Catalysts for chemical reactions in water-surfactant mixtures

Abstract

This invention relates to reaction mixtures comprising water-surfactant mixtures, wherein the catalyst comprises a compound having a solubilizing group. This technique improves the solubility of the reactants in the water-surfactant mixture, thereby significantly increasing the productivity and selectivity of the chemical reaction.

Description

Technical Field

[0001] This invention relates to improving chemical reactions using a surfactant-water reaction medium. The solubility of the reactants is increased by modifying the catalyst compound with solubilizing groups. This significantly enhances the yield and selectivity of the chemical reaction. Therefore, this invention relates to chemical reaction mixtures comprising separately modified catalyst compounds and surfactant-water mixtures. Background Technology

[0002] The identification of sustainable, harmless solvents for general purposes has been a focus of attention for many chemical communities worldwide for decades. This is not only because well-known ozone-depleting chlorinated solvents were labeled many years ago, but also because the reproductive toxicity of such commonly used polar aprotic solvents such as DMF, DMAC, or NMP has become apparent. To address this particular topic, numerous groups around the world have followed a variety of more or less general strategies, such as developing novel solvents that produce solvents like bio-based polystyrene, or ethers like CPME or the more potent MeTHF, other harmless derivatives of problematic solvents developed directly by chemical manufacturers, ionic liquids, or more complex systems utilizing compressed gases or phase-transfer catalysis, convertible solvents, and fluorinated systems. While timely success stories can be found and have occasionally proven to be of great benefit, generalization has lagged behind. Unfortunately, this has not yet led to the necessary shift in mindset. For example, time-critical experiments continue to rely on, for example, the most established, but undesirable, DMF or NMP. This is even more critical and relevant in the pharmaceutical industry, where the physical properties of the target compound often exhibit limited solubility.

[0003] Professor Lipshutz has developed a method to replace undesirable polar aprotic solvents, revealing his latest application of harmless design surfactant chemistry.

[0004] However, there is a need in the field to improve the chemical reactions in surfactant solvent systems to increase productivity and reduce unwanted byproducts. Summary of the Invention

[0005] This invention is based on the discovery that in reaction mixtures using surfactant-water mixtures as the reaction medium, solubilizing groups attached to the catalyst compound significantly enhance the solubilization of the reaction couple. This has a substantial impact on the productivity and selectivity of the reaction. In particular, highly promising results are shown when alkyl and poly(ethylene glycol) groups of medium length are attached to the complexed ligands of coupling agents or metal catalysts.

[0006] In a first aspect, the present invention provides a reaction mixture comprising one or more reactants, a catalyst, and a surfactant-water mixture, wherein the catalyst is (a) a coupling agent comprising one or more solubilizing groups; or (b) a metal ion complexed with a ligand comprising one or more solubilizing groups; wherein the solubilizing group comprises a C5-50 alkyl group or a poly(alkylene glycol) group having 2 to 20 repeating units.

[0007] In a second aspect, the present invention provides a method for carrying out a chemical reaction, the method comprising the following steps:

[0008] (a) Providing a reaction mixture according to a first aspect of the invention, and

[0009] (b) Allow the chemical reaction to proceed.

[0010] In a third aspect, the present invention provides a method for increasing the yield of a chemical reaction and / or reducing the amount of byproducts generated in the chemical reaction, wherein the chemical reaction is carried out in a surfactant-water mixture, the method comprising the following steps:

[0011] (a) A reaction mixture comprising one or more reactants, a catalyst, and a surfactant-water mixture, wherein the catalyst is a coupling agent comprising one or more solubilizing groups or a metal ion complexed with a ligand comprising one or more solubilizing groups; wherein the solubilizing group comprises C 5-50 Alkyl groups or poly(alkylene glycol) groups having 2 to 20 repeating units; and

[0012] (b) Allow the chemical reaction to proceed.

[0013] The above aspects can be combined. Other objects, features, advantages, and aspects of the invention will become apparent to those skilled in the art from the following description and appended claims. However, it should be understood that the following description, appended claims, and specific examples indicating preferred embodiments of the application are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will readily become apparent to those skilled in the art upon reading the following. Detailed Implementation

[0014] In a first aspect, the present invention provides a reaction mixture comprising one or more reactants, a catalyst, and a surfactant-water mixture, wherein the catalyst is (a) a coupling agent comprising one or more solubilizing groups; or (b) a metal ion complexed with a ligand comprising one or more solubilizing groups; wherein the solubilizing group comprises a C5-50 alkyl group or a poly(alkylene glycol) group having 2 to 20 repeating units.

[0015] The technology of this invention is applicable to all chemical reactions that can be carried out in media containing surfactant-water mixtures. It is particularly applicable to organic chemistry, for example, compounds having at least a partial hydrophobicity. Exemplary suitable chemical reactions include those selected from the group consisting of: cross-coupling reactions such as Suzuki cross-coupling, Suzuki-Miyaura cross-coupling, Sonogashira cross-coupling, Heck cross-coupling, Buchwald-Hartwig cross-coupling, Negishi cross-coupling, Stille cross-coupling, Miyauura borylation, Hiyama cross-coupling, Chan-Ma cross-coupling, and olefin translocation; copper-mediated cross-coupling, nickel-mediated cross-coupling, nucleophilic substitution such as nucleophilic aromatic substitution (S... N Ar); electrophilic halogenation, aromatic and heteroaromatic halogenation; biocatalytic conversion; amidation; oxidation; reduction, such as reduction of nitro groups, oxime groups, azide groups, nitrile groups and amide groups; hydrolysis of nitrile and imine; hydrogenation and debenzylation. In some embodiments, the chemical reaction is amidation. In these embodiments, the catalyst is preferably a coupling agent. The reactants and catalyst present in the reaction mixture are suitable for the specific chemical reaction. In particular, the reactants and catalyst are specifically selected so that the chemical reaction can be carried out.

