Nucleophilic aromatic substitution in aqueous media in presence of poloxamers

Abstract

The present invention relates to nucleophilic aromatic substitution reactions accomplished in an aqueous micellar solvent system, wherein the micelles are formed from specific alkoxylated alcohols.

Description

TECHNICAL FIELD

[0001] The present invention relates to nucleophilic aromatic substitution reactions accomplished in aqueous media in the presence of a surfactant, which surfactant is a poloxamer. BACKGROUND

[0002] N. A. Isley et al. in Organic Letters, 2015, 17, 4734-4737 (Isley) disclose nucleophilic aromatic substitution reactions in water enabled by micellar catalysis, the micelles being formed from TPGS-750-M.

[0003] J. D. Smith et al., Green Chemistry, 2018, 20 1784-1790 disclose the reaction of pentafluorobenzonitrile with sodium methylphenylsulfinate in an aqueous medium containing 3 wt% Pluronic F-127, 20% acetone and a 10-fold molar excess of NaCI.

[0004] Poloxamers are described in the handbook "Solubility Enhancement with BASF Pharma Polymers - Solubilizer Compendium - Thomas Reintjes (Editor)" on pages 103 to 111 of BASF SE, Pharma Ingredients & Services, 68623 Lampertheim, Germany, October 2011, which is referred to herein as "BASF handbook".

[0005] TPGS-750-M is susceptible to hydrolysis at pH < 5 and pH > 8 due to its ester linkage, which narrows its applicability, as many reactions involve conditions outside of neutral or near-neutral pH.

[0006] There is a need to provide surfactants for aqueous micellar solvent systems operating over a wide temperature range, a wide pH range, which show low persistence of emulsions in work-up, which do not lead to non-separable - or slowly separable - emulsions of aqueous and organic phases during work-up, which minimize or eliminate residual surfactants from downstream processes such as recrystallization, distillation or lyophilization, as non-limiting examples.

[0007] The inventors found that poloxamers as surfactants provide aqueous micellar solvent systems enabling high operating temperatures, a wide operating pH range (e.g. high operating pH) and high reaction yields. The reaction yields are actually improved over the yields obtained by the use of TPGS-750-M. Furthermore poloxamers allow for rather low concentrations of surfactants. Summary of the Invention

[0008] The subject of this invention is a method for carrying out nucleophilic aromatic substitution reactions, comprising: Combining nucleophiles and aromatic electrophiles in aqueous media; The aqueous medium comprises water, alkali, and a surfactant, wherein the surfactant is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer; The amount of water in the aqueous medium is at least 50 wt%; and The combined amount of water, the alkali, and the surfactant is at least 70 wt% of the aqueous medium. wt% is based on the weight of the aqueous medium. Attached Figure Description

[0009] Figure 1 The data in Table 2 show a comparison of conversion rates in water versus in 2 wt% poloxamer 407 at 90°C compared to reaction time. Detailed Implementation

[0010] For ease of reading, nucleophilic aromatic substitution reactions will also be referred to as reactions in this article.

[0011] As used in this article, “nucleophilic aromatic substitution reaction” (NAS or S) N Ar) indicates a chemical reaction in which a nucleophile replaces the leaving group of the aromatic ring of the substrate (electrophilic aromatic reagent), resulting in the substitution of one functional group (leaving group) on the aromatic ring of the substrate (electrophilic aromatic reagent) by another. Typical leaving groups of the substrate can be nitro (NO2), fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0012] S N The reactants of Ar are the nucleophile and the substrate, which is the electrophile of the aromatic ring. The reaction occurs via a series of concerted electron migrations involving the nucleophile's attack on the electrophilic carbon atom of the aromatic ring (which destroys aromaticity), via a negatively charged carbanion intermediate and subsequent rearrangement of π electrons. Functional substitution of inner ring carbon atoms occurs on the aromatic ring, particularly on it. ortho- bit or para- The presence of an electron-withdrawing group (EWG) at the 0-position can accelerate the reaction. The substrate may contain one or more electron-withdrawing substituents.

[0013] Nucleophilic aromatic substitution reactions occur in the presence of surfactants, preferably poloxamer, wherein the surfactant provides an aqueous micelle system in an aqueous medium. In one embodiment, the present invention relates to nucleophilic aromatic substitution reactions in an aqueous micelle solvent system, wherein the micelles are formed by the surfactant.

[0014] At least a portion of the surfactant exists as micelles contained in the aqueous medium. Another term sometimes used for surfactants is emulsifier; these two terms are used interchangeably within the meaning of this invention.

[0015] As used herein, the term "aqueous micelle system" refers to a dispersion consisting of micelles in an aqueous medium. Micelles are spontaneously formed aggregates or clusters of surfactant molecules in an aqueous medium.

[0016] As used herein, “dispersion” refers to a two-phase system in which a first phase (dispersed phase) is emulsified, suspended, or colloidally dispersed within a second phase (liquid continuous phase). The terms “emulsion,” “suspension,” and “colloidal dispersion” are used interchangeably throughout this document. In aqueous micelle systems, the dispersed phase is micelles and the continuous phase is a liquid component of an aqueous medium.

[0017] Micelles form when the concentration of surfactant molecules in a given solvent exceeds the critical micelle concentration (CMC). The CMC is the concentration at which surfactant molecules begin to self-assemble and form micelles. At and above the CMC, additional surfactant essentially forms micelles. Typically, there exists a relatively small range of concentrations separating the boundary below which micelles are essentially undetectable and the boundary above which virtually all additional surfactant molecules form micelles.

[0018] In aqueous micelle systems, hydrophobic tails are clustered or shielded within the micelle core, while hydrophilic head groups form an outer layer that interacts with the surrounding solvent. This arrangement allows micelles to solubilize and disperse hydrophobic substances within the hydrophobic core, resulting in a stable system with an efficient and uniform distribution of hydrophobic molecules in the solvent.

[0019] As used herein, the term "surfactant" refers to amphiphilic surfactant molecules that help form stable and homogeneous emulsions (i.e., mixtures of two or more immiscible liquid substances, one of which is dispersed as small droplets in another). The amphiphilic nature of surfactant molecules enables them to reduce the surface tension between immiscible substances by forming a layer around the dispersed droplets of one substance (called the dispersed phase), thereby preventing them from coalescing or separating from the continuous phase.

