Method for producing organometallic compounds

Abstract

The present invention relates to a method for producing at least one organometallic compound, comprising the steps of: loading solid metal or metal-containing solid particulates into a reactor column comprising a metal bed; continuously contacting at least one substrate fluid, preferably said fluid comprising a non-aqueous solvent, with the metal bed; transporting the fluid against gravity through the metal bed; and partially recirculating the fluid over the metal bed. The present invention also relates to an apparatus for producing at least one organometallic compound, the organometallic compound itself, and chemicals produced from said compound.

Description

[Technical field]

[0001] The present invention relates to a method for producing organometallic compounds from solid metals or metal-containing solids or mixtures thereof. In a second aspect, the present invention also relates to an apparatus for the production of organometallic compounds. In another aspect, the present invention also relates to organometallic compounds produced according to said method or using said apparatus. In another aspect, the present invention also relates to chemicals produced from such organometallic compounds as chemical intermediates. [Background technology]

[0002] Organometallic compounds are compounds that have at least one carbon-metal bond (compounds also include hydride compounds with hydrogen-metal bonds). Metal or carbon atoms can also be bonded to other elements, e.g. halogens. In general, carbon-metal bonds are highly reactive. Organometallic compounds are highly flammable and some can spontaneously combust on contact with air. Solutions can be corrosive and react violently with water. Their solvents can evaporate and form explosive mixtures with air. The synthesis of organometallic compounds from solid metals is often characterized by a very high exothermicity, making industrial production particularly delicate.

[0003] Organometallic compounds have become essential reagents in the modern chemical industry. Organometallic compounds such as organomagnesium compounds (e.g., Grignard reagents) are commonly used due to the great variety of reactions that can be carried out with Grignard reagents. Some of these reactions include transmetallation reactions, alkylation reactions to prepare metal alkyls, metal aryls, and metal alkenyls, and addition reactions of organomagnesium compounds to C=O, C=NR, and C≡N multiple bonds to prepare alcohols, aldehydes, ketones, carboxylic acids, esters, and amines. The Grignard reaction is also a commonly used method for coupling C-C bonds. Compounds containing one or more aluminum-carbon bonds are also important to industry, resulting in the production of large quantities and high value organoaluminums. Compounds such as trialkylaluminum compounds and alkylaluminum sesquichlorides are industrially important organoaluminum compounds used primarily as catalyst components in Ziegler-Natta type systems for olefin polymerization.

[0004] Organozinc compounds are compounds that contain at least one zinc-carbon bond. Although they are less reactive than other organometallic compounds, they are used as reagents in industrially important reactions such as the Reformatsky reaction and the Negishi cross coupling.

[0005] Organolithium compounds are also important industrially, often used in deprotonation and carbon chain rearrangements by nucleophilic addition reactions. Industrially, they are used to initiate the polymerization of synthetic elastomers, but also in the synthesis of pharmaceutical ingredients. Methyllithium, n-butyllithium, n-hexyllithium and phenyllithium are important organolithium compounds.

[0006] The organometallic compounds mentioned above are preferably prepared by reaction of a substrate, as defined below, such as an organic halide, defined as a compound containing a carbon-halogen bond, an organometallic salt, etc., with the relevant solid metal or a metal-containing solid, optionally in the presence of an activating component. Most of such reactions require activation of the metallic solid and are characterized by being particularly exothermic, which increases the risk of runaway if the process is not thermally well managed.

[0007] The present invention relates to a continuous process and apparatus for preparing organometallic compounds from metal-containing solids, such as solid metals or metal halides, which process allows for proper management of the high exothermicity, regardless of reactor size.

[0008] Some examples of industrially important organometallic compounds that can be prepared from solid metals or metal-containing solids are given in Table 1. The table also lists the nature of the metals, the substrates that react with such metals, as defined below, and the solvents, if necessary.

[0009] [Table 1]

[0010] The operating and reaction techniques for preparing organometallic compounds from solid metals have remained largely unchanged for the past 100 years. Usually, the reactions are carried out in a batch process, i.e. a batch or fed-batch process in which the metal solid or a metal-containing solid is gradually contacted with the pure substrate or substrate in a solvent, as defined below. However, the main disadvantage of such batch processes arises from the long induction phase required to activate metals such as magnesium, zinc, and aluminum, and the resulting difficulty in managing the highly exothermic nature of the reaction.

[0011] Direct metal insertion into organohalide substrates for the production of organometallic compounds is highly exothermic. Therefore, care must be taken to ensure that the reaction does not go out of control. For this reason, the induction step is performed in a very gradual and therefore slow approach. Various strategies can be used to activate the metal, such as the addition of iodine or the addition of a previously generated organometallic compound. In any case, a small amount of organohalide is added to ensure that the reaction is initiated. Once the reaction has started, the addition of organohalide is maintained at an appropriate rate to ensure that the reaction is maintained and controlled until all the organohalide is consumed. The supernatant organometallic solution is removed from the reaction mixture by filtration. Such methods are cumbersome and have a high risk of runaway reactions.

[0012] Due to the above-mentioned difficulties in managing the high exothermicity in large batch reactors, many attempts have been made to produce organometallic compounds from metal solids in a continuous manner. DE 1293767 discloses a process in which Mg particles are contacted with at least one organohalide by feeding the organohalide dissolved in a cyclic ether to the bottom of a column packed with Mg turnings and replenished from the top. US 2464685 describes a continuous process for effectively reacting Mg with an organohalide, in which the organohalide in ether solution is fed to a body of Mg particles under continuous stirring. WO 2021 / 056193 describes a process for reacting zinc powder with halocarbon in a continuous reactor with heating and cooling sections. US 4105703 describes a continuous Grignard process in which a cyclohexyl halide solution is fed to the bottom of a column reactor packed with magnesium turnings and magnesium turnings are fed from the top of the column. In US Patent 3911037, Grignard reagents are produced continuously by feeding organic halides and solvents to at least one stirred reactor, simultaneously feeding Mg and collecting the product overflow. The disadvantage of such processes, which use stirred bed reactors or packed column reactors, is that the heat and mass transfer during the highly exothermic reaction is not optimal. A further difficulty is the relatively slow conversion, which also limits the throughput achievable in a continuous mode.