[0016] The surfactant in the surfactant-water mixture can be any surfactant. In particular, the surfactant should not interfere with the chemical reaction. In some embodiments, the surfactant is a nonionic surfactant. Surfactants are typically amphiphilic and comprise both hydrophilic and hydrophobic moieties. In specific embodiments, the surfactant is capable of forming micelles in the surfactant-water mixture.

[0017] In some embodiments, the hydrophilic portion of the surfactant comprises a polyalkylene glycol portion, particularly a polyethylene glycol portion or a polypropylene glycol portion. The polyalkylene portion, particularly the polyethylene glycol portion, may have an average molecular weight in the range of about 100 to about 10,000 g / mol, particularly in the range of about 300 to about 3,000 g / mol, and especially in the range of about 400 to about 2,000 g / mol. Some examples of surfactants containing a polyalkylene glycol moiety include tocopherol polyethylene glycol succinates (TPGS), particularly DL-α-tocopherol polyethylene glycol succinates such as TPGS-750-M, TPGS-1000, TPGS-1500, TPGS-400, TPGS-1100-M, TPGS-2000, TPGS-860-oleate, TPGS-PEG-PPG-PEG-1100 and TPGS-PPG-PEG-70-butyl, and DL-α-tocopherol polyethylene glycol succinates such as TPPG-1000 and PPG-1000-butyl; Triton X-100; polyethylene glycol alkyl ethers such as Brij surfactants, particularly Brij 30, Brij 35, Brij 52, Brij 56, Brij 58, Brij 72, Brij 76, Brij 78, Brij 92, and Brij 98. 96, Brij 98, Cremophor A6, Cremophor A25 and Thesit; polyethylene glycol esters such as polyethylene glycol (15)-hydroxystearate (Solutol HS15); polyethylene glycol dehydrated sorbitan fatty acid esters, also known as polysorbates or Tween, such as polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85 and polysorbate 120; cholesterol PEG succinates such as cholesterol PEG1000 succinate; (deoxy)cholic acid PEG such as cholic acid PEG1000 and deoxy-cholic acid PEG1000; chromoalkyl alcohol polyethylene glycol succinates such as pigment-400 and pigment-1000; β-sitosterol methoxyethylene glycol succinate (Nok); and other derivatives of PEG such as C4-azo-PEG. In specific embodiments, the surfactant is DL-α-tocopherol polyethylene glycol succinate, particularly TPGS-750-M.

[0018] In addition, other surfactants may be used, including, for example, hexadecyltrimethylammonium bromide (CTAB); phase transfer surfactants (PTS) such as sodium deoxycholate; polyoxyethyl panthenol sebacate (PQS) and functionalized PQS; and octanoic acid and other long alkyl chain acids, especially C6-C20 alkyl chain acids.

[0019] The concentration of the surfactant in the surfactant-water mixture is particularly in the range of 0.1% to 10% (w / w). In some embodiments, the concentration of the surfactant in the surfactant-water mixture is in the range of 0.5% to 5% (w / w), particularly in the range of 0.8% to 4% (w / w), 1% to 3% (w / w), or 1.5% to 2.5% (w / w), such as about 2% (w / w). In specific embodiments, the concentration of the surfactant in the surfactant-water mixture is higher than its critical micelle concentration.

[0020] The catalyst in the reaction mixture is a coupling agent containing one or more solubilizing groups or a metal ion complexed with a ligand containing one or more solubilizing groups. Suitable catalysts and ligands are known in the art and can be readily selected by those skilled in the art. The coupling agent or the metal ion complexed with the ligand is not limited to a specific compound, as long as it is suitable for catalyzing a chemical reaction in which the reactants become the desired product. Therefore, the choice of catalyst depends on the type of chemical reaction to be carried out in the reaction mixture.

[0021] In embodiments where the catalyst is a coupling agent, it is particularly a coupling agent for amide formation. Specifically, it can be selected from the group consisting of: (i) coupling agents that couple via activated esters, such as carbodiimides, particularly N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide and 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide; phosphonium salts, particularly (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate and (benzotriazol-1-yloxy)-tris(pyrrolidine)-phosphonium hexafluorophosphate; guanidinium and ureonium salts, particularly N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)ureonium hexafluorophosphate, N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]- N-methylmethane-ammonium hexafluorophosphate N-oxide, N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethane-ammonium tetrafluoroborate N-oxide, 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyltetrafluoroborate ureonium and O-[(cyano(ethoxycarbonyl)-methyleneamino]-N,N,N',N'-tetramethyltetrafluoroborate ureonium; and triazine compounds, particularly cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; and (ii) coupling agents coupled by boron substances such as boric acid and 3-nitrophenylboronic acid.