[0020] The surfactant of this invention is capable of forming micelles.

[0021] When surfactants are present above the CMC, they can act as emulsifiers that allow compounds that are normally insoluble in the solvents used to dissolve. This occurs because insoluble species can be incorporated into the micelle core, which itself is solubilized in the bulk solvent by the favorable interaction between the head groups and the solvent species.

[0022] In one embodiment, this invention discloses a nucleophilic aromatic substitution reaction catalyzed by the micelle catalysis of the said surfactant. As used herein, the term "micelle catalysis" refers to a chemical reaction in an aqueous medium in the presence of a surfactant capable of forming micelles, preferably in the presence of a surfactant at a concentration above its critical micelle concentration that allows micelle formation and the reaction to occur within the micelle environment. Without wishing to be bound by a particular theory, it is believed that the occurrence of the reaction may be due to, for example, a higher concentration of reactants in the micelles, a more favorable orientation of the reactants, and solvation or an increased reaction rate constant in the micelles.

[0023] The surfactant is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, which is an ABA-type triblock copolymer, wherein A is poly(ethylene oxide) (PEO) and B is poly(propylene oxide) (PPO), i.e., a PEO-PPO-PEO triblock copolymer. This type of surfactant can be obtained by synthesis according to scheme (S) comprising two steps. In the first step (step-1), propylene oxide (S-2) is reacted with propylene glycol (S-1) to form PPO (S-3). In the second step (step-2), PPO is reacted with ethylene oxide (S-4) to form a PEO-PPO-PEO triblock copolymer (S-5). Both of these steps can be alkali-catalyzed, for example with potassium hydroxide.

[0024] Option (S) Step-1 Solution (S) continued Step 2 In the sense of this invention, any ethoxylated and / or propoxylated surfactant is a mixture of species containing blocks of varying amounts of ethylene oxide (EO) units and / or varying amounts of propylene oxide (PO) units.

[0025] The number of EO units in the poly-EO block and the number of PO units in the poly-PO block are averages.

[0026] The surfactant mentioned is known to those skilled in the art as poloxamer, for example, BASF AG, Pluracare of Germany. TM Or Kolliphor TM Other product names include Pluronic. TM Synperonic™ and Lutrol TM .

[0027] In one embodiment, the surfactant is a compound of formula (I). a is an integer between 5 and 250. b is an integer between 15 and 70; Preferably, a is an integer from 10 to 150 and b is an integer from 15 to 70; More preferably, a is 30 to 110, even more preferably 50 to 110, particularly 70 to 110, and even more particularly 90 to 110; More preferably, b is an integer from 20 to 70, even more preferably from 20 to 60, particularly from 30 to 60, and even more particularly from 50 to 60; Even more preferably, a is 90 to 110 and b is 50 to 60.

[0028] In specific embodiments of the compounds of formula (I), a = 11 and b = 21, a = 80 and b = 27, a = 141 and b = 44, or a = 101 and b = 56; Preferably, a = 80 and b = 27, a = 141 and b = 44, or a = 101 and b = 56; More preferably, a = 141 and b = 44 or a = 101 and b = 56; Even more preferably, a = 101 and b = 56.

[0029] In a specific embodiment, the compound of formula (I) is a poloxamer having the following values ​​of a and b: Poloxams 124a = 11b = 21 Poloxamer 188a = 80b = 27 Poloxamer 237a = 64b = 37 Poloxams 238a = 207b = 39 Poloxamer 334a = 54b = 61 Poloxamer 335a = 74b = 56 Poloxamer 338a = 141b = 44 Poloxamer 407a = 101b = 56.

[0030] Surfactants can also be defined by the molecular weight of their polypropylene oxide moiety (PPO moiety) and the weight percentage (wt%) of their polyethylene oxide moiety (PEO moiety), where wt% is based on the weight of the surfactant.

[0031] Any molecular weight of the polypropylene oxide portion described herein is an average molecular weight and any weight percentage of the polyethylene oxide portion is an approximate or average weight percentage of the polyethylene oxide portion, due to the fact that any surfactant is a mixture of independent species containing different numbers of EO units and / or different numbers of PO units due to the inherent polydispersity of the polymerization of ethylene oxide and propylene oxide.

[0032] In one embodiment, the surfactant is a PEO-PPO-PEO triblock copolymer and has The molecular weight of the polyoxypropylene moiety ranging from 1,450 to 4,100 g / mol and 35 to 85 wt% of the weight percentage of the polyethylene oxide portion; Preferably, the molecular weight of the polypropylene oxide moiety is between 1,925 and 4,100 g / mol. 45 to 85 wt% of the weight percentage of the polyethylene oxide portion; More preferably, the molecular weight of the polyoxypropylene moiety of 2,150 to 4,100 g / mol and 65 to 85 wt% of the weight percentage of the polyethylene oxide portion; Even more preferably, the molecular weight of the polypropylene oxide moiety is 2,500 to 4,100 g / mol and 65 to 85 wt% of the weight percentage of the polyethylene oxide portion; Specifically, the molecular weight of the polypropylene oxide moiety of 3,000 to 4,100 g / mol and 65 to 85 wt% of the weight percentage of the polyethylene oxide portion; More specifically, the molecular weight of the polypropylene oxide moiety ranging from 3,625 to 4,100 g / mol and 65 to 85 wt% of the weight percentage of the polyethylene oxide portion; Where wt% is based on the weight of the surfactant.

[0033] For certain poloxamers, Table 4 shows the corresponding values ​​for the average molecular weight of the polypropylene oxide portion and the approximate or average weight percentage of the polyethylene oxide portion for a specific poloxamer. The values ​​shown in Table 4 are not precise values ​​because, as mentioned above, surfactants are (and any poloxamer is thus also) mixtures of species containing varying amounts of EO units and / or varying amounts of PO units.

[0034] BASF explains in its BASF manual that a three-digit number represents each poloxamer grade: the last of the three digits representing each poloxamer grade is related to the PEO content (e.g., 18). 8 = 80% m / m PEO), and multiplying the preceding number by 100 gives the information on the average molecular weight of the PPO fraction (e.g., 18 8 = Molecular weight of the PPO portion: 1800).

