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    • 专利摘要:
    Improved Process for Reductive Amination and Selective Hydrogenation of Halogen-containing Substrates. A method is described for conducting a chemical reaction selected from the reductive amination and the hydrogenation of a first functional group in an organic feed substrate, which feed substrate further comprises at least one further functional group containing a halogen atom, in the presence of hydrogen and a heterogeneous catalyst comprising at least one metal from the list of Pd, Pt, Rh, Ir and Ru, together with at least a second metal from the list consisting of Ag, Ni, Co, Fe, Sn, Pb, Bi and Cu. The process is preferably used for the reductive amination of 2-chloro-benzaldehyde to form 2-chlorobenzyldimethylamine, as an intermediate in the production of agrochemically active compounds and microbicides of the methoximinophenyl glyoxyl ester series. Furthermore, a particularly advantageous composition rich in 2-chlorobenzyl dimethylamine is described, further comprising an amount of 2-chlorobenzyl alcohol and few chlorotoluene isomers.
    公开号:BE1021017B1
    申请号:E2014/0383
    申请日:2014-05-19
    公开日:2014-12-18
    发明作者:Kristof Moonen；Bart Vandeputte；Daan Scheldeman；Kim Dumoleijn
    申请人:Taminco；
    IPC主号:
    专利说明:

    Improved process for the reductive amination and the selective hydro-generation of halo-containing substrates
    TECHNICAL FIELD
    The present invention relates to chemical reactions that include the chemical conversion of a first functional group into an organic feed substrate in the presence of hydrogen, wherein the organic feed substrate comprises at least one further functional group containing a halogen atom. More particularly, the invention relates to the noble metal catalyzed reactions selected from the reductive amination and the selective hydrogenation of only the first functional group on the substrate while the further functional group containing the halogen atom remains substantially unaffected and present in the reaction product . BACKGROUND ART.
    The selective conversion of one functional group into a multifunctional supply substrate has always been a domain of great importance for the chemical, pharmaceutical and agrochemical industries. Halogen atoms in particular are often included in addition to other functional groups in active ingredients or precursors of these active ingredients.
    The goal of high selectivity was often quite difficult to achieve because most processes are sensitive to side reactions that lead to significant amounts of by-products. These side reactions consume valuable amounts of feed substrate, and the by-products are often quite useless. Some of the by-products may also be difficult to separate from the desired product. When the desired product is an intermediate for the production of a further derivative, some by-products may also be disturbing to the further synthesis steps because they may be reactive in such a downstream process step and may lead to undesirable additional consumption of valuable raw materials and even to undesirable and / or unacceptable contamination of the end product.
    Multi-step synthesis protocols of complex multifunctional chemicals include more and more catalytic conversion steps as they often perform better than their stoichiometric alternatives with regard to atomic efficiency and reduced waste production. Reductive conversion steps with hydrogen gas as a reducing agent usually use metal-based catalysts to achieve commercially interesting rates.
    However, metals often interfere with carbon-halogen bonds in organic compounds. Pd in particular is capable of inserting into a carbon-halogen bond, for example. Such behavior is desirable in its use as a catalyst in the so-called coupling reactions. Such reactions are often used as important steps in multi-step synthesis paths for complex organic compounds, such as active ingredients in the pharmaceutical and agrochemical industries. In a coupling reaction, a halogen-containing first fragment is coupled to a second fragment using a catalyst, the second fragment being coupled to the first fragment where the halogen was originally located. The second fragment can be linked via a wide variety of functional groups, and different versions of such coupling reactions have often received specific names, such as the Heck coupling, which uses an olefin, the Sonogashira coupling, which uses an alkyn, the Suzuki coupling, which uses a boronic acid and the Stille coupling, which uses an alkyl tin group. This list is not exhaustive, because many more different functional groups can possibly be used for such linking.
    Insertion of a metal such as Pd into a carbon-halogen bond in the presence of hydrogen, but in the absence of a suitable fragment for coupling usually results in the replacement of the halogen atom with a hydrogen atom and hence the loss of the halogen (X) as part of the substrate. Such a hydrogenolysis reaction is especially enhanced in the presence of a base capable of capturing the liberated acid HX. This reaction can be used advantageously in some applications, such as environmental treatment of halogenated organic contaminants.
    In order for the production of the halogenated fragments to be used in later coupling reactions, or if halogen atoms are required in the structure of the end product, the introduction of the metal catalyst into the carbon-halogen bond is not desirable, since it usually leads to side reactions and associated material losses .
    Various methods have therefore been attempted to increase the selectivity of metal-catalyzed reductive aminations and selective hydrogenations of one functional group in the presence of one or more halogen atoms elsewhere in the substrate molecule. The methods currently available in the art can be divided into three classes.
    A first method involves the addition of modifiers to the reaction mixture or working in alternative reaction environments. For example, US 6429335 B1 describes a method for reductive amination of ortho-chlorobenzaldehyde with ammonia under 140 bar of hydrogen using Raney nickel or Raney-cobalt to produce the primary amines ortho-chlorobenzylamine. The process works in the presence of an amount of disodium tetraborate decahydrate (borax), optionally together with a small amount of bis (hydroxyethyl) sulfide, and obtains a product selectivity of at most 95.87% by weight. The major by-product is 3.19% by weight of ortho-chlorobenzyl alcohol and only 0.1% by weight of benzylamine was found.
    Cheng et al., In "The effect of water on the hydrogenation of o-chloronitrobenzene in ethanol, n-heptane and compressed CO2", Applied Catalysis A: General 455 (2013), pp. 8-15, Elsevier, describes the effect of water or compressed carbon dioxide as a reaction medium for the hydrogenation of o-chloronitrobenzene to o-chloroaniline with 5% Pd or Pt as a catalyst on a carbon carrier. The reaction is carried out at 35 ° C and under a hydrogen pressure of 40 bar. However, the Pd catalysts suffer from poor stability under these conditions.
    Dan-Qian Xu et al., "Hydrogenation of ionic liquids: An alternative methodology toward highly selective catalysis or halonitrobenzenes to corresponding haloanilines," Journal of Molecular Catalysis A: Chemical, 235 (2005), pp. 137-142, Elsevier, directs to the same reaction. The process uses Raney nickel, 5% Pt / C and 5% Pd / C catalysts in various ionic liquids, with methanol as the reference solvent. A considerably lower dehalogenation was observed for the ionic liquid catalyst systems compared to the methanol reference. The disadvantage of using special reaction environments or the addition of modifiers is the extra complexity that must be built into the process.
    A second method involves modifying the catalyst support to improve selectivity. Kratky V. et al., "Effect of catalyst and substituents on the hydrogenation of chloronitrobenzenes," Applied Catalysis A: General, 235 (2002), pp. 225-231, Elsevier, discloses a liquid phase hydrogenation process of chloronitrobenzene isomers the corresponding chloroanilines. The process uses either a palladium-on-carbon catalyst (Pd / C) or a palladium-on-sulfonated poly (styrene-co-divinylbenzene) catalyst (Pd / D). Only the Pd / D catalyst was activated, therefore reduced prior to use in the reaction. The highest selectivity obtained with the desired end product was lower than 95%. Significant dechlorination was observed, especially from the feed substrate via the Pd / C catalyst and from the reaction product via the Pd / D catalyst.