[0022] In some embodiments, the coupling agent is a 1,3,5-triazine derivative. The 1,3,5-triazine derivative may contain a quaternary ammonium, which may be specifically attached to the 2-position of the triazine ring. The quaternary ammonium can be formed by a trialkylamino group such as trimethylamino, or an N-alkyl-N-morpholino group such as N-methyl-N-morpholino, attached to the triazine ring. Furthermore, the 1,3,5-triazine derivative may be substituted with methyl, ethyl, propyl, methoxy, ethoxy, and / or propoxy groups, particularly at the 4- and / or 6-positions of the triazine ring. In some embodiments, the one or more solubilizing groups are attached to the quaternary ammonium and / or the 4- and / or 6-positions of the triazine ring.

[0023] In a specific embodiment, the coupling agent has the general formula (I).

[0024]

[0025] in

[0026] R1 is -N + (R3)3;

[0027] R2 is independently a C1-5 alkoxy, C1-5 alkyl, hydroxyl, an amino group optionally substituted with one or two C1-5 alkyl groups, or -N. + (R3)3, wherein the C1-5 alkyl or alkoxy group is optionally substituted with one or two groups selected from hydroxy, amino, methoxy and ethoxy, and / or wherein one or two carbon atoms are optionally substituted with oxygen, sulfur or nitrogen;

[0028] R3 is each independently a C1-5 alkyl group optionally substituted with one or two groups selected from hydroxyl, amino, methoxy and ethoxy, and / or wherein one or two carbon atoms are optionally substituted with oxygen, sulfur or nitrogen, and wherein two R3 groups may optionally form a C4-7 heterocycle with the nitrogen atom to which they are attached, wherein one or more carbon atoms are optionally substituted with oxygen, sulfur or nitrogen.

[0029] Furthermore, at least one of R2 and / or R3 is replaced by a solubilizing group.

[0030] In some embodiments, R1 is -N + (R3)3, wherein all R3 are methyl groups. In these embodiments, preferably one of the R3 groups is replaced by a solubilizing group, and in particular both R2 are methoxy groups. In other embodiments, R1 is -N + (R3)3, wherein one of R3 is methyl and the other two R3 form a morpholine ring with nitrogen. In these embodiments, preferably at least one, and particularly both, R2 groups are replaced by solubilizing groups. In these embodiments, the R2 groups that are not replaced by solubilizing groups are in particular methoxy or N-methylmorpholin-4-yl.

[0031] In some embodiments, the charged coupling agent further comprises counterions such as chloride ions, bromide ions, iodide ions, hexafluorophosphate ions, or tetrafluoroborate ions.

[0032] In some embodiments, the catalyst is an amide coupling agent such as a triazine compound. In these embodiments, the reaction mixture is specifically used for an amidation reaction. In these embodiments, the reaction mixture preferably contains carboxylic acids and amines as reactants. In other embodiments, the triazine compound is used as a coupling agent in selective reduction or cross-coupling reactions with organometallic compounds.

[0033] In embodiments where the catalyst is a metal ion complexed with a ligand, the metal ion may be selected from the group consisting of: copper, ruthenium, rhodium, palladium, nickel, zinc, gold, manganese, iron, and cobalt. The ligand may be any ligand suitable for the complexed metal ion. It may be selected from the group consisting of: biphenyl compounds; carbene compounds such as N-heterocyclic carbene, particularly 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylene; and di-N-heteroaromatic compounds such as bipyridine compounds.

[0034] In a specific embodiment, the ligand is a biphenyl compound having the general formula (II).

[0035]

[0036] in

[0037] R1, R2 and R3 are independently hydrogen or C1-5 alkyl groups optionally substituted with one or two groups selected from hydroxyl, amino, methoxy and ethoxy, and / or wherein one or two carbon atoms are optionally substituted with oxygen, sulfur or nitrogen.

[0038] R0 is H, or C1-5 alkyl, especially methyl, or CH2-Ar, wherein Ar is a phenyl or benzyl group optionally substituted with 1, 2, 3, 4 or 5 R4 groups, and wherein the C1-5 alkyl group is optionally substituted with one or two groups selected from hydroxyl, amino, methoxy and ethoxy, and / or wherein one or two carbon atoms are optionally substituted with oxygen, sulfur or nitrogen.

[0039] Each R4 is independently a C1-5 alkoxy group, a C1-5 alkyl group, a poly(ethylene glycol) having 2, 3, or 4 repeating units, a poly(propylene glycol) having 2, 3, or 4 repeating units, a hydroxyl group, or an amino group optionally substituted with one or two C1-5 alkyl groups, wherein the C1-5 alkyl or alkoxy group is optionally substituted with one, two, or three groups selected from hydroxyl, halogen, amino, methoxy, and ethoxy, and / or wherein one or two carbon atoms are optionally substituted with oxygen, sulfur, or nitrogen, and wherein the poly(ethylene glycol) and poly(propylene glycol) are optionally substituted with methyl, ethyl, or propyl groups at the terminal oxygen.

[0040] Furthermore, at least one of R0, R1, R2 and R4, preferably at least one of R1 and R2, especially R1 and R2 are replaced by solubilizing groups.

[0041] In some embodiments, Ar is a phenyl group substituted with an electron-withdrawing group such as isopropyl or trifluoromethyl. For example, Ar can be 2,4,6-tri-isopropylphenyl or 3,5-bis-trifluoromethylphenyl. Furthermore, R3 is preferably tert-butyl. R1 and R2, if not substituted with a solubilizing group, are preferably methyl.

