).

AgF can be used either directly or in its components, i.e. via a cationic silver component (e.g. AgNO<NUM>, AgOTf) and nucleophilic fluoride (e.g. KF, NaF).

It should be noted that the isothiocyanate R-NCS and/or the electrophilic C<NUM>-compound and/ or the AgF may be formed in situ during the course of the reaction. Therefore it is a preferred embodiment of the present invention that the method comprises another step a0) which is performed before step a).

According to a preferred embodiment of the present invention, AgOCF<NUM> is used to directly transform R-NCS to N-CF<NUM> carbamoyl fluorides. The AgOCF<NUM> generates AgF and COF<NUM> in situ.

Other OCF<NUM>-containing compounds can also be used as COF<NUM> source.

It is especially advantageous that the molar ratio of AgOCF<NUM> to isothiocyanate is ≥<NUM>, preferably ≥ <NUM> to ≤ <NUM>, more preferred ≥ <NUM> to ≤ <NUM>,<NUM>, most preferred ≥ <NUM> to ≤ <NUM>.

The AgOCF<NUM> itself can be provided in substance or itself be generated in situ (either in a separate step or during step a0).

According to a further preferred embodiment of the present invention, AgF is formed in situ by cross-reaction of a silver salt and a nucleophilic fluoride compound, whereby suitable silver salt precursors include AgOTf, AgNO<NUM>, Ag halides (other than fluoride) and nucleophilic fluoride compounds include tetraalkylammonium fluorides and alkali fluorides. The fluoride can also be formed in situ from an organic compound that contains fluoride by suitable chemical transformation, e.g. by a nucleophilic aromatic substitution reaction of a suitable aryl fluoride with a nucleophile or by displacement from alternative fluorine containing compounds, such as, for example R-SO<NUM>-F.

Without being bound to any chemical theory, the inventors believe that when an excess of AgF is used (cf. the further description) then in most applications of the present invention a conversion of the isothiocyanate to an N-trifluoromethylcarbamoyl fluoride occurs according to the mechanism shown in <FIG> of this application for a special embodiment of the present invention:
Accordingly, the sulfur of the isothiocyanate is replaced by two fluorides via an exchange reaction with the AgF, which subsequently reacts to Ag<NUM>S. Thus a compound of the structure R-N=CF<NUM> is formed. Additional fluoride forms the CF<NUM>-unit following a nucleophilic attack of the nitrogen to the carbon of the electrophilic C<NUM>-compound. If fluoride is used in excess, then another substitution leads to the N-trifluoromethylcarbamoyl fluoride.

According to a preferred embodiment of the present invention, in step a) the molar ratio of effective electrophilic C<NUM> compound to isothiocyanate is ≥<NUM> to ≤ <NUM>, preferably ≥ <NUM> to ≤ <NUM>. The term "effective" means that if in the course of the reaction the additional electrophilic C<NUM> compound is formed then this is taken into account, e.g. when triphosgene is used as electrophilic C<NUM> compound then the amount of effective electrophilic C<NUM> compound is three times the amount of triphosgene. When diphosgene Cl-CO-OCl<NUM> is used, the effective electrophilic C<NUM> compound is twice the amount of diphosgene.

According to a preferred embodiment step a) is carried out in the presence of one or more additional fluoride compounds, which are preferably used in a molar ratio of ≥<NUM> (compared to the isothiocyanate). Preferred fluorine compounds are alkali and earth alkali fluorides, especially LiF, NaF, KF, RbF, CsF, CaF<NUM>, MgF<NUM>, fluorides from quaternary amines, especially TMAF and TBAF (NMe<NUM>F, NBu<NUM>F) and other metal fluorides, especially CuF<NUM>. Preferably the fluorine compound is used in a molar ratio of this fluorine compound to the isothiocyanate in ≥<NUM>, still preferred ≥<NUM> and most preferred ≥<NUM> to ≤ <NUM>.

According to a preferred embodiment of the present invention, in step a) the molar ratio of AgF to isothiocyanate in step a) is ≥<NUM>, preferably ≥ <NUM> to ≤ <NUM>. When doing so usually the N-trifluoromethylcarbamoyl fluoride is formed, as described above. In many cases the yields are so high that AgF can be used as sole fluorine compound which is therefore an embodiment of the present invention.

