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    • 专利摘要:
    Process for obtaining β -amino alcohols in which, from amines and a diol/water mixture, the steps of: adding a catalytic mixture to the starting amine, then adding the diol/water mixture; subsequently, carry out the reaction at a temperature of between 130 and 200º c, for 2-24 hours, filter the reaction product, based on β -amino alcohol, by at least a first extraction with hexane and then, at least a second extraction with ethyl acetate, in order to purify the β-amino alcohol obtained. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2644751A1
    申请号:ES201600468
    申请日:2016-05-31
    公开日:2017-11-30
    发明作者:Rafael BALLESTEROS CAMPOS；Mª Belén ABARCA GONZÁLEZ；Rafael BALLESTEROS GARRIDO；Pedro Juan LLABRÉS CAMPANER
    申请人:Universitat de Valencia；
    IPC主号:
    专利说明:

    DESCRIPTION

    Procedure for obtaining β-amino alcohols.

    Object of the invention 5

    The present invention relates to a process for obtaining β-amino alcohols.

    The invention is included within the sector of the chemical-organic industry, specifically, which is responsible for the manufacture of biologically important compounds such as amino acids or morpholines.

    Background of the invention

    The activation of alcohols to rent amines by processes or reactions of hydrogen self-transfer, which are also known as hydrogen lending or self-supply system of active hydrogens, is a technique widely used in organic synthesis (Scheme 1) of products of industrial interest. Samples of this are the works of J. Williams et al (1); Krische et al (2) and M. Yus et al (3). One of the advantages, among others, of these processes is that the use of more toxic alkyl halides is avoided. Within the type of alcohols used as a starting material for this type of reaction, most of the results have been described with easily oxidizable alcohols, for example, benzyl alcohol and derivatives. The use of alkyl alcohols represents a greater challenge.
     25


    These processes or reactions are carried out through the use of catalysts. Catalysts with a greater dehydrogenation potential are described in the state of the art, an example of which are those described by Q. Yang et al 30 (4). However, most of the catalysts, whose use has been published, are homogeneous, such as those described by Yang et al. (4). These catalysts consist of a transition metal complex with nitrogen or phosphorus ligands. Homogeneous catalysts, although they are very effective, have limited industrial applicability due to their cost (most are complexes of Os, Ru, Ir), their instability and the inability to reuse them. In addition, in many of these hydrogen autotransfer reactions, co-reagents such as alkali metal tert-butoxide and organic solvents are required.
    Due to the interest of this type of reaction (Scheme 1), different heterogeneous catalyst systems have also been used, but mainly based on benzyl-type alcohols, for example, K. Shimizu (5). The heterogeneous systems are based on transition metals (gold, iridium, palladium, ruthenium ...) supported on alumina, titania or ferrite. 5

    In general, the use of diols as a starting material, specifically ethylene glycol, in this type of reaction (Scheme 1) can lead to the obtaining of β-amino alcohols in one step, but represents a challenge or obstacle for two reasons. On the one hand, ethylene glycol is much harder to activate than benzyl alcohols. The products of the reaction, the β-amino alcohol or the 2-hydroxethanal (Scheme 2), have an alcohol group that can be activated by the catalyst, which could degrade. On the other hand, and being a technical disadvantage to take into account, using very powerful catalysts, ethylene glycol can also be degraded.
     fifteen


    Β-Amino alcohols represent a product of the highest industrial interest given their applicability in the synthesis of biologically relevant compounds such as amino acids or morpholines. Therefore, the provision of a process that allows obtaining β-amino alcohols in a way that is as inexpensive as possible and in a way that is as respectful as possible with the environment is especially important and relevant.

    Β-Amino alcohols have potential in the preparation of heterocyclic carbons, which are those used in many catalysis reactions. An example of its many applications can be found in the work of T. J. Donohoe et al. (6). However, in this publication there is no reaction that meets the criteria of green chemistry, known in the art as ecological chemistry, that which respects the environment, and much less, that uses ethylene glycol as a starting material. in the preparation of β-amino alcohols.

    Two references have been found, as examples of ethylene glycol activation reaction, to obtain another type of product: a first, the publication of S. Michlik et al (7), which, to synthesize pyrroles, uses a homogeneous catalyst ( a complex of iridium), which is very expensive, unstable and with few possibilities of use on an industrial scale, and where the product is generated by 32%; and a second, patent document CN103539718, from China Petroleum & Ch. Sinopec Shanghai Research Institute, where they assume that β-amino alcohol is a byproduct of a catalysis at 300 ° C, whose objective is the synthesis of indole and use of a metal (Ag, Cu) as catalyst. However, in this last reference the β-amino alcohol is not isolated.