[0042] In another embodiment, the ligand is an N-heterocyclic carbene compound having general formula (III).

[0043]

[0044] in

[0045] Ar is a phenyl group that is independently substituted by 1, 2, 3, 4 or 5 R1 ions;

[0046] R1 is independently of each other a C1-5 alkoxy, C1-5 alkyl, poly(ethylene glycol) having 2, 3 or 4 repeating units, poly(propylene glycol) having 2, 3 or 4 repeating units, hydroxyl, or an amino group optionally substituted with one or two C1-5 alkyl groups, wherein the C1-5 alkyl or alkoxy group is optionally substituted with one or two groups selected from hydroxyl, amino, methoxy and ethoxy, and / or wherein one or two carbon atoms are optionally substituted with oxygen, sulfur or nitrogen, and wherein the poly(ethylene glycol) and poly(propylene glycol) are optionally substituted with methyl, ethyl or propyl at the terminal oxygen;

[0047] Furthermore, at least one, preferably one, of the R1 groups on each Ar group is replaced by a solubilizing group.

[0048] In a specific embodiment, each Ar is a phenyl group substituted with three R1s at the 2, 4 and 6 positions, wherein each R1 is a methyl group, and wherein at least one R1, preferably one R1, on each Ar is substituted with a solubilizing group.

[0049] In another embodiment, the ligand is a bipyridine compound having the general formula (IV).

[0050]

[0051] in

[0052] R1 is independently of each other a C1-5 alkoxy, C1-5 alkyl, poly(ethylene glycol) having 2, 3 or 4 repeating units, poly(propylene glycol) having 2, 3 or 4 repeating units, hydroxyl, or an amino group optionally substituted with one or two C1-5 alkyl groups, wherein the C1-5 alkyl or alkoxy group is optionally substituted with one or two groups selected from hydroxyl, amino, methoxy and ethoxy, and / or wherein one or two carbon atoms are optionally substituted with oxygen, sulfur or nitrogen, and wherein the poly(ethylene glycol) and poly(propylene glycol) are optionally substituted with methyl, ethyl or propyl at the terminal oxygen;

[0053] Furthermore, at least one, preferably two, of the R1 groups is replaced by a solubilizing group.

[0054] In a specific embodiment, one R1 is a methoxy group and the other is replaced by a solubilizing group, or both R1s are replaced by solubilizing groups.

[0055] The concentration of the catalyst in the reaction mixture is chosen such that it can catalyze the desired chemical reaction. In embodiments where the catalyst is a metal ion complexed with a ligand, a suitable catalyst concentration relative to one or more of the reactants is, for example, 0.1 mol% to 25 mol%, particularly 1 mol% to 20 mol%, 3 mol% to 15 mol%, or 5 mol% to 10 mol%. In embodiments where the catalyst is a coupling agent, the catalyst is present in stoichiometric amounts. In particular, the concentration of the coupling agent relative to one or more of the reactants is 75 mol% to 250 mol%, particularly 90 mol% to 200 mol%, 100 mol% to 150 mol%, or 110 mol% to 130 mol%.

[0056] The coupling agent or ligand contains one or more solubilizing groups. That is, the coupling agent or ligand contains one, two, three, four, five or more solubilizing groups. In one embodiment, the coupling agent or ligand contains one solubilizing group. In another preferred embodiment, the coupling agent or ligand contains two solubilizing groups. In embodiments where the coupling agent or ligand contains more than one solubilizing group, the solubilizing groups can be different or the same, and particularly the same. Each solubilizing group contains C 5-50Alkyl groups or poly(alkylene glycol) groups having 2 to 20 repeating units. The solubilizing groups are attached to the remainder of the coupling agent or ligand via covalent bonds or functional groups such as ether groups, ester groups, amine groups, amide groups, thioether groups, thioester groups, or thioamide groups.

[0057] In a specific embodiment, the solubilizing group includes C 5-50 Alkyl group. The alkyl group can be straight-chain, branched, or cyclic, and particularly straight-chain. The alkyl group has 5 to 50 carbon atoms, particularly 5 to 25 carbon atoms, preferably 6 to 20 carbon atoms, 7 to 18 carbon atoms, 8 to 15 carbon atoms, or 10 to 14 carbon atoms, particularly about 12 carbon atoms. The alkyl group of the solubilizing group can be substituted with one or more groups selected from methoxy, ethoxy, propoxy, hydroxy, and optionally with one or two amino groups substituted with methyl, ethyl, and / or propyl, particularly methoxy, ethoxy, or hydroxy, and / or one or more carbon atoms, particularly one, two, three, or four carbon atoms, can be substituted with oxygen, sulfur, or nitrogen. In some embodiments, the solubilizing group is a straight-chain C8-40 alkyl group attached to the remainder of the coupling agent or ligand by an ether group and optionally substituted with a methoxy group at its end. Suitable examples of solubilizing groups include 12-methoxy-n-dodecyloxy and n-dodecyloxy.

