JP2008514696A - Process for producing heterocyclic aromatic carboxylic acids - Google Patents

Abstract

  A method for the production of a heterocyclic aromatic carboxylic acid, comprising the step of contacting said carboxylic acid precursor with an oxidant in the presence of a catalyst, wherein said contacting comprises supercritical conditions or supercriticality. A method comprising using the precursor and an oxidizing agent in an aqueous solvent comprising water near near point supersupercritical conditions.

Description

  The present invention relates to a process for the selective partial oxidation of alkyl heterocyclic aromatic compounds, in particular nitrogen-containing heterocyclic aromatic compounds, for the production of heterocyclic aromatic carboxylic acids such as nicotinic acid.

  Pyridinecarboxylic acid obtained from methylpyridine is an important intermediate in the pharmaceutical industry. In particular, 3-pyridinecarboxylic acid or nicotinic acid used as a precursor of vitamin B3 has been produced on a large scale. Two basic methods are used for the synthesis of pyridinecarboxylic acid. One method is based on the hydrolysis of pyridinecarboxamide obtained from pyridinecarbonitrile, the other is the oxidation of alkylpyridine with air, nitric acid, selenium dioxide and the like. Ammoxidation of methylpyridine forms pyridinecarbonitrile, which is then hydrolyzed to pyridinecarboxylic acid by pyridinecarboxamide. 3-pyridinecarboxylic acid is produced commercially by nitric acid oxidation of 5-ethyl-2-methylpyridine.

  It is known that the selective oxidation of alkylheteroaromatic compounds to carboxylic acids is significantly more difficult than the corresponding carbocyclic compounds. The residence time required for the oxidation of alkyl heteroaromatic compounds to carboxylic acids is significantly longer than equivalent carbocyclic alkyl aromatic compounds. For example, (Patent Document 1) (Nissan Chemical International) uses 3-methyl cerium bromide catalyst to oxidize in acetic acid with a required reaction time of 3 hours. A method for the production of nicotinic acid from methylpyridine has been disclosed. A similar study on the oxidation of p-xylene to terephthalic acid gives the required residence time of 40 minutes or less (US Pat.

  Conventional methods require long residence times and produce significant amounts of undesirable by-products. By-products include partially oxidized intermediates of the desired carboxylic acid, such as aldehyde intermediates. For example, oxidation of 3-methylpyridine (3-Mpy) to produce 3-pyridinecarboxylic acid (3-PyA) can result in significant levels of 3-pyridinecarboxaldehyde (3-PyAl). Furthermore, decarboxylation of the product can give rise to unsubstituted heterocyclic aromatic compounds themselves, which is pyridine in the oxidation of 3-methylpyridine.

  (Patent Document 3) (Daicel Chemical Industries Ltd.) uses N-hydroxyphthalimide as an accelerator for oxidation in acetic acid, using nicotinic acid from 3-methylpyridine in acetic acid. A method for production has been disclosed. However, this method requires a long residence time and is not economically feasible because it produces significant amounts of phthalimide and phthalate impurities from the added accelerator. .

  The commercial gas phase method for the oxidation of 3-methylpyridine to nicotinic acid described in US Pat. Since the reaction is exothermic, doing it in the gas phase creates a heat transfer limitation, which reduces the efficiency with which energy can be extracted from the reaction. Also, because the reaction is performed on a fixed bed heterogeneous catalyst, the reaction can be performed only on the surface of the catalyst, not over the entire fluid medium.

  There remains a need to provide an improved process for the production of heteroaromatic carboxylic acids, particularly heteroaromatic carboxylic acids with reduced reaction time and by-product formation.

  It would also be desirable to avoid the use of significant amounts of organic solvents such as acetic acid, which are relatively expensive and environmental regulations may require recovery and recycling. A further problem in the use of acetic acid is that it is flammable when mixed with air or oxygen under certain conditions. A further problem in the use of organic solvents is that the oxidizing agent can have a low solubility in it. For example, when dioxygen is used as the oxidant, the dioxygen exists primarily as separate bubbles in the reaction medium, and only a small amount of dioxygen dissolves in the solvent. To the extent that the reaction between the precursor and dioxygen results from the diffusion of dioxygen from the bubbles into the bulk liquid, the reaction rate is limited by the low solubility of dioxygen in the solvent.

  It has now been found that heterocyclic aromatic carboxylic acids can be synthesized by oxidation of precursors in supercritical water.