[0035] The term "poloxamer" within the meaning of this invention refers not only to the specific representative characterized by the three digits, but also generally includes PEO-PPO-PEO triblock copolymers; therefore, the term "poloxamer" is used herein as a synonym for surfactant.

[0036] Table 5 provides information on the range of molecular weights and weight percentages of the polyethylene oxide moiety for the five specific poloxamers 124, 188, 237, 338, and 407. The surfactant is preferably a commercially available surfactant.

[0037] In one embodiment, surfactant I is selected from... Polosham 184, Polosham 185, Polosham 188 Polosham 205, Polosham 207 Polosham 234, Polosham 235, Polosham 237, Polosham 238, Polosham 278, Polosham 334 Polosham 335, Polosham 338 and The group consisting of Polosham 407; Preferably, the choice is free. Polosham 205, Polosham 207 Polosham 235, Polosham 237, Polosham 238 Polosham 278 Polosham 335, Polosham 338 and The group consisting of Polosham 407; More importantly, freedom of choice Polosham 237, Polosham 238 Polosham 278 Polosham 338 and The group consisting of Polosham 407; Even more importantly, choose freely Polosham 278 Polosham 338 and The group consisting of Polosham 407; Specially chosen freedom Polosham 338 and The group consisting of Polosham 407; More specifically, surfactant I is poloxamer 407.

[0038] In yet another embodiment, surfactant I is selected from the group consisting of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 238, poloxamer 334, poloxamer 335, poloxamer 338 and poloxamer 407. Preferably, the group consisting of free poloxamer 124, poloxamer 188, poloxamer 338 and poloxamer 407 is selected; More preferably, the group consisting of poloxamer 188, poloxamer 338 and poloxamer 407 is selected; Even more preferably, surfactant I is poloxamer 407.

[0039] Aqueous media contain water as a solvent component.

[0040] The aqueous medium may contain at least 60 wt%, preferably at least 70 wt%, more preferably at least 80 wt%, even more preferably at least 85 wt%, particularly at least 90 wt% water, where wt% is based on the weight of the aqueous medium.

[0041] Preferably, the combined amount of water, the alkali, and the surfactant is at least 80 wt%, more preferably at least 90 wt%; wt% is based on the weight of the aqueous medium.

[0042] In one embodiment, the aqueous medium does not contain organic solvents.

[0043] In another embodiment, the solvent component of the aqueous medium is composed of water.

[0044] In another embodiment, the aqueous medium contains an organic solvent.

[0045] The organic solvent is a solvent component other than water in an aqueous medium.

[0046] The organic solvent can be an organic solvent used in nucleophilic aromatic substitution reactions. The organic solvent is preferably an organic solvent that is soluble in water or at least partially soluble in water.

[0047] Organic solvents can be selected from THF, Me-THF, NMP, NBP, DMSO, DMF, DMA, nitromethane, C 1-3 Alcohols, Ethylene Glycol C 1-4 Monoalkyl ethers, diethylene glycol C 1-4The group consisting of monoalkyl ethers, MeCN, and any mixtures thereof; Preferably, it is selected from the group consisting of THF, Me-THF, DMF, DMA, methanol, ethanol, n-propanol, isopropanol, 2-butoxyethanol, 2-ethoxyethanol, diethylene glycol monobutyl ether, diethylene glycol monomethyl ether, MeCN, and any mixture thereof.

[0048] The aqueous medium may have more than one liquid phase, preferably one or two liquid phases, more preferably one liquid phase.

[0049] Preferably, the selected amount of organic solvent present in the aqueous medium is soluble in the water of the aqueous medium.

[0050] The aqueous medium may contain 20 wt% or less, preferably 15 wt% or less, and even more preferably 10 wt% or less of an organic solvent, wherein wt% is based on the weight of the aqueous medium.

[0051] In another embodiment, the solvent component of the aqueous medium consists of water and an organic solvent, preferably the solvent component of the aqueous medium consists of water and an organic solvent.

[0052] The amount of surfactant required to obtain an aqueous micelle system depends on the chemical properties of the surfactant and the amount and composition of the aqueous medium. Such surfactants that form micelles in an aqueous medium are preferably used in an amount based on the weight of the aqueous medium that causes the surfactant to form micelles in the aqueous medium.

[0053] The lower limit of the surfactant amount is typically 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.075 wt%, 0.1 wt%, 0.25 wt%, 0.5 wt%; wherein a higher value is preferred over a lower value; and / or The upper limits for the amount of surfactant are typically 20 wt%, 15 wt%, 10 wt%, 7.5 wt%, 5 wt%, and 3 wt%, with lower values ​​preferred over higher values.

[0054] It is possible to combine any of the mentioned lower bounds with any of the mentioned upper bounds; Preferably, the amount of surfactant is typically 0.01 to 20 wt%, 0.01 to 15 wt%, 0.01 to 10 wt%, 0.02 to 10 wt%, 0.05 to 10 wt%, 0.075 to 10 wt%, 0.1 to 10 wt%, 0.1 to 7.5 wt%, 0.1 to 5 wt%, 0.25 to 5 wt%, 0.5 to 5 wt%, or 0.5 to 3 wt%, wherein a narrower range is preferred over a wider range.

[0055] Any amount of surfactant used in this article is given in wt%, where wt% is the weight based on the aqueous medium.

[0056] Preferably, the surfactant is present at a concentration higher than its CMC for the selected aqueous medium at the selected reaction temperature.

[0057] The combined amount of reagent (i.e. nucleophile) and substrate in the reaction mixture can be from 0.01 to 30 wt%, preferably from 0.01 to 25 wt%, more preferably from 0.01 to 20 wt%, wherein wt% is based on the weight of the aqueous medium.

[0058] The terms “reagent” and “nucleophile” are used interchangeably in this document.

[0059] The terms “substrate,” “electrophilic reagent,” and “aromatic electrophilic reagent” are used interchangeably in this document.

[0060] The amount of reagent can be at least a stoichiometric molar amount based on the molar amount of the substrate. Preferably, the amount of reagent is 1 to 1.5 equivalents, more preferably 1 to 1.2 equivalents, and even more preferably 1 to 1.1 equivalents, where the equivalent is a molar equivalent based on the molar amount of the substrate.