[0058] In another embodiment, the solubilizing group comprises a poly(alkylene glycol) group having 2 to 20 repeating units. The poly(alkylene glycol) is particularly poly(ethylene glycol), poly(propylene glycol), or poly(butanediol), preferably poly(ethylene glycol). The poly(alkylene glycol) group may have 2 to 15 repeating units, particularly 2 to 12 repeating units, 3 to 10 repeating units, 3 to 8 repeating units, or 4 to 6 repeating units, preferably about 5 repeating units. The poly(alkylene glycol) group may be substituted with one or more groups selected from: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, hydroxyl, and an amino group optionally substituted with one or both of methyl, ethyl, and / or propyl, particularly methyl, ethyl, or propyl. In some embodiments, the poly(alkylene glycol) group is particularly substituted with methyl or ethyl at the terminal oxygen. In another embodiment, the poly(alkylene glycol) group comprises the same substituent, particularly methyl or ethyl, at each repeating unit. Suitable examples of solubilizing groups include poly(ethylene glycol) having 4 to 6 repeating units and optionally a methyl group at the terminal oxygen.

[0059] One or more reactants in the reaction mixture can be any reactant suitable for carrying out a chemical reaction. The reactants depend particularly on the type of chemical reaction to be carried out in the reaction mixture. In some embodiments, the reaction mixture contains one, two, or three reactants. In specific embodiments, at least one of the reactants is not water-miscible or only partially water-miscible. Reactants that are only partially water-miscible are miscible with water only at concentrations of 20 g / L or less, especially 10 g / L or less, or 5 g / L or less, at room temperature. Exemplary reactants include boric acids, borate esters, organosilanes, halides, acids and / or their corresponding activated esters, amines, alcohols, and alkenes. In embodiments where the reaction mixture is intended for carrying out an amidation reaction, the reaction mixture particularly contains a reactant that is a carboxylic acid and a reactant that is an amine, especially a primary amine.

[0060] Reactants can be used at any concentration in which a chemical reaction is feasible. In particular, reactants are used at high concentrations. For example, the concentration of reactants in the reaction mixture, especially at least one of all reactants, is at least 0.1 M, particularly at least 0.5 M, at least 1.0 M, at least 1.1 M, at least 1.2 M, at least 1.3 M, at least 1.5 M, at least 1.7 M, or at least 2.0 M. In some embodiments where the reaction mixture additionally contains an organic solvent, the concentration of one or more reactants in the reaction mixture is higher than their saturation concentration for solubility or miscibility in the surfactant-water mixture. In particular, it is at least about 5%, preferably at least about 10%, at least about 20%, at least about 30%, or at least about 50% higher than said saturation concentration. In these embodiments, the solubility or miscibility of the reactants is provided by the organic solvent in the reaction mixture. Those skilled in the art are able to select suitable reactants and their concentrations.

[0061] In some embodiments, the reaction mixture may additionally contain a base. The presence of the additional base in the reaction mixture depends on the type of chemical reaction to be carried out in the reaction mixture. The base may be an organic or inorganic base. In particular, the base is at least partially water-soluble or at least partially miscible with water. Exemplary bases include trialkylamines such as triethylamine (TEA), N-methylmorpholine (NMM), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), K3PO4, NaHCO3, and Na2CO3. The concentration of the base in the reaction mixture is particularly in the range of 0.5 to 10 molar equivalents of one of the reactants, particularly in the range of 0.9 to 6, 1.0 to 5, 1.2 to 4, or 1.5 to 3.5 molar equivalents of one of the reactants. If the reaction mixture is intended to carry out a chemical reaction that does not require a base, the reaction mixture need not contain a base.

[0062] In specific embodiments, the reaction mixture further comprises an organic solvent. The organic solvent in the reaction mixture can be any organic solvent. Preferably, it should not interfere with or inhibit the chemical reaction and, in particular, should increase the homogeneity of the reaction mixture. In some embodiments, the organic solvent is water-miscible or partially water-miscible. Organic solvents are especially aprotic organic solvents. Suitable examples of organic solvents include acetone, tetrahydrofuran (THF) and its derivatives such as methyltetrahydrofuran, pyridine, polyethylene glycol (PEG), polypropylene glycol (PPG), particularly PEG having an average molecular weight of about 100 g / mol to about 2000 g / mol, such as PEG200, PEG600, PEG1000 and PEG2000, and their derivatives such as mono- or dialkyl PEG, particularly mono- or dimethyl PEG, mono- or diethyl PEG and mono- or dipropyl PEG. Other examples include acetonitrile, dimethylformamide (DMF), dichloromethane (DCM), toluene, and alcohols such as C 1-10 Fatty alcohols, especially 2-butanol. In some embodiments, the organic solvent is not a base and / or does not act as a base in the chemical reaction.

[0063] In specific embodiments, organic solvents that increase the viscosity of the reaction mixture are used. For example, the viscosity of the reaction mixture containing the organic solvent is at least 1.25 cSt, particularly at least 1.5 cSt, at least 1.75 cSt, or at least 2.0 cSt. Suitable organic solvents for increasing the viscosity of the reaction mixture include PEGs such as PEG200, PEG600, and PEG1000 (PEGs having average molecular weights of 200 g / mol, 600 g / mol, and 1000 g / mol, respectively).