(1) describe, inter alia, a batch process for the synthesis of aromatic carboxylic acids from alkylaromatic compounds in a reaction medium of subcritical water using molecular oxygen as the oxidant. As the dielectric constant of water approaches its critical point (374 ° C. and 220.9 bara), it decreases significantly from a room temperature value of about 80 C ² / Nm ^{2 to} a value of 5 C ² / Nm ² , which is an organic molecule. Makes it possible to solubilize. As a result, water then behaves like an organic solvent to the extent that hydrocarbons such as toluene are completely miscible with water under supercritical or near supercritical conditions. For example, terephthalic acid is virtually insoluble in water below about 200 ° C. Dioxygen is also highly soluble in subcritical and supercritical water.

  (Patent Document 5) describes a method of oxidizing one or more precursors of a carboxylic acid in an aqueous solvent under supercritical conditions or near supercritical conditions close to a supercritical point, such as terephthalic acid or isophthalic acid. A continuous process for the production of aromatic carboxylic acids is disclosed.

JP 7-233150 A US Pat. No. 3,354,202 JP 2002-226404 A DE-19822788 Specification International Publication No. 02/06201 Pamphlet Holiday R.L., et al. (J. Supercritical Fluids 12, 1998, 255-260) Lin, Smith et al. (International Journal of Chemical Kinetics, Vol 23, 1991, p971)

  The object of the present invention is an improved alternative for the production of heterocyclic aromatic carboxylic acids in high yield and selectivity, with reduced reaction time and without the use of organic materials as solvent. Is to provide a way. A further object of the present invention provides an alternative and improved method for the production of heterocyclic aromatic carboxylic acids, wherein substantially all of the reactants and products are maintained in a common phase during the reaction. That is.

  According to the present invention, a method for the production of a heterocyclic aromatic carboxylic acid, the step of contacting the carboxylic acid precursor with an oxidizing agent in the presence of a catalyst, wherein the contacting comprises: There is provided a method comprising a step performed using the precursor and an oxidizing agent in an aqueous solvent containing water under supercritical conditions or near supercritical conditions close to a supercritical point.

  The process of the present invention is advantageous in that it involves a short residence time and exhibits a high yield of product formation and good selectivity. Furthermore, by using water under supercritical or near supercritical conditions, the desired heterocyclic aromatic carboxylic acid can be produced without using an aliphatic carboxylic acid such as acetic acid as the main solvent.

  Substantially all of the produced heterocyclic aromatic carboxylic acid is maintained in solution during the reaction, after which the carboxylic acid is recovered from the reaction medium.

  Preferably, the process is performed with reactants and solvents that form a substantially homogeneous fluid phase in which the components of interest are mixed at the molecular level. This is in contrast to existing methods where dioxygen is present as separate bubbles in the reaction medium. To the extent that the reaction between the precursor and dioxygen results from the diffusion of dioxygen from the bubbles into the bulk liquid, the reaction rate of the conventional method is limited by the solubility of dioxygen in the organic solvent. Is not expensive. The use of water as a solvent under supercritical or near supercritical conditions changes the reaction kinetics, as it approaches the supercritical point and beyond it, the concentration of dioxygen in the water increases significantly. Because. Furthermore, the reaction kinetics are further improved by the high temperature that prevails when the aqueous solvent is under supercritical or near supercritical conditions. The combination of high temperature, high concentration, and homogeneity means that the reaction to convert the precursor to carboxylic acid can occur very rapidly compared to the residence time used in conventional methods.

  Under these conditions, intermediate impurities such as aldehyde intermediates are readily oxidized to the desired carboxylic acid. Furthermore, autocatalytic destruction reactions between the precursor and the oxidant and catalyst consumption are minimized.

  Preferably, the contacting is performed such that the precursor, oxidant, and aqueous solvent constitute substantially one homogeneous phase within the reaction zone, wherein at least a portion of the oxidant of the precursor. Contact with the catalyst occurs simultaneously with contact of the catalyst with at least a portion of the oxidant.

  Preferably, the contacting takes place in a continuous flow reactor. In an alternative embodiment, the method can be performed as a batch reaction in a batch type reactor.

  Using the method, a heterocycle containing 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, more preferably 1 heteroatom, preferably selected from nitrogen and oxygen, preferably nitrogen. Cyclic aromatic carboxylic acids can be prepared. Preferably, the heterocyclic aromatic carboxylic acid comprises a 5 or 6 membered ring system, preferably a 6 membered ring system. Preferably, the heterocyclic aromatic carboxylic acid is monocyclic or bicyclic, preferably monocyclic. The method is particularly applicable to the generation of nitrogen-containing heterocyclic aromatic compounds, particularly those containing 1, 2, or 3 nitrogen atoms, and especially those containing 6-membered rings. In a preferred embodiment, the heterocyclic aromatic carboxylic acid comprises a pyridine ring or a pyrimidine ring, preferably a pyridine ring. In a preferred embodiment, the heterocyclic aromatic carboxylic acid is nicotinic acid.