    A third method involves modifying the parent hydrogenation catalysts with additional metals, so-called promoters. Wang, Y. et al., "A green synthesis route of ortho-chloroaniline: solvent-free selective hydrogentation or ortho-chloronitrobenzene over Pt-Ru / Fe304 / C catalyst", Catalysis Communications 19 (2012) 110-114, Elsevier, discloses the use of a Pt-Ru / Fe 3 O 4 / C catalyst for the selective hydrogenation of o-chloro nitrobenzene at temperatures between 75 and 85 ° C and a pressure between 17 and 40 bar. High conversion is reported with virtually no dehalogenation. US 3666812 reports the use of Bi, Pb and Ag-modified Pt / C catalysts and a Pb-modified Pd / C catalyst for the hydrogenation of chlorinated nitrobenzenes at temperatures between 75 and 100 ° C and a pressure of 750 psig . While the parent Pd and Pt catalyst exhibited complete (100%) dehalogenation under these conditions, the modified catalysts exhibited reduced dehalogenation to levels below 5%. Mahata, N. et al., "Promotional effect of Cu on the structure and chloronitrobenzene hydrogenation performance of carbon nanotube and activated carbon supported Pt catalysts", Applied Catalysis A: General 464-465 (2013) 28-34, Elsevier, shows that the presence of Cu as a promoter in a Pt catalyst with carbon nanotubes or activated carbon as the carrier results in a reduction in the level of dehalogenation and an increase in the stability of the catalyst in the hydrogenation of chloronitrobenzene at 120 ° C and 15 bar . US 5512529 discloses the use of a platinum catalyst on an active carbon support and modified by copper in the hydrogenation of halonitro compounds to aromatic haloamines.
    Pt-based catalysts are often considered in the case of sensitive hydrogenation reactions. However, these catalysts are very expensive due to the scarcity of the platinum metal. US 5689021 discloses the use of a Raney nickel catalyst prepared from the nickel-rich crystalline precursor Ni2Al3 and doped with the additive element molybdenum to obtain 2ί2.χ / ΑΙ3 / Μοχ, with x = 0.4 ± 0.05, to selectively hydrogenate various halonitroaromatic compounds to form the corresponding haloaminoaromatic compounds. The hydrodehalogenation side reaction was found to be practically nil.
    Other chemical routes to obtain these particularly valuable polyfunctional halogen-containing products have also been investigated.
    The stoichiometric alternative to the catalytic reductive amination of o-chlorobenzaldehyde to obtain o-chlorobenzyl dimethylamine is illustrated by WO 2013/017611 A1, which describes a method for obtaining o-chlorobenzyl dimethylamine from o-chlorobenzyl chloride and dimethylamine. The yield of the reaction was at most 95.4% of the theory. The reaction was carried out without any intervention of a catalyst and a chloride salt was obtained as an undesirable by-product. Such methods based on stoichiometric chemistry generally suffer from poor atomic efficiency and a production of large amounts of waste.
    Therefore, there remains a need for a highly selective conversion to chemical reactions selected from the reductive amination and selective hydrogenation of only the first functional group, on a substrate comprising at least one further functional group comprising a halogen atom. The desire is to achieve industrially acceptable reaction rates in which the further functional group comprising the halogen atom remains substantially unaffected and remains in the reaction product.
    The present invention has for its object to remedy or at least reduce the problem described above and / or to offer improvements in general.
    DESCRIPTION OF THE INVENTION
    According to the invention there is provided a method and a particularly useful composition that can be prepared by the method as defined in the appended claims.
    The invention therefore provides a method for carrying out a chemical reaction selected from the reductive amination and the selective hydrogenation of a first functional group in an organic feed substrate, which feed substrate comprises at least one further functional group containing a halogen atom, wherein the halogen atom is selected from the list consisting of chlorine, bromine, iodine, and combinations thereof, in the presence of hydrogen and a heterogeneous catalyst which comprises at least one first metal selected from the list consisting of palladium, Pd, rhodium, Rh, and ruthenium, Ru , together with at least one second metal selected from the list consisting of silver, Ag, nickel, Ni, cobalt, Co, tin, Sn, and copper, Cu.
    Applicants preferably select the first metal from the list consisting of palladium, Pd, rhodium, Rh, and ruthenium, Ru. More preferably, the applicants use palladium as the first metal. Palladium is more available than most other precious metals in the list of the first metals and is therefore more easily available as a raw material, usually also at a lower cost for the production of the catalyst. Palladium is also a metal that is easier to recover or recover from a used catalyst, and to recycle to a new use. Even more preferably, applicants use a bimetallic catalyst with Pd selected as the first metal and only one metal selected as the second metal. A bimetallic catalyst is easier to manufacture and the quality can be more easily controlled: More preferably, applicants use a bimetallic Pd / Cu catalyst, e.g. with copper alone as the second metal. Applicants have found that copper is also very available in a suitable form for catalyst preparation, and that copper simply performs better than the other metals of the second list in at least some of the selected chemical reactions of the present invention.
    Although palladium is not recognized as a highly selective catalyst for carrying out reductive aminations and hydrogenation reactions of halogen-containing substrates, we have found that the catalysts comprising palladium as the first metal, such as bimetallic Pd-Cu catalysts, surprisingly benefit from the high activity of the Pd catalysts with greatly improved selectivity in reacting halogen-containing substrates. Applicants believe that this benefit may also be present with a selected number of other first metals, as indicated, and in combination with a number of second metals, also as specified.
    We have found that the process of the present invention is highly selective in carrying out the desired chemical conversion of the first functional group, while the further functional group containing the halogen atom remains substantially intact so that the halogen remains present in the reaction product. For example, we have found that the dehalogenation of a halide function as the further functional group on the substrate, a side reaction that occurs when using a monometallic palladium catalyst, can be substantially suppressed, and essentially avoided, when using the method of the present invention. The dehalogenated by-product is usually useless, if not a nuisance. The same may apply to the halide-containing by-product (e.g., HX) of the undesired dehalogenation reaction, which may, for example, cause corrosion to the reactor or downstream equipment. The secondary reaction thus typically represents a degradation of valuable raw materials, and adds additional load for removing the secondary products from the desired reaction product or for selecting more expensive building materials. The method according to the present invention thus has the advantage that a very purely desired reaction product is produced, which requires much less remediation, if necessary, before it can be used further. The method also has a very efficient use of the organic substrate starting material, with very low degradation, if any, to by-products that may be useless or undesirable in the first reaction product, whereby the by-products must be separated and usually discarded or even extra efforts are made. require for disposal in a responsible manner. Furthermore, the process of the present invention avoids the use of expensive and generally less active platinum as a metal in the catalyst without compromising selectivity.
    Applicants have found that the process of the present invention is particularly suitable for the reductive amination of ortho-chlorobenzaldehyde in the presence of dimethylamine, DMA, to produce ortho-chlorobenzyl dimethylamine, o-CI-BDMA. Applicants have found that the method of the present invention can produce the desired o-CI-BDMA, also known as ortho-CI-BDMA or 2-CI-BDMA in very high yield and in very high purity, with very few by-products.
    The invention therefore also provides a composition comprising, as measured by gas chromatography, GC, a) at least 98.0% by weight of o-chlorobenzyl dimethylamine, o-CI-BDMA, b) at most 0.40% by weight of ortho-chlorotoluene, at preferably the total of all chlorotoluene isomers, and c) at least 0.05 wt% o-chlorobenzyl alcohol.
    Applicants have found that this composition is particularly suitable as an intermediate for the production of more complex structures in multi-step synthesis routes. Such routes can lead to agrochemical or pharmaceutical active ingredients. Applicants believe that the low presence in the composition of ortho-chlorotoluene, more generally the total of all chlorotoluene, in particular the monochlorotoluene, and preferably also of chlorodichloromethylbenzenes, also known as chlorobenzalchlorides, in particular o-chloro dichloromethylbenzene , also known as 2-chlorobenzyl chloride or ortho-chlorobenzal chloride, preferably below the detection limit of the most suitable analytical technique, and more preferably its total absence, ensures that the composition is very suitable for use as a raw material in the further steps of many synthesis routes. Applicants have found that the compounds such as chlorotoluene, such as monochlorotoluene and orthochlorodichloromethylbenzene, are impurities that participate in downstream steps when the composition is used as an intermediate for the synthesis of complex chemical compounds. However, they do not lead to the desired compound and thus represent a loss of valuable reagents. The compounds resulting from these contaminants are at best inert, but can also have undesirable effects in the final composition, with excessive occurrence of these side reactions creating a need for additional purification steps in the overall synthesis process.
    The composition is particularly useful if such further steps include metallation reactions such as lithiation or Grignard reactions, as described in US 2010/0113778 A1, or coupling reactions such as the reactions known as the Hake, the Sonogashira, the Suzuki, or the Still coupling.