[0061] However, the substrate can also exist in excess relative to the reagent, therefore The amount of substrate can be at least a stoichiometric molar amount based on the molar amount of the reagent. Preferably, the amount of substrate is 1 to 1.5 equivalents, more preferably 1 to 1.2 equivalents, and even more preferably 1 to 1.1 equivalents, where equivalents are molar equivalents based on the molar amount of the reagent.

[0062] The reaction temperature, i.e. the temperature at which the reaction takes place, can be 30 to 200°C, preferably 45 to 180°C, and more preferably 60 to 160°C.

[0063] The reaction can be carried out at atmospheric pressure or at elevated pressure; preferably at a pressure higher than the vapor pressure of the reaction mixture.

[0064] The reaction time can be from 5 sec to 24 h, preferably from 10 sec to 24 h, and more preferably from 30 sec to 24 h.

[0065] The reaction is carried out in the presence of a base. The base can be any base known to promote nucleophilic aromatic substitution reactions; preferably, the base is a base soluble in an aqueous medium, more preferably a water-soluble base.

[0066] Preferably, the base has a pKb of 0 to 6.8, more preferably 1 to 6.8, more preferably 1 to 5, and even more preferably 1.5 to 4.5.

[0067] The base can be selected from the group consisting of R20(R21)(R22)N, alkali metal salts of carbonates, phosphoric acids and hydroxides, and any mixtures thereof; Preferably, it is selected from the group consisting of R20(R21)(R22)N, as well as Li, Na, K and Cs salts of carbonates, phosphoric acids and hydroxides, and any mixtures thereof; More preferably, it is selected from the group consisting of R20(R21)(R22)N, Na and K salts of carbonates, phosphoric acids and hydroxides, and any mixtures thereof; Even more preferably, it is selected from the group consisting of R20(R21)(R22)N, potassium salts of carbonates, phosphoric acids and hydroxides, and any mixtures thereof; Specifically selected are the groups consisting of R20(R21)(R22)N, potassium salts of carbonic acid and phosphoric acid, and any mixture thereof; Any of the mentioned R20, R21 and R22 that are the same or different and are independently selected from the group consisting of methyl, ethyl, 2-hydroxyethyl, n-propyl, isopropyl, 2-hydroxypropyl, n-butyl, isobutyl and tert-butyl; More preferably, R20, R21, and R22 are the same or different and are independently selected from the group consisting of ethyl and isopropyl groups; Even more preferably, R20(R21)(R22)N is Et3N, triisopropylamine, or DIPEA; Specifically, the base is selected from the group consisting of Et3N, triisopropylamine, DIPEA, K2CO3, K3PO4, KOH and any mixture thereof.

[0068] The base may be present in the reaction mixture in at least a stoichiometric molar amount based on the molar amount of the electrophilic reagent; Preferably, the amount of base is 1 to 10 equivalents, more preferably 1 to 7.5 equivalents, even more preferably 1 to 5 equivalents, and particularly 1 to 4 equivalents, where the equivalent is a molar equivalent based on the molar amount of the electrophilic reagent.

[0069] Preferably, the nucleophile donates electrons from an atom selected from N, O, or S(II) to the electrophile.

[0070] Preferably, the nucleophile is selected from aniline, substituted aniline, heteroarylamine, or an inner ring sp containing an NH bond. 2 - The group consisting of heterocycles with hybrid nitrogen atoms, primary and secondary alkylamines, phenols, substituted phenols, heteroaryl phenols, primary and secondary alcohols, and thiols.

[0071] The inner ring sp with NH bonds 2 - Hybridized nitrogen atoms are commonly known as "pyrrole-type" inner ring nitrogen atoms.

[0072] In a more preferred embodiment, the nucleophile is selected from aniline, substituted aniline, heteroarylamine, and inner ring sp containing an NH bond. 2 - A group consisting of heterocycles with hybrid nitrogen atoms and primary and secondary alkylamines.

[0073] In another preferred embodiment, the nucleophile is selected from the group consisting of phenol, substituted phenol, heteroaryl phenol, and primary and secondary alcohols.

[0074] In another, more preferred embodiment, the nucleophile is selected from the group consisting of thiols.

[0075] Preferably, the electrophilic reagent is a monohalogenated, dihalogenated, trihalogenated, or tetrahalogenated aromatic hydrocarbon or heteroaromatic hydrocarbon.

[0076] The halogen can be F, Cl, Br or I.

[0077] Preferably, the electrophilic reagent has a leaving group selected from nitro (NO2), F, Cl, Br and I.

[0078] S N Non-limiting examples of Ar are reactions A, B, C, D, E, and F, which are shown in ●Regarding reaction scheme A for reaction A, ●Regarding reaction scheme B for reaction B, ●For reaction scheme C, ●For reaction scheme D, ●Regarding reaction scheme E and ●Reaction scheme F for reaction F.

[0079] Reaction scheme A for reaction A Reaction scheme B for reaction B Reaction scheme C for reaction C Reaction scheme D Reaction scheme E for reaction E Reaction scheme F Another subject of the invention is a method for carrying out nucleophilic aromatic substitution reactions as described herein, and also with all its embodiments, wherein The nucleophilic aromatic substitution reaction is selected from the group consisting of reaction A, reaction B, reaction C, reaction D, reaction E, and reaction F; Each of these reactions is shown in the corresponding reaction schemes A, B, C, D, E, and F.

[0080] In one embodiment of the invention, the subject matter of the invention is a method for carrying out nucleophilic aromatic substitution reactions as described herein, and also in all its embodiments, wherein The nucleophilic aromatic substitution reaction is reaction A as shown in reaction scheme A.

[0081] Reaction A is preferably carried out using a surfactant as poloxamer 407; and / or Reaction A is preferably carried out using a base such as K2CO3, K3PO4 or KOH.

[0082] In one embodiment of the invention, the subject matter of the invention is a method for carrying out nucleophilic aromatic substitution reactions as described herein, and also in all its embodiments, wherein The nucleophilic aromatic substitution reaction is reaction B as shown in reaction scheme B.

[0083] Reaction B is preferably carried out using a surfactant as poloxamer 407 or poloxamer P338; and / or Reaction B is preferably carried out using a base that is K2CO3.