  Suitable precursors are alkyl-substituted heterocyclic aromatic compounds, particularly methyl-substituted heterocyclic aromatic compounds. In a preferred embodiment, the precursor is an alkyl pyridine or an alkyl pyrimidine, preferably an alkyl pyridine, preferably methyl pyridine, preferably 3-methyl pyridine. In the methods described herein, preferably only one precursor of the desired carboxylic acid is used. However, alternatively, more than one precursor of the desired carboxylic acid can be used. In addition to alkyl substituents, the heterocyclic precursor can optionally have one or more other substituents, such as hydroxy groups, nitrate groups, and halide groups.

  In the method of the present invention, the process pressure and temperature are selected to ensure supercritical or near supercritical conditions. Thus, the operating temperature is typically within the range of 300 to 480 ° C., more preferably 330 to 450 ° C., typically from a lower limit of about 340 to 370 ° C. to an upper limit of about 370 to about 420 ° C. The operating pressure is typically in the range of about 40 to 350 bara, preferably 60 to 300 bara, more preferably 200 to 280 bara.

  As used herein, “near supercritical conditions” means that the reactants and solvent constitute substantially one homogeneous phase, which in fact is less than the critical temperature of water. It can be achieved under low conditions. In one embodiment, the term “near supercritical conditions” means that the solvent is at least 100 ° C., preferably at least 50 ° C., more preferably at least 35 ° C., especially 20 ° C. below the critical temperature of water at 220.9 bara. This means that the temperature is lower.

  As used herein, “continuous flow reactor” refers to a reactor in which reactants are introduced and mixed and product is withdrawn simultaneously and continuously, as opposed to batch type reactors. To do. For example, the reactor can be a tubular flow reactor (with turbulent or laminar flow), but the various aspects of the invention defined herein apply to this particular type of continuous flow reactor. It is not limited. Residence time in a continuous flow reactor is defined as the reactor volume divided by the reactant volume flow at operating conditions.

  As used herein, a “carboxylic acid precursor” or “precursor” can be oxidized to a particular carboxylic acid in a large yield in the presence of selective oxidation conditions. An organic compound, preferably a hydrocarbon. An example of a pyridinecarboxylic acid precursor is methylpyridine, for example, the nicotinic acid precursor is 3-methylpyridine. Correspondingly, methylpyrimidine can be used to produce a pyrimidine carboxylic acid.

  As used herein, reference to the production of a carboxylic acid includes reference to the production of its anhydride. As will be apparent to those skilled in the art, whether the process of the present invention produces carboxylic acids or their anhydrides is used in the reaction conditions and / or to isolate or separate the products. Depending on conditions.

  Preferably, in the method of the present invention, substantially all of the heterocyclic aromatic carboxylic acid produced in the reaction is maintained in solution during the reaction, in any case, more than 98% by weight, and the solution is oxidized. It does not begin to settle until it leaves the zone and undergoes cooling.

  The residence time for the reaction can be matched to achieving the conversion of the precursor to the desired heterocyclic aromatic carboxylic acid without significant formation of degradation products. The residence time of the reaction medium in the reaction zone is generally 10 minutes or less, usually about 2 minutes or less, preferably 1 minute or less, more preferably 30 seconds or less.

  In a preferred embodiment, the selectivity for the desired carboxylic acid is at least 90%, preferably at least 95%, more preferably at least 98%, and the selectivity is the desired acid expressed as a percentage. Is divided by the combined weight yield of the desired acid and partially oxidized aldehyde impurities and other reaction products excluding decomposition products.

  In a preferred embodiment, the yield of the carboxylic acid of interest is preferably at least 50% by weight of the precursor, preferably at least 60% by weight, preferably at least 70% by weight, preferably at least 80% by weight, preferably Is at least 90% by weight.

  A reactor system suitable for carrying out the method of the present invention can generally be configured as described below. The following description relates to a preferred embodiment of a continuous flow reactor. However, as indicated above, the present invention is not limited to such a configuration and the following description is for illustration only.

  There can be more than one reaction zone in series or in parallel. For example, if multiple reaction zones in parallel are used, the reactants and solvent can form separate streams for passage through the reaction zone and, if desired, production from such multiple reaction zones. The logistics can be merged to form one product stream. If more than one reaction zone is used, conditions such as temperature can be the same or different within each reactor. Each reactor can be operated adiabatically or isothermally. Isothermal or controlled temperature rise can be maintained by heat exchange to define a predetermined temperature profile as the reaction proceeds through the reactor.

  In one embodiment of the present invention, the heat of reaction is performed by conventional techniques known to those skilled in the art, for example as described in US Pat. And is removed from the reaction by heat exchange with a heat receiving fluid. Conveniently, the heat receiving fluid comprises water.