    Applicants have found that a small amount of o-chlorobenzyl alcohol present in the composition of the present invention, which may be present, for example, when the composition is obtained by the method of the present invention, is of little importance for the further use of the composition, as with many other synthesis steps and / or many applications of the products thereof.
    EMBODIMENTS OF THE INVENTION
    The present invention is described below with respect to certain embodiments and with reference to certain drawings, but the invention is not limited thereto but only by the claims. The drawings described are only schematic and are not limitative. In the drawings, the size of certain elements may be exaggerated and not drawn to scale for illustrative purposes. The dimensions and the relative dimensions do not necessarily correspond to actual reductions in the practice of the invention.
    In addition, the terms first, second, third and the like are used in the description and in the claims to distinguish between similar elements and not necessarily for describing a sequential or chronological order. The terms are interchangeable under appropriate conditions and the embodiments of the invention may function in sequences other than described or illustrated herein.
    In addition, the terms top, bottom, top, bottom and the like in the description and claims are used for descriptive purposes and not necessarily for describing relative positions. The terms used as such are interchangeable under appropriate conditions and the embodiments of the invention described herein may function in orientations other than those described or illustrated herein.
    The term "comprising" used in the claims is not to be construed as being limited to the means listed thereafter; it does not exclude other elements or steps. It is to be interpreted as indicating the presence of the aforementioned characteristics, integers, steps or components as intended, but does not exclude the presence or addition of one or more other characteristics, integers, steps or components, or groups thereof. Thus, the scope of the expression "a device comprising means A and B" should not be limited to devices consisting only of components A and B. It means that with regard to the present invention, the only relevant parts of the device A and B to be. Accordingly, the terms "comprising" and "including" include the more restrictive terms "essentially consisting of" and "consisting of".
    The terms "ortho", "meta" and "para", abbreviated by o, m, p, respectively, are used to indicate the relative position of two substituents on an aromatic cycle, as defined by the International Union of Pure and Applied Chemistry (IUPAC). Taking into account the standard rules of priority for functional groups and substituents, the location can also be indicated by numbers in the chemical nomenclature. In this respect, the indication 2, 3 and 4 corresponds to o, m and p, respectively.
    In one embodiment, the present invention includes the use of a Pd-Cu catalyst for the reductive conversion of halogenated substrates in the presence of hydrogen, in particular the reductive amination of such substrates. As a catalytically highly active metal, Pd has the advantage over Pt that it is much cheaper and easier to recover.
    Bimetal Pd-Cu catalysts have already found application in environmental chemistry for nitrate reduction with hydrogen in waste water treatment, where biological denitrification is no longer appropriate.
    Also described in the art is the effect of the hydrogen reduction on the structure of a silica-supported bimetal Pd-Cu catalyst. A process for the preparation of such a catalyst with successive deposition of Pd and Cu on a silica support has been described, but the use of the catalyst has not been demonstrated.
    Bimetal Pd-Cu catalysts have so far found limited applications in the manufacture of organic chemicals. One reference describes the use of unsupported Pd-Ni, Pd-Cu and Pd-Ag catalysts for the hydrogenation of nitrobenzene to aniline. An improved activity was observed in comparison with a palladium black as a reference. The highest activity was observed for the Pd-Ni catalyst. The introduction of a second metal was thought to lead to a better dispersion of the active centers on the catalyst surface.
    Another reference describes the preparation of an active carbon Pd-Cu catalyst. Its use has been demonstrated in the hydrogenation of acid halides to the corresponding aldehydes and in the stereospecific reduction of 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline.
    Yet another reference describes that alloying copper with palladium deposited on carbon in the respective weight ratio of less than 0.5: 1.0 significantly increases the catalytic activity of that palladium as a catalyst in the reduction of formylbenzoic acid impurities in crude phthalic acid.
    Still another reference describes the preparation and use of bimetal Pd-Cu and Pt-Cu catalysts, optionally on a support, for the hydrogenation in the gas phase of succinic acid or maleic acid or their anhydrides with gamma butyrolactone. The catalysts have the advantage of being able to hydrogenate both the carbonyl group and the site of ethylenic unsaturation in a single step.
    Still another reference discloses the use of bimetal Pd-Cu nanoparticles as a catalyst for the reduction of p-nitrophenol to p-aminophenol using NaBH4. EP 0312253 A2 describes a process for preparing tridodecylamine via an amination reaction of dodecyl alcohol with ammonia using Cu / Ni and Cu / Ni / Pd catalysts. It is shown that the presence of palladium reduces the reaction time and improves the yield of tridodecylamine.
    In none of these references describing a multimetallic Pd-Cu catalyst, the effect of such a catalyst on halogenated substrates, in particular in maintaining the halogen atom in the structure of the final product, is not suggested or demonstrated.
    The process of the present invention is carried out in the presence of hydrogen. The use of hydrogen (H 2) as a reducing agent is preferred due to the presence of a metal catalyst. Such a catalyst is believed to be instrumental in activating the molecular hydrogen by weakening the H-H bond. This functionality is not special for, or limited to, reductive aminations, but is the same for all types of hydrogenation reactions in organic chemistry. In addition to the activation of H2, the catalyst can also play a role in other reaction steps, such as the other steps in the reductive amination mechanism. This role as well as the characteristics of the reaction conditions (such as the presence of free amine, water, the characteristic temperature and pressure range, etc. ...) ensure that the reductive amination catalysts are often designed for this specific process, especially when sensitive (e.g. multifunctional) ) substrates are involved. It was therefore surprising to find that the Pd-Cu catalyst of this invention exhibit such good halogen retention characteristics for a wide range of hydrogenation reactions of halogenated substrates, and that it is therefore also applicable in a much broader technical field than only in reductive aminations.
    Suitable organic feed substrates for the process of the present invention are organic molecules comprising at least one reducible functional group in addition to at least one halogen atom.
    In an embodiment of the process of the present invention, the first functional group is selected from the list consisting of an aldehyde, a ketone, a nitro group, a carboxylic acid, a carboxylic acid ester, a carboxylic acid amide, an unsaturated carbon-carbon bond, a nitrile, an imine and an oxime, and combinations thereof. Reducable functional groups that can be suitably hydrogenated with the Pd / Cu catalyst according to the process of the present invention are ketones, aldehydes, nitro groups, carboxylic acids, carboxylic acid esters, carboxylic acid amides, unsaturated carbon-carbon bonds, nitrile, imine and oxime groups. Such functional groups may already be present in the substrate when it is introduced into the reactor, but may also be formed in $ Hu in the course of a chemical reaction.
    In one embodiment of the method of the present invention, the first functional group in the feed substrate is first converted to in situ by reaction with an additional ... reagent to form a reducible functional group. In particular, ketones and aldehydes can be converted to various intermediates, under the conditions of a reductive amination reaction, and which intermediates are subsequently hydrogenated with hydrogen to the final product of the reaction.
    The halogen atom (X) is an element from group 17 of the IUPAC periodic table of 22 June 2007. In an embodiment of the method according to the present invention, the further functional group is selected from the list consisting of a chloride, a bromide and an iodide. The halogen is usually attached to the substrate by means of a covalent bond with a carbon atom (C-X bond). The carbon atom to which the halogen is attached can be hybridized to either sp, spJ or sps.
    In one embodiment, the process of the present invention for the reductive amination of a halogen-benzaldehyde in the presence of a nitrogen-containing compound, preferably the nitrogen compound being selected from ammonia, a primary amine and a secondary amine, and mixtures thereof, preferably for the production of ortho-chlorobenzyl dimethylamine, o-CI-BDMA, by reductive amination of ortho-chlorobenzaldehyde in the presence of dimethylamine, DMA.
    For a reductive amination, chlorobenzaldehydes (ortho, meta or para) are particularly interesting substrates, because they can lead to the corresponding chlorobenzylamines. Both the chlorine and the amine functionality in these reaction products provide products of interest as further chemical building blocks, because the functionalities represent suitable sites for further functionalization in subsequent synthesis steps. The chlorine atom offers possibilities for metallation reactions, such as lithiation or Grignard reactions, while the amine group offers possibilities for a further reductive amination or in the case of a tertiary amine for quaternization and conversion into other suitable leaving groups.