    As alternatives for industrial application, in the case of ethylene glycol, the introduction of a further stage with diethyl carbonate has been described in order to activate it, according to ML Kantam et al (8) and A B. Shivarkar et al (9), where ethylene glycol is transformed into 1,3-dioxola-2-one. However, this process reduces atomic efficiency and, furthermore, is far from giving acceptable yields.
    It is important to note that, except for the examples cited above (Michlik and the Chinese patent document), which use ethylene glycol, there is no known real process that obtains β-amino alcohols directly from ethylene glycol as starting material without any modification, in a heterogeneous catalytic system.
     5
    While there are many published reactions to activate any type of alcohol by different routes, all of them give rise to compounds other than β-amino alcohols. An example is the publication of A Corma et al (10), where Pd / MgO is used to react ethylene glycol with amines; however, it is not possible to obtain amino alcohols, but piperazines or other derivatives, fruit of the polyfunctionalization of ethylene glycol. In addition, a fundamental problem with this reaction is that ethylene glycol can be degraded by giving polymers or gas mixtures (CO / CO2), depending on the potential of the catalyst. Although there are many and varied references on the processes of hydrogen self-transfer to give amines, as far as β-amino alcohols are concerned there are only the two examples cited above. fifteen

    Therefore, it is necessary a procedure that is capable of monofunctionalizing ethylene glycol and in which the product obtained, in this case, a β-amino alcohol is not degraded.
     twenty
    Protocols have been developed for the generation of amines by green methodologies, that is, methodologies that respect the environment. For example, two of the latest publications, cited below, represent the authors' first developments in the field of hydrogen self-transfer: "An efficient one pot transfer hydrogenation and N-alkylation of quinolines with alcohols mediated by Pd / C / Zn "de B. 25 Abarca, R. Adam, R. Ballesteros, Organic Biomolecular Chemistry, 2012, 10, 1826-1833. DOI: 10.1039 / C1OB05888F and "Triazolopyridines. Part 30.1. Hydrogen transfer reactions; pyridylcarbene formation". B. Covers: R. Adam: S. Alom: R. Ballesteros: S. López-Molina. ARKIVOC, Vol. 2014, Issue 2, pp. 175-186.
     30
    However, in none of these two publications has it been possible to obtain β-amino alcohols. It is true that the Pd / C catalyst is capable of hydrogenation-dehydrogenation processes; However, in the case of these two publications, the products obtained have been tertiary amines or pyridines. In the particular case of the first of the two publications cited above, a combination described as 35 Pd / C / Zn is used. However, it must be taken into account that this combination is not a catalyst, since Zn (metal in oxidation state 0) provides electrons that are used to reduce quinolines (passing to Zn + 2), but that it is a reagent (in addition, used in a large excess) and cannot be recovered at the end of the reaction, also generating scaling problems due to the instability of metals in oxidation state 0 at high temperature. Ethylene glycol is used in this first publication, but the preparation process does not use, as starting materials, amines, but tetrahydroquinolines, which have different properties and result in a product other than β-amino alcohols. Note that tetrahydroquinolines are compounds that are much more difficult to degrade and have a higher resistance to generating polyfunctionalized systems. Therefore, although the above-mentioned methodologies are relatively innovative, taking into account the large number of catalysts for the functionalization of amines, they do not allow in any case to obtain β-amino alcohols.
     fifty
    Thus, a publication, teaching or patent document that can functionalize ethylene glycol to generate β-amino alcohols, through the use of heterogeneous catalytic systems, has not been found in the state of the art.
    Because, today, the trend is directed towards the production of catalysts with greater potential, this represents a problem when making reactions with more than one active center, such as the formation of β-amino alcohols at from ethylene glycol. This is because very active or high potential catalysts degrade the products obtained, inducing multi-functionalizations, as is the case, for example, 5 of the publication of Corma et al (10).

    The present invention solves the problems mentioned above and satisfies the need for a process to obtain β-amino alcohols that is ecological, is carried out in a heterogeneous catalytic system and at the lowest possible economic cost, 10 and in which the degradation of the product obtained.