However, according to an alternative preferred embodiment of the present invention, in step a) the molar ratio of AgF to isothiocyanate is ≥<NUM> to ≤ <NUM>. When doing so then - in case no further fluoride compound is present, which is, however, a preferred embodiment of the invention - in many applications in the product R-N(CF<NUM>)CO-LG the moiety LG will be the LG of the electrophilic C<NUM>-compound or a mixture of this compound with N-trifluoromethylcarbamoyl fluoride can be observed as reaction products. It goes without saying that in case the leaving group of the electrophilic C<NUM>-compound is -OCHal<NUM> then of course LG will be Hal.

Yet another to an alternative preferred embodiment of the present invention in step a) the molar ratio of AgF to isothiocyanate is ≥<NUM> and another fluorine compound is used in a molar ratio of ≥<NUM> (compared to the isothiocyanate). Also here, depending on the fluoride concentration, in many applications in the product R-N(CF<NUM>)CO-LG the moiety LG will be the LG of the electrophilic C<NUM>-compound or a mixture of this compound with N-trifluoromethylcarbamoyl fluoride can be observed as reaction products.

Preferably step a) is carried out in an organic nonpolar or dipolar aprotic solvent. Especially preferred are nitrile-based solvents, especially acetonitrile, benzonitrile, propionitrile, ether-based solvents, especially glyme, diglyme, triglyme, MeTHF, Et<NUM>O, THF, dioxane, NMP, DCM, toluene, THF with acetonitrile being most preferred.

Preferably step a) is carried out at a temperature of ≥ <NUM> and ≤ <NUM>, more preferred ≥ <NUM> and ≤ <NUM>. In case that AgOCF<NUM> is used as an AgF and/or COF<NUM> precursor, preferably the method is carried out at a temperature of ≥ <NUM> and ≤ <NUM>, more preferred ≥ <NUM> and ≤ <NUM>.

The object of the present invention is furthermore met by the method of Claim <NUM> of the present invention. Accordingly a method for the synthesis of N-trifluoromethyl amides is provided comprising the step of contacting a compound R-N(CF<NUM>)CO-LG, with R and LG as defined above, with a organometallic compound.

Surprisingly it has been shown that by doing so, N-trifluoromethyl amides can be obtained in excellent yields for many applications. For most applications within the present invention, at least one of the following advantages could be observed:.

Preferred metal-organic compounds are organomagnesium compounds (Grignard Reagents), organolithium compounds and organozinc compounds.

Preferably the method is carried out in an organic nonpolar or dipolar aprotic solvent. Especially preferred are DCM, Et<NUM>O, toluene, THF with toluene being most preferred.

Preferably the method is carried out at a temperature of ≥ -<NUM> and ≤ <NUM>, more preferred ≥ <NUM> and ≤ <NUM>.

The object of the present invention is furthermore met by the method of claim <NUM> of the present invention. Accordingly a method for the synthesis of N-trifluoromethyl ureas, N-trifluoromethyl carbamates, N-trifluoromethyl thiocarbamates and/or N-trifluoromethyl selenocarbamates is provided, comprising the step of reacting a compound R-N(CF<NUM>)CO-LG, whereby R is an organic moiety and LG is a leaving group, with an amine, alcohol, thiol and selenol, whereby the compound R-N(CF<NUM>)CO-LG is prepared as described above.

Surprisingly it has been shown that by doing so these compounds can be obtained in excellent yields for many applications. For most applications within the present invention, at least one of the following advantages could be observed:.

N-trifluoromethyl carbamates and/or N-trifluoromethyl thiocarbamates which are both very suitable compounds, especially in the pharma sector, are so far unknown, same as selenocarbamates derivatives. Many of them have, however, shown to have a greater stability than their N-methyl-counterparts. Therefore, the present invention also relates to compounds of the structure R-N(CF<NUM>)-CO-X-R' with R and R' being organic moieties and X being S, O or Se.

Preferably the method is carried out in an organic nonpolar or dipolar aprotic solvent. Especially preferred are DCM, Et<NUM>O, toluene, THF with DCM and THF being most preferred.

Preferably the method is carried out at a temperature of ≥ <NUM> and ≤ <NUM>, more preferred ≥ <NUM> and ≤ <NUM>.

Preferably the method is carried out using a base in an amount of ≥ <NUM> and ≤ <NUM> equivalents, relative to the reactant R-N(CF<NUM>)CO-LG. Preferred bases are inorganic bases such as, carbonate, bicarbonate and phosphate, such as cesium carbonate, sodium bicarbonate and potassium phosphate, tertiary amines, especially trialkylamines such as triethylamine, Hünig's base (N,N-diisopropylethylamine), N-methylmorpholine, pyridine, <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU), <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]non-<NUM>-ene (DBN), <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]octane (DABCO) or mixtures thereof.