    Reductive amination is the reaction known in chemistry for the synthesis of primary, secondary or tertiary amines from a suitable ketone or aldehyde. The term "amination" refers to the reaction part in which an amine functionality is incorporated in the substrate. The term "reductive" refers to the observation, when comparing the feed substrate and the product of a reductive amination reaction, that a reduction has necessarily also taken place. In chemistry, a reduction reaction generally refers to the gain of electrons from an atom or molecule In organic chemistry, reductions are usually related to the disappearance of unsaturations, such as double bonds of the substrate molecules.The net result of a reductive amination of a ketone or aldehyde is the conversion of a C = 0 double bond to a CN single bond.
    In an embodiment of the process of the present invention, the reductive amination is carried out in two steps, in the first step reacting the aldehyde with the nitrogen-containing compound, and in the next step introducing hydrogen and the catalyst, preferably the two steps are performed in the same reaction vessel. The general mechanism of reductive aminations is believed to begin with the nucleophilic addition of ammonia or a primary or secondary amine to the carbonyl group of the ketone or aldehyde. Such addition can occur with or without the help of a catalyst. The resulting adduct, sometimes referred to as "hemiamic", can further react by eliminating water to the corresponding imine. The occurrence of imine formation is not essential to the outcome of the reductive amination, and in the case of the use of secondary amines as reagents, this is even impossible. In this case, enamines can be formed as intermediates.
    The next step in the mechanism of the reductive amination comprises a reduction step. All three of an imine, a hemiaminal or an enamine can be the substrate before and on which the reduction takes place. This step requires a reducing agent, which itself is oxidized after the reaction has been carried out. As for other hydrogenation reactions, stoichiometric reagents are sometimes used for this purpose, such as, for example, formic acid or hydrides, such as borohydrides or aluminum hydrides, but from the point of view of atomic efficiency and process economy, the use of hydrogen gas is particularly beneficial.
    In one embodiment, the process of the present invention for producing chloroaniline from nitrochlorobenzene using a catalyst other than a bimetal Pt / Cu-on-carbon catalyst. Halogenated nitrobenzenes are another industrially interesting class of substrates, since they are often used as precursors to produce halogenated anilines that are used in the dye industry and as building blocks in multi-step synthesis protocols of complex active ingredients in the agrochemical and pharmaceutical industries. The catalyst used in the process of the present invention can represent a cost-effective alternative to the expensive Pt catalysts commonly used in the art. The applicants have surprisingly found that a Pd / Cu catalyst, despite the reputation that Pd is presumably much less selective than Pt, can achieve very high selectivities in these reactions of great economic importance. The Pd / Cu thus constitutes a cost-effective alternative to the Pt / Cu (10: 1 weight ratio) catalyst on active carbon powder proposed for this reaction in U.S. Pat. 5512529. The applicants believe that this advantage can also apply to a number of other first metals other than Pd, in combination with a number of other second metals other than Cu.
    In an embodiment of the process of the present invention, the heterogeneous catalyst comprises the first metal in a concentration in the range of 0.1-10.0% by weight, preferably at a concentration of at least 0.5% by weight, with more preferably at least 1.0%, even more preferably at least 1.5%, even more preferably at least 2.0%, preferably at least 2.5% by weight, more preferably at least 3.0%, even more preferably at least 3.5%, even more preferably at least 4.0%, preferably at least 4.5% by weight, and optionally at a concentration of at most 8.0%, preferably at most 7 0%, more preferably at most 6.0% by weight, even more preferably at most 5.0% by weight, preferably at most 4.0% by weight, all based on the total weight of the catalyst. Applicants have found that these levels provide an advantageous balance between catalyst performance and the costs and efforts associated with catalyst production.
    In an embodiment of the process of the present invention, the heterogeneous catalyst comprises the second metal in a concentration in the range of 0.05-40% by weight, preferably at a concentration of at least 0.1% by weight, more preferably at least at least 0.5%, even more preferably at least 1.0% by weight, even more preferably at least 1.5% by weight, preferably at least 2.0% by weight, more preferably at least 3.0% by weight , even more preferably at least 4.0 wt%, even more preferably at least 4.5 wt%, preferably at least 5.0 wt%, more preferably at least 5.5 wt%, even more preferably at least 6.0% by weight, and optionally in a concentration of at most 35.0% by weight, preferably at most 30.0% by weight, more preferably at most 25.0% by weight, even more preferably at most 20% 0% by weight, even more preferably at most 18.0% by weight, preferably at most 16.0% by weight, more preferably at most 14.0% by weight, even more preferably at most 12.0% by weight, with even more preferably at most 10.0% by weight, preferably at most 9.5%, more preferably at most 9.0% by weight, even more preferably at most 8.5% by weight, still more preferably at most 8.0 % by weight, preferably at most 7.5% by weight, more preferably at most 7.0% by weight, even more preferably at most 6.5% by weight, all based on the total weight of the catalyst. Applicants have found that these levels of the second metal also bring a favorable compromise between the performance of the catalyst in the process and the complexity and efforts in the production of the catalyst.
    In one embodiment, the method of the present invention further comprises the step of depositing the first metal on a support. Applicants have found that the precipitation method is a very suitable method for applying a metal such as palladium to a support. Suitable precipitation methods for depositing the palladium metal on a support are well known in the art. .
    In one embodiment, the method of the present invention comprises the step of applying the second metal to a support by precipitation. This step can be performed at the same time as applying the first metal to the support, or can be performed after the first metal has been applied to the support. Applicants prefer the second metal to be applied to the catalyst after the first metal has been placed on the support because they have found that the catalyst prepared in this way exhibited even lower dehalogenation compared to a catalyst prepared via co-precipitation.
    In an embodiment of the process of the present invention, the chemical conversion is selected from reductive amination and hydrogenation carried out in the presence of a solvent, preferably an organic solvent, preferably the solvent comprising at least one alkanol, preferably methanol, preferably the solvent is present in a weight ratio to the organic feed substrate in the range of 0.1-20 g / g, preferably at least 0.2 g / g, more preferably at least 0.3 g / g, optionally at most 15.0 g / g, preferably at most 10.0 g / g, more preferably at most 5.0 g / g, even more preferably at most 4.0 g / g, even more preferably at at most 3.0 g / g, preferably at most 2.0 g / g, more preferably at most 1.0 g / g. Reductive amination reactions or selective hydrogenations according to the method of the present invention can occur in any suitable environment. Solvents such as water, alcohols (e.g. methanol), tetrahydrofuran (THF), dioxane, alkanes are advantageously used. A solvent can provide advantages for such a reductive amination or hydrogenation reaction, such as an improved solubility of hydrogen, a lower viscosity of the reaction mixture, an improved mixing element, an improved heat transfer, etc. ... The concentration of the substrate and the products in such a solvents can be between 1 and 50%, preferably between 5 and 40%, more preferably between 10 and 40% by weight based on the total reaction mixture. Strongly diluted reaction mixtures can lead to poor space-time yields, while in the case of highly concentrated reaction mixtures, the benefits of the solvent can be minimized. If the reaction substrates and the products are liquids under the applied reaction conditions, the reaction can be carried out without the addition of a solvent. One may also choose to add small amounts of solvents to the reaction mixture, e.g. 1 to 50%, preferably 5 to 40%, more preferably 10 to 30% by weight, relative to the total reaction mixture. This addition can have special advantages such as improving catalyst performance, reducing the autogenous pressure of the reaction mixture, preventing the occurrence of phase separation, etc. ...
    In the reductive amination of o-chlorobenzaldehyde with dimethylamine (DMA), we have found that adding small amounts of methanol to the reaction mixture significantly improves the yield and usability of the process. Without wishing to be bound by this theory, the methanol presumably increases the solubility of the highly volatile amine and improves the reaction rate in the liquid phase. In addition, the presence of methanol may prevent the formation of two liquid phases during the reductive amination, possibly due to the release of water as a by-product during the reaction.