    Description of the invention

    The present invention provides a process for obtaining β-amino alcohols which, from an amine and a diol / water mixture, is carried out in a heterogeneous catalytic system and comprises the following steps:

    - to the starting amine, a solid catalytic mixture is added comprising a supported metal and a solid inorganic acid-base coactivant, 20

    - then the diol / water mixture is added;

    - subsequently, the reaction is carried out, at a temperature between 130 and 200 ° C, for 2 to 24 hours. 25

    - the reaction product, based on β-amino alcohol, is filtered through a microporous filter, at least one extraction with hexane and then at least a second extraction with ethyl acetate, in order to purify the β -amino alcohol obtained. 30

    Therefore, the present process raises a turning point in the conception of catalysts used in hydrogen transfer processes. On the other hand, it is the only example of using a heterogeneous catalyst system that is capable of mono functionalizing ethylene glycol to generate β-amino alcohols and not degrade the product formed (β-amino alcohol).

    This procedure works with a catalytic mixture comprising a metal, supported on a substrate, and an inorganic solid coactivant, whose function is also catalytic. Optionally, this metal is selected from among the metals of the 40 groups IIIB to IIB of the periodic system of elements. Also, optionally, this may be oxides and hydroxides of said transition metals, and an alloy of Pt-Sn. Preferably, the supported metal is a metal selected from the following elements: Pd, Au, Pt, Cu, Ag, Ru, oxides and hydroxides thereof.
     Four. Five
    Optionally, the metal is supported on a solid substrate that is selected from the following elements: TiO2, Al2O3, SiO2, Fe3O4, Fe2O3, MgO, Ga2O, CeO2, NiO, zeolites, graphite, graphene, graphene oxide, diamond, nanotubes of coal, carbon black.
     fifty
    This catalytic mixture, that is, the metal supported on a solid substrate and the solid inorganic coactivant, allows the diol present in a diol / gua mixture to be activated, thereby generating aldehydes and hydrogen. In the presence of aromatic amines, imines are formed, which are hydrogenated (with the same hydrogen that had been generated in
    the first part) to obtain a secondary amine and a water molecule as a byproduct. This procedure makes it possible to obtain β-amino alcohols, avoiding poly functionalization, since when passing through imine, the reaction is more difficult for the product. In addition, by using the diol as a solvent, degradation of the product by the catalyst itself is avoided. 5

    Optionally, after obtaining the β-amino alcohols, the catalytic mixture (supported metal and solid inorganic acid-base co-activator) is recovered through a filtering and washing operation with hexane / ethyl acetate and, subsequently, drying between 140 and 160 ° C, for 2 to 6 hours. 10

    Optionally, the acid-base inorganic solid co-activator is selected from the following oxides: CaO, BaO, ZnO, CeO2, Al2O3, MgO, TiO2, SiO2. Preferably, ZnO, SiO2 and Al2O3 are selected. These solid coactivants, being in their most stable oxidation state and given the reaction conditions, remain unchanged throughout the catalytic process and act (despite their quantity) as catalysts. Therefore, they are denoted as co-activators. All solids that cannot withstand such conditions (metals in low oxidation states or in metallic form) are excluded. As a preferred coactivating option, ZnO is selected. twenty

    Optionally, the catalytic mixture that is added to the amine comprises palladium supported on carbon and ZnO (inorganic solid coactivant).

    By using this catalytic mixture (supported catalyst and inorganic solid coactivating agent with acid-base character), β-amino alcohols are obtained, since the coactivant helps the supported metal to carry out the first stage, but being two independent solids, the reaction is much milder and the products are not degraded (β-amino alcohols). This mixture of two solids is extremely rare in catalysis, since only one of the compounds used is solid in almost 100% of the catalysts. In the present invention they are two solids. This logically leads to longer reaction times, leaving in any case acceptable values (12-70 h).

    It has been found that the reaction where a catalyst is used and a co-activator of ethylene glycol participates, performing a catalytic function, that is, without being transformed throughout the reaction, surprisingly allows to obtain β-amino alcohols. And, in addition, this coactivant is not able to degrade these products.

    Thus, amino alcohols are obtained and isolated by a catalytic mixture 40 in a heterogeneous system, contrary to what occurs in virtually all reactions with ethylene glycol described so far in the prior art.