Preferably the method is carried out using ≥ <NUM> and ≤ <NUM> equivalents (relative to the reactant R-N(CF<NUM>)CO-LG) of a nucleophilic catalyst selected out of the group comprising pyridine-based catalysts, especially pyridine and DMAP and five-membered N-heterocyclic compounds, especially imidazole. This has shown to furthermore increase yields in many embodiments of the invention.

It goes without saying that in the two methods described before the reactant R-N(CF<NUM>)CO-LG is preferably synthesized as described before, which is insofar a preferred embodiment of the invention. Therefore the present invention relates to a method comprising the steps:.

The aforementioned components, as well as the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept such that the selection criteria known in the pertinent field can be applied without limitations.

Additional details, characteristics and advantages of the object of the invention are disclosed in the sub-claims and the following description of the respective examples -which in an exemplary fashion--show preferred embodiments according to the invention.

A <NUM> vial was charged with the isothiocyanate (<NUM> mmol, <NUM> equiv. ), silver fluoride (<NUM> mmol, <NUM> equiv. ) and triphosgene (<NUM>, <NUM> mmol, <NUM> equiv. Acetonitrile (<NUM>) was added quickly and the vial was sealed (if the isothiocyanate was a liquid or an oil it was added as a solution in the solvent). The mixture was stirred at room temperature. Afterwards the crude mixture was added at once to Et<NUM>O (<NUM>) and stirred for <NUM> minutes. The solid was filtered through celite and the solvents were then evaporated. The obtained crude material was dissolved in Et<NUM>O and filtered on a pad of celite again to remove the last traces of salt byproducts. The N-trifluoromethylcarbamoyl fluoride was then obtained in a technical grade purity ranging from <NUM> to <NUM>%.

Using this general procedure, the following compounds <NUM> to <NUM> were synthesized:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

Exemplarily the synthesis of compound <NUM> is described in more detail:
[<NUM>,<NUM>'-Biphenyl]-<NUM>-yl-N-trifluoromethylcarbamoyl fluoride <NUM> : The title compound was obtained as a white solid after <NUM> in <NUM>% yield (<NUM>) using <NUM>-isothiocyanato-<NUM>,<NUM>'-biphenyl (<NUM>) following the general procedure for N-trifluoromethylcarbamoyl fluorides. : <NUM>-<NUM>. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM> (brs, 1F), -<NUM> (brs, 3F). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM> (d, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (q, J = <NUM>). MS (70eV, EI): m/z (%): <NUM> (<NUM>) [M+], <NUM> (<NUM>), <NUM> (<NUM>). HRMS (EI) calculated for C<NUM>H<NUM>ONF<NUM>: <NUM> [M-F]+, Found: <NUM>.

A <NUM> vial was charged with the N-trifluoromethylcarbamoyl fluoride (<NUM> mmol, <NUM> equiv. ), toluene (<NUM>) and placed into a water bath at room temperature. The corresponding Grignard reagent (<NUM> mmol, <NUM> equiv. ) was subsequently added to the solution. The reaction mixture was stirred for <NUM> minutes at room temperature. Saturated aqueous ammonium chloride solution (<NUM>) was then added. The phases were separated and the aqueous phase was further extracted with EtOAc (2x), dried over MgSO<NUM> and concentrated under reduced pressure. The obtained crude material was then purified by column chromatography.

Using this general procedure the compounds <NUM> to <NUM> were synthesized:
<CHM>
<CHM>
<CHM>
<CHM>.

Exemplarily the synthesis of compound <NUM> is described in detail:
<NUM>-Chloro-<NUM>-(N-(trifluoromethyl) thiophene-<NUM>-carboxamido)phenyl trifluoromethanesulfonate <NUM> : The title compound was obtained as a colorless oil in <NUM>% yield (<NUM>) using <NUM>-chloro-<NUM>-((fluorocarbonyl)(trifluoromethyl)amino)phenyl trifluoromethanesulfonate <NUM> (<NUM>) with <NUM>-thienylmagnesium bromide (<NUM>µL, <NUM> in THF) after column chromatography on silica gel with EtOAc/hexane (<NUM>/<NUM>, Rf = <NUM>). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>). <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM> (s, 3F), -<NUM> (s, 3F). <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (q, J = <NUM>), <NUM> (q, J = <NUM>). HRMS (ESI) calculated for C<NUM>H<NUM>O<NUM>N<NUM>ClF<NUM>Na<NUM>S<NUM>: <NUM> [M+Na]+, Found: <NUM>.

