New amine N-oxide compounds
Patent Information
- Application Number
- JP2024518094
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2021-09-21
- Filing Date
- 2022-09-21
- Publication Date
- 2025-09-29
AI Technical Summary
Existing methods for synthesizing amine N-oxides as surfactants are inefficient and rely on non-renewable starting materials, with low yields and high environmental impact, limiting their industrial applicability.
A three-step process involving Betti/Mannich aminoalkylation, Williamson etherification, and oxidation is used to synthesize amine N-oxides from lignin-derived phenol derivatives, utilizing environmentally friendly conditions and achieving yields over 90%.
The process produces amine N-oxides suitable as surfactants with high hydrophilicity and hydrophobicity, suitable for industrial use, and demonstrates improved yield and environmental sustainability.
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Abstract
Description
[Technical field]
[0001] The present invention relates to a process for preparing novel amine N-oxide compounds, the compounds so prepared, and their use as surfactants. [Background technology]
[0002] 2. Background of the Invention Lignin is an abundant aromatic biopolymer, the structure of which is mainly based on three substituted phenols, the so-called monolignols (p-coumaryl, coniferyl and sinapyl alcohol), characterized by a variety of different C-O and C-C bonds that form an amorphous three-dimensional structure. Various methods have been developed that allow the catalytic decomposition of lignin by depolymerization to obtain industrially usable monomolecular phenol and / or benzaldehyde derivatives. In addition to monomers, the products of these depolymerization processes may also include di-, tri- and oligomers of phenols.
[0003] More recently, various methods have been developed that allow for the selective depolymerization of lignin, mainly involving reductive or oxidative reaction strategies. The former usually produce phenols, guaiacol or syringol derivatives with aliphatic radicals, usually 1 to 3 carbon atoms in length, bearing alcohol, aldehyde, ester and / or ketone functionality, whereas the latter usually give aromatic aldehydes, such as vanillin and syringaldehyde, or similarly functionalized guaiacol and syringol derivatives. The main products of such depolymerization processes include guaiacol and syringol, or vanillin and syringaldehyde, respectively, which often bear one or more alkyl and / or alkoxy substituents on the aromatic ring.
[0004] All the mentioned lignin degradation products are valuable biologically based resources from which many different products have been produced in recent years. Our research shows that surfactants are few and far between, but even in this field there is a need for products that can be synthesized based on non-edible, renewable raw materials.
[0005] In the literature, zwitterionic amine N-oxides are disclosed for use as surfactants, in addition to a large number of other amphiphilic compounds, generally consisting of hydrophobic hydrocarbons with one or more ionic hydrophilic groups, such as carboxylic acids, sulfonic acids and quaternary ammonium salts. However, these are in fact almost exclusively N-oxides of fatty amines, i.e. tertiary alkylamines with 8 or more, for example at least 12, carbon atoms. However, among them, it is virtually impossible to find amine N-oxides with aromatic radicals.
[0006] The inventors are currently aware of only a handful of publications in which such amine N-oxides are disclosed as surfactants, for example Goracci et al., ChemBioChem 6(1), 197-203 (2005), Cesareti et al., Phys. Chem. Chem. Phys. 17(26), 17214-17220 (2015), and Gabriele et al., Langmuir 34(38), 11510-11517 (2018). However, in all cases the same amine N-oxide is always described and discussed, namely 4- or p-dodecyloxybenzyldimethylamine N-oxide (abbreviation: "pDoAO"):
[0007] [ka]
[0008] Goracci et al. in 2005 described a process for the preparation of this material, involving the reaction of p-dodecyloxybenzyl bromide with dimethylamine, followed by oxidation of the amine with hydrogen peroxide, with a combined yield of 88% for both stages, according to the following scheme:
[0009] [ka]
[0010] A few years later, Di Crescenzo et al., Eur. J. Org. Chem. 28, 5641-5648 (2011) also described the synthesis of p-dodecyloxybenzyl bromide starting from 4-hydroxybenzaldehyde by first etherifying the OH group with dodecyl bromide, then reducing the aldehyde group to OH with NaBH4, which is exchanged for bromine with PBr3 (however, this bromide is not then converted to the amine N-oxide pDoAO, but rather reacts with trimethylamine to form the quaternary ammonium salt p-dodecyloxybenzyltrimethylammonium bromide, called pDoTABr), as shown below:
[0011] [ka]
[0012] The combined yield of the first two of these three steps is given by Di Crescenzo et al. as 85%, but there is no corresponding value for the final bromination step. If the optimal yield of the bromination step is taken as 100%, the overall yield of the entire reaction sequence for the synthesis of pDoAO from 4-hydroxybenzaldehyde is about 75%; however, if a more realistic yield of 95% is assumed for the bromination step, the overall yield is only about 70%. In principle, this is not a bad value for a five-step synthesis process, but in practice it is still not satisfactory for industrial-scale synthesis.
[0013] Moreover, 4-hydroxybenzaldehyde is not one of the usual lignin degradation products. Rather, as mentioned above, they mainly contain phenols or benzaldehydes, multiply substituted with alkyl and / or alkoxy. Therefore, 4-hydroxybenzaldehyde is not considered an economic starting product, and in any case not a biologically based resource. The same applies to the reagents NaBH4 and PBr3 used in stoichiometric amounts in the above synthetic process to produce pDoAO.
[0014] Against this background, the object of the present invention was to develop a novel synthetic process for the preparation of aromatic amine N-oxides suitable as surfactants by functionalization of products occurring in large amounts in the course of lignin decomposition or similar compounds, and preferably in an environmentally friendly manner. Summary of the Invention
[0015] In a first aspect, the present invention provides a compound represented by the following formula (I) or (II):
[0016] [ka]
[0017] [In the formula, Each R 1 is selected from linear, branched or cyclic hydrocarbon radicals having from 4 to 26 carbon atoms, where optionally at least one carbon atom is replaced by an oxygen or sulfur atom; R 2 , R 3 and R 5 are each independently hydrogen, R 1 -O-, R 8 and in formula (I) is selected from -CH2-N + (O - )R 6 R 6 Also selected from, where R 8represents a linear, branched or cyclic hydrocarbon radical having 1 to 26 carbon atoms, where optionally at least one carbon atom is replaced by an oxygen or sulfur atom; R 4 is hydrogen and R 8 Selected from; and Each radical R 6 are independently selected from saturated linear or branched hydrocarbon radicals having from 1 to 6 carbon atoms, where optionally at least one carbon atom is replaced by a nitrogen, oxygen or sulfur atom; where, optionally, two radicals R bound to the same nitrogen atom 6 may be joined to form a 5- or 6-membered nitrogen-containing ring, or wherein optionally, the amine N-oxide moiety -N + (O - )R 6 R 6 One or both radicals R 6 is a radical R of one or both of such moieties of other molecules of formula (I) 6 Binding to the structure
[0018] [ka]
[0019] (wherein the dashed lines represent the two radicals R 6 The symbols indicate optional bonds between the rings, and the asterisks indicate the connection of bridges to the two aromatic rings. to form a bridge having the formula (II). 1. A process for preparing an amine N-oxide compound according to The method of the present invention comprises the steps of: 1) In a polar solvent, in the presence of formaldehyde, the Betti / Mannich aminoalkylation reaction can be carried out to give the following formula (III):
[0020] [ka]
[0021] [In the formula, each R 7 are independently hydrogen, hydroxy, and R 8 Selected from. The phenol derivative is converted to a secondary amine HNR 6 R 6 whereby the hydrogen atom ortho to the phenolic OH group and optionally other replaceable hydrogen atoms R of the phenol derivative of formula (II) are reacted with 7 -CH2-NR 6 R 6 With the moiety (respectively) of formula (IV) or (V):
[0022] [ka]
[0023] [In the formula, each R 7 are independently hydrogen, hydroxy, R 8 and in formula (IV) is selected from -CH-NR 6 R 6 Also selected from. to obtain the corresponding Betti base; 2) the (two) phenolic OH groups and, optionally, any further free OH groups R of the Betti base of formula (IV) or (V), respectively, by etherification according to Williamson in the presence of a base, in an organic solvent or without a solvent; 7 , the formula R 1 -X, where X represents a leaving group selected from halide and sulfonate, to give a compound of formula (VI) or (VII):
[0024] [ka]
[0025] [In the formula, each R 7 are independently hydrogen, R 1 -O-, R8 and in formula (VI) is selected from -CH-NR 6 R 6 Also selected from. to obtain the corresponding ether; and 3) by reaction with an oxidizing agent in water, an organic solvent or a mixture thereof, to afford any amino group -NR 6 R 6 to obtain an amine N-oxide compound of formula (I) or (II); This object is achieved by providing a method, which includes:
[0026] Thus, according to the invention, it is possible to synthesize amine N-oxide compounds from phenol derivatives of formula (III) by a relatively simple and inexpensive method involving a series of known individual reactions. The method according to the invention involves only three reaction steps, i.e. two less than the process for the preparation of the only known aromatic amine, N-oxide pDoAO, derivable from the combined disclosure of Di Crescenzo et al. and Goracci et al. mentioned at the beginning, whereby, according to the invention, compounds according to formula (I) or (II) may be obtained even in total yields of more than 90%. In a preferred embodiment, the starting compounds are also readily accessible products of lignin depolymerization, and the method is carried out in the most environmentally friendly way possible, since in particular both the aminoalkylation according to Betti / Mannich and the etherification of the products according to Williamson are characterized by a high level of atom economy.
[0027] Furthermore, in a preferred embodiment of the process, the Betti / Mannich aminoalkylation in step 1) is carried out in water, more preferably at room temperature, which avoids the use of solvents and large amounts of energy and, surprisingly, also allows for high yields. However, organic solvents such as alcohols, e.g. methanol, ethanol, (iso)propanol, acetonitrile or toluene, can also be used instead of or mixed with water. However, it is preferred to use water as the only solvent, as long as the solubility of the phenol derivative of formula (III) allows this.