    In one embodiment of the process of the present invention, the heterogeneous catalyst was heat-treated, such as prior to its use in the process, preferably at a temperature in the range of 50-500 ° C, preferably at a temperature of at least 60 ° C, more preferably at least 70 ° C, even more preferably at least 80 ° C, even more preferably at least 100 ° C, preferably at least 150 ° C, more preferably at least 200 ° C, more still preferably at least 250 ° C, and optionally at a temperature of at most 450 ° C, preferably at most 400 ° C, even more preferably at most 350 ° C, the heat treatment is preferably carried out for at least 2 hours , more preferably 3 hours. Applicants prefer to heat-treat the catalyst at about 300 ° C, in air, for a period of about 3 hours, and this after drying the catalyst at about 60 ° C for 3 hours, if there is no further substantial weight loss could be noticed more.
    The catalyst used in the process of the present invention is preferably a bimetal catalyst comprising Pd and Cu. The metals can act as a real alloy or as a layered catalyst. With a real alloy, it is no longer possible to distinguish a separate Pd or Cu phase. With a layered catalyst, a Pd and a Cu phase can occur alternately in the catalyst at a molecular level. The catalyst of the present invention can also contain a combination of alloyed and pure metal phases. In all cases, it is important that the two metals, Pd and Cu, are in contact with each other and do not exist as separate entities in the reaction mixture or on a support.
    In an embodiment of the process of the present invention, the catalyst comprises Pd and Cu in a weight ratio of Cu to Pd in the range of 0.05: 1.0 to 10.0: 1.0, preferably at least 0 , 1: 1.0, more preferably at least 0.5: 1.0, even more preferably at least 1.0: 1.0, even more preferably at least 1.5: 1.0, preferably at least 2.0: 1.0, and optionally at most 8.0: 1.0, preferably at most 6.0: 1.0, more preferably at most 5.0: 1.0, with even more preferably at most 4.0: 1.0, even more preferably at most 3.5: 1.0, preferably at most 3.0: 1.0, more preferably at most 2.5: 1.0. Applicants have found that with the two metals in the ratios as indicated, both the activity of the catalyst and the desired reaction selectivity to the desired product improves.
    In an embodiment of the process of the present invention, the heterogeneous catalyst has a support selected from the list consisting of carbon, alumina, silica, zeolite, clay, porous polymer and hybrid polymer, preferably a carbon carrier, more preferably a carbon filter, even more preferably an activated carbon activated by treatment with an acid.
    For ease of handling, the catalyst is preferably supported on a solid support. A suitable carrier for supporting the metals in the catalyst of the process of the present invention is activated carbon because of the large surface area and good adhesion. Further treatment, such as steaming, acid washing, sulfonation, or the like, can be given to the carrier, as this often increases the adsorption properties of the activated carbon. Other carbon carriers such as graphite or carbon nanotubes (CNB) can be used as the catalyst support. Carbon supports offer the additional advantage that the process for recovering the metal or metals, at the end of the life of the catalyst, is much simpler compared to other supports.
    Other types of materials known to those skilled in the art can suitably be used as catalyst supports: alumina, silica, zeolite, clay, porous polymer and hybrid polymer and combinations thereof.
    The total metal charge on the catalyst support may be in the range of 0.1 to 40% by weight, more preferably at least 0.2%, more preferably 0.5%, most preferably 1.0%, and optionally at least at most 35% by weight, preferably at most 30%, more preferably at most 25%, the levels relative to the total weight of the catalyst being expressed.
    The supported catalyst may be in a form most suitable and desirable for the process, such as a powder, a granule, an extrudate or combinations thereof. With a powder catalyst, the catalyst can be separated from the reaction mixture after use by filtration. With granules and / or extrudates, the catalyst and the reaction mixture can be separated from each other by simply draining the reactor vessel containing the catalyst, which can be applied, for example, in a fixed bed arrangement.
    In an embodiment of the process of the present invention, the heterogeneous catalyst has a metal surface, measured by carbon monoxide chemistry, of at least 0.5 m2 / g, preferably at least 1.0 m2 / g, more preferably at least 2.0 m2 / g, even more preferably at least 3.0 m2 / g, even more preferably at least 4.0 m2 / g, optionally at most 12.0 m2 / g.
    In one embodiment of the process of the present invention, the heterogeneous catalyst is pre-reduced prior to the step of contacting the catalyst with the organic feed substrate, preferably by subjecting the catalyst to a temperature of at least 120 ° C , preferably at least 140 ° C in a hydrogen atmosphere of at least 5 bar overpressure, preferably at least 8 bar overpressure during a period of at least 30 minutes, preferably at least 45 minutes, the pre-reduction preferably being carried out with the catalyst in contact with an organic liquid phase, preferably an alkanol, more preferably methanol. Applicants prefer to perform this pre-reduction step with the catalyst in contact with methanol, at a temperature of about 150 ° C, and under a hydrogen partial pressure of about 10-11 bar absolute, and this for a period of about an hour. Applicants have found that this pre-reduction step allows the catalyst to display its desired advantageous performance from very early in the process initiation.
    In one embodiment of the method of the present invention, at least 80% of the feed substrate retains the at least one further functional group after the conversion, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, preferably at least 97%, more preferably at least 98%, even more preferably at least 99.0%, preferably at least 99.4%, more preferably at least 99.5%, even more preferably at least 99.6% of the feed substrate retains the at least one further functional group after the conversion. Applicants have found that these results can be easily achieved with the catalyst of the process of the present invention.
    In an embodiment of the process of the present invention, the chemical conversion is selected from reductive amination and hydrogenation carried out at an H 2 partial pressure in the range of 0.01-250 bar excess pressure, preferably at least 0.1, more preferably at least 1, even more preferably at least 5.0 bar overpressure, even more preferably at least 10.0 bar overpressure, even more preferably at least 20 bar overpressure, preferably at least 30 bar overpressure, more preferably at least at least 40 bar overpressure, even more preferably at least 50 bar overpressure, and optionally at most 200 bar overpressure, preferably at most 150 bar overpressure, more preferably at most 100 bar overpressure, even more preferably at most 80, with still more preferably 70, and preferably at most 60 bar excess pressure.
    In an embodiment of the process of the present invention, the chemical conversion selected from reductive amination and hydrogenation is carried out at a temperature in the range of 0-300 ° C, preferably at least 10 ° C, more preferably at least 20 ° C, even more preferably at least 30 ° C, even more preferably at least 40 ° C, preferably at least 60 ° C, more preferably at least 80 ° C, and even more preferably at least 90 ° C , and optionally at most 250 ° C, preferably at most 200 ° C, more preferably at most 180 ° C, even more preferably at most 150 ° C, even more preferably at most 130 ° C, preferably at most 120 ° C, more preferably at most 110 ° C, even more preferably at most 100 ° C.
    In one embodiment, the method of the present invention is performed in continuous mode. Applicants have found that the catalyst itself, as well as the performance, can be controlled as such to be relatively stable over time, so that the process is very suitable for continuous mode. This brings important benefits in terms of production speed, volumetric efficiency of the process equipment, control equipment, performance stability, operator attention and intervention frequency, automation options, many of which represent significant benefits for the process owner.
    Applicants have found that the method of the present invention can also be performed in batch mode. Applicants have found that the catalyst, after separation from the reaction medium after a first execution of the process, can easily be used in a second execution of the process, preferably without intermediate treatment. Applicants have found that at least 5, preferably at least 10, and more preferably at least 15 recycling cycles are performed with the same catalyst in the process of the present invention. Applicants have found that a portion of metal can leach out of the catalyst during the early performance of a fresh catalyst in the process of the present invention, but that this metal leaching is at a level that is substantially insignificant in terms of amount of metal lost from the catalyst, and also caused no substantial loss of catalyst performance.
    In one embodiment, the method of the present invention further comprises purifying the converted substrate, preferably by distillation of the reaction product to reduce the content of at least one compound selected from a reaction by-product, a feed impurity, a solvent, and unreacted feed substrate .
    In an embodiment wherein the method of the present invention is used for the production of ortho-chloro-benzyl-dimethylamine, 2-CI-BDMA, the method further comprises subjecting the 2-CI-BDMA to a Grignard reaction, including, for example, in a first step is the preparation of a Grignard reagent, wherein a magnesium atom is introduced between the benzene ring and the chlorine atom, followed by a second step wherein the Grignard reagent is reacted with an oxalic acid dialkyl ester.