[0064] In a specific embodiment, the reaction mixture comprises, respectively, 0.1 to 50 volume equivalents of an organic solvent and 1 to 50 volume equivalents of a surfactant-water mixture per mass of reactant or product. The amounts of the organic solvent and the surfactant-water mixture are defined in relation to the amount of the theoretical product of the chemical reaction or, alternatively, the reactant. When the amount is defined based on the theoretical product, one volume equivalent is equal to the total weight of the theoretical product obtained at 100% conversion in the chemical reaction. The weight of the theoretical product is converted to volume using a theoretical density of 1 g / ml. Therefore, if, for example, 1.5 kg of product is calculated based on 100% conversion, one volume equals 1.5 l. When the amount is defined based on the reactants, one volume equivalent is equal to the total weight of the reactants. The weight of the reactants is converted to volume using a theoretical density of 1 g / ml. Therefore, if, for example, 1.5 kg of reactants is used in the reaction mixture, one volume equals 1.5 l.

[0065] In some embodiments, the amount of organic solvent in the reaction mixture is at least 0.2 volume equivalents, particularly at least 0.4 volume equivalents, at least 0.6 volume equivalents, at least 0.8 volume equivalents, at least 1.0 volume equivalents, at least 1.5 volume equivalents, or at least 2.0 volume equivalents. In other embodiments, the amount of organic solvent in the reaction mixture is at most 40 volume equivalents, particularly at most 30 volume equivalents, at most 25 volume equivalents, at most 20 volume equivalents, at most 15 volume equivalents, at most 12 volume equivalents, or at most 10 volume equivalents. In specific embodiments, the amount of organic solvent in the reaction mixture is in the range of 0.4 to 25 volume equivalents, particularly 0.8 to 15 volume equivalents. In some embodiments, the amount of organic solvent in the reaction mixture is in the range of 1% to 70%, particularly from 2% to 65%, from 3% to 60%, from 4% to 55%, or from 5% to 50%.

[0066] In some embodiments, the amount of the surfactant-water mixture in the reaction mixture is at least 1.5 volume equivalents, particularly at least 2.0 volume equivalents, at least 2.5 volume equivalents, at least 3.0 volume equivalents, at least 3.5 volume equivalents, at least 4.0 volume equivalents, or at least 5.0 volume equivalents. In other embodiments, the amount of the surfactant-water mixture in the reaction mixture is at most 45 volume equivalents, particularly at most 40 volume equivalents, at most 35 volume equivalents, at most 30 volume equivalents, at most 25 volume equivalents, at most 22 volume equivalents, or at most 20 volume equivalents. In specific embodiments, the amount of the surfactant-water mixture in the reaction mixture is in the range of 1.5 to 25 volume equivalents, particularly 2.0 to 20 volume equivalents. In some embodiments, the amount of the surfactant-water mixture in the reaction mixture is in the range of 30% to 98%, particularly 35% to 95%, 40% to 92%, 45% to 90%, or 50% to 85%.

[0067] In some embodiments, the total amount of the organic solvent and the surfactant-water mixture may particularly not exceed 30 volumes, especially 25 volume equivalents or less, 20 volume equivalents or less, or even 15 volume equivalents or less. In specific embodiments, the volume of the organic solvent in the reaction mixture ranges from about 1% to about 200% of the volume of the surfactant-water mixture, particularly from about 2% to about 150%, about 3% to about 120%, about 4% to about 110%, or about 5% to about 100%.

[0068] In one embodiment, the reaction mixture is industrial-scale. It can have a volume of, for example, at least 1 l, particularly at least 10 l, at least 100 l, or at least 1000 l. In another embodiment, the reaction mixture is micro-scale. It can have a volume of, for example, 10 ml or less, particularly 1 ml or less, 100 μl or less, 10 μl or less, or 1 μl or less.

[0069] A reaction mixture is a feed or batch mixture used to carry out a chemical reaction. In some embodiments, the reaction mixture does not contain any products of the reaction or contains only residual amounts of any products of the reaction. In other embodiments, it may also contain a significant amount of products of the chemical reaction. In still other embodiments, the reaction mixture does not contain all the reactants necessary to carry out the chemical reaction. In particular, the reaction mixture contains only one reactant. For example, in these embodiments, a reactant may be slowly added to the reaction mixture and consumed directly by the chemical reaction. In some embodiments, the reaction mixture is a homogeneous mixture, especially a colloidal suspension. In particular, the reaction mixture does not contain aggregated or oiled-out components such as reactants or products.

[0070] In a second aspect, the present invention provides a method for carrying out a chemical reaction, the method comprising the following steps:

[0071] (a) Provide the reaction mixture as described herein, and

[0072] (b) Allow the chemical reaction to proceed.

[0073] The reaction mixture particularly comprises one or more reactants, a catalyst, and a surfactant-water mixture, wherein the catalyst is (a) a coupling agent comprising one or more solubilizing groups; or (b) a metal ion complexed with a ligand comprising one or more solubilizing groups; wherein the solubilizing group comprises a C5-50 alkyl group or a poly(alkylene glycol) group having 2 to 20 repeating units. The reaction mixture may particularly exhibit any of the features, examples, and instances (including combinations thereof) described herein.