[0013] A process for achieving activation in a continuous manner and increasing conversion by mechanical friction is described in WO 2017 / 178230. Two streams are mixed in a reactor. One stream is composed of an alkyl or aryl halide and an anhydrous solvent, and the other is composed of magnesium fine particles. The magnesium fine particles are activated by vibrations with frequencies between 20 and 200 Hz.

[0014] WO 2014 / 207206 relates to a process for the preparation of Grignard reagents comprising reacting magnesium powder in a fluidized bed reactor. The continuous process involves a solvent flowing against gravity through a fluidized bed of fine magnesium particles at a flow rate of 0.1-0.3 cm / sec to form a fluidized bed of fine magnesium particles in the solvent. Powder particles of 10-1000 microns are required for fluidization.

[0015] China Patent Publication No. 111718279 discloses a method and apparatus for continuously producing sartan biphenyl. China Utility Model No. 212595730 discloses a fixed-bed reactor for Grignard reaction. International Publication No. 2002 / 020151 discloses a method for carrying out a chemical reaction between a particulate material and a liquid containing a reagent.

[0016] WO 2014 / 207206 discloses a continuous process that includes fluidizing magnesium fine particles in a reactor and forming a Grignard reagent. US 3,285,968 provides a process for producing calcium alkoxyalkoxides by reacting calcium carbide with glycol ethers. GB 809,310 discloses a reactor divided by a screening plate with perforations. US 3,911,037 describes a continuous Grignard reactor in which an excess of magnesium is always maintained. Summary of the Invention [Problem to be solved by the invention]

[0017] If the liquid in the reactor flows from top to bottom, the solids in the reactor are more likely to clog, and the filters are more likely to clog quickly.

[0018] However, scale-up for industrial production of these methods remains inherently limited by limitations in heat removal due to unfavourable surface / volume ratios, and the use of metal powders, which are known to pose safety hazards.

[0019] Starting from the known prior art, the object of the present invention is to provide a process for the continuous preparation of organometallic compounds from solid metals or metal-containing solids, which process simultaneously offers the following advantages compared to the processes described in the prior art: - Improved mass transfer allows for faster reactions and higher conversions. - Improved heat transfer allows for optimal temperature control. - High heat removal capacity, greatly improving process safety. - The use of non-powdered metals significantly reduces safety risks. - Straightforward extensibility. - Significant reduction in procedural steps. [Means for solving the problem]

[0020] The present invention and its embodiments serve to provide a solution to one or more of the above mentioned drawbacks. To this end, the present invention relates to a method for the preparation of at least one organometallic compound according to claim 1.

[0021] A continuous process including a thermally controlled recirculation loop provides a very effective way of removing heat from the reactor, regardless of the size and aspect ratio of the reactor. Moreover, for a given input throughput of substrate, the recirculation flow, which can be adapted to the specific circumstances, can increase the turbulence and flow motion in the metal particulate bed, which tends to act as a static mixer. Such turbulence and flow motion not only offers the advantage of significantly increasing the heat transfer in the reactor, but also of higher and faster mass transfer, thus significantly enhancing the reaction rate. The result is a process that is more productive, safer, more flexible and more scalable than batch or continuous processes with thermal control through the reactor wall.

[0022] A preferred embodiment of the method of the present invention relates to the handling of solid particles in a continuous process and is shown in any of claims 3 to 6. A specific preferred embodiment relates to the invention as defined in claim 3.

[0023] In a second aspect, the present invention relates to an apparatus as defined in claim 10. More particularly, the apparatus described herein provides a well-controlled environment for carrying out reactions between solid metals and / or metal-containing solids and substrates as defined below.

[0024] In a final aspect, the invention relates to compounds produced by the methods and / or apparatus of the previous aspects, and also to chemical compounds produced as chemical intermediates from such organometallic compounds.

[0025] The following description of figures of specific embodiments of the present invention are merely exemplary in nature and are not intended to limit the present teachings, their application, or uses. Corresponding reference characters indicate like or corresponding parts and features throughout the drawings. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 is a schematic diagram showing one embodiment of the present invention. [Diagram 2] FIG. 2 shows an injection section according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] (definition) As used herein, the following terms have the following meanings.

[0028] As used herein, "a," "an," and "the" refer to singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compartment" refers to one or more compartments.

[0029] As used herein, "about" refers to a measurable value, such as a parameter, amount, time period, etc., and is meant to encompass a variation of no more than ±20%, preferably no more than ±10%, more preferably no more than ±5%, even more preferably no more than ±1%, and most preferably no more than ±0.1% of the specified value, to the extent that such variations are appropriate for the practice of the disclosed invention, although it should be understood that the value to which the modifier "about" refers is itself specifically disclosed.

[0030] As used herein, "comprise," "comprising," "comprises," and "comprising of" are synonymous with "include," "including," "includes," or "contain," "containing," or "contains," and are inclusive or open-ended terms that specify the presence of what follows (e.g., components), but do not exclude or preclude the presence of additional, unrecited components, features, elements, materials, or steps that are known in the art or disclosed therein.

[0031] Moreover, in this specification and claims, terms such as "first," "second," "third," etc. are used to distinguish between similar elements and are not necessarily used to describe a sequential or chronological order, unless specified. The terms so used are interchangeable under appropriate circumstances, and it is to be understood that the embodiments of the invention described herein are capable of operating in sequences other than those described or illustrated herein.

[0032] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints.

[0033] The terms "% by weight", "percent by weight", "% wt" or "wt%" here and throughout the specification refer to the relative weight of each component based on the total weight of the formulation, unless otherwise defined.

[0034] The term "one or more" or "at least one" is clear in itself, e.g., one or more or at least one member of a group of members, but by way of further illustration, the term specifically encompasses any one of said members, or any two or more of said members, e.g., any three or more, four or more, five or more, six or more or seven or more of said members, and up to all of said members.