    In an embodiment wherein the method of the present invention is used for the production of ortho-chloro-benzyl-dimethylamine, 2-CI-BDMA, the method further comprises the conversion of 2-CI-BDMA to o-chloromethylphenylglyoxyl esters by a method such as described in US 2010/113778 A1. o-Chloromethylphenyl glyoxyl esters are important intermediates for the preparation of agrochemically active compounds or microbicides from the methoximinophenyl glyoxyl ester series. More specifically, US 2010/113778 A1 describes the production of strobilurins, a type of fungicides that is said to be able to inhibit the respiratory system of the fungi and for which kresoxim-methyl and dimoxystrobin are described and explained as particularly interesting family members. In a further embodiment, therefore, the method of the present invention further comprises the production of a fungicide with a methoximinophenyl glyoxyl ester derived from 2-CI-BDMA, in particular derived from the composition of the present invention, as well as the use of the ester as a fungicide .
    In an embodiment of the composition of the present invention, the composition comprises at least 98.5% by weight of 2-chlorobenzyl-dimethylamine, preferably at least 99.0% by weight, more preferably at least 99.1% by weight, even more preferably at least 99.2% by weight, even more preferably at least 99.3% by weight of 2-chlorobenzyl-dimethylamine. The higher the content of 2-chloro-benzyl-dimethylamine, the more advantageously the composition can be applied in the desired application, such as a conversion to a further chemical derivative.
    In one embodiment, the composition of the present invention comprises at most 0.04% by weight of 2-chloro-dichloromethylbenzene, preferably at most 0.030% by weight, more preferably at most 0.020% by weight, even more preferably at most 0.015% by weight , preferably at most 0.010% by weight, more preferably at most 50 ppm by weight, even more preferably at most 10 ppm, of 2-chloro-dichloromethylbenzene. This component can represent an additional burden in the application of the composition, such as the generation of corrosive components in subsequent reactions and / or leading to undesirable by-products in subsequent conversions. The lower the content of 2-chloro-benzyl chloride, the more advantageously the composition can be applied in the desired application, such as a conversion to a further chemical derivative.
    In one embodiment, the composition of the present invention comprises at least 0.07 wt% of 2-chlorobenzyl alcohol, preferably at least 0.09 wt%, more preferably at least 0.10 wt%, even more preferably at least at least 0.12% by weight, even more preferably at least 0.15% by weight of 2-chlorobenzyl alcohol.
    In one embodiment, the composition of the present invention comprises at most 1.0 wt% of 2-chlorobenzyl alcohol, preferably at most 0.80 wt%, more preferably at most 0.60 wt%, even more preferably at least at most 0.50% by weight, even more preferably at most 0.40% by weight of 2-chlorobenzyl alcohol.
    Applicants have found that the 2-chlorobenzyl alcohol can be present in the composition in an acceptable manner without affecting or compromising the performance of the composition, or in many of the applications, such as certain conversions into further chemical derivatives, in particular those conversions and uses described in more detail elsewhere in this document. Applicants have found that for many such applications there is little to no necessity prior to the removal of 2-chlorobenzyl alcohol which may be present in the composition, especially not when it is present at the indicated levels. This is an advantage because the removal of 2-chloro-benzyl alcohol from the top product 2-chloro-benzyl-dimethylamine, and this to very low levels, could result in considerable additional complexity for the process.
    In one embodiment, the composition of the present invention comprises at most 0.20% by weight of 2-chlorobenzaldehyde, preferably at most 0.15% by weight, more preferably at most 0.10% by weight, preferably at most 0 05% by weight, more preferably at most 0.020% by weight, even more preferably at most 0.010% by weight, preferably at most 50 ppm by weight, more preferably at most 10 ppm, even more preferably at most 5 ppm, even more preferably at most 1 ppm by weight, as determined by gas chromatography, GC, optionally aided by mass spectrometry. The 2-chloro-benzaldehyde does not contribute to many of the uses of the composition. A presence at a lower level of this component therefore represents greater efficiency and entails improved efficiencies in the further use and application of the composition.
    In one embodiment, the composition of the present invention comprises at most 0.40% by weight of 4-chlorobenzyl dimethylamine, preferably at most 0.30% by weight, more preferably at most 0.20% by weight, even more preferably at most at most 0.10% by weight of 4-chlorobenzyl dimethylamine, preferably at most 0.05% by weight, more preferably at most 0.020% by weight, even more preferably at most 0.010 wt%, preferably at most 50 ppm by weight, with more preferably at most 10 ppm, even more preferably at most 5 ppm, even more preferably at most 1 ppm by weight as determined by gas chromatography, GC. Applicants have found that this component may represent an additional burden in applying the composition, for example in subsequent reactions, and / or may lead to undesirable by-products in subsequent conversions which, moreover, are quite difficult to separate from the desired product of such a conversion . The lower the 4-chloro-benzyl dimethylamine content, the more advantageously the composition can be applied in the desired application, such as a conversion to a further chemical derivative.
    In one embodiment, the composition of the present invention comprises at most 0.35% by weight of ortho-chlorotoluene, preferably at most 0.30% by weight, more preferably at most 0.20% by weight, even more preferably at most 0, 10% by weight of ortho-chlorotoluene, preferably at most 0.05% by weight, more preferably at most 0.03% by weight, even more preferably at most 0.01% by weight, preferably at most 0.05% by weight, more preferably at most 0.020% by weight, even more preferably at most 0.010% by weight, preferably at most 50 ppm by weight, more preferably at most 10 ppm, even more preferably at most 5 ppm, even more preferably at most 1 ppm by weight as determined by gas chromatography, GC. Preferably, the specified levels apply to the total of all chlorotoluene isomers. Applicants have found that this component, and also its isomers, may represent an additional burden in the use of the composition, such as, for example, in subsequent reactions, and / or may lead to undesirable by-products in subsequent conversions which, moreover, are quite difficult to separate from the desired product of such a conversion. The lower the content of chlorotoluene, in particular ortho-chlorotoluene, the more advantageously the composition can be applied in the desired application, such as, for example, a conversion to a further chemical derivative.
    In one embodiment, the composition of the present invention comprises at most 0.40% by weight of benzyldimethylamine, preferably at most 0.30% by weight, more preferably at most 0.20% by weight, even more preferably at most 0.10% by weight % benzyldimethylamine, preferably at most 0.05% by weight, more preferably at most 0.020% by weight, even more preferably at most 0.010% by weight, preferably at most 50 ppm by weight, more preferably at most 10 ppm, with even more preferably at most 5 ppm, even more preferably at most 1 ppm by weight, as determined by gas chromatography, GC. This benzyl dimethylamine does not contribute to many of the uses of the composition. A presence at a lower level of this component therefore represents greater efficiency and entails improved efficiencies in the further use and application of the composition.
    In one embodiment, the composition of the present invention comprises at most 0.40% by weight of 2-dimethylaminobenzyldimethylamine, preferably at most 0.30% by weight, more preferably at most 0.20% by weight, more preferably at most 0, 10% by weight of 2-dimethylaminobenzyldimethylamine, preferably at most 0.05% by weight, more preferably at most 0.020% by weight, even more preferably at most 0.010 wt%, preferably at most 50 ppm by weight, more preferably at least at most 10 ppm, even more preferably at most 5 ppm, even more preferably at most 1 ppm by weight, as determined by gas chromatography, GC. The 2-dimethylamino-benzyldimethylamine does not contribute to many of the uses of the composition. A presence at a lower level of this component therefore represents greater efficiency and entails improved efficiencies in the further use and application of the composition.
    In one embodiment, the composition of the present invention comprises at most 0.40% by weight of benzaldehyde, preferably at most 0.30% by weight, more preferably at most 0.20% by weight, even more preferably at most 0.10% by weight % benzaldehyde, preferably at most 0.05% by weight, more preferably at most 0.020% by weight, even more preferably at most 0.010% by weight, preferably at most 50 ppm by weight, more preferably at most 10 ppm by weight even more preferably at most 5 ppm, even more preferably at most 1 ppm by weight, as determined by gas chromatography, GC. This benzaldehyde does not contribute to many of the uses of the composition. A presence at a lower level of this component therefore represents greater efficiency and entails improved efficiencies in the further use and application of the composition.