[0028] The latter is preferably reacted with 1.05 equivalents, more preferably 1.5 equivalents each of secondary amine and formaldehyde in step 1) to ensure complete aminoalkylation at only one aromatic position if a monomeric amine N-oxide compound of formula (I) is desired. If double aminoalkylation is desired, two -CH-NR 6 R 6 To introduce moieties into the ortho positions, the starting compound used is preferably a phenol derivative of formula (III) in which the two ortho positions are unsubstituted, but the para position is very fully substituted, e.g., alkylated. When only one ortho hydrogen atom can be substituted, an isomeric mixture of doubly aminoalkylated Betti bases of formula (IV) is often obtained. However, when preparing dimeric amine N-oxide compounds according to formula (II), the phenol derivative of formula (III) is preferably used in a ratio of 2:1 to the secondary diamine (or dimer of secondary amine).
[0029] Alternatively or additionally, in some preferred embodiments of the process, the etherification step 2) is carried out using a solid base in the presence of a phase transfer catalyst in a solid-liquid phase transfer reaction to increase the conversion. Our experiments using the standard protocol of etherification according to Williamson, i.e., in single phase in various solvents at various temperatures with various base solutions, also gave the desired compounds, but with the formation of by-products to a greater or lesser extent. This is because the Betti base of formula (IV) with a free OH group in the ortho position tends to decompose to form the respective ortho quinone methide, as shown below:
[0030] [ka]
[0031] Orthoquinone methides are highly reactive and prone to polymerization, so no Betti aminoalkylation reactions using similar starting compounds are known in the literature.
[0032] The fact that both heat and the presence of base (or acid) promote the decomposition of the Betti base and the polymerization of the ortho-quinone methide is another reason for our favorable reaction control in step 1), on the one hand, and for our progress in the solid-liquid phase transfer reaction in step 2), on the other hand. This is especially true for the dimeric Betti base of formula (V), which is more prone to decomposition and polymerization due to the presence of two susceptible moieties.
[0033] In a particularly preferred embodiment, the base is added in solid form to the respective Betti base of formula (IV) or (V), and the reactants react with each other in an organic solvent or without solvent, especially at room temperature. Particularly preferred is the use of chloride or bromide as the leaving group, especially bromide, and the use of anhydrous solvent to suppress the formation of by-products. After a series of tests with other solvents such as acetonitrile, especially anhydrous 2-methyltetrahydrofuran proved to be successful, since it was the most capable of promoting the conversion and selectivity of the desired product. Sulfonates such as mesylates and tosylates can also be used as the leaving group, but the use of long-chain fatty alcohol sulfonates is uneconomical, since they are already surfactants in themselves.
[0034] As mentioned above, various aqueous solutions of alkali metal carbonates and hydroxides were initially considered as the base, but then, for the reasons mentioned above, solid powders of the base were used, with NaOH and especially powdered KOH proving to be successful. Tetra-n-butylammonium bromide (TBAB) is particularly preferred as the phase transfer catalyst according to the present invention, although other common catalysts, such as various other quaternary ammonium compounds, can also be used.
[0035] In preferred embodiments of the method according to the invention, since the purification of amphiphilic molecules is usually very complicated, step 3) is also carried out in a mild and environmentally friendly manner and with as high a quantitative conversion as possible. In some of these preferred embodiments, an aqueous solution of H2O2 is used as the oxidizing agent, optionally with methyl formate added as additional solvent, and the ether of formula (VI) or (VII) is reacted with more preferably 2.5 to 3 equivalents of H2O2 to ensure complete conversion.
[0036] When using a catalyst, an aqueous solution of H2O2 (e.g. 30%) has proven to be a good oxidizing agent, although organic solvents such as dichloromethane or acetonitrile are also suitable. To increase the solubility, especially in the case of dimeric amine N-oxides, a small amount of organic solvent can be added, for which purpose methyl formate is preferred according to the invention.
[0037] In a second aspect, the present invention also relates to a compound of formula (I) or (II) prepared by a method according to the first aspect:
[0038] [ka]
[0039] [In the formula, R 1 Or R 6 are as defined above.] The present invention provides an amine N-oxide compound according to the above.
[0040] Such amine N-oxide monomers according to formula (I) or the corresponding dimers according to formula (II) can not only be prepared in a relatively simple and environmentally friendly manner from readily available lignin degradation products, but are also highly suitable as surfactants. The high hydrophilicity of the N-oxide group and the hydrophobicity of the aromatic radical R 1 Or R 5 Even a single digit number of carbon atoms in is sufficient to confer the required amphiphilicity to the compound.
[0041] However, the radical R 1 Or R 5 The number of carbon atoms in is preferably at least 9. This means that there are two or more amine N-oxide moieties -CH2-N + (O - )R 6 R 6is aromatically linked, which is particularly favorable with respect to hydrophobicity. But also the fact that the main products of the depolymerization of lignin include not only the derivatives of guaiacol and syringol mentioned at the beginning, but also those of catechol, in particular those which are mono- or doubly substituted with lower alkyl and / or lower alkoxy, simplifies the synthesis of amine N-oxide compounds having at least 9 carbon atoms, since it only requires etherification of each free phenolic OH group with a readily available and biodegradable fatty alkyl radical.
[0042] On the one hand, fatty alcohols naturally exist in both saturated and unsaturated form, i.e. with one or more C=C double bonds, and on the other hand, as mentioned at the beginning, lignin degradation products can have more than one aromatic ring as well as non-aromatic rings (e.g. dioxolanes) as substituents, so that R 1 Or R 5 The definition includes both saturated and unsaturated as well as cyclic radicals.
[0043] The fact that in addition to the amine N-oxide monomers according to formula (I), also dimers according to formula (II) are part of the present invention is due to the synthesis starting with the aminoalkylation reaction according to Betti / Mannich, which proceeds in an analogous manner with secondary mono- or diamines, as explained in more detail in connection with the first aspect of the invention and as evidenced by the subsequent examples.
[0044] Radical R 1 Or R 5 The lower and upper limits for the number of carbon atoms indicate that fatty alkyl radicals are preferred for the etherification of the free phenolic OH groups in the starting product, the chain length of which is specified in the literature as between 4 and 6 as the lower limit and between 22 and 26 as the upper limit.
[0045] According to the invention, for the fatty alkyl radicals introduced in the course of the synthesis process by etherification, a maximum length of 18 carbon atoms is preferred, for the alkyl or alkoxy radicals or optionally alkylthio radicals already bonded to aromatics in the starting materials, a maximum length of 4 carbon atoms is preferred in each case, and the ether group R 1 Radical R in para position to -O- 4 This applies in particular to
[0046] The option that some carbon atoms may be replaced by oxygen or sulfur also refers primarily to the substitution pattern of the starting compounds, preferably obtained by lignin depolymerization, which, as mentioned at the beginning, may carry various oxygen-containing functionalities, sometimes also their sulfur analogues. Other heteroatoms, such as halogens and nitrogen, are rarely present in such compounds. The former do not interfere with the synthesis method according to the first aspect of the invention, but the radical R 1 Or R 5 The nitrogen atom in will also most likely be oxidized to an N-oxide in the final oxidation step, which will reduce the hydrophobicity of this part of the compounds according to the invention, especially if the nitrogen atom is not located very close to an aromatic ring. Therefore, for the purposes of the present invention, heteroatoms other than oxygen and sulfur need not be considered.
[0047] However, the radical R 2 , R 3 and R 5 One or more of the amine-N-oxide moieties -CH2-N + (O - )R 6 R 6 The option that it can also be represented refers specifically to a synthetic process in which, in a first step, the aromatic ring can also be aminoalkylated in more than one position, which is indeed done, as the examples demonstrate.
[0048] Thus, in some preferred embodiments of the present invention, R 1 is C6-C 22Alkyl, more preferably C8-C 18 It is an alkyl.
[0049] Alternatively or additionally, in some preferred embodiments, R 2 is C1-C 22 Alkyl, C1-C 22 Alkoxy, and -CH2-N + (O - )R 6 R 6 More preferably, C1-C 18 Alkoxy and -CH2-N + (O - )R 6 R 6 Alternatively or additionally, in some preferred embodiments, R 3 and R 5 are hydrogen and -CH2-N, respectively. + (O - )R 6 R 6 Particularly preferably, R 3 and R 5 One of the groups is hydrogen and the other is -CH2-N + (O - )R 6 R 6 R 2 , R 3 and R 5 Option -CH2-N + (O - )R 6 R 6 refers to aromatic multiple aminoalkylation, as described above.
[0050] Alternatively or additionally, in some preferred embodiments, R 4 is selected from hydrogen, C1-C4 alkyl and C1-C4 alkoxy, more preferably selected from hydrogen and C1-C4 alkyl, most preferably C1-C4 alkyl.
[0051] In some particularly preferred embodiments, after only a single amino alkylation in the synthetic process, the following applies: R 1 But, C8-C 18 is alkyl; R 2 But, C1-C 18 is alkoxy; R 3 and R 5 are each hydrogen; and R 4 is C1-C4 alkyl, most preferably ethyl or propyl.
[0052] When a derivative of catechol with two adjacent phenolic OH groups is used as the starting material in the synthesis process, R 2 is particularly preferably C1-C 18 however, when this is not the case, for example when derivatives of guaiacol or syringol are used, R 2 is most preferably methoxy. In the latter case, when syringol is used, R 5 is also methoxy.
[0053] However, in some particularly preferred embodiments, after the double aminoalkylation in the synthesis process, the following applies: R 1 But, C8-C 18 is alkyl; R 2 But -CH2-N + (O - )R 6 R 6 and; R 3 and R 5 are each hydrogen; and R 4 is C1-C4 alkyl, most preferably ethyl or propyl.
[0054] Radical R 6can generally contain up to six carbon and optionally heteroatoms (O, S or especially N), which in certain preferred embodiments of the second aspect of the invention are each independently selected from methyl, ethyl and dimethylaminoethyl.