[0035] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearance of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, but may. Furthermore, particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments, as would be apparent to one of ordinary skill in the art from this disclosure. Furthermore, although some embodiments described herein include some features and not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the present invention and form different embodiments, as would be understood by one of ordinary skill in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

[0036] Unless otherwise defined, all terms used in disclosing the present invention, including technical and scientific terms, have the meaning commonly understood by those skilled in the art to which the present invention belongs. As a further guide, definitions of terms used herein are included to better understand the teachings of the present invention. Terms or definitions used herein are provided solely to aid in the understanding of the present invention.

[0037] "Organometallic compounds" include, for example, compounds of the formula RM, RMR, MR, RMX, or M(-R) m (-X) n (-Het) Owhere R is an organic compound, X is a halogen atom, Het is any heteroatom-based functionality, and M is a metal. Examples of metals are Mg, Li, Na, Al, Fe, Si, Zn, Cu, Ru, Al, Sn, Ca. Examples of halogens are F, Cl, Br or I. As organic compounds, all known alkyl, alkenyl, alkynyl, aryl, aryl and heteroaryl groups can be used. Further preferred are alkyl groups with 1 to 20 C atoms, alkenyl and alkynyl groups with 2 to 20 C atoms, and aryl groups with 3 to 20 C atoms. The alkyl, alkenyl, alkynyl and aryl groups can be linear or branched. Furthermore, one or more CH2 groups in the alkyl, alkenyl, alkynyl and allyl groups may be substituted, each independently of the other, with -O-, -S- or -NRR'-, such that the heteroatoms are not directly linked to each other. Preferred aryl or heteroaryl groups contain one or more aromatic or heteroaromatic rings, which may be optionally substituted. Preferred substituents are halogens, linear or branched, optionally chiral, unsubstituted, mono- or polysubstituted alkyl groups having 1 to 10 carbon atoms, or alkenyl or alkynyl groups having 2 to 10 carbon atoms, in which one or more CH2 groups may be substituted, each independently of the other, with -O- or -S-, such that the heteroatoms are not directly linked to each other. The heteroatom-based functionality may be a hydride or any organic functional group in which an oxygen, nitrogen, phosphorus, arsenic or sulfur atom is directly linked to M. In the following text, RX, i.e., the organic halide, is referred to as the substrate.

[0038] An "organohalide" is a compound that contains at least one carbon-halogen bond. Examples of halogens are F, Cl, Br, or I.

[0039] A "substrate" is a compound that participates in a chemical reaction with at least one other reactant or reagent. Thus, the above-defined organic halides, metal salts, organometallic compounds, molecular hydrogen, unsaturated organic compounds, such as olefins or alkynes or carbonyl compounds, can be referred to as substrates in the context of reactions with solid metal particles and / or metal-containing solids. Furthermore, the above-defined organic halides, metal salts, organometallic halides, organometallic complexes, aldehydes, ketones, imines, activated carboxylic acids, acyl halides and any carbonyl compounds, nitriles, carbon dioxide, oxygen, sulfur, transition metal-based complexes and catalysts (whether supported or not), silanes and their derivatives, boranes and their derivatives, phosphines and their derivatives, or other suitable electrophilic compounds, or acidic compounds known to those skilled in the art as alcohols, amines, amides or acidic hydrocarbons, can be referred to as substrates in the context of reactions involving the above-defined organometallic compounds prepared according to the present invention.

[0040] Detailed Description of the Invention The present invention relates to a method for preparing at least one organometallic compound.

[0041] In a first aspect, the present invention provides a method for producing at least one organometallic compound, comprising the steps of: loading solid metal or metal-containing solid particulates into a reactor column comprising a metal bed; continuously contacting at least one substrate fluid, preferably the fluid comprising a non-aqueous solvent, with the metal bed; and transporting the fluid against gravity through the metal bed, The method is characterized in that the fluid is partially recirculated over a metal bed.

[0042] In a preferred embodiment, the fluid is comprised of a substrate and a non-aqueous solvent, hi another embodiment, the fluid is comprised solely of one or more substrates.

[0043] In one embodiment, recirculating the fluid includes pumping the fluid through a heat exchanger, hi a further embodiment, a pump is present in the recirculation loop and is suitable for pumping the fluid at an appropriate flow rate.

[0044] Optimization of the appropriate recirculation flow rate is discussed below.

[0045] The advantage of the recirculation loop is twofold. First, the reaction is exothermic, so managing the heat generated by the chemical change is an important part of the process. Heat management, heat distribution in the reactor, and stabilization of the reactor temperature are ensured by the recirculation loop. At the top of the reactor tower, a portion of the fluid is pumped out of the reactor, filtered, cooled, and then sent back to the bottom of the reactor. The recirculation flow and the temperature control of the loop are important to regulate and homogenize the reaction temperature in the reactor. Second, the reaction of the present invention is a mass transfer dependent reaction, so a high flow rate and turbulence in the reactor improves the reaction rate. Besides, better heat and mass transfer control is expected to be beneficial to the efficiency of the reaction.

[0046] However, despite the above statements that would be apparent to one skilled in the art, it has been surprisingly observed that too high a recycle rate can adversely affect the process, and such recycle rates and ratios need to be optimized as described below.

[0047] Furthermore, it has been observed that precise temperature control leads to fewer side reactions and by-products.

[0048] In one embodiment, the fluid is partially recirculated again through a heat exchanger and over the metal bed at a recirculation ratio, where the recirculation ratio is the ratio between the mass flow rate through the metal bed and the mass flow rate of the substrate entering the reactor, and the recirculation ratio is used to optimize the production of at least one organometallic compound. The production of at least one organometallic compound is optimized using the reaction conditions.

[0049] The highly efficient temperature regulation resulting from the recirculation loop described in this invention, combined with appropriate pressure and temperature instrumentation, allows the addition of reactants to be stopped instantly, making it a safer alternative for producing organometallic compounds in a continuous mode compared to typical batch modes. In yet another embodiment, the present invention is directed to minimizing hot spot formation, a problem frequently encountered in packed beds or when using metal turnings, which has been overcome by the turbulence resulting from the use of a recirculation loop.