    Optionally, the diol comprised in the diol-water mixture may be one of the following group consisting of: 1,2-ethanediol (ethylene glycol), 1,2-propanediol, 2,3-butanediol, 1-45 phenylethane-1,2- diol, 1,3-propanol, 1,2-cyclohexanediol, 1,3-butanediol and triol glycerol, as well as cyclic derivatives which, by transformation, give diols, such as styrene oxide. Preferably, 1,2-ethanediol (ethylene glycol), and 1,2-propanediol are selected. The mixtures comprise different proportions, from 1/100 (diol / water) to 100/1, v / v. In no case are other solvents used, much less halogenated. fifty

    Difficult oxidation amines comprise amines that cannot give rise to an imine via dehydrogenation rapidly. Optionally, as the starting material of the present invention, aromatic amines of formula H2N-Ar are selected, where Ar
    (aryl group) may be phenyl, ortho / meta / for methylphenyl, ortho / meta / for nitrophenyl ortho / meta / for fluorophenyl, ortho / meta / for aminophenyl, ortho / meta / for trifluoromethylphenyl, ortho / meta / for trifluoromethoxyphenyl, 2 ,3; 3.4; 4.5; 2.4; 2,5 dimethylphenyl, 3,4,5-trimethylphenyl, anthracil or naphthyl. Optionally, tertbutylamine can be selected.
     5
    According to another optional embodiment, the amine is a heterocyclic amine. For example, pyridines, thiophenes, thiazoles, triazoles, quinolines. Optionally, tetrahydroquinoline is selected.

    The process is characterized by being a catalytic reaction in a heterogeneous system, that is to say that both the catalyst itself and the coactivant can be recovered by filtration and reused. In addition, diol pre-activation is not required. Both reagents and solvents do not have halogen atoms and working temperatures are industrially available. In addition, the yields are higher than all those published to date for said reaction or those derived with diethyl carbonate. It is important to note that the mixture referred to in this invention is the only one capable of activating diols in a controlled manner avoiding polymerizations.

    Advantages of the present procedure with respect to the prior art:
     twenty
    - Cost reduction: water and ethylene glycol are economically acceptable; The present method of obtaining β-amino alcohols is the only heterogeneous protocol that does not require activation with diethyl carbonate at high temperatures. No transition metal in solution is used, which significantly reduces the cost of the process. The reaction does not require phosphorus ligands to function, which also has an impact on the total cost of the process. No molecule used in this process requires anhydrous conditions or in an inert atmosphere. Both catalysts and reagents, solvents and products are stable to air and moisture, and can be stored in normal containers. That is, the use of a glove chamber is not required to preserve the catalysts, as is the case with many transition metal complexes that are used in homogeneous catalysis. Therefore, the indirect costs of applying the methodology are greatly reduced. The products used are commercial and are used without any extra purification. No pretreatment of any of the components of this application is necessary.
     35
    - Waste reduction: being a procedure characterized by being a heterogeneous catalysis, the catalyst can be removed without much difficulty; it can be reactivated and reused, thus minimizing waste and maximizing its price; on the other hand, the present invention allows not to degrade the solvent excessively, by generating clean reaction crude and very few by-products. In addition, a purification of the products is possible by selective extraction, a first one, which takes away the impurities and a second one, which remains with the amino alcohol.

    - Reduction of halogenated compounds: no halo-derivative (carcinogens) is used, either as a reagent or as a solvent in the extraction or purification. The catalyst can be reactivated with ethyl acetate.

    - Atomic economy: the diol acts as a solvent and reagent, being also activated without the need for chemical transformation; In addition, the reaction only generates a water molecule as a byproduct. fifty

    - Moderate temperatures: the present invention allows a method of use where working in a temperature range between 130 and 200 ° C, preferably
    a working temperature of around 150ºC, and can be easily applied at industrial level.

    Examples of realization
     5
    The starting amine (1 mmol), a palladium on carbon catalyst, Pd / C (7%), and ZnO (3 eq) were first mixed in a Teflon vessel; and, secondly, 12 ml of a 50% v / v ethylene glycol / water mixture was added to form a reaction mixture. The reaction mixture was placed in an autoclave, which was closed and placed in an oven at 150 ° C, for 24 h. It was allowed to cool to room temperature, for about 2 h.

    The reaction mixture was subjected to filtration by means of a 0.45 µm microporous syringe filter and polytetrafluoroethylene material, PTFE, (VWR International). It was then extracted with ethyl acetate, AcOEt, (3x30 ml). The organic phase was dried with Na2S04, filtered by gravity and the solvent was evaporated in vacuo.