[0084] In one embodiment of the invention, the subject matter of the invention is a method for carrying out nucleophilic aromatic substitution reactions as described herein, and also in all its embodiments, wherein The nucleophilic aromatic substitution reaction is reaction C as shown in reaction scheme C.

[0085] Reaction C is preferably carried out using a surfactant as poloxamer P338; and / or Reaction C is preferably carried out using a base, K2CO3.

[0086] In one embodiment of the invention, the subject matter of the invention is a method for carrying out nucleophilic aromatic substitution reactions as described herein, and also in all its embodiments, wherein The nucleophilic aromatic substitution reaction is reaction D as shown in reaction scheme D.

[0087] Reaction D is preferably carried out using a surfactant as poloxamer P407 or poloxamer P338; and / or Reaction D is preferably carried out using a base such as KOH, K2CO3 or K3PO4.

[0088] In one embodiment of the invention, the subject matter of the invention is a method for carrying out nucleophilic aromatic substitution reactions as described herein, and also in all its embodiments, wherein The nucleophilic aromatic substitution reaction is reaction E as shown in reaction scheme E.

[0089] Reaction E is preferably carried out using a surfactant selected from the group consisting of poloxamer 407, poloxamer 338, poloxamer 188, and poloxamer 124; more preferably using a surfactant selected from the group consisting of poloxamer 407, poloxamer 338, and poloxamer 188; and / or Reaction E is preferably carried out using a base, K3PO4.

[0090] In one embodiment of the invention, the subject matter of the invention is a method for carrying out nucleophilic aromatic substitution reactions as described herein, and also in all its embodiments, wherein The nucleophilic aromatic substitution reaction is reaction F as shown in reaction scheme F.

[0091] Reaction F is preferably carried out using a surfactant as poloxamer 407; and / or Reaction F is preferably carried out using a base, K3PO4.

[0092] In one embodiment, the aqueous medium contains NaCl in a molar excess of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 molar excess based on the substrate (aromatic electrophilic reagent), wherein a lower excess is preferred over a higher excess. In particular, the aqueous medium does not contain NaCl.

[0093] In one embodiment, the aqueous medium contains sodium halide in a molar excess of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 molar excess based on the substrate (aromatic electrophilic reagent), wherein a lower excess is preferred over a higher excess. In particular, the aqueous medium does not contain sodium halides.

[0094] In one embodiment, the aqueous medium contains an alkali metal chloride in a molar excess of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 times the molar excess of the substrate (aromatic electrophilic reagent), wherein a lower excess is preferred over a higher excess. In particular, the aqueous medium does not contain alkali metal chlorides.

[0095] In one embodiment, the aqueous medium contains an alkali metal halide with a molar excess of less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 times the molar excess of the substrate (aromatic electrophilic reagent), wherein a lower excess is preferred over a higher excess. In particular, the aqueous medium does not contain alkali metal halides.

[0096] This invention provides a method for carrying out the reaction, comprising the following steps: (a) A reaction mixture comprising an aqueous medium and reactants as said nucleophile and aromatic electrophile, and (b) Allowing chemical reactions to proceed in order to produce products.

[0097] The products can be separated by means and techniques known in the art after the reaction, including, for example, solvent evaporation, coagulation or crystallization and filtration, phase separation, chromatographic separation and others.

[0098] Abbreviations and definitions used throughout the instruction manual MeCN acetonitrile Critical micelle concentration (CMC) DCM dichloromethane DIPEAN, N-diisopropylethylamine DMAN, N-dimethylacetamide DMFN, N-dimethylformamide DMSO dimethyl sulfoxide EO ethylene oxide or ethylene oxide residues (as applicable) EOW enhancement relative to water EWG electron-withdrawing group In this invention, halides are defined as fluorides, chlorides, bromides, or iodides. HLB hydrophilic-lipophilic balance Me-THF2-methyltetrahydrofuran na is not applicable NAS nucleophilic aromatic substitution reaction NBPN-Butyl-2-pyrrolidone, IUPAC 1-Butylpyrrolidone-2-one, sometimes also called N-Butylpyrrolidone, CAS 3470-98-2 NMPN-Methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, IUPAC 1-methylpyrrolidone-2-one, CAS872-50-4 PO propylene oxide or propylene oxide residue, depending on the situation. PEO (polyethylene oxide) or polypropylene oxide residues (as the case may be). PPO (polypropylene oxide) or polypropylene oxide residues (as applicable) RPM (revolutions per minute) SnAr nucleophilic aromatic substitution reaction THF tetrahydrofuran TLC (Thin-Layer Chromatography) wt% (weight percentage) is also abbreviated as "% m / m" in the BASF manual.

[0099] Unless otherwise explicitly stated, any wt% (weight %) of surfactants is based on the amount in the aqueous medium.

[0100] The wt% or % m / m of PEO in poloxamer is based on the weight of poloxamer.

[0101] Examples and materials Material Poloxamer 124 was obtained from Spectrum Chemical (Pluracare) TM L 44) Poloxamer 188 is sourced from Aldrich (Kolliphor™ P188). Poloxamer 338 is derived from Aldrich (Kolliphor™ P338), and will be abbreviated as P338 in this article. Poloxamer 407 is sourced from BASF and is referred to as P407 (Kolliphor™ P407) in this article. TPGS-750-MCAS 1309573-60-1, Source: Aldrich The average value of n is between 16 and 17. TPGS-1000 CAS 9002-96-4, also known as Vitamin E TPGS or Kolliphor TM TPGS, source: BASF The average value of n is between 22 and 23. Example (I) Model reaction 1 of 2-bromo-1-fluoro-4-nitrobenzene with benzimidazole Model reaction 1, used to evaluate various surfactants, involves nucleophilic aromatic substitution between 2-bromo-1-fluoro-4-nitrobenzene and benzimidazole as shown in Scheme 1, and is an example of reaction E shown in Scheme E: Option 1 (A) Scheme for the procedure of Model Reaction 1: The reaction is carried out in a 20 ml glass vial placed in an aluminum block heater equipped with a thermostat and magnetic stirrer. The aluminum block is preheated to the desired temperature.