[0050] In some embodiments, a filter and purge can be used in the loop circuit to remove solid impurities or products from the system that would otherwise accumulate in the reactor.

[0051] In some embodiments, a recirculation pump is installed to generate a flow through the recirculation loop. For this purpose, a centrifugal pump is a good choice since the pressure loss in the recirculation loop is relatively small while the recirculation flow rate is quite large. In a further embodiment, the recirculation relates to a higher bed-to-surface heat transfer. In yet another embodiment, a nearly uniform temperature is maintained even under highly exothermic reaction conditions, which is very difficult or impossible to achieve when using a conventional packed bed without a recirculation loop. ΔT represents the difference between the maximum and minimum temperatures measured from five probes in the reactor, and one experiment showed that ΔT=62°C when no recirculation was applied, ΔT=41°C when the recirculation ratio was 1:1, and ΔT=6°C when the recirculation ratio was 10:1.

[0052] In another embodiment, it is surprising that in addition to heat exchange efficiency, particle entrainment and chemical reaction selectivity must be considered when optimizing recycle rates and ratios, as described below.

[0053] In one embodiment, the liquid passes through a heat exchanger before being pumped back to the reactor. In conventional column reactors, the flow must be maintained at a low ascending velocity to ensure sufficient residence time to complete the reaction. Increasing the throughput by increasing the column diameter is limited by the low heat transfer in the reactor (slow flow environment) and the available heat exchange surface (which increases with the square of the reactor diameter, while the heat generation increases with the cube of the reactor diameter). The use of a recirculation loop with a heat exchanger firstly allows the flow in the reactor to be more turbulent while maintaining the average residence time, and secondly allows a heat removal capacity that can be adjusted independently of the reactor diameter. As one skilled in the art would expect, several types of heat exchangers and cooling fluids can be used, allowing a large amount of heat removal capacity to be obtained independent of the overall process throughput. The reaction temperature can be precisely maintained at the desired set temperature depending on the organometallic compound to be produced. In one embodiment, the reactor temperature is maintained at a temperature in the range of about 10°C to about 150°C, or in the range of about 75°C to about 125°C. In another embodiment, the temperature is maintained at about 40° C. In yet another embodiment, the temperature is maintained in the range of about −20° C. to about 50° C. If the reaction is slow, the reaction rate is increased by increasing the temperature of the reactor under pressure.

[0054] The pressure before and after the heat exchanger is measured to monitor possible fouling of the small internal tubes.

[0055] The preferred residence time of the substrate within the bed of metal particulate will vary depending on the particular substrate, other solvents (if present), and temperature. One skilled in the art will know how to vary the flow conditions, temperature, and residence time based on the particular reactants to optimize the reaction conditions.

[0056] In one embodiment, the reactor head is designed to prevent solid metal particles from being sucked into the recirculation loop and / or reactor outlet by slowing down the upward velocity of the liquid, thus facilitating the settling of the metal particles. In one embodiment, the reactor head is shaped so that the metal particles are optimally retained within the reactor body, preferably the reactor head has a conical shape. In one embodiment, the settling zone has a cross-sectional area that is at least 100%, preferably 400% larger compared to the cross-sectional area of ​​the reactor tower. The head is designed so that the upward velocity of the liquid reaching the top is sufficiently low to prevent most of the metal parts from being washed out of the reactor outlet. This reduces fouling and clogging and improves process control.

[0057] In one embodiment, an optimal recirculation rate must be determined. As mentioned above, a high recirculation rate allows for efficient thermal regulation of the process. Thus, those skilled in the art recommend a maximum recirculation rate. However, it has been surprisingly found that a recirculation rate that is too high is detrimental to the process because the vertical velocity through the metal bed tends to fluidize the metal particles faster than would be expected from the particle size distribution of the fed metal. This premature particle entrainment eventually causes plugging and process interruption.

[0058] In one embodiment, experiments have shown that recirculation rates, i.e. absolute flow rate through the metal bed, below 2 m / h result in thermal misregulation leading to by-product formation and ultimately process interruption, while rates above 40 m / h pose the risk of reactor clogging and process shutdown. In one embodiment, the recommended recirculation rate is in the range of 3-25 m / h, preferably 8-20 m / h, most preferably 12-16 m / h.

[0059] In yet another embodiment, the optimal recycle ratio, i.e. the ratio between the mass flow rate through the metal bed and the mass flow rate of the injection, must be determined. A high recycle ratio allows for a high mass transfer efficiency. Thus, those skilled in the art recommend a high ratio to favor the mass transfer of the process. However, it has been surprisingly observed that a recycle ratio that is too high can adversely affect the selectivity of the reaction, resulting in less of the desired product. In one example, under steady flow conditions for a certain Grignard reagent, a recycle ratio of 4 or 6 both gave a yield of less than 94% of the Grignard reagent, while a recycle ratio of 5 gave a yield of more than 97%.

[0060] JPEG2025505718000002.jpg2381

[0061] However, the prior art does not thoroughly optimize the recycle ratio, recommending a high ratio to maximize heat exchange without considering the above-mentioned adverse effects on particle entrainment and reaction yield.

[0062] In one embodiment, the recirculation ratio is from 10:1 to 1:1. In one embodiment, the recirculation ratio is from 25:1 to 42:1. In one embodiment, the recirculation ratio is from 15:1 to 25:1. In one embodiment, the recirculation ratio is from 15:1 to 20:1. In one embodiment, the recirculation ratio is from 15:1 to 25:1. In one embodiment, the recirculation ratio is from 3:1 to 7:1. In one embodiment, the recirculation ratio is from 40:1 to 70:1. In one embodiment, the recirculation ratio is from 10:1 to 70:1.

[0063] In one embodiment, the reaction is initiated by the addition of an activator such as iodine or an organometallic compound. An advantage of the continuous mode is that such activators can be easily separated from the organometallic compound produced by simply discarding the amount initially produced. Once the reaction is initiated, the addition of initiator can be stopped as the organometallic compound is constantly recirculated through the loop over the metal bed.