[0055] Alternatively or additionally, in some preferred embodiments, two radicals R attached to the same nitrogen atom 6 are connected together and together with the nitrogen atom form the group:
[0056] [ka]
[0057] (wherein the asterisks indicate the respective connections to the aromatic rings). forms one of the
[0058] In some particularly preferred embodiments, all radicals R 6 is methyl, and the moiety -N + (O - One or both methyl groups of (CH3)2 are bonded to one or both methyl groups of such moieties of other molecules of formula (I) to form the structure
[0059] [ka]
[0060] (where the dashed line indicates an optional bond between the two methyl groups, and the asterisk indicates the connection of a bridge to the two aromatic rings.) to form a bridge with, thereby forming a dimer of the amine N-oxide compound according to formula (II).
[0061] In particular, the amine N-oxide compound according to the second aspect of the invention is selected from the following compounds: N,N-Dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine N-oxide (1)
[0062] [ka]
[0063] N,N-Dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (2)
[0064] [ka]
[0065] N,N-Dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (3)
[0066] [ka]
[0067] N,N-Dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine N-oxide (4)
[0068] [ka]
[0069] N,N-Dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine N-oxide (5)
[0070] [ka]
[0071] N,N-Dimethyl-1-(5-ethyl-3-methoxy-2-octadecyloxyphenyl)methanamine N-oxide (6)
[0072] [ka]
[0073] 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine-1-oxide (7)
[0074] [ka]
[0075] 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine-1-oxide (8)
[0076] [ka]
[0077] 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine-1,4-dioxide (9)
[0078] [ka]
[0079] N,N-Dimethyl-N'-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N'-methylethane-1,2-diamine di-N-oxide (10)
[0080] [ka]
[0081] 1,1'-(2,3-dioctyloxy-5-ethyl-1,4-phenylene)-bis(N,N-dimethylmethanamine N-oxide) and 1,1'-(2,3-dioctyloxy-5-ethyl-1,6-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (11)
[0082] [ka]
[0083] 1,1'-(5-ethyl-2-octyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (12)
[0084] [ka]
[0085] 1,1'-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (13)
[0086] [ka]
[0087] 1,1'-(5-ethyl-2-hexadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (14)
[0088] [ka]
[0089] 1,1'-(5-ethyl-2-octadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (15)
[0090] [ka]
[0091] 1,4-Bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine-1,4-dioxide (16)
[0092] [ka]
[0093] 1,4-Bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine-1,4-dioxide (17)
[0094] [ka]
[0095] N,N'-Bis(5-ethyl-3-methoxy-2-octyloxybenzyl)-N,N'-dimethylethane-1,2-diamine di-N-oxide (18)
[0096] [ka]
[0097] And in a third aspect, the present invention provides a compound comprising a radical R 1 Or R 5 The present invention relates to the use as surfactants of novel amine N-oxide compounds according to formula (I) or (II), wherein the total number of carbon atoms is at least 9. [Brief description of the drawings]
[0098] [Figure 1] The only FIG. 1 shows a cryo-electron microscope image of an aqueous solution of the amine N-oxide compound (13) from Example 13, together with a schematic diagram of the micelles observed therein. EXAMPLES
[0099] The present invention is explained in more detail below by means of examples, which should not be construed as limiting the scope of protection. For illustrative purposes, two representative model compounds of common lignin depolymerization products, which are preferred as starting materials in the process according to the invention, have been used.
[0100] For this purpose, one phenol and one diphenol derivative, namely 4-ethylguaiacol (4-ethyl-2-methoxyphenol) and 4-ethylcatechol (1,2-dihydroxy-4-ethylbenzene), were reacted to give the amine N-oxide compounds according to the invention:
[0101] [ka]
[0102] These were first aminomethylated once or twice with a variety of secondary amines and diamines in the presence of formaldehyde to give the corresponding Betti bases, then etherified once or twice with a series of fatty alkyl halides, and finally oxidized to the amine N-oxides.
[0103] Example 1 Preparation of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine N-oxide (1)
[0104] [ka]
[0105] Step 1: Variant 1.1: An aqueous solution of 4-ethylguaiacol (15.20 g, 100 mmol) was added dropwise to a 40 wt% aqueous solution of dimethylamine (6.76 g, 150 mmol) in an ice-water bath within 15 min under constant stirring. Paraformaldehyde (4.50 g, 150 mmol) was added in 0.5 g aliquots every 10 min and stirred for 3 h in an ice-water bath and then at room temperature for 9 h. The volatile components were then removed on a rotary evaporator at room temperature, after which the water was removed under vacuum at 50° C. and the residue was thoroughly dried in a vacuum desiccator. The aminomethylated intermediate product 2-dimethylaminomethyl-4-ethyl-6-methoxyphenol was obtained as a viscous yellow oil (yield: 20.83 g; 99.5% of theory).
[0106] Variant 1.2: An aqueous solution of 4-ethylguaiacol (15.20 g, 100 mmol) was added dropwise to a 40 wt% aqueous solution of dimethylamine (4.56 g, 101 mmol) in an ice-water bath within 15 min under constant stirring. Paraformaldehyde (4.50 g, 150 mmol) was added in 0.5 g aliquots every 10 min and stirred for 3 h in an ice-water bath and then for 72 h at room temperature. The reaction mixture was then extracted five times with 25 ml of petroleum ether (bp.: 40-60 °C) and the combined organic phases were concentrated under reduced pressure in a rotary evaporator, after which the residue was completely dried in a vacuum desiccator. The aminomethylated intermediate 2-dimethylaminomethyl-4-ethyl-6-methoxyphenol was obtained as a viscous yellowish oil (yield: 19.43 g; 93.0% of theory).
[0107] Step 2: Variant 2.1: 2-Dimethylaminomethyl-4-ethyl-6-methoxyphenol (1.05 g, 5 mmol), 1-bromooctane (0.95 g, 4.9 mmol) and tetrabutylammonium bromide (TBAB) (0.16 g, 0.5 mmol) as catalyst were vigorously stirred in 10 ml of 2-methyltetrahydrofuran (2-MeTHF) as solvent at room temperature until a homogeneous solution was obtained, after which solid powdered KOH (0.56 g, 10 mmol) was added and stirred at room temperature for 8 h. The inorganic solid was then centrifuged and washed three times with 10 ml of diethyl ether. The combined organic phase was concentrated on a rotary evaporator, the residue was redissolved in 45 ml of petroleum ether and washed four times with 5 ml of water. The organic phase was then concentrated on a rotary evaporator and the residue was thoroughly dried in a vacuum desiccator. The etherified intermediate, N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine, was obtained as a viscous yellow oil (yield: 1.45 g; 92.3% of theory).
[0108] Variant 2.2: 2-Dimethylaminomethyl-4-ethyl-6-methoxyphenol (1.05 g, 5 mmol), 1-bromooctane (1.06 g, 5.5 mmol) and tetrabutylammonium bromide (TBAB) (0.16 g, 0.5 mmol) were vigorously stirred in 10 ml of 2-MeTHF at room temperature until a homogeneous solution was obtained, after which solid powdered KOH (0.56 g, 10 mmol) was added and stirred at room temperature for 8 h. Then 25 ml of Et2O and 5 ml of H2O were added and the aqueous phase was extracted three times with 10 ml of Et2O. The combined organic phase was concentrated on a rotary evaporator and the residue was retained on 5 g of silica gel. The residue was purified using flash chromatography on a filter column, and the etherified intermediate product, N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine, was eluted with EtO and obtained after evaporation of the ether as a viscous yellow oil (yield: 1.45 g; 92.9% of theory).
[0109] Step 3: N,N-Dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine (0.96 g, 3 mmol) was charged and 3 equivalents of 30 wt% H2O2 in water (9 mmol) was added in one portion. The cloudy reaction mixture was stirred at room temperature overnight or until it appeared clear and homogeneous, indicating complete consumption of the starting material. A catalytic amount of activated carbon or MnO2 was then added and the mixture was stirred for 24 h, or oven-dried Na2CO3 (1.06 g, 10 mmol) in 5 ml of ethanol was added and the mixture was stirred for 30 min to decompose the excess H2O2. The solid precipitate was then centrifuged and washed three times with abs. EtOH. The combined organic phase was filtered through a 0.2 μm syringe filter, then concentrated under reduced pressure on a rotary evaporator, mixed with hexane and concentrated again to completely remove EtOH. The residue was then thoroughly dried under vacuum to give the title compound (1) as a clear yellow oil (yield: 0.98 g; 97.3% of theory).
[0110] 1 H-NMR: δ H (600 MHz, chloroform-d) 6.90 (d, J = 2.0 Hz, 1H, C3), 6.81 (d, J = 2.0 Hz, 1H, C5), 4.54 (s, 2H, C12), 3.94 (t, J = 6.9, 6.9 Hz, 2H, C17), 3.86 (s, 3H, C11), 3.18 (s, 6H, C14, C15), 2.61 (q, J = 7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J = 7.1, 7.1, 6.8, 6.8 Hz, 2H, C19), 1.35-1.19 (m, 11H, C8, C20-23), 0.88 (t, J = 6.9, 6.9 Hz, 3H, C24). 13 C-NMR: (151 MHz, CDCl3) δ C152.7 (C6), 146.0 (C1), 140.4 (C4), 124.6 (C3), 123.9 (C2), 114.0 (C5), 74.0 (C17), 70.5 (C12), 57.4 (C14, C15), 55.9 (C11), HRMS: (ESI + , m / z) C 20 H 36 NO3[M+H] + Calculated value: 338.26929; Measured value: 338.26292.
[0111] Example 2 Preparation of N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (2)
[0112] [ka]
[0113] Step 1: The synthesis and production were the same as in Example 1.