    The reaction product, crude, was purified on a chromatotron, using hexanes and AcOEt as eluents, obtaining pure amino alcohols.
     twenty
    2-p-tolylaminoethanol, starting from p-tolylamine and ethylene glycol

    1H NMR (300 MHz, CDCI3) δ: 7.01 (d. 2H, J = 8 Hz, ArH), 6.61 (d. 2H, J = 8 Hz, ArH), 3.80 (t, 2H, J = 5 Hz, CH2 ), 3.27 (1, 2H, J = 5Hz), 2.9 (br s, 2H, NH and OH), 2.26 (s, 3H, Me) 25

    13C NMR (75 MHz, CDCI3) δ: 146.0 (1C, C), 130.0 (1C, C), 127.4 (1C, CH), 113.7 (1C, CH), 61.4 (1C, CH2), 46.7 (1C, CH2 ), 20.6 (1 C, CH3),

    Isolated yield: 84% 30

    Isolated yield 1 gram scale, with selective extraction, two extractions with hexane followed by two with ethyl acetate (the latter two contain the product) 45%.
     35
    2-o-tolylaminoethanol, starting from o-tolylamine and ethylene glycol

    1H NMR (300 MHz, CDCl3) δ: 7.03 (m, 2H), 6.60 (m, 2H), 3.78 (t, J = 5.1 Hz, 2H), 3.26 (t, J = 5.1 Hz, 2H), 2.09 ( s, 3H).
     40
    13C NMR (75 MHz, CDCl3) δ: 145.9 (1C, C), 130.2 (1C, C), 127.1 (1C, CH), 122.6 (1C, CH), 117.6 (1 C, CH), 110.2 (1C, CH), 61.1 (1C, CH2), 46.1 (1C, CH2), 17.7 (1 C, CH3).

    HRMS (M + H +]: 152.0994
     Four. Five
    Isolated yield: 28%

    2-m-tolylaminoethanol, starting from m-tolylamine and ethylene glycol

    1 H NMR (300 M Hz, COCl 3) δ: 7.00 (dd, J = 11.0; 5.1 Hz, 1 H). 6.44 (m, 3 H). 3.71 (t, J = 5.2 50 Hz, 2H), 3.19 (t. J = 5.2 Hz, 2H), 2.82 (s, 1H), 2.20 (s, 3H).

    13C NMR (75 MHz, CDCI3) δ: 148.44 (1C, C), 139.54 (1C, C), 129.59 (1C, CH), 119.41 (1C, CH), 114.54 (1C, CH), 110.90 (1C, CH ), 61.71 (1C, CH2), 46.66 (1C, CH2), 22.00 (1C, CH3).

    Isolated yield: 39% 5

    2 - ((2,3-dimethylphenyl) amino) ethanol, starting from 2,3-dimethylaniline and ethylene glycol

    1H NMR (300 MHz, CDCI3) δ: 7.04 (t. J = 7.8 Hz, 1 H), 6.64 (d, J = 7.5 Hz, 1 H), 6.56 (d, J = 8.1 Hz, 1H), 3.87 ( t, J = 5.2, 2H), 3.34 (t, J = 5.2, 2H), 2.30 (s, 3H), 2.09 (s, 3H). 10

    13C NMR (75 MHz, CDCI3) δ: 146.06 (1C, C), 136.87 (1C, C), 126.29 (1C, CH), 121.15 (1C, C), 120.03 (1C, CH), 108.55 (1C, CH ), 61.37 (1C, CH2), 46.48 (1C, CH2), 20.81 (1C, CH3), 12.65 (1C, CH3).
     fifteen
    HRMS [M + H +): 166.1219

    Isolated yield: 35%

    2 - ((2,4-dimethylphenyl) amino) ethanol, starting from 2,4-dimethylaniline and ethylene glycol

    1H NMR (300 MHz, CDCI3) δ 6.94 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.58 (d, J = 8.0 Hz, 1H), 3.86 (t, J = 5.2, 2H) , 3.33 (t, J = 5.2, 2H), 2.24 (s, 3H), 2.15 (s, 3H).

    13C NMR (75 MHz, CDCI3) δ 143.77 (1C, C), 131.27 (1C, CH), 127.47 (1C, CH), 126.97 25 (1C, C), 122.99 (1C, C), 110.61 (1C, CH ), 61.37 (1C, CH2), 46.53 (1C, CH2), 20.46 (1C, CH3), 17.58 (1C, CH3).

    HRMS [M + H +]: 166.1217
     30
    Isolated yield: 23%

    2 - ((3,5-dimethylphenyl) amino) ethanol, starting from 3,5-dimethylaniline and ethylene glycol

    1H NMR (300 M Hz, CDCI3) δ: 6.43 (s, 1H), 6.31 (s, 2H), 3.80 (t. J = 5.2 Hz, 2H), 3.28 (t, 35 J = 5.2 Hz, 2H), 2.27 (s, 6H).