    In one embodiment, the composition of the present invention is made by the method of the present invention. Applicants have found that the process of the present invention is particularly suitable for producing the composition because the process is capable of providing a high reaction rate and conversion to the desired 2-chloro-benzyl-dimethylamine, which achieves low levels of unreacted feed substrate 2-chloro-benzaldehyde and thanks to the high selectivity of the indicated catalyst, with low presence of less desirable by-products, such as 2-chloro-benzyl alcohol and / or benzyl dimethylamine and / or 2-dimethylamino-benzyl dimethylamine. Moreover, the process according to the present invention for the production of 2-chloro-benzyl-dimethylamine has little to no presence of other undesirable components 2-chloro-benzyl chloride and / or 4-chloro-dimethylbenzylamine and / or chlorotoluene isomers, in particular ortho chlorotoluene. The composition of the present invention as available with the method of the present invention is therefore particularly suitable for use in many applications, such as certain conversions into further chemical derivatives, particularly those conversions and applications described in more detail elsewhere in this document.
    ANALYTICAL METHODS
    For analyzing the composition of the present invention, as well as for monitoring the method of the present invention, the applicants prefer the following gas chromatography, GC, analysis method.
    The GC device is preferably an Agilent 6890N with a split injector and a flame ionization detector (FID). The device is equipped with a capillary column coated with a stationary phase type CP-Sil 5 CB with dimensions 60 x 320 µm x 5.0 µm. Applicants prefer to use an injector temperature of 280 ° C, an injector volume of 1 pliter and a split ratio of 1/30. Applicants preferably use helium as carrier gas with a flow rate of 2 ml / min at constant flow. The oven receives a temperature program whereby the temperature is kept at 60 ° C for 3 minutes and then the temperature is raised at a speed of 20 ° C per minute to 290 ° C, at which temperature the column is kept for another 15 minutes. The FID detector is held at 300 ° C and fed with a hydrogen flow of 45 ml / min and an air flow of 450 ml / min. Make-up gas, preferably nitrogen, and column flow are put together at a total of 45 ml / min.
    Applicants have found that the following components can be easily identified by specific retention peaks: methanol, DMA, TMA, ethylbenzene, benzaldehyde, benzyldimethylamine, ortho-chlorobenzaldehyde, ortho-chlorobenzyl alcohol, ortho-chlorobenzyldimethylamine, para-chlorobenzyl dimethylamine, ortho- (dimino) -lamino (dimino) benzyldimethylamine. Applicants have further found that this GC technique can be easily assisted by the addition of mass spectrometry, such as for the determination of concentrations in the lower levels up to 1 ppm by weight or even lower.
    Depending on the sample, the sample can be diluted up to 10 times in isopropanol. Preferably, 1% of the internal standard is added, after which the sample is preferably vigorously mixed for at least one minute and after which 1 μΙ sample can be injected into the gas chromatograph. .
    EXAMPLES
    Example 1: Preparation and activation of the Pd / Cu catalyst: 10 g of a 5 wt% palladium-on-carbon catalyst as commercially available under the reference E196NN / W from the Evonik company was stirred in 300 ml of an aqueous solution of copper nitrate (6.7 g / L). 50 ml of an aqueous solution of sodium carbonate (38.4 g / L) was added slowly with vigorous stirring at room temperature over a 3 minute period. This solution was then stirred for a further 15 minutes at room temperature and 15 minutes at a temperature of 75 ° C. The catalyst was then filtered off and dried in an oven at a temperature of 60 ° C until complete dryness.
    The catalyst was then calcined in air at 300 ° C for 3 hours and reduced in methanol at a temperature of 150 ° C and under a partial pressure of hydrogen of 10 bar. The catalyst was then filtered off until a paste was obtained. This paste contained 5.67% palladium and 13.7% copper.
    Example 2: Reductive amination of 2-chloro-benzaldehyde with DMA to produce 2-CI-BDMA.
    A 300 ml autoclave (Parr) was charged with 90 g of 2-chlorobenzaldehyde (Sigma Aldrich) and 54 g of methanol (industrial grade). The reactor was sealed and the gas phase was purged with nitrogen three times. Subsequently, 40 g of dimethylamine was added to the reaction mixture, whereby the temperature increased to 55 ° C in 5 minutes. The reactor was further heated in 10 minutes to the desired temperature of 80 ° C. The reactor pressure was set at 10 bar by the addition of nitrogen gas. Stirring was then continued for 60 minutes at a temperature of 80 ° C and a pressure of 10 bar. The reactor was then cooled to 30 ° C and degassed. 0.1 g of the catalyst from Example 1 was added to the autoclave. The autoclave was heated to 90 ° C in 15 minutes and hydrogen was added to a final pressure of 55 bar. The hydrogenation reaction was allowed to continue for 5 hours at 90 ° C. The reactor was then cooled and degassed at room temperature. A sample was taken and analyzed with GC and ICP. The catalyst was then filtered and reused in a repeat experiment under the same conditions, in a second run.
    The tables below show the results obtained, all expressed in units of weight relative to the total weight of the reaction product with neglect of water, methanol and any remaining dimethylamine that may still be present.
    Product of the first reaction:
    Product of the second run:
    Legend:
    Nd Not Detected 2-CI-BZA 2-chloro-benzaldehyde BDMA Benzyldimethylamine 2CI-BDMA 2-chlorobenzyldimethylamine DMA-BDMA 2-dimethylaminobenzyldimethylamine 2-CI-BOH 2-chlorobenzyl alcohol
    It is noted that the selectivities and yields remained essentially the same for both runs and that they were exceptionally high in favor of the desired product 2CI-BDMA. It can further be noted that some leaching of Cu metal occurred in the first run, but that this was already greatly reduced during the second run.
    Now that the invention has been fully described, it will be apparent to those skilled in the art that the invention can be implemented within a wide range of parameters within what is set, without departing from the scope of the invention as defined by the claims.
    权利要求:
    Claims (14)
    [1]
    CONCLUSIONS
    A method for carrying out a chemical reaction selected from the reductive amination and hydrogenation of a first functional group in an organic feed substrate, said feed substrate comprising at least one further functional group containing a halogen atom, the halogen atom being selected from the list consisting of chlorine, bromine, iodine, and combinations thereof, in the presence of hydrogen and a heterogeneous catalyst comprising at least one first metal selected from the list consisting of palladium, Pd, rhodium, Rh, and ruthenium, Ru, together with at least one second metal selected from the list consisting of silver, Ag, nickel, Ni, cobalt, Co, tin, Sn, and copper, Cu.
    [2]
    The method of claim 1, wherein the further functional group comprising a halogen atom is selected from the list consisting of a chloride, a bromide and an iodide.
    [3]
    The method according to claim 1 or 2, wherein the first functional group is selected from the list consisting of an aldehyde, a ketone, a nitro group, a carboxylic acid, a carboxylic acid ester, a carboxylic acid amide, an unsaturated carbon-carbon bond, a nitrile, an imine and an oxime, and combinations thereof.
    [4]
    The method of any one of the preceding claims wherein the first functional group in the feed substrate is first converted in situ by reaction with an additional reagent to form a reducible functional group.
    [5]
    The method according to any one of the preceding claims for the reductive amination of a halogen-benzaldehyde in the presence of a nitrogen-containing compound, preferably the nitrogen compound selected from ammonia, a primary amine and a secondary amine and mixtures thereof, preferably for the preparation of ortho-chloro-benzyldimethylamine, o-CI-BDMA, by the reductive amination of ortho-chloro-benzaldehyde in the presence of dimethylamine, DMA.
    [6]
    The process according to any of claims 1 to 3 for the production of chloroaniline from chloronitrobenzene.