[0114] Step 2: The reaction was carried out in a manner similar to that in Example 1, except that 1-bromodecane was used instead of 1-bromooctane, to give N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine as a viscous yellow oil. Variant 2.1: Yield: 1.50 g; 87.6% of theory Variant 2.2: Yield: 1.63 g; 93.2% of theory
[0115] Step 3: The reaction was carried out in a manner similar to that of Example 1, except that only 2 mmol of N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine was used, to give the title compound (2) as a clear yellow oil (yield: 0.70 g; 96.1% of theory).
[0116] 1 H-NMR: δ H (600 MHz, chloroform-d) 6.89 (d, J = 2.0 Hz, 1H, C3), 6.79 (d, J = 2.0 Hz, 1H, C5), 4.52 (s, 2H, C17), 3.93 (t, J = 6.9, 6.9 Hz, 2H, C18), 3.84 (s, 3H, C11), 3.16 (s, 6H, C14, C15), 2.60 (q, J = 7.6, 7.6, 7.6 Hz, 2H, C7), 1.76 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.39 (p, J = 7.4, 7.4, 6.9, 6.9 Hz, 2H, C19), 1.34-1.17 (m, 16H, C8, C20-C25), 0.86 (t, J = 7.0, 7.0 Hz, 3H, C26). 13 C-NMR: δ C (151 MHz, Chloroform-d) 152.6 (C6), 145.9 (C1), 140.3 (C4), 124.5 (C3), 124.0 (C2), 113.9 (C5), 74.0 (C17), 70.5 (C12), 57.5 (C14, C15), 55.8 (C11), 32.0 (C18), 30.4 (C19), 29.7 (C20, C21), 29.5 (C22), 29.4 (C23), 28.7 (C7), 26.1 (C24), 22.8 (C25), 15.6 (C8), 14.2 (C26). HRMS: (ESI + , m / z) C 22 H 40 NO3[M+H] + Calculated value: 366.30027; Measured value: 366.30049.
[0117] Example 3 Preparation of N,N-dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine-N-oxide (3)
[0118] [ka]
[0119] Step 1: The synthesis and production were the same as in Example 1.
[0120] Step 2: The reaction was carried out in a manner similar to that in Example 1, except that 1-bromododecane was used instead of 1-bromooctane, to give N,N-dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine as a viscous yellow oil. Variant 2.1: Yield: 1.77 g; 96.0% of theory Variant 2.2: Yield: 1.67 g; 88.4% of theory
[0121] Step 3: The reaction was carried out in a similar manner to Example 1, except that only 2 mmol of N,N-dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine was used, to give the title compound (3) as a clear yellow oil (yield: 0.50 g; 95.2% of theory).
[0122] 1 H-NMR: δ H(600 MHz, chloroform-d) 6.90 (d, J = 2.0 Hz, 1H, C3), 6.81 (d, J = 2.0 Hz, 1H, C5), 4.54 (s, 2H, C12), 3.94 (t, J = 6.9, 6.9 Hz, 2H, C18), 3.86 (s, 3H, C11), 3.18 (s, 6H C14, C15), 2.61 (q, J = 7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J = 7.3, 7.3, 6.9, 6.9 Hz, 2H, C19), 1.37-1.20 (m, 20H, C8, C20-C27), 0.87 (t, J = 6.9, 6.9 Hz, 3H, C28). 13 C-NMR: δ C (151 MHz, Chloroform-d) 152.7 (C6), 146.0 (C1), 140.4 (C4), 124.5 (C3), 123.9 (C2), 114.0 (C5), 74.0 (C17), 70.5 (C12), 57.5 (C14, C15), 55.9 (C11), 32.0 (C18), 30.4 (C19), 29.8 (C20), 29.8, (C21), 29.8 (C22), 29.7 (C23), 29.6 (C24), 29.5 (C25), 28.7 (C7), 26.1 (C26), 22.8 (C27), 15.7 (C8), 14.3 (C28); HRMS: (ESI + , m / z) C 24 H 44 NO3[M+H] + Calculated value: 394.33157; Measured value: 394.33176.
[0123] Example 4 Preparation of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine N-oxide (4)
[0124] [ka]
[0125] Step 1: The synthesis and production were the same as in Example 1.
[0126] Step 2: The reaction was carried out in a manner similar to that of Example 1, except that 1-bromotetradecane was used instead of 1-bromooctane, to give N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine as a viscous yellow oil. Variant 2.1: Yield: 1.91 g; 96.1% of theory Variant 2.2: Yield: 1.85 g; 91.1% of theory
[0127] Step 3: The reaction was carried out in a similar manner to Example 1, except that only 2 mmol of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine was used, to give the title compound (4) as a clear yellow oil (yield: 0.80 g; 94.3% of theory).
[0128] 1 H-NMR: δ H(600 MHz, chloroform-d) 6.89 (d, J = 2.0 Hz, 1H, C3), 6.80 (d, J = 2.0 Hz, 1H, C5), 4.55 (s, 2H, C12), 3.93 (t, J = 6.9, 6.9 Hz, 2H, C17), 3.85 (s, 3H, C11), 3.19 (s, 6H, C14, C15), 2.60 (q, J = 7.6, 7.6, 7.6 Hz, 2H, C7), 1.76 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.40 (p, J = 7.3, 7.3, 6.9, 6.9 Hz, 2H, C19), 1.34-1.19 (m, 23H, C18, C20-C29), 0.86 (t, J = 7.0, 7.0 Hz, 3H, C30). 13 C-NMR: δ C (151 MHz, Chloroform-d) 152.6 (C6), 145.9 (C1), 140.4 (C4), 124.6 (C3), 123.7 (C2), 114.0 (C5), 74.0 (C17), 70.2 (C12), 57.2 (C14, C15), 55.9 (C11), 32.0 (C18), 30.4 (C19), 29.8 (C20, C21), 29.8 (C22, C23), 29.8 (C24), 29.7 (C25), 29.5 (C26), 29.5 (C27), 28.7 (C7), 26.1 (C28), 22.8 (C29), 15.7 (C8), 14.2 (C30); HRMS: (ESI + , m / z) C 26 H 48 NO3[M+H] + Calculated value: 422.36287; Measured value: 422.36323.
[0129] Example 5 Preparation of N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine N-oxide (5)
[0130] [ka]
[0131] Step 1: The synthesis and production were the same as in Example 1.
[0132] Step 2: The reaction was carried out in a manner similar to that of Example 1, except that 1-bromohexadecane was used instead of 1-bromooctane, to give N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine as a viscous yellow oil. Variant 2.1: Yield: 2.00 g; 94.0% of theory Variant 2.2: Yield: 2.11 g; 97.4% of theory
[0133] Step 3: The reaction was carried out in a similar manner to Example 1, except that only 2 mmol of N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine was used, to give the title compound (5) as a clear yellow oil (yield: 0.87 g; 97.0% of theory).
[0134] 1 H-NMR: δ H(600 MHz, Chloroform-d) 6.90 (d, J = 1.9 Hz, 1H, C3), 6.81 (d, J = 1.9 Hz, 1H, C5), 4.53 (s, 2H, C11), 3.94 (t, J = 6.9, 6.9 Hz, 2H, C17), 3.86 (s, 3H, C11), 3.18 (s, 6H, C14, C15), 2.62 (q, J = 7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J = 7.3, 7.3, 6.9, 6.9 Hz, 2H, , C19), 1.36-1.20 (m, 29H, C8, C20-C31), 0.87 (t, J = 6.9, 6.9 Hz, 3H, C32). 13 C-NMR: δ C (151 MHz, Chloroform-d) 152.7 (C6), 146.0 (C1), 140.4 (C4), 124.5 (C3), 123.9 (C2), 114.0 (C5), 74.0 (C17), 70.5 (C12), 57.5 (C14, C15), 55.9 (C11), 32.1 (C18), 30.4 (C19), 29.8 (C20), 29.8 (C21, C22), 29.8 (C23, C24), 29.8 (C25), 29.7 (C26), 29.6 (C27), 29.5 (C28), 28.7 (C29) (C7), 26.1 (C30), 22.8 (C31), 15.7 (C8), 14.3 (C32). HRMS: (ESI + , m / z) C 28 H 52 NO3[M+H] + Calculated value: 450.39417; Measured value: 450.39428.
[0135] Example 6 Preparation of N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octadecyloxyphenyl)methanamine N-oxide (6)
[0136] [ka]
[0137] Step 1: The synthesis and production were the same as in Example 1.
[0138] Step 2: The reaction was carried out in a manner similar to that of Example 1, except that 1-bromooctadecane was used instead of 1-bromooctane, to give N,N-dimethyl-1-(5-ethyl-2-octadecyloxy-3-methoxyphenyl)methanamine as a viscous yellow oil (variant 2.1; yield: 2.06 g; 91.0% of theory) or a white waxy solid (variant 2.2; yield: 2.00 g; 86.3% of theory).
[0139] Step 3: The reaction was carried out in a similar manner to Example 1, except that only 2 mmol of N,N-dimethyl-1-(5-ethyl-2-octadecyloxy-3-methoxyphenyl)methanamine was used and 0.5 ml of MeOH was added to improve solubility, to give the title compound (6) as a white waxy solid (yield: 0.916 g; 95.9% of theory).
[0140] 1 H-NMR: δ H(600 MHz, chloroform-d) 6.91 (d, J = 2.0 Hz, 1H, C3), 6.82 (d, J = 2.0 Hz, 1H, C5), 4.56 (s, 2H, C12), 3.95 (t, J = 6.9, 6.9 Hz, 2H, C17), 3.86 (s, 3H, C11), 3.19 (s, 6H, C14, C15), 2.62 (q, J = 7.6, 7.6, 7.6 Hz, 2H, C7), 1.77 (p, J = 7.1, 7.1, 7.1, 7.1 Hz, 2H, C18), 1.41 (p, J = 7.2, 7.2, 6.9, 6.9 Hz, 2H, C19), 1.36-1.19 (m, 30H, C8, C20-C33), 0.87 (t, J = 7.0, 7.0 Hz, 3H, C34). 13 C-NMR: δ C (151 MHz, Chloroform-d) 152.7 (C6), 146.0 (C1), 140.4 (C4), 124.5 (C3), 123.7 (C2), 114.0 (C5), 74.0 (C17), 70.3 (C12), 57.3 (C14, C15), 55.9 (C11), 32.1 (C18), 30.4 (C19), 29.8 (C20, C21, C22, C23), 29.8 (C24, C25, C26, C27), 29.8 (C28), 29.7 (C29), 29.6 (C30), 29.5 (C31), 28.7 (C7), 26.1 (C32), 22.8 (C33), 15.7 (C8), 14.3 (C34); HRMS: (ESI + , m / z) C 30 H 56 NO3[M+H] + Calculated value: 478.42547; Measured value: 478.42540.