    13C NMR (300 MHz, CDCI3) δ: 148.28 (1C, C), 139.06 (2C, C), 120.08 (1C, CH), 111.37 (2C, CH), 61.35 (1C, CH2), 46.31 (1C, CH2 ), 21.56 (2C, CH3).
     40
    HRMS (M + H +]: 166.1219

    Isolated yield: 30%

    2 - ((3,4-dimethylphenyl) amino) ethanol, starting from 3,4-dimethylaniline and ethylene glycol 45

    1H NMR (300 MHz, CDCI3) δ: 6.96 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.0; 2.5, 1H), 3.81 (t J = 5.4 Hz, 2H), 3.28 (t, J = 5.3 Hz, 2H), 2.72 (s, 1H), 2.21 (s, 3H), 2.17 (s, 3H).
     fifty
    13C NMR (300 MHz, CDCI3) δ: 146.33 (1C, C), 137.52 (1C, C), 130.45 (1C, CH), 126.22 (1C, C), 115.40 (1C, CH), 110.96 (1C, CH ), 61.43 (1C, CH2), 46.69 (1C, CH2), 20.14 (1C, CH3), 18.80 (1C, CH3).

    HRMS [M + H +]: 166.1225

    Isolated yield: 30%

    2 - ((2,5-dimethylphenyl) amino) ethanol, starting from 2,5-dimethylaniline and ethylene glycol 5

    1H NMR (300 MHz, CDCI3) δ: 6.96 (d. J = 7.4 Hz, 1 H), 6.53 (d, J = 7.5 Hz, 1 H), 6.49 (s, 1H), 3.87 (t, J = 5.3 Hz, 2H), 3.35 (t, J = 5.3 Hz, 2H), 2.31 (s, 3H), 2.14 (s, 3H).

    13C NMR (300 MHz, CDCI3) δ: 146.24 (1C, C), 137.15 (1C, C), 130.50 (1C, CH), 120.04 10 (1C, C), 118.59 (1C, CH), 111.51 (1C, CH), 61.68 (1C, CH2), 46.48 (1C, CH2), 20.93 (1C, CH3), 17.45 (1C, CH3).

    HRMS [M + H +]: 166.1220
     fifteen
    Isolated yield: 30%

    2- (naphthalen-2-ylamino) ethanol, starting from 2-amino naphthalene and ethylene glycol

    1H NMR (300 MHz, CDCI3) δ: 7.68 (dd, J = 8.1; 0.6 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1C), 7.62 20 (dd, J = 8.1; 0.6 Hz, 1H) , 7.37 (ddd, J = 8.2; 6.8; 1.3 Hz, 1C). 7.22 (ddd, J = 8.1; 6.9; 1.2 Hz, 1C), 6.94 (dd, J = 8.7; 2.4 Hz. 1C), 6.90 (d, J = 2.3 Hz, 1C), 3.91 (t, J = 5.2 Hz , 2H), 3.42 (d, J = 5.2 Hz, 2H), 3.00 (s, 1H).

    13C NMR (300 MHz, CDCI3) δ: 145.5 (1C, C), 135.16 (1C, C), 129.22 (1C, CH), 128.05 25 (1C, C), 127.79 (1C, CH), 126.56 (1C, CH), 126.17 (1C, CH), 122.53 (1C, CH), 118.38 (1C, CH), 105.64 (1C, CH), 61.20 (1C, CH2), 46.57 (1C, CH2).

    HRMS [M + H +]: 188.1058
     30
    Isolated yield: 19%

    2 - ((3-fluorophenyl) amino) ethanol, starting from 3-fluoroaniline and ethylene glycol

    1H NMR (300 MHz, CDCI3) δ: 7.03 (td, J = 8.1; 6.7 Hz, 1C), 6.34 (m, 2H), 6.26 (dt, J = 11.5; 35 2.3 Hz, 1C), 3.76 (t, J = 5.2 Hz, 2H), 3.21 (t, J = 5.2 Hz, 2H).

    13C NMR (300 MHz, CDCI3) δ: 162.48 (1C, C), 149.78 (1C, C), 130.40 (1C, CH), 109.07 (1C, CH), 104.39 (1C, CH), 99.96 (1C, CH ), 61.07 (1C, CH2), 45.94 (1C, CH2).
     40
    HRMS [M + H +]: 156.0807

    Isolated yield: 32%

    2 - ((2-fluorophenyl) amino) ethanol, starting from 2-fluoroaniline and ethylene glycol 45

    1H NMR (300 MHz, CDCI3) δ: 7.00 (m, 2H), 6.76 (td, J = 8.4; 1.5 Hz, 1H), 6.66 (m, 1H), 3.86 (t, J = 5.2 Hz, 2H), 3.35 (t, J = 5.2 Hz, 2H).