[0064] In one embodiment, a portion of the liquid is withdrawn from the reactor at a certain height and recirculated to the same height or to the lower zone of the reactor to generate turbulence that is useful for temperature control and reaction kinetics. In another embodiment, the reactor can have multiple recirculation loops. A portion of the fluid is also directed to the reactor outlet to a recovery tank. Figure 1 shows a schematic representation of the reactor configuration. In a preferred embodiment, a portion of the liquid is recirculated from the top of the reactor to the bottom of the reactor. Figure 2 shows the bottom of the reinjection. In one embodiment, the reactor tower is about 70 cm long and about 100 mm in diameter. A person skilled in the art would know how to adjust the dimensions to achieve the desired capacity of the device. The residence time can be tailored to a particular desired reaction by adjusting flow parameters such as fluid injection rate and recirculation rate.

[0065] In one embodiment, the portion of the liquid that is recycled is equal to 20% to 100% of the portion that is directed to the reactor outlet. In a preferred embodiment, the portion of the liquid that is recycled is equal to the portion that is directed to the reactor outlet, or most preferably is 1 to 15 times the portion that is directed to the reactor outlet.

[0066] In one embodiment, the portion of the liquid that is recycled is equal to the portion that is directed to the reactor outlet, or most preferably is 1 to 30 times the portion that is directed to the reactor outlet. In one embodiment, the portion of the liquid that is recycled is 1 to 30 times greater than the portion that is directed to the reactor outlet. In one embodiment, the portion of the liquid that is recycled is 1 to 15 times greater than the portion that is directed to the reactor outlet. In one embodiment, the portion of the liquid that is recycled is 15 to 30 times greater than the portion that is directed to the reactor outlet. In one embodiment, the portion of the liquid that is recycled is 10 to 20 times greater than the portion that is directed to the reactor outlet.

[0067] In one embodiment, the top of the reactor is also where the liquid level is measured, where nitrogen is injected into the reactor to maintain reactor pressure while maintaining an inert atmosphere for the process, and where metals are injected into the reactor, helping to ensure reliable operation of the process.

[0068] In one embodiment, the reactor is pressurized, preferably to 0.01 to 10 barg, more preferably to 2 to 4 barg. In one embodiment, the reactor is pressurized, preferably to 2 to 10 barg, more preferably to about 3 barg. The reaction is carried out in a pressurized apparatus and can reach temperatures above the boiling point of the substrate or the mixture of substrate and solvent under normal pressure and temperature conditions. High temperatures have a positive effect on the chemical reaction rate, improving the conversion and reducing the required residence time.

[0069] In one embodiment, the solid metal particles have a size in the range of 1 μm to 10 mm when added. In one embodiment, the solid metal particles have a size in the range of 100 μm to 10 mm, preferably 500 μm to 5 mm when added. Preferably, the diameter is in the range of 100 μm to 7 mm, more preferably 500 μm to 5 mm. In one embodiment, the solid metal particles have a size in the range of 1.1 to 3.0 mm.

[0070] In one embodiment, the size of the solid metal particles is in the range of 100 μm to 5 mm. In one embodiment, the size of the solid metal particles is in the range of 100 μm to 300 μm. In one embodiment, the size of the solid metal particles is in the range of 1 mm to 3 mm.

[0071] In one embodiment, the metal in the metal bed comprises a metal, preferably magnesium, zinc or lithium, hi one embodiment, the metal is an alkali metal, preferably lithium, an alkaline earth metal, preferably magnesium, an earth metal, preferably aluminum, a transition metal, preferably zinc, or any other metal.

[0072] In one embodiment, the metal particulate is provided such that there is a molar excess of the metal particulate in the reactor relative to the substrate, preferably the organohalide, In a further embodiment, the molar excess is at least 5-fold, preferably 20-80-fold molar excess.

[0073] In one embodiment, the solvent is selected from saturated hydrocarbons, aromatic hydrocarbons, ethers, polyethers, tertiary amines, other aprotic solvents, or a mixture of one or more of the above. In a further embodiment, the non-aqueous solvent comprises an ether, preferably cyclopentyl methyl ether (CPME), tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, 2-methyltetrahydrofuran, 4-methyltetrahydropyran (4-MeTHP), methyl-tert-butyl ether (MTBE), a mixture thereof, or a mixture thereof with other aprotic organic solvents, in particular toluene. In another embodiment, the substrate is contacted with the metal bed without the use of a solvent.

[0074] In one embodiment, the temperature of the substrate entering the reactor is altered to optimize the production of at least one organometallic compound. In one embodiment, a heat exchanger is used to modify the temperature of the substrate before entering the reactor. In one embodiment, the temperature of the substrate entering the reactor and the output of the heat exchanger are altered to optimize the production of at least one organometallic compound.

[0075] In one embodiment, the reactor volume can be varied depending on the capacity requirements of the facility. The reactor scalability is not limited by the surface-to-volume ratio, since the thermal management of the reaction is ensured through a recirculation loop, possibly equipped with a heat exchanger. Reactors with reactor volumes from 0.2 L to 24 L and throughputs from 0.1 to 30 L / h have been operated under the same reaction conditions. No further scale-up limitations have been identified. In one embodiment, the thermal management of the reaction is ensured by a combination of a recirculation loop as described above and a double-jacketed tower containing a refrigerating fluid. In one embodiment, the inner diameter of the tower is about 3 cm to 8 cm, or about 10 cm to about 35 cm.

[0076] In one embodiment, the substrate (R) is selected from (i) a substituted or unsubstituted linear, branched or cyclic alkyl group having 1 to 20 carbon atoms, (ii) a substituted or unsubstituted aryl group, alkenyl group, alkynyl group, aryl group, aryl group and heteroaryl group.

[0077] The process of the present invention achieves high conversions and yields of organometallic compounds, regardless of reactor size or throughput. Table 2 summarizes some of the compounds tested and their conversions.

[0078] [Table 2]

[0079] In another embodiment, the metal particulate has a native oxide layer formed on its surface. The activation of the metal particulate is then carried out by removing the oxide layer with 1,2-dibromoethane, iodine etching, diisobutylaluminum hydride, any organic halide, preferably an organic bromide or an organic iodide, or preferably by pre-washing the particulate with a pre-prepared organometallic compound. In a preferred embodiment, the reactor with the magnesium particulate is heated in the presence of a pre-existing Grignard reagent. In another embodiment, the reactor with the magnesium particulate is filled with a pre-existing Grignard reagent at room temperature without heating.