[0102] Add 8.00 ml of water or an aqueous surfactant (2 wt% surfactant based on the amount of water) to a vial containing a magnetic stir bar and placed in a preheated heating block. Add approximately 4.02 mmol (weighed 0.475 g + / - 2%) of benzimidazole, followed by approximately 4.04 mmol (weighed 0.890 g + / - 2%) of 2-bromo-1-fluoro-4-nitrobenzene, and then 0.880 g (4.14 mmol) of K3PO4. Seal the vial and stir at 400 RPM for 18 h at 45 °C.

[0103] The reaction was quenched by extracting the organic reagent and product into ethyl acetate: the reaction mixture was poured into a 40 ml vial. The first extraction was completed by adding 20 ml of EtOAc and heating to near reflux in a 90°C heating block with stirring, followed by phase separation. The next four extractions, each using 10 ml of EtOAc, were similarly heated and stirred, and then spotted onto a fluorescent TLC plate to determine when the extraction was complete. After the fifth extraction, no spots were visible on the fluorescent TLC plate, indicating that the extraction was complete. The organic fractions were combined and rotary evaporated to dryness to provide the dried product.

[0104] (B) Protocol for NMR analysis of the reaction mixture: To accurately and reproducibly determine the extent of the reaction, the dried product obtained from (A) was redissolved in a mixture of 20 ml DCM and 6 ml MeOH to accurately reflect the integral of the imide protons in the NMR spectra of both the reactants and products. Approximately 1 ml of this solution was dried in a vial by rotary evaporation and then redissolved in d6-DMSO. Proton spectra were recorded on a 600 MHz Varian NMR. The benzimidazole imide protons were observed as a singlet at approximately 8.24 ppm and decreased as the reaction progressed. The imide protons of the product were observed as a singlet at approximately 8.56 ppm and increased as the reaction progressed. The areas of these peaks were used to determine the extent of the reaction, i.e., % conversion: Table 1 shows the conversion rates with and without the use of multiple surfactants (2 wt% surfactant based on the amount of water). (C) Scheme used to determine the extent of reaction at 90°C relative to time. Compare the conversion rates in water versus in 2 wt% poloxamer 407, where wt% is based on the amount of water. Using protocol (A), a separate reaction was established and stirred at 90°C for a specific time period. At predetermined time points, the reaction mixture was quenched by pouring it onto ice (8 to 10 g) in 40 ml vials, followed by extraction of the organic compound into 10 ml aliquots of ethyl acetate until no spots were visible on a fluorescent TLC plate. The extracts were combined and rotary evaporated to dryness. NMR analysis and calculation of the extent of reaction (% conversion) were performed as described in protocol (B). Table 2 shows the results. Figure 1 The data in Table 2 show a comparison of conversion rates in water versus in 2 wt% poloxamer 407 at 90°C compared to reaction time.

[0105] (II) Model reaction of 4-methoxyphenol with 2-bromo-1-fluoro-4-nitrobenzene 2 Scheme 2, an example of reaction F shown in reaction scheme F, shows a model reaction 2 of 4-methoxyphenol with 2-bromo-1-fluoro-4-nitrobenzene.

[0106] Option 2 Example 16 - Water 8.00 ml of distilled water was placed in a 20 ml vial and preheated to 45°C. Approximately 4.02 mmol of 4-methoxyphenol (weighed at 0.4988 g + / - 2%) was added with stirring. Then, approximately 4.05 mmol of 2-bromo-1-fluoro-4-nitrobenzene (weighed at 0.8902 g + / - 2%) was added with stirring. Finally, K3PO4 (0.8802 g, 4.15 mmol) was added with stirring. The vial was sealed and placed in a 90°C heating block with stirring for 1 h. The organic reagent and product quenching reaction were extracted from the aqueous layer using an aliquot of 20 ml EtOAc. A total of four 20 ml extractions were performed, with no obvious spots observed in the fourth extract when analyzed on a fluorescent TLC plate. All four extracts were combined and rotary evaporated to dryness. The entire sample was redissolved in a mixture of 20 ml DCM and 6 ml MeOH. 1 ml of the solution was rotary evaporated to dryness and redissolved in d6-DMSO. Proton NMR was acquired on a Varian 600 MHz spectrometer, and the resulting proton spectra were integrated relative to the four aromatic protons on the starting phenol (6.68 to 6.80 ppm) and the same four protons on the product (7.05 to 7.23 ppm). The percentage conversion was given by multiplying the area of ​​the signal of these protons on the product by the sum of the areas of the signals of these protons on the starting phenol and the product by 100. The reaction was determined to be 68% complete (68% conversion rate).

[0107] Example 17 - 2 wt% Poloxamer 407 Example 16 was repeated, except that 2 wt% poloxamer 407 in 8.00 ml of distilled water was used instead of 8.00 ml of distilled water in a 20 ml vial and preheated to 45°C. 4-Methoxyphenol (0.4996 g, 4.02 mmol) was added with stirring. 2-Bromo-1-fluoro-4-nitrobenzene (0.8896 g, 4.04 mmol) was added with stirring. Finally, K3PO4 (0.8803 g, 4.15 mmol) was added with stirring. The vial was sealed and placed in a 90°C heating block with stirring for 1 hour. The organic reagent and product quenching reaction were extracted from the aqueous layer using an aliquot of 20 ml EtOAc. A total of 4 x 20 ml extractions were performed, with no obvious spots observed in the fourth extract when spotted onto a fluorescent TLC plate. All four extracts were combined and rotary evaporated to dryness. The entire sample was redissolved in a mixture of 20 ml DCM and 6 ml MeOH. 1 ml of the solution was rotary evaporated to dryness and redissolved in d6-DMSO. Proton NMR was acquired on a Varian 600 MHz spectrometer, and the resulting proton spectra were integrated relative to the starting phenol and the product. The reaction was confirmed to be 96% complete (96% conversion) by the corresponding NMR analysis described in Example 16, significantly higher than in water alone.

[0108] Example 18 – Surfactant Concentration Model reaction 1 was completed according to scheme (A) using various amounts of surfactant P407 as shown in Table 3: (*) Enhanced efficiency (EOW) relative to water is the percentage conversion in the presence of a surfactant divided by the percentage conversion without the surfactant, all other things being equal. For example, for 0.05 wt% P407, the EOW is 27 / 6 = 4.5. Further examples 21 to 29, and comparative examples Comparative Example A and Comparative Example B Complete the following reactions A, B, C, and D according to the corresponding reaction schemes A, B, C, and D.