    13C NMR (300 MHz, CDCI3) δ: X (1C, C), X (1C, C), 124.76 (1C, CH), 117.58 (1C, CH), 50 114.88 (1C, CH), 112.74 (1C, CH), 61.38 (1C, CH2), 46.04 (1H, CH2).

    HRMS (M + H +]: 156.0811

    Isolated yield: 23%

    2 - ((2- (trifluoromethyl) phenyl) amino) ethanol, starting from 2-trifluormethylaniline and ethylene glycol

    1H NMR (300 MHz, CDCI3) δ: 7.81 (ddd, J = 8.0; 1.6; 0.5 Hz. 1H), 7.21 (m, 1H), 6.58 (m, 5 2H), 4.34 (t, J = 4.6 Hz, 2H), 3.87 (t, J = 4.6 Hz, 2H).

    13C NMR (300 MHz, CDCl3) δ: 168.78 (1C, C), 150.97 (1C, C), 134.79 (1C, CH), 131.63 (1C, CH), 117.19 (1C, CH), 116.76 (1C, CH ), 66.50 (1C, CH2), 61.96 (1C, CH2).
     10
    Isolated yield: 41%

    2 - ((2- (trifluoromethoxy) phenyl) amino) ethanol, starting from 2-methoxyaniline and ethylene glycol

    1H NMR (300 MHz, CDCI3) δ: 7.07 (m, 2H), 6.70 (dd, J = 8.5; 1.5 Hz, 1H), 6.62 (m, 1H), 15 3.78 (t, J = 5.2 Hz, 2H) , 3.28 (t, J = 5.2 Hz, 2H).

    13C NMR (300 MHz, CDCI3) δ: 140.88 (1C, C), 134.89 (1C, C), 128.08 (1C, CH), 121.39 (1C, CH), 117.40 (1C, CH), 112.75 (1C, CH ), 61.49 (1C, CH2), 46.05 (1C, CH2).
     twenty
    Isolated yield: 8%

    2 - ((3,4,5- (trimethoxy) phenyl) amino) ethanol, starting from 3,4,5-trimethoxyaniline and ethylene glycol

    1H NMR (400 MHz, CDel3) δ: 5.89 (s, 2 H), 3.83 (t. J = 5.3 Hz, 2 H), 3.81 (s, 6 H), 3.76 (s, 25 3H). 3.27 (t. J = 5.3 Hz, 2H).

    13C NMR (100 MHz, CDC13) δ: 153.9 (1C, C), 144, (1C, C) 9, 92.6 (1C, CH), 90.8 (1C, CH), 61.3, (1C, CH3 61.1, (1C , CH3) 55.9, (1C, CH2) 46.6 (1C, CH2).
     30
    HRMS [M + H +]: 228.1230

    Isolated yield: 16%

    Bibliographic references 35

    1. "Borrowing Hydrogen in the Activation of Alcohols". Advanced Synthesis Catalysis, Volume 349, Issue 10, pp. 1555-1575. Jul. 2, 2007.

    2. "Catalytic carbonyl addition through transfer hydrogenation: a departure from preformed 40 organometallic reagents". ACIEE (Angewandte Chemical International Edition in English), Vol. 48 (1). 34-46 (Online ISSN: 1521-3773). 2009

    3. "Hydrogen Autotransfer in the N-Alkylation of Amines and Related Compounds using Alcohols and Amines as Electrophiles". Chemicals Review, 110 (3), pp 1611-1641. 2010. 45

    4. "Substitution of alcohols by N-nucleophiles via transition metal-catalyzed dehydrogenation". Chemical Society Review, 44, pp. 2305-2329. 2015

    5. "Heterogeneous catalysis for the direct synthesis of chemicals by borrowing hydrogen 50 methodology". Catalysis Science & Technology, 5, 1412-1427. 2015

    6. "Recent Developments in Methodology for the Direct Oxyamination of Olefins". Chemistry A European Journal. Vol. 17, Issue 1, pp. 58-76. Jan. 3, 2011.
    7. "A sustainable catalytic pyrrole synthesis". Nature Chemistry 5,140-144. Jan. 20, 2013.