  The oxidizing agent in the method of the present invention is preferably molecular oxygen, such as air or oxygen-enriched air, but preferably dissolved in a gas containing oxygen as its main component, more preferably pure oxygen, or liquid. Contains oxygen. The use of air is not excluded from the scope of the present invention but is not preferred because of the high nitrogen content of the air, resulting in high compression costs and off-gas handling equipment to cope with large amounts of off-gas. It is necessary. On the other hand, pure oxygen or oxygen-enriched gas allows the use of smaller compressors and smaller off-gas processing equipment. The use of dioxygen as an oxidant in the process of the present invention is particularly advantageous because it is highly soluble in water under supercritical or near supercritical conditions. Thus, at a particular point, the oxygen / water system becomes one homogeneous phase.

  Instead of molecular oxygen, the oxidant can include compounds containing one or more oxygen atoms per molecule, such as atomic oxygen obtained from liquid phase compounds at room temperature. One such compound is hydrogen peroxide that acts as a source of oxygen by reaction or decomposition, as described, for example, in US Pat.

The process according to the invention is carried out in the presence of an oxidation catalyst. The catalyst can be soluble in the reaction medium comprising the solvent and the heterocyclic aromatic carboxylic acid precursor, or a heterogeneous catalyst can be used. The catalyst, whether homogeneous or heterogeneous, typically comprises only one or more heavy metal compounds, such as cobalt compounds and / or manganese compounds, preferably manganese compounds, optionally with an oxidation promoter. Can be included. For example, the catalyst may be in the form used in a liquid phase oxidation reaction to produce an aromatic carboxylic acid (such as terephthalic acid) in an aliphatic carboxylic acid solvent, eg, bromide, bromoalkanoate of cobalt and / or manganese. (Bromoalkanoates), or alkanoates (alkanoates) (usually, C _l -C ₄ alkanoates, such as acetates) may take any of the. Other heavy metal compounds such as lanthanides such as vanadium, chromium, iron, molybdenum, cerium, zirconium, hafnium, and / or nickel can be used in place of cobalt and / or manganese. Advantageously, the catalyst system comprises manganese bromide (MnBr ₂ ). When used, the oxidation promoter is elemental bromine, ionic bromide (eg, HBr, NaBr, KBr, NH ₄ Br) and / or organic bromide (eg, bromobenzene, benzyl-bromide, mono- and di-bromoacetic acid). , Bromoacetyl bromide, tetrabromoethane, ethylene-di-bromide, etc.). Alternatively, the oxidation promoter can include a ketone such as methyl ethyl ketone, or an aldehyde such as acetaldehyde.

  If the catalyst is in a heterogeneous form, it can be appropriately placed in the reaction zone to ensure contact between the continuously flowing reaction medium and the catalyst. In this case, the catalyst can be properly supported and / or constrained within the reaction zone to ensure such contact without excessively narrowing the flow cross section. For example, the heterogeneous catalyst may be coated onto static elements (eg, elements that form an open work structure) positioned within the reaction zone, such that the reaction medium flows over the heterogeneous catalyst, or Can be provided in other manners or included within them. Such static elements can further serve to improve mixing of the reactants as they pass through the reaction zone. Alternatively, the catalyst can be in the form of moving pellets, particles, micronized form, metal sponge form, etc., and if necessary, means are provided to limit the catalyst to the reaction zone, so that during operation, Catalyst pellets or the like become suspended or immersed in the reaction medium flowing through the reaction zone. The use of a heterogeneous catalyst in any of these methods provides the advantage that the catalytic effect can be limited to a distinct zone, so that once the reaction medium has crossed the zone, further oxidation is not possible. Can be done at a reduced speed or significantly suppressed.

  The oxidation reaction is initiated by heating and pressurizing the reactants and then bringing the heated and pressurized reactants together in the reaction zone. This can be done in several ways, either before or after achieving supercritical or near supercritical conditions, one or both of the reactants are mixed with an aqueous solvent, and such mixing is performed together in the reaction zone. This is done to keep the reactants isolated from one another until

  In the batch process of the present invention, water, precursor, and catalyst solution are mixed in an autoclave before being heated to the reaction temperature and pressure. An oxidant can optionally be added to the mixture under reaction conditions or it can be added prior to sealing and heating the batch reactor autoclave. After the desired reaction time, the reaction autoclave is cooled and the product is discharged. The heterocyclic aromatic carboxylic acid product can then be recovered using any suitable product recovery system, such as extraction, concentration, and recrystallization.

  In the continuous process of the present invention, the reactor system preferably has a contact between the oxidant and at least a portion of the precursor, and preferably substantially all of the catalyst, and at least a portion of the oxidant, And preferably configured to take place between substantially all and the same point in the reactor system.