[0109] raw materials Use the following raw materials: Scheme of the reaction Surfactant solution preparation To prepare a 2 wt% solution (wt% of surfactant is based on the weight of the surfactant solution), 2 g of surfactant was placed in a 250 mL flask, followed by the addition of 98 mL of deionized water. The mixture was then incubated at ambient temperature with stirring at 1000 rpm for 2 hours.

[0110] Experimental Procedure The reaction was carried out in a 5 mL microwave-safe bottle equipped with a magnetic stir bar, placed in an aluminum block, and connected to a temperature probe.

[0111] Add the substrate (0.70 – 0.85 mmol, 1 equivalent) to the vial, followed by the reagent (0.70 – 0.85 mmol, 1 equivalent) and the base (0.71 – 0.87 mmol, 1.02 equivalent).

[0112] Then, 2 mL of surfactant aqueous solution was added, the vial was sealed, placed in an aluminum block, and the heterogeneous mixture was stirred at 700 rpm for 16 h at 50 °C.

[0113] To quench the reaction, 6 mL of ethyl acetate was added and the resulting mixture was stirred for 20 minutes, followed by phase separation, in which the aqueous layer was at the bottom and the organic layer was at the top.

[0114] Scheme of the analysis Calibration curve Calibration curves were generated by preparing five standard solutions (0.1 mg / mL, 0.2 mg / mL, 0.4 mg / mL, 0.8 mg / mL, and 1.0 mg / mL) of analytical reference standards with known concentrations.

[0115] The analytical reference standard is the corresponding product of the corresponding reaction, which is not purchased, but synthesized internally and quantified according to a known and standardized procedure.

[0116] These standard solutions were analyzed by HPLC, and the peak area of ​​each injection was used to generate a graph of peak area (AU) versus concentration (mg / mL), thus obtaining a high coefficient of determination (R²). 2 (≥ 0.9995) Fits a linear curve to the measured data.

[0117] Method: HPLC analysis Using YMC Triart C18 columns (50 mm x 3 mm ID, 3 µm) and: Eluent A: 0.05 vol% TFA (trifluoroacetic acid) in water Eluent B: 0.05 vol% TFA (trifluoroacetic acid) in acetonitrile was analyzed by HPLC. Yield calculation via HPLC Generally, to maintain within the calibration curve range, an aliquot of the organic layer (contained in a 5 mL microwave-safe vial for the reaction) is taken and diluted to 1 mL with acetonitrile to obtain a solution with a final concentration of 0.7 mg / mL. Then, 400 µL of the latter is transferred to a filter flask and subsequently injected into the HPLC. The volume of the aliquot to be sampled is calculated according to Equation 1.

[0118] Equation 1: C1 x V1 = C2 x V2 in: C1 = 0.7 mg / mL was used as a fixed value (to keep it within the calibration curve range).

[0119] V1 = The volume used for dilution (i.e., diluting with acetonitrile to 1 mL).

[0120] C2 = Maximum theoretical concentration of the product in 6 mL of ethyl acetate V2 = Volume of the equal portions of the sample to be taken.

[0121] The peak area obtained from the HPLC chromatogram was measured to determine the concentration using a calibration curve; simultaneously, the actual yield was calculated according to Equation 2: Equation 2 Table with parameters and yields of the examples The reaction A is carried out using substrate SA as the substrate and reagent RA as the reagent, and product PA is provided as the product.

[0122] The reaction B is carried out using substrate SB as the substrate and reagent RB as the reagent, with product PB as the product.

[0123] The reaction C is carried out using substrate SC as the substrate and reagent RC as the reagent, and product PC is provided as the product.

[0124] The reaction D was carried out using substrate SD as the substrate and reagent RD as the reagent, with product PA provided as the product.

[0125] The table shows several examples completed according to the "Reaction Protocol" and analyzed according to the "Analysis Protocol". Comparative Example (Comp) refers to a comparative instance. Comparative Example A was completed without the use of a surfactant, while Comparative Example B was completed using TPGS-750-M as the surfactant.

Claims

1. A method for performing a nucleophilic aromatic substitution reaction, comprising: combining a nucleophile and an aromatic electrophile in an aqueous medium; the aqueous medium comprising water, a base, and a surfactant, the surfactant being a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer; the amount of water in the aqueous medium being at least 50 wt%; the combined amount of water, the base, and the surfactant being at least 70 wt% of the aqueous medium; the wt% being based on the weight of the aqueous medium.

2. The method according to claim 1, wherein the surfactant is a compound of formula (I), a is an integer from 5 to 250, b is an integer from 15 to 70; preferably, a is an integer from 10 to 150 and b is an integer from 15 to 70; more preferably, a is from 30 to 110, even more preferably 50 to 110, in particular 70 to 110, more in particular 90 to 110; more preferably, b is an integer from 20 to 70, even more preferably 20 to 60, in particular 30 to 60, more in particular 50 to 60; even more preferably, a is from 90 to 110 and b is from 50 to 60.

3. The method according to claims 1 to 2, wherein the surfactant has a molecular weight of the polypropylene oxide fraction of 1'450 to 4'100 g / mol and a weight percentage of the polyethylene oxide fraction of 35 to 85 wt%; preferably, a molecular weight of the polypropylene oxide fraction of 1'925 to 4'100 g / mol and a weight percentage of the polyethylene oxide fraction of 45 to 85 wt%; more preferably, a molecular weight of the polypropylene oxide fraction of 2'150 to 4'100 g / mol and a weight percentage of the polyethylene oxide fraction of 65 to 85 wt%; even more preferably, a molecular weight of the polypropylene oxide fraction of 2'500 to 4'100 g / mol and a weight percentage of the polyethylene oxide fraction of 65 to 85 wt%; in particular, a molecular weight of the polypropylene oxide fraction of 3'000 to 4'100 g / mol and a weight percentage of the polyethylene oxide fraction of 65 to 85 wt%; more in particular, a molecular weight of the polypropylene oxide fraction of 3'625 to 4'100 g / mol and a weight percentage of the polyethylene oxide fraction of 65 to 85 wt%; wherein the wt% is based on the weight of the surfactant.