[0141] Example 7 Preparation of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine-1-oxide (7)
[0142] [ka]
[0143] Step 1: An aqueous solution of 4-ethylguaiacol (4.56 g, 30 mmol) was added dropwise to an aqueous solution of pyrrolidine (2.21 g, 31 mmol) in an ice-water bath with constant stirring within 15 min. Paraformaldehyde (1.35 g, 45 mmol) was added in 0.5 g aliquots every 10 min and stirred for 3 h in an ice-water bath and then at room temperature for 72 h. The reaction mixture was then extracted five times with 25 ml of petroleum ether and the combined organic phases were concentrated under reduced pressure in a rotary evaporator, after which the residue was thoroughly dried in a vacuum desiccator. The aminomethylated intermediate 4-ethyl-6-methoxy-2-(pyrrolidinomethyl)phenol was obtained as a viscous yellowish oil (yield: 6.50 g; 92.1% of theory).
[0144] Step 2: The reaction was carried out in a manner similar to Example 1, variant 2.1, except that 1-bromododecane was used instead of 1-bromooctane, to give 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine as a viscous yellowish oil (yield: 1.93 g; 97.6% of theory).
[0145] Step 3: The reaction was carried out in a similar manner to Example 1, except that only 2 mmol of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine was used, to give the title compound (7) as a clear yellow oil (yield: 0.80 g; 95.5% of theory).
[0146] 1 H-NMR: δ H(300 MHz, chloroform-d) 6.94 (d, J = 2.0 Hz, 1H, 2), 6.76 (d, J = 2.0 Hz, 1H, 4), 4.64 (s, 2H, 12), 3.91 (t, J = 6.9 Hz, 2H, 19), 3.83 (s, 3H, 9), 3.50-3.21 (m, 4H, 14', 17'), 2.58 (q, J = 7.6 Hz, 2H, 10), 2.49-2.34 (m, 2H, 20), 1.87-1.69 (m, 4H, 15'', 16''), 1.37-1.15 (m, 21H, 11, 21, 22, 23, 24, 25, 26, 27, 28, 29), 0.85 (t, J = 6.9 Hz, 3H, 30). 13 C-NMR: δ C (75 MHz, chloroform-d) 13 C-NMR: δ C (75 MHz, chloroform-d) 152.5 (5), 145.7 (6), 140.2 (3), 125.1 (2), 124.3 (1), 113.4 (4), 73.9 (19), 65.5 (14, 17), 65.5, (12), 55.8 (9), 32.0 (20), 30.3 (21), 29.7 (22, 23), 29.7 (24, 25), 29.7 (26), 29.5 (27), 29.4 (28), 28.6 (10), 26.1, 22.8 , (15, 16), 21.3 (29), 15.6 (11), 14.2 (30); HRMS: (ESI + , m / z) C 26 H 46 NO3[M+H] + Calculated value: 420.34777; Measured value: 420.347257.
[0147] Example 8 Preparation of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine-1-oxide (8)
[0148] [ka]
[0149] Step 1: The reaction was carried out in a similar manner to Example 7, except that piperidine (2.64 g, 31 mmol) was used instead of pyrrolidine, to give 4-ethyl-6-methoxy-2-(piperidinomethyl)phenol as a yellowish oil (yield: 7.06 g; 94.4% of theory).
[0150] Step 2: The reaction was carried out in a manner similar to Example 1, variant 2.1, except that 10 mmol of 4-ethyl-6-methoxy-2-(piperidinomethyl)phenol and 1-bromododecane instead of 1-bromooctane were used, to give 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine as a yellowish oil (yield: 3.93 g; 94.1% of theory).
[0151] Step 3: The reaction was carried out in a manner similar to that of Example 1, except that 5 mmol of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine was used, to give the title compound (8) as a clear yellow oil (yield: 2.10 g; 96.8% of theory).
[0152] 1 H-NMR: δ H (300 MHz, chloroform-d) 6.99 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 4.50 (s, 2H), 3.92 (t, J =1 6.9 Hz, 2H), 3.85 (s, 3H), 3.29 (d, J = 11.8 Hz, 2H), 3.04 (td, J = 12.2, 3.1 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.47-2.26 (m, 2H), 1.85-1.02 (m, 28H), 0.87 (t, J = 7.0, 6.2Hz, 3H).13 C-NMR: δ C (75 MHz, chloroform-d) 152.4, 146.0, 140.1, 125.3, 123.5, 113.5, 74.0, 70.6, 63.7, 55.8, 32.0, 30.4, 29.8, 29.8, 29.8, 29.6, 29.5, 28.7, 26.2, 22.8, 22.0, 20.6, 15.6, 14.2. HRMS: (ESI + , m / z) C 27 H 48 NO3[M+H] + Calculated value: 434.36342; Measured value: 434.362833.
[0153] Example 9 Preparation of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine-1,4-dioxide (9)
[0154] [ka]
[0155] Step 1: An aqueous solution of 4-ethylguaiacol (3.04 g, 20 mmol) was added dropwise to an aqueous solution (5 ml) of 1-methylpiperazine (2.64 g, 30 mmol) in an ice-water bath within 15 min under constant stirring. A 37 wt% aqueous solution of paraformaldehyde (0.90 g, 30 mmol) was added in 0.1 g aliquots every 10 min and stirred for 3 h in an ice-water bath and then at room temperature for 9 h. The precipitated solid was then centrifuged and redissolved in 45 ml of Et2O. The solution was washed five times with 5 ml of water and then concentrated under reduced pressure on a rotary evaporator to give the aminomethylated intermediate 4-ethyl-6-methoxy-2-(4-methylpiperazinomethyl)phenol as a white powder (yield: 1.65 g; 31.1% of theory).
[0156] Step 2: The reaction was carried out in a manner similar to Example 1, variant 2.2, except that 1-bromododecane was used instead of 1-bromooctane, to give 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine as an off-white powder (yield: 0.28 g; 12.9% of theory).
[0157] Step 3: The reaction was carried out in a manner similar to that of Example 1, except that 0.125 mmol of 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine was used, to give the title compound (9) as an off-white powder (yield: 0.058 g; 99.9% of theory).
[0158] 1 H-NMR: δ H (300 MHz, CDCl3) 6.97 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 4.46 (s, 2H), 4.39-4.18 (m, 4H), 3.95 (t, J = 7.0, 7.0 Hz, 2H), 3.83 (s, 3H), 3.25 (s, 3H), 3.01 (dd, J = 15.4, 9.6 Hz, 4H), 2.60 (q, J = 7.6, 7.6, 7.6 Hz, 2H), 1.81-1.68 (m, 2H), 1.45-1.13 (m, 22H), 0.85 (d, J = 6.8 Hz, 3H). 13 C-NMR: δ C (75 MHz, CDCl3) 152.2, 145.8, 140.3, 125.4, 121.6, 114.4, 74.0, 69.3, 60.0, 59.1, 57.8, 55.8, 32.0, 29.9, 29.8, 29.8, 29.7, 29.5, 29.4, 28.6, 25.8, 22.8, 15.5, 14.2. HRMS: (ESI + , m / z) C 27 H 48 N2O4[M+H] +Calculated value: 465.368684 Measured value: 465.367767.
[0159] Example 10 Preparation of N,N-dimethyl-N'-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N'-methylethane-1,2-diamine di-N-oxide (10)
[0160] [ka]
[0161] Step 1: The reaction was carried out in a manner similar to that in Example 7, except that N,N,N'-trimethylethane-1,2-diamine (3.07 g, 30 mmol) was used instead of pyrrolidine, to give 2-(2-dimethylaminoethyl)aminomethyl-4-ethyl-6-methoxyphenol as an off-white powder (yield: 4.59 g; 86.3% of theory).
[0162] Step 2: The reaction was carried out in a manner similar to Example 1, variant 2.2, except that 1-bromododecane was used instead of 1-bromooctane, to give N,N-dimethyl-N'-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N'-methylethane-1,2-diamine as an off-white powder (yield: 1.17 g; 53.8% of theory).
[0163] Step 3: The reaction was carried out in a manner similar to that in Example 1, except that 1 mmol of N,N-dimethyl-N'-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N'-methylethane-1,2-diamine was used to give the title compound (10) as an off-white powder (yield: 0.97 g; 69.0% of theory).
[0164] 1 H-NMR: δ H(300 MHz, CDCl3) 6.95 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 4.49 (d, J = 12.4 Hz, 1H), 4.36 (d, J = 12.4 Hz, 1H), 4.07-3.92 (m, 2H), 3.91-3.79 (m, 3+3H), 3.67 (q, J = 7.0, 7.0, 7.0 Hz, 1H), 3.33-3.17 (m, 6H), 3.04 (s, 3H), 2.70-2.56 (m, 2H), 1.75 (dd, J = 10.8, 4.7Hz, 2H), 1.45-1.35 (m, 2H), 1.35-1.17 (m, 28H), 0.85 (t, J = 6.9 Hz, 3H). 13 C-NMR: δ C (75 MHz, CDCl3) 152.6, 146.0, 140.4, 124.2, 114.1, 74.0, 64.6, 55.9, 32.0, 30.4, 29.8, 29.7, 29.6, 29.5, 28.7, 26.1, 22.8, 15.7, 14.2.