[0074] The chemical reaction can be any chemical reaction carried out in a medium containing a surfactant-water mixture. In particular, organic chemical synthesis reactions, such as those with at least partially hydrophobic compounds, can be carried out. Exemplary chemical reactions include those selected from the group consisting of: cross-coupling reactions such as Suzuki cross-coupling, Suzuki-Miyaura cross-coupling, Sonogashira cross-coupling, Heck cross-coupling, Buchwald-Hartwig cross-coupling, Negishi cross-coupling, Stille cross-coupling, Miyauura borylation, Hiyama cross-coupling, and olefin translocation; copper-mediated cross-coupling, nickel-mediated cross-coupling, nucleophilic substitution (S... N 2) Such as nucleophilic aromatic substitution (S N Ar); amidation; oxidation; reduction, such as reduction of nitro groups, oxime groups, azide groups, nitrile groups, and amide groups; hydrogenation and debenzylation. In some embodiments, the chemical reaction is an amidation reaction. The reactants and catalysts present in the reaction mixture are suitable for the specific chemical reaction. In particular, the reactants and catalysts are specifically selected so that the chemical reaction proceeds as desired.

[0075] In some embodiments, the chemical reaction is permitted to proceed in step (b) under reaction conditions suitable for carrying out the chemical reaction. Specifically, reaction conditions include temperatures of 90°C or less, particularly 80°C or less, 70°C or less, 60°C or less, 50°C or less, 40°C or less, or 30°C or less. For example, the chemical reaction may be permitted to proceed at approximately room temperature. In specific embodiments, the reaction mixture is stirred, particularly during the chemical reaction process.

[0076] For some chemical reactions, the order and rate of addition of the various components of the reaction mixture are important. In some embodiments, one or more reactants, optionally containing other components of the reaction mixture such as other reactants, catalysts, and bases, are slowly added to the surfactant-water mixture. This is particularly suitable for reactants with low solubility in water. In this regard, slow addition means, for example, adding the reactant over a time period of at least 5 min, particularly at least 7 min, at least 10 min, at least 15 min, at least 20 min, at least 30 min, at least 45 min, or at least 60 min. Low solubility in water specifically refers to a water solubility of 20 g / L or less, particularly 10 g / L or less, or 5 g / L or less at room temperature. In these embodiments, the organic solvent may be added to the surfactant-water mixture before the reactants are added, or it may be added together with the reactants. For example, the reactants may be mixed with or dissolved in an organic solvent and then added to the surfactant-water mixture.

[0077] Methods for carrying out a chemical reaction may include additional steps to separate the products of the chemical reaction. Specifically, this step is performed after the chemical reaction is complete. The products are separated, in particular, from one or more components of the reaction mixture, especially substantially all other components. For example, the products are separated from one or more of the remaining reactants, byproducts, catalysts, bases, organic solvents, and / or surfactant-water mixtures. The separation of the products can be achieved by means and techniques known in the art, including, for example, solvent evaporation, aggregation or crystallization and filtration, phase separation, chromatographic separation, and others.

[0078] In some embodiments, the reaction mixture is a homogeneous mixture, particularly a colloidal suspension, throughout the entire chemical reaction. In this regard, "throughout the entire chemical reaction" specifically means from the establishment of the final reaction mixture until the chemical reaction is completed or terminated.

[0079] This invention improves the solubility of reactants and products in surfactant-water mixtures and provides a stable and homogeneous reaction mixture. Consequently, the yield of the chemical reaction is increased and the amount of unwanted byproducts obtained through the chemical reaction is reduced. Therefore, in another aspect, this invention provides a method for increasing the yield of a chemical reaction carried out in a surfactant-water mixture, the method comprising the following steps:

[0080] (a) A reaction mixture comprising one or more reactants, a catalyst, and a surfactant-water mixture, wherein the catalyst is a coupling agent comprising one or more solubilizing groups or a metal ion complexed with a ligand comprising one or more solubilizing groups; wherein the solubilizing group comprises C 5-50Alkyl groups or poly(alkylene glycol) groups having 2 to 20 repeating units; and

[0081] (b) Allow the chemical reaction to proceed.

[0082] In another aspect, the present invention provides a method for reducing the amount of byproducts generated in a chemical reaction in a surfactant-water mixture, the method comprising the following steps:

[0083] (a) A reaction mixture comprising one or more reactants, a catalyst, and a surfactant-water mixture, wherein the catalyst is a coupling agent comprising one or more solubilizing groups or a metal ion complexed with a ligand comprising one or more solubilizing groups; wherein the solubilizing group comprises C 5-50 Alkyl groups or poly(alkylene glycol) groups having 2 to 20 repeating units; and

[0084] (b) Allow the chemical reaction to proceed.

[0085] The methods and reaction mixtures described herein, including combinations thereof, for carrying out chemical reactions are equally applicable to methods for increasing the yield of chemical reactions carried out in surfactant-water mixtures, methods for reducing the amount of byproducts generated in chemical reactions carried out in surfactant-water mixtures, and the reaction mixture provided in step (a).

[0086] The reaction mixture can be provided in step (a) by adding the different components to each other in any suitable order. For example, providing the reaction mixture in step (a) may include providing a surfactant-water mixture and adding a catalyst and one or more reactants to the surfactant-water mixture.

[0087] The present invention also provides the use of a catalyst for increasing the yield of a chemical reaction carried out in a surfactant-water mixture and / or reducing the amount of byproducts generated in a chemical reaction carried out in a surfactant-water mixture, the catalyst being...

[0088] (a) A coupling agent containing one or more solubilizing groups; or

[0089] (b) Metal ions complexed with ligands containing one or more solubilizing groups;

[0090] The solubilizing group contains C 5-50 Alkyl groups or poly(alkylene glycol) groups having 2 to 20 repeating units.