    [7]
    The process according to any of the preceding claims wherein the heterogeneous catalyst was heat treated, preferably at a temperature in the range of 50-500 ° C, wherein the heat treatment was preferably conducted for at least 2 hours, more preferably 3 hours.
    [8]
    The method of any one of the preceding claims wherein the heterogeneous catalyst comprises the first metal and the second metal in a weight ratio of the second metal to the first metal in the range of 0.05: 1.0 to 10.0: 1.0.
    [9]
    The method according to any of the preceding claims, further comprising purifying the converted substrate, preferably by distillation of the reaction product, to reduce the content of at least one compound selected from a reaction by-product, a feed impurity, a solvent and an unreacted feed substrate .
    [10]
    The method of any one of the preceding claims for preparing ortho-chlorobenzyl dimethylamine, 2-CI-BDMA, further comprising subjecting the
    2-CI-BDMA to a Grignard reaction, for example comprising in a first step the preparation of a Grignard reagent in which a magnesium atom is introduced between the benzene ring and the chlorine atom, followed by a second step in which the Grignard reagent is esterified with an oxalic acid dialkyl ester. The method of any one of the preceding claims further comprising the preparation of a methoximinophenyl glyoxyl ester, preferably further comprising the preparation of a fungicide containing the methoximinophenyl glyoxyl ester, more preferably further comprising the use of the fungicide.
    [12]
    A composition comprising, as measured by gas chromatography, GC, a) at least 98.0% by weight of 2-chlorobenzyl dimethylamine, b) at most 0.40% by weight of ortho-chlorotol toluene, preferably the total of all chlorine toluene isomers, and c) at least 0.05 wt% 2-chlorobenzyl alcohol.
    [13]
    The composition of claim 12 comprising at most 0.04% by weight of 2-chloro dichloromethylbenzene.
    [14]
    The composition of any one of claims 12-13 comprising at most 0.20 wt% 2-chlorobenzaldehyde as determined by gas chromatography.
    [15]
    The composition of any one of claims 12-14 obtainable with the method of any one of claims 1-9.
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    EP3041819A1|2016-07-13|
    US10252979B2|2019-04-09|
    US20170342019A1|2017-11-30|
    US10167248B2|2019-01-01|
    WO2015032653A1|2015-03-12|
    EP3041819B1|2020-05-13|
    US20160207874A1|2016-07-21|
    CN106034401B|2019-03-19|
    CN106034401A|2016-10-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3499034A|1966-08-01|1970-03-03|Du Pont|Hydrogenation of aromatic nitro compounds|
    US3546297A|1969-07-01|1970-12-08|Du Pont|Process for preparation of aromatic chloroamines|
    US3666813A|1969-08-27|1972-05-30|Engelhard Min & Chem|Process for preparing aromatic haloamines from aromatic nitroamines|
    US3830756A|1972-08-04|1974-08-20|Grace W R & Co|Noble metal catalysts|
    DE2403138A1|1974-01-23|1975-07-31|Hoechst Ag|BENZYLAMINE DERIVATIVES AND PROCESS FOR THEIR PRODUCTION|
    US4212824A|1978-07-11|1980-07-15|E. I. Du Pont De Nemours And Company|Hydrogenation catalyst with improved metallic distribution, its preparation and use for the reduction of aromatic nitro compounds|
    EP0312253B1|1987-10-16|1993-05-12|Kao Corporation|Process for preparing n-substituted amine|
    US5011996A|1988-07-20|1991-04-30|Bayer Aktiengesellschaft|Process for the preparation of amines|
    DE4218866C1|1992-06-09|1994-01-20|Degussa|Catalyst for the selective hydrogenation of halogen nitroaromatics to aromatic halogenamines and process for its preparation|
    FR2710856B1|1993-10-07|1995-12-29|Rhone Poulenc Chimie|Composition of matter useful as a Raney-type catalyst for the hydrogenation of halonitroaromatics to haloaminoaromatics and process using them.|
    EP0820808B1|1996-07-23|2002-09-04|Degussa AG|Multi-metallic catalyst and method for producing substituted aromatic amines|
    DE19929345A1|1999-06-26|2000-12-28|Bayer Ag|Primary aliphatic or aromatic amine preparation in high yield, for use in plant protectant or pharmaceutical applications, by reductive amination of aldehyde in presence of disodium tetraborate|
    JP3899764B2|2000-01-19|2007-03-28|住友化学株式会社|Method for producing α-phenylethyl alcohol|
    EP1195192A1|2000-10-03|2002-04-10|Dsm N.V.|Process for the preparation of a mixture of epsilon-caprolactam and/or epsilon-caprolactam precursors|
    DE10053380A1|2000-10-27|2002-05-08|Basf Ag|Process for the production of amines|
    DE10138140A1|2001-08-09|2003-02-20|Degussa|Preparation of optionally functionalized enantio-pure/enriched amines useful as intermediates for e.g. pharmaceuticals by reductive hydridotransfer amination of carbonyl compounds comprises use of Group VIII metal complex catalyst|
    DE102005047288A1|2005-10-01|2007-04-05|Clariant Specialty Fine Chemicals Gmbh|Amine preparation for reductively aminating ketones and aldehydes, comprises catalytic hydrogenating amination of carbonyl compound with nitrogen compound in presence of bifunctional catalyst having hydrogenation-active catalyst component|
    US20100113778A1|2007-04-12|2010-05-06|John-Matthias Wiegand|Process for preparing o-chloromethylphenylglyoxylic esters, improved process for preparing -2--2-alkoximinoacetic esters, and novel intermediates for their preparation|
    US8415500B2|2007-12-21|2013-04-09|Basf Se|One-stage reductive amination|
    EP2301660A1|2009-09-25|2011-03-30|LANXESS Deutschland GmbH|Method for hydrating halogenated nitroaromatics|
    CN103781757A|2011-08-04|2014-05-07|朗盛德国有限责任公司|Method for producing ring-halogenated N,N-dialkylbenzylamines|
    CN102503836A|2011-10-11|2012-06-20|浙江新化化工股份有限公司|Preparation method of dibenzylamine|
    HUE040536T2|2013-03-06|2019-03-28|Lanxess Deutschland Gmbh|Process for the preparation of halogen-n, n-dimethylbenzylamines|
    EP2774911A1|2013-03-06|2014-09-10|LANXESS Deutschland GmbH|Process for the preparation of halogen-N, N-dimethylbenzylamines|
    WO2014202436A1|2013-06-21|2014-12-24|Basf Se|Method for producing 2-chlorodialkylbenzylamines by hydrogenation|
    WO2014202441A1|2013-06-21|2014-12-24|Basf Se|Method for producing 2-chlorodialkylbenzylamines|
    BE1021017B1|2013-09-04|2014-12-18|Taminco|IMPROVED METHOD FOR REDUCTIVE AMINATION AND SELECTIVE HYDROGENATION OF HALOGEN-BASED SUBSTRATES|
    EP3215480B1|2014-11-04|2019-08-14|Taminco Bvba|Improved process for the reductive amination of halogen-containing substrates|BE1021017B1|2013-09-04|2014-12-18|Taminco|IMPROVED METHOD FOR REDUCTIVE AMINATION AND SELECTIVE HYDROGENATION OF HALOGEN-BASED SUBSTRATES|
    EP3215480B1|2014-11-04|2019-08-14|Taminco Bvba|Improved process for the reductive amination of halogen-containing substrates|
    US10464879B2|2015-11-10|2019-11-05|Taminco Bvba|Process for the reductive amination of halogen-containing substrates|
    CN108339551B|2018-02-09|2021-05-28|扬州虹光生物科技有限公司|Preparation method of novel antibacterial drug linezolid intermediate|
    CN108525675A|2018-04-08|2018-09-14|上海应用技术大学|It is a kind of to prepare magnetic carbon/palladium-cobalt multiplex catalyst of aminated compounds, preparation method and application for being catalyzed reduction amination|
    CN111620769A|2020-06-04|2020-09-04|南通汇顺化工有限公司|Method for preparing 3,3 ', 4, 4' -biphenyl tetracarboxylic dianhydride|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    EP13183017|2013-09-04|
    EP131830176|2013-09-04|
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