[0165] Example 11 Preparation of 1,1'-(2,3-dioctyloxy-5-ethyl-1,4-phenylene)-bis(N,N-dimethylmethanamine N-oxide) and 1,1'-(2,3-dioctyloxy-5-ethyl-1,6-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (11)
[0166] [ka]
[0167] Step 1: An aqueous solution of 4-ethylcatechol (1.0 g, 7.24 mmol) was added dropwise to a 40 wt% aqueous solution of dimethylamine (0.98 g, 21.7 mmol) in an ice-water bath under argon atmosphere within 15 min with constant stirring. 10 ml of a 37 wt% aqueous solution of paraformaldehyde (0.65 g, 21.7 mmol) was added in 5 aliquots every 10 min and stirred for 2 h in an ice-water bath and then for 58 h at room temperature. The reaction mixture was then extracted 5 times with 10 ml of Et2O, the combined organic phase was washed 5 times with 5 ml of water, then concentrated under reduced pressure in a rotary evaporator, after which the residue was thoroughly dried in a vacuum desiccator to obtain a mixture of the twice aminomethylated intermediates 3,4- and 3,6-bis(dimethylaminomethyl)-5-ethylcatechol as an off-white powder (yield: 1.20 g; 65.5% of theory).
[0168] Step 2: The reaction was carried out in a similar manner to Example 1, variant 2.2, except that the reaction was carried out under argon atmosphere for 12 h and flash chromatography was performed using a petroleum ether / ethyl acetate gradient to give a mixture of 1,1'-(2,3-dioctyloxy-5-ethyl-1,4-phenylene)-bis(N,N-dimethylmethanamine) and 1,1'-(2,3-dioctyloxy-5-ethyl-1,6-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 0.15 g; 12.3% of theory).
[0169] 1 H-NMR: δ H(300 MHz, chloroform-d) δ 6.91 (s, 1H), 3.92 (dt, J = 8.2, 6.7 Hz, 4H), 3.40 (d, J = 7.1 Hz, 4H), 2.71 (q, J = 7.5 Hz, 2H), 2.24 (d, J = 6.6 Hz, 12H), 1.75 (dt, J = 8.3, 6.3 Hz, 4H), 1.53-1.39 (m, 4H), 1.36-1.25 (m, 18H), 1.19 (t, J = 7.5 Hz, 3H), 0.94-0.83 (m, 6H). 13 C-NMR: δ C (75 MHz, chloroform-d) 151.5, 148.9, 139.9, 131.4, 129.7, 125.3, 73.4 (d, J = 2.2 Hz), 58.2, 54.2, 45.7, 32.0, 30.7 (d, J = 2.0 Hz), 29.7, 29.5, 26.4 (d, J = 1.5 Hz), 25.3, 22.8, 15.7, 14.3. Elemental analysis: Estimated: C, 75.57; H, 11.84; N, 5.88; Found: C, 75.34; H, 11.85; N, 5.56; HRMS: (ESI + , m / z) C 30 H 57 N2O2[M+H] + Calculated value: 477.4420; Measured value: 477.441284.
[0170] Step 3: The reaction was carried out in a similar manner to Example 1, except that 0.25 mmol of the amine mixture was used; however, as a result of side reactions, the title compound (11) was obtained mixed with several by-products. Optimization of this oxidation reaction is currently the subject of our research.
[0171] Example 12 Preparation of 1,1'-(5-ethyl-2-octyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (12)
[0172] [ka]
[0173] Step 1: An aqueous solution of 4-ethylphenol (6.11 g, 50 mmol) was added dropwise to a 40 wt% aqueous solution of dimethylamine (6.76 g, 150 mmol) in an ice-water bath within 15 min under constant stirring. Paraformaldehyde (4.50 g, 150 mmol) was added in 1.5 g aliquots every 10 min and stirred for 2 h in an ice-water bath and then for 58 h at room temperature. The reaction mixture was then extracted five times with 25 ml of petroleum ether, the combined organic phases were washed five times with 4 ml of water, then concentrated under reduced pressure in a rotary evaporator, after which the residue was thoroughly dried in a vacuum desiccator. The twice aminomethylated intermediate 2,6-bis(dimethylaminomethyl)-4-ethylphenol was obtained as a viscous clear oil (yield: 11.02 g; 93.3% of theory).
[0174] Step 2: The reaction was carried out in a similar manner to Example 1, variant 2.2, except that KOH was added in two portions (0.28 g at the beginning and after 2 h, respectively) and flash chromatography was performed using a petroleum ether / ethyl acetate gradient to give 1,1'-(5-ethyl-2-octyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 1.54 g; 8.6% of theory).
[0175] Step 3: The reaction was carried out in a similar manner to Example 1 to give the title compound (12) as a viscous clear yellow oil (yield: 1.12 g; 97.9% of theory).
[0176] 1 H-NMR: δ H(300 MHz, Chloroform-d) 7.51 (s, 2H, C2, C4), 4.48 (s, 4H, C8, C11), 3.71 (t, J = 6.8, 6.8 Hz, 2H, C19), 3.16 (s, 12H, C13, C14, C16, C17), 2.67-2.54 (m, 2H, C9), 1.89-1.76 (m, 2H, C20), 1.45-1.34 (m, 2H, C21), 1.33-1.04 (m, 14H, C10, C22-C25), 0.85 (t, J = 6.7 Hz, 3H, C26). 13 C-NMR: δ C (75 MHz, Chloroform-d) 156.4 (C6), 141.1 (C3), 136.7 (C1, C5), 124.0 (C2, C4), 69.4 (C8, C11), 57.6 (C13, C14, C16, C17), 31.9 (C20), 30.4 (C21), 29.5 (C22), 29.3 (C23), 28.0 (C9), 26.2 (C24), 22.7 (C25), 15.3 (C10), 14.2 (C26). HRMS: (ESI + , m / z) C 22 H 41 NO3[M+H] + Calculated value: 381.31172; Measured value: 381.310922.
[0177] Example 13 Preparation of 1,1'-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (13)
[0178] [ka]
[0179] Step 1: The synthesis and production were the same as in Example 12.
[0180] Step 2: The reaction was carried out in a similar manner to Example 1, variant 2.2, except that 1-bromododecane was used instead of 1-bromooctane, KOH was added in two portions (0.28 g at the beginning and after 2 h each), and flash chromatography was performed with a petroleum ether / ethyl acetate gradient to give 1,1'-(2-dodecyl-oxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 1.53 g; 75.7% of theory).
[0181] Step 3: The reaction was carried out in a manner similar to that of Example 1, except that only 2.5 mmol of 1,1′-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine) was used, to give the title compound (13) as an off-white waxy solid (yield: 0.70 g; 96.1% of theory).
[0182] 1 H-NMR: δ H (300 MHz, Chloroform-d) 7.53 (s, 2H, C2, C4), 4.49 (s, 4H, C8, C11), 3.74 (t, J = 6.8 Hz, 2H, C19), 3.19 (s, 12H, C13, C14, C16, C17), 2.64 (q, J = 7.6 Hz, 2H, C9), 1.84 (t, J = 7.4 Hz, 2H, C20), 1.46-1.37 (m, 2H, C21), 1.32-1.17 (m, 22H, C10, C22-C29), 0.87 (t, J = 6.9 Hz, 3H, C30). 13 C-NMR: δ C(75 MHz, Chloroform-d) 156.4 (C6), 141.2 (C3), 136.8 (C1, C5), 123.9 (C2, C4), 69.4 (C8, C11), 57.6 (C13, C14, C16, C17), 32.0 (C20), 30.5 (C21), 29.8 (C22, C24, C25), 29.6 (C26), 29.5 (C27), 28.1 (C9), 26.3 (C28), 22.8 (C29), 15.4 (C10), 14.3 (C30); 26 H 49 NO3[M+H] + Calculated value: 437.37432; Measured value: 437.373256.
[0183] Example 14 Preparation of 1,1'-(5-ethyl-2-hexadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (14)
[0184] [ka]
[0185] Step 1: The synthesis and production were the same as in Example 12.
[0186] Step 2: The reaction was carried out in a manner similar to that of Example 13, except that 1-bromohexadecane was used instead of 1-bromooctane, to give 1,1'-(5-ethyl-2-hexadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine) as a yellow oil (yield: 1.57 g; 68.1% of theory).
[0187] Step 3: The reaction was carried out in a similar manner as in Example 13 to give the title compound (14) as an off-white waxy solid (yield: 1.20 g; 97.2% of theory).
[0188] 1 H-NMR: δ H (300 MHz, Chloroform-d) 7.54 (s, 2H, C2, C4), 4.50 (s, 4H, C8, C11), 3.74 (t, J = 6.8 Hz, 2H, C19), 3.17 (s, 12H, C13, C14, C16, C17), 2.65 (q, J = 7.5 Hz, 2H, C9), 1.88-1.82 (m, 2H, C20), 1.48-1.39 (m, 2H, C21), 1.30-1.21 (m, 29H, C10, C22-C33), 0.86 (t, J = 7.0 Hz, 3H, C34). 13 C-NMR: δ C (75 MHz, Chloroform-d) 156.4 (C6), 141.2 (C3), 136.7 (C1, C5), 124.2 (C2, C4), 69.6 (C8, C11), 57.8 (C13, C14, C16, C17), 32.0 (C20), 30.5 (C21), 30.0-29.3 (m) (C22-C31), 28.1 (C9), 26.3 (C32), 22.8 (C33), 15.4 (C10), 14.3 (C34). HRMS: (ESI + , m / z) C 30 H 57 N2O3[M+H] + Calculated value: 493.43692; Measured value: 493.436311.
[0189] Example 15 Preparation of 1,1'-(5-ethyl-2-octadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (15)
[0190] [ka]
[0191] Step 1: The synthesis and production were the same as in Example 12.