[0080] In a preferred method of operation, the present invention provides a continuous process that includes contacting particulate metal with a substrate in a reactor, continuously forming an organometallic intermediate, and reacting the intermediate with another substrate.

[0081] Organometallic compounds are often very sensitive to air and moisture. They may also be pyrophoric. This makes them difficult to store and handle safely. In one embodiment of the invention, the organometallic compound once formed is consumed in situ in a subsequent reactor, e.g. a flow reactor, in the presence of another substrate as defined above to obtain the desired product.

[0082] In another embodiment, a first substrate as defined above and a second substrate can be mixed and circulated as a mixture through the metal bed, such that the formation of the organometallic reagent and its subsequent reaction with the second substrate occurs in one step.

[0083] In a second aspect, the present invention relates to an apparatus for the production of at least one organometallic compound, comprising an element for adding solid fine metal particles, a reactor column comprising a reactor head having an injection lower portion and an outlet, and a recirculation loop.

[0084] In one embodiment, the reactor head comprises a settling zone having a cross-sectional area at least 100% greater than the cross-sectional area of ​​the reactor column, hi one embodiment, the recirculation loop comprises a heat exchanger and a recirculation pump.

[0085] In one embodiment, the reactor head comprises a settling zone having a cross-sectional area at least 200%, preferably 300% greater than the cross-sectional area of ​​the reactor column.

[0086] In one embodiment, the ratio of the height of the settling zone to the total height of the reactor is between 1:2 and 1:10, preferably between 1:5 and 1:9.

[0087] In one embodiment, the organometallic compound is a Grignard reagent.

[0088] In one embodiment, a supply of fresh metal particles continuously replenishes the reactor to replace metal consumed by the reaction. In another embodiment, a grinding device is attached to the cutting chamber, which may be attached to the reactor tower. In one embodiment, solid metal particles are added to the reactor by two gas-tight valves flushed with an inert gas, preferably nitrogen gas. The valves isolate a chamber, called the lock, from the reactor. The inventors have determined that the method provides a reliable supply of metal to a pressurized reactor without contaminating the reactor with oxygen or water.

[0089] In one embodiment, the apparatus further comprises at least one metal delivery system, a reactor tower with a recirculation loop, an inlet, an outlet, measurement devices, pumps, valves, and a control system.

[0090] In one embodiment, the injection lower section is designed to allow for uniform distribution of the fluid over the reactor section and ensure homogeneous distribution of the fluid from the lower section to reduce the occurrence of channeling into the reactor embodiment (Figure 2). In a further embodiment, the fluid circulates within the metal bed at a vertical velocity of 3 mm / s to 30 mm / s.

[0091] In one embodiment, the fluid circulates through the metal bed at a vertical velocity of 25 mm / sec to 50 mm / sec. In one embodiment, the fluid circulates through the metal bed at a vertical velocity of 3 mm / sec to 30 mm / sec. In one embodiment, the fluid circulates through the metal bed at a vertical velocity of 3 mm / sec to 10 mm / sec. In one embodiment, the fluid circulates through the metal bed at a vertical velocity of 10 mm / sec to 20 mm / sec. In one embodiment, the fluid circulates through the metal bed at a vertical velocity of 20 mm / sec to 30 mm / sec. In one embodiment, the fluid circulates through the metal bed at a vertical velocity of 3 mm / sec to 50 mm / sec.

[0092] In one embodiment, the reactor tower is made of glass, metal (such as, for example, steel or stainless steel), or polymeric material (such as, for example, Teflon), or a combination thereof. Preferably, the reactor tower is a stainless steel column, preferably ASME-BPE pharmaceutical grade 316L stainless steel.

[0093] In another aspect, the invention relates to a compound prepared according to the first aspect or using the second aspect. The compound is an organometallic compound. The invention also relates to organic compounds (when used as chemical intermediates) prepared from such organometallic compounds.

[0094] The present invention also provides downstream industrial scale processes that rely on a recycle loop continuous mode to prepare organometallic intermediates. In one embodiment, organometallic intermediates used as raw materials for the manufacture of active pharmaceuticals are prepared under the present process for reaction with a substrate. In another embodiment, the present process is integrated as part of a larger process for preparing flavor chemicals, pesticides or other industrial chemicals.

[0095] In another aspect, the invention relates to chemical compounds prepared from the compounds according to the previous aspect.

[0096] The present invention is further illustrated by the following non-limiting examples which further illustrate the invention but are not intended to, and should not be construed as, limiting the scope of the invention.

[0097] The invention will now be described in more detail with reference to non-limiting examples. EXAMPLES

[0098] Example 1: Synthesis of vinylMgBr (14% by weight in THF)

[0099] From an unstarted reactor: The pressurized reactor is filled with magnesium fines and tetrahydrofuran under an inert atmosphere. The recirculation pump is then switched on, the flow rate in the reactor is set to 6-18 L / h, and the reaction mixture is heated to 20-60 °C using a heat exchanger. Then, vinyl bromide solution (11.5 wt. % in THF) is injected at 60-300 g / h until an exotherm is measured with a temperature probe. Then, the temperature of the reaction mixture is reduced to 30-50 °C and the recirculation flow rate is set to 4-7 L / h. The quality of the product is continuously monitored with an online analytical monitoring tool before being collected under an inert atmosphere. During the production process, tetrahydrofuran, vinyl bromide, and magnesium fines are continuously fed into the reactor at a constant rate. The process was run for several hours without interruption.

[0100] From a started reactor that is paused: A pressurized reactor filled with magnesium fine particles and vinylmagnesium bromide (10% by mass in tetrahydrofuran) is heated to a set temperature, i.e., 5-20°C, and the recirculation pump is switched on with a flow rate of 5-7 L / hr. Then, vinyl bromide solution (11.5% by mass in THF) is injected at 360-480 g / hr. The product quality is continuously monitored with online analytical monitoring tools before being recovered under an inert atmosphere. During the production process, tetrahydrofuran, vinyl bromide and magnesium fine particles are continuously fed into the reactor at a constant rate.