A <NUM> vial was charged with the N-trifluoromethylcarbamoyl fluoride (<NUM> mmol, <NUM> equiv. ) and CH<NUM>Cl<NUM> (<NUM>). The corresponding amine (<NUM> mmol, <NUM> equiv. ), Hunig's base (<NUM>µL, <NUM> mmol, <NUM> equiv. ) and DMAP (<NUM>, <NUM> mmol, <NUM> equiv. ) were subsequently added to the solution. The reaction mixture was stirred for <NUM> at room temperature. Hexane (<NUM>) was then added and the reaction mixture was filtered through a pad of celite before evaporation. The obtained crude material was then purified by column chromatography.

To challenge the stability of N-CF<NUM> amides, we subjected amide <NUM> to a solution of <NUM> HCl and also <NUM> NaOH at <NUM> for <NUM> (in <NUM>:<NUM> THF/H<NUM>O) and observed essentially no decomposition, whereas the corresponding N-Me and N-H analogues showed decomposition. This suggests that many N-trifluoromethyl amides are more stable than their 'conventional' amide counterparts.

A <NUM> vial was charged with the N-trifluoromethylcarbamoyl fluoride (<NUM> mmol, <NUM> equiv. ) and CH<NUM>Cl<NUM> (<NUM>). The corresponding alcohol (<NUM> mmol, <NUM> equiv. ), Hunig's base (<NUM>µL, <NUM> mmol, <NUM> equiv. ) and DMAP (<NUM>, <NUM> mmol, <NUM> equiv. ) were subsequently added to the solution. The reaction mixture was stirred for <NUM> at room temperature. Hexane (<NUM>) was then added and the reaction mixture was filtered through a pad of celite before evaporation. The obtained crude material was then purified by column chromatography.

A <NUM> vial was charged with the N-trifluoromethylcarbamoyl fluoride (<NUM> mmol, <NUM> equiv. ) and THF (<NUM>). The corresponding sodium thiolate or selenolate (<NUM> mmol, <NUM> equiv. ) was subsequently added to the solution. The reaction mixture was stirred for <NUM> at room temperature. Hexane (<NUM>) was then added and the reaction mixture was filtered through a pad of celite before evaporation. The obtained crude material was then purified by column chromatography.

Using the above general methods, the following compounds <NUM> to <NUM> were synthesized:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

Exemplarily the synthesis of compound <NUM> is described in greater detail:
Methyl (S)-<NUM>-(<NUM>-(<NUM>-bromo-<NUM>-chlorophenyl) -<NUM>-(trifluoromethyl)ureido)-<NUM>-(((S)-<NUM>-methoxy-<NUM>-oxo-<NUM>-phenylpropan-<NUM>-yl)amino)-<NUM>-oxobutanoate <NUM> : The title compound was obtained as a colorless oil in <NUM>% yield (<NUM>) using (<NUM>-bromo-<NUM>-chlorophenyl)-N-trifluoromethylcarbamoyl fluoride <NUM> (<NUM>) with methyl (S)-<NUM>-amino-<NUM>-(((S)-<NUM>-methoxy-<NUM>-oxo-<NUM>-phenylpropan-<NUM>-yl)amino)-<NUM>-oxobutanoate hydrochloride [aspartame-OMe. HCl] (<NUM>) in presence of N,N diisopropylethylamine [Hunig's base] (<NUM>µL, <NUM> mmol, <NUM> equiv. ) after column chromatography on silica gel with EtOAc/hexane (<NUM>/<NUM>, Rf = <NUM>). [α]D = +<NUM> (c = <NUM> , CHCl<NUM>, <NUM>). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>). <NUM>F NMR (<NUM>, CDCl<NUM>) δ -<NUM>. <NUM>C NMR (<NUM>, CDCl<NUM>) δ <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> (q, J = <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. HRMS (ESI) calculated for C<NUM>H<NUM><NUM>Br<NUM>ClF<NUM>N<NUM>NaO<NUM>: <NUM> [M+Na]+, Found: <NUM>.

Claim 1:
A method for the synthesis of N-trifluoromethylcarbonyl compounds having the structure R-N(CF<NUM>)CO-LG, whereby R is an organic moiety and LG is a leaving group, from isothiocyanates R-NCS, comprising the step of
a) contacting the isothiocyanate R-NCS with AgF and an electrophilic C<NUM>-compound where the carbon is in the formal oxidation state (+IV).