[0091] As used herein, the expression "comprising / including" includes, in addition to its literal meaning, expressions "substantially consisting of" and "consisting of". Therefore, the expression "comprising / including" means that the subject matter of the elements specifically "comprising / including" may and / or does cover embodiments of additional elements, as well as embodiments of the subject matter of the elements specifically "comprising / including" that do not include additional elements. Similarly, the expression "having" should be understood to mean "comprising / including", and specifically refers to expressions "substantially consisting of" and "consisting of".

[0092] The numerical ranges described herein include numbers within defined ranges. The headings provided herein are not intended to limit the various aspects or embodiments of the invention, which can be derived by referring to this specification as a whole. According to one embodiment, subject matter described herein as including certain steps in the case of a method or comprising certain ingredients in the case of a composition refers to subject matter consisting of the respective steps or ingredients. Specific aspects and embodiments described herein are preferably selected and combined, and specific subject matter arising from corresponding combinations of specific embodiments also falls within the scope of this disclosure. Attached Figure Description

[0093] Figure 1 The chemoselective conversion of 4-bromobenzoic acid with 0.5 equivalents of 3-methylphenol and 0.5 equivalents of 3-ethylaniline is shown in TPGS-750-M (2 wt%) in water using triazine 6c (A) or 6h (B) as a coupling agent. In (A), the total conversion (triangles) and the conversion to amides (rhombuses) and to esters (circles) are shown. In (B), no conversion to esters was observed, making the conversion to amides identical to the total conversion.

[0094] Example

[0095] Add a solution of triazine (1.1 equivalent) in a water-miscible cosolvent (1 volume equivalent) to a mixture of carboxylic acid (1 equivalent), NaHCO3 (1 equivalent), and amine (1.1 equivalent) in TPGS-750-M (2%, in water, 10 volume equivalents). Allow the reaction to be stirred at 25°C until complete (typically 2 to 5 hours). Upon completion, precipitate the product by adding more water or extract in isopropyl acetate and filter through a short silica gel stopper to provide the desired amide product.

[0096] The various derived triazines (6b to 6h) were compared with the reference (6a) regarding the following challenging mode transitions:

[0097]

[0098] Evaluate the following triazine derivatives and provide the indicated conversion rates:

[0099]

[0100] The conversion rate (without competing side reactions) was monitored as a direct indicator of yield. This demonstrates that the reagents used in the media have a profound impact on the results.

[0101] Then, amidation was performed using coupling agents 6C or 6H with different amines and carboxylic acids. The conversion rates are as follows:

[0102]

[0103] We demonstrate here that uninvolved sidechains have the most profound impact and always exhibit good or better selectivity and yield.

[0104] Another, and even more striking, feature is the resulting selectivity. In the demanding reactions below, triazine 6C or 6H were used as coupling agents, and the formation of amides and esters was monitored.

[0105]

[0106] The result is Figure 1 As shown in the diagram. It can be seen that at 6 hours ( ) of triazine... Figure 1 In case B), near-perfect selectivity was obtained. This is even more noteworthy because it is virtually impossible to achieve under any other conditions. Similarly, with triazine 6c, only very small amounts of ester were obtained. Figure 1 A).

Claims

1. A reaction mixture for carrying out an amidation reaction, comprising one or more reactants, a catalyst and a surfactant-water mixture, characterized in that, This catalyst is a coupling agent, a 1,3,5-triazine derivative, and has the following characteristics: (i) It contains a quaternary ammonium group attached to the 2-position of the triazine ring, wherein the quaternary ammonium group is an N-methyl-N-morpholino group; and (ii) Solubilizing groups are attached to the 4 and 6 positions of the triazine ring; The solubilizing group is attached to the coupling agent by a functional group selected from ether group, amine group, amide group, thioether group, thioester group or thioamide group, and the solubilizing group is 12-methoxydodecyl. And the surfactant thereon is selected from the group consisting of: DL-α-tocopherol polyethylene glycol succinate, polyethylene glycol alkyl ether, polyethylene glycol ester, polyethylene glycol sorbitan fatty acid ester, polyoxyethyl panthenol sebacate, polyethylene glycol, and β-sitosterol methoxyethylene glycol succinate.

2. The reaction mixture according to claim 1, characterized in that, The solubilizing group is attached to the coupling agent via an ether bond.

3. The reaction mixture according to claim 1, characterized in that, The concentration of the surfactant in the surfactant-water mixture is 0.5% to 5% w / w.

4. The reaction mixture according to claim 1, characterized in that, The reaction mixture contains one or two reactants.

5. The reaction mixture according to claim 1, characterized in that, The reaction mixture further contains an organic solvent.

6. The reaction mixture according to claim 1, characterized in that, The reaction mixture is a homogeneous mixture.

7. The reaction mixture according to claim 1, characterized in that, The reaction mixture is a colloidal suspension.

8. A method for carrying out a chemical reaction, characterized in that, The method includes the following steps: (a) Providing a reaction mixture according to any one of claims 1 to 7, and (b) Allow the chemical reaction to proceed.

9. The method according to claim 8, characterized in that, The method further includes the step of separating the products of the chemical reaction.

10. The method according to claim 8, characterized in that, The reaction mixture is a homogeneous mixture throughout the entire chemical reaction.

11. The method according to claim 8, characterized in that, The reaction mixture is a colloidal suspension throughout the entire chemical reaction.

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