[0192] Step 2: The reaction was carried out in a manner similar to that of Example 13, except that 1-bromooctadecane was used instead of 1-bromododecane, to give 1,1'-(5-ethyl-2-octadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine) as an off-white waxy solid (yield: 1.61 g; 66.0% of theory).
[0193] Step 3: The reaction was carried out in a similar manner to Example 13 to give the title compound (15) as a yellowish waxy solid (yield: 1.00 g; 96.2% of theory).
[0194] 1 H-NMR: δ H (300 MHz, chloroform-d) 7.51 (s, 2H, C2, C4), 4.40 (s, 4H, C8, C11), 3.72 (t, J = 6.8 Hz, 2H, C19), 3.08 (s, 12H, C13, C14, C16, C17), 2.65 (q, J = 7.7 Hz, 2H, C9), 1.88-1.77 (m, 2H, C20), 1.45-1.36 (m, 2H, C21), 1.26-1.18 (m, 33H, C10, C22-C35), 0.84 (t, J = 7.0 Hz, 3H, C36). 13 C-NMR: δ C(75 MHz, Chloroform-d) 156.2 (C6), 141.2 (C3), 136.3 (C1, C5), 124.6 (C2, C4), 70.2 (C8, C11), 58.1 (C13, C14, C16, C17), 32.0 (C20), 30.5 (C21), 29.9-29.6 (m) (C22-C31), 29.5 (C32), 29.4 (C33), 28.1 (C9), 26.2 (C34), 22.8 (C35), 15.3 (C10), 14.2 (C36); HRMS: (ESI + , m / z) C 32 H 61 NO3[M+H] + Calculated value: 521.46822; Measured value: 521.467246.
[0195] Example 16 Preparation of 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine-1,4-dioxide (16)
[0196] [ka]
[0197] Step 1: An aqueous solution of 4-ethylguaiacol (3.04 g, 20 mmol) was added dropwise to an aqueous solution (10 ml) of piperazine (1.29 g, 15 mmol) in an ice-water bath within 15 min under constant stirring. A 37 wt% aqueous solution of formaldehyde (0.90 g, 30 mmol) was added in 0.1 g aliquots every 10 min and stirred for 3 h in an ice-water bath and then at room temperature for 9 h. The precipitated solid was then filtered off (glass frit, porosity 4), suspended in 10 ml petroleum ether, mixed by sonication, then centrifuged and thoroughly dried in a vacuum desiccator to obtain the dimeric intermediate 6,6'-(piperazine-1,4-dimethylene)-bis(4-ethyl-2-methoxyphenol) in the form of white needle-like crystals (yield: 3.40 g; 82.1% of theory).
[0198] Step 2: The reaction was carried out in a similar manner to Example 1, variant 2.2, except that 2.12 g (11 mmol) of 1-bromooctane was used, 40 ml of 2-MeTHF was used as the solvent, and flash chromatography was performed with a petroleum ether / ethyl acetate gradient to give 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine as a white powder (yield: 1.45 g; 45.4% of theory).
[0199] Step 3: The reaction was carried out in a similar manner to Example 1, except that only 1 mmol of 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine was used and methyl formate (15 ml) was added as additional solvent, to give the title compound (16) as a white wax solid (yield: 0.21 g; 31.6% of theory).
[0200] 1 H-NMR: δ H (300 MHz, chloroform-d) 6.94 (d, J = 2.0 Hz, 2H), 6.77 (d, J = 2.0 Hz, 2H), 4.45 (s, 4H), 4.28 (d, J = 8.3 Hz, 4H), 3.93 (t, J = 7.0 Hz, 4H), 3.82 (s, 6H), 3.02 (d, J = 8.1 Hz, 4H), 2.59 (q, J = 7.6 Hz, 4H), 1.74 (q, J = 7.0 Hz, 4H), 1.44-1.15 (m, 26H), 0.93-0.82 (m, 6H). 13 C-NMR: δ C (75 MHz, chloroform-d) 152.4, 139.8, 125.2, 122.4, 114.1, 73.7, 58.6, 55.9, 32.0, 30.4, 29.5, 29.4, 28.6, 26.0, 22.8, 15.4, 14.3. HRMS: (ESI + , m / z) C 40 H67 N2O6[M+H] + Calculated value: 671.49991; Measured value: 671.498929.
[0201] Example 17 Preparation of 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine-1,4-dioxide (17)
[0202] [ka]
[0203] Step 1: The synthesis and production were the same as in Example 16.
[0204] Step 2: The reaction was carried out in a manner similar to that of Example 16, except that 1-bromododecane was used instead of 1-bromooctane, to give 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine as a white powder (yield: 1.61 g; 79.6% of theory).
[0205] 1 H-NMR: δ H (600 MHz, Chloroform-d) 6.77 (2 H, d, J 2.0), 6.63 (2 H, d, J 2.0), 3.89 (4 H, t, J 6.8), 3.82 (6 H, s), 3.52 (4 H, s), 2.66-2.32 (12 H, m), 1.75 (4 H, p, J 6.9), 1.48-1.40 (4 H, m), 1.37-1.23 (36 H, m), 1.22 (6 H, t, J 7.6), 0.88 (6 H, t, J 7.0). 13 C-NMR: δ C(151 MHz, chloroform-d) 152.7, 145.2, 139.5, 131.8, 121.9, 110.9, 73.6, 56.8, 55.9, 53.4, 32.1, 30.5, 29.9-29.8 (m), 29.7, 29.5, 28.9, 26.3, 22.8, 15.8, 14.3. Elemental analysis: Estimated: C, 76.75; H, 11.00; N, 3.73; Found: C, 76.18; H, 10.51; N, 3.67; HRMS: (ESI + , m / z) C 48 H 83 N2O4[M+H] + Calculated value: 751.63474; Measured value: 751.63595.
[0206] Step 3: The reaction was carried out in a similar manner to Example 1; however, due to the low solubility of 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine in water, only very low conversions were observed. Optimization of this oxidation reaction using methyl formate as an additional solvent is currently the subject of our research.
[0207] Example 18 Preparation of N,N'-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)-N,N'-dimethylethane-1,2-diamine di-N-oxide (18)
[0208] [ka]
[0209] Step 1: The reaction was carried out in a manner similar to that of Example 16, except that N,N'-dimethylethylenediamine was used instead of piperazine, to give 6,6'-(N,N'-dimethylethane-1,2-diamine-N,N'-dimethylene)-bis(4-ethyl-2-methoxyphenol) as a yellowish oil (yield: 1.90 g; 91.4% of theory).
[0210] Step 2: The reaction was carried out in a similar manner to Example 16 to give N,N'-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)-N,N'-dimethylethane-1,2-diamine as an off-white powder (yield: 0.91 g; 28.5% of theory).
[0211] Step 3: The reaction was carried out in a manner similar to that of Example 16, using methyl formate (15 ml) as an additional solvent, to give the title compound (17) as a white waxy solid. However, due to the decomposition reaction of the diamine during the oxidation, the target product was mixed with numerous by-products that were difficult to separate even using column chromatography. Optimization of this oxidation reaction is currently the subject of research by the inventors.
[0212] Example 19 Testing isolated amine N-oxide compounds according to formula (I) and (II) for their suitability as surfactants
[0213] As a parameter of the surfactant properties of the new amine-N-oxide compounds, the critical micelle concentration (CMC), i.e. the concentration of the protonated or cationic form of the surfactant at which micelles can be formed, was used as usual, measured at 25° C. and pH 3 according to the Wilhelmy plate method using a K100C force tensiometer from Kruss Scientific. For comparison, dodecyldimethylamine N-oxide ("C1") was measured under the same conditions. The results are shown in Table 1 below. The lower the value, the stronger the surfactant effect of the respective substance.
[0214] [Table 1]
[0215] It can be seen that, with the exception of Example 1, the examples according to the invention have CMC values that are lower, and in most cases significantly lower, than the comparative material C1, which is used in many commercial products. However, the radical R 1 Or R 5 The highest CMC value of 4.1 mol / l for the amine N-oxide (1) from Example 1, which contains the smallest number of carbon atoms in the formula, is also nearly identical to that of the commercially available compound C1, thus proving its suitability as a surfactant.
[0216] One skilled in the art can expect that due to analogies or high similarities in the substitution patterns of other compounds according to the invention that have not yet been tested, a strong surfactant effect will also be detected for most of them.
[0217] Furthermore, when solutions of these amine N-oxide surfactants, each at a concentration of 10 mg / ml, were examined in double distilled water by cryo-electron microscopy, a surprising and previously unknown phenomenon was discovered: the edges of the worm-like micelles formed by the surfactants are folded, i.e., they do not exist in an elongated shape as has been consistently reported so far. As an example, a cryo-electron microscopy image of such a solution of the amine N-oxide compound (13) from Example 13 is shown in Figure 1, together with a schematic diagram of the worm-like micelles observed therein, with sizes between 40 nm and 76 nm.
[0218] Thus, the present invention provides a process for the preparation of novel amine N-oxide compounds, involving only three relatively simple synthetic steps, which makes it possible to obtain novel amine N-oxides, most of which are suitable for use as surfactants, in very good yields and in an economical and environmentally friendly manner.
Claims
1. The following formula (I) or (II): 【Chemical 1】 [In the formula, Each R １ is selected from linear, branched or cyclic hydrocarbon radicals having 4 to 26 carbon atoms, wherein optionally at least one carbon atom is replaced by an oxygen or sulfur atom; R ２ , R ３ and R ５ are each independently hydrogen, R １ -O-, R ８ and in formula (I) is selected from -CH ２ -N ＋ (O - ) R ６ R ６ where R ８ represents a linear, branched or cyclic hydrocarbon radical having 1 to 26 carbon atoms, wherein optionally at least one carbon atom may be replaced by an oxygen or sulfur atom; R ４ is hydrogen and R ８ Selected from: Each radical R ６ are independently selected from saturated linear or branched hydrocarbon radicals having 1 to 6 carbon atoms, wherein optionally at least one carbon atom is replaced by a nitrogen, oxygen, or sulfur atom; where optionally two radicals R bonded to the same nitrogen atom ６ may be joined to form a 5- or 6-membered nitrogen-containing ring, or wherein optionally, the amine N-oxide moiety -N ＋ (O - ) R ６ R ６ one or both radicals R ６ is a radical R of one or both of such moieties of other molecules of formula (I) ６ Binding to the structure 【Chemistry 2】 (where the dashed lines represent the two radicals R ６ The asterisk indicates the connection of a bridge to two aromatic rings. to form a bridge having the formula (II).