  In the first embodiment, after the aqueous solvent is heated and pressurized to ensure a supercritical or near supercritical state, the oxidant is mixed with the aqueous solvent and before mixing with the aqueous solvent, With proper pressurization and heating if desired. The precursor is pressurized and heated if desired. In the case of a process that uses a homogeneous catalyst, the catalyst component is pressurized and heated if desired. The precursor, catalyst, and oxidant / solvent mixture are then contacted simultaneously. In the case of a process using a heterogeneous catalyst, the precursor is contacted with the oxidant / solvent mixture in the presence of the catalyst.

  In a second embodiment of the invention, after the aqueous solvent is heated and pressurized to ensure a supercritical or near supercritical state, the precursor is mixed with the aqueous solvent and before mixing with the aqueous solvent, With proper pressurization of the precursor and, if desired, heating. In one configuration, the homogeneous catalyst component is contacted with the aqueous solvent after pressurization and optional heating, simultaneously with the contact of the precursor with the aqueous solvent. In an alternative configuration, as described herein, a heterogeneous catalyst is used and limited to the reaction zone. After the aqueous solvent is heated and pressurized to ensure a supercritical or near supercritical state, the oxidant is mixed with the aqueous solvent after pressing and, if desired, heating. In the case of a process using a homogeneous catalyst, the oxidant / aqueous solvent mixture is then contacted with a mixture comprising a precursor, a catalyst, and an aqueous solvent. In the case of a process using a heterogeneous catalyst, the oxidant / aqueous solvent mixture is contacted with the mixture comprising the precursor and the aqueous solvent in the reaction zone, ie, in the presence of the heterogeneous catalyst.

  Various flow contacts can be made as separate feeds to the device, where the feeds merge to form one homogeneous fluid phase, thus reacting the oxidant and precursor. Devices in which the feeds are merged can be, for example, in a single flow path where separate feeds form a continuous flow reactor, or in some cases multiple flow paths that form two or more continuous flow reactors. It can have Y, T, X, or other configurations that allow it to be merged. The one or more flow passages where the feeds are merged may include sections of tubular configuration with or without internal dynamic or static mixing elements.

  In preferred embodiments, in-line mixers or static mixers are advantageous to ensure rapid mixing and homogeneity, for example, to facilitate dissolution of the oxidant in an aqueous solvent and the formation of a single phase. used.

  The oxidant feed and precursor feed can be combined at one location, or at least a portion of one or both feeds is progressively increased, for example, relative to the direction of flow through the reactor. The contact can be made in two or more stages so that it is introduced through the injection point. For example, one feed can be passed along a continuous flow path, where the other feed is introduced at a number of points spaced along the length of the continuous flow path, thereby The reaction is progressive. The feed passed along the continuous flow path can contain an aqueous solvent, as well as feed introduced at multiple locations.

  Similarly, the addition of a catalyst, in particular a homogeneous catalyst, can be carried out progressively, for example via a number of injection points with respect to the direction of flow through the reactor.

  In one embodiment, the oxidant is introduced into the reaction at two or more locations. Such a position is advantageously for the bulk flow of solvent and reactants through the oxidation zone so that the oxidant is introduced into the reaction at the initial position and at least one additional position downstream of said initial position. Is positioned.

  After traversing the continuous flow reactor, the reaction mixture contains a solution of a heterocyclic aromatic carboxylic acid. The solution also contains catalyst (if used) and relatively small amounts of by-products such as intermediates (eg aldehydes), decarboxylation products, and degradation products, and any unused reactions. Thing can be contained.

  The invention will now be further described by way of example only with reference to the accompanying drawings.

Referring to FIG. 1A, after water is heated, dioxygen is mixed with water after pressurization, and the mixture is pressurized and optionally further heated in preheater 1 to achieve a supercritical state. To do. The precursor and catalyst are added to the O ₂ / water stream after pressurization at the beginning or just before reactor 2 and the mixture is passed through the reactor. Upon exiting the reactor, the stream is cooled and depressurized in the back pressure regulator 3. The product is carried out with the flow of cooling water. In the corresponding FIG. 1B, the catalyst already exists as a heterogeneous catalyst in the reactor.

Referring to FIGS. 2A and 2B, after water is pressurized and optionally heated, the precursor and catalyst are added to the water after pressurization and optionally further heated in preheater 1A to become supercritical. Achieve state. The dioxygen gas is mixed with water in a supercritical state after pressurization, and optionally further heated in the preheater 1. In FIG. 2A, the two streams are mixed at the beginning or just before reactor 2, and the mixture is passed through the reactor. In FIG. 2B, the O ₂ / water stream is progressively added to the reactor at multiple injection points. Upon exiting the reactor, the stream is cooled and depressurized in the back pressure regulator 3. The product is carried out with the flow of cooling water. In the corresponding FIGS. 2C and 2D, the catalyst already exists as a heterogeneous catalyst in the reactor.

  Referring to FIG. 3, feed components including water, precursor, and dioxygen gas are pressurized to operating pressure and continuously fed from respective sources 10, 12, and 14 through a preheater 16, and the components Is heated to a temperature from 300 ° C. to 480 ° C., more preferably from 330 ° C. to 450 ° C., typically from a lower limit of about 340 ° C. to 370 ° C. to an upper limit of about 370 ° C. to about 420 ° C., and the pressure and temperature are Selected to ensure supercritical or near supercritical conditions. A portion of the heat used to preheat the raw material components can be derived from the exotherm generated during the subsequent reaction between the precursor and the oxidant. The heat from other sources can be in the form of, for example, a high pressure stream and / or the heating can be performed by direct calcination heating of the water stream. The heat of reaction can be recovered in any suitable manner, for example, by heat exchange between the post-reaction fluid and a suitable heat receiving fluid such as water. For example, the heat receptive fluid can be arranged to flow in a heat exchange relationship in countercurrent and / or cocurrent with the reactants and solvent passing through the reaction zone. The one or more passages along which the heat receptive fluid flows as it traverses the reaction zone can be external to the reaction zone and / or can extend through and through the reaction zone. . Such internally extending flow passages can, for example, extend generally parallel to and / or transverse to the general direction of reactant / solvent flow through the reaction zone. For example, the heat receiving fluid can traverse the reaction zone by the passage of one or more coiled tubes located within the interior of the reactor. Using the enthalpy of the reaction, power can be recovered by a suitable power recovery system such as a turbine, for example using a heat receiving fluid, for example water, and a high pressure saturated stream, for example a temperature of about 300 ° C./100 bara And can be raised to pressure, which can be superheated by external heat and fed to a high efficiency condensing steam turbine to recover power. In this way, the reactor can be maintained at an optimum temperature and effective energy efficiency can be achieved. In an alternative method, the reactor can be operated under adiabatic conditions and an appropriately high rate of water flow through the reaction zone can be used to suppress temperature rise across the reactor during operation. If desired, a combination of both methods can be used, i.e. recovery of the enthalpy of the reaction with the heat receptive fluid combined with an appropriate water flow rate through the reaction zone.

  After heating the raw material components, oxygen is mixed with water, which results in supercritical or near supercritical conditions as a result of preheating and pressurization, thus allowing the raw material to be solubilized. In the embodiment shown in FIG. 3, oxygen and water are mixed in premixer 18A. The precursor is also mixed with water in the premixer 18B. Of course, the precursor can also be premixed separately with water before entering the preheater 16.

  The premixer (or multiple premixers if premixing of each reactant and water is contemplated) is Y, as shown in FIGS. 4A, 4B, 4C, 4D, and 5, respectively. It can take various forms such as a piece configuration, an L piece configuration, or a T piece configuration, a double T configuration, or a static mixer. 4A to 4D and FIG. 5, reference A indicates the preheated water supply to the premixer, B indicates the reactant (precursor or oxygen), and P indicates the resulting mixed stream. In the double T configuration of FIG. 4D, two mixed streams are generated P1 and P2. These can be passed through separate continuous flow reactors or combined into one stream and then passed through one continuous flow reactor. An X-piece configuration can also be used, as is known to those skilled in the art.

  Instead of premixing one or both reactants with water before introduction into the reaction zone, the reactant and water are introduced separately into the reaction zone and some form of mixing mechanism (eg, a static mixer) is used. It will be appreciated that mixing can occur within the reaction zone, whereby substantially all of the components are mixed within the reaction zone.

  If a homogeneous catalyst is to be used in the reaction, the catalyst will be premixed with oxygen / immediately before entering the reactor or at the beginning of the reactor (ie, as shown in FIG. 1A). Simultaneously with the water stream, it is added as a solution from the source 19 to the premixed oxygen / water stream.

  After preheating and premixing, the feed components are combined in reaction zone 20 to form one homogeneous fluid phase with the reactants combined. Reaction zone 20 provides adequate reaction time in conjunction with combined reactant flow rates to ensure conversion of precursor to carboxylic acid with high conversion efficiency and low intermediate aldehyde content. It can consist of a simple mixer mechanism in the form of a tubular plug flow reactor, for example a length of pipe.

  When the reaction is performed in the presence of a heterogeneous catalyst system (ie, as shown in FIG. 1B), the catalyst system can be distributed longitudinally with respect to the flow direction and the reaction zone So that once the supercritical or near supercritical fluid has traveled beyond the section of the pipe occupied by the catalyst system, the rate of reaction is significantly reduced and the decomposition products Suppresses the generation of

  The reactants can be combined “once” upstream of the reactor 20. Alternatively, they can be combined progressively by injecting one reactant into a stream containing the other reactant at multiple points along the length of the reactor. One way to implement a multi-injection mechanism is shown in the continuous flow reactor of FIG. In embodiments where the premixed oxygen / water stream is added to the premixed precursor / water stream (as shown in FIG. 2D), the premixed precursor / supercritical or near supercritical water stream W is at the upstream end of the pipe P. Supplied to the department. In the case of a process in which a homogeneous catalyst is used, the water stream W also contains the catalyst, and in a process using a heterogeneous catalyst, the catalyst is present inside the pipe P. The flow passes through the reactor pipe P, and preheated and compressed oxygen dissolved in supercritical or near supercritical water is injected at a series of spaced locations along the length of the pipe P. Supplied via passages A to E to produce a product stream S containing the desired heterocyclic aromatic carboxylic acid in a supercritical or near supercritical aqueous solution. Thus, the oxygen required to effect complete oxidation of the precursor to carboxylic acid controls the oxidation and side reactions and possible combustion of the precursor, carboxylic acid product, or carboxylic acid intermediate. In order to minimize the infusion, it is injected gradually.

  Referring now again to FIG. 3, after the reaction to the desired extent, the supercritical or near supercritical fluid is passed through the heat exchanger 22, through which the heat exchange fluid is circulated by the closed loop 24, Thereby, heat can be recovered for use in the preheater 16.

  The cooled solution is then fed to the product recovery section 26, where the carboxylic acid is recovered from the solution. Any suitable method of product recovery known to those skilled in the art can be used.

Experimental work was performed on a laboratory scale by continuous oxidation of precursors in supercritical water with MnBr ₂ catalyst. The exotherm was minimized by using a relatively dilute solution (<5% organic w / w). The basic configuration of the system is as described in FIG. 1A. A more detailed view of the system used for these laboratory scale experiments is shown in FIG.

Hydrogen peroxide (100 vol) was diluted to an appropriate concentration such as a 2% solution, fed to a pump and cooled to 5 ° C. or lower. Next, hydrogen peroxide was ¼ inch O.D. cast into an aluminum block. D. Heating was performed in a preheater 152 consisting of a 5 m coil of stainless steel tube. Proper mixing of oxidant and water was achieved by using a relatively long coil in the preheater 152. The oxidant / water fluid was then passed through the crosspiece 154 and contacted with the precursor and the solution of MnBr ₂ catalyst supplied from its own pump.

  The other components are labeled in FIG. 7 as follows: 162A-E: valve; 163A-B: pressure release valve; 164A-E: check valve; 165A-F: pressure transducer; T: thermocouple (The aluminum heater block of the preheater 152 includes a thermocouple, not shown). The preheater was obtained from NWA GmbH; the pumps were Gilson 302, 305, 306, and 303; the back pressure regulator was obtained from Tescom (model 26-1722-24-090). .

  Maximum corrosion occurs in the region of the crosspiece 154 where the oxidant, precursor, and catalyst solution meet, particularly in the incoming unheated catalyst feed pipe where the high temperature gradient is consistent with bromide ions. Reaction of Hastelloy C276 (or titanium) before the final section of the catalyst feed pipe and the mixer section for the addition of NaOH solution, if used, where a temperature gradient of about 100 ° C. occurs over a length of about 5 cm. Used downstream of the vessel and 316L stainless steel was used for the other components. All pipework that is prone to corrosion failure is protected inside the polycarbonate shield.

Before each run, the device was hydrostatically pressure tested when cold and then heated with a stream of pure 18 Mohm water (5-10 ml min). Once the operating temperature was reached, the hydrogen peroxide supply and pump for the precursor and MnBr ₂ were started. Typically, the experiment was performed for 4 to 5 hours. The product was usually collected and analyzed over a sequential period of 15 or 30 minutes. Purity was confirmed primarily by HPLC. The yield of solid product was calculated as the molar concentration of different products in solution divided by the molar concentration of feed fed to the reactor.

Example 1
A dilute stock solution was prepared using 56 volumes of peroxide and 760 ml of nanopure water (18.3 megohm resistance) using 100 volumes of hydrogen peroxide. A dilute catalyst stock solution was prepared by dissolving manganese bromide in nanopure water to a concentration of 5000 ppm w / w of Br. 3-methylpyridine was kept undiluted separately. A stock solution of sodium hydroxide (0.5M) was prepared and fed downstream of the reactor, but before the back pressure regulator.

  Only deionized water was pumped through the preheater, mixing piece, reactor, caustic mixer, cooler, and back pressure regulator at a rate that controlled the final residence time through the reactor to 10 seconds. The residence time is a tube reaction between the mixing piece, the first for mixing the reactants to initiate the reaction and the second for quenching the reaction with the addition of sodium hydroxide. The volume of the vessel, pipework, and fixture was defined as divided by the volume flow rate. Volumetric flow rates are based on the physical properties of water at mixing conditions, as published by the International Steam Tables and by the US National Institute of Standards and Technology. It was.

  The back pressure regulator was set to control the reactor pressure to 220 bar. The heater was set to control the mixing piece at 380 ° C and the reactor at 374 ° C.

  Each of the reactants was pumped separately into the mixing piece. Methylpyridine is fed to the reactor at a concentration of 0.50% w / w and oxygen is fed at a rate slightly above the stoichiometric rate required for the oxidation of 3-methylpyridine to nicotinic acid; The catalyst solution was fed to the mixing piece to produce a concentration of 1640 ppm Br in the reactor.

  After reaching stable set point conditions, samples were collected over a 15 minute interval and then analyzed. This experiment was carried out for 1.5 hours. The results show good selectivity for nicotinic acid (about 95%) at about 30% conversion. Some 3-pyridinecarboxaldehyde was detected in 1-2% yield. Unreacted precursor is stable in the reaction medium and is recovered at the end of the reaction.

1 is a schematic flow sheet showing the basic configuration described for the first embodiment above, and FIG. 1A shows the use of a homogeneous catalyst. 1 is a schematic flow sheet showing the basic configuration described for the first embodiment above, and FIG. 1B shows the use of a heterogeneous catalyst. 2 is a schematic flow sheet showing the basic configuration described for the second embodiment above, and FIG. 2A shows the use of a homogeneous catalyst. 2 is a schematic flow sheet showing the basic configuration described for the second embodiment above, and FIG. 2B shows the use of a homogeneous catalyst. In FIG. 2B, the oxidant is gradually introduced at multiple injection points along the reaction zone. 2B is a schematic flow sheet showing the basic configuration described for the second embodiment above, and FIG. 2C shows the use of a heterogeneous catalyst. 2 is a schematic flow sheet showing the basic configuration described for the second embodiment above, and FIG. 2D shows the use of a heterogeneous catalyst. In FIG. 2D, the oxidant is gradually introduced at multiple injection points along the reaction zone. 2 is a schematic flow sheet showing in more detail the configuration in which the precursor is added to the premixed flow of oxygen and water (ie, the configuration according to the process shown in FIG. Fig. 4 illustrates various premixer configurations that can be used to effect mixing of at least one of the reactants with an aqueous solvent. Fig. 4 illustrates various premixer configurations that can be used to effect mixing of at least one of the reactants with an aqueous solvent. Fig. 4 illustrates various premixer configurations that can be used to effect mixing of at least one of the reactants with an aqueous solvent. Fig. 4 illustrates various premixer configurations that can be used to effect mixing of at least one of the reactants with an aqueous solvent. Figure 2 shows a premixer configuration that can be used to mix at least one of the reactants with an aqueous solvent. It is the schematic which shows the multistage injection | pouring of an oxidizing agent. This will be described in connection with the examples.

Claims (10)

  A method for the production of a heterocyclic aromatic carboxylic acid, comprising the step of contacting said carboxylic acid precursor with an oxidant in the presence of a catalyst, wherein said contacting comprises supercritical conditions or supercriticality. A process comprising using the precursor and the oxidant in an aqueous solvent comprising water near near point supercritical conditions.   The process of claim 1, wherein the contacting is performed in a continuous flow reactor.   The process according to claim 2, characterized in that the contact of the precursor takes place in the reaction zone and the residence time is less than 2 minutes.   4. The method of claim 3, wherein substantially all of the heteroaromatic carboxylic acid produced is maintained in solution during the reaction.   The method according to claim 1, wherein the heterocyclic aromatic carboxylic acid is a nitrogen-containing heterocyclic aromatic compound.   The method of claim 1, wherein the heterocyclic aromatic carboxylic acid comprises a 6-membered ring.   The method of claim 1, wherein the heterocyclic aromatic carboxylic acid comprises a pyridine ring.   2. The method of claim 1, wherein the heterocyclic aromatic carboxylic acid is nicotinic acid.   The method of claim 1, wherein the precursor for the heterocyclic aromatic carboxylic acid is an alkyl pyridine.   The method of claim 1, wherein the precursor for the heterocyclic aromatic carboxylic acid is 3-methylpyridine.

Images