4. The method according to one or more of claims 1 to 3, wherein the aqueous medium comprises at least 60 wt%, preferably at least 70 wt%, more preferably at least 80 wt%, even more preferably at least 85 wt%, in particular at least 90 wt% of water, wherein the wt% is based on the weight of the aqueous medium.

5. The method according to one or more of claims 1 to 4, wherein the combined amount of water, the base, and the surfactant is at least 80 wt%, more preferably at least 90 wt%; the wt% being based on the weight of the aqueous medium.

6. The process according to one or more of claims 1 to 5, wherein the aqueous medium comprises an organic solvent, the organic solvent is an additional solvent component to the aqueous medium other than the water.

7. The process according to claim 6, wherein said organic solvent is selected from the group consisting of THF, Me-THF, NMP, NBP, DMSO, DMF, DMA, nitromethane, C 1-3 alcohols, ethylene glycol C 1-4 monoalkyl ethers, diethylene glycol C 1-4 monoalkyl ethers, MeCN and any mixture thereof; the organic solvent is preferably selected from the group consisting of THF, Me-THF, DMF, DMA, methanol, ethanol, n-propanol, isopropanol, 2-butoxyethanol, 2-ethoxyethanol, diethylene glycol monobutyl ether, diethylene glycol monomethyl ether, MeCN, and any mixture thereof.

8. The process according to claim 6 or 7, wherein the aqueous medium comprises 20 wt% or less, preferably 15 wt% or less, even more preferably 10 wt% or less of the organic solvent, wherein the wt% is based on the weight of the aqueous medium.

9. The process according to one or more of claims 1 to 8, wherein the lower limit of the amount of surfactant is 0.01 wt%, 0.02 wt%, 0.05 wt%, 0.075 wt%, 0.1 wt%, 0.25 wt%, 0.5 wt%; wherein a higher value is preferred compared to a lower value; and / or the upper limit of the amount of surfactant is 20 wt%, 15 wt%, 10 wt%, 7.5 wt%, 5 wt%, 3 wt%, wherein a lower value is preferred compared to a higher value; preferably, the amount of surfactant is 0.01 to 20 wt%, 0.01 to 15 wt%, 0.01 to 10 wt%, 0.02 to 10 wt%, 0.05 to 10 wt%, 0.075 to 10 wt%, 0.1 to 10 wt%, 0.1 to 7.5 wt%, 0.1 to 5 wt%, 0.25 to 5 wt%, 0.5 to 5 wt%, 0.5 to 3 wt%, wherein a broader range is preferred compared to a narrower range; wherein the wt% is based on the weight of the aqueous medium.

10. The process according to one or more of claims 1 to 9, wherein the reaction temperature is 30 to 200 °C, preferably 45 to 180 °C, more preferably 60 to 160 °C.

11. The process according to one or more of claims 1 to 10, wherein the base has a pKb of 0 to 6.8, preferably 1 to 6.8, more preferably 1 to 5, even more preferably 1.5 to 4.

5.

12. The process according to one or more of claims 1 to 11, wherein the base is selected from the group consisting of R20(R21)(R22)N, alkaline earth metal salts of carbonates, phosphates and hydroxides, and any mixture thereof; preferably selected from the group consisting of R20(R21)(R22)N, and Li, Na, K and Cs salts of carbonates, phosphates and hydroxides, and any mixture thereof; more preferably selected from the group consisting of R20(R21)(R22)N, and Na and K salts of carbonates, phosphates and hydroxides, and any mixture thereof; even more preferably selected from the group consisting of R20(R21)(R22)N, potassium salts of carbonates, phosphates and hydroxides, and any mixture thereof; in particular selected from the group consisting of R20(R21)(R22)N, potassium salts of carbonic acid and phosphoric acid, and any mixture thereof; wherein any of the mentioned R20, R21and R22are the same or different and independently from each other selected from the group consisting of methyl, ethyl, 2-hydroxyethyl, n-propyl, isopropyl, 2-hydroxypropyl, n-butyl, isobutyl and tert-butyl; more preferably, R20, R21and R22are the same or different and independently from each other selected from the group consisting of ethyl and isopropyl; even more preferably, R20(R21)(R22)N is Et3N, triisopropylamine or DIPEA; in particular, the base is selected from the group consisting of Et3N, triisopropylamine, DIPEA, K2CO3, K3PO4, and any mixture thereof.

13. The method according to one or more of claims 1 to 12, wherein the base is present in the reaction mixture in at least stoichiometric molar amounts based on the molar amount of the electrophile; preferably, the amount of base is 1 to 10 equivalents, more preferably 1 to 7.5 equivalents, even more preferably 1 to 5 equivalents, in particular 1 to 4 equivalents, the equivalents being molar equivalents based on the molar amount of the electrophile.

14. The method according to one or more of claims 1 to 13, wherein the nucleophile provides an electron to the electrophile from an atom selected from N, O or S (II).

15. The method according to one or more of claims 1 to 14, wherein The nucleophile is selected from the group consisting of anilines, substituted anilines, heteroaryl amines, internal ring sp 2 - heterocycles with hybridized nitrogen atoms, primary and secondary alkyl amines, phenols, substituted phenols, heteroaryl phenols, primary and secondary alcohols, and mercaptans.

16. The method according to one or more of claims 1 to 15, wherein the electrophile is a mono-, di-, tri- or tetra-halogenated arene or heteroarene.

17. The method according to one or more of claims 1 to 15, wherein the electrophile has a leaving group selected from nitro (NO2), F, CI, Br and I.

18. The method according to one or more of claims 1 to 13, wherein the nucleophilic aromatic substitution reaction is selected from the group of Reaction A, Reaction B, Reaction C, Reaction D, Reaction E and Reaction F; wherein each of these reactions is as exhibited in the corresponding reaction schemes A, B, C, D, E and F; Reaction Scheme A for Reaction A Reaction Scheme B for Reaction B Reaction Scheme C for Reaction C Reaction Scheme D for Reaction D Reaction Scheme E for Reaction E Reaction Scheme F for Reaction F Reaction Scheme E for Reaction E preferably, the nucleophilic aromatic substitution reaction is selected from the group of Reaction A, Reaction B, Reaction C and Reaction D.

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