1. A process for preparing an amine N-oxide compound according to The method comprises the following steps: 1) In a polar solvent, in the presence of formaldehyde, by Betti / Mannich aminoalkylation reaction to give the following formula (III): 【Chemistry 3】 [In the formula, each R ７ are independently hydrogen, hydroxy, and R ８ Selected from. The phenol derivatives of the formula (I) are converted into secondary amines HNR ６ R ６ thereby reacting the hydrogen atom ortho to the phenolic OH group and, optionally, other displaceable hydrogen atoms R of the phenol derivative of formula (II) ７ to -CH ２ -NR ６ R ６ and (IV) or (V) with a moiety (respectively): 【Chemistry 4】 [In the formula, each R ７ are independently hydrogen, hydroxy, R ８ and in formula (IV) is selected from -CH ２ -NR ６ R ６ Also selected from. to obtain the corresponding Betti base by 2) by etherification according to Williamson in the presence of a base in an organic solvent or without a solvent, to remove the (two) phenolic OH groups and, optionally, any further free OH groups R of the Betti base of formula (IV) or (V), respectively. ７ into the formula R １ -X, where X represents a leaving group selected from halide and sulfonate, to give a compound of formula (VI) or (VII): 【Chemistry 5】 [In the formula, each R ７ are independently hydrogen, R １ -O-, R ８ and in formula (VI) is selected from -CH ２ -NR ６ R ６ Also selected from. to obtain the corresponding ether; and 3) by reaction with an oxidizing agent in water, an organic solvent or a mixture thereof, to remove any amino group -NR of the respective ether of formula (VI) or (VII). ６ R ６ to obtain an amine N-oxide compound of formula (I) or (II); A method comprising:
2. In step 1), the phenol derivative of formula (III) is reacted with 1.5 equivalents each of a secondary amine and formaldehyde, and the reaction is carried out in water at room temperature; The method of claim 1, characterized by:
3. In step 2), A solid-liquid phase transfer reaction is carried out using a solid base in the presence of a phase transfer catalyst; and / or Chloride or bromide is used as the leaving group X; and / or An anhydrous solvent is used, 3. The method according to claim 1 or 2, characterized in that
4. In step 2), Powdered KOH is used as the solid base; Tetra-n-butylammonium bromide (TBAB) is used as the phase transfer catalyst; bromide is used as the leaving group X; and Anhydrous 2-methyltetrahydrofuran is used as the solvent. The method according to claim 3, characterized by:
5. In step 3), H ２ O ２ is used as the oxidizing agent, whereby optionally formic acid methyl ester may be added as an additional solvent; and / or The ether of formula (VI) or (VII) is reacted with 2.5 to 3 equivalents of H ２ O ２ reacts with 3. The method according to claim 1 or 2, characterized in that
6. 3. A compound represented by the following formula (I) or (II): 【Chemistry 6】 [In the formula, Each R １ is selected from linear, branched or cyclic hydrocarbon radicals having 4 to 26 carbon atoms, wherein optionally at least one carbon atom is replaced by an oxygen or sulfur atom; R ２ , R ３ and R ５ are each independently hydrogen, R １ -O-, R ８ and in formula (I) is selected from -CH ２ -N ＋ (O - ) R ６ R ６ where R ８ represents a linear, branched or cyclic hydrocarbon radical having 1 to 26 carbon atoms, wherein optionally at least one carbon atom may be replaced by an oxygen or sulfur atom; R ４ is hydrogen and R ８ Selected from: Each radical R ６ are independently selected from saturated linear or branched hydrocarbon radicals having 1 to 6 carbon atoms, wherein optionally at least one carbon atom is replaced by a nitrogen, oxygen, or sulfur atom; where optionally two radicals R bonded to the same nitrogen atom ６ may be joined to form a 5- or 6-membered nitrogen-containing ring, or wherein optionally, the amine N-oxide moiety -N ＋ (O - ) R ６ R ６ one or both radicals R ６ is a radical R of one or both of such moieties of other molecules of formula (I) ６ Binding to the structure 【Chemistry 7】 (where the dashed lines represent the two radicals R ６ The asterisk indicates the connection of a bridge to two aromatic rings. to form a bridge having the formula (II). Amine N-oxide compounds according to
7. R １ But C ６ -C ２２ is alkyl; and / or R ２ But C １ -C ２２ Alkyl, C １ -C ２２ Alkoxy, and —CH ２ -N ＋ (O - ) R ６ R ６ and / or R ３ and R ５ are hydrogen and -CH ２ -N ＋ (O - ) R ６ R ６ and / or R ４ But hydrogen, C １ -C ４ Alkyl, and C １ -C ４ selected from alkoxy, 7. The amine N-oxide compound according to claim 6, wherein
8. R １ But C ８ -C １８ is alkyl; and / or R ２ But C １ -C １８ Alkoxy and —CH ２ -N ＋ (O - ) R ６ R ６ and / or R ４ and R ５ are hydrogen and C, respectively. １ -C ４ selected from alkyl, 8. The amine N-oxide compound according to claim 7, wherein
9. R １ But C ８ -C １８ is alkyl; R ２ But C １ -C １８ is alkoxy; R ３ and R ５ One of them is hydrogen and the other is -CH ２ -N ＋ (O - ) R ６ R ６ and R ４ But C １ -C ４ is alkyl, 8. The amine N-oxide compound according to claim 7, wherein
10. R １ But C ８ -C １８ is alkyl; R ２ But C １ -C １８ is alkoxy; R ３ and R ５ are each hydrogen; and R is C １ -C ４ is alkyl, 8. The amine N-oxide compound according to claim 7, wherein
11. R ２ is methoxy; and R ４ is ethyl or propyl; 11. The amine N-oxide compound according to claim 10, wherein
12. R １ But C ８ -C １８ is alkyl; R ２ But -CH ２ -N ＋ (O - ) R ６ R ６ and R ３ and R ５ are each hydrogen; and R ４ But C １ -C ４ is alkyl, 8. The amine N-oxide compound according to claim 7, wherein
13. Each radical R ６ is independently selected from methyl, ethyl, and dimethylaminoethyl; and / or Two radicals R attached to the same nitrogen atom ６ is connected to the nitrogen atom and forms, together with the nitrogen atom, one of the following groups: 【Chemistry 8】 (wherein the asterisks indicate the respective connections to the aromatic rings.) and / or All radicals R ６ is methyl and the moiety -N ＋ (O - ) (CH ３ ) ２ is a methyl group of one or both of the methyl groups R ６ Binding to the structure 【Chemistry 9】 (where the dashed line indicates an optional bond between two methyl groups, and the asterisk indicates the connection of a bridge to two aromatic rings.) thereby forming a dimer of the amine N-oxide compound according to formula (II), 7. The amine N-oxide compound according to claim 6, wherein
14. The following compounds: N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octyloxyphenyl)methanamine N-oxide (1) 【Chemistry 10】 N,N-dimethyl-1-(2-decyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (2) 【Chemistry 11】 N,N-dimethyl-1-(2-dodecyloxy-5-ethyl-3-methoxyphenyl)methanamine N-oxide (3) 【Chemistry 12】 N,N-dimethyl-1-(5-ethyl-3-methoxy-2-tetradecyloxyphenyl)methanamine N-oxide (4) 【Chemistry 13】 N,N-dimethyl-1-(5-ethyl-2-hexadecyloxy-3-methoxyphenyl)methanamine N-oxide (5) 【Chemistry 14】 N,N-dimethyl-1-(5-ethyl-3-methoxy-2-octadecyloxyphenyl)methanamine N-oxide (6) 【Chemistry 15】 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)pyrrolidine-1-oxide (7) 【Chemistry 16】 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperidine-1-oxide (8) 【Chemistry 17】 1-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-4-methylpiperazine-1,4-dioxide (9) 【Chemistry 18】 N,N-dimethyl-N'-(2-dodecyloxy-5-ethyl-3-methoxybenzyl)-N'-methylethane-1,2-diamine di-N-oxide (10) 【Chemistry 19】 1,1'-(2,3-dioctyloxy-5-ethyl-1,4-phenylene)-bis(N,N-dimethylmethanamine N-oxide) and 1,1'-(2,3-dioctyloxy-5-ethyl-1,6-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (11) 【Chemistry 20】 1,1'-(5-ethyl-2-octyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (12) 【Chemical formula 21】 1,1'-(2-dodecyloxy-5-ethyl-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (13) 【Chemical 22】 1,1'-(5-ethyl-2-hexadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (14) 【Chemical 23】 1,1'-(5-ethyl-2-octadecyloxy-1,3-phenylene)-bis(N,N-dimethylmethanamine N-oxide) (15) 【Chemistry 24】 1,4-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)piperazine-1,4-dioxide (16) 【Chemistry 25】 1,4-bis(2-dodecyloxy-5-ethyl-3-methoxybenzyl)piperazine-1,4-dioxide (17) 【Chemical 26】 N,N'-bis(5-ethyl-3-methoxy-2-octyloxybenzyl)-N,N'-dimethylethane-1,2-diamine di-N-oxide (18) 【Chemical 27】 Selected from 7. The amine N-oxide compound according to claim 6, wherein
15. 7. Use of an amine N-oxide compound of formula (I) or (II) as a surfactant according to claim 6, wherein the radical R １ Or R ５ wherein the total number of carbon atoms is at least 9.