    8. "An Efficient Synthesis of Organic Carbonates using Nanocrystalline Magnesium Oxide". Advanced Synthesis & Catalysis, Vol. 349, Issue 10, pp 1671-1675. 2007
     5
    9. "Tandem Synthesis of β-Amino Alcohols from Aniline, Dialkyl Carbonate, and Ethylene Glycol". Industrial & Engineering Chemistry Research, 47 (8), pp 2484-2494. 2008

    10. "A Bifunctional Pd / MgO Solid Catalyst for the One-Pot Selective N-Monoalkylation of Amines with Alcohols". Chemistry A European Journal, Vol. 16, Issue 1, pp. 254-260. 10 2010.
    权利要求:
    Claims (10)
    [1]

    1. Procedure for obtaining β-amino alcohols which, from an amine and a diol / water mixture, is characterized by being carried out in a heterogeneous catalytic system and comprising the following steps:
    - a solid catalytic mixture comprising a supported metal and a solid inorganic acid-base co-activator is added to the starting amine,
    - then the diol / water mixture is added, 10
    - subsequently, the reaction is carried out at a temperature between 130 and 200 ° C, for 2-24 hours.
    - the reaction product, based on β-amino alcohol, is filtered through a microporous filter, by at least a first extraction with hexane and then at least a second extraction with ethyl acetate to purify the β- amino alcohol obtained.

    [2]
    2. Method according to claim 1, characterized in that the amine is of the type H2 H2N-Ar, where Ar is one of the following elements: phenyl, ortho / meta / for methylphenyl, ortho / meta / for nitrophenyl ortho / meta / for fluorophenyl , ortho / meta / for aminophenyl, ortho / meta / for trifluoromethylphenyl, ortho / meta / for trifluoromethoxyphenyl, 2,3; 3.4; 4.5; 2.4; 2,5 dimethylphenyl, 3,4,5-trimethylphenyl, anthracil or naphthyl.
     25
    [3]
    3. Method according to claim 1, characterized in that the amine is a heterocyclic amine.

    [4]
    4. Process according to claim 1, characterized in that after obtaining the β-amino alcohols, the catalytic mixture is recovered through filtration and washing with hexane / ethyl acetate and, subsequently, drying between 140 and 160 ° C, for 2 to 6 hours.

    [5]
    5. Method according to claim 1, characterized in that the diol of the diol / water mixture is selected from the following elements: 1,2-ethanediol (ethylene glycol), 1,2-propanediol, 2,3-butanediol, 1 -phenylethane-1,2-diol, 1,3-propanol, 1,2-cycloexanodiol, 1,3-butanediol, di-ethylene glycol, tri-ethylene glycol, tetr-ethylene glycol and triol glycerol, and cyclic derivatives thereof.

    [6]
    Method according to claim 1, characterized in that the solid inorganic acid-base co-activator 40 is selected from the following elements: CaO, BaO, ZnO, CeO2, AI2O3, MgO, TiO2, SiO2.

    [7]
    Method according to claim 1, characterized in that the supported metal is a metal selected from the following elements: transition metals of the groups IIIB to IIB of the periodic system of elements, oxides and hydroxides thereof and a Pt alloy -Sn.

    [8]
    Method according to claim 7, characterized in that the supported metal is a metal selected from the following elements: Pd, Au, Pt, Cu, Ag, Ru, oxides and hydroxides thereof.

    [9]
    9. Method according to claim 1, characterized in that the metal is supported on a solid substrate that is selected from the following elements: TiO2,
    Al2O3, SiO2, Fe3O4, Fe2O3, MgO, Ga2O, CeO2, NiO, zeolites, graphite, graphene, graphene oxide, diamond, carbon nanotubes, carbon black.

    [10]
    10. Method according to claim 1, characterized in that the catalytic mixture comprises palladium supported on carbon and ZnO. 5
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    公开号 | 公开日
    ES2644751B1|2018-09-11|
    EP3466920A1|2019-04-10|
    EP3466920A4|2020-01-22|
    WO2017207839A1|2017-12-07|
    引用文献:
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    CN103539718A|2012-07-12|2014-01-29|中国石油化工股份有限公司|Indole production method|
    US2391139A|1943-12-15|1945-12-18|Eastman Kodak Co|Process for alkylating arylamines|CN110947397A|2019-10-23|2020-04-03|广东工业大学|Cerium dioxide loaded low-dose PtCu superfine alloy catalyst and preparation method and application thereof|
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