[0101] Example 2: Synthesis of cyclopentylMgBr (10% by weight in THF)

[0102] From a started reactor that is paused: A pressurized reactor filled with magnesium fine particles and cyclopentyl magnesium bromide (10% by mass in tetrahydrofuran) is heated to the set temperature (50°C) and the recirculation pump is switched on with a flow rate of 7 L / h. Cyclopentyl bromide solution (8.7% by mass in THF) is then injected at 120-240 g / h. The product quality is continuously monitored with an online analytical monitoring tool before being collected under an inert atmosphere. During the production process, tetrahydrofuran, cyclopentyl bromide, and magnesium fine particles are continuously fed into the reactor at a constant rate. At the steady production stage of the reactor, 75 grams of Grignard solution are collected with an average concentration of 9.2% by mass.

[0103] Example 3: Synthesis of n-amylMgCl (33% by weight in THF)

[0104] From an unstarted reactor: The pressurized reactor is filled with magnesium fines and tetrahydrofuran under an inert atmosphere. The recirculation pump is then switched on, the flow rate in the reactor is 5-7 L / h, and the reaction mixture is heated to 50 °C using a heat exchanger. Then, n-pentyl chloride solution (28.7% by mass in THF) is injected at 120 g / h until an exotherm is measured with a temperature probe. The temperature of the reaction mixture is kept at 50 °C and the recirculation flow rate is set to 7-8 L / h. The quality of the product is continuously monitored with an online analytical monitoring tool before being collected under an inert atmosphere. During the production process, tetrahydrofuran, n-pentyl chloride, and magnesium fines are continuously fed into the reactor at a constant rate. During the steady production phase of the reactor, 72 grams of Grignard solution were collected, with an average concentration of 29.7% by mass.

[0105] Example 4: Synthesis of iPrMgCl (20% by weight in THF)

[0106] a) From an unstarted reactor: A pressurized reactor is filled with magnesium fines and tetrahydrofuran under an inert atmosphere. The circulation pump is then switched to minimum flow rate and the reaction mixture is heated to 30-40°C using a heat exchanger. An isopropyl chloride solution (1.0 M in THF) is then injected into the reactor at a flow rate of 20 L / h until an exotherm is measured with a temperature probe. The concentration of the injected mixture is then gradually increased to 1.9 M, the heat exchanger setpoint is set to (T5+T1) / 2, and the recycle ratio (mass flow recycle loop / mass flow injection) is set between 15-20. The product quality is continuously monitored with an online analytical monitoring tool before being recovered under an inert atmosphere. During the production process, tetrahydrofuran, isopropyl chloride, and magnesium fines are continuously fed into the reactor at constant rates. The mass balance of the process is 99.9%.

[0107] b) From a started reactor that is paused: A pressurized reactor filled with magnesium fines and isopropylmagnesium chloride (20% by weight in tetrahydrofuran) is heated to the set temperature (47°C) and the recirculation pump is started. When the reaction mixture reaches 35°C, the flow of isopropyl chloride (1.9M in tetrahydrofuran) is resumed. Under continuous process conditions, the recirculation ratio (mass flow recirculation loop / mass flow injection) is in the range of 15-20. The product quality is continuously monitored with an online analytical monitoring tool before being withdrawn under an inert atmosphere. During the production process, tetrahydrofuran, isopropyl chloride, and magnesium fines are continuously fed into the reactor at constant rates. During the steady-state production phase of the reactor, 573 kilograms of Grignard solution were recovered, with a concentration of 19.4-20.4% by mass. The mass balance of the process is 99.9%.

[0108] Example 5: Synthesis of n-BuMgCl (24% by weight in THF)

[0109] From a started reactor: A pressurized reactor is filled with pre-activated magnesium fines and tetrahydrofuran under an inert atmosphere. The recirculation pump is then switched on, the flow rate in the reactor is 75 L / h, and the reaction mixture is heated to 55-65°C using a heat exchanger. Then, n-butyl chloride solution (8-10% by mass in THF) is injected at 1.8-3.0 L / h until an exotherm is measured with a temperature probe. The concentration of injected n-butyl chloride is increased to 19-21% by mass, and the recirculation ratio (mass flow rate) is increased to 1.8-3.0 L / h. 再循環ループ / mass flow rate 注入 ) is maintained between 25 and 42. The product quality is continuously monitored with online analytical monitoring tools before being withdrawn under an inert atmosphere. During the manufacturing process, tetrahydrofuran, n-butyl chloride, and magnesium fines are continuously fed into the reactor at a constant rate. During the steady-state production phase of the reactor, 43 kilograms of Grignard solution were recovered with an average concentration of 23.4% by mass. The mass balance of the process is 99.9%.

[0110] Example 6: Synthesis of n-amylmagnesium bromide (37% by weight in EtO)

[0111] From an unstarted reactor: The pressurized reactor is filled with magnesium fines and diethyl ether under an inert atmosphere. The recirculation pump is then switched on, the flow rate in the reactor is 0-12 L / h, and the reaction mixture is heated to 45 °C using a heat exchanger. Then, n-pentyl bromide solution (33.6% by mass in Et2O) is injected at 120-180 g / h until an exotherm is measured with a temperature probe. Then, the temperature of the reaction mixture is increased to 65 °C and the recirculation flow rate is set to 8-15 L / h. The quality of the product is continuously monitored with an online analytical monitoring tool before being collected under an inert atmosphere. During the production process, diethyl ether, n-pentyl bromide, and magnesium fines are continuously fed into the reactor at a constant rate. During the steady-state production phase of the reactor, 84 g of Grignard solution was collected, with an average concentration of 37.4% by mass.

[0112] Example 7: Synthesis of cyclohexylmagnesium chloride (20% by weight in THF / toluene)

[0113] From an unstarted reactor: A pressurized reactor is filled with magnesium fines and tetrahydrofuran / toluene (50% by mass) under an inert atmosphere. The recirculation pump is then switched on, the flow rate in the reactor is 5-13 L / h, and the reaction mixture is heated to 85 °C using a heat exchanger. Cyclohexyl chloride solution (17.2% by mass in THF / toluene) is then injected at 120 g / h until an exotherm is measured with a temperature probe. The temperature of the reaction mixture is kept at 85 °C, the recirculation flow rate is maintained at 7-13 L / h, and cyclohexyl chloride solution is injected at 120-300 g / h. The quality of the product is continuously monitored with an online analytical monitoring tool before being collected under an inert atmosphere. During the production process, tetrahydrofuran, toluene, cyclohexyl chloride, and magnesium fines are continuously fed into the reactor at a constant rate. During the steady production phase of the reactor, 569 grams of Grignard solution were collected, with an average concentration of 18.3% by mass.

[0114] Example 8: Synthesis of (2-ethoxy-2-oxo-ethyl)zinc bromide (13% by weight in THF)

[0115] From an unstarted reactor: A pressurized reactor is filled with zinc fine particles and (2-ethoxy-2-oxo-ethyl) zinc bromide (about 6% by weight in THF) under an inert atmosphere. The recirculation pump is not running and the reaction mixture is heated to 80-90°C using a heat exchanger. Ethyl bromoacetate solution (9.7% by weight in THF) is then injected at 60-120 g / h until an exotherm is measured with a temperature probe. The temperature of the reaction mixture is then maintained at 80°C, the recirculation flow rate is adjusted to 2-10 L / h, and ethyl bromoacetate solution is injected at 60-600 g / h. The product quality is continuously monitored with an online analytical monitoring tool before being withdrawn under an inert atmosphere. During the production process, tetrahydrofuran, ethyl bromoacetate, and zinc fine particles are continuously fed into the reactor at a constant rate. During the steady-state production phase of the reactor, 66 grams of Grignard solution were recovered with an average concentration of 7.2% by weight.

[0116] Description of the drawings The invention will now be further illustrated with reference to the following examples, it being clear that the method according to the invention and its applications are not limited to the presented examples.

[0117] The invention is in no way limited to the embodiments described in the examples and / or shown in the figures: on the contrary, the method according to the invention can be realized in many different ways without departing from the scope of the invention.

[0118] Figure 1 is a schematic diagram showing one embodiment of the present invention. Metal particles are introduced into the reactor (1) through the lock (2). The lock is a chamber isolated from the reactor by two gas-tight valves. The lock is flushed with nitrogen, thereby ensuring that the metal is surrounded by an inert atmosphere before it is inserted into the reactor (1). A recirculation loop allows temperature regulation of the fluid pumped back into the reactor (1). The recirculation loop is composed of one self-cleaning filter element (3) and one heat exchanger (5) that protects the centrifugal pump (4). The metal inlet (6), the nitrogen inlet (7), the RMX outlet (8) and the solvent RX inlet (9) are indicated by arrows in the diagram.

[0119] Figure 2 shows an injection lower section (14) according to one embodiment of the present invention. The inlet at the bottom of the reactor is designed to evenly distribute the liquid entering the reactor and to allow the liquid to be injected through a threaded insert from the bottom of the flange (15). The bottom gasket installed between the injection lower section and the bottom of the reactor is a screen gasket (16). The gasket has a wire mesh screen molded into it. This allows the liquid to be distributed homogeneously over the reactor section while preventing magnesium particles from exiting the reactor from the bottom. [Explanation of symbols]

[0120] 1. Reactor 2. Rock 3 Filter elements 4. Centrifugal Pump 5 Heat exchanger 6 Metal inlet 7 Nitrogen Inlet 8 RMX outlet 9 Solvent / RX inlet

Claims

1. loading solid metal particles or metal-containing solid particles into a reactor tower comprising a metal bed; continuously contacting at least one substrate fluid (preferably said fluid comprising a non-aqueous solvent) with said metal bed; transporting the fluid against gravity through the metal bed; 1. A method for preparing at least one organometallic compound, comprising: the fluid is partially recirculated through a heat exchanger and over the metal bed at a recycle ratio, the recycle ratio being the ratio of the mass flow rate through the metal bed to the mass flow rate of the substrate entering the reactor column, and the recycle ratio being used to optimize the production of the at least one organometallic compound.

2. 10. The method of claim 1, wherein the recycle ratio is from 1:1 to 70:

1.

3. 10. The method of claim 1, wherein the reactor tower comprises a settling zone having a cross-sectional area that is at least 100% greater than the cross-sectional area of ​​the reactor tower.

4. 10. The method of claim 1, wherein the solid metal particles are added to the reactor column through two gas-tight valves purged with an inert gas, preferably nitrogen gas.

5. 2. The method of claim 1, wherein the size of the solid metal particles when added is in the range of 100 μm to 10 mm, preferably 500 μm to 5 mm.

6. 10. The method of claim 1, wherein the temperature of the substrate entering the reactor column is varied to optimize the production of the at least one organometallic compound.

7. 2. The process of claim 1, wherein the reactor column is pressurized preferably to from 0.01 to 10 barg, more preferably from 2 to 4 barg.

8. 10. The method of claim 1, wherein metal particulate is provided such that there is a molar excess of said metal particulate relative to said substrate in said reactor column, and preferably said substrate is an organic halide.

9. 2. The method of claim 1, wherein the fluid is circulated through the metal bed at a vertical velocity of between 3 mm / s and 50 mm / s, preferably between 25 mm / s and 50 mm / s.

10. an element for adding solid metal particles; a reactor column comprising a reactor head having an injection lower portion and a discharge port; a recirculation loop; An apparatus for producing at least one organometallic compound, comprising:

11. 11. The apparatus of claim 10, wherein the reactor head comprises a settling zone having a cross-sectional area that is at least 100% greater than the cross-sectional area of ​​the reactor column.

12. The apparatus of claim 10 , wherein the recirculation loop comprises a heat exchanger and a recirculation pump.

13. A compound produced by the method of claim 1.

14. A compound produced using the apparatus of claim 10.

15. A chemical compound produced from the compound of claim 13 